The Electronic Cigarette: The Good, the Bad, and the Ugly

The Electronic Cigarette: The Good, the Bad, and the Ugly

Clinical Commentary Review The Electronic Cigarette: The Good, the Bad, and the Ugly Andrew Cooke, MDa, Jennifer Fergeson, DOa, Adeeb Bulkhi, MDa,b, ...

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Clinical Commentary Review

The Electronic Cigarette: The Good, the Bad, and the Ugly Andrew Cooke, MDa, Jennifer Fergeson, DOa, Adeeb Bulkhi, MDa,b, and Thomas B. Casale, MDa Tampa, Fla; and Makkah, Saudi Arabia Electronic cigarettes (EC) are battery-powered nicotine delivery systems that have increased in popularity since they entered the US market. EC has been reported to contain less carcinogens than traditional cigarettes, cause less acute lung effects in healthy individuals, and may help with smoking cessation. It has also been viewed as a potential safer alternative for asthmatic smokers, but its effects on lung functions are unclear. However, EC do carry some harmful aspects as they contain formaldehyde and formaldehyde-forming hemiacetals as well as potentially toxic particulate matter that deposits on surfaces. EC are an increasingly popular device that could serve as a gateway into traditional cigarette smoking or illicit drugs. The popularity of EC has brought with it money from large tobacco corporations and mass marketing. Lack of regulation has generated product inconsistency and potential health hazards. This review highlights what is known and what still needs to be answered about EC. Ó 2015 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2015;3:498-505) Key words: Electronic cigarettes; Vaping; Tobacco cessation; Asthma; Smokers; Carcinogen; Toxic; Formaldehyde

Electronic cigarettes (EC) are battery-powered devices that deliver aerosolized nicotine and other additives to users.1 EC were first commercialized in China in 2003 and entered the US market in 2007.2,3 Most devices resemble cigarettes, whereas others resemble pens, hookah tips, or screw drivers (Figure 1).3,4 The liquid contained in the EC, referred to as eliquid, generally consists of nicotine, water, propylene glycol (PG), glycerin, flavorings, and/or other additives.5 The e-liquid may be packaged in replaceable cartridges, refill liquids, or contained in disposable EC themselves. The EC device, usually powered by a small rechargeable lithium-ion battery, is activated by inhalation at the tip or, on some models, by pressing a button. The microprocessor controls the power light-emitting

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Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, Fla b Department of Internal Medicine, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia No funding was received for this work. Conflicts of interest: T.B. Casale is the Executive Vice President of the American Academy of Allergy, Asthma & Immunology. The other authors declare they have no relevant conflicts. Received for publication March 26, 2015; revised manuscript received and accepted for publication May 22, 2015. Corresponding author: Thomas B. Casale, MD, Department of Internal Medicine, Division of Allergy and Immunology, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 19, Tampa, FL 33612. E-mail: [email protected] 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.05.022

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diode (LED) tip and the heating element once the EC is activated. The LED tip glows when the vaporizer is in use and the heating element produces the vapor mist that carries the nicotine vapor (Figure 2).3 EC are currently not federally regulated in the United States, and there are only limited safety data regarding their acute and long-term use.5 Despite this, the sale and use of EC is rising.5 This article is a structured review of the available literature regarding the health effects of EC and a summary of the potential harms and benefits of their use in comparison with combustible cigarettes.

