Toxicity of E-Cigarettes on Human Health
While often touted as less harmful than traditional smoking, use of electronic cigarettes is not without risks.
This course was published in the August 2020 issue and expires August 2023. The authors have no commercial conflicts of interest to disclose. This 2 credit hour self-study activity is electronically mediated.
After reading this course, the participant should be able to:
- Identify potential toxins in e-cigarettes that contribute to lung injury.
- Discuss how e-cigarette use impacts risk for nicotine dependency.
- Describe key talking points from the U.S. Centers for Disease Control and Prevention that clinicians can use when counseling patients about e-cigarette use and related harms.
Widespread electronic cigarette (EC) use has led to increased interest in its adverse health effects. U.S. Surgeon General Jerome M. Adams, MD, MPH, describes the rising use of EC among youth as an epidemic,1 and advises the need for immediate action to protect young people from avoidable health risks associated with nicotine addiction — including risks to respiratory health and brain development.1 This article will review current knowledge about the adverse health effects caused by EC use, and the role of oral health professionals in assessment and patient education to reduce associated harms.
As of February 18, 2020, a total of 2807 hospitalized e-cigarette, or vaping, product use-associated lung injury (EVALI) cases had been reported to the U.S. Centers for Disease Control and Prevention (CDC) from all 50 states, the District of Columbia, Puerto Rico and U.S. Virgin Islands. The outbreak in EVALI cases began in June 2019 and peaked in September 2019. Although the number of new hospitalized cases and possible cases presenting to emergency departments have been declining since September 2019, EVALI remains a major public health concern.2
New information is emerging about how EC use contributes to lung disease. Bronchoscopy data taken from healthy never-smokers who volunteered to vape an EC containing 50% each of the solvents propylene glycol (PG) and vegetable glycerin (no nicotine) for four weeks revealed minimal, but measurable, signs of inflammation in both lung tissue and lung fluid. The level of PG found in their urine significantly correlated with elevation in macrophages and several pro-inflammatory cytokines (IL-8, IL-13 and TNF-ɑ). These pilot data are among the first to demonstrate the development of inflammation caused by EC use among never-smokers.3
A research group at the Center for the Study of Tobacco Products at Virginia Commonwealth University suggests PG and vegetable glycerin dry up tissues, and are being inhaled across membranes in the throat and upper airways that need to remain moist.4 Further, because PG and vegetable glycerin both act as solvents, they may dissolve lung surfactant that otherwise keeps the alveoli from collapsing, thus compromising proper gas exchange.
Macrophages not only protect against infection, but they help to recycle surfactant.5 Findings in mice support that chronic exposure to EC vapor compromises macrophage immune function and alters the homeostasis of surfactant independently from nicotine.5 Biopsy data taken from eight men with vaping-associated pulmonary illness revealed acute lung injury and diffuse alveolar damage, with macrophages found in the airspaces in all cases.6 Among these eight cases, all reported vaping tetrahydrocannabinol (THC)-containing products, implicating that either the THC itself or a toxic component within the THC-containing vape fluid produced tissue injury.6
TOXINS IN E-CIGARETTES AND ASSOCIATED PRODUCTS
A recent human study examined toxicants found in the fluid obtained following a bronchoalveolar lavage (BAL) in 51 hospitalized patients with EVALI.7 Investigators reported that 48 of the 51 EVALI patients (94%) had vitamin E acetate present in the fluid. Most (94%) had detectable THC or its metabolites in BAL fluid or had reported vaping THC products in the 90 days before the onset of illness. Nicotine or its metabolites were detected in 30 out of 47 patients (64%), confirming dual vaping of nicotine and THC. The CDC notes that 152 different THC-containing product brands were reported by patients with EVALI.2
Vitamin E acetate is a cutting agent often used in illicit THC-containing products as a thickener to reduce product cost.8,9 While vitamin E acetate is generally recognized as safe for ingestion and topical use in dermatologic products, it is not safe for inhalation. Once in the lungs, its biotransformation allows vitamin E to penetrate the surfactant layer, reducing the surface tension needed to keep alveolar sacs open and functional during respiration.10,11 In addition, the byproduct of heating vitamin E acetate is ketene, a reactive compound that acts as a lung irritant.12
While vitamin E acetate remains a chemical of concern, the U.S. Food and Drug Administration (FDA) is currently testing more than 1300 samples from across the country to look for additional compounds with implications in EVALI. Approximately 1060 of these samples are linked to patient cases being tracked by the CDC; others come from vaping devices and associated products. As of January 15, 2020, approximately 810 samples had undergone testing; among these, two-thirds were found to contain THC, and half of those contained vitamin E as a diluent. Among 79 CDC case patients, 76% had samples containing THC. Of these, the diluents identified in the samples included vitamin E acetate (77%), aliphatic esters (33%), and PG (8%).13 The concentrations, source, and pattern of use/exposure of these and other substances are all critical variables in the development of respiratory disease and require ongoing study. It is likely there is more than one cause for EVALI.13
Aerosols from EC also contain toxic agents, including heavy metals, nitrosamines, diethylene glycol and carbonyls (formaldehyde, acetaldehyde, acrolein), and reactive oxygen species that are directly inhaled by the user. Carbonyls and reactive oxygen species are formed when the cartridge liquid contacts the heating element.14 Reactive oxygen species and other free radicals induce oxidative stress, which damages cell proliferation and survival. Most tobacco-related diseases, including cancer, are associated with oxidative stress.15 Bitzer et al16 found that generation of free radicals was highly dependent on the PG content of the EC liquid. In addition, it was reported that after testing 49 commercially available e-liquid flavors, 43% resulted in significant increases in free radical production, as compared to the base liquid containing PG and glycerin.15 Additional research is needed to understand how various flavoring agents contribute to potential harm, given that flavor is appealing to youth and young adults.17
