Thomas Eissenberg, PhD - US grants

DESCRIPTION: (Applicant's Abstract) This project explores how drug craving is influenced by pharmacologic and associative factors, and develops a human laboratory model of associative drug craving. Drug craving is thought to be important in maintaining regular drug use in the current drug user and in leading to relapse in the former user. A complete understanding of drug craving and successful treatments that reduce drug craving are likely to involve both pharmacologic and associative factors. Pharmacologic factors that influence drug craving might be agonist or antagonist administration. Associative factors that influence drug craving might be stimuli that are related to drug delivery. This laboratory-based project uses cigarette smokers and cigarette craving to understand better how subjective craving and drug self-administration are influenced by agonist (nicotine) and antagonist (mecamylamine) administration, and by drug-related stimuli (e.g., smoke, cigarette, etc.). The project consists of four studies of cigarette smokers. The first study systematically examines the influence of nicotine and mecamylamine on subjective cigarette craving and on cigarette self-administration. The two medications will be presented alone and in combination, as recent data suggest that the combination may reduce craving more than either medication alone. The second study uses a Pavlovian extinction procedure to determine the associative nature of craving reductions elicited by denicotinized cigarettes. The study is based upon data from the animal laboratory demonstrating that extinction of the responses elicited by drug-related stimuli can require an extended period of unreinforced exposure. The third study examines the combined impact of pharmacologic and associative factors on cigarette craving. This study uses the most effective nicotine/mecamylamine combination from the first study to examine pharmacologic craving reduction while smokers smoke denicotinized or nicotinized cigarettes. The fourth study explores a human laboratory model of associative nicotine craving by pairing nicotine administration with environmental stimuli. In sum, this project examines how pharmacologic and associative factors influence subjective craving and drug self-administration using nicotine as a model drug, and cigarette smokers as model drug users. This rigorously designed project uses controlled, safe, and convenient laboratory methods, multidimensional measures, and powerful within-subjects designs. Data from this project will yield specific knowledge regarding cigarette craving and, more generally, will guide theoretical understanding of drug craving and influence medications development for drug abuse treatment.

To investigate the effects of concurrent agonist/antagonist treatment on cigarette craving and cigarette self-administration. Specifically transdermal nicotine, a nicotinic agonist, and oral mecamylamine, a nicotinic antagonist, will administered alone and in combination to investigate how these compounds work together to influence subject-reported cigarette craving and withdrawal and cigarette self-administration.

Cigarette smoking costs an estimated 418,000 American lives annually. Cessation reduces this cost, but is difficult because smoking is maintained by factors such as withdrawal, tobacco's direct effects, and smoking-related stimuli. Current cessation methods address these factors: nicotine replacement treatments (NRTs) suppress withdrawal and/or blunt the effects of cigarettes. Behavioral treatments reduce the influence of smoking-related stimuli. Nonetheless, about 70 percent of smokers who try to quit, fail. Improving smoking cessation rates is a national priority that may be achieved by tailoring treatment to the separate needs of subgroups, such as men and women. Treatment studies demonstrate that current cessation techniques are less effective for women. There is no clear explanation for this difference, but it may involve a differential response NRT and/or smoking-related stimuli. For women, NRT may be less effective at suppressing withdrawal (Hypothesis 1) or blunting the effects of smoking during a quit attempt (Hypothesis 2). Women may also be more sensitive to smoking-related stimuli, such as the taste, sight, and smell of smoke (Hypothesis 3). These hypotheses can be examined efficiently in the clinical laboratory. Strengths of this setting include control over extraneous variables, repeated measure designs that yield dose effect curves, and validated tools for measuring puff topography, tobacco withdrawal, and the direct effects of nicotine and/or cigarettes. Three such studies are proposed. In each study, 64 men and 64 women who smoke will participate in 4 double blind, randomly ordered, 6.5-hour sessions. Objectively verified cigarette abstinence will be required before each session. Studies 1 and 2 will compare, in men and women, the NRT dose response functions for suppression of tobacco and blunting the effects of cigarettes; study 3 will compare the effects of smoking-related stimuli. Thus hypotheses 1, 2, and 3 are each addressed in separate studies. Overall, this project may improve cessation interventions for all smokers, particularly women. Given the costs of smoking and the dramatic reduction in these costs when smokers quit smoking, improving the treatment options for all smokers is essential.