THE GOOD Combustible cigarette smoke contains at least 70 carcinogens including formaldehyde, free radicals, toxic gases, heavy metals, and tobacco-specific nitrosamines.6 These toxins have been measured at 9-fold to 450-fold greater than those found in EC aerosol.5 Another form of toxin exposure, termed thirdhand smoke, results from the particulate matter (PM) depositing on surfaces and can linger for months.7 Pellegrino et al found that the PM emissions from EC aerosol were 15 times lower than emissions found in combustible cigarette smoke, though the levels still exceeded the World Health Organization (WHO) air quality guidelines.8 These findings should be interpreted with caution as the actual levels of toxicants in this study may be higher than what was measured due to variations in puff topography among naïve and experienced users and variability between various EC devices and liquids.5 Combustible cigarettes are estimated to cause more than 480,000 deaths annually. Smokers who quit before the age of 40 reduce the risk of dying from tobacco-related diseases by up to 90%.9,10 The large health burden related to combustible cigarette use has led to efforts to identify healthier alternatives and means to quit smoking, including the use of EC. Bullen et al conducted one of the largest studies investigating the efficacy of EC versus nicotine patches in achieving smoking cessation.11 This study enrolled 657 smokers interested in quitting. Subjects were randomized in a 4:4:1 ratio to either 16 mg nicotine EC, 21 mg nicotine patch, or placebo EC, respectively. They were followed for a 6-month period, with assessments at 1 and 3 months. At 6 months, tobacco cessation was evident in 7.3% with nicotine EC, 5.3% with nicotine patches, and 4.1% with placebo EC.11 Although this study was one of the largest trials, tobacco cessation was significantly lower than that expected for the power calculation. As a result, nicotine EC use did not demonstrate any advantage in tobacco cessation when compared with nicotine patches or placebo EC. A recent Cochrane review analyzed studies evaluating the use of EC in tobacco cessation and concluded that the role of EC is limited by the small number

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Abbreviations used CO- Carbon monoxide EC- Electronic cigarette FDA- Food and Drug Administration LED- Light-emitting diode PG- Propylene glycol PM- Particulate matter WHO- World Health Organization

of trials, low event rates, and the wide confidence intervals around the estimates mean.12 EC are marketed as a safer alternative to combustible cigarettes. To help assess the acute effect of EC usage, Flouris et al evaluated 30 healthy volunteers separated into 2 groups: 15 smokers and 15 never-smokers.2 The smokers were exposed to room air (as a control), active tobacco smoking (2 cigarettes of their favorite brand), and an active EC smoking session for 30 minutes. The nonsmokers were exposed to room air (as a control), a passive tobacco cigarette session (smoke chamber for 1 hour), and a passive EC session (1 hour in a vapor chamber). Spirometry was measured before, immediately after, and 1 hour after each exposure. The authors concluded that no change was detected in FEV1 or FEV1/FVC with active or passive EC exposure in either group, whereas combustible cigarette use reduced FEV1/FVC by 7.2%.2 Research regarding the acute health effects of EC is limited due to user variability, EC use experience, and differences between devices. Vansickel et al sought to describe a consistent clinical laboratory method that could be used to characterize EC users’ nicotine and carbon monoxide (CO) exposure and to evaluate a variety of acute effects resulting from active “vaping.” They enrolled 32 adult EC naïve combustible cigarette smokers to each of the following 4 conditions: 150 minutes of own brand cigarette, 150 minutes of “NPRO” EC (18 mg cartridge), 150 minutes of “Hydro” EC (16 mg cartridge), and 150 minutes of sham (unlit cigarette). Plasma nicotine, expired air CO, and heart rate were measured and questionnaires were used to assess a reduction in desire to smoke.13 Results demonstrated an increase in plasma nicotine levels, expired air CO, and heart rate only after own brand cigarette use. Interestingly, despite failure to deliver nicotine, acute use of EC demonstrated a reduced craving for cigarettes and a feeling of satisfaction.13 Vansickel et al further evaluated the effects of EC use in 8 adult experienced EC users during a single 5-hour session that consisted of 4 phases: baseline, 10 puffs from the device, 1-hour ad lib puffing period, and a 2-hour rest period (no puffing). Participants had a history of at least 3 months of EC use with 2-3 mL of nicotine solution or 2 cartridges per day, used nicotine solution of at least 10 mg/mL nicotine, and smoked less than 5 cigarettes per day. For the study intervention, participants used their own EC devices and the flavor and/or strength they preferred. As in the prior study, plasma nicotine, expired air CO, and heart rate were measured and questionnaires were used to assess a reduction in desire to smoke.14 The study revealed that when compared with baseline measurements, plasma nicotine and heart rate increased significantly within 5 minutes of the first puff and remained elevated throughout the ad lib puffing period. Additionally, subjects reported pleasurable effects of EC use when compared with baseline, such as “feel awake,” “calm you down,” and “concentrate.”15 In comparison to the previous study