Some believe EC use is safer than conventional cigarettes. Levels of known carcinogens in EC liquids and aerosols are lower than levels found in tobacco and tobacco smoke, with the exception of formaldehyde and other small aldehydes.18 However, many EC users are also concurrent tobacco users, placing them at risk for increased exposure to carcinogens. It is likely these dual users have precancerous cells in their oral cavity.19 New research found that a condensate of EC aerosol enhances the metabolism of a known tobacco carcinogen — benzo(a)pyrene — in human oral keratinocytes.19 This is the first study to show that EC use may enhance carcinogenic risk in current smokers, and may also predispose EC users to developing oral cancer upon initiation of conventional tobacco use. Research indicates that EC vapor, with or without nicotine, causes DNA strand breaks — another potential mechanism for promoting oral cancer.20
A recent study in mice found that daily exposure to nicotine vapor for six months activates nicotine dependence pathways.21 Notably, the study found decreased concentrations of the inhibitory neurotransmitter GABA and excitatory stimulation in central reward areas of the brain. This stimulation may facilitate nicotine-seeking behavior.21 D’Souza and Markou22 report that GABA inhibits the release of dopamine, which normally surges after exposure to nicotine and other drugs, suggesting that GABA has a role in dampening nicotine cravings and smoking behavior. But, if chronic exposure to EC vapor decreases the concentration of available GABA, dopamine increases following exposure to nicotine in the aerosol could go unchecked, promoting dependency.21
Study findings underscore ongoing concerns that younger EC users who report the highest rates of vaping may become addicted to nicotine.23 Concerns are magnified given that young EC users are also more likely to start smoking traditional cigarettes.24 Several studies support the idea that EC use is a gateway to conventional cigarette use, with results from a recent meta-analysis noting that EC use was associated with a three-fold higher risk of subsequent conventional cigarette initiation among ever (versus never) EC users, and four-fold higher likelihood for initiating conventional cigarette use within the past month among past 30-day EC users.25,26
However, experimentation among adolescent never-smokers and transitioning to use is bidirectional. While EC experimentation has been positively associated with progression to conventional cigarette use,27 ever using a combustible tobacco product has also been associated with initiating EC use.28,29 Impulsiveness and risk-taking behaviors may predispose young people to experimenting with either of these products.29
There is good news. A recent meta-analysis found that among adolescents in the United Kingdom, most EC experimentation does not turn into regular use, and regular EC use among those who have never smoked traditional cigarettes remains low.30 Similar findings have been found in the United States.31 Traditional smoking has consistently declined over the past decade among adolescents, despite the rise in experimenting with EC. The bad news is that the number of individuals who vape nicotine and marijuana daily continues to rise. Adolescents reported their reasons for vaping included experimentation, flavor, social reasons, and to feel good.32
Given comparable THC levels, vaping marijuana produces greater adverse physiological and psychological effects — such as lung disease — compared with smoking marijuana.33 In October 2019, the FDA issued a warning to consumers to stop using THC-containing vaping products and any vaping products obtained on the street.34
In adult smokers, the evidence strongly suggests that vaping nicotine is safer than smoking conventional cigarettes.35 Randomized clinical trials support that vaping nicotine is more appealing and effective than using FDA-approved nicotine replacement therapies for smoking cessation.36,37 Completely substituting vaping nicotine for smoking traditional cigarettes reduces exposure to toxins and carcinogens.38 Like young users, adults also prefer flavored EC, which may help them transition away from cigarette smoking. Evidence shows most adults who completely switch to vaping do so only after a period of dual use.37 There is an increasing number of EC users who are former smokers, thus supporting the argument in favor of EC use for smoking cessation.25
IMPLICATIONS FOR DENTAL TEAMS
On December 16, 2019, the American Dental Association announced its new interim policy on vaping, calling for a “total ban on vaping products that aren’t approved [by the FDA] for tobacco cessation purposes.” The policy stresses advocacy for banning the sale and distribution of all EC and vaping products (except those approved by the FDA for tobacco cessation — and made available by prescription only), and advocacy for research into the safety and efficacy of EC and vaping products for tobacco cessation purposes, and their effects on the oral cavity.39
Dental professionals play an important role in assessing patients for EC use and educating users about associated risks. Patients who are using EC to quit smoking should be instructed to avoid conventional cigarettes and encouraged to use FDA-approved smoking cessation therapies.2 Additionally, patients should be counseled to avoid the use of THC-containing EC or other vaping products, particularly those obtained illegally, and to never add anything to EC or other vaping products.2 Individuals who demonstrate signs (or who report symptoms) of respiratory disease should be referred for immediate medical evaluation. Similarly, patients dependent on cannabis should be referred to an appropriate healthcare professional and/or substance abuse program for recovery.2 Clinicians are urged to remain current with new knowledge about the adverse health effects of EC so they can effectively advise patients.
