Elsevier

Toxicology

Volume 365, 15 July 2016, Pages 67-75
Toxicology

Review
A decade of e-cigarettes: Limited research & unresolved safety concerns

https://doi.org/10.1016/j.tox.2016.07.020Get rights and content

Abstract

It is well known that tobacco consumption is a leading cause of preventable deaths worldwide and has been linked to major diseases ranging from cancer to chronic obstructive pulmonary disease, atherosclerosis, stroke and a host of neurological/neurodegenerative disorders. In the past decade a number of alternative vaping products have hit the market, rapidly gaining consumers especially among the younger population. Electronic nicotine delivery systems or e-cigarettes have become the sought-after product due to the belief that they are much safer than traditional cigarettes. However, inadequate research and lack of regulatory guidelines for both the manufacturing process and the content of the vaping solution of the e-cigarette has become a major concern. Highly debated and unresolved questions such as whether e-cigarettes may help smokers quit and whether e-cigarettes will promote the use of nicotine among non-smokers add to the confusion of the safety of e-cigarettes. In this review article, we summarize the current understanding (and lack thereof) of the potential health impacts of e-cigarettes. We will also highlight the most recent studies (in vivo/in vitro) which seem to conflict with the broad safety claims put forward by the manufacturers. Finally, we provide potential solutions to overcome the research gap of the short and long-term health impact of e-cigarettes.

Introduction

Electronic cigarettes (e-cigarettes), also known as electronic nicotine delivery systems (ENDS), are battery powered devices designed to vaporize (by heat) a solution of nicotine (e-liquid) and other additives (including propylene glycol, vegetable glycerin and ad hoc flavoring agents) into an aerosol which is then inhaled by the user (called vaping). These products are often made to look like cigarettes, cigars, pens or pipes in order to closely resemble traditional tobacco-based combustion products (TC) (Naik and Cucullo, 2015). Hon Lik, a Chinese pharmacist, invented the modern version of the e-cigarette in 2003, which was later patented internationally in 2007 (Electronic Atomization Cigarette: US 20070267031 A1) and was subsequently introduced into the global market including the U.S. (Rahman et al., 2014). The market size of this non-regulated product is booming because of the increase in popularity among young adults of the millennial generation (Grana et al., 2014). The accelerated adoption of e-cigarettes is supported by the common belief that they are indeed a safer alternative to traditional tobacco-based products (Goniewicz et al., 2014b) (Regan et al., 2013) or that they can be used to facilitate smoking cessation despite some opposing evidence (Kalkhoran and Glantz, 2016). A recent study on e-cigarette awareness and harm perception has shown that  95% of interviewed subjects (US adult population) believe e-cigarettes to be; 1) cleaner and healthier than conventional products, 2) cheaper (93%), 3) can be used to circumvent smoke-free policies (76–88%) and 4) are trendy (≈73%) (Pearson et al., 2012, Grana and Ling, 2014).

A recent report (Zhu et al., 2014) states that an astonishing 7764 unique flavors were available online in January 2014, with 242 new flavors being added per month, and sales occurring under 466 brands. A number of e-cigarette manufacturers minimized the health risk concerns on their products stating that the ingredients, including the flavoring agents, are not dangerous since they are all ‘food grade’ and ‘generally recognized as safe’ (GRAS). However, GRAS designation by the Flavor Extracts Manufacturers Association (FEMA) refers to use of these substances up to specific concentrations for specific purposes in specific foods and does not pertain to the use of the same compounds for inhalation. In some instance e-liquids contain very high levels of flavoring agents, possibly exceeding concentrations sufficient to elicit irritant effects and inflammation in the respiratory and cardiovascular systems. This concern was recently brought up by a study from Farsalinos et al. (2015b) in which the authors tested 159 sweet e-cigarette flavors including chocolate, toffee, and caramel. The results clearly showed that  74% of the samples contained diacetyl and/or acetyl propionyl which has been associated with bronchiolitis obliterans. Furthermore, certain flavored e-liquids demonstrated nicotine-independent in vitro cytotoxicity to various cells (Farsalinos et al., 2013a, Tierney et al., 2016). In addition to propylene glycol, glycerin and other flavoring agents, e-liquids contain a number of aldehydes (formaldehyde, benzaldehyde, acrolein, etc.) that form during the heating process. Small amounts of heavy metals and at least 20 known carcinogens and teratogenic agents have also been identified in the e-liquid as well as the vapors (Bahl et al., 2012, Grana et al., 2014, McAuley et al., 2012). Toxic aerosols released by e-cigarettes contain ultra-fine particles that can, in conjunction with air pollution, contribute to pulmonary and systemic inflammatory processes while decreasing macrophage and neutrophil antimicrobial activities (Hwang et al., 2016). Despite the proof that e-cigarettes are not as safe as popular belief, the long term health effects of e-cigarette vaping has only been marginally addressed (Orellana-Barrios et al., 2015). Hence, many unanswered questions remain about the overall toxicological effects, safety, efficacy of harm reduction, as well as the overall health impact of e-cigarettes.

