Wicked Wizard Eliquid Electronic Cigarettes: A Policy Statement From the American Heart Association
Electronic Cigarettes A Policy Statement From the American Heart Association Aruni Bhatnagar, PhD, FAHA, Chair; Laurie P. Whitsel, PhD; Kurt M. Ribisl, PhD; Chris Bullen, MBChB, PhD; Frank Chaloupka, PhD; Mariann R. Piano, PhD; Rose Marie Robertson, MD, FAHA; Timothy McAuley, PhD; David Goff, MD, PhD, FAHA; Neal Benowitz, MD; on behalf of the American Heart Association Advocacy Coordinating Committee, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Quality of Care and Outcomes Research Downloaded from by guest on December 16, 2015 2 Circulation August 25, 2014 Hispanic residents.12 E cigarette availability in retail outlets is also higher in states with weak or nonexistent laws for clean indoor air and low cigarette taxes.12 Although the sale of e cigarettes is prohibited in some countries (Australia, Brazil, Canada, Mexico, Panama, Singapore, and Switzerland), it is allowed in most others, including the United States.13 The number of e cigarettes sold has increased exponentially year by year. Wells Fargo has predicted that sales margins for e cigarettes could grow to $10 billion by 2017, surpassing conventional cigarette sales margins.14 The big 3 major tobacco companies have been purchasing independent e cigarette companies and may share 75% of the profit pool in 10 years.14 E cigarettes are battery-powered devices that have cartridges or refillable tanks containing a liquid mixture composed primarily of propylene glycol and/or glycerol and nicotine, as well as flavorings and other chemicals.5 During use, inhalation activates a pressure-sensitive circuit that heats the atomizer and turns the liquid into an aerosol that is inhaled by the user through the mouthpiece and exhaled as a fine mist.5 Some e cigarettes have buttons that allow the user to manually activate the heating element. The exhaled aerosol does not contain smoke, tar, or carbon monoxide. Studies of specific types of e cigarettes have shown that compared with conventional cigarettes, the byproducts from their aerosols produce very low levels of air toxins.15–17 Proponents of e cigarettes maintain that these products emulate smoking behavior without exposing the user to the toxic smoke constituents of conventional cigarettes that are deleterious to health, so there would be a public health benefit if individual smokers completely switched or substantially reduced their cigarette smoking habit.18–20 However, the use of e cigarettes could be a problem at the population level. For instance, e cigarettes could fuel and promote nicotine addiction, especially in children, and their acceptance has the potential to renormalize smoking behavior. E cigarette use could also potentially serve as a gateway to other drugs and harmful substances.21 E cigarettes: Design and Operation Since their initial manufacturing in 2003, there has been a rapid growth and evolution in the types, design, and overall engineering characteristics of e cigarettes.22,23 This has resulted in a large degree of product variability in size, potential nicotine concentrations, and e liquid formulations. There have also been changes in electrical circuitry (eg, heating element or atomizer) and battery life that allow for more e liquid delivery, adjustments in flavor, and longer device use. Different types of e cigarettes are being developed continuously. Table 1 lists some of the different e cigarette types and name brands on the market today. Newer second- and thirdgeneration devices allow for multiple types of user customization. This has resulted in cross-product and within-product differences in aerosol production, nicotine delivery, and product use risk.22 These developments significantly complicate the ability to assess the impact of e cigarettes on individual and population health.22,23 Regardless of type, there are 3 basic e cigarette components: a battery, an e liquid–containing cartridge, and an atomizer (ie, a vaporization chamber with heating element).21 Other components include an airflow sensor (sensing inhalation), a microchip for controlling the heating element, and a light-emitting diode light at the tip that simulates a burning cigarette tip.21 All devices have air holes, which control the pressure drop and facilitate the flow of air required for puffing.22 E cigarettes are available with automatic or manual button–activated batteries. The battery in an automatic device is activated by inhalation or the drag, whereas manual devices require the depression of a button for battery activation.22 The smokelike aerosol produced by these devices is not because of the combustion of organic material; rather, it is an aerosol of the e liquid. As noted, the “atomizers” contain the heating elements that convert the fluid