Advances in Behavioral Laboratory Methods that Inform Tobacco Regulatory Science: A TCORS Working Group Special Issue

Abstract

Objective

The 2009 Family Smoking Prevention and Tobacco Control Act (TCA) created unprecented enabling conditions for establishing national regulatory policy that reduces the burden of public health and societal problems associated with tobacco product use. The Center for Tobacco Products (CTP), created by the FDA to implement the TCA, developed a first-of-its-kind FDA/National Institutes of Health (NIH) collaborative program to fund Tobacco Centers of Regulatory Science (TCORS).

Methods

To assist the TCORS with addressing research priorites, working groups (WGs) comprised of FDA-CTP liasions and TCORS investigators were formed. Under the direction of the Center for Evaluation and Coordination of Trainin and Research (CECTR), the TCORS WGs seek to develop tangible work products in their respective areas of focus.

Results

The focus of the behavioral pharmacology WG evolved from publishing a narrow paper on behavioral methods in electronic cigarette research to a collection of papers on advances in behavioral laboratory methods that may inform tobacco regulatory science.

Conclusion

This Special Issue contains articles that address all of the CTP research priorities and demonstrates how advances in behavioral laboratory methods made by TCORS investigators can inform FDA efforst to regulate tobacco products.

The 2009 Family Smoking Prevention and Tobacco Control Act (TCA) created unprecedented enabling conditions for establishing national regulatory policy that reduces the burden of public health and societal problems associated with tobacco product use.¹ Because the U.S. Food and Drug Adminstration (FDA) is ‘… a regulatory agency with the scientific expertise to identify harmful substances in products to which consumers are exposed, to design standards to limit exposure to those substances,…and to evaluate the impact of labels, labeling, and advertising on consumer behavior in order to reduce the risk of harm and promote understanding of the impact of the product on health…’ it was in the public interest for the TCA to grant FDA authority in regulating the tobacco industry.

To orchestrate the implementation of all its provisions, the TCA also mandated the creation of the FDA Center for Tobacco Products (CTP). Among its varied responsibilities, CTP forms selective partnerships with other governmental agencies and institutions to address particular components of the TCA. For example, the Tobacco Centers of Regulatory Science (TCORS), a first-of-kind FDA/National Institutes of Health (NIH) collaborative program, was created to generate scientific data that can inform regulatory actions taken by FDA. In fiscal year 2013, fourteen TCORS were established that are coordinated by the NIH’s Office of Disease Prevention and funded by CTP. To efficiently develop and expand the science base related to regulatory action and product evaluation, the TCORS utilized the focused set of research priorities delineated by CTP’s Office of Science.^2,3 These priorities include:

• understanding the properties of a diverse group of tobacco products (eg, constituents, design features, use patterns, attitudes),

• reducing addiction to tobacco products,

• reducing toxicity and carcinogenicity of tobacco products and smoke,

• understanding adverse health consequences of tobacco use,

• understanding communication about tobacco products, including tobacco product marketing, and

• understanding economics and policies on tobacco use and perceptions.

To assist the TCORS with addressing these research priorities, working groups (WG) comprised of FDA-CTP liaisons and TCORS investigators were formed. Under the direction of the Center for Evaluating and Coordination of Training and Research (CECTR), the TCORS WG seek to develop tangible work products in their respective areas of focus including health communications, behavioral pharmacology, biomarkers, nicotine, vulnerable populations, eye tracking, vape shops, and training.

Within the behavioral pharmacology WG, an iterative process of defining a work product of mutual interest to its members and of direct relevance to the TCA ensued. The focus of the behavioral pharmacology WG evolved from publishing a narrow paper on behavioral methods in electronic cigarette research to a collection of papers on advances in behavioral laboratory methods that may inform tobacco regulatory science. Ultimately, the WG agreed to include behavioral research articles from TCORS investigators who were not members of the behavioral pharmacology WG. This special issue contains articles that address all of the CTP research priorities and is timely because behavioral laboratory methods may be of particular importance to the regulation of other tobacco products (eg, waterpipe tobacco, e-cigarettes, dissolvable forms of nicotine).

Many behavioral methods can be used in both clinical and nonclinical studies. Although clinical data are important to understanding tobacco addiction, as well as the determinants, patterns and consequences of tobacco product use, there are limitations to the types of questions that can be answered with human subjects. For instance, ethical considerations restrict experiments with humans that might otherwise determine the cognitive impact of repeated tobacco use during adolescence. However, nonclinical data regarding the developmental psychopharmacology of tobacco constituents can contribute important information regarding causality.

