Loading...
The URL can be used to link to this page
Your browser does not support the video tag.
SR-06-24-2014-8B
City Council Meeting: June 24, 2014 Agenda Item: To: Mayor and City Council From: Marsha Jones Moutrie, City Attorney Subject: Report And Recommendation That Council Amend The City's Smoking Ordinance To Regulate Electronic Smoking Devices The Same As Traditional Cigarettes Recommended Action Staff recommends that City Council direct Staff to prepare an Ordinance for first reading which would include electronic smoking devices within the definition of "smoke" and "smoking" for purposes of the City's smoking laws. Executive Summary This report provides information requested by Council relating to recent studies and government actions with respect to electronic cigarettes. It includes staff's recommendation that Council direct the preparation of an ordinance to treat electronic cigarettes and other electronic smoking devices the same as traditional tobacco products for purposes of the City's smoking laws. Background At its meeting on March 18, 2014. Council directed the City Attorney's Office to research and analyze the regulation of electronic cigarettes with consideration of recent actions in neighboring cities. Two weeks earlier, on March 4, 2014, the cities of Los Angeles, Long Beach and Beverly Hills each had adopted ordinances that expanded their definitions of smoking to include electronic cigarettes for purposes of local regulation. Since receiving Council's direction, staff has reviewed news reports on this subject and the underlying scientific studies being cited by both sides in the debate; reviewed the newly enacted laws of other jurisdictions; and analyzed the arguments for and against the regulation of e- cigarettes as they pertain to Santa Monica. 1 Discussion Electronic cigarettes or "e- cigarettes" are products that deliver a nicotine - containing aerosol (commonly called vapor) to users by heating a liquid chemical solution. The liquid typically is made up of propylene glycol or glycerin, nicotine, and flavored chemicals. It is heated electronically and produces a chemical vapor that is inhaled and exhaled by the user. Most e- cigarettes use a delivery device similar in size and shape to a traditional cigarette. The process is often referred to as "vaping." E- cigarettes were introduced in China in 2003 and entered the U.S. market in 2008. During the past few years their popularity in this country has grown exponentially, especially among young people. For example, between 2011 and 2012 their use among American youth more than doubled according to the Centers for Disease Control and Prevention. The most common users are those who also smoke cigarettes. The marketing and advertising of e- cigarettes is expanding rapidly. They are promoted in television, radio, online and print advertisements. Unlike with cigarettes, there are no restrictions or regulations on e- cigarette advertising. Much of the advertising is directed at children, using social media and celebrities and featuring flavors such as Cotton Candy and Gummi Bear. Since 2013, e- cigarettes have been the subject of frequent media coverage, public discussion and increasing scientific research. At the same time many local and state governments are moving to regulate e- cigarettes in a similar fashion to traditional tobacco, products. Arguments For And Against E- cigarettes Proponents (and advertisers) of e- cigarettes generally cite two main arguments in favor of the devices. First, they claim that e- cigarettes are an effective tool for smokers to quit smoking cigarettes. By providing a dose of nicotine, the argument goes, they satisfy the addiction to that chemical and thus enable smokers to end their tobacco habit, similar to the nicotine patch or gum. Second, they claim that e- cigarettes are safer than cigarettes — both for the user and for those nearby — since their vapor contains fewer dangerous 2 chemicals than cigarette smoke. Some take this argument further and claim (or advertise) that e- cigarettes pose no risk at all, consisting merely of "water vapor." Those who favor restrictions on e- cigarettes make the following arguments: • They get people addicted to nicotine and so make it more likely that users will take up smoking cigarettes; • They are popular among teens, are marketed to children, glamorize smoking in general, and lead to increased smoking of cigarettes by children; • They are visually similar to cigarettes, thereby creating problems in locations where smoking is currently prohibited including: (a) making enforcement of no- smoking laws difficult; (b) undermining compliance with smoking laws by giving the visual impression that the laws are being violated; and (c) undermining efforts to reduce smoking in general. • Their marketing includes false and exaggerated claims and is completely unregulated, meaning that consumers have no way to know the levels of various chemicals contained in e- cigarettes; • They contain and emit chemicals that are known to be hazardous to human health, both for users and those nearby; and • They pose many still- unknown potential health risks, and until they are proven safe their use should be restricted similarly to that of traditional tobacco products. Assessment of the Arguments and Related Scientific Research On May 12, 2014, just prior to the creation of this staff report, the American Heart Association ( "AHA ") published a major new analysis of prior scientific studies on electronic cigarettes. "E- Cigarettes: A Scientific Review," authored by researchers at the University of California, San Francisco and published in the AHA's journal Circulation, is the first -ever comprehensive assessment of peer- reviewed published research on the subject. The authors of the UCSF meta - analysis reviewed 84 prior scientific studies and stated conclusions and policy recommendations regarding e- cigarettes. The work was a condensed version of a larger meta -study previously prepared for the World Health 9 Organization. A copy of the meta - analysis is attached to this report as Attachment A. Its conclusions will be addressed as they pertain to the various arguments and issues in the public debate over e- cigarettes. 1) Potential as smoking cessation tool One of the main arguments in favor of e- cigarettes is that they help smokers quit smoking. A recent study estimated that e- cigarette manufacturers make this claim on more than half of the products being sold. There is anecdotal evidence that e- cigarettes do enable some cigarette smokers to quit. However, thus far no scientific studies have proven their efficacy for that purpose. The UCSF meta - analysis, after reviewing all available peer- reviewed studies on the subject, concluded that claims of e- cigarettes as a smoking cessation tool were not supported by the evidence. In fact, when they pooled the available data from prior studies the UCSF researchers found that e- cigarette users actually had "significantly lower odds of quitting smoking cigarettes," by more than 30 percent. (Emphasis added.) Another recent study calls the claim into question. In findings published in March 2014 in the Journal of the American Medical Association's Internal Medicine, researchers found as part of a broader study analyzing population data that smokers who tried e- cigarettes were no more likely to quit smoking than those who did not try them. In 2012 the World Medical Association stated that e- cigarettes "are not comparable to scientifically - proven methods of smoking cessation" and that "neither their value as therapeutic aids for smoking cessation nor their safety as cigarette replacements is established." 2) Potential health risks of e- cigarettes The other main argument made in favor of e- cigarettes is that they are safer than cigarettes and therefore are a preferable alternative for smokers that should be promoted rather than restricted. There are numerous studies to back the claim that e- cigarettes are safer than cigarettes. As noted in the UCSF meta - study, "[t]oxins in the e- 12 cigarette aerosol [are] at much lower levels compared with the conventional cigarette emissions." A 2013 study from Drexel University concluded that e- cigarette vapor posed no significant cause for health concerns either for the user or for second -hand recipients of the vapor. The study found that exposures from e- cigarettes fell "well below the threshold for concern for compounds with known toxicity." Another 2013 study from the journal Nicotine and Tobacco Research found that although e- cigarette vapor caused nicotine exposure, it did not include the "combustion toxicants" present in cigarette smoke. That study noted the need for further research. Aside from a direct comparison with cigarettes, there is increasing evidence backing the argument that e- cigarettes may be hazardous to the health of both users and those nearby. First, the key ingredient in e- cigarettes is nicotine, a highly addictive neurotoxin derived from tobacco that is included in the California Proposition 65 list of chemicals known to cause cancer or reproductive toxicity. The liquid form of nicotine used in e- cigarettes is claimed to be especially hazardous when it comes into contact with human skin, as described in a recent New York Times article. The U.S. Centers for Disease Control recently reported a sharp rise in emergency calls to poison centers due to exposure to e- cigarette liquids contemporaneous with the rise in e- cigarette use: such emergency calls rose from around one per month in 2010, to 215 per month in 2014. Second, there is growing evidence of potential health risks from the vapor of e- cigarettes. As the UCSF review points out, "e- cigarette aerosol is not merely 'water vapor' as is often claimed in the marketing for these products." Rather, it contains comparable size distribution and number of particles to cigarette smoke, with most particles in the ultra -fine range. Although few studies have directly measured the health effects of exposure to e- cigarette emissions, some show the ability of e- cigarette aerosol "to result in biological effects." The authors concluded: "Long -term biological effects are unknown at this time because e- cigarettes have not been in widespread use 5 long enough for assessment." A team of Greek scientists in 2012 found that a ten - minute use of an e- cigarette causes a "significant" increase in airway resistance (lung damage) for the user. A study published in April 2014 in Nature found that e- cigarette vapor causes cell mutations similar to those caused by cigarette smoke. A 2013 study found a total of 22 different elements in the vapors of electronic smoking devices, three of which appear on the FDA's list of harmful and potentially harmful chemicals. The Los Angeles County Department of Public Health in 2013 voiced its support for local governments' inclusion of e- cigarettes in tobacco laws since "studies indicate that [they] pose potential dangers for users, as well as for non -users who passively inhale these chemical vapors." Third, at least one study has found evidence for "third- hand" (residue) exposure to nicotine from the use of e- cigarettes. Researchers at the Roswell Park Cancer Institute in 2014 found "significant" but varying levels of nicotine residue from the devices and called for further study. Finally, a common argument made in favor of regulating e- cigarettes is that the health risks of the devices are still largely unknown and their safety is unproven. Under this rationale, given the strong potential for health hazards given the known ingredients and mechanisms, it is reasonable to restrict their usage unless and until their safety is proven. 3) Visual confusion and enforcement issues An often -cited reason for treating e- cigarettes the same as cigarettes is that they appear visually similar from even a short distance. Since it is difficult to distinguish the two, if e- cigarettes are allowed in locations where cigarettes are prohibited, then both government and private enforcement will be hampered. A related argument is that the growing use of e- cigarettes in public places where tobacco is now banned creates confusion among the public and, worse, gives the visual impression that smoking is again allowed in these locations. There is particular concern that youth may be influenced in this way. A 2012 report published in the Journal of Environmental and Public Health states that electronic smoking devices "may have the capacity to 're- normalize' tobacco use in a demographic that has had significant denormalization of tobacco use previously." One important factor in the regulation of public cigarette smoking has been that the laws themselves, by making smoking less convenient and discouraging it in subtle ways, have helped reduce the incidence in smoking in communities with such laws. Studies in the past decade have shown that local regulation of smoking — especially smoke -free policies in defined areas — has had a measurable effect on cigarette use in this way. Allowing the use of e- cigarettes in the same places where smoking is banned, could hamper this effect. 4) Potential "gateway" to cigarette use Opponents of e- cigarettes claim they are a "gateway" to cigarette use since they contribute to nicotine addiction and glamorize smoking. A study from March 2014 in the AMA's Pediatrics found that teens who tried e- cigarettes were more likely to become addicted to cigarettes than those who did not. It also found that vaping did not lower the rate of smoking among teens. 5) Marketing of E- cigarettes A related argument is that electronic smoking devices are especially likely to increase smoking among children since their marketing is specifically targeted at young people and the devices tend to glamorize smoking in general, undoing years of efforts to reduce youth smoking. A 2014 Report from the staff of ten U.S. Senators and Rep. Henry Waxman stated that electronic cigarettes are heavily marketed toward children, including the use of child- oriented flavors, social media, and youth- targeted events; and that the devices are a gateway to smoking cigarettes among youth. 7 Other studies have examined the marketing claims of e- cigarettes for their reliability. A February 2014 survey found that over one quarter of the e- cigarette refill products inaccurately state the level of nicotine by more than 20 percent. The same study discovered nicotine in some products that were advertised as nicotine -free. Another recent news report noted that 95 percent of online e- cigarette advertisers are making health claims about their products, with more than half claiming that the devices are an effective cessation tool for cigarette smokers. These findings are troubling given the lack of scientific evidence to back the claims. A 2010 study in the American Journal of Public Health similarly found that e- cigarettes had poor quality control, misrepresentation of the nicotine delivered, and insufficient evidence of an overall public health benefit. E- cigarette manufacturers have not submitted clinical studies about the safety or efficacy of the devices to the U.S. Food and Drug Administration (FDA), so a concern is that consumers have no way of knowing what types or concentrations of potentially harmful chemicals they are inhaling and exhaling when they consume them or are exposed to them. Update on Regulation of E- cigarettes By Other Jurisdictions In recent months there has been increasing action among California cities and across the country to regulate e- cigarettes similarly to other tobacco products. On March 4, 2014, three California cities adopted local ordinances which included electronic devices within the definition of smoking for purposes of local regulations. In Los Angeles, the new law treats e- cigarettes the same as tobacco products for all restrictions; the main exception is that "vaping" lounges are exempted from the indoor workplace ban on smoking, similar to the current exemption of certain smoking shops. Long Beach and Beverly Hills both also brought e- cigarettes under the definition of smoking but, unlike Los Angeles, did not exempt 'taping" at indoor lounges. The city of San Francisco adopted similar rules which went into effect in April 2014. San Diego has tentatively approved similar regulations. 