into an aerosol. Such atomizers are an essential component of all vaporizers, and they consist of a small heating element that evaporates the fluid and a wicking device that draws in the fluid. Since the inception of e cigarettes, the atomizers have undergone dramatic engineering changes. Developments include the evolution of the atomizer into “cartomizers” (cartridge plus atomizer), which is a combination of an e liquid distribution system and a wick/ fiber and heating element.23 Second- and third-generation e cigarettes models, which are larger than the first “cigarette-like” e cigarettes (cigalikes), are referred to as “clearomizers,” “tankomizers,” or “carotanks” because they can hold several milliliters of fluid in refillable reservoirs. Some second- and third-generation e cigarette batteries are available in different voltages (3.0 to 7.0 V) and with greater battery life (greater milliampere-hour) than earlier models. Within the atomizer, a resistance wire is encircled around the wicking device that draws the fluid in. When activated by the sensing device, the resistance wire rapidly heats up, turning the fluid into an aerosol, which is then inhaled by the user. The resistance and voltage applied to the heating element, as well as the material from which the heating element is made, are important determinants of the temperature achieved, which determines in part the amount and quality of the aerosol produced by the atomizer. Some second- and third-generation e cigarettes have programmed pumps, diaphragms, or micropumps on microelectromechanical systems. These allow for a specific programmed amount or a combination of e liquid delivery to the aerosol generator.22 Some e cigarettes contain programmable logic units, integrated circuits, and other electronic components that are used to display average use cycle and safety warnings.22 Ongoing product development and evolution are likely to continue, and therefore, new regulatory policies will be important to ensure appropriate quality control. Profile of Users The number and duration of surveys are increasing and variably include current, former, and nonsmoker categories.24,25 These surveys are difficult to consolidate because they have been undertaken in different populations and jurisdictions, using different sampling methods and definitions, over a number of years while e cigarette types, visibility, and use have increased dramatically. Generally, non-Hispanic whites, current smokers, young adults, and those with a higher education and higher income perceive e cigarettes as less harmful than combustible tobacco products and are more likely to use Downloaded from by guest on December 16, 2015 Bhatnagar et al Electronic Cigarettes 3 them.24,26–29 European and North American surveys conducted in 2012 and 2013 report that most e cigarette users are current or former smokers30; 40% to 70% of all adults have heard about them, with awareness highest in smokers and growing.26,31–33 Such surveys also report that ≈3% to 7% of the adult population has ever used e cigarettes26,34 Among smokers in the United States and Great Britain, ≈11% report ever having used e cigarettes, whereas the use of e cigarettes is significantly lower (0.5%–1.0%) in nonsmokers.25,26,35 A study conducted in the Czech Republic in 2012 revealed that almost 20% of smokers who try e cigarettes go on to become regular users.36 It is uncertain how many e cigarette users are smokers who really want to stop cigarette smoking or ex-smokers but persistent e cigarette users, or who want to be dual users. At present, there are few longitudinal studies to assess how many smokers are able to completely quit cigarette use, whether they continue e cigarette use after quitting or whether they continue dual use, that is, using them concurrently with combustible products.36 Epidemiological studies and population surveys also indicate that although many e cigarette users plan to use the devices to quit or reduce their smoking, they are usually using them in a dual-use capacity, especially in places where smoking is restricted.35–40 A survey conducted in 2012 showed that >80% of current e cigarette users do not use them on a daily basis, and almost half of all smokers indicated they may use e cigarettes in the future.35 Finally, among college students, another e cigarette user group, e cigarette use may not be motivated by the desire to quit smoking, nor may it lead to quitting.41 In conclusion, the overall use patterns are unclear and constantly changing, which makes it difficult to draw firm conclusions about the prevalence, preference, and purpose of e cigarette use. Youth Concerned public health advocates see e cigarettes as a route to nicotine addiction and possibly as a potential gateway to tobacco use in youth or nonsmokers and to reinitiation