Preventive Medicine 68 (2014) 11–16

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Commentary

The tobacco endgame: It's all about behavior Jack E. Henningfield ⁎ Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, USA

a r t i c l e

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Available online 16 September 2014 Keywords: Tobacco Nicotine End game Addiction Light cigarettes Menthol Food and Drug Administration Surgeon general World Health Organization Framework Convention

a b s t r a c t One of the ten great public health achievements in the 20th century was turning the tide on one of the greatest public health disasters of that century: the tobacco use and related disease epidemic. The premature death and disease caused by tobacco can be considered largely as a side-effect of tobacco use behavior and the disease of addiction. The spread of that disease was fostered by an industry that researched the behavioral and biological basis of tobacco use and addiction and applied its findings and knowledge to develop products and marketing approaches to increase the likelihood that people, especially young people, would try tobacco products and develop persistent use and addiction. Researchers outside of the tobacco industry also investigated the behavioral biology of tobacco use and their research has been critical in turning the tide of the tobacco and disease epidemic. The behavioral factors are considered vital to understand and address by United States Food and Drug Administration and Surgeon General, as well as the World Health Organization in their tobacco control efforts. This commentary discusses key behavioral factors in the rise and fall of the epidemic, as well as some of those increasingly discussed as potential contributors to the endgame. © 2014 Elsevier Inc. All rights reserved.

Introduction One of the Ten Great Public Health Achievements in the 20th century was turning the tide on one of the great public health disasters of that century: the tobacco use and related disease epidemic (Centers for Disease Control and Prevention, 1999a, 1999b; Koop, 2003, 2010). As described by Schroeder and Koh (2014) in their article summarizing accomplishments and challenges in the 50 years since the landmark Surgeon General's report on Smoking and Health (U.S. Department of Health, Education, and Welfare, 1964), after smoking rates increased to a peak of about 43% of the adult population in 1964, they have plummeted to about 18% in 2012, with cigarettes smoked per day also having declined sharply from about 20 to 13. This has been accompanied by declining rates in lung cancer after more than a century of steadily increasing rates (Schroeder and Koh, 2014). There is now active discussion about “the endgame” for the tobacco epidemic and increasing focus on the importance of efforts to drastically reduce combusted tobacco use (Cole and Fiore, 2014; USDHHS, 2014; Warner, 2013; Zeller, 2013; Zeller and Hatsukami, 2009). Abbreviations: ENDS, electronic nicotine delivery systems; FCTC, Framework Convention on Tobacco Control; FDA, Food and Drug Administration; FSPTCA, Family Smoking Prevention and Tobacco Control Act; TPSAC, Tobacco Products Scientific Advisory Committee; USDHHS, United States Department of Health and Human Services; WHO, World Health Organization. ⁎ Pinney Associates, 4800 Montgomery Lane, Suite 400, Bethesda, MD 201814, USA. Fax: +1 301 718 8440. E-mail address: [email protected].

http://dx.doi.org/10.1016/j.ypmed.2014.09.003 0091-7435/© 2014 Elsevier Inc. All rights reserved.

Tobacco-attributable disease may be considered a side-effect of tobacco use and addiction, but just as the tobacco epidemic has been all about behavior so too has the beginning to the end of the epidemic; endgame scenarios have also focused on behavior. This is not to understate the importance of physical product factors on disease risk because not all tobacco products carry equal risks: combusted products are by far the most hazardous, with the cigarette which must be inhaled and is designed to facilitate inhalation (USDHHS, 2014; World Health Organization, 2008; Zeller and Hatsukami, 2009). However, behavior is the interface between the product and the health consequences. With respect to cigarettes, the most important aspect of product factors has been their impact on behavior, as they are virtually non-differentiated with respect to delivery of toxicants and nicotine, and hence do not differ in their risk of causing disease and premature death (National Cancer Institute, 2001). As discussed in this commentary and elsewhere, the promise and the peril of new types of tobacco products will also be very much about behavior (Arnott, 2013; Malone, 2013; Warner, 2013; Zeller, 2013). Insofar as the emergence and now the decline of the tobacco epidemic in the Unites States and some other countries have been all about behavior, it makes for a fascinating case history of the importance of behavioral research by the tobacco industry in fostering the epidemic, as well as the application of behavioral research by non-tobacco industry scientists in providing a foundation for turning the tide on the epidemic. Many other scientific disciplines in addition to behavioral research were brought to bear and also contributed mightily of course. These include epidemiology, neuroscience, pharmacology, toxicology,