0 At last count more than 45 California cities had taken action to regulate e- cigarettes similarly to traditional tobacco products. In addition, the cities of New York, Chicago, Washington, D.C. and Boston, and at least five states, are among the other jurisdictions that recently have regulated e- cigarettes as tobacco products. The state of California already prohibits the sale of electronic cigarettes to minors. Health and Safety Code section 119405 makes such sales a criminal infraction. A pending bill, S.B. 648, would include e- cigarettes within the definition of cigarettes for essentially all legal purposes in the state; but the hearing on that bill has been postponed indefinitely. On April 24, 2014, the FDA issued proposed rules that would regulate e- cigarettes as a drug, at the federal level, for the first time. The rules would also do the following with respect to the electronic devices: ® ban their sale to minors (as California law already does); ® prohibit the distribution of free samples; ® ban vending machine sales except in places that never admit minors; ® require a warning that they contain nicotine which is addictive; and ® require manufacturers to disclose their ingredients. The proposed FDA rules would not regulate advertising or restrict child- oriented marketing. The rules are now in a 75 -day comment phase and are not expected to take effect for at least one year. The FDA has long expressed concern about health risks connected to e- cigarettes and it is continuing to study the issue. In the meantime, there is no indication in the proposed regulations of any intent to preempt local laws in this area. 0 Alternatives Council could consider whether to include e- cigarettes in the Tobacco Retailer Licensing ( "TRL ") law, Municipal Code Chapter 4.45. This would mean that all retailers of e- cigarettes in the City would be required to obtain a City license the same as tobacco sellers are currently. The purpose of the TRL law is "to encourage responsibility in tobacco retailing and to discourage violations of tobacco - related laws, especially those which prohibit or discourage the sale or distribution of tobacco products to minors." The license revenue under the TRL law funds undercover investigations and similar enforcement measures to help ensure that minors are not sold unlawful and dangerous products. Since the sale of e- cigarettes to minors already is prohibited by state law, their inclusion in the TRL law seems fair and logical. Moreover, the need for parallel regulation of e- cigarette retailing is seen in the recent sharp rise in the use of e- cigarettes by children, even in places where sales to minors are illegal. For example, despite such a law in the state of Utah, e- cigarette use among the state's youth tripled between 2012 and 2013. This inclusion could be accomplished by expanding the definition of "tobacco product" in Municipal Code section 4.45.020(c). Under California state law, tobacco shops and lounges are exempted from the general ban on smoking at indoor workplaces. Council could consider exempting retail vaping lounges from the state law. To staff's knowledge, only one of the many cities to legislate e- cigarettes thus far — Los Angeles — has created this sort of exemption. There appear to be two currently licensed vaping establishments in Santa Monica that might be affected by this decision. Given the policy concerns about e- cigarette consumption and its possible effects on efforts to reduce smoking in the community, staff does not recommend creating a special exemption for vaping lounges. Recommendation Based on all of the above factors, staff recommends that Council direct the preparation of an ordinance for first reading to include electronic smoking devices within the 10 definition of "smoking" for purposes of the City's smoking laws. This would effectively prohibit the use of the devices in all locations where cigarette smoking currently is prohibited, a central recommendation of the UCSF meta -study and the main feature of other jurisdictions' e- cigarette regulations. It would also require businesses that sell e- cigarettes to comply with the City's Tobacco Retailer Licensing law. Staff does not recommend creating a separate exemption from the indoor workplace smoking law for vaping lounges. Financial Impacts & Budget Actions An ordinance adding electronic smoking devices to the definition of smoking under local law is not expected to have a substantial financial impact. It would restrict the locations where e- cigarettes can be consumed and it might result in modestly increased enforcement activity in locations where smoking is already prohibited. Prepared by: Adam Radinsky, Head, Consumer Protection Unit Approved: Forwarded to Council: Rod Gould City Manager Attachment A: "E- Cigarettes: A Scientific Review," Circulation 2014;129:1972 (May 12, 2014) 11 L' ATTACHMENT A E- Cigarettes: A Scientific Review Rachel Grana, Neal Benowitz and Stanton A. Glantz t ' Circulation. 2014;129:1972 -1986 doi: 10 .1161 /CIRCULATIONAHA.114.007667 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009 -7322. Online ISSN: 1524 -4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http: / /cire.ahajoumals.org /content /129/19/1972 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: htq)://www.lww.com/repi-ints Subscriptions: Information about subscribing to Circulation is online at: http: / /eire,aliajoumals.org/ /subscriptions/ Downloaded from http: / /circ.ahajoumals.org/ by guest on May 15, 2014 OPEN E ®Cigarettes A Scientific Review Rachel Grana, PhD, MPH; Neal Benowitz, MD; Stanton A. Glantz, PhD lectronic cigarettes (e- cigarettes) are products that deliver a nicotine- containing aerosol (commonly called vapor) to users by heating a solution typically made up of propylene glycol or glycerol (glycerin), nicotine, and flavoring agents (Figure 1) invented in their current form by Chinese pharma- cist Hon Lik in the early 2000s.1 The US patent application describes the e- cigarette device as "an electronic atomization cigarette that functions as substitutes [sic] for quitting smok- ing and cigarette substitutes" (patent No. 8,490,628 B2). By 2013, the major multinational tobacco companies had entered the e- cigarette market. E- cigarettes are marketed via televi- sion, the Internet, and print advertisements (that often feature celebrities)2 as healthier alternatives to tobacco smoking, as useful for quitting smoking and reducing cigarette consump- tion, and as a way to circumvent smoke -free laws by enabling users to "smoke anywhere:" There has been rapid market penetration of e- cigarettes despite many unanswered questions about their safety, effi- cacy for harm reduction and cessation, and total impact on public health. E- cigarette products are changing quickly, and many of the findings from studies of older products may not be relevant to the assessment of newer products that could be safer and more effective as nicotine delivery devices. In addition, marketing and other environmental influences may vary from country to country, so patterns of use and the ulti- mate impact on public health may differ. The individual risks and benefits and the total impact of these products occur in the context of the widespread and continuing availability of conventional cigarettes and other tobacco products, with high levels of dual use of e- cigarettes and conventional ciga- rettes at the same time among adults" and youth.9 11 It is important to assess e- cigarette toxicant exposure and indi- vidual risk, as well as the health effects, of e- cigarettes as they are actually used to ensure safety and to develop an evidence -based regulatory scheme that protects the entire population —children and adults, smokers and nonsmok- ers—in the context of how the tobacco industry is marketing and promoting these products. Health claims and claims of efficacy for quitting smoking are unsupported by the scien- tific evidence to date. To minimize the potential negative impacts on prevention and cessation and the undermining of existing tobacco control measures, e- cigarette use should be prohibited where tobacco cigarette use is prohibited, and the products should be subject to the same marketing restrictions as tobacco cigarettes. Methods Initial searches conducted via PubMed using the key words elec- tronic cigarette, e- cigarette, and electronic nicotine delivery systems yielded 151 studies (Figure 2). Seventy-one articles presented origi- nal data and were included. Eighty articles were excluded because they were not relevant, were not in English, or were reviews or com- mentaries that did not provide original data, although some are cited for background and context. Searches using the same search terms were conducted using World Health Organization regional databases; only BB3LIOTECA Virtual em Salude Latin America and Caribbean included relevant papers, all of which had already been located with PubMed. Working with the World Health Organization, we also con- tacted investigators to locate other studies, some of which had not yet been published (submitted or in press). We also reviewed technical reports prepared by health organizations," -11 news articles, and rel- evant Web sites. The results of these searches were used to prepare a report commissioned by the World Health Organization Tobacco Free Initiafive, which provides details of individual studies, including some studies that are not discussed in this article because of length constraints.' After the manuscript was submitted for peer review, 5 more articles became available, resulting in a total of 82 articles form- ing the basis for this review. The Product E- cigarette devices are manufactured mainly in China. As of late 2013, there was wide variability in e- cigarette prod- uct engineering, including varying nicotine concentrations in the solution used to generate the nicotine aerosol (also called e- liquid), varying volumes of solution in the product, different carrier compounds (most commonly propylene glycol with or without glycerol [glycerin]), a wide range of additives and flavors, and battery voltage. Quality control is variable,16 and users can modify many of the products, including using them to deliver other drugs such as mari- juana. 17, 18 These engineering differences result in variability in how e- cigarettes heat and convert the nicotine solution to an aerosol and consequently the levels of nicotine and other From the Center for Tobacco Control Research and Education (R.G, N.B., S.A.G.) and Department of Medicine and Cardiovascular Research Institute (N.B., S.A.G.), University of California, San Francisco. Correspondence to Stanton A. Glantz, PhD, Center for Tobacco Control Research and Education, University of California, San Francisco, 530 Parnassus Ave, No. 366, San Francisco, CA 94143 -1390. E -mail glantz@medicine.ucsf.edu (Circulation. 2014;129:1972- 1986.) © 2014 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer, This is an open access article under the terms of the Creative Commons Attribution Non - Commercial- NoDervis License, which permits use, distribution, and reproduction in any medium, provided that the Contribution is properly cited, the use is non- commercial, and no modifications or adaptations are made. Circulation is available at http: / /circ.ahajournals.org DOI: 10 .116UCIRCULATIONAHA.114.007667 Downloaded from http: / /cire.aliajlgnls.org/ by guest on May 15, 2014 Product Grana et at E- Cigarettes: A Scientific Review 1973 Description Some Rechargeable e- cigarette Brands Disposable e- cigarette Cigarette- shaped device consisting of a NJOY battery and a cartridge containing an atomizer OneJoy, Aer 1 to heat a solution (with or without nicotine). Disposable, Not rechargeable or refillable and is intended Flavorvapes to be discarded after product stops producing aerosol. Sometimes called an e- hookah. duration and /or how many puffs may be Rechargeable e- cigarette Cigarette- shaped device consisting of a Blu, battery that connects to an atomizer used to GreenSmoke, heat a solution typically containing nicotine. EonSmoke Often contains an element that regulates puff duration and /or how many puffs may be taken consecutively. Pen - style, medium -sized Larger than a cigarette, often with a higher Vapor King rechargeable e- cigarette capacity battery, may contain a prefilled Storm, cartridge or a refillable cartridge (often called Totally a clearomizer). These devices often come with Wicked a manual switch allowing to regulate length Tornado and frequency of puffs. Tank - style, large -sized Much larger than a cigarette with a higher Volcano rechargeable e- cigarette capacity battery and typically contains a large, Lavatube refillable cartridge. Often contains manual a` "'switches and a battery casing for customizing t� k xa , t tbattery capacity. Can be easily modified. Figure 1. Examples of different electronic cigarette (e- cigarette) products. Reproduced from Grana at al.' chemicals delivered to users and the air pollution generated by the exhaled aerosol.19 E- liquids are flavored, including tobacco, menthol, coffee, fruit, candy, and alcohol flavors, as well as unusual flavors such as cola and Belgian waffle.3 Flavored (conventional) tobacco products are used disproportionately by youth and initiators,20 and cigarettes with characterizing flavors (except menthol) have been banned in the United States. Marketing and Media Research Consumer perceptions of the risks and benefits and deci- sions to use e- cigarettes are heavily influenced by how they are marketed. Celebrities have been used to mar- ket e- cigarettes since at least 2009 21 Grana and Ling' reviewed 59 single -brand e- cigarette retail Web sites in 2012 and found that the most popular claims were that the products are healthier (95 %), cheaper (93 %), and cleaner (95 %) than cigarettes; can be smoked anywhere (88 %); can be used to circumvent smoke -free policies (71 %); do not produce secondhand smoke (76 %); and are modern (73 %). Health claims made through text and pictorial and video representations of doctors were present on 22% of sites. Cessation - related claims (direct and indirect state- ments) were found on 64% of sites. Marketing on the sites commonly stated that e- cigarettes produce only "harmless water vapor." Similar messaging strategies were being used in the United Kingdom .22 These marketing messages have been repeated in the media. A thematic analysis of newspaper and online media cover- age about e- cigarettes in the United Kingdom and Scotland from July 2007 to June 2012 found 5 themes: healthier choice, circumventing smoke -free restrictions, celebrity use, price, and risk and uncertainty.23 Coverage often included anecdotes about having tried nicotine replacement therapies (NRTs), failing to quit, and then trying the e- cigarette (such as the celebrity endorsement by actress Katherine Heigl on the US David Letterman television program21), implying that e- cigarettes are a more effective form of NRT. E- cigarette companies also have a strong presence in social media, which reinforces their marketing messages, including repeating the use of celebrity endorsements (eg, Heigl) and spreading images of the UK musical group Girls Aloud "puff- ing on e- cigarettes to cope with the stress of their 10th anni- versary tour. "22 Cigarette and other tobacco companies have been unable to market their products on television and radio since the 1970s. E- cigarette advertising on television and radio is mass market- ing of an addictive nicotine product for use in a recreational manner to new generations who have never experienced such marketing. In an online convenience sample of 519 adult Downloaded from http://circ.ahajoumals.org/ by guest on May 15, 2014 1974 Circulation May 13, 2014 PRISMA Flow Diagram Records excluded Articles identified through database (n =80) searching > - Editorials, commentaries, review articles (n =54) (n =151) - Not relevant to report (n =20) or - No available English translation (n =6) Records after duplicates and excluded removed (n =71) Additional relevant studies or data identified through other sources (n =11) Studies included in review (n =82) Figure 2. Studies screened and selected for inclusion. PRISMA indicates Preferred Reporting Items for Systematic Reviews and Meta - Analyses. smokers and recent quitters who viewed a television com- mercial for Blu e- cigarettes, 76% of current smokers reported that the ad made them think about smoking cigarettes, 74% reported it made them think about quitting, and 66% said it made them likely to try an e- cigarette in the future.24 The 34% of participants who had used e- cigarettes were significantly more likely to think about smoking cigarettes after viewing the ad than nonusers (83% and 72 %, respectively), suggesting that viewing an e- cigarette commercial may induce thoughts about smoking and cue the urge to smoke.24 Prevalence Awareness of e- cigarettes and e- cigarette trial have at least doubled among both adults and adolescents in several coun- tries from 2008 to 2012. In the United States, awareness is more prevalent among men, but trying e- cigarettes is more prevalent among women. Almost the same percent of European Union and US adult respondents to national sur- veys reported having tried e- cigarettes (7% in 2012 versus 6.2 % in 2011, respectively) 5.21 All population -based studies of adult use show the highest rate of e- cigarette use among current smokers, followed by former smokers, with little use among nonsmokers, although e- cigarette trial and use rose in all of these categories.