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in naïve EC users, these findings likely reflect the impact of longer puff duration on nicotine delivery in experienced EC users. Patients with asthma experience many health benefits from smoking cessation including less symptoms and improvements in lung function.16e18 Polosa et al assessed the effects of smoking abstinence and reduction in asthmatic smokers who switched to EC.14 The 18 patients with asthma who participated in the study were tobacco smokers of approximately 1 pack per day and reported regular use of EC during the study at 2 consecutive visits. All participants had either mild to moderate disease based on the Global Initiative for Asthma criteria. The baseline treatment for a majority of the participants consisted of daily use of inhaled corticosteroids and/or long-acting b2-agonist and, as needed, short-acting b2-agonists.14 Participant data were obtained at each clinic visit: prebaseline visit (confirm disease stability, 6-12 months before baseline visit), baseline visit (before switching to EC), follow-up visit 1 (6 months after baseline visit), and followup visit 2 (12 months after baseline visit). During each visit, participants were evaluated through clinical examination, review of smoking history, questionnaires, spirometry, and, if indicated, methacholine challenge.14 Results of the study demonstrated that at 6 months both single users (use of EC alone) and dual users (use of EC and 5 or less conventional cigarettes/day) exhibited significant improvements in forced expiratory flow 25%-75% and Asthma Control Questionnaire scores when compared with baseline measurements. At 12 months, a substantial improvement was observed in all asthma outcome parameters measured (except FVC in single users), including methacholine challenge. Additionally, a total of 10 patients with asthma switched solely to EC use during this study, whereas the other 8 were dual users and reduced their cigarette consumption to less than 5 cigarettes per day. Although there was a reduction in asthma exacerbations at 6 months, this was not statistically significant. This trial was the first study to demonstrate improvement in airway hyperresponsiveness, pulmonary function, and asthma control in asthmatic smokers who switched to EC use either completely or by reducing daily combustible tobacco consumption. Many questions remain regarding the possible harms and benefits of long-term EC versus combustible cigarette use. EC appear to be here to stay and do have some “good” aspects. Table I summarizes the beneficial effects of EC versus combustible cigarette use noted in the literature to date. Although EC may appear to be the safer alternative to combustible cigarettes, the regulation and standardization of EC is needed to allow further evaluation of safety and the impact on health with long-term use.

THE BAD The greatest fear for the majority of health care professionals is that EC might pose unforeseen health problems either in the short term or long term. These harms stem from the toxic or carcinogenic constituents of the vapor, deleterious effects on lung function, or some unexpected consequence. The potential harms go beyond an individual vaping, as others may experience secondhand or thirdhand exposures through direct physical contact with product components or inhalation of the vapor or possible exposure even after vapor has cleared from the room.19,20 The refill liquids of EC generally contain a mixture of nicotine, glycerin, and PG with water and flavor. However, once

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FIGURE 1. Electronic cigarette models. Reprinted from Grana et al 2013.4

FIGURE 2. Components of the electronic cigarette. Reprinted from Grana et al 2013.4