- U.S. Department of Health and Human Services. Surgeon General Releases Advisory on E-Cigarette Epidemic Among Youth. Available at: hhs.gov/about/news/2018/12/18/ surgeon-general-releases-advisory-e-cigarette-epidemic-among-youth.html. Accessed June 16, 2020.
- U.S. Centers for Disease Control and Prevention. Outbreak of Lung Injury Associated with the Use of E-Cigarette, or Vaping, Products. Available at: cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html. Accessed June 16, 2020.
- Song MA, Reisinger SA, Freudenheim JL, et al. Effects of electronic cigarette constituents on the human lung: a pilot clinical trial. Cancer Prev Res. 2020;13:145–152.
- Couzin-Frankel J. Questions churn about vaping’s long-term risks. Science. 2019;366:1059–1060.
- Madison MC, Landers CT, Gu BH, et al. Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine. J Clin Invest. 2019;129:4290–4304.
- Mukhopadhyay S, Mehrad M, Dammert P, et al. Lung biopsy findings in severe pulmonary illness associated with e-cigarette use (vaping). Am J Clin Pathol. 2020;153:30–39.
- Blount BC, Karwowski MP, Shields PG, et al. Vitamin E acetate in bronchoalveolar-lavage fluid associated with EVALI. N Engl J Med. 2020;382:697–705.
- Downs D. Vape pen lung injury: here’s what you need to know. Available at: leafly.com/news/health/vape-pen-lung-disease-advice-consumers. Accessed June 16, 2020.
- Eisenberg Z, Moy D, Lam V, Cheng C, Richard J, Burack B. Contaminant analysis of illicit vs regulated market extracts. San Francisco: Anresco Laboratories. Available at: https://cannabis.anresco.com/analysis-of-illicit-vs-regulated-market-extracts. Accessed June 16, 2020.
- Kamal MA, Raghunathan VA. Modulated phases of phospholipid bilayers induced by tocopherols. Biochim Biophys Acta. 2012;1818:2486–2493.
- Zuo YY, Veldhuizen RA, Neumann AW, Petersen NO, Possmayer F. Current perspectives in pulmonary surfactant — inhibition, enhancement and evaluation. Biochim Biophys Acta. 2008;1778:1947–1977.
- Wu D, O’Shea DF. Potential for release of pulmonary toxic ketene from vaping pyrolysis of vitamin E acetate. Available at: https://chemrxiv.org/articles/Potential_ for_Release_of_Pulmonary_Toxic_Ketene_from_Vaping_Pyrolysis_of_Vitamin_E_Acetate/10058168. Accessed June 16, 2020.
- U.S. Food and Drug Administration. Lung Illnesses Associated with Use of Vaping Products. Information for the Public, FDA Actions, and Recommendations. Available at: fda.gov/news-events/public-health-focus/lung-illnesses-associated-use-vaping-products. Accessed June 16, 2020.
- Cirillo S, Urena JF, Lambert JD, et al. Impact of electronic cigarette heating coil resistance on the production of reactive carbonyls, reactive oxygen species and induction of cytotoxicity in human lung cancer cells in vitro. Regul Toxicol Pharmacol. 2019;109:104500.
- Bitzer ZT, Goel R, Reilly SM, et al. Effect of flavoring chemicals on free radical formation in electronic cigarette aerosols. Free Radic Biol Med. 2018;120:72–79.
- Bitzer ZT, Goel R, Reilly SM, et al. Effects of solvent and temperature on free radical formation in electronic cigarette aerosols. Chem Res Toxicol. 2018;31:4–12.
- Harrell MB, Weaver SR, Loukas A, et al. Flavored e-cigarette use: characterizing youth, young adult, and adult users. Prev Med Rep. 2017;5:33–40.