of tobacco product use by former users.42 Data from the 2011 to 2012 National Youth Tobacco Survey43 showed that among students in grades 6 through 12, current e cigarette use (≥1 day in the past 30 days) increased from 1.1% in 2011 to 2.1% in 2012 and any use of e cigarettes (ever use) increased from 3.3% to 6.8% in the same corresponding years. Overall, by 2012, 1.78 million high school and middle school students nationwide had tried e cigarettes. For those students who had ever used e cigarettes, 9.3% reported never smoking conventional cigarettes, whereas 76.3% of current e cigarette users responded that they also smoke conventional cigarettes. Among never-smokers, 0.7% were currently users (past 30 days), which indicates that few never-smokers who try e cigarettes continue their use.44 A survey of 40000 middle school and high school students from ≈200 schools has shown that e cigarette use is higher in current smokers and ever-smokers Table 1. Types of E cigarettes Generation Examples First generation First generation e cigarettes were designed to look and feel like tobacco cigarettes. Although there is some variation in size, most resemble cigarettes and therefore have also been referred to as “cigalikes.” These battery-operated devices were initially composed of 3 pieces: a battery, atomizer, and cartridge. Now, the atomizer and cartridge have been replaced by a combined “cartomizer,” which screws into and connects with a battery, some of which are rechargeable. The disposable e cigarettes are designed for 1-time use and are discarded after use. These cigalike devices are all available in various nicotine concentrations and with different flavorings. Halo White Cloud Green Smoke Apollo Blu South Beach V2 Cigs Atlantic Second generation These e cigarette devices are larger and typically do not resemble a cigarette. These medium-battery (rechargeable)–style e cigarettes are also referred to as “tank-styled” e cigarettes. Sizes, shapes, and colors can resemble pens, small screwdrivers, or the tip of a hookah pipe. These larger e cigarette devices have the basic e cigarette components: the battery, the atomizer, and the cartridge. However, there are some key differences between these devices and the first-generation e cigarette devices: second-generation e cigarette devices have larger-capacity batteries (greater milliampere-hours) and therefore stay charged longer, have larger atomizers and electronic circuits that deliver greater energy (which enhances nicotine delivery to the user), and have large, separate cartridges (“tanks”) that the user can fill up using different purchased e liquids and flavorings. Some also have a manual switch that allows modulation of both puff length and frequency. eGo Riva Tornado KGo Third generation These devices are similar to the second generation but are larger and allow for more personal and custom modifications; therefore, they are sometimes referred to as “personalized vapors” or aerosols. Similar to the second-generation devices, these devices come with a range of different cartridge and atomizer options (eg, cartomizer, clearomizer, tankomizer) and batteries (greater milliampere-hours coupled with a certain voltage [3.0–6.0 V]). Some e cigarettes devices allow the user to adjust the resistance on the atomizer/cartomizer. A low-resistance cartomizer produces higher heating element temperatures, thus generating more heat and affecting the amount and quantity of the aerosol. Users of these devices can pair different atomizers (that allow different resistances) with high-capacity batteries to maximize both aerosol production and battery life. E cigars could either be classified as a second- or third-generation e cigarette device. Available in disposable and rechargeable forms. Designed to simulate a cigar in terms of size. Some e cigars have an LED tip that is partially hidden behind some type of screen to mimic a real cigar’s ash. Companies with personal vapors: Apollo Henly Vapor Zone Volcano E cigar: Cuvana Marcello-rechargeable Vapor Zeus Royale premium E cigars indicates electronic cigars; e cigarettes, electronic cigarettes; LED, light-emitting diode. Downloaded from by guest on December 16, 2015 4 Circulation August 25, 2014 and among those intending to quit.43 This surveillance does not address whether adolescents are using e cigarettes as a gateway to smoking cigarettes, but adolescents do consider e cigarettes as high-tech, accessible, and convenient, especially in places where smoking cigarettes is not allowed.45 Increasingly, there is robust marketing and advertising using celebrities and appealing flavors (eg, chocolate, strawberry, and vanilla) to make e cigarettes especially more attractive and appealing to children and adolescents.45 Much of the marketing for e cigarettes has been through the