TABLE I. The “good” side of electronic cigarettes (EC)  EC use may potentially contribute to a modest tobacco cessation effect through mimicry of conventional smoking behaviors  EC use decreased airway hyperresponsiveness and had little to no effects on pulmonary functions in comparison to combustible cigarettes in mild to moderate asthmatic smokers  An increase in expired CO levels is found in conventional cigarette users but not in EC users  An increase in white blood cell, lymphocyte, and granulocyte count is seen acutely in conventional smokers but not in EC users

volatilized these chemical components undergo chemical reactions that create new potentially harmful compounds not present in the original liquid.6 Another concerning aspect about

the composition of the EC liquid is that reports indicate that the nicotine-free products may still contain nicotine and many stores make their own formulations without regulation or oversight.21 All these findings point toward possible harms that can occur with EC use.6,22 EC have side effects that can acutely affect users, including nausea, vomiting, dizziness, burn injuries, and upper respiratory tract irritation.23 The e-liquid contains chemicals that directly cause airway irritation when aerosolized, including nicotine and PG.24,25 Additionally, Lim and Kim demonstrated that exposure to nicotine-containing e-liquid in “asthmatic” mice resulted in TH2 airway inflammation with increased airway eosinophils and IL-4, IL-5, and IL-13 levels and airway hyperresponsiveness.26 The adverse effects of EC may not be

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TABLE II. Levels of toxicants in electronic cigarette (EC) aerosol compared with nicotine inhaler and cigarette smoke

Toxicant

Formaldehyde (mg) Acetaldehyde (mg) Acrolein (mg) o-Methylbenzaldehyde (mg) Toluene (mg) p,m-Xylene (mg) NNN (ng) NNK (ng) Cadmium (ng) Nickel (ng) Lead (ng)

Content in nicotine inhaler mist per 15 puffs*

0.2 0.11 ND 0.07 ND ND ND ND 0.003 0.019 0.004

Range in content in aerosol from 12 EC samples per 15 puffs*

0.2-5.61 0.11-1.36 0.07-4.19 0.13-0.71 ND-0.63 ND-0.2 ND-0.00043 ND-0.00283 ND-0.022 0.011-0.029 0.003-0.057

Range in content in conventional cigarette micrograms (mg) in mainstream smoke from 1 cigarette

1.6-52 52-140 2.4-62 — 8.3-70 — 0.0005-0.19 0.012-0.11 — — —

mg, microgram; ng, nanogram; ND, not detected; NNN, N0-nitrosonornicotine; NNK, N0-nitrosonornicotine (NNN) and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone. Data were taken from Tables 3 and 4 in Goniewicz et al 2014.5 Lowest and highest values reported in each table were used for the range presented for each toxicant. Table adopted from Grana et al.4 *Fifteen puffs were selected to approximate the same nicotine delivery of 1 conventional cigarette.

limited to rodents, as one small study of 30 healthy smokers found an increase in impedance and peripheral airway flow resistance after acute use of EC.27 Additionally, the glycol component found in EC fluid is commonly used as theatrical smoke, which has been reported to decrease lung function after both acute and chronic exposure.28 Another potential harmful aspect of EC is the direct cytotoxicity of e-liquids. Bahl et al evaluated 41 EC refill fluids obtained from 4 companies for cytotoxicity, ability to kill 50% of the cells.29 They found that cytotoxicity varied among products, with some being highly toxic and others having little or no cytotoxicity. The cytotoxicity was mainly related to the concentration and number of flavorings used and not the nicotine. Additionally, the human embryonic stem cells were the most sensitive, which raises concerns for pregnant women who use EC or are exposed to secondhand EC aerosol.29 Other studies examined the cytotoxicity of EC liquids and confirmed their potential cytotoxicity with certain flavors of EC liquids and different cells types.30,31 To determine the presence of toxicants and address the question of secondhand aerosol exposure, Schripp et al analyzed the aerosol exhaled by EC users in 3 different protocols.32 In the first protocol, a volunteer smoker sat in an 8 m3 emission test chamber with an air exchange rate of 0.3 L/hour for 20 minutes of conditioning. This was followed by 6 puffs at 60-second intervals from an EC. This first protocol, in the chamber, was repeated with 3 EC liquids (nicotine-free apple flavor, 18 mg nicotine apple flavor, 18 mg nicotine tobacco flavor) and 1 combustible tobacco cigarette. In the second protocol, 3 different types of EC devices were filled with the same stock of liquid (0 mg nicotine apple flavor). The volunteer then puffed for 3 seconds on each device and transferred the aerosol into a separate 10 L glass chamber with an air exchange rate of 3 L/hour. In the third protocol, an EC consumer exhaled 1 EC puff into a 10 L glass chamber. The authors found that aerosol from the first protocol analysis contained low levels of formaldehyde, acetaldehyde, isoprene, acetic acid, 2-butanodione (methyl ethyl ketone), acetone, and proponal. Analyses of the aerosol in the second