It should be noted that there are important distinctions between addiction in humans and animal models of drug abuse and that there are no animal models that completely emulate human addiction.⁴ Despite this limitation, information obtained under controlled conditions in nonclinical models is valuable because behavior in this context is lawful and the complex determinants of addictive behavior can be systematically manipulated.^5,6 The complexity of the relationship between factors that control behavior requires researchers to pay a great deal of attention to research methodology. Seemingly minor methodological details can affect experimental outcomes and alter the generalizability of the findings.^7,8 Therefore, behavioral laboratory methods used in tobacco product research should be clearly articulated so that both their utility and limitations can be meaningfully discerned within the context of the expanding scientific foundation that informs tobacco regulatory policies.

Nicotine, the primary psychoactive constituent of tobacco, activates the α4β2 nicotinic acetylcholine receptor (nAChR) subtype ^9–12 and elevates dopamine in the mesolimbic dopamine reward system.^13,14 Nicotine is similar to other abused drugs in provoking this response,^15,16 although it appears to be less reinforcing than stimulants like cocaine.^17,18 Though nicotine is required to establish and maintain tobacco addiction,¹⁹ FDA lacks the legal authority to require complete removal of nicotine from tobacco products (21 USC, §907).²⁰ It may be possible, however, to reduce nicotine content below the threshold required to establish tobacco addiction.^21,22 Here, Mercincavage et al.²³ detail a behavioral method for understanding the psychological influences on consumer acceptance of reduced nicotine products. Their approach demonstrates how consumer reactions to such products can be modeled in a laboratory setting prior to the implementation of a nicotine reduction policy. These data may also offer insight into the attitudes about, and marketing strategies for, tobacco products that are intended to reduce the risk of addiction and other adverse health consequences from the use of combusted cigarettes.

The combination of stimuli and pharmacological effects found in tobacco products can facilitate addiction^24,25 and less than 15% of smokers are typically able to stop smoking for at least 6 months without pharmacotherapy.^26–28 It should also be noted, however, that tobacco products and tobacco smoke can contain thousands of chemical constituents in addtion to nicotine, some of which may increase the potential for initiating tobacco product use and addiction.^29–31 For instance, menthol masks respiratory irritation produced by cigarette smoke,³² may increase abuse liability of tobacco by acting as a conditioned reinforcer,³³ and may also increase the apparent dose of nicotine by inhibiting metabolism.^34,35 However, the utility of standard laboratory approaches that use cigarette smoking for studying the influence of nicotine and menthol interactions on smoking behavior is substantially constrained by the robust personal cigarette preferences within smokers. Here, DeVito et al.³⁶ contribute a brief report that demonstrates how subjective responses to smoking abstinence and acute nicotine delivery differ between menthol and non-menthol preferring smokers in a human laboratory paradigm that administers nicotine intravenously.

The most reliable nonclinical index of the reinforcing properties of nicotine is nicotine self-administration (NSA),³⁷ which has been demonstrated in a variety of nonclinical models, most prominently in rats³⁸ and squirrel monkeys.³⁹ The schedules under which nicotine infusions are delivered can be manipulated to determine reinforcement under a variety of contingencies, including those serving as indices of reinforcing efficacy.^40,41 Animal models of tobacco addiction typically involve exposure to nicotine alone or nicotine combined with isolated tobacco constituents (eg, minor alkaloids). The use of extracts derived directly from tobacco products and containing a range of tobacco constituents would more accurately model tobacco exposure in humans.^42–44 This issue contains a report from LeSage et al.⁴⁵ suggesting that the abuse liability of smokeless tobacco extract does not differ from nicotine alone in their nonclinical model indicating that nicotine content is the primary determinant of the abuse liability of smokeless tobacco extracts in this assay. This model may be useful for comparing the relative abuse liability of other tobacco products and for modelling tobacco product standards that may be enacted under Section 907 of the TCA. In addition, Jensen et al.⁴⁶ review the translational potential of laboratory-based NSA with human subjects for illuminating the relationships between pharmacogenetics, nicotine reward thresholds, and dose-response functions of reward and aversiveness in a variety of different experimental conditions.