Internet and social media outlets such as YouTube,46 but increasingly, e cigarettes are advertised on television, radio, and in the print media, where broadcast cigarette ads have been banned since 1971.47 Data from a US population survey indicated that for those reporting they have heard about e cigarettes, the majority (48%) reported television as their primary source, followed by “in-person conversation” and the Internet.35 Another study found that youth exposure to television advertisements for e cigarettes increased 256% between 2011 and 2013, with 24 million youth reached.48 Online searches for e cigarettes have surpassed those for nicotine replacement therapies (NRTs) and snus, products that have been on the market much longer.49 E cigarettes and Public Health The major public health issues regarding e cigarettes include whether or not they may contribute to reducing overall tobacco-related harm through complete cessation or possibly through reduction of the number of cigarettes smoked, denormalization of smoking, reduction in prevalence of use of combustible products (especially cigarettes), reduction of second-hand smoke exposure, and diminishing the influence of the tobacco industry. Although some believe that acceptance of e cigarettes has the potential to reverse the social norm for prohibiting smoking in public places achieved over decades of advocacy work, others see these products as a way to denormalize smoking because they are a potential mechanism for quitting.20 It is not known whether the emerging e cigarette technology will shift people from combustible products to the exclusive use of e cigarettes or whether dual use will persist.50 E cigarettes as a Cessation Aid Current evidence evaluating the efficacy of these products as a cessation aid is sparse, confined to 2 randomized controlled trials and 1 large cross-sectional study, anecdotal reports, and Internet-based surveys. A large cross-sectional study showed that smokers who wanted to quit without professional help were significantly more likely to report abstinence using e cigarettes than with traditional cessation aids or going “cold turkey.”51 The adjusted odds ratio for self-reported cigarette abstinence in e cigarette users was 1.63 (95% confidence interval 1.17–2.27) higher than with NRT use and 1.61 (95% confidence interval 1.19–2.18) higher than for those using no aid. In a survey in the United Kingdom, 67.8% of e cigarette users “completely replaced tobacco cigarettes with electronic cigarettes”; however, these reports are confounded by a selfselection bias in that the respondents are often e cigarette enthusiasts.39 In contrast, other surveys suggest that compared with never-users, e cigarette users are less likely to be tobacco abstinent52 and that e cigarette users were no more likely than cigarette smokers to have quit permanently despite having reduced their cigarette consumption.24 The largest randomized controlled trial conducted to date, which used e cigarettes available on the market in 2010 that are now obsolete, had cartridges labeled as containing 16 mg of nicotine and showed that the study e cigarettes were modestly effective with or without nicotine at helping smokers quit, on par with the abstinence achieved with nicotine patches.53 At 6 months, the verified quit rates were 7.3% with nicotine e cigarettes, 5.8% with nicotine patch, and 4.1% with placebo e cigarette treatment. This study also found that dual use persisted at 6 months at moderately high levels (approximately one third of participants); dual use also occurred with patch users but at much lower levels (7%). Health Effects and Safety The overall health effects of e cigarettes should be considered both in the context of the intrinsic toxicity of e cigarettes and with regard to their relative toxicity compared with the wellknown injurious effects of smoking conventional cigarettes. Even if there are some intrinsic adverse health effects of e cigarettes, there would be a public health benefit if e cigarettes proved to be much less hazardous than combustible cigarettes and if smokers could switch entirely from conventional cigarettes to e cigarettes. However, in general, the health effects of e cigarettes have not been well studied, and the potential harm incurred by long-term use of these devices remains completely unknown. Nevertheless, some studies have examined the health effects of e cigarettes by considering the constituents of their aerosol and their known toxicities and through toxicological evaluation of e cigarette liquids and aerosols. Current data from human exposures, including experimental studies, and surveys of adverse effects and accidental exposure are discussed below. Available data on the safety and health effects of e cigarettes have been reviewed elsewhere.54–56 The constituent