protocol revealed high levels of 1,2-propanediol (PG), 1,2,3-propanetriol, diacetin (from flavorings), traces of apple oil (3-methylbutyl-3-methylbutanoate), and nicotine. When EC aerosol was directly pumped into a glass chamber, the third protocol PG was the predominant element, with lower levels of others. The authors concluded that EC are a source of volatile organic compounds that can be found in the environment surrounding an EC smoker.31 Goniewicz et al examined the vapor generated by 12 different EC cartridges and further supported the findings that EC aerosol contains toxic substances. Table II shows the toxic substances including some that are carcinogenic to humans.5 Recently, Jensen et al found that formaldehyde-containing hemiacetals are detectable in EC aerosol by means of nuclear magnetic resonance spectroscopy.33 They analyzed EC liquid vaporized with a variable-voltage battery. At low voltage (3.3 V), no formations of any formaldehyde-releasing agents were detected; however, at high voltage (5.0 V), a mean of 380  90 mg per sample (10 puffs) of formaldehyde was detected as formaldehyde-releasing agents. The authors extrapolated from the results that at high voltage, an EC user, vaping at a rate of 3 mL/day, would inhale 14.4  3.3 mg of formaldehyde per day in formaldehydereleasing agents. They calculated that the lifetime cancer risk was 4.2  10 3, estimated to be 5 to 15 times higher than the risk of cancer associated with long-term cigarette smoking (Figure 3). Another study, performed by Hecht et al, evaluated the urine of EC smokers for toxic and carcinogenic metabolites. They then compared it with the urine of combustible cigarettes users.34 They found that multiple carcinogens were significantly lower in the EC users compared with tobacco users.34 Although the levels of these substances are much lower in EC than those in conventional cigarettes, regular exposure over many years could present some degree of health hazard.6 Although all of the inhalational effects of using EC are still unknown, there are known risks from both the devices and the EC liquid. As stated earlier, the materials that are used to make EC devices include multiple metals, plastics, fibers, ceramics, and lithium made batteries, which carry a potential fire and explosion

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FIGURE 3. Daily exposures to formaldehyde associated with cigarettes and electronic cigarettes. (Reproduced from Jensen et al33 with permission). TABLE III. The “bad” side of electronic cigarettes (EC)  EC have secondhand and thirdhand effects  The chemical components of aerosol can be different from those found in liquids due to the heating effect  The labeled nicotine-free EC products may still contain nicotine  EC might increase TH2 airway inflammation and airway hyperresponsiveness in patients with asthma  The glycol component of EC has effects on lung function on short- and long-term exposure  Aerosol of EC liquids contains various toxic substances in low levels  Depending on heating degree, the toxic products can exceed the levels of combustible cigarettes  Concerns of EC effects on fetus during pregnancy  There is concern of suicidal and incidental poisoning due to EC liquids

hazard.23,35 Recently, the Centers for Disease Control and Prevention (CDC) analyzed the total monthly poison center calls involving EC and conventional cigarettes from 2010 to 2014.36 They found that the proportion of EC calls increased from 0.3% in 2010 to 41.7% in 2014.36 In addition to the frequent calls received by the poison control centers, the Center of Tobacco Products, a division of the Food and Drug Administration (FDA), has received 47 reports of adverse effect related to EC liquid consumption, 8 of which were deemed serious.37 With the exception of 2, no serious adverse events were attributed to the EC. The 2 were infant deaths caused by choking on an EC cartridge and facial burns caused by an EC exploding.37 Several suicide attempts were recorded where victims either drank EC liquid or injected themselves.1,38e41 Table III highlights the “bad” side of EC that is currently available, but future prospective studies are required to elaborate the putative harmful effects of EC.