DESCRIPTION (provided by applicant): Use of cigarettes and smokeless tobacco (SLT) in the U.S. costs over 400,000 lives and $100 billion annually. These tobacco-related deaths and health care costs are due to tobacco-delivered toxicants, especially carcinogens. Tobacco cessation is the most effective way of reducing toxicant exposure, though relapse rates are high. High relapse rates and continued tobacco use have provoked interest in harm reduction for people who continue to use tobacco. Harm reduction for tobacco users can involve lowering the total adverse health consequences of continued tobacco use by reducing toxicant exposure. The tobacco industry appears to embrace this type of harm reduction, and markets several potential reduced exposure products (PREPs) for smokers and SLT users. The National Cancer Institute and Institute of Medicine argue for objective testing of these PREPs. No accepted testing method exists, though we have had success using a short-term clinical model for evaluating cigarette-like PREPs for smokers. This short-term model could be improved and must be adapted to evaluate oral PREPs for SLT users and smokers. A longer-term model is necessary to measure PREP-induced reductions in carcinogen exposure. The specific aims of this proposal are to: (1) Improve the short-term clinical model for evaluating cigarette-like PREPs by allowing ad libitum puffing so that PREP-induced changes in smoking behavior can be measured, and introducing pre- and post-exposure blood sampling so that PREP nicotine delivery can be assessed. (2) Adapt the short-term clinical model so that it can be used to evaluate oral products intended for SLT users and/or smokers, and (3) Develop a longer-term clinical model for evaluating PREP carcinogen delivery. This project's overarching goal is to establish a clinical model that can be used to evaluate the marketing claims and harm reduction potential of PREPs for tobacco users. The project is consistent with NCI's Plans and Priorities for Cancer Research in 2004: "Smokers may feel a false sense of security that they can significantly reduce their risk of disease by using these new products [PREPs], when no data exists to suggest that they are in fact less harmful. Scientists must examine the toxicity of these products as well as evaluate whether or not 'harm reduction' is a viable public health strategy." This proposal's clinical model will likely be an important component of a comprehensive approach to predict if PREPs for tobacco users increase, decrease, or fail to change tobacco's health risks.

DESCRIPTION (provided by applicant): Globally, tobacco use accounts for 4.9 million deaths each year, including 400,000 in the U.S. These deaths are caused by inhaled smoke toxicants like carcinogens, carbon monoxide (CO), and nitric oxide (NO). Another smoke toxicant, nicotine, produces dependence with prolonged use. Cigarette smoke toxicant content and smoker toxicant exposure has been well characterized, as have the subjective and cardiovascular effects of cigarette smoking. However, in the U.S. and globally, millions of people use waterpipes (hookah or shisha) to smoke tobacco: the smoker fills the "head" with sweetened and flavored tobacco, covers it with perforated aluminum foil, and tops the foil with lit charcoal. Charcoal and tobacco smoke pass to the user via a half-filled water bowl, hose, and mouthpiece. Waterpipe tobacco smoking is increasing in the U.S., especially among college students for whom prevalence rates may be 15-20%. Relative to one cigarette, one waterpipe use episode can generate 100 times the smoke, with user toxicant exposure, effects, and smoke toxicant content that are largely unknown. These outcomes may depend upon an individual's use frequency and whether the individual uses the waterpipe alone or with a group. This project combines clinical laboratory methods, analytical chemistry, and cellular biology to achieve three specific aims. 1) Learn about individual waterpipe user toxicant exposure, effects, and smoke toxicant content. In two separate sessions, 130 waterpipe users (65 reporting 2-5 uses/month and 65 reporting >21 uses/month) will use a waterpipe loaded with preferred brand/flavor of waterpipe tobacco or placebo. Outcome measures include CO and NO, plasma nicotine, subjective, cardiovascular, and pulmonary response, and puff topography (puff number, volume, duration, and interpuff interval). Topography records will be replayed in an analytical laboratory to study smoke toxicant content and cytotoxicity/mutagenicity. 2) Learn how group use influences waterpipe toxicant exposure, effect, and smoke toxicant content. In an observational study, trained staff will use rigorous sampling and data collection procedures to study group waterpipe tobacco smoking in local cafs. In a laboratory study informed by observational study results, 65 waterpipe- sharing groups will use a waterpipe in the laboratory as a group in one session, and as individuals in another session, and user toxicant exposure and effects, and smoke toxicant content will be assessed as in Study 1. 3) Compare the toxicant exposure and effects of waterpipe tobacco smoking and cigarette smoking. In two sessions, 100 waterpipe users who also smoke cigarettes will either use a waterpipe or smoke a cigarette;outcome measures include exposure to CO, NO, and nicotine, as well as cardiovascular, respiratory, and subjective effects. Waterpipe use is disturbingly common among U.S. young adults. More information is needed about waterpipe effects, and it can be obtained from clinical laboratory studies and smoke toxicant analysis. This information is necessary to understand this potentially dangerous behavior, while shaping knowledge, opinions, and attitudes in a way that enhances public health. This project is relevant to public health because waterpipe tobacco smoking is a little-understood but rapidly emerging strain in the nation's tobacco use epidemic. The project will inform nascent efforts to prevent waterpipe tobacco smoking from contributing substantially to tobacco's morbidity and mortality by revealing the user toxicant exposure, subjective, cardiovascular, and pulmonary effects, and cytogenicity and mutagenicity of waterpipe tobacco smoke produced by individuals and groups;it will also address frequent but probably erroneous statements regarding waterpipe filtering and lower toxicant levels relative to cigarette smoke. The positive health impact of this type of research on tobacco cigarette smoking is well-documented;this project seeks similar positive outcomes on another potentially lethal form of tobacco use.