^ Etter and Bullen26 followed up a sample of e- cigarette users recruited from Web sites dedicated to e- cigarettes and smoking cessation, most (72 %) of whom were former smokers at baseline. At the 1 -year follow up, 6% of former smokers who were daily e- cigarette users at base- line relapsed to smoking cigarettes, and almost all (92 %) of the former smokers using e- cigarettes daily at baseline were still using e- cigarettes daily at follow -up. Among 36 dual users at baseline, 16 (44 %) had stopped smoking after 1 year. The epidemiological, population -based studies indicate that, across countries, e- cigarettes are most commonly being used concurrently with conventional tobacco cigarettes (dual use). Consistent with marketing messages, the most common rea- sons given for trying e- cigarettes are for use in places where smoking is restricted, to cut down on smoking, and for help with quitting smoking.6,21 10 Choi and Forster" followed up a cohort of Midwestern young adults (mean age, 24.1 years) who had never used e -cig- arettes from 2010 to 2011 and found that 21.6% of baseline current smokers, 11.9 % of baseline former smokers, and 2.9% of baseline nonsmokers reported having ever used e- cigarettes at follow -up. Those who believed at baseline that e- cigarettes could help with quitting smoking and perceived e- cigarettes to be less harmful than cigarettes were more likely to report experimenting with e- cigarettes at follow -up (adjusted odds ratio [OR], 1.98; 95% confidence interval [CI], 1.29 -3.04; and adjusted OR, 2.34; 95% Cl, 1.49 -3.69, respectively). Data on e- cigarette use among adolescents are more fim- ited but, like for adults, show rapid increases in awareness and use in 5 countries (United States, Poland, Latvia, Finland, and Korea), with higher rates of trial and current use in European countries than the United States or Korea.9,10,32.33 In Korea, youth ever use of e- cigarettes rose from 0.5% in 2008 to 9.4% in 2011," and in the United States, it rose from 3.3% in 2011 to 6.8% in 2012.9 As with adult population -based studies, data Downloaded from http: / /oire.ahajomtials.org/ by guest on May 15, 2014 suggest that e- cigarette use is most appealing and prevalent among youth who are also experimenting with or are current users of tobacco cigarettes. Dual use with conventional ciga- rettes is the predominant pattern of e- cigarette use: 61% in US middle school students and 80% among US high school stu- dents in 2011? These results indicate rapid market penetration of e- cigarettes among youth, with trial among US high school students (10.0 %) in 2012 even higher than the 2011 rate for adults (6.2%).5 Despite a law prohibiting e- cigarette sales to minors, e- cigarette use among Utah youth (grades 8, 10, and 12) tripled between 2011 and 2013, with youth 3 times more likely to report current e- cigarette use than adults 34 Although dual use with cigarettes is high, some youth exper- imenting with e- cigarettes have never tried a tobacco cigarette, which indicates that some youth are initiating use of nicotine, an addictive drug, with e- cigarettes. In 2012,20.3% of middle school and 7.2 % of high school ever e- cigarette users reported never smoking conventional cigarettes? Similarly, in 2011 in Korea, 15% of students in grades 7 through 12 who had ever used e- cigarettes had never smoked a cigarette.10 The Utah Department of Health found that 32% of ever e- cigarette users reported that they had never smoked conventional cigarettes.34 E- Cigarette E -Fluid and Vapor Chemical Constituents The nicotine content of the cartridge e- liquid from some brands revealed poor concordance of labeled and actual nico- tine content'" Simulated e- cigarette use revealed that indi- vidual puffs contained from 0 to 35 µg nicotine per puff.37 Assuming a high nicotine delivery of 30 pg per puff, it would take -30 puffs to deliver the 1 mg nicotine typically delivered by smoking a conventional cigarette. A puff of the e- cigarette with the highest nicotine content contained 20% of the nicotine contained in a puff of a conventional cigarette.37 Actual nicotine delivery from an e- cigarette would likely be affected by users' smoking behavior. An analysis of UK brand e- cigarettes and the resulting aerosol demonstrated that, across brands, nicotine content of the e- liquid in the cartridges was not significantly correlated with the amount found in the Grans et at E- Cigarettes: A Scientific Review 1975 resulting aerosol, indicating differences in the engineering characteristics of the device that strongly influence nicotine delivery even with a consistent puffing protocol .40 Goniewicz et al41 analyzed the aerosol from 12 brands of e- cigarettes, a conventional cigarette, and a nicotine inhaler for toxic and carcinogenic compounds. The levels of toxicants in the aerosol were 1 to 2 orders of magnitude lower than in ciga- rette smoke but higher than with a nicotine inhaler (Table 1). Kim and Shin 12 analyzed the tobacco - specific nitrosamines NNN, NNK, and NAT and total tobacco- specific nitrosa- mines in 105 refill fluids from 11 companies in the Korean market and found nearly a 3- order -of- magnitude variation in tobacco- specific nitrosamine concentrations, with total tobacco - specific nitrosamine concentration ranging from 330 to 8600 Ag/mL. Cytotoxicity Bahl et a143 screened 41 e- cigarette refill fluids from 4 com- panies for cytotoxicity using 3 cell types: human pulmonary fibroblasts, human embryonic stem cells, and mouse neural stem cells. Cytotoxicity varied among products from highly toxic to low or no cytotoxicity. The authors determined that nicotine did not cause cytotoxicity, that some products were noncytotoxic to pulmonary fibroblasts but cytotoxic to both types of stem cells, and that cytotoxicity was related to the concentration and number of flavorings used. The finding that the stem cells are more sensitive than the differentiated adult pulmonary fibroblasts cells suggests that adult lungs are probably not the most sensitive system to assess the effects of exposure to e- cigarette aerosol. These findings also raise concerns about pregnant women who use e- cigarettes or are exposed to secondhand e- cigarette aerosol. In a study funded by the FlavorArt e- cigarette liquid man- ufacturers, Romagna et al" compared the cytotoxicity of aerosol produced from 21 nicotine- containing, flavored (12 tobacco flavored and 9 fruit or candied flavored) brands of e- cigarette liquid with smoke from a conventional cigarette using embryonic mouse fibroblast cells. Only aerosol from coffee- flavored e- liquid produced a cytotoxic effect (average, 51% viability at 100% concentration of solution). Table 1. Levels of Toxicants in E- Cigarette Aerosol Compared With Nicotine Inhaler and Cigarette Smoke Toxicant Range in Content in Aerosol From 12 E- Cigarette Samples per 15 Puffs` Range in Content in Conventional Cigarette Micrograms in Mainstream Smoke From 1 Cigarette Content in Nicotine Inhaler Mist per 15 Puffs' Formaldehyde, pg 0.2 -5.61 1.6-52 0.2 Acetaldehyde, pg 0.11 -1.36 52 -140 0.11 Acrolein, pg 0.07 -4.19 2.4 -02 ND o- Methylbenzaldehyde, pg 0.13 -0.71 ... 0.07 Toluene, pg ND -0.63 8.3 -70 ND pm- xylene, pg Ni ... ND NNN, ng ND -0.00043 0.0005 -0.19 ND NNK, ng ND -0.00283 0.012 -0.11 ND Cadmium, ng ND -0.022 ... 0.003 Nickel, ng 0.011 -0.029 ... 0.019 Lead, ng 0.003-0.057 ... 0.004 Prepared using data from Goniewicz at al.41 E- cigarette indicates electronic cigarette; and ND, not determined Downloaded from http: / /cire.ahajoumals.org/ by guest on May 15, 2014 1976 Circulation May 13, 2014 Farsalinos et aP$ tested cytotoxicity in cultured rat cardiac myoblasts of exposure to aerosol generated from 20 refill solutions from 5 manufacturers containing 6 to 24 mg/mL nicotine in various flavors, a "base" -only solution (50% pro- pylene glycol and 50% glycerol), and conventional cigarette smoke. The aerosol from 3 fluids was cytotoxic at 100 % and 50% dilution; 2 were tobacco flavored and 1 was cinnamon cookie flavored. Cigarette smoke was cytotoxic at 100% and all dilutions except 6.25 %. Secondhand Exposure E- cigarettes do not burn or smolder the way conventional cig- arettes do, so they do not emit side -stream smoke; however, bystanders are exposed to aerosol exhaled by the user. Schripp et a146 conducted chamber studies in which subjects used 3 e- liquids (0 mg nicotine, apple flavor; 18 mg nicotine, apple flavor; 18 mg nicotine, tobacco flavor) and 1 tobacco ciga- rette and measured levels of several toxins and nicotine in the resulting aerosol. Three e- cigarette devices were used for these experiments: 2 that used a tank system that is directly filled with e- liquid and one that used a cartridge with a cotton fiber on which to drip the liquid. They found low levels of form- aldehyde, acetaldehyde, isoprene, acetic acid, 2- butanodione, acetone, propanol, propylene glycol, and diaeetin (from flavor- ing), traces of apple oil (3- methylbutyl -3- methylbutanoate), and nicotine (with differing levels depending on the specific protocols) emitted into the air. Toxins in the e- cigarette aero- sol were at much lower levels compared with the conventional cigarette emissions .46 In another chamber study, Flouris et a147 compared emis- sions of conventional cigarettes and e- cigarettes in condi- tions designed to approximate a smoky bar (target air CO of 23 ppm) using machine- smoked e- cigarettes and cigarettes. E- cigarette aerosol (using a single brand of e- cigarette made in Greece and a single e -liquid with at least 60% propylene glycol, 11 mghnL nicotine) was generated with a pump that operated for the same duration as the cigarette smoking, and aerosol was released into the room. (A person inhaling a nico- tine aerosol usually absorbs 80% of the nicotine '48 whereas the pump discharges all nicotine into the environment, so the nicotine exposure may be higher in this study than would be the case with actual secondhand aerosol exposure.) Serum cotinine in nonsmokers sitting in the chamber was similar for cigarette smoke and e- cigarette aerosol exposure (average, 0.8 ng/mL for tobacco cigarette and 0.5 ng/mL for e- cigarette). Schober et al" measured indoor pollution from 3 people using e- cigarettes over a 2 -hour period in a realistic envi- ronment modeled on a cafe. They found elevated nicofine, 1,2- propanediol, glycerin, aluminum, and 7 polycyclic aro- matic hydrocarbons classified as probable carcinogens by the International Agency for Research on Cancer in the room air. Czogala et a199 conducted a chamber study of secondhand exposure to e- cigarette aerosol compared with cigarette smoke, finding that, on average, bystanders would be exposed to nico- tine but at levels 1 /10th that of cigarette smoke (e- cigarette aerosol, 3.32 ±2.49 ttg/m3; cigarette smoke, 31.60 ±6.91 gg/m3; P= 0.008). Both e- cigarette aerosol and cigarette smoke con- tained fine particles (PM25), with e- cigarette aerosol particle concentrations ranging from 6.6 to 85.0 ggim3. E- cigarette aerosol was not a source of exposure to carbon monoxide, a key combustion element of conventional cigarette smoke. Particulate Matter E- cigarettes deliver nicotine by creating an aerosol of ultra - fine particles. Fine particles can be variable and chemically complex, and the specific components responsible for toxic- ity and the relative importance of particle size and particle composition are generally not known .5' Given these uncer- tainties, it is not clear whether the ultrafine particles deliv- ered by e- cigarettes have health effects and toxicity similar to the ambient fine particles generated by conventional cigarette smoke or secondhand smoke. There is strong evidence, how- ever, that frequent low or short -term levels of exposure to fine and ultrafine particles from tobacco smoke or air pollution can contribute to pulmonary and systemic inflammatory processes and increase the risk of cardiovascular and respiratory disease and death. 5r -54 Fuoco et at" examined particle number concentration and distribution and performed a volatility analysis of the e- cigarette aerosol generated from 3 devices (2 rechargeable and 1 disposable) using 4 refill e- liquids with varying levels of nicotine and flavorants. They found that higher e- liquid nicotine content was associated with higher particle numbers in the resulting aerosol, with little effect on the particle size distribution. Longer puffing time resulted in more particles. Flavor was not associated with differences in particle num- ber or size distribution. Consistent with other studies, 46.55-58 the particle size distribution (range of modes, .120 -165 nm) was similar to that of conventional cigarettes, with some e- cigarettes delivering more particles than conventional ciga- rettes (Figure 3). Zhang et a157 examined the size of e- cigarette aerosol par- ticles and likely deposition in the human body (using a single brand, B1oogMaxXFusion) with both propylene glycol and vegetable glycerin -based liquids. Using particle size and lung ventilation rates (1 for a "reference worker" and 1 for a "heavy worker ": 1.2 and 1.688 & /h, respectively), their human depo- sition model estimated that 73% to 80% of particles would be distributed into the exhaled aerosol, whereas 9% to 18% of particles would be deposited in alveoli resulting in arterial delivery, and 9% to 17% would be deposited in the head and airways, resulting in venous delivery. As expected, the heavy worker model showed more alveolar delivery across puffs compared with the reference worker, who would have more head and airway delivery. In total, z20% to 27% of particles are estimated to be deposited in the circulatory system and into organs from e- cigarette aerosol, which is comparable to the 25 % to 35% for conventional cigarette smoke. In their study of passive exposure to exhaled e- cigarette aerosol in a simulated cafe, Schober et a139 found that con- centrations of fine particles in the air increased from a median of 400 particles per 1 cm3 with people simply sitting in the room for 2 hours to medians of 49000 to 88000 particles per 1 cm3 (depending on the e- cigarette fluid used) after 2 hours of e- cigarette use in the same room Both the e- liquid and the Poly -fil fibers that are used to absorb the e- liquid for heating and conversion to an aerosol come into contact with heating elements that contain heavy Downloaded from http: / /ciro.ahajoumals.org/ by guest on May 15, 2014 A 120s +101 °' liquid 1 - low nicotine content 1.002 +t0I — Liquid l -high nicotinecontern ep 6.002109 6.002+09 9 4.001: +09 2,002+09 t j i 0.0oL +o0 �.... `�....... ,... 