and toxicant levels within the e liquid and aerosol vary depending on the type of e liquid (or e juice) formulation and the specific design of the device.57 Typically, e liquid formulations contain nicotine, flavors, water, glycerin, and propylene glycol.57 Exposure to levels and types of metals or other materials within the aerosol depends on the material and other engineering features of the heating coils.57 Potential metallic and nanoparticles derived from the heating coils can include tin, iron, nickel, and chromium.22,58 Other materials in e cigarettes could include ceramics, plastics, rubber, filament fibers, and foams. Some of these materials can be aerosolized and inhaled. Importantly, low levels of harmful or potentially harmful metals such as lead, nickel, and chromium are listed as having been detected.22,59 The e liquids typically contain many flavorings, including tobacco flavoring. In tobacco-flavored products, other tobacco “contaminants” may be present. Trace levels of tobacco-specific N-nitrosamines, polycyclic aromatic hydrocarbons, and volatile organic compounds in the e liquid and vapor have been reported; however, the amounts are deemed too low to cause human risk.57,60 Other flavorings include fruit and spices (eg, strawberry, black cherry, and Ceylon cinnamon) or flavorings such as “bubble gum” or “chocolate truffle.” Downloaded from by guest on December 16, 2015 Bhatnagar et al Electronic Cigarettes 5 Propylene glycol is a major ingredient in e cigarettes. It is approved by the FDA as a solubilizing agent for different types of medications and is considered generally nontoxic.59 However, in 1 product, small amounts of diethylene glycol, a potential byproduct of nonpharmaceutical grade propylene glycol, have been detected.61 Other contaminants found in particular products have included the weight-loss chemical rimonabant (Zimulti) and the erectile dysfunction medication tadalafil (the active ingredient in Cialis). As a result, the FDA has issued warnings to several e cigarette companies for selling e-cartridges with these contaminants.61 Nicotine Nicotine is delivered by most but not all e cigarette products. Most e liquids contain 24 mg/mL, 18 mg/mL, 12 mg/mL, or 6 mg/mL nicotine and are qualified by the manufacturers as high, medium, or low nicotine strength.62 Some e liquids are available in 36 mg/mL concentrations.62 Nicotine solutions of 100 mg/mL for use in making e cigarette refill liquids are available over the Internet. As a point of context, 1 regular cigarette contains ≈10 to 15 mg of nicotine and delivers a systemic dose of ≈1 mg of nicotine. Testing has revealed that the nicotine content noted in some e cigarette products and refill solutions has been incorrect and either overestimates or underestimates the amount of nicotine,61 which indicates a need for regulatory oversight.61 The overall total amount of nicotine in the e liquid depends on the size of the refill vial; for example, a 10-mL bottle of 24 mg/mL contains a total of 240 mg of nicotine. Blood levels of nicotine are generally lower from e cigarette use than from conventional cigarettes, but users of some e cigarette tank systems with more powerful batteries that heat liquids to higher temperatures may achieve blood nicotine levels comparable to those of cigarette smokers.63,64 The extent to which nicotine inhaled from an e cigarette is absorbed through the lungs or via the throat and upper airway has not been determined. The size distribution of particles generated by e cigarettes, discussed later in this report, suggests that at least some pulmonary absorption is likely. In 1 study,58 it was found that absorption of nicotine from e cigarettes was lower than from tobacco cigarettes even with the new-generation cartomizers, which suggests that most absorption from the devices occurs in the buccal mucosa or upper airways. Compared with smoking 1 tobacco cigarette, the electronic devices and liquid used in this study delivered one third to one fourth the amount of nicotine after 5 minutes of use. Newgeneration e cigarette devices were more efficient in nicotine delivery but still delivered nicotine much more slowly than tobacco cigarettes. The main health concern for nicotine in cigarette smokers is maintenance of addiction. Most of the adverse health effects of smoking are caused by tobacco combustion products,65 but there are some health concerns that are related to nicotine per se. Many of these concerns are related to the ability of nicotine to release catecholamines, including hemodynamic effects (increase in heart rate, a transient increase in blood pressure, vasoconstriction of coronary and other vascular beds), adverse effects on lipids, and induction of insulin resistance.65 Nicotine has also been reported to produce endothelial dysfunction