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psychiatry, consumer marketing, and more as have been described elsewhere (Brandt, 2007; Henningfield, 2011; Kessler, 2001; Kluger, 1996; Proctor, 2011; Rabinoff, 2006; USDHHS, 2014). This commentary, however, will focus on the contribution of behaviorally-focused research including abuse liability assessment, and some of the many scientists who applied such methods as has been described in greater detail elsewhere (Henningfield, 2011; Henningfield, Shiffman, Ferguson, and Gritz, 2009; U.S. Department of Health and Human Services, 2010; USDHHS, 2014). Behavioral science was hijacked by the tobacco industry to make more addictive products and increase the prevalence of tobacco use Tobacco is by nature addictive and toxic, and the simplest cigarette rolled by hand of organically grown tobacco and pristine paper would be addictive and deadly because of the nicotine and hundreds of potent toxins occurring in the product, with many more emerging when the product is combusted (Hoffman and Hoffman, 2010; U.S. Department of Health and Human Services, 2010; USDHHS, 2014). Over the course of the 20th century, the tobacco industry and the cigarette industry in particular have made the products far worse from a public health perspective. They have done this through extensive research on how to make them more addictive and readily deliver far higher levels of tar and nicotine than advertised, as well as research on how to market them so as to maximize the likelihood that people would try the products, develop addiction, and undermine the motivation to stop using (Federal Trade Commission, 2008; Gray, 2000; Henningfield, 2004; National Cancer Institute, 2001; U.S. Department of Health and Human Services, 2010; U.S. Department of Justice, 2006; USDHHS, 2014). The tobacco industry extensively researched the interoceptive and exteroceptive factors that influence the reinforcing, discriminative, and eliciting stimulus functions of nicotine and other constituents in cigarettes. The tobacco industry understood, long before organizations, such as the U.S. National Institute on Drug Abuse, the U.S. Public Health Service, the WHO, and other health focused agencies, that nicotine was the constituent in tobacco that drove repeated use and dependence by acting as a pharmacological reinforcer much like heroin and cocaine in the genesis and maintenance of other forms of drug dependence (Henningfield, 2011; Kessler, 2001; USDHHS, 1988; USDHHS, 2010, 2014). To accomplish this, every conceivable aspect of cigarette design, contents, and manufacture was explored with respect to impact on initiation, development of dependence, smoke intake per puff, inhalation topography, cigarettes smoked per day, nicotine “kick”, taste, color of the ashes, whiteness of the paper, and more. For example, the reinforcing, withdrawal-relieving, and brain-modulating effects, as well as the effects of trigeminal stimulation by oral nicotine deposition to contribute to the immediate impact and kick of smoking were studied, as were the effects of manipulating the free base fraction of nicotine and smoke pH, and the addition and manipulation of a wide variety of other substances such as ammonia-based substances and acetaldehyde (DeNoble and Mele, 2006; Ferris Wayne, Connolly, and Henningfield, 2006; Henningfield, 2004; Henningfield, Hatsukami, Zeller, and Peters, 2011; Kessler, 2001; Megerdichian, Rees, Wayne, and Connolly, 2007; U.S. Department of Health and Human Services, 2010; USDHHS, 2014; Wayne, Connolly, & Henningfield, 2004; Wayne, Connolly, Henningfield, and Farone, 2008; WHO, 2001, 2007, 2012). As concluded by the FDA, WHO committees, and the Uniteds States Department of Justice, this research, product development, and marketing by the tobacco industry were done with the intent to increase tobacco use and addiction, despite the understanding that these actions would be likely to increase morbidity and mortality associated with tobacco use (Brandt, 2007; Henningfield, 2004; Kessler, 2001; Kluger, 1996; Proctor, 2011; Rabinoff, 2006; U.S. Department of Justice, 2006; USDHHS, 2014; WHO, 2001). As described in the foregoing reports, among the many strategies of the cigarette industry to increase its market and profits, the “light” and low tar cigarette strategy was among the