10 100 D (nm) B 1.200 +10 1,002 +10 convendonal cisorette p 8.005 +09 6.00E+09 9 4.0011+09 2.0011 +09 0.002+00` to Grana et at 100 D (nm) metals (tin, nickel, copper, lead, chromium). Williams et all' found heavy metals in samples of e- cigarette liquids and aerosol. Tin, which appeared to originate from solder joints, was found as both particles and tin whiskers in the fluid and Poly -fil, and e- cigarette fluid containing tin was cytotoxic to human pulmonary fibroblasts. E- cigarette aerosol also con- tained other metals, including nickel, 2 to 100 times higher than found in Marlboro cigarette smoke. The nickel and chro- mium nanoparticles ( <100 ma) possibly originated from the heating element. It is likely that engineering features, includ- ing the nature of the battery, the heating temperature of the liquid, and the type of heating element and reservoir, will influence the nature, number, and size of particles produced. These metal nanoparticles can deposit into alveolar sacs in the lungs, potentially causing local respiratory toxicity and entering the bloodstream. In summary, the particle size distribution and number of particles delivered by e- cigarettes are similar to those of con- ventional cigarettes, with most particles in the ultrafine range (modes, =100 -200 nn). Particle delivery appears to depend on the nicotine level in the e- cigarette fluid but not the pres- ence of flavors. Smokers exhale some of these particles, which exposes bystanders to "passive vaping." Like cigarettes, e- cigarette particles are small enough to reach deep into the E- Cigarettes: A Scientific Review 1977 1000 Figure 3. Particle number distribution from (A) mainstream aerosol in e- liquid 1 and from (B) con- ventional cigarette. Reproduced from Fuoco et aP _ -- -- ` with permission from the publisher. Copyright 2013 Elsevier Ltd. 1000 lungs and cross into the systemic circulation. At a minimum, these studies show that e- cigarette aerosol is not merely "water vapor" as is often claimed in the marketing for these products. Tests on e- cigarettes show much lower levels of most toxicants, but not particles, than conventional cigarettes. The thresholds for human toxicity of potential toxicants in e- cigarette vapor are not known, and the possibility of health risks to primary users of the products and those exposed pas- sively to their emissions must be considered. Nicotine Absorption Early studies of nicotine absorption in 2010 found that e- cigarettes delivered much lower levels of plasma nicotine than conventional cigarettes,590 whereas a more recent study demonstrated that more experienced users using their own product who engaged in more puff intervals have nicotine absorption similar to that with conventional cigarettes,61�3 perhaps as a result of a combination of characteristics of the devices and user vaping topography.63 Another study of smok- ers smoking e- cigarettes using a specified protocol found a similar rise in serum cotinine immediately after use (mean increase, =20 nghnL).47 Several studies reported that regard- less of nicotine delivery, e- cigarettes can modestly alleviate some symptoms of withdrawal, and participants positively Downloaded from http: / /cire.ahajotimats.org/ by guest on May 15, 2014 1978 Circulation May 13, 2014 appraised the use of e- cigarettes62�' In a study comparing the nicotine inhalator and e- cigarettes,60 the nicotine inhalator delivered an amount of nicotine similar to that in the 16 -mg e- cigarette; however, the authors noted that the e- cigarette malfunctioned and did not deliver any nicotine in a third of participants. These results highlight the need for product regu- lation in terms of drug delivery and effects, as well as device functioning and labeling. Health Effects Propylene glycol and glycerin are the main base ingredients of the e- liquid. Exposure to propylene glycol can cause eye and respiratory irritation, and prolonged or repeated inhalation in industrial settings may affect the central nervous system, behavior, and the spleen.66In its product safety materials, Dow Chemical Company states that "inhalation exposure to [pro- pylene glycol] mists should be avoided , "6' and the American Chemistry Council warns against its use in theater fogs because of the potential for eye and respiratory irritation.68 When heated and vaporized, propylene glycol can form pro- pylene oxide, an International Agency for Research on Cancer class 2B carcinogen,69 and glycerol forms acrolein, which can cause upper respiratory tract irritation.70•71 Major injuries and illness have resulted from e- cigarette use '72 including explosions and fires .71,74 Less serious adverse events include throat and mouth irritation, cough, nausea, and vomiting.J2 A study's of healthy smokers' pulmonary function after acute ad Lib puffing of an e- cigarette (Nobacco, medium, 11 mg) for 5 minutes (after refraining from smoking tobacco cigarettes for 4 hours) found no effect on spirometry but did find significantly increased dynamic airway resistance (18 %) and decreased expired nitric oxide (16 %). Sham e- cigarette use had no significant effect. This study is limited by the small sample size, the short period of tobacco use abstinence before protocol execution, the short length of exposure to e- cigarette aerosol, and the lack of comparison with smoking conven- tional cigarettes. In addition, smokers in general have high airway resistance with dynamic testing and lower expired nitric oxide, likely as a result of oxidant stress. Despite these limitations, this study suggests that e- cigarette use constricts peripheral airways, possibly as a result of the irritant effects of propylene glycol, which could be of particular concern in people with chronic lung disease such as asthma, emphysema, or chronic bronchitis. Flouris of al"' assessed the short -term effects of e- cigarette use on pulmonary function in 15 cigarette smokers who puffed an e- cigarette ( >60% propylene glycol, 11 mglmL nicotine) and a conventional cigarette according to a speci- fied protocol, and passive exposure to e- cigarette aerosol and conventional cigarette smoke with 15 never smokers. Active cigarette smoking resulted in a significant decrease in expired lung volume (forced expiratory volume in the first second of expiration/forced inspiratory vital capacity) that was not seen with active e- cigarette use or with passive tobacco cigarette or e- cigarette exposure. Additional analysis of the data collected in this stud y76 found that white cell count increased after ciga- rette smoking, reflecting inflammatory process— associated risk for acute cardiovascular events. Active e- cigarette use and passive exposure to e- cigarette vapor did not result in a sig- nificant increase in these biomarkers over 1 hour of exposure. Schober et al19 found elevated levels of exhaled nitric oxide in people using a nicotine e- cigarette (but not a nicotine -free e- cigarette), which the authors attributed to pulmonary inflammation. National Vaper's Club, a pro -e- cigarette advocacy group, published a "risk assessment" of e- cigarette and cigarette use that concluded that `neither vapor from e- Liquids or cigarette smoke analytes posed a condition of `significant risk' of harm to human health via the inhalation route of exposure. " The authors failed to detect benzo(a)pyrene in conventional ciga- rette smoke despite the fact that it is an established carcino- gen in cigarette smoke, and their assessment of conventional cigarettes concluded that they did not pose significant risk, both of which point to fatal errors in the data, data analysis, or both. Another report" funded by the Consumer Advocates for Smoke -free Alternatives Association and published on the Internet used occupational threshold limit values to evalu- ate the potential risk posed by several toxins in e- cigarettes, concluding that "there is no evidence that vaping produces inhalable exposures to contaminants of the aerosol that would warrant health concerns by the standards that are used to ensure safety of workplaces." Threshold limit values are an approach to assessing health effects for occupational chemi- cal exposures that are generally much higher (often orders of magnitude higher) than levels considered acceptable for ambi- ent or population -level exposures. Occupational exposures also do not consider exposure to sensitive subgroups such as people with medical conditions, children, and infants who might be exposed to secondhand e- cigarette emissions, most notably nicotine. In summary, only a few studies have directly investigated the health effects of exposure to e- cigarette aerosol, but some demonstrate the ability of e- cigarette aerosol exposure to result in biological effects. Long -term biological effects are unknown at this time because e- cigarettes have not been in widespread use long enough for assessment. Effects on Cessation of Conventional Cigarettes E- cigarettes are promoted as smoking cessation aids, and many individuals who use e- cigarettes believe that they will help them quit smoking conventional cigarettes .',2," The assumption that e- cigarettes will be as effective as or more effective than pharmaceutical NRTs has also motivated sup- port for e- cigarettes among some public health researchers and policy makers's and (as discussed later) formed the basis for some public policies on the regulation of e- cigarettes. Population -Based Studies There are 4 longitudinal studies4,'"' and 1 cross- sectional study82 of the association between e- cigarette use and quitting conventional cigarettes (Table 2). Adkison et a14 studied current and former smokers in the International Tobacco Control study in the United States, Canada, the United Kingdom, and Australia at baseline and 1 year later and found that e- cigarette users had a statistically significant greater reduction in cigarettes per day (e- cigarette users, 20.1 to 16.3 cigarettes per day; nonusers, 16.9 to 15.0 Downloaded from litip:Hcire.ahajotiriiils.org/ by guest on May 15, 2014 Grana et al E- Cigarettes: A Scientific Review 1979 Table 2. Population Studies of the Association Between E- Cigarette Use and Cessation of Conventional Cigarette Smoking All studies Pooled$ 0.61 Cl indicates confidence interval; E- cigarette, electronic cigarette; and ITC, International Tobacco Control. 'Odds ratios obtained by contacting authors. tGomputed by authors of this report on the basis of the numbers reported. #Estimated with a random - effects meta - analysis using State 12.1 metan. There was no evidence of heterogeneity (P =0.28) or evidence of publication bias with the use of a funnel plot, cigarettes per day). Although 85% of e- cigarette users reported they were using the product to quit smoking at the initial wave, e- cigarette users were no more likely to have quit 1 year later than nonusers (OR, 0.81; 95% CI, 0.43 -1.53; P= 0.52). Vickerman et al'O found that =31% of quit -line callers surveyed 7 months after enrollment reported that they had ever tried e- cigarettes. The majority used them for <1 month (67.1%), and 9.2% were using them at the 7 -month survey. The main reason for e- cigarette use was tobacco cessation (51.3 %a), but it is not known whether ever use occurred as part of a quit attempt in the preceding 7 months. Although quit -line callers represent a small population of smokers motivated to quit, these data present a real -world estimate of the potential effectiveness of using e- cigarettes for cessation in a popula- tion of smokers motivated to quit. Although this study had a low response rate (34.6 %) and may be subject to recall bias because e- cigarette use and perceptions were assessed only at the 7 -month follow -up, those who reported using e- cigarettes were statistically significantly less likely to quit than those who had not used e- cigarettes (21.7% among callers who used for 21 month, 16.6% among those who used for <1 month, and 31.4% among never users; P <0.001). The unadjusted odds of quitting were statistically significantly lower for e- cigarette users compared with nonusers (OR, 0.50; 95% CI, 0.40-0.63). Grana et al79 explored predictors of quitting among a national sample of smokers who participated in a study in 2011 and follow -up in 2012. Current e- cigarette use (past 30 days) at baseline did not predict a greater likelihood of having quit at the follow -up (OR, 0.71; 95% Cl, 0.35 - 1.46). In a sec- ond logistic regression model that included baseline cigarettes per day, time to first cigarette, and intention to quit, in addition to baseline current e- cigarette use, only intention to quit (OR, 5.59; 95% CI, 2.41- 12.98) and cigarettes per day (OR, 0.97; 95% CI, 0.94-0.99) were significant predictors of having quit at follow -up; current e- cigarette use remained nonsignificant (OR, 0.76; 95% CI, 0.36- 1.60). Choi and Forster&' followed up a cohort of young adults in Midwestern (recruited October 2010 -March 2011 and followed up for 1 year). Among those who were smoking cigarettes at baseline, 11% of those who used e- cigarettes at least 1 day in the past 30 days at baseline quit smoking at follow -up com- pared with 17% of smokers who never used e- cigarettes. In a logistic regression controlling for demographics and baseline cigarettes per day, baseline past 30 -day e- cigarette use was not a significant predictor of having quit at follow -up (OR, 0.93; 95% CI, 0.19 -4.63; P= 0.93). There was also no significant change in the number of conventional cigarettes smoked per day between those who did and did not use e- cigarettes (differ- ence, 0.2 cigarettes per day; 95% CI, -3.72 to 4.18; P= 0.91). In a national cross - sectional sample, Popova and Ling62 found that adult smokers who ever used e- cigarettes were sig- nificantly less likely to be former smokers compared to those who never used e- cigarettes (OR, 0.69; 95% CI, 0.52 -0.94), controlling for demographics (Lucy Popova, personal com- munication). In an examination of only those who tried to quit, those who ever used e- cigarettes were significantly less likely to be former smokers than never users (adjusted OR, 0.61; 95% CI, 0.45 - 0.83). Combining these results in a random - effects meta - analysis (Table 2) yields a pooled OR of 0.61 (95% CI, 0.50-0.75), indicating that e- cigarette use in the real world is associated with significantly lower odds of quitting smoking cigarettes. A limitation of 3 of these studi&.80,82 is that they did not con- trol for level of nicotine dependence. It is possible that more dependent smokers, who would have more difficulty quitting in general, would be the ones who would be more likely to experiment with e- cigarettes, which could contribute to the finding that e- cigarette use is associated with a lower quit rate. Clinical 'Mals Four clinical trials (2 with very small samples) examined the efficacy of e- cigarettes for smoking cessation. 8346 Three trials" -as did not have a control group who were not using e- cigarettes. The other study 86 compared e- cigarette efficacy to a standard -of -care regimen with a 21 -mg nicotine patch. None of the trials were conducted with the level of behav- ioral support that accompanies most pharmaceutical trials for smoking cessation. Downloaded from http: / /cire.aliajoumals.org/ by guest on May 15, 2014 Odds of Quitting Study Location and Study Design (95% Cl) Longitudinal studies Addison at al° (2013) US, UK, Canada, Australia (ITC), surveyed, l y apart 0.81 (0.43 - 1.53)` Vickerman at all° (2013) US quit -line callers from 6 states surveyed at enrollment and 7 me later 0.50 (0.40-0.63)1 Grana etal79 (2014) US sample drawn from a nationally representative Internet panel, l y apart 0.76 (0.36 -1.60) Choi and Forster81 (2014) Midwestern young adults, l y apart 0.93 (0.194.63) Cross - sectional study Popova and LingB2 (2013) US sample drawn from a nationally represented Internet panel 0.69 (0.52-0.94)' All studies Pooled$ 0.61 Cl indicates confidence interval; E- cigarette, electronic cigarette; and ITC, International Tobacco Control. 