Section snippets

The device: basic design & operation

A variety of e-cigarette models have emerged over the last decade. Although the complexity in design and features has evolved, the key principle is the same. An e-cigarette has three basic parts: a rechargeable lithium battery, an atomizer and a reservoir (collectively known as a cartomizer; see Fig. 1) containing the e-liquid. Activation of the heating coil within the atomizer generates the nicotine aerosol (or mist).

Automatic models feature an airflow sensor which activates the heating coil

Chemical profile of e-liquid and nicotine intake

e-Cigarettes are either disposable (both the battery and the cartridge are to be discarded once the e-liquid has been consumed) or intended for multiple uses in which case, the reservoir (tank style) needs to be refilled with e-liquid or the prefilled cartridge needs to be replaced. E-liquid is the solution or “smoke juice” containing nicotine in an edible solvent approved by the FDA (usually propylene glycol or a mixture of propylene glycol and glycerin). Nicotine-free e-cigarettes are also

Toxicological studies and public health concern

The most common solvents used in the preparation of e-liquids are either propylene glycol and/or vegetable glycerin. Glycol mist (the same additive used in e-cigarettes) is also used in the show business and aviation industries to create “fog machine smoke”. Varughese et al. studied the lung function of 101 employees at 19 theatres exposed to glycol fog during their work. The study revealed impaired lung function associated with dry throat and cough upon either acute or chronic exposure (

The success of e-Cigarette in smoking cessation program

The “Center for Drug Evaluation and Research” of the FDA assesses the potential therapeutic benefit over the risks of smoking cessation products and regulates their production, advertisement and sale. Accordingly, nicotine replacement therapies (NRTs)—e.g. nicotine patch/gum, bupropion SR, and varenicline are approved by the FDA for smoking cessation. This however, is not the case for e-cigarettes (despite the popular belief) since the rather scarce and quite contradictory scientific evidences

e-Cigarette: regulatory issues

There is a rising demand by the regulatory authorities to bring the marketing, production and sale of e-cigarettes under legislative control and to limit their accessibility to vulnerable populations. Few countries have already developed regulatory guidelines for e-cigarettes such as Brazil, Uruguay, Singapore, Canada etc. In the US e-cigarettes will be brought under the FDA authority by August 8 2016 although the regulatory guidelines and the approaches to implement them are still a working in

Secondary exposure and non-user risk of e-cigarette:

e-Cigarettes have been reported to cause secondary exposure to nicotine but to a much lesser extent compared to TCs. The exhaled e-cigarette aerosol is also free from combustible toxic ingredients present in traditional cigarettes (Czogala et al., 2014). Schober et al. conducted a study on indoor air quality after six vaping sessions of two-hour duration by nine e-cigarette smokers. The results demonstrated an elevated number of suspended particles containing nicotine, glycerin and

Promoting e-Cigarette research

To establish a rationale and sustainable policy to regulate e-cigarette manufacturing, marketing and usage, the long term biological and physiological impact on these products need to be dissected out and evaluated accordingly. The physical characteristics and mode of operation of e-cigarettes are rapidly evolving and their modulatory effects on aerosol generation (time & force required while inhaling), composition (presence of any unwanted degradation products), physical characteristics

Conclusion and future directions

The common belief that “e-cigarettes release merely water-based vapors” is incorrect. In addition to nicotine, e-cigarette vapors contain potentially toxic substances which are solvent byproducts (generated by heat) released in the vapor and/or trace constituents of the flavoring additives. Many of the toxic substances present in TC’s sidestream and mainstream smoke are absent or negligible although e-cigarette vapors have been shown to contain traces of heavy metals as well as carcinogenic and

Conflict of interest

None.

Authors contribution

Mohammad A. Kaisar drafted the review; Shikha Prasad and Taylor Liles also contributed to the drafting of the manuscript and proof reading. Luca Cucullo supervised the work and provided guidance during manuscript preparation and revisions. All authors have read and approved the final version of the manuscript.

Acknowledgements

Manuscript preparation was supported in part by NIH/NIDA R01-DA029121-01A1 and Alternative Research Development Foundation grants received by Luca Cucullo.

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