single most devastating to public health, and it was very much about product design and marketing to manipulate behavior. It took nearly three decades for public health scientists and legal and regulatory investigators to unravel key elements of the strategy and its scientific foundation. It wasn't until the 1990s that it became apparent that such cigarettes were not reducing disease risk as had been predicted by many (USDHHS, 1981) but were actually associated with increased risk of lung cancer and other diseases as well as increased acceptability among youth (National Cancer Institute, 2001). To accomplish this, the tobacco industry researched and developed design features that facilitated and occasioned adjustments in puffing topography and other aspects of smoking so as to enable maintenance of high levels of smoke intake regardless of the machine-tested tar and nicotine ratings provided to consumers in advertising (Cummings, Hyland, Bansal, and Giovino, 2004; National Cancer Institute, 2001; Wilkenfeld, Henningfield, Slade, Burns, and Pinney, 2000). A goal of the industry was to produce cigarettes that would be advertised as low tar and nicotine (i.e., “light”), based on the Federal Trade Commission (FTC) and International Standards Organization (ISO) cigarette test methods, in order to undermine the motivation to quit by providing “reassurance” and an “alternative to quitting”; however, these cigarettes actually provided no clinically meaningful reduction in actual tar or nicotine intake (Cummings et al., 2004; Hurt and Robertson, 1998; National Cancer Institute, 2001; Shiffman, Pillitteri, Burton, Rohay, and Gitchell, 2001; Shopland, 2001; Slade, Bero, Hanauer, Barnes, and Glantz, 1995). The behavioral research that enabled and accompanied this was extensive. For example, in the 1960s before the widespread use of filter tip ventilation, Philip Morris discovered that such ventilation was associated with compensatory changes in smoking that maintained high levels of nicotine intake (Dunn, 1967; Kozlowski and O'Connor, 2002; Kozlowski, Pillitteri, and Sweeney, 1994; Martin and Dunn, 1967; Osmalov, 1967). It was not until the 1980s that researchers found that such vents produce smoother, more reassuring smoke and enable subtle changes in finger and lip placement to provide far higher levels of tar and nicotine than advertised, actually increasing the risk of some diseases such as adenocarcinoma of the lungs, possibly by increasing inhalation of the smoke deep into the lung (Kozlowski and O'Connor, 2002; Kozlowski et al., 1994; National Cancer Institute, 2001; USDHHS, 2014). As concluded by Kozlowski and O'Connor (2002), “Cigarette filter ventilation is a defective design because of misleading taste, bigger puffs, and blocked vents”. The public health impact of “light” cigarettes was all about behavior. The FTC rescinded the cigarette test method in 2008 concluding that “…the statements of tar and nicotine yields as measured by this test method are confusing at best, and are likely to mislead consumers who believe they will get proportionately less tar and nicotine from lower-rated cigarettes than from higher-rated brands. The Commission will not allow its stamp of approval on a test method that is confusing or misleading to consumers” (Federal Trade Commission, 2008). In announcing the ruling, FTC Commissioner Leibowitz wrote, “Our action today ensures that tobacco companies may not wrap their misleading tar and nicotine ratings in a cloak of government sponsorship. Simply put, the FTC will not be a smokescreen for tobacco companies' shameful marketing practices” (Federal Trade Commission, 2008). The use of menthol in cigarette manufacture and marketing is another fascinating example of the importance of behavior in the epidemic (Lawrence, Cadman, and Hoffman, 2011). The FDA's Tobacco Products Scientific Advisory Committee (TPSAC) addressed menthol in cigarettes as its first priority consistent with the 2009 Family Smoking Prevention and Tobacco Control Act (FSPTCA) which gave the FDA authority to regulate cigarettes and smokeless tobacco products. The overall conclusions of the TPSAC report were that the use of menthol in cigarette manufacture and marketing has an “adverse impact on public health” and that “removal of menthol cigarettes from the marketplace would benefit public health in the United States”. These conclusions were not based on findings that menthol makes cigarettes more toxic than