'Odds ratios obtained by contacting authors. tGomputed by authors of this report on the basis of the numbers reported. #Estimated with a random - effects meta - analysis using State 12.1 metan. There was no evidence of heterogeneity (P =0.28) or evidence of publication bias with the use of a funnel plot, cigarettes per day). Although 85% of e- cigarette users reported they were using the product to quit smoking at the initial wave, e- cigarette users were no more likely to have quit 1 year later than nonusers (OR, 0.81; 95% CI, 0.43 -1.53; P= 0.52). Vickerman et al'O found that =31% of quit -line callers surveyed 7 months after enrollment reported that they had ever tried e- cigarettes. The majority used them for <1 month (67.1%), and 9.2% were using them at the 7 -month survey. The main reason for e- cigarette use was tobacco cessation (51.3 %a), but it is not known whether ever use occurred as part of a quit attempt in the preceding 7 months. Although quit -line callers represent a small population of smokers motivated to quit, these data present a real -world estimate of the potential effectiveness of using e- cigarettes for cessation in a popula- tion of smokers motivated to quit. Although this study had a low response rate (34.6 %) and may be subject to recall bias because e- cigarette use and perceptions were assessed only at the 7 -month follow -up, those who reported using e- cigarettes were statistically significantly less likely to quit than those who had not used e- cigarettes (21.7% among callers who used for 21 month, 16.6% among those who used for <1 month, and 31.4% among never users; P <0.001). The unadjusted odds of quitting were statistically significantly lower for e- cigarette users compared with nonusers (OR, 0.50; 95% CI, 0.40-0.63). Grana et al79 explored predictors of quitting among a national sample of smokers who participated in a study in 2011 and follow -up in 2012. Current e- cigarette use (past 30 days) at baseline did not predict a greater likelihood of having quit at the follow -up (OR, 0.71; 95% Cl, 0.35 - 1.46). In a sec- ond logistic regression model that included baseline cigarettes per day, time to first cigarette, and intention to quit, in addition to baseline current e- cigarette use, only intention to quit (OR, 5.59; 95% CI, 2.41- 12.98) and cigarettes per day (OR, 0.97; 95% CI, 0.94-0.99) were significant predictors of having quit at follow -up; current e- cigarette use remained nonsignificant (OR, 0.76; 95% CI, 0.36- 1.60). Choi and Forster&' followed up a cohort of young adults in Midwestern (recruited October 2010 -March 2011 and followed up for 1 year). Among those who were smoking cigarettes at baseline, 11% of those who used e- cigarettes at least 1 day in the past 30 days at baseline quit smoking at follow -up com- pared with 17% of smokers who never used e- cigarettes. In a logistic regression controlling for demographics and baseline cigarettes per day, baseline past 30 -day e- cigarette use was not a significant predictor of having quit at follow -up (OR, 0.93; 95% CI, 0.19 -4.63; P= 0.93). There was also no significant change in the number of conventional cigarettes smoked per day between those who did and did not use e- cigarettes (differ- ence, 0.2 cigarettes per day; 95% CI, -3.72 to 4.18; P= 0.91). In a national cross - sectional sample, Popova and Ling62 found that adult smokers who ever used e- cigarettes were sig- nificantly less likely to be former smokers compared to those who never used e- cigarettes (OR, 0.69; 95% CI, 0.52 -0.94), controlling for demographics (Lucy Popova, personal com- munication). In an examination of only those who tried to quit, those who ever used e- cigarettes were significantly less likely to be former smokers than never users (adjusted OR, 0.61; 95% CI, 0.45 - 0.83). Combining these results in a random - effects meta - analysis (Table 2) yields a pooled OR of 0.61 (95% CI, 0.50-0.75), indicating that e- cigarette use in the real world is associated with significantly lower odds of quitting smoking cigarettes. A limitation of 3 of these studi&.80,82 is that they did not con- trol for level of nicotine dependence. It is possible that more dependent smokers, who would have more difficulty quitting in general, would be the ones who would be more likely to experiment with e- cigarettes, which could contribute to the finding that e- cigarette use is associated with a lower quit rate. Clinical 'Mals Four clinical trials (2 with very small samples) examined the efficacy of e- cigarettes for smoking cessation. 8346 Three trials" -as did not have a control group who were not using e- cigarettes. The other study 86 compared e- cigarette efficacy to a standard -of -care regimen with a 21 -mg nicotine patch. None of the trials were conducted with the level of behav- ioral support that accompanies most pharmaceutical trials for smoking cessation. Downloaded from http: / /cire.aliajoumals.org/ by guest on May 15, 2014 1980 Circulation May 13, 2014 Polosa et all' conducted a proof -of- concept study in Italy in 2010 with smokets18 to 60 years of age not intending to quit in the next 30 days. Subjects were offered Categoria e- cigarettes and instructed to use up to 4 cartridges (7.4 -mg nicotine con- tent) per day as desired to reduce smoking and to keep a log of cigarettes per day, cartridges per day, and adverse events. Six -month follow -up was completed with 68% of participants (27 of 40): 13 were using both e- cigarettes and tobacco ciga- rettes, 5 maintained exclusive tobacco cigarette smoking, and 9 stopped using tobacco cigarettes while continuing to use e- cigarettes. Cigarette consumption was reduced by at least 50% in the 13 dual users (25 cigarettes per day at baseline to 6 cigarettes per day at 6 months; P<0.001). Polosa et a187 continued follow -up of this sample at 18 and 24 months with 23 subjects (58% of the original 40 enrolled). Among the 23 participants who completed a 24 -month visit, 18 continued to smoke, and I1 had reduced cigarette consumption by 250% with a statistically significant reduction from an average of 24 to 4 cigarettes per day (P= 0.003). Five participants had quit tobacco cigarettes at 24 months. Study limitations included the use of a poor - quality product and the lack of a comparison or control group, which could make it difficult to determine whether quit rates achieved were not due to chance. Caponnetto et al" conducted a similar study with 14 smok- ers with schizophrenia not intending to quit in the next 30 days. Participants were provided the same Categoria e- cigarette, and carbon monoxide, product use, number of cigarettes smoked, and positive and negative symptoms of schizophre- nia were assessed at baseline and 4, 8, 12, 24, and 52 weeks. Seven of 14 participants (50 %) sustained a 50% reduction in the number of cigarettes per day smoked at week 52, and the median of 30 cigarettes per day decreased to 15 cigarettes per day (P= 0.018). Sustained abstinence from smoking occurred with 2 participants (14.3 %) by week 52. Positive and nega- tive aspects of schizophrenia were not increased after smok- ing cessation. The most common outcome was dual use of e- cigarettes with conventional cigarettes. Study findings are not generalizable to smokers with mental illness because of the very small sample size and lack of a control group. Caponnetto et a184 also conducted a randomized, quasi - controlled trial to examine the efficacy of e- cigarettes of different strengths for smoking cessation and reduction in 3 study arms: 12 weeks of treatment with the 7.2 -mg nicotine e- cigarette, a 12 -week nicotine- tapering regimen (6 weeks of treatment with a 7.2 -mg e- cigarette and 6 weeks with a 5.4 -mg e- cigarette), and a 12 -week treatment with a nonnicotine e- cigarette. Similar reductions in the median cigarettes per day were seen at all study visits for all 3 treatment arms (7 -10 cigarettes per day at 1 year). There was no statistically sig- nificant difference in 6 -month or 1 -year quit rate among the 3 conditions (1 -year rates: 4% for placebo e- cigarette users, 9% for low- nicotine e- cigarette users, and 13% for high- nicotine e- cigarette users). The authors noted that those who initiated quitting in the first few weeks of the study stayed quitters, whereas those who did not remained dual users throughout the study. Twenty -six percent of quitters continued to use e- cigarettes at I year. Problems with the study include the lack of a control group not using e- cigarettes and noted lack of product quality (the devices malfunctioned often, and new ones had to be sent frequently). An author on all of these studies, R. Polosa, served as a consultant for the Arbi Group SRL, the manufacturer of the Categoria e- cigarette used in the study, beginning in February 2011. Bullen et a186 conducted a randomized, controlled, clini- cal trial of e- cigarettes compared with medicinal NRT in Auckland, New Zealand. Adult smokers motivated to quit were randomized to the 3 study arms (16 -mg e- cigarette, 21 -mg NRT patch, no- nicotine e- cigarette). Voluntary tele- phone counseling was offered to all subjects. Subjects were observed at baseline, 1 week (quit day), 12 weeks, and 6 months. Fifty-seven percent of participants in the nicotine e- cigarettes group reduced their cigarettes per day by 250% at 6 months compared with 41% in the patch group (P= 0.002) and 45% in the nonnicotine e- cigarette group (P= 0.08). Those randomized to the nicotne patch group were less adherent to the treatment (46 %) than the 16 -mg e- cigarette group (78 %) and the no- nicotine e- cigarette group (82 %). Of note, the study methodology may have introduced bias against success in the nicotine patch group because e- cigarettes were mailed for free directly to participants randomized to either the nico- tine or no- nicotine e- cigarette group, whereas participants in the patch group were mailed cards redeemable for nicotine patches at a pharmacy and vouchers to cover the modest fee. Therefore, although the protocol for providing the patches represented "usual care" for New Zealand quit -line callers, this procedure may have introduced bias against NRT, making it difficult to view the study as a head -to -head comparison of e- cigarettes and NRT for cessation. There were no statistically significant differences in biochemically confirmed (breath CO) self- reported continuous abstinence from quit day to the 6 -month follow -up between the nicotine e- cigarette (7.3 %), nicotine patch (5.8 %), and nonnicotine e- cigarette (4.1 %). Neither Capponnetto et all' nor Bullen et all' found effects of e- cigarette use on quitting beyond what is seen in unassisted or low- assistance studies of smokers using NRT to quit 88 In determining the effectiveness of smoking cessation therapy, active drug is considered efficacious when it outperforms pla- cebo; therefore, the evidence to date from clinical trials does not demonstrate that e- cigarettes are efficacious for cessation. However, it is possible that e- cigarettes even without nico- tine act as substitutes for the sensory and behavioral effects of conventional cigarettes. If this is the case, the nonnicotine placebo e- cigarette would be considered an active treatment condition and, as discussed previously, has been shown to reduce withdrawal symptoms.59, 0,63,89 Important limitations of the current research include the use of e- cigarettes that deliver relatively low levels of nicotine and the provision of minimal behavioral counseling. Another important limita- tion of studies assessing the effectiveness of e- cigarettes for smoking cessation is that, because they are not approved as cessation therapy, there are no therapeutic instructions for using them as replacements or to quit smoking (eg, dosage tapering, duration of use, how to combine them with behav- ioral strategies, guidance for discontinuation). In contrast to the assumption that e- cigarettes would func- tion as a better form of NRT, population -based studies that reflect real -world e- cigarette use found that e- cigarette use is not associated with successful quitting; a114'79,",' had point Downloaded from http: / /circ.aliajotimals.org/ by guest on May 15, 2014 estimates of the odds of quitting of <1.0. The 1 clinical trial examining the effectiveness of e- cigarettes (both with and without nicotine) compared with the medicinal nicotine patch found that e- cigarettes are no better than the nicotine patch and that all treatments produced very modest quit rates with- out counseling." Taken together, these studies suggest that e- cigarettes are not associated with successful quitting in gen- eral population -based samples of smokers. Health Implications of Cigarette Reduction in the Context of Dual Use Among adults, reductions in cigarettes per day were observed in several of the clinical studies 13,M,16 and in 1 population -based study4 among those who did not quit. Reduction in cigarettes smoked per day could have benefit if it promotes subsequent cessation, as has been found with NRT,90 but this pattern has not yet been seen with e- cigarettes. In the cigarette reduction analyses presented in some of the studies, many participants were still smoking about half a pack cigarettes per day at the end of the study. Both duration (years of cigarette use) and intensity (ciga- rettes per day) determine the negative health effects of smok- ing.91 People who stop smoking at younger ages have lower age- adjusted mortality compared with those who continued to smoke later into adulthood92 Findings for decreased smoking intensity have been less consistent, with some studies showing lower mortality with reduced daily cigarette consumption93 and others not finding a significant overall survival benefit 94 The 2014 report of the US Surgeon General concluded that "reducing the number of cigarettes smoked per day is much less effective than quitting entirely for avoiding the risks of premature death from all smoking - related causes of death . "95 Use of electronic cigarettes by cigarette smokers to cut down on the number of cigarettes smoked per day is likely to have much smaller beneficial effects on overall survival compared with quitting smoking completely. This situation is particularly likely to exist for cardiovas- cular disease because of the highly nonlinear dose - response relationship between exposure to fine particles and the risk of cardiovascular disease .13,16 Light smoking, even 1 to 4 ciga- rettes per day, is associated with markedly elevated risk of car- diovascular disease97In addition, e- cigarettes deliver loads of fine particles similar to those of conventional cigarettes. The relative risk of death from lung cancer increases with years smoked and cigarettes per day,9B as well as pancreatic cancer99 and esophageal cancer.100 The relative risk of both lung cancer and bladder cancer levels off after a certain num- ber of cigarettes per day,101 suggesting that above a certain intensity, the specific levels of exposure may not cause sig- nificant differences in risk for these cancers. Doll and Peto102 found a dose - response relationship between duration of smoking and number of cigarettes smoked per day and risk of lung cancer, with models suggesting the impact of dura- tion to be greater than that of intensity. Using participants from the Cancer Prevention Study IL Flanders et a1103 found a greater increase in lung cancer mortality with a greater dura- tion of cigarette smoking compared with a greater intensity of smoking. Overall, these data suggest that lung cancer mor- tality increases more with additional years of smoking than Grana et at E- Cigarettes: A Scientific Review 1981 additional cigarettes per day. Thus, if dual use of e- cigarettes and cigarettes results in reductions in the number of ciga- rettes per day for current smokers, any reduction malignancy risk will be less than proportional to the reduction in ciga- rette consumption because of the (likely larger) importance of duration of smoking. What to Tell Patients About E- Cigarettes and Cessation First and foremost, clinicians must support a smoker's quit attempt and try to ensure any that advice given does not undermine