While nonclinical inhalation studies can offer information about nicotine pharmacology that may have more face validity because the route of administration is similar to cigarette smoking, the variability in breathing patterns make it difficult to control nicotine dose in nonclinical inhalation models. However, it is clear that physiologically relevant doses of nicotine can be inhaled by rats^47–49 and rhesus monkeys^50–52 and appear to produce pharmacological effects that are distinct from those produced by subcutaneous nicotine injections, even when drug levels in the brain are similar.⁵³ The dose-response curve for nonclinical NSA resembles a flattened, inverted U,^17,18 perhaps suggesting that increasing dose beyond a threshold level produces only minor changes in stimulation until aversive effects are encountered. Interestingly, humans engaged in NSA adjust response patterns⁵⁴ and smokers modify behavior to maintain relatively constant levels of nicotine exposure.^55,56 Although recent data suggest that waterpipes and e-cigarettes are popular among teens⁵⁷ and adults,⁵⁸ how these modes of tobacco product exposure compare to the behavioral, pharmacological and toxicological effects of smoking cigarettes is understudied. This issue contains three articles on the use of behavioral laboratory methods in research on e-cigarettes as well as brief report on the topography of waterpipe smoking. The article by Blank et al.⁵⁹ describes the methodological challenges of adapting traditional behavioral laboratory methods to studies on e-cigarette use and the determinants of e-cigarette toxicity. In addition, an original research article from Strasser et al.⁶⁰ features a novel clinical method that determines the influence of smoking topography on nicotine intake, withdrawal symptoms, and craving in e-cigarette users while St. Helen et al.,⁶¹ provide data on the relationship between inhalation patterns and nicotine intake in e-cigarette users. In addition, Kim et al.⁶² examine within-subject variability in puffing behaviors among experienced waterpipe smokers using a waterpipe designed and validated for standardized, laboratory-based assessment. Because waterpipe smoking is very different from cigarette smoking with respect to smoking time, puff duration, puff volume, and flow rate, data on how puffing behaviors vary between- and within-individuals during waterpipe use are useful determining how waterpipe components, including tobacco and coal, influence puffing behavior and exposures to harmful and potentially harmful chemicals. All of these articles are timely and important because of the evolving regulatory status of e-cigarettes and waterpipes and the rapid expansion of their use. A science-base for understanding how the different contexts and patterns of e-cigarette and waterpipe use influence possible adverse health consequences can inform the development of regulation that reduces addiction, toxicity, or carcinogenicity.

The first tobacco product used each day is likely to be the most rewarding because nAChRs in the mesolimbic dopamine reward system are rapidly desensitized by nicotine exposure.⁶³ A variety of factors can stimulate subsequent tobacco use, including cues previously paired with nicotine. For instance, visual cues associated with nicotine availability and delivery play an important role in maintenance of nicotine-seeking behavior.^25,64 For example, these cues can increase operant response rates, inhibit response extinction, and provoke the resumption of NSA. This effect is certainly influenced by conditioning, but nicotine appears to enhance the rewarding effects of the stimuli themselves. For instance, nicotine can enhance the rewarding effects of palatable food,^65,66 even though it tends to reduce food intake.^67,68 Here, Rupprecht et al.⁶⁹ present nonclinical data demonstrating that nicotine enhances the rewarding effects of calorie-free sweeteners found in e-cigarette flavors. These data highlight the need to understand the potential interaction of flavorings and nicotine exposure on addiction in e-cigarette users. This may be especially true for young users because of other nonclinical data suggesting that adolescents are more sensitive than adults to the rewarding effects of nicotine^70–72 and recent data from humans suggesting adolescents prefer e-cigarettes over combusted cigarettes.⁵⁷

Laboratory research that uses eye-tracking technologies can offer valuable information regarding the impact of tobacco product communication, especially on how consumers respond to health warnings and on the role of attentional or cognitive bias. For instance, eye-tracking studies have shown that daily cigarette smokers attend less than others to health warnings printed on tobacco product packaging,^73–76 though the roles of familiarity, distraction, and deliberate avoidance are unclear. This issue is especially relevant to tobacco regulatory science because the TCA mandates that FDA issue regulations for graphic health warnings for cigarettes.¹ An increasing amount of research in tobacco regulatory science involves the use of eye tracking, but, to date, the existing evidence has not been comprehensivley examined. In a systematic review, Meernik et al.⁷⁷ synthesize the evidence from eye tracking technology that will add to the body of scientific data informing regulatory policy and guide improvements in the efficacy of tobacco product communications.

This special issue also contains a review from Robinson et al.⁷⁸ of human behavioral laboratory methods that can be adapted to evaluate the impact of point of sale tobacco marketing on the attention, memory, implicit attitudes and behavior of smokers, while Tidey et al.⁷⁹ contribute a review of how behavioral economic laboratory measures provide an expedited simulation of the behavioral effects of tobacco control policies within specific subpopulations of interest to FDA. These laboratory approaches are particularly important to tobacco regulatory science because the behavior of persons under the age of 18 is especially sensitive to the influence of tobacco product advertising and to product cost. Finally, Peters et al.⁸⁰ review the role of behavioral laboratory research in legal decision making and efforts to avoid behavioral research findings being ‘lost in the translation’ when they are presented to non-scientific audiences, especially when the judicial system is evaluating future challenges to FDA rulemaking.

FDA has the legal authority to regulate tobacco products themselves, as well as the advertising, marketing, promotion, distribution, and sales of tobacco products.^1,81 FDA also has the authority to support and develop regulatory science related to the Agency’s mission and activities. The reviews and original research presented in this special issue demonstrate how advances in behavioral laboratory methods made by TCORS investigators can inform FDA efforts to regulate tobacco products.