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cigarettes without menthol. Rather, the harmful public health outcome is primarily due to the impact of menthol in contributing to perpetuating the tobacco epidemic by increasing experimentation and regular smoking in youth, particularly in African Americans, and by reducing smoking cessation success in African Americans (Tobacco Products Scientific Advisory Committee, 2011). More specifically, as discussed in the TPSAC report, the evidence suggested several biobehavioral mechanisms operative in contributing to initiation, dependence, and difficulty quitting smoking. These include its physiologically cooling and anesthetic effects that reduce the harshness of cigarette smoke and which provide sensory and conditioned stimulus effects that can contribute to the reinforcement and pleasure of smoking, as well as reducing health concerns about smoking by ameliorating the harsh and noxious aspects of smoke. Menthol was also found to be an important tool in marketing and product branding which also contribute to initiation, patterns of use, and relapse. Harm reduction strategies: the promise and the peril are all about behavior Despite the extraordinarily high addictiveness and harmfulness of cigarettes, no major regulatory agency or country, nor the WHO Framework Convention on Tobacco Control (“Tobacco Treaty” WHO, 2014b) have proposed banning the products outright, though there are proponents of such a strategy (Proctor, 2011, 2013). Tobacco control efforts focused on prevention, cessation, and protection from secondhand smoke are the cornerstones of reducing smoking and disease, but the public health benefits have been very slow to accrue (Slade and Henningfield, 1998; Warner, 2013). Since the 1990s, there have been increasing calls to add harm reduction approaches involving noncombustible tobacco products to tobacco control programs on the premise that combusted tobacco products in general, and cigarettes in particular, are so extraordinarily harmful and addictive, that virtually any noncombusted tobacco or nontobacco nicotine product would be less harmful to the individual users if substituted completely for the combusted product (Zeller and Hatsukami, 2009). This potential of smokeless tobacco products (e.g., snuff and snus) to offer pathways away from combustion tobacco products was the focus of the first major effort of the Strategic Dialog on Tobacco Control (Zeller and Hatsukami, 2009). The report concluded that “A world in which no one uses combustible tobacco products would have a profound impact on reducing death and disease” (p. 326), and it discussed the potential role of non-combusted tobacco products to achieve that goal, as an adjunct to the preeminent tobacco control interventions of prevention and cessation (see also (Fiore, Schroeder, and Baker, 2014). During approximately two years of meetings leading up to the 2009 report of the Strategic Dialog, electronic nicotine delivery systems (ENDS) were just emerging on the public health radar screen with one of the first international reports, which proposed the term ENDS from the WHO Tobacco Regulation Study Group (TobReg) (Henningfield and Zaatari, 2010; WHO, 2010). At that time, the products were viewed more as drug products making unsubstantiated cessation claims, and with relatively little serious consideration as to their potential public health promise. The main concerns of tobacco harm reduction approaches were related to behavior such as undermining advances in prevention and cessation if the products increased the risk of smoking (“gateway” effect) or undermined cessation by their use where smoking is not permitted, instead of as a complete substitute for combusted cigarettes (i.e., persistent “dual use”) (Henningfield and Fagerstrom, 2001; Henningfield and Slade, 1998; Koop, 2010; Kozlowski, Strasser, Giovino, Erickson, and Terza, 2001; Shiffman et al., 2002; Slade et al., 2000; Slade and Henningfield, 1998; Stratton, Shetty, Wallace, and Bondurant, 2001; Warner, 2013; Warner and Martin, 2003; Warner, Peck, Woosley, Henningfield, and Slade, 1998; Warner, Slade, and Sweanor, 1997; Zeller and Hatsukami, 2009). The prevailing