their motivation to quit. Clinicians should follow the 5 As of evidence -based treatment: ask, advise, assess, assist, and arrange.104 They should assess their patient's motivation and readiness to quit and recommend a treatment plan that should include setting a quit date and obtaining ces- sation counseling and, if appropriate, conventional smoking cessation medications. The safest and most proven smoking cessation pharmacotherapies are the nicotine replacement medications varenicline and bupropion, which have been approved by the US Food and Drug Administration (FDA). Referral to a free telephone quit line (eg, 1- 800 - QUIT -NOW) or another counseling support program enhances the effec- tiveness of smoking cessation medications.tO If a patient has failed initial treatment, has been intolerant of or refuses to use conventional smoking cessation medication, and wishes to use e- cigarettes to aid quitting, it is reasonable to support the attempt. However, subjects should be informed that, although e- cigarette aerosol is likely to be much less toxic than cigarette smoking, the products are unregulated, contain toxic chemicals, and have not been proven as cessa- tion devices. The patient should also be advised not to use the product indoors or around children because studies show that bystanders may be exposed to nicotine and other toxins (at levels much lower than cigarettes) through passive expo- sure to the e- cigarette aerosol. Because there are no long -term safety studies of e- cigarette use, patients should be urged to set a quit date for their e- cigarette use and not plan to use it indefinitely. It is also important to stress that patients should quit smoking cigarettes entirely as soon as possible because continued cigarette smoking, even at reduced levels, contin- ues to impose tobacco - induced health risks (particularly for cardiovascular disease). Tobacco Industry and Involvement By 2013, the major tobacco companies had purchased or developed e- cigarette products (Table 3). There is no evidence that the cigarette companies are acquiring or producing e- cigarettes as part of a strategy to phase out regular cigarettes, even though some claim to want to participate in "harm reduction." Lorillard CEO Murray Kessler stated in an interview with the Wall Street Journal that e- cigarettes will provide smokers an unprecedented chance to reduce their risk from cigarettes.105 He also published an op -ed in USA Today on September 23, 2013, stating: "E- cigarettes might be the most significant harm- reduction option ever made available to smokers ;."' 5 Shortly before this op -ed was published, however, Lorillard won approval from the US FDA to market new nonmentholated Newport conventional Downloaded from httl):Hoire.ahajoumals.org/ by guest on May 15, 2014 1982 Circulation May 13, 2014 Table 3. Tobacco Companies That Have Acquired or Created E- Cigarette Companies and Brands (as of January 2014) E- cigarette Indicates electronic cigarette. cigarettes, expanding their cigarette line while touting their ability to offer a product they claim reduces harm from cig- arettes. This allows the cigarette companies to have it both ways. (Likewise, after evaluating the cigarette companies' internal documents and public positions on suns [a form of moist snuff tobacco in a pouch popular in Sweden] as "harm reduction" in Europe, Gilmore et al' 1 found that they were entering the anus market10' and adopting "harm reduction" rhetoric101 to protect their cigarette business as long as pos- sible.) As noted in the 2010 Surgeon General's report,109 the tobacco industry has used every iteration of cigarette design to undermine cessation and prevention. The tobacco companies address e- cigarette issues as part of their policy agenda. As they did beginning in the 1980s,110.11' they continue to engage in creating and supporting "smok- ers' rights" groups, seemingly independent groups that interact with consumers directly on political involvement in support of their agenda. "' Altria and R.J. Reynolds Tobacco Company maintain Web sites called Citizens for Tobacco Rights and Transform Tobacco. E- cigarette news and action alerts are featured on the home pages of these websites and include instructions for taking action against bills designed to include e- cigarette use in smoke -free laws. E- cigarette companies engage in similar tactics, using the same politi- cal and public relations strategies as the tobacco companies (most notably featuring organized `tapers" like the organized smokers). They also use social media that is tightly integrated with their product marketing campaigns to press their pol- icy agenda." These strategies were successfully deployed in Europe to convince the European Parliament to substan- tially weaken the proposed EU Tobacco Product Directive in October 2013.112 Current State of Global Regulation (March 2014) Like e- cigarette products, the policy environment related to e- cigarettes is rapidly developing despite the fact that the sci- ence is just emerging. Policy makers in many countries are under considerable pressure to provide regulatory guidance regarding e- cigarettes, often on the basis of the assumption that e- cigarettes will contribute to reducing the harms of smoking either by serving as a smoking cessation aid or by replacing combusted cigarettes. The data reviewed here, together with evidence of dual use and youth initiation of e- cigarette use, do not demonstrate any hypothesized harm - reducing effect. Some countries (including Brazil, Singapore, Canada, the Seychelles, and Uruguay) have prohibited the sale of e- cigarettes, and many others are developing policies.' The United States, European Union, and United Kingdom illus- trate the range of regulatory approaches being developed. The United States In the United States, as of March 2014, e- cigarette products remained unregulated by any federal authority, particularly the US FDA. The Sottera Inc case ruling that was upheld on appeal in the US court found that e- cigarettes could be regulated as tobacco products unless they are marketed with health and therapeutic claims. "3 The US FDA has stated its intent to assert ( "deem ") authority over e- cigarettes but has yet to act. The US FDA does not have the authority to regulate where e- cigarettes are used; that is the domain of state and local governments, where almost all activity on smoke -free laws has occurred. Since e- cigarettes entered the US market in 2008, there has been a rapid increase in the number of municipalities and states that have adopted legislation regulating where e -ciga- rettes can be used and laws restricting sales to minors. As of March 2014, 27 states had laws restricting sales to minors, 1 state (Minnesota) taxed e- cigarettes as tobacco products, and 3 states (New Jersey, North Dakota, and Utah) and >100 municipalities (including New York, Los Angeles, San Francisco, and Chicago) prohibited the use of e- cigarettes in 100% smoke -free indoor environments.' 14 An additional 9 states restricted e- cigarettes in other venues such as school district property, Department of Connections /prisons, public educational facilities and grounds, and commuter transit sys- tems.114 Some local and statewide smoke -free laws enacted before the introduction of e- cigarettes include language . that could be interpreted as including e- cigarettes. European Union Tobacco Product Directive In February 2014, the European Parliament approved a revised European Union Tobacco Product Directive that regu- lates e- cigarettes with nicotine concentrations up to 20 mg/mL (an amount equal to that in a pack of cigarettes) as tobacco products' "I E- cigarettes with higher nicotine concentrations or intended therapeutic uses will be regulated as medical devices. 116 The directive stipulates that e- cigarettes must be childproof and that packaging must include information about ingredients, adverse effects, and health warnings.1' Refillable cartridges are allowed as long as their volume does not exceed 2 mL (but could be banned by the European Commission if at least 3 member states prohibit them on the basis of risks to human health).115 Marketing and advertising restrictions will mirror those of tobacco products.1' The United Kingdom In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency announced a plan to regulate e- cigarettes as medicines on the basis of the assumption that e- cigarettes func- tion like NRTs for smokers wishing to cut down or quit. 18 As of January 2014, Medicines and Healthcare Products Regulatory Agency policies did not include any restrictions on e- cigarette marketing. 117 The antismoking advocacy group Action on Smoking and Health UK has announced that it "does not Downloaded from hhp: / /6rc,ahajoui nals.org/ by guest on May 15, 2014 Acquired E- Cigarette Tobacco Company Company E- Cigarette Brands) Atria Inc GreenSmoke Mark Ten Reynolds American Inc No Was Lorillard Btu Gigs, Inc Btu British American Tobacco CN Creative vype Imperial Tobacco Dragombe Holdings Ltd Ruyan Swisher No E- Swisher E- cigarette Indicates electronic cigarette. cigarettes, expanding their cigarette line while touting their ability to offer a product they claim reduces harm from cig- arettes. This allows the cigarette companies to have it both ways. (Likewise, after evaluating the cigarette companies' internal documents and public positions on suns [a form of moist snuff tobacco in a pouch popular in Sweden] as "harm reduction" in Europe, Gilmore et al' 1 found that they were entering the anus market10' and adopting "harm reduction" rhetoric101 to protect their cigarette business as long as pos- sible.) As noted in the 2010 Surgeon General's report,109 the tobacco industry has used every iteration of cigarette design to undermine cessation and prevention. The tobacco companies address e- cigarette issues as part of their policy agenda. As they did beginning in the 1980s,110.11' they continue to engage in creating and supporting "smok- ers' rights" groups, seemingly independent groups that interact with consumers directly on political involvement in support of their agenda. "' Altria and R.J. Reynolds Tobacco Company maintain Web sites called Citizens for Tobacco Rights and Transform Tobacco. E- cigarette news and action alerts are featured on the home pages of these websites and include instructions for taking action against bills designed to include e- cigarette use in smoke -free laws. E- cigarette companies engage in similar tactics, using the same politi- cal and public relations strategies as the tobacco companies (most notably featuring organized `tapers" like the organized smokers). They also use social media that is tightly integrated with their product marketing campaigns to press their pol- icy agenda." These strategies were successfully deployed in Europe to convince the European Parliament to substan- tially weaken the proposed EU Tobacco Product Directive in October 2013.112 Current State of Global Regulation (March 2014) Like e- cigarette products, the policy environment related to e- cigarettes is rapidly developing despite the fact that the sci- ence is just emerging. Policy makers in many countries are under considerable pressure to provide regulatory guidance regarding e- cigarettes, often on the basis of the assumption that e- cigarettes will contribute to reducing the harms of smoking either by serving as a smoking cessation aid or by replacing combusted cigarettes. The data reviewed here, together with evidence of dual use and youth initiation of e- cigarette use, do not demonstrate any hypothesized harm - reducing effect. Some countries (including Brazil, Singapore, Canada, the Seychelles, and Uruguay) have prohibited the sale of e- cigarettes, and many others are developing policies.' The United States, European Union, and United Kingdom illus- trate the range of regulatory approaches being developed. The United States In the United States, as of March 2014, e- cigarette products remained unregulated by any federal authority, particularly the US FDA. The Sottera Inc case ruling that was upheld on appeal in the US court found that e- cigarettes could be regulated as tobacco products unless they are marketed with health and therapeutic claims. "3 The US FDA has stated its intent to assert ( "deem ") authority over e- cigarettes but has yet to act. The US FDA does not have the authority to regulate where e- cigarettes are used; that is the domain of state and local governments, where almost all activity on smoke -free laws has occurred. Since e- cigarettes entered the US market in 2008, there has been a rapid increase in the number of municipalities and states that have adopted legislation regulating where e -ciga- rettes can be used and laws restricting sales to minors. As of March 2014, 27 states had laws restricting sales to minors, 1 state (Minnesota) taxed e- cigarettes as tobacco products, and 3 states (New Jersey, North Dakota, and Utah) and >100 municipalities (including New York, Los Angeles, San Francisco, and Chicago) prohibited the use of e- cigarettes in 100% smoke -free indoor environments.' 14 An additional 9 states restricted e- cigarettes in other venues such as school district property, Department of Connections /prisons, public educational facilities and grounds, and commuter transit sys- tems.114 Some local and statewide smoke -free laws enacted before the introduction of e- cigarettes include language . that could be interpreted as including e- cigarettes. European Union Tobacco Product Directive In February 2014, the European Parliament approved a revised European Union Tobacco Product Directive that regu- lates e- cigarettes with nicotine concentrations up to 20 mg/mL (an amount equal to that in a pack of cigarettes) as tobacco products' "I E- cigarettes with higher nicotine concentrations or intended therapeutic uses will be regulated as medical devices. 116 The directive stipulates that e- cigarettes must be childproof and that packaging must include information about ingredients, adverse effects, and health warnings.1' Refillable cartridges are allowed as long as their volume does not exceed 2 mL (but could be banned by the European Commission if at least 3 member states prohibit them on the basis of risks to human health).115 Marketing and advertising restrictions will mirror those of tobacco products.1' The United Kingdom In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency announced a plan to regulate e- cigarettes as medicines on the basis of the assumption that e- cigarettes func- tion like NRTs for smokers wishing to cut down or quit. 18 As of January 2014, Medicines and Healthcare Products Regulatory Agency policies did not include any restrictions on e- cigarette marketing. 