CrossTalk Opposing View: E-cigarettes expose users to adverse effects of vapors and the potential for nicotine addiction

Introduction

The use of e-cigarettes has risen in popularity over the past decade, especially among adolescents. E-cigarette is a generic term that covers a variety of nicotine delivery systems using vapor. These devices were invented and initially marketed as a safer alternative to tobacco cigarettes. However, vast advertising campaigns on social media highlighting pleasant flavors made them appealing to adolescents. The dearth of evidence regarding their safety compelled research efforts to understand how e-cigarette use, or “vaping,” affects human physiology. Current literature highlights their potential for adverse effects on human health and nicotine addiction.

What is E-cigarette vapor?

E-cigarette vapor is typically generated from a mixture of propylene glycol and vegetable glycerin, serving as a vehicle for nicotine plus countless flavoring agents. Heating e-cigarette liquid (e-liquid) generates aerosols that contain reactive oxygen species (ROS) and other volatile chemicals (e.g., acrolein, formaldehyde). The important question is whether levels of these agents generated in e-cigarettes are sufficient to cause harm. Increasing applied wattage to the heating coil generally reduces particle size, allowing greater lung penetration (Son et al., 2019), but also increases ROS generation and toxic metal concentrations (Olmedo et al., 2018). Other diluents are also used, including vitamin E acetate (VEA) and medium-chain triglycerides, but typically with tetrahydrocannabinol-containing liquids (Blount et al., 2019).

Documented adverse health effects of vaping

Vaping has been touted as a safer form of nicotine delivery, given the reduction in measured chemicals in vapor compared to cigarette smoke (Goniewicz et al., 2014). However, reduced number or concentration of chemicals does not linearly relate to risk reduction. The Public Health England report advocates e-cigarettes to quit smoking (McNeill, 2018), but longitudinal information on safety is sparse. Moreover, FDA approval for oral ingestion of common e-liquid constituents cannot equate to or predict safety for inhalation. For example, inhalation of diacetyl, a butter-like flavoring added to popcorn, also found in some e-liquids, can cause bronchiolitis obliterans. New vaping-related case reports, including cases of bronchiolitis obliterans (Landman et al., 2019) and hard metal pneumoconiosis (Fels Elliott et al., 2019), underscore adverse effects unique to e-cigarette vapor exposure.

Studies in cell culture models, animals, and humans have begun to reveal adverse respiratory effects of vaping (Gotts et al., 2019). Acute exposure of human bronchial epithelial cells (HBECs) to e-cigarette vapor impaired apical ion channel function (Garcia-Arcos et al., 2016), which was consistent with another study that implicated elevated acrolein levels causing this effect (Lin et al., 2019). Acute exposure of HBECs to nicotine or nicotine-containing vapor impaired mucociliary clearance (MCC) by increasing mucus viscosity and reducing airway surface liquid volume that was dependent on the function of the transient receptor potential ankyrin 1 (TRPA1), a novel nicotine receptor (Chung et al., 2019). Nicotine-containing vapor exposure of sheep increased their airway mucus concentrations and reduced tracheal mucus velocity in a TRPA1-dependent manner (Chung et al., 2019). These data seem to be supported by human studies: preliminary data show serious peripheral and central dysfunctions of the mucociliary apparatus associated with vaping, compared to those who had not smoked or vaped (Dr. William Bennett, University of North Carolina, Chapel Hill; personal communication). Historically, Dr. Bennett’s lab did not find any difference in clearance between young “healthy” smokers and nonsmokers (both non-vapers). Consistent with these data on mucociliary dysfunction, adolescent e-cigarette users were found to have an almost two-fold increase in risk of chronic bronchitis compared to those who never vaped (McConnell et al., 2017). Moreover, e-cigarette users were 1.81 times as likely to report asthma-like symptoms than non-users (Perez et al., 2019).

Animal models further reveal inflammation and tissue damage caused by e-cigarette vapor. Chronic exposure of mice to nicotine-containing vapor increased airway protease activity, caused emphysematous changes, and also increased lung cancer susceptibility (Garcia-Arcos et al., 2016; Tang et al., 2019). Again, data from humans confirm inflammatory changes: chronic vaping increased bronchoalveolar lavage (BAL) protease activity equal to that of smoking, even though many in this group were ex-smokers (Ghosh et al., 2019). Furthermore, proteomic approaches showed that unique changes in BAL fluid can be detected with vaping (Ghosh et al., 2018). These in vitro and in vivo studies suggest that vaping leads to dysfunction of airway ion channels such as TRPA1 and the epithelial sodium channel (ENaC), which has been shown to be activated by airway proteases (Donaldson et al., 2002). These channels are critical for mucociliary clearance and their activation potentially leads to chronic airway disease similar to smoking.