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assumption that the tobacco industry would use harm reduction products with the intent of undermining smoking prevention and cessation efforts, e.g., by advocating the use of the products for where smoking is not allowed (cf., Henningfield and Zaatari, 2009; Kessler, 2001; Kluger, 1996), compounds concerns about the risks of endorsement of harm reduction approaches by public health advocates. In addition to the forgoing concerns about tobacco harm reduction, the viability has also been limited by the general lack of appeal of potential harm reduction products such as smokeless tobacco to females and novel products to tobacco users in general, as well as formidable regulatory challenges (Warner, Peck, Woosley, Henningfield, and Slade, 1998; Zeller and Hatsukami, 2009). The explosive growth of ENDS has reignited debate about the promise and the peril of tobacco harm reduction. This is a diverse and rapidly evolving category of products that includes products marketed as electronic cigarettes, electronic waterpipes, customized nicotine vaporizing devices, and more variants (Cressey, 2014; Friedman, 2014; WHO, 2014a). Compared to other new and novel tobacco products such as snus, dissolving tobacco strips, and tobacco rolls heated by burning carbon and heating elements (e.g., Stratton et al., 2001; USDHHS, 2014; Zeller and Hatsukami, 2009) ENDS have captured a much higher level of attention by diverse stakeholders. These include tobacco control experts, health organizations such as the Centers for Disease Control and Prevention and the World Health Organization, research organizations such as the U.S. National Institutes of Health, regulatory agencies such as the U.S. Food and Drug Administration and European Commission, financial centers such as “Wall Street”, and perhaps most importantly, consumers who are migrating to the products at a pace that has surprised leaders from all of foregoing constituencies (Abrams, 2014; Chen and Husten, 2014; Cressey, 2014; Food and Drug Administration, 2014a; Friedman, 2014; Sarewitz, 2014; (Walton et al., 2014; WHO, 2014a). The promise of ENDS is also supported by the fact that since 2009 there has been a rapid escalation and dissemination of ENDS research, the development of apparently higher quality products that are more effective at nicotine delivery, and increasing support for research by the FDA and the National Institutes of Health (Abrams, 2014; Benowitz and Goniewicz, 2013; Farsalinos et al., 2014; Hajek, Etter, Benowitz, Eissenberg, and McRobbie, 2014; Nides, Leischow, Bhatter, and Simmons, 2014; Vansickel, Weaver, and Eissenberg, 2012). Equally important, from a potential public health perspective, is that consumer acceptance and market growth in the US and some other countries are rapidly expanding to the point that by 2013 many financial analysts and tobacco industry experts were predicting that ENDS could substantially reduce the traditional cigarette market and that some tobacco companies may see a larger proportion of their revenue from ENDS than from traditional cigarettes in less than ten years, referring to the products as potential “game-changers” and “disruptive technologies” (Abrams, 2014; Craver, 2013; Mangan, 2013; Romell, 2013). The market place itself is subject to behavioral forces and by the third quarter of 2014, it was clear that ENDS products designed to simulate cigarettes were losing market share to those designed to more readily accept diversely flavored liquids and allow easy adjustment over vapor delivery (Esterl, 2014). The stakes from every quarter are very high: this noncombustible product category is alternately heralded as the most viable path away from combusted tobacco products and “game changer” since the ascendancy of the cigarette (e.g., Abrams, 2014;), and demonized with concerns that the products will undermine the substantial advances that have been made in tobacco control prevention, cessation, secondhand smoke protection (e.g., Glantz, 2014; also see summary of major issues raised by Glantz and a critique by Bates (2014). The science is advancing rapidly (e.g., Farsalinos and Polosa, 2014; Hajek et al., 2014); but is in relative infancy leaving regulatory agencies and public health organizations calling for more research to guide their recommendations even as they must make decisions on a precautionary basis as they

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believe will serve the public health and avoid unintended consequences (e.g., Sarewitz, 2014; Chen & Husten, 2014; (Walton et al., 2014), WHO, 2014). The major debates concerning the public health impact continue to be about behavior as illustrated by the research questions emerging from a conference convened by the U.S. National Institutes of Health in October, 2013 (Walton et al., 2014). Major research questions include the need to know more about current and emerging patterns and determinants of initiation and use by youth, by adults, by pregnant women, and ethnic minorities, how the products should be regulated with respect to their addictiveness and sensory attractiveness, whether they will be more likely to contribute to the cessation of cigarette smoking or to enabling continuation of smoking by their use by cigarette smokers where cigarette smoking is not allowed as some products have been marketed. Although the greatest peril of ENDS is not about their emissions which are far lower in toxicants than from combusted tobacco (e.g., (Benowitz and Goniewicz, 2013; Farsalinos and Polosa, 2014; Goniewicz et al., 2014; Hajek et al., 2014), the product contents, emissions and designs were also identified as important targets for research and regulation because they vary quite widely in their contents and emissions from a toxicological perspective with some products appearing to deliver much higher levels of toxicants of concern than other products. It has also been proposed that such products may be key to what could be among the most powerful potential strategies proposed to reduce smoking prevalence, namely setting cigarette performance standards to reduce the nicotine content to levels so low that that they pose little risk of satisfying nicotine cravings or causing addiction (Benowitz & Henningfield, 1994; U.S. Department of Health and Human Services, 2014; Warner, 2013). A subsequent analysis of the conditions that would likely need to be in place to enable such a strategy included much more widely available acceptable forms of medicinal nicotine for people who were unable to completely abstain from nicotine (Henningfield et al., 1998). At present, ENDS appear to have potential to provide a source of nicotine substitution for those who find medicinal nicotine unacceptable (see also Abrams, 2014; U.S. Department of Health Human Services, 2014; Warner, 2013). Benowitz and Henningfield (2013) concluded that “Such products [ENDS and novel smokeless products] and NRT products may provide the support that is at least temporarily needed for some smokers to give up cigarettes entirely and to manage a world in which nicotine use by burning tobacco is less available” (p. i16). The process of ENDS regulation has commenced in various countries and the European Union (Cressey, 2014; Friedman, 2014; Sarewitz, 2014) but regulation will likely take several years to emerge with meaningful restrictions on product designs, contents, emissions, labeling, and allowable marketing (Cressey, 2014; Friedman, 2014). For example, in the U.S. the FDA released its proposed regulatory starting point for comment in July, 2014: the FDA Proposed “Deeming” Rule or “Regulation” (FDA, 2014). This was preceded by publication of a series of articles by FDA staff addressing various issues considered in the development of the Rule (Chen and Husten, 2014; Chen and Husten, 2014). Among the many regulatory challenges is the diversity of the ENDS industry. Whereas the cigarette industry was relatively unified in its opposition to meaningful regulation (Kessler, 2001), the ENDS industry is heterogeneous in origin, goals, and strategies. It includes major cigarette companies but it emerged from and continues to include many companies that have no history of or commitment to conventional tobacco products and rather are making explicit their goals of contributing to the end of conventional tobacco products (Cressey, 2014; Friedman, 2014). How regulation of ENDS, deemed to be tobacco products by the FDA's Center for Tobacco Products (CTP), is harmonized with the regulation of medicinal products by the FDA's Center for Drug Evaluation and Research (CDER) is another challenge. For example, ENDS would be most ideally (from a public health perspective) adopted by cigarette