117 The antismoking advocacy group Action on Smoking and Health UK has announced that it "does not Downloaded from hhp: / /6rc,ahajoui nals.org/ by guest on May 15, 2014 consider it appropriate to include e- cigarettes under smokefree regulations,""' supporting one of the e- cigarette companies' key marketing messages that e- cigarettes can be used every- where without the restrictions and social stigma of smoking.3,19 Policy Recommendations E- cigarettes deliver lower levels of some of the toxins found in cigarette smoke. Main concerns about the potential of e- cigarettes to make a contribution to reducing the harm caused by cigarette smoking arise from effects on youth, dual use with cigarettes resulting in delayed or deferred quitting (among both adults and youth), and renormalization of smok- ing behavior. The ultimate effect of e- cigarettes on public health will depend on what happens in the policy environment. These policies should be implemented to protect public health: • Prohibit the use of e- cigarettes anywhere that use of con- ventional cigarettes is prohibited. • Prohibit the sale of e- cigarettes to anyone who cannot legally buy cigarettes or in any venues where sale of con- ventional cigarettes is prohibited. • Subject e- cigarette marketing to the same level of restric- tions that apply to conventional cigarettes (including no television or radio advertising). • Prohibit cobranding e- cigarettes with cigarettes or mar- keting in a way that promotes dual use. • Prohibit the use of characterizing flavors in e- cigarettes, particularly candy and alcohol flavors. • Prohibit claims that e- cigarettes are effective smoking cessation aids until e- cigarette manufacturers and com- panies provide sufficient evidence that e- cigarettes can be used effectively for smoking cessation. • Prohibit any health claims for e- cigarette products until and unless approved by regulatory agencies to scientific and regulatory standards. • Establish standards for regulating product ingredients and functioning. In addition to being important in their own right, should these policies be put in place together with polices designed to make combustible tobacco products (eg, cigarettes, cigars, cigarillos) less desirable and available, it is possible that cur- rent conventional cigarette smokers who will not quit nicotine would shift to e- cigarettes without major dual use or youth initiation to nicotine addiction with e- cigarettes. Absent this change in the policy environment, it is reasonable to assume that the behavior patterns that have been observed for e- cigarettes will persist, which makes it unlikely that they will contribute to reducing the harm of tobacco use and could increase harm by perpetuating the life of conventional cigarettes. Conclusions Although most of the discussion of e- cigarettes among health authorities has concentrated on the product itself, its potential toxicity, and use of e- cigarettes to help people quit smoking, the e- cigarette companies have been rapidly expanding using aggressive marketing messages similar to those used to promote cigarettes in the 1950s and 1960s. E- cigarette advertising is on Grans et at E- Cigarettes: A Scientific Review 1983 television and radio in many countries that have long banned similar advertising for cigarettes and other tobacco products and may be indirectly promoting smoking conventional cig- arettes. Although it is reasonable to assume that, if existing smokers switched completely from conventional cigarettes (with no other changes in use patterns) to e- cigarettes, there would be a lower disease burden caused by nicotine addiction, the evidence available at this time, although limited, points to high levels of dual use of e- cigarettes with conventional cigarettes, no proven cessation benefits, and rapidly increas- ing youth initiation with e- cigarettes. Although some cite a desire to quit smoking by using the e- cigarette, other common reasons for using the products are to circumvent smoke -free laws and to cut down on conventional cigarettes, which may reinforce dual use patterns and delay or deter quitting. The trajectory of the dual use pattern among adults or chil- dren is unclear, but studies of youth find that as many as one third of youth who use e- cigarettes have never smoked a con- ventional cigarette. Nicotine is a highly addictive substance with negative effects on animal and human brain development, which is still ongoing in adolescenceaz"'o Furthermore, high rates of dual use may result in greater total public health bur- den and possibly increased individual risk if a smoker main- tains an even low -level tobacco cigarette addiction for many years instead of quitting. Although data are limited, his clear that e- cigarette emissions are not merely "harmless water vapor," as is frequently claimed, and can be a source of indoor air pollution. Smoke -free poli- cies protect nonsmokers from exposure to toxins and encourage smoking cessation.1z One hundred percent smoke -free policies have larger effects on consumption and smoking prevalence,125 as well as hospital admissions for myocardial infarction, stroke, and other cardiovascular and pulmonary emergencies '116 than weaker policies. Introducing e- cigarettes into clean air envi- ronments may result in population harm if use of the product reinforces the act of smoking as socially acceptable or if use undermines the benefits of smoke -free policies. Acknowledgments We thank the following individuals for their advice and feedback: Cort Anastasio, PhD; John Balmes, MD; Cynthia Hallett, MPH; Sara Kalkhoran, MD; Lauren Lempert, JD, MPH; C. Arden Pope III, PhD; Martina P6tschke- Langer, MD, MA; Prudence Talbot, PhD; Michael Than, MD; Gemma Vestal, JD, MPH, MBA; and the reviewers solic- ited by the World Health Organization Tobacco Free Initiative of the longer report prepared for it. Sources of Funding This article is a greatly condensed version of a report prepared for (and supported by) the World Health Organization Tobacco Free Initiative. Additional support came from the University of California Tobacco Related Disease Research Program 21FT- -0040 and grant IP50CA180890 from the National Cancer Institute and Food and Drug Administration Center for Tobacco Products. The content is solely the responsibility of the authors and does not necessarily rep- resent the official views of the National Institutes of Health, the US FDA, or the World Health Organization. Dr Glantz is an American Legacy Foundation Distinguished Professor in Tobacco Control. Downloaded from http : / /cire.ahajotimals.org/ by guest on May 15, 2014 1984 Circulation May 13, 2014 Disclosures Dr Benowitz is a consultant to several pharmaceutical companies that market smoking cessation medications and has been a paid expert witness in litigation against tobacco companies. Drs Grana and Glantz report no conflicts. References 1. Grana R, Benowitz N, Glantz SA. Background paper on E- cigarettes (elec- tronic nicotine delivery systems). Center for Tobacco Control Research and Education, University of California, San Francisco, a WHO Collaborating Center on Tobacco Control. Prepared for World Health Organization Tobacco Free Initiative. December 2013. http: / /pvw.escholuship.orgtuc/ iwm/13p2b72n. Accessed March 31, 2014. 2. Felberbaum M. Old Tobacco Playbook Gets New Use by E- Cigarettes. The Associated Press. 2013. http: //bigstory,ap.org/article /old- tobacco- playbook -gets- new - use -e- cigarettes. Accessed August 16, 2013. 3. Grana RA, Ling PM. Smoking revolution? A content analysis of electronic cigarette retail websites. Am JPrev Med. 2014;46:395 -403. 4. Adkison SE, O'Connor Ell, Banal- Travers M, Hyland A, Borland R, Yong HH, Cummings KM, McNeill A, Thrasher IF, Hammond D, Fong GT. Electronic nicotine delivery systems: international tobacco control four - country survey. Am J Prev Med. 2013;44:207 -215. S. King BA, Alan S, Promoff G, Arrazola R, Dube SR. Awareness and ever use of electronic cigarettes among US adults, 2010 -2011. Nicotine Tob Res. 2013;15:1623 -1627. 6. Dockrell M, Morrison R, Bauld L, McNeill A. E- cigarettes: prevalence and attitudes in Great Britain. Nicotine Tob Res. 2013;15:1737 -1744. 7. Pearson JL, Richardson A, Niamat RS, Vallone DM, Abrams DB. e- Cigarette awareness, use, and harm perceptions in US adults. Am J Public Health. 2012;102:1758 -1766. 8. Regan AK, Promoff G, Dube SR, Arrazola R. Electronic nicotine deliv- ery systems: adult use and awareness of the "e- cigarette" in the USA. Tob Control. 2013;22:19 -23. 9. Centers for Disease Control and Prevention. Notes from the field: elec- tronic cigarette use among middle and high school students - United States, 2011 -2012. Morb Mortal Wkly Rep. 2013;62:729-730. 10. Lee S, Grana RA, Glantz SA. Electronic- cigarette use among Korean adolescents: a cross - sectional study of market penetration, dual use, and relationship to quit attempts and former smoking [published online ahead of print November 22, 2013]. J Adolesc Health. doi: 10.1016 /j. jadohealth.2013.11.003. http: / /www.jahonline.orgtm icle /S1054 -139X% 2813%2900748 -9. Accessed November 22, 2013. 11. Duna L, Glantz SA. E- cigarettes and conventional cigarette use among U.S. adolescents: a cross - sectional study [published online ahead of print March 6, 20141. JAMA Ped. doi: 10 .1001 /jamapediatries.2013.5488. http://archpedi.jamanetwork.com/article.aspx?articleid=1840772. Accessed March 6, 2013. 12. World Health Organization. WHO Study Group on Tobacco Product Regulation: report on the scientific basis of tobacco product regulation. WHO Technical Report Series, 2009:1 -21. 13. FCTCI COP /5/13. Report: Electronic Nicotine Delivery Systems, Including Electronic Cigarettes. Seoul, Republic of Korea; 2012. 14. Schaller K, Ruppert L, Kahnert S, Bethke C, Nair U, Pdtschke- Langer M. Electronic Cigarettes: An Overview. Heidelberg, Germany: German Cancer Research Center (DKFZ); 2013. 15. Burstyn I. Peering through the Mist: What Does the Chemistry of Contaminants in Electronic Cigarettes Tell Us About Health Risks? Technical Report July- August 2013. http : / /publichealth.dmxel.edu / -/ media /Files /publichealth/ms08.pdf. Accessed September 23, 2013. 16. Trtchounian A, Talbot P. Electronic nicotine delivery systems: is there a need for regulation? Tob Control. 2011;20:47 -52. 17. Givens A, Cheng P -S. I -Team: E- cigarettes, used to smoke marijuana, spark new concerns. 4 New York. October 11, 2013. http: /INww. nbcnewyork.com/investigat ions /ECigarettes- Drugs- Marijuana - Vapor- Pens- Smoking -I- Team- 227269001.htmi. Accessed November 12, 2013. 18. Shuman P, Bums M. Latest cannabis craze: marijuana known as "wax." myFoxLA.com. May 24, 2013. http: / /www.myfoxla.com/story/22305076/ its -the- latest- cannabis - craze- a- concerntrated- marijuana - known -as -wax. Accessed November 12, 2013. 19. Williams M, Talbot P. Variability among electronic cigarettes in the pressure drop, airflow rate, and aerosol production. Nicotine Tob Res. 2011;13:1276 -1283. 20. US Department of Health and Human Services. Preventing tobacco use among youth and young adults: a report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2012. 21. Grana RA, Glantz SA, Ling PM. Electronic nicotine delivery systems in the hands of Hollywood. Tob Control. 2011;20:425-426. 22. de Andrade M, Hastings G, Angus K. Promotion of electronic cigarettes: tobacco marketing reinvented? BMJ. 2013;347:£7473. 23. Rooke C, Amos A. News media representations of electronic cigarettes: an analysis of newspaper coverage in the UK and Scotland [published online ahead of print July 24, 2013]. Tob Control. doi: 10.1136 1tobaccocon- tro1- 201 3 -05 1 043. ht tp:// tobaccocontrol .bmj.conVcontenYmly /2013 /07/241 tobaccocontrol- 2013- 0510415hort. Accessed September 9, 2013, 24. Kim AE, Lee YO, Shafer P, Nonnemaker J, Makarenko O. Adult smok- ers' receptivity to a television advert for electronic nicotine delivery sys- tems [published online ahead of print October 3, 20131. Tob Control. doi:10.1136 /tobaccocontrol- 2013 -051130. http://tobaccocontrol.bmj.com/ content(early/ 2013 / 10103 / tobaccocontrol - 2013- 051130.short. Accessed November 21,2013. 25. TNS Opinion & Social. Attitudes of Europeaps Towards Tobacco. Special Eurobarometer 385, Wave Eb77j commissioned by the Directorate General Health and Consumers of the European Commission; Brussels, Belgium; 2012. 26. Etter JF, Bullen C. A longitudinal study of electronic cigarette users. Addict Behav, 2014;39:491 -494. 27. Douptcheva N, Gmel G, Studer J, Deline S, Etter IF. Use of electronic cigarettes among young Swiss men. J Epidemiol Community Health. 2013;67:1075 -1076. 28. Kralikova E, Novak 1, West O, Kmetova A, Hajek E Do e- cigarettes have the potential to compete with conventional cigarettes? A survey of conventional cigarette smokers' experiences with e- cigarettes. Chest. 2013;144:1609 -1614. 29. Etter JF, Button C. Electronic cigarette: users profile, utilization, satisf ac- tion and perceived efficacy. Addiction. 2011;106:2017-2028. 30. Goniewicz ML, Lingua ED, Hajek P. Patterns of electronic cigarette use and user beliefs about their safety and benefits: an internet survey. Drug Alcohol Rev. 2013;32:133 -140. 31. Choi K, Forster JL. Beliefs and experimentation with electronic ciga- rettes: a prospective analysis among young adults. Am J Prev Med. 2014;46:175 -178. 32. Reddy A. Personal communication: GYTS data Latvia and Finland, November 12,2013. 33. Goniewicz ML, Zielinska -Danch W. Electronic cigarette use among men - agers and young adults in Poland. Pediatrics, 2012; 130:e87)_c885. 34. Utah Department of Health. Utah health status update: electronic ciga- rette use among Utah students (grades 8, 10, and 12) and adults. Updated December 2013. http:// tobacco .ucsf.edu /e- eigarette-use- among -kids- skyrocketing-utah- levels- much - higher - among- adults. Accessed February 2, 2014. 35. Hadwiger ME, Trehy ML, Ye W, Moore T, Allgire J, Westenberger B. Identification of amino - tadalafil and da onalum in electronic ciga- rette products using high pressure liquid chromatography with diode away and tandem mass spectrometric detection. ✓ Chromatogr A. 2010;1217:7547 -7555. 36. Trehy ML, Ye W, Hadwiger ME, Moore TW, Atigire JF, Woodruff JT, Ahadi SS, Black JC, Westenberger BE Analysis of electronic cigarette cartridges, refill solutions, and smoke for nicotine and nicotine related impurities. JLiq Chrommogr Relat Technol. 2011;34:1442 -1458, 37. Goniewicz ML, Kuma T, Gawron M, Knysak J, Kosmider L. Nicotine levels in electronic cigarettes. Nicotine Tob Res. 2013;15:158 -166. 38. Cameron JM, Howell DN, White JR, Andrenyak DM, Layton ME, Roll JM. Variable and potentially fatal amounts of nicotine in e- cigarette nico- tine solutions. Tob Cenral. 2014;23:77 -78. 39. Schober W, Szendrei K, Matzen W, Osiander -Fuchs H, Heitman D, Schettgen T, Jorres RA, Froane H. Use of electronic cigarettes (e- cigarettes) impairs indoor air quality and increases FeNO levels of e- cigarette consumers [published online ahead of print December 6, 2013]. hit J Hyg Environ Health. doi: 10.1016 /j.ijheh.2013.11.003. hup: // dx. doi. org /10.1016 /j.ijheh.2013.11.003. Accessed February 10, 2014. 40. Goniewicz ML, Hajek P, McRobbie H. Nicotine content of electronic cig- arettes, its release in vapour and its consistency across batches: regulatory implications. Addiction. 2014;109:500 -507. 41. Goniewicz ML, Knysak J, Gae ron M, Kosmider L, Sobczak A, Kurek J, ProkopowiczA, Jablonska - Czapla M, Rosik- Dulewska C, Havel C. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Central. 2014;23:133 -139. Downloaded from http: / /ciro.al)ajournals.org/ by guest on May 15, 2014 42. Kim HJ, Shin HS. Determination of tobacco-specific nitrostraines in replace- ment liquids of electronic cigarettes by liquid chromatography- tandem mass spectrometry. JChromatogrA. 2013;1291:48 -55. 43. Bahl V, Lin S, Xu N, Davis B, Wang YH, Talbot P. Comparison of elec- tronic cigarette refill fluid cytotoxicity using embryonic and adult models. Reprod Toxicol. 2012;34:529 -537. 44. Romagna G, Allifranchinl E, Bocchietto E, Todeschi S, Esposito M, Farsalinos KE. Cytotoxicity evaluation of electronic cigarette vapor extract on cultured mammalian fibroblasts (ClearStream- LIFE): compari- son with tobacco cigarette smoke extract. Inhal Toxicol. 2013;25:354 -361. 45. Farsahnos RE, Romagna G, Allifranchini E, Ripamond E, Bocchietto E, Todeschi S, Tsiapras D, Kyrzopoulos S, Vourlds V. Comparison of the cytotoxic potential of cigarette smoke and electronic cigarette vapour extract on cultured myocardial cells. hit J Diction Res Public Health. 2013;10:5146 -5162. 46 Schripp T, Markowitz D, Glide E, Salthammer T. Does e- cigarette con- sumption cause passive vaping? htdoorAir. 2013;23:25 -31. 47. Houris AD, Churn MS, Poulianiti KP, Jamurtas AZ, Kostikas K, Tzatzarakis MN, Wallace Hayes A, Tsatsakis AM, Koutedakis Y Acute impact of active and passive electronic cigarette smoking on serum cofi- nine and lung function. Inhal Toxicol. 2013;25:91 -101. 48. Armitage AK, Dollery CT, George CF, Houseman TH, Lewis Pi, Turner DM. Absorption and metabolism of nicotine from cigarettes. Br Med L 1975;4:313 -316. 49. Czogala J, Gon]ewicz ML, Fidelus B, Zielinska -Danch W, Travers MJ, Sobezak A. Secondhand exposure to vapors from electronic ciga- rettes [published online ahead of print December 11, 2013]. Nicotine Tob Res. doi: 10.1093 1norma203. htt p : / /ntroxfordjournals.org /eontenV early /2013 112 /10hisratt203.1ong. Accessed February 12, 2014. 