and to cause fetal teratogenicity, operating by different mechanisms.66 Nicotine in vitro and in animals can inhibit apoptosis and enhance angiogenesis, effects that raise concerns about a role of nicotine in promoting the development and spread of cancer and in the acceleration of atherosclerotic disease.67 Because most people use nicotine in the form of tobacco products, there are relatively few data on the health effects of prolonged exposure to pure nicotine. There are some studies of prolonged NRT in smokers who have quit smoking.68,69 In these studies, no adverse effects have been found when nicotine medication was administered for months to several years. Other studies indicate that patients with known cardiovascular disease tolerate NRT well for periods up to 12 weeks.65 Because most of the toxicity from cigarette smoking derives from combustion products, the health effects of smokeless tobacco could be examined to assess potential long-term adverse effects of nicotine without exposure to combustion products. Smokeless tobacco users take in as much nicotine as cigarette smokers, although not by the pulmonary route.70 The most extensive and rigorous epidemiological studies on smokeless tobacco use come from Scandinavia, where a large percentage of men use snus, a smokeless tobacco product that contains nicotine but relatively low levels of carcinogens and other toxins. These studies report only a very small cardiovascular disease risk in snus users compared with tobacco smokers.71 However, discontinuation of snus use after MI has been found to be associated with nearly halved mortality risk, which is similar in magnitude to the benefit associated with smoking cessation.72 Thus, although the adverse health effects of e cigarettes are not known, they are likely to be much less than those of cigarette smoking, but could be significant in individuals with heart disease. Acute nicotine toxicity is a concern if e cigarette liquids are ingested, which may occur accidentally by children or intentionally by adults as a suicidal overdose, or with dermal exposure. Nicotine is well absorbed through the skin when in an alkaline solution, and e cigarette liquids are alkaline. Nicotine intoxication commonly causes dizziness, nausea, vomiting, pallor, tachycardia, and sweating. Abdominal pain, salivation, lacrimation, and diarrhea have also been noted. Confusion, agitation, lethargy, convulsions, and possibly death are seen in cases of severe poisonings that cause hypotension and respiratory muscle weakness.73 In such cases, respiratory arrest is the most likely the cause of death.73 Symptoms usually begin within 15 minutes of acute liquid nicotine exposure and resolve within 1 to 2 hours.73 Cutaneous exposure may lead to delayed onset and prolonged symptoms. A number of cases of accidental exposure in children and adults have been reported by poison control centers.74,75 The concentrations of nicotine in e cigarette liquids are high enough to be fatal to a child if even a few milliliters is ingested.76,77 There are isolated reports of severe toxicity, including death, in children who ingested e cigarette liquids. Nationally, calls to poison control centers attributable to accidental exposure to e cigarettes have increased dramatically (161%–333%), mostly involving children who were exposed to the replacement cartridges and liquids containing nicotine.78.79 Downloaded from by guest on December 16, 2015 6 Circulation August 25, 2014 Minor Tobacco Alkaloids and Tobacco-Specific Nitrosamines Some but not all e cigarette liquids contain minor tobacco alkaloids (such as nornicotine, anabasine, or anatabine) and tobacco-specific nitrosamines, such as N′-nitrosonornicotine and 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK).76 These may be present in the liquids because nicotine is extracted from tobacco, and these compounds are present in tobacco. Several minor tobacco alkaloids have nicotine-like actions, although they are less potent than nicotine. Extensive evidence has shown that tobacco-specific nitrosamines are highly carcinogenic80; however, the levels of both minor alkaloids and nitrosamines present in most e cigarette products are low and are unlikely to pose a significant human health risk.81 Minor alkaloids and tobacco-specific nitrosamine are undetectable in nicotine medications.82 Carbonyls and Other Volatile Chemicals Thermal degradation of propylene glycol can generate propylene oxide, which is classified by the International Agency for Research on Cancer as a class 2B carcinogen. The heating of glycerol can form acrolein, which is an irritant and oxidizing agent thought to contribute to adverse pulmonary and cardiovascular effects of cigarette smoking.83–85 Analyses of emissions from cigarettes have found primarily formaldehyde, acetaldehyde, and