- Cheng T. Chemical evaluation of electronic cigarettes. Tob Control. 2014;23(Suppl 2):ii11–ii17.
- Sun YW, Kosinska W, Guttenplan JB. E-cigarette aerosol condensate enhances metabolism of benzo(a)pyrene to genotoxic products, and induces CYP1A1 and CYP1B1, likely by activation of the aryl hydrocarbon receptor. Int J Environ Res Public Health. 2019;16:2468.
- Yu V, Rahimy M, Korrapati A, et al. Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines. Oral Oncol. 2016;52:58–65.
- Alasman F, Crotty Alexander LE, Hammad AM, Bojanowski CM, Moshensky A, Sari Y. Effects of chronic inhalation of electronic cigarette vapor containing nicotine on neurotransmitters in the frontal cortex and striatum of C57BL/6 mice. Front Pharmacol. 2019;10:885.
- D’Souza MS, Markou A. The “stop” and “go” of nicotine dependence: role of GABA and glutamate. Cold Spring Harb Perspect Med. 2013;3:012146.
- Crotty Alexander LE, Vyas A, Schraufnagel DE, Malhotra A. Electronic cigarettes: the new face of nicotine delivery and addiction. J Thorac Dis. 2015;7:E248–E251.
- Goldenson NI, Levanthal AM, Stone MD, McConnell RS, Barrington-Trimis JL. Associations of electronic cigarette nicotine concentration with subsequent cigarette smoking and vaping levels in adolescents. JAMA Pediatr. 2017;171:1192–1199.
- Farsalinos K. E-cigarettes: an aid in smoking cessation, or a new health hazard? Ther Adv Respir Dis. 2018;12:1–20.
- Soneji S, Barrington-Trimis JL, Wills TA, et al. Association between initial use of e-cigarettes and subsequent cigarette smoking among adolescents and young adults: a systematic review and meta-analysis. JAMA Pediatr. 2017;171:788–797.
- Chaffee BW, Watkins SL, Glantz SA. Electronic cigarette use and progression from experimentation to established smoking. Pediatrics. 2018;141:4.
- Leventhal AM, Strong DR, Kirkpatrick MG, et al. Association of electronic cigarette use with initiation of combustible tobacco product smoking in early adolescence. JAMA. 2015;314:700–707.
- Niaura RS, Glynn TJ, Abrams DB. Youth experimentation with e-cigarettes: another interpretation of the data. JAMA. 2014;312:641–642.
- Bauld L, MacKintosh AM, Eastwood B, et al. Yong people’s use of e-cigarettes across the United Kingdom: findings from five surveys 2015–2017. Int J Environ Res Public Health. 2017;14:E973.
- Polosa R, Russell C, Nitzkin J, Farsalinos KE. A critique of the U.S. Surgeon General’s conclusions regarding e-cigarette use among youth and young adults in the United States of America. Harm Reduct J. 2017;14:61.
- National Institute of Drug Abuse. Vaping of marijuana on the rise among teens. Monitoring the Future 2019. Available at: drugabuse.gov/news-events/news-releases/2019/12/vaping-marijuana-rise-among-teens. Accessed June 16, 2020.
- Spindle TR, Cone EJ, Schlienz NJ, et al. Acute effects of smoked and vaporized cannabis in healthy adults who infrequently use cannabis: a crossover trial. JAMA Netw Open. 2018;1:e184841–e184841.
- U.S. Food and Drug Administration. Vaping Illness Update: FDA Warns Public to Stop Using Tetrahydrocannabinol (THC)-Containing Vaping Products and Any Vaping Products Obtained Off the Street. Available at: fda.gov/consumers/consumer-updates/vaping-illness-update-fda-warns-public-stop-using-tetrahydrocannabinol-thc-containing-vaping. Accessed June 16, 2020.
- Fairchild A, Healton C, Curran J, Abrams D, Bayer R. Evidence, alarm, and the debate over e-cigarettes. Prohibitionist measures threaten public health. Science. 2019;366:1318–1320.
- Warner KE, Mendez D. E-cigarettes: Comparing the possible risks of increasing smoking initiation with the potential benefits of increasing smoking cessation. Nicotine Tob Res. 2019;21:41–47.
- Abrams DB, Glasser AM, Villanti AC, Pearson JL, Rose S, Niaura RS. Managing nicotine without smoke to save lives now: evidence for harm minimization. Prev Med. 2018;117:88–97.
- National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems. Eaton DL, Kwan LY, Stratton K, eds. Public Health Consequences of E-Cigarettes. Washington, DC: National Academies Press; 2018.
- American Dental Association. American Dental Association Announces Interim Policy on Vaping. Available at: ada.org/en/press-room/news-releases/2019-archives/december/american-dental-association-announ. Accessed June 16, 2020.
From Decisions in Dentistry. July/August 2020;6(7):36-39.