50. Ostro B, Feng WY, Broadwin R, Green S, Lipsett M. The effects of com- ponents of fine particulate air pollution on mortality in California: results from CALFINE. Envimn Health Perspect. 2007;115:13 -19. 51. Secondhand Smoke Exposure and Cardiovascular Effects: Making Sense of the Evidence. Washington, DC: Institute of Medicine; 2010. 52. Brook RD, Rajagopalan S, Pope CA, Brook JR, Bhatnagar A, Diez- Roux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA. Particulate matter air pollution and cardiovascular disease: an update to the sci- entific statement from the American Heart Association. Circulation. 2010;121:2331 -2378. 53. Pope CA 3rd, Bumett RT, Krewski D, Jewett M, Slid Y, Calle EE, Than MJ. Cardiovascular mortality and exposure to airborne fine particulate matter and cigarette smoke: shape of the exposure - response relationship. Cirmdation.2009; 120:941 -948. 54. Mehra S, Shin H, Burnett R, North T, Cohen Al. Ambient particulate air pollution and acute lower respiratory infections: a systematic review and implications for estimating the global burden of disease. Air Qual Altura Health. 2013:1 -15. 55. Ponca FC, Eronanno G, Stabile L, Vigo P. Influential parameters on par- ticle concentration and size distribution in the mainstream of e- cigarettes. Environ Pallor. 2014;184:523 -529. 56. Ingebrethsen BJ, Cole SK, Alderman SL. Electrone cigarette aerosol par- Ocle size distribution measurements. Inhal Toxicol. 2012;24:976 -984. 57. Zhang Y, Sumner W, Chen DR. In vitro particle size distributions in elec- tronic and conventional cigarette aerosols suggest comparable deposition patterns. Nicotine Tob Res. 2013; 15:501-508. 58. Williams M, Villarreal A, Bozhilov K, Lin S, Talbot P. Metal and silicate particles including nanopa i icles are present in electronic cigarette carto- mizer fluid and aerosol. PLoS One. 2013;8:e57987. 59. Vansickel AR, Cobb CO, Weaver MF, Eissenberg TE. A clinical labo- ratory model for evaluating the acute effects of electronic "cigarettes ": nicotine delivery profile and cardiovascular and subjective effects. Cancer Epidemiol Biomarkers Pier. 2010;19:1945 -1953. 60. Hinton C, McRobb[e H, Thomley S, Glover M, Lin R, Laugesen M. Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross -over trial. Tob Control. 2010;19:98 -103. 61. Etter JE Bullen C. Saliva cotinine levels in users of electronic cigarettes. Eur RespirL 2011;38:1219 -1220. 62. Vansickel AR, Eissenberg T. Electronic cigarettes: effective nicotine deliv- ery after acute administration. Nicotine Tob Res. 2013;15:267 -270. 63. Dawkins L, Corcoran O. Acute electronic cigarette use: nicotine delivery and subjective effects in regular users. Psychophannacology. 2013:1 -7. 64. Dawkins L, Timer J, Hasna S, Soar K. The electronic - cigarette: effects on desire to smoke, withdrawal symptoms and cognition. Addict Behay. 2012;37;970 -973. Grana et at E- Cigarettes: A Scientific Review 1985 65. Nides MA, Leischow SJ, Bhatter M, Simmons M. Nicotine blood levels and short-term smoking reduction with an electronic nicotine delivery sys- tem. Ain J Health Belt. 2014;38265 -274. 66. Sciencelab.com, Inc. Material Data Safety Sheet: Propylene Glycol. Updated May 21, 2013. Sciencelab.com, Inc., Houston, TX. 67. Dow Chemical Co. Product Safety Assessment (PSA): propylene glycol. 2013. http : / /wwNv.do%v.com/productsafety /finder /prog.htmgHealthlafo. Accessed November 21, 2013. 68. The American Chemistry Council. Propylene glycol: considerations against use in theatrical fogs, July 2001. http: /hvwNv.lyondenbascH.com/ techlit/techlit/2280.pdf. Accessed November 21, 2013. 69. Laino T,TtimaC, Moor P, Martin E, Stolz S,CurioniA. Mechanisms ofpro- pylene glycol and tr]acetin pyrolysis. JPhys CheinA. 2012;116:4602 -4609. 70. US Environmental Protection Agency. Acroleln. http: / /www.epa.gov/ ttnatwOl/hlthef /acrolein.html. Accessed November 24, 2013. 71. Henderson TR, Clark CR, Marshall TC, Hanson RL, CH H. Heat degrada- tion studies of solar heat transfer fluids Solar Energy. 1981;27:121 -128. 72, Chen IL. FDA summary of adverse events on electronic cigarettes. Nicotine Tob Res. 2013;15:615 -616, 73. CBS News. Electronic cigarette explodes in man's mouth, causes serious injuries. February 16, 2012. http:/hvwiv.cbsnews.com/news/eleennic- cigarette- explodes -in -mans- mouth - causes - serious - injuries /. Accessed November 24,2013. 74. Strickland J. Woman says e- cigarette exploded, shot flames 4 feet across living room. WSB -TV Atlanta. 2013. hup: / /www.wsbtv.conVnews /news/ local/woman- says -e- cigarette- exploded- shot - flames- 4- feet/nZkCX/. 75. Vardavas CI, Anagnostopoutos N, Kougias M, Evangelopoulou V, Connolly GN, Behrakis PK. Short -term pulmonary effects of using an electronic cigarette: impact on respiratory flow resistance, impedance, and exhaled nitric oxide. Chest. 2012;141:1400 -1406. 76. Floods AD, Poulianiti KP, Chorti MS, Jamurtas AZ, Kouretas D, Owolabi BO, Tzatzarakis MN, Tsatsakis AM, Koutedakis Y. Acute effects of elec- tronic and tobacco cigarette smoking on complete blood count. Food Chem Toxicol. 2012;50:3600 -3603. 77. McAuley TR, Hopke PK, Zhao J, Babaian S. Comparison of the effects of e- cigarette vapor and cigarette smoke on indoor air quality. Inhal Toxicol. 2012;24:850 -857. 78. Medicines and Healthcare Products Regulatory Agency. The Regulation of Nicotine Containing Products (NCPS). London, UK: Public Summary Report, Medicines and Healthcare Products Regulatory Agency; June 12, 2013. 79. Grana R, Popova L, Ling P. A longitudinal analysis of electronic ciga- rette use and smoking cessation [published online ahead of print March 24, 2014]. JAMA Int Med. doi :10.1001 /jamainternmed,2014.187. http://archinte.jamanetwork.com/article.aspx?articleid=1846627. Accessed March 24, 2014. 80. Vickerman KA, Carpenter KM, Altman T, Nash CM, Zb]kowski SM. Use of electronic cigarettes among state tobacco cessation quinine callers. Nicotine Tob Res. 2013;15:1787 -1791, 81. Choi K, Forster JL. Response to Letter to the Editor Regarding "Beliefs and Experimentation with Electronic Cigarettes: A Prospective Analysis Among Young Adults." Am J Prev Med. In press. 82. Popova L, Ling PM. Alternative tobacco product use and smoking cessa- tion: a national study. Ann J Public Health. 2013;103:923 -930. 83. Polosa R, Caponnetto P, Morjaria JB, Papate G, Campagna D, Russo C. Effect of an electronic nicotine delivery device be-cigarette) on smoking reduction and cessation: a prospective 6 -month pilot study. BMC Public Health. 2011;11:786. 84. Caponnetto P, Campagna D, Cibella F, Morjaria 1B, Caruso M, Russo C, Polosa R. EffiCiency and Safety of an eLectronic cigAmTre (ECLAT) as tobacco cigarettes substitute: a prospective 12 -month randomized control design study. PLoS One. 2013;8:e66317. 85. Caponnetto P, Auditore R, Russo C, Cappello GC, Polosa R. Impact of an electronic cigarette on smoking reduction and cessation in schizophrenic smokers: a prospective 12 -month pilot study. /nt J Environ Res Public Health. 2013;10:446 -461. 86. Batten C, Howe C, Laugesen M, McRobbie H, Parag V, Wildman J, Walker N. Electronic cigarettes for smoking cessation: a randomised con- trolled trial. Lancet. 2013;382:1629 -1637. 87. Polosa R, Morjaria JB, Caponnetto P, Campagna D, Russo C, Alamo A, Amaradio M, Fisichella A. Effectiveness and tolembiflty of electronic cigarette in mat -life: a 24 -month prospective observational study. Intent Emerg Med. 2013:1 -10. 88. Hughes JR, Shipman S, Callas P, Zhang J. A meta - analysis of the efficacy of over - the - counter nicotine replacement. Tob Control. 2003;12:21 -27. Downloaded from hltp:Hcire.ahajournals.org/ by guest on May 15, 2014 1986 Circulation May 13, 2014 89. Eissenberg T. Electronic nicotine delivery devices: ineffective nicotine delivery and craving suppression after acute administration. Tob Control. 2010;19:87 -88. 90. Moore D, Aveyard P, Connock M, Wang D, Fry-Smith A, Barton P. Effectiveness and safety of nicotine replacement therapy assisted reduction to stop smoking: systematic review and meta - analysis. BMJ. 2009;338:61024. 91. Godtfredsen N, Oster M, Vestbo J, Andersen I, Prescott E. Smoking reduction, smoking cessation, and incidence of fatal and non -fatal myocardial infarction in Denmark 1976 -1998: a pooled cohort study. J Epidemiol Commun Health. 2003;57:412 -416. 92. JhaP, Ramasundaraheuige C, Landsman V, RosMnB,ThunM,Anderson RN, McAfee T, Peto R. 21 "-Century hazards of smoking and benefits of cessation in the United States. NEngl J Med. 2013;368:341 -350. 93. Gerber Y, Myers V, Goldbourt U. Smoking reduction at midlife and life- time mortality risk in men: a prospective cohort study. Ara J Epidemiol. 2012;175:1006 -1012. 94. Tverdal A, Bjartveit K. Health consequences of reduced daily cigarette consumption. Tob Control. 2006;15:472 -480. 95. USDepartmentof Health and Human Services. The Health Consequences of Smoking: 50 Year's of Progress: A Report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention, National Center on Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014. 96. Barnoya J, Glantz SA. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation. 2005;111:2684 -2698. 97. Bjartveit K, Tverdal A. Health consequences of smoking 1 -4 cigarettes per day. Tob Control. 2005;14:315 -320. 98. Than ML Carter BD, Feskanich D, Freedman NO, Prentice R, Lopez AD, Hartge P, Gapstur SM. 50 -Year trends in smoking - related mortality in the United States. N Engl J Med. 2013;368:351 -364, 99. Lynch SM, Vrieling A, Lubin III, Kraft P, Mendelsohn JB, Har ge P, Canzian F, Steplowski E, Arslan AA, Gross M, Helzlsouer K, Jacobs EL LaCroix A, Petersen G, Zheng W, Allures D, Amundadottir L, Bingham SA, Boffetta P, Bout an- Ruault MC, Chanock SJ, Clipp S, Hoover RN, Jacobs K, Johnson KC, Kooperberg C, Luo J, Messina C, Pall! D, Patel AV, Ribol! E, Shut XO, Rodriguez Suarez L, Thomas G, Tjonneland A, Tobias GS, Tong E, Trichopoulos D, Virtamo L Ye W, Yu K, Zelenluch- Jacquette A, Buena- de- Mesquita HE, Stolzenberg- Solomon RZ. Cigarette smoking and pancreatic cancer: a pooled analysis from the pan- creatic cancer cohort consortium, Am J Epidemiol. 2009;170:403 -413. 100. Pandeya N, Williams GM, Sadhegi S, Green AC, Webb PM, Whiteman DC. Associations of duration, intensity, and quantity of smoking with adenocarcinoma and squamous cell carcinoma of the esophagus. Am J Ep iderniol. 2008;168:105 -114. 101. Vineis P, Kogevinas M, Simonsen L, Brennan E Boffetta P. Levelling -off of the risk of lung and bladder cancer in heavy smokers: an analysis based on multicentric case - control studies and a metabolic interpreta- tion. Murat Res. 2000;463:103 -110. 102. Doll R, Pets, R. Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non - smokers. JEpidemrol Community Health. 1978;32:303 -313. 103. Flanders WD, Lally CA, Zhu BP, Henley SJ, Than MJ. Lung cancer mortality in relation to age, duration of smoking, and daily cigarette consumption: results from Cancer Prevention Study II. Cancer Res. 2003;63:6556 -6562. 104. Fiore M. Treating Tobacco Use and Dependence: 2008 Update: Clinical Practice Guideline. Darby, PA: DIANE Publishing; 2008. 105. Esterl M. Lorillard isn't backing away from menthol or e- cigarettes. Wall Street J. August 27, 2013. http : // online.wsj.com/news /anietes /SB 10001 4241 27887324906304579038844211701578. Accessed November 24, 2013. 106. Kessler MS. E- cigarettes could reduce harm: opposing vlew: regula- tory actions, including tax policy should encourage cigarette smokers to switch. USA Today, September 22, 2013. http: /Avww.usatoday.com/ story /opinion/2013 /09/22 /electronic - cigarettes- btu- ecigs- editorials- debates /2850859/. Accessed November 24, 2013. 107. Peeters S, Gilmore AB. Transnational tobacco company interests in smokeless tobacco in Europe: analysis of internal industry documents and contemporary industry materials. PLoS Med. 2013;10:e3001506. 108, Porters S, Gilmore AB. Understanding the emergence of the tobacco industry's use of the term tobacco harm reduction in order to inform public health policy [published online ahead of print January 22, 20141. Tab Control, doi; 10.1136 /tobaccocontrol- 2013 - 051502. httpr // tobaccocontrol.bmj.com/ content/ early /2014 /01 /22 /tobaccocontrol- 2013-051502.1ong. Accessed February 2, 2014. 109. US Department of Health and Human Services, How Tobacco Smoke Causes Disease: The Biology mid Behavioral Basis for Smoking - Attributable Disease: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Centel and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2010. 110. Samuels B, Glantz SA. The politics of local tobacco control. JAMA. 1991;266:2110 -2117. 111. Fallin A, Grano R, Glantz SA. '"Po quarterback behind the scenes, third -party efforts ": the tobacco industry and the tea party [published online ahead of print February 20, 20131. Tob Control, doi:10.1136/ tobaccocontrol- 2012 -050815. http: / /tobaccocontrol.bmi.com/contentl early/ 2013 /02 /20 / tobaccocontol- 2012- 050815.1ong. 112. Higgins A. Aided by army of ' °vapers," e- cigarette indus- try woos and wins Europe. The New York Junes. November 9, 2013. http: //Nvww.nytimes.com /2013 /11 /10 /world/europe /aided -by- army- of- vapers -e- cigarette- industry -woos- and - wins- europe. html ?pagewanted =l & -r =1 &seid=auto&smi d=tw-nytimeshe alth. Accessed November 12, 2013. 113. Seneca, law. v Food & Drug Administration, 627 E3d 891 (2010). 114. American Nonsmokers' Rights Foundation. U.S. state and local laws regulating use of electronic cigarettes October 1, 2013. hapd /no- smoke. orggpdf /ecigslaws.pd£ Accessed December 14, 2013. 115. European Parliament and European Council of the European Union. Directive of the European Parliament and of the Council on the Approximation of the Laws, Regulations, and Administrative Provisions of the Member States concerning the manufacture, pre- servation and sale of tobacco and related products. Pe -Cons No/ Yy - 2012/0366 (Cod). February 26, 2014. http: / /www.eumpul. europa. eu /sides /getDoc. do ?type= REPORT &reference= A7 -2013- 0276&format =XML &language =EN. Accessed March 25, 2014.. 116. European Commission. Memo: questions & answers: new rules for tobacco products. March 5, 2014. http : / /europa.eu/rapid/pmss- relens - MEMO-14-134_en.htm. Accessed March 5, 2014. 117. Medicines and Healthcare Products Regulatory Agency. The regulation of nicotine containing products: questions and answers. 2013, http: / /www. mhra.gov.uk/ home / groups /comms -ic /documents /websiteresoumes/ con286835.pdf. Accessed October 4, 2013. 118. Action on Smoking and Health. Electronic cigarettes. ash briefing. June 2013. http: /hvww.mh.org.uk/files /documents /ASH- 715.pdf. Accessed October 4, 2013. 119. McKee M. E- cigarettes and the marketing push that surprised everyone. BMJ. 2013;347:£5780. 120. DwyerJB,Brolde RS, Leslie FM. Nicotine and brain development. Birth Defects Res C Embryo Today. 2008;84:30 -14, 121. Liao C -Y, Chen Y -J, Lee J -F, Lu C -L, Chen C -H. Cigarettes and the developing brain: picturing nicotine as a neuroteratogen using clinical and preclinical studies. Tzu Chi Med J. 2012;24:157 -161. 122. Lichtensteiger W, Ribary U, Schlumpf M, Odemtatt B, Widmer HR. Prenatal adverse effects of nicotine on the developing brain. Prog Brain Res. 1988;73:137 -157. 123. Longo CA, Fried PA, Cameron I, Smith AM. The long -term effects of prenatal nicotine exposure on response inhibition: an fMRI study of young adults. Neurotoxieol Towel, 2013;39:9 -18. 174. US Departmento£Health and Human Services. The Health Consequences of Involuntary Exposure to Tobacco Snake: A Report of the Surgeon General Washington, DC: Department of Health and Human Services PHS, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health; 2006. 125. Fichumberg CM, Glantz SA. Effect of smoke -free workplaces on smok- ing behaviour: systematic review. BMJ. 2002;325:188. 126, Tan CE, Glantz SA. Association between smoke -free legislation and hospitalizations for cardiac, cerebrovascular, and respiratory diseases: a meta - analysis. Circulation. 2012;126:2177 -2183. KEY Wows: adolescent m particulate matter is public policy m smoking Downloaded from httli:Hcircathajoumals.org/ by guest on May 15, 2014