acrolein, along with low levels of toluene, xylene, benzene, and butadiene.86 Although these compounds are potentially toxic, the levels in e cigarette emissions are many-fold lower than those found in cigarette smoke and in some cases similar to those found in the mist of medicinal nicotine inhalers. The risk of exposure to low levels of these compounds is unknown. With intense heating, such as from the use of tank models with large batteries, higher amounts of formaldehyde are generated, in some cases similar to levels found in cigarettes smoke.60,87 Formaldehyde is a carcinogen and an irritant, but the risks of prolonged inhalation of formaldehyde at the levels found in e cigarette aerosols are unknown. Propylene glycol and glycerol are added in e cigarette liquids to generate an aerosol that resembles cigarette smoke. Animal studies of propylene glycol inhalation for up to several months have revealed little or no toxicity.88,89 Propylene glycol is used to generate theater fog and is used in aviation industries. It can cause eye and respiratory irritation, and there have been concerns about respiratory irritation in the theater.90 Thus, there are concerns about potential harm from the inhalation of propylene glycol from e cigarettes, particularly for people with asthma or chronic obstructive lung disease, although there is little research on the effects in susceptible populations. Metals Detectable levels of metals such as tin, silver, iron, nickel, cadmium, and copper have been detected in some but not all e cigarettes in which they could be generated from the heating element.58 Some e cigarette solutions contain tin “whiskers,” microscopic crystals that emanate from tin in the solder joints.58 The nature and amount of metals generated depend on the design of the e cigarette product, and some generate few or no metals. The levels of metals in e cigarette emission are generally low, but little is known about the toxicity of prolonged inhalation of low levels of metals. Particles E cigarettes generate an aerosol that consists of fine and ultrafine particles in a gas phase. These particles are likely generated from supersaturated 1,2-propanediol vapor. Nanoparticles present in some e cigarette aerosols have been reported also to contain trace levels of tin, chromium, and nickel.58 It has been reported that particle number concentration of the mainstream aerosol generated by e cigarettes, averaged across several liquids and types of e cigarettes, was similar to that of conventional tobacco cigarettes.91,92 The number of particles in e cigarette aerosol has been found to be influenced by the liquid nicotine content and puffing time, and higher levels of particles were generated by e cigarettes that contained higher nicotine concentrations.91 The particle size distribution from the few e cigarette devices that have been tested has been reported to be similar to that of conventional cigarettes.92 Particles such as those generated by e cigarettes can reach deep into the lungs and potentially cross into the systemic circulation. Carbonaceous particles present in cigarette smoke and ambient air have been demonstrated to have adverse cardiovascular and respiratory effects in both human and animal models.93,94 It is not known whether the type of particles generated by e cigarettes have the same toxicity as particles present in ambient air or those generated by conventional cigarettes, but this is an important question for determining the long-term safety of e cigarettes. Toxicology Studies Results of several toxicology studies with e cigarette liquids and aerosols have been published. These studies show that e cigarette liquids and aerosols affect the viability of established cultured cell lines, such as human or mouse fibroblasts, human embryonic stem cells, mouse neural stem cells, and cardiomyoblasts.95–97 For example, using 3 different cell types (ie, human embryonic stem cells, mouse-derived neural stem cells, and human pulmonary fibroblasts), Bahl et al95 examined the cytotoxicity of several flavored e cigarette refill extracts from 4 different manufacturers. They reported that extract flavorings such as Ceylon cinnamon were toxic to all 3 cell types tested. In addition, 1 butterscotch sample was highly toxic, whereas 2 other butterscotch samples from the same company had low toxicity, which shows the within-product and between- product variability.95 Overall, the human embryonic and neonatal mouse–derived stem cells were more sensitive than adult lung fibroblasts to the cytotoxic effects of the extracts. Cytotoxicity was not caused by nicotine but was correlated with the number and concentrations of flavoring chemicals. In general, cytotoxicity appeared to be related to the concentrations and numbers of flavorings used and unrelated to nicotine.