smokers and other combustible tobacco users who have been unable to otherwise quit smoking to the complete exclusion of their combusted product use. Some fraction of current ENDS users have achieved that goal claiming to have thus “quit smoking” (Farsalinos and Polosa, 2014; Hajek et al., 2014; WHO, 2014a), thus demonstrating their potential as cessation aids but not meeting conventional regulatory criteria for labeling and promotion as cessation aids.1 There are no simple answers to how ENDS should be regulated or how they should be positioned in comprehensive tobacco control efforts and tobacco control messaging, but one thing is clear: the promise and the peril will be very much about behavior and regulation must address this with as much attention as it does to the physical performance standards for the products. Ideally ENDS will serve to facilitate mass migration from combusted to non-combusted tobacco products in cigarette smokers, without undoing the gains of tobacco control with respect to prevention and cessation. The greatest public health benefits would be expected if ENDS and other non-combusted tobacco products are primarily used to completely substitute for cigarettes by existing smokers of conventional cigarettes. This in turn would be expected to be more likely if ENDS are more affordable, more convenient to use, and understood to be less harmful than cigarettes. Thus, behaviorally focused public health strategies need to consider factors such as ENDS taxation rates, the impact of restrictions on where ENDS can be used, and communications about their relative risks, as these factors are among those which will likely influence whether cigarette smokers who cannot quit continue to smoke, or switch to ENDS.

Employment of behavioral strategies by FDA and WHO to curb the tobacco epidemic As is now evident, behavioral science, including behavioral pharmacology, was hijacked by the tobacco industry to take an epidemic to a level matching many of the worst in history, in the US and globally. Fortunately, in the US and globally, the science foundation for strategies to more rapidly reduce tobacco and associated disease is escalating, as is the political will and social support for efforts that make a difference such as increased taxation of tobacco products, more widespread clean air laws, stronger efforts to prevent easy youth procurement, banning of marketing and branding with imagery of light and low tar cigarettes, and more. These approaches are grounded in decades of study indicating that factors such increased economic cost resulting from increased cigarette taxation rates, increased behavioral cost resulting from restrictions on where smoking is allowed, increased product fears and concerns produced by health messaging contribute to reduced cigarette smoking (USDHHS, 2014). Such approaches are embodied in the 2005 WHO FCTC, internationally (WHO, 2014b). Such approaches help make the Tobacco End Game a viable target (Warner, 2013; Zeller, 2013). The evidence that tobacco product preference is related to behavioral factors such as cost, convenience, and attractiveness in addition to pharmacological factors (Henningfield et al., 2011) will be important to consider in regulation development and policy implementation concerning ENDS. Fostering the migration of cigarette smokers from cigarettes to ENDS would likely be enhanced by keeping ENDS taxation rates lower than for cigarettes and by communications and marketing that fall short of health claims (unless substantiated to the requirements of regulatory agencies) but truthfully represent the differences in the risks of the products to users.

1 The opinion of this author is that such demonstrations are not adequate to meet regulatory standards for approval as smoking cessation products (see also, WHO, 2014a) but that a path needs to be developed to encourage the use of the products by combusted tobacco users who are unable to quit smoking, and to the complete exclusion of combusted tobacco use to the greatest extent possible by the individual.