TABLE IV. Big tobacco and electronic cigarettes (EC) Tobacco company

Subsidiary company

Electronic cigarette

Lorillard

Lorillard Vapor Corporation

British American Tobacco RJ Reynolds Altria* Imperial Tobacco Japan Tobacco International

CN Creative and Nicoventures

BluCigs and SkyCig Vype

R.J. Reynolds Vapor Company Nu Mark, LLC Fontem Ventures and Dragonite Ploom

Vuse MarkTen Puritane E-lites

*Philip Morris International has partnered with Altria to market EC and gained the rights to exclusively sell Atria’s EC outside of the United States, whereas Altria has the right to exclusively sell in the United States 2 modified tobacco products being developed as EC.

THE UGLY There are many “ugly” aspects regarding EC that concern health care professionals, one of which is the rise in EC usage. Utilizing the HealthStyles survey, an annual consumer-based survey of US adults, King et al found that awareness of ECs increased from 40.9% to 79.7% among US adults between 2010 and 2013, irrespective of smoking status.42 Ever use increased from 3.3% to 8.5% and current use increased from 1.3% to 1.9%. The greatest increase was amongst current cigarette smokers, rising from 4.9% in 2010 to 9.4% in 2013.42 The 2012-2013 National Adult Tobacco Survey found that the highest prevalence of EC use was in young adults aged 18-24 at 8.3%, nearly double that of the overall adult population prevalence.43 Additionally, the CDC estimated that EC usage had more than doubled from 3.3% to

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TABLE V. The “ugly” side of electronic cigarettes  Limited safety data  Variability among different devices  Lack of consistency among e-liquid product and product label  Lack of regulation  Smoking in public often permitted  Increasing popularity  Sale to minors  Potential gateway to combustible cigarettes

6.8% in youths grades 6-12 from 2011 to 2012, with nearly 1.8 million youths ever trying EC.44,45 Multiple studies have addressed reasons for this rise in EC popularity. Among active smokers, the reasons for using EC were to try something new, try to quit or reduce traditional cigarette smoking, and to replace other tobacco products.46,47 Nonsmoking adults have been reported to try EC because of curiosity, a family member was using EC, or they were offered an EC.48 The top reasons for EC usage among youths were curiosity, appealing flavors, and peer influences.49 Surveys show that EC popularity is rising and sales of EC are estimated at around 3.5 billion dollars worldwide.50 This popularity has coincided with the involvement of big tobacco companies, shown in Table IV, and the rapid rise of marketing of EC through twitter and social media outlets.50e52 The marketing is effective at piquing the interest of smokers, as EC are often portrayed as a healthier, cheaper, and cleaner alternative to combustible tobacco smoking.53e55 These safety claims are based on limited scientific evidence that, as devices change, may be irrelevant in the future. Another worry is that EC could serve as a gateway to use of conventional cigarettes and illicit drugs. Ever use of EC has been associated with openness to combustible cigarette smoking and intention to smoke combustible cigarettes.56,57 In middle and high school students, ever use of EC was associated with a higher likelihood of ever smoking (odds ratio 7.42) or current cigarette smoking (odds ratio 7.88).58 Kandel and Kandel demonstrated that priming mice with nicotine could enhance the effect of cocaine. This appeared to occur by disinhibiting dopaminergic neurons in the ventral tegmental area via inhibition of histone deacetylase activity in the striatum and creating an environment primed for FosB gene expression.59 Additionally, reports have confirmed use of marijuana and cocaine with EC devices.60e62 A recent study by Camenga et al found that in a survey of more than 3000 high school students, EC users were more likely to use hookah and blunts than did cigarette smokers.63 A major limitation to the generalizability of studies occurs because of the large EC device variety. Although the basic design has remained consistent, specific features vary significantly across brands.64 Studies have shown that different devices varied with airflow rate required to generate aerosol, pressure drop, and aerosol density.65 Additionally, the amount of aerosol produced for a certain pressure decreases the longer it is used.66 Individuals also vary in how they use EC. Naïve EC users tend to smoke with shorter inhalations when compared with experienced EC users.67 Even amongst experienced EC users, there is a large range of puff duration.68 These differences in devices and how they are used had led to reports of variable serum levels of nicotine in spite of a constant nicotine concentration in the liquid.15