Less known are possible cardiovascular effects of e-cigarette use (Buchanan et al., 2019). Nicotine-containing e-cigarettes caused acute increases in arterial stiffness and blood pressure in young smokers (Vlachopoulos et al., 2016), which was seen by others. Even nicotine- and flavoring-free e-cigarettes increase blood pressure and systemic inflammation (Caporale et al., 2019), suggesting that e-liquid vehicles alone may not be benign.

E-cigarette users are susceptible to nicotine addiction

Adolescent e-cigarette use is a significant risk factor for future smoking (Miech et al., 2017). A meta-analysis showed that current e-cigarette users had 3.5 times the odds of smoking compared to never-smokers and never-vapers (Soneji et al., 2017). This may be due to the increased nicotine craving that is no longer satiated even with nicotine salt e-liquids containing >50 mg/ml nicotine (Gotts et al., 2019).

The α4β2-nicotinic acetylcholine receptor is highly expressed in the brain and mediates nicotine’s neurophysiological outcomes such as increased dopamine levels, eliciting reward effects (Benowitz, 2010). Chronic nicotine exposure causes desensitization and requires higher nicotine concentrations to be effective. Thus, vaping nicotine is expected to lead to addiction in never-smokers. Indeed, recent studies demonstrate that cotinine levels and vaping frequency increased in adolescent e-cigarette users who continued to vape over 12 months and that 28.8% of previous sole e-cigarette users started using traditional cigarettes to satisfy their craving (Vogel et al., 2019).

Most e-liquids contain flavors that increase their appeal to users who normally wouldn’t smoke. A survey of U.S. adolescents found that wide availability of flavors is the most frequent factor for decision to vape (Ambrose et al., 2015). Users who vape non-menthol flavors have greater odds of continuing to vape and more frequent vape use after 6 months (Leventhal et al., 2019). However, flavoring compounds themselves can have adverse effects on airway epithelial cells (Sassano et al., 2018). For instance, direct exposure to cinnamaldehyde has irreversible effects on ciliary beating of airway cultures (Clapp et al., 2019) and impair immune responses (Clapp et al., 2017).

A special consideration: E-cigarette or vaping product use-associated lung injury (EVALI)

A recent surge in vaping-related acute lung injury in the U.S., coined EVALI, highlights the unique risks associated with unregulated modification of e-liquid with VEA and other harmful substances. As of January 14^th, 2020, 2,668 hospitalized EVALI cases have been reported (Krishnasamy et al., 2020). Though the main culprit for EVALI is unknown, a candidate is VEA found in all BAL samples from EVALI patients who underwent bronchoscopy (Blount et al., 2019). While differing degrees of respiratory disease are observed in EVALI patients, the potential for recovery from EVALI and long-term health implications are currently unknown.

Closing Remarks

Accumulating novel evidence indicates that vaping may not be as benign as perceived. In addition, e-cigarettes may not necessarily be a “harm reduced” tobacco smoke alternative (Hiemstra & Bals, 2018), especially since quitting rates with vaping seem equal to smoking cessation attempts with nicotine replacement and medication therapy, but with a high continued vaping rate at one year (Hajek et al., 2019). Worse, widespread e-cigarette use is exposing a new generation of non-smokers to possible nicotine addiction and adverse health effects. Therefore, we should advocate against vaping in nonsmokers and possibly pause with recommending vaping for smoking cessation.

Biographies

Samuel Chung is a Postdoctoral Scholar in the Salathe Lab. His work focuses on how airway nicotine receptors mediate e-cigarette vapor constituents effects on mucociliary clearance.

Charles D. Bengtson is an Assistant Professor of Medicine at the University of Kansas Medical Center (KUMC). His clinical and research interests include the acute health effects of e-cigarette use and the role of hyperglycemia on pulmonary outcomes in cystic fibrosis.

Michael D. Kim is a Research Assistant Professor of Medicine at KUMC. His interests include the role of glucose metabolism on ion channel function in the airway epithelium, with particular focus on cystic fibrosis.

Matthias Salathe is the Peter T. Bohan Professor of Medicine and Chair of the Department of Internal Medicine at KUMC. His research focuses on mechanisms regulating homeostasis of the airway epithelium and impaired mucociliary clearance observed in smoking-related chronic bronchitis and cystic fibrosis. His group specializes in basic and translational studies on the acute and chronic health effects of vaping amongst nonsmokers and current smokers.