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Clean air law application to ENDS is very complex because the emissions are not combusted tobacco and the very low toxicant levels in many products suggest that product performance standards for legally marketed products could ensure that their exposure risk is very low by ordinary consumer product standards (Farsalinos and Polosa, 2014; Hajek et al., 2014). Nonetheless there would remain concerns about normalizing smoking for youth, and enforcement of no smoking in public settings since many of the ENDS are designed to look very much like cigarettes and release emissions that have the appearance of tobacco smoke (WHO, 2014a). These concerns need to be addressed by researched and appropriately implemented policy. Consumers need assurance that product labeling and communications are truthful and not misleading which is the premise of the WHO FCTC and the FDA regulation. Furthermore, it is not clear to this author that requiring ENDS users who have given up cigarette smoking to use their products only where smoking is allowed and in proximity to cigarette smoke is ethical or preferentially supports their switch from cigarette smoking to ENDS use. It is clear that such a requirement would result in their exposure to known harmful levels of known deadly toxicants well-documented in cigarette smoke but not in ENDS, as well as place them in situations that may precipitate relapse to cigarette smoking. Although the FDA does not have the authority to determine tax rates on tobacco or any other product or where people can smoke, many of the provisions of the FSPTCA are consistent with those of the international FCTC. The two approaches share much in common with their efforts to reduce demand and support prevention and cessation; however, the FDA regulation is more focused on the regulation of the products whereas the Framework Convention provides for a more comprehensive set of strategies and goals to reduce tobacco product supply and demand. Both the FDA and WHO approaches ban misleading product descriptors such as “light” and “low tar”, encourage research, population surveillance, and product regulation to potentially reduce addictiveness, attractiveness (“appeal”), toxicity, and other measures expected to alter behaviors consistent with prevention, cessation, and public health improvement. In developing product performance standards, and determining whether new products should be allowed on the marketplace and labeled as modified risk products, FDA must consider factors such as whether the new product or constituent will increase or decrease initiation, increase or decrease dependence, increase or decrease cessation, and must consider diverse populations and particular population risks (e.g., youth, pregnant women, and ethnic minorities) (FDA, 2014). To achieve its goals, the FSPTCA enables FDA to support research through contract mechanisms as well as in collaboration with the National Institutes of Health. Much of this is behaviorally-focused research that would guide regulation to promote prevention, cessation, as well as product standards that might lead to less addictive and less harmful products. The research includes the Population Assessment of Tobacco and Health (PATH) study which is a very large scale longitudinal study that will provide a comprehensive evaluation of tobacco use and biomarkers potentially associated with tobacco and nicotine use and disease risk. In his 2002 address to the Society for Research on Nicotine and Tobacco, former Surgeon General C. Everett Koop predicted that “… as early as mid 21st century we will look back at tobacco-induced disease as we now look back at various destructive plagues as important history but history nonetheless” (p. 619) (Koop, 2003). Dr. Koop understood that changing the course of the epidemic would involve changing behavior at the individual and population levels and the importance of basing interventions on a science foundation (Koop, 2003, 2010). He discussed the importance of science in “service to public health” as a noble endeavor. The intent of this commentary is to illustrate some of the ways that behavioral science has contributed to the beginning of the end of the tobacco epidemic and will be critical in the development, implementation, and realization of the Tobacco End Game. It will be very much about behavior and a noble application of behavioral science.

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Conflicts of interest Through my employer, Pinney Associates, I provide consulting services to GlaxoSmithKline Consumer Healthcare regarding matters relating to smoking cessation and, since January, 2014, to NJOY, a marketer of electronic nicotine delivery systems, also known as “electronic cigarettes”. I have a financial interest in a potential nicotine replacement therapy.