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There is also a marked lack of consistency amongst e-liquids. The FDA conducted a chemical analysis of 2 brands of EC for nicotine content and other impurities. They found that 3 different cartridges of the same labeled e-liquid emitted different amounts of nicotine, and only 1 cartridge labeled nicotine free actually was nicotine free.69 This finding has been consistently reproduced with the actual content of nicotine often varying from the package label.70e72 Product variability creates a challenge for researchers and distrust for the public. Tobacco products are currently regulated by the FDA Center for Tobacco Products under the Family Smoking Prevention and Tobacco Control Act. Tobacco products are defined as any product that is made from or derived from tobacco that is not a drug, device, or combination. Currently, the regulation of sale and use of EC is at the level of state and local governments. Federally, the FDA proposed a rule in April 2014 to consider EC as subject to the regulatory oversight by the Tobacco Control Act. This would set age verification, prohibit sales to persons 18 and younger, require health warnings as to the addictiveness of nicotine and authority, but this has not been passed into law.73 Other countries have already enacted some policy regarding the use and sale of EC, either banning the product outright or regulating it as a medical device.74 The rise in EC popularity coupled with the many unknowns has compelled governments to regulate EC usage.

CONCLUSION EC are a relatively novel means of nicotine delivery that carry many ugly aspects, as illustrated in Table V. The discrepancies between packaging and content of the e-liquid, sale to minors, and unsubstantiated health claims are clearly concerning. Further research is needed to assess whether EC could be an effective smoking cessation tool, whether EC use is a gateway to other drugs, whether device variability impacts users, and both the short- and long-term health effects of EC. Finally, as smokers often concomitantly use EC and combustible cigarettes, the potential consequences of this behavior need to be addressed. This review has sought to highlight the positive and negative aspects of EC versus combustible cigarettes as well as those that do not fit into either category. REFERENCES 1. Marynak K, Holmes CB, King BA, Promoff G, Bunnell R, McAfee T, et al. State laws prohibiting sales to minors and indoor use of electronic nicotine delivery systems—United States, November 2014. MMWR Morb Mortal Wkly Rep 2014;63:1145-50. 2. Flouris AD, Chorti MS, Poulianiti KP, Jamurtas AZ, Kostikas K, Tzatzarakis MN, et al. Acute impact of active and passive electronic cigarette smoking on serum cotinine and lung function. Inhal Toxicol 2013;25:91-101. 3. Harrell PT, Simmons VN, Correa JB, Padhya TA, Brandon TH. Electronic nicotine delivery systems (“e-cigarettes”): review of safety and smoking cessation efficacy. Otolaryngolog Head Neck Surg 2014;151:381-93. 4. Grana R, Benowitz N, Glantz SA. Background paper on E-cigarettes (Electronic Nicotine Delivery Systems). WHO Tobacco Control Papers. 2013. Available online from: https://escholarship.org/uc/item/13p2b72n. Accessed June 4, 2015. 5. Drummond MB, Upson D. Electronic cigarettes. Potential harms and benefits. Ann Am Thorac Soc 2014;11:236-42. 6. Goniewicz ML, Knysak J, Gawron M, Kosmider L, Sobczak A, Kurek J, et al. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control 2014;23:133-9. 7. Escoffery C, Bundy L, Carvalho M, Yembra D, Haardorfer R, Berg C, et al. Third-hand smoke as a potential intervention message for promoting smoke-free homes in low-income communities. Health Educ Res 2013;28:923-30.

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