Role of funding source I am a full time employee of Pinney Associates, a health, science and policy consulting firm. Neither Pinney Associates, nor, its clients had a role in developing this commentary beyond providing the assistance of the acknowledged employees. Acknowledgments I greatly appreciate assistance with referencing and editing by Yolanda Green, Janine Pillitteri, and Daniel Wang. References Abrams, D.B., 2014. Promise and peril of e-cigarettes: can disruptive technology make cigarettes obsolete? JAMA 311 (2), 135–136. http://dx.doi.org/10.1001/jama.2013.285347. Arnott, D., 2013. There's no single endgame. Tob. Control. 22 (Suppl. 1), i38–i39. http://dx. doi.org/10.1136/tobaccocontrol-2012-050823. Bates, C., 2014. Critical commentary on the public comments on the FDA deeming rule submitted by UCSF faculty and fellows. http://www.clivebates.com/documents/ BatesFDA1.pdf. Benowitz, N.L., Goniewicz, M.L., 2013. The regulatory challenge of electronic cigarettes. JAMA 310 (7), 685–686. http://dx.doi.org/10.1001/jama.2013.109501. Benowitz, N.L., Henningfield, J.E., 1994. Establishing a nicotine threshold for addiction – The implications for tobacco regulation. New England Journal of Medicine 331, 123–125. Brandt, A., 2007. The Cigarette Century: The Rise, Fall, and Deadly Persistence of the Product that Defined America: Basic Books. Centers for Disease Control and Prevention, 1999a. Ten great public health achievements— United states, 1900–1999. MMWR Morb. Mortal. Wkly Rep. 48 (12), 241–243. Centers for Disease Control and Prevention, 1999b. Tobacco use—United states, 1900–1999. MMWR Morb. Mortal. Wkly Rep. 48 (43), 986–993. Chen, I.L., Husten, C.G., 2014. Introduction to tobacco control supplement. Tob. Control. 23 (Suppl. 2), 1–3. http://dx.doi.org/10.1136/tobaccocontrol-2013-051504. Cole, H.M., Fiore, M.C., 2014. The war against tobacco: 50 years and counting. JAMA 311 (2), 131–132. http://dx.doi.org/10.1001/jama.2013.280767. Craver, R., 2013. E-cigs will overtake traditional tobacco revenue at Reynolds in 2021, Winston-Salem Journal. Retrieved from http://www.journalnow.com/business/ business_news/local/article_948674ca-1ca9-11e3-a0ae-0019bb30f31a.html. Cressey, D., 2014. E-cigarettes: the lingering questions. Nature 513, 24–26. http://dx.doi. org/10.1038/513024a. Cummings, K.M., Hyland, A., Bansal, M.A., Giovino, G.A., 2004. What do Marlboro Lights smokers know about low-tar cigarettes? Nicotine Tob. Res. 6 (Suppl. 3), S323–S332. DeNoble, V.J., Mele, P.C., 2006. Intravenous nicotine self-administration in rats: effects of mecamylamine, hexamethonium and naloxone. Psychopharmacology (Berl) 184 (3–4), 266–272. Dunn, W.L., 1967. A study of the effect of lip occlusion of air holes on main stream delivery in air diluted cigarettes. Retrieved March 27, 2014, from http://tobaccodocuments. org/filters/1001892531-2534.html?pattern=dunn+lip+occlusion+of+air+holes+ on+main+stream+delivery+in+air+diluted+cigarettes.+Philip+Morris%3B+ 1967#images. Esterl, M., 2014. Big tobacco's e-cig push gets a reality check. http://online.wsj.com/ articles/big-tobaccos-e-cig-push-gets-a-reality-check-1409078319. Farsalinos, K.E., Polosa, R., 2014. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review. Ther. Adv. Drug Saf. 5 (2), 67–86. http://dx.doi.org/10.1177/2042098614524430. Farsalinos, K.E., Spyrou, A., Tsimopoulou, K., Stefopoulos, C., Romagna, G., Voudris, V., 2014. Nicotine absorption from electronic cigarette use: comparison between first and new-generation devices. Sci. Rep. 4 (4133). http://dx.doi.org/10.1038/srep04133. FDA, 2014. Population Assessment of Tobacco and Health (PATH) Study. Retrieved March 25, 2014, from http://www.fda.gov/downloads/TobaccoProducts/NewsEvents/ UCM324243.pdf. Federal Trade Commission, 2008. FTC rescinds guidance from 1966 on statements concerning tar and nicotine yields. Retrieved March 27, 2014, from http://www.ftc. gov/news-events/press-releases/2008/11/ftc-rescinds-guidance-1966-statementsconcerning-tar-nicotine. Ferris Wayne, G., Connolly, G.N., Henningfield, J.E., 2006. Brand differences of free-base nicotine delivery in cigarette smoke: the view of the tobacco industry documents. Tob. Control. 15 (3), 189–198. http://dx.doi.org/10.1136/tc.2005.013805. Fiore, M.C., Schroeder, S.A., Baker, T.B., 2014. Smoke, the chief killer—strategies for targeting combustible tobacco use. N. Engl. J. Med. 370 (4), 297–299. http://dx.doi. org/10.1056/NEJMp1314942. Friedman, J., 2014. Congressional Quarterly. E-cigarettes (in press). Glantz, S., 2014. List of public comments on FDA deeming rule by UCSF faculty and fellows (and others) with links to the comments. http://tobacco.ucsf.edu/list-publiccomments-fda-deeming-rule-ucsf-faculty-and-fellows-and-others-links-comments.

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