DESCRIPTION (provided by applicant): Globally, tobacco use accounts for 4.9 million deaths each year. The contribution of cigarette smoking to this toll has been well-documented. However, millions smoke tobacco using other methods, including waterpipes ("hookah" or "shisha"). As the WHO notes, waterpipe tobacco smoking is spreading globally and has been associated with tobacco-caused disease. Global popularity and disease risk highlight the need to learn more about waterpipe smoking, including its regional prevalence and user toxicant exposure profile. They also highlight a worldwide need for tobacco-related research capacity. This capacity is particularly needed in the countries of Southwest Asia, where tobacco use rates can exceed 50% and waterpipe tobacco smoking is common. Some countries, like Syria and Lebanon, have been building tobacco research capacity [e.g., NIH- funded research at the Syrian Center for Tobacco Studies (SCTS) and the American University of Beirut (AUB)]. Others may require more research capacity before they can join regional tobacco research efforts. For example, Jordan has high tobacco use rates and waterpipe tobacco smoking seems common. Studying Jordanian waterpipe use prevalence and user toxicant exposure would provide needed local data while developing regional tobacco-related research capacity. This response to PAR-08-223 describes work to be completed primarily in Irbid, Jordan with Drs. Mohammed Azab and Omar Khabour of the Jordan University of Science and Technology (JUST), and is an extension of R01CA120142 (02-21-2008 to 01-31-2013). The three specific aims of that parent grant, which involves U.S. waterpipe tobacco smokers, are to: 1) learn about waterpipe smoke toxicant yield and user toxicant exposure and effects when an individual uses a waterpipe to smoke tobacco;2) learn how to group use influences waterpipe toxicant yields and effects, and 3) learn how the toxicant exposure and acute effects of waterpipe tobacco smoking differ from those of cigarette smoking. The specific aims of this grant application are to: 1) study, over three years, changes in waterpipe tobacco smoking prevalence, knowledge and beliefs among Jordanian university students;2) examine relationships among waterpipe users'dependence, smoking behavior, and CO exposure;and 3) enhance local and regional tobacco-related research capacity. Formal training opportunities (e.g., SCTS'International Summer Program for Tobacco Control Research;project-focused workshops in Years 1 and 2) will be supported by on-line collaboration and mentorship to develop capacity and foster long-term professional relationships. These relationships strengthen JUST, SCTS, and AUB separately while increasing regional capacity and encouraging future joint research activity. Thus, this project provides an opportunity to learn more about tobacco use in Jordan while strengthening that country's tobacco-related research capacity. In so doing, the project establishes a foundation for regional tobacco-related research while simultaneously addressing the aims of the parent grant regarding user toxicant exposure and extending them to include waterpipe prevalence rates. PUBLIC HEALTH RELEVANCE: This project is relevant to public health because waterpipe tobacco smoking is a little-understood but rapidly emerging strain in the global tobacco epidemic. The project will inform nascent efforts to prevent waterpipe tobacco smoking from contributing substantially to tobacco's morbidity and mortality by revealing the use prevalence and user toxicant exposure among Jordanian university students. Perhaps more important, the project builds Jordanian tobacco-related survey and laboratory research capacity while strengthening regional capacity and fostering international collaboration. The positive health impact of this type of research capacity and collaboration on tobacco cigarette smoking is well-documented;this project seeks similar positive outcomes on another potentially lethal form of tobacco use.

DESCRIPTION (provided by applicant): Globally, tobacco use accounts for 4.9 million deaths each year. These deaths are caused by inhaled smoke toxicants. Extensive research describes cigarette smoke toxicant content (or yield), a vital link to understanding user toxicant exposure. However, millions of people use waterpipes (WP) to smoke tobacco. WP tobacco smoking may also be deadly, though little is known about WP smoke toxicant yield. A WP (hookah, shisha) has a hose, water bowl, body, and a head filled with sweetened and flavored tobacco that is heated with charcoal. WP tobacco smoking is increasing in the U.S., especially among college students. Relative to one cigarette, one WP use episode can generate 100 times the smoke. Current technology demands that, if we are to learn about WP smoke, we must use machines to generate it. Machine-generated smoke may limit validity because generation of WP smoke involves several key variables that differ by user and use episode which cannot be standardized in the analytical lab. This response to PAR-08-212 integrates mechanical engineering, chemistry, and clinical behavioral pharmacology to develop and test an unobtrusive WP smoke sampling instrument for the purpose of assessing the toxicant content of smoke produced in the natural environment. The specific aims are to: 1) Characterize a real-time WP smoke sampling device (Years 1-3). We have developed a prototype device that measures puff topography and samples WP smoke in real- time (REALTIME). Because particle deposition in the device may alter smoke toxicant content, correction factors need to be developed to infer true toxicant content from that measured. We will therefore measure toxicant-specific deposition fractions in the device, in particular for: particle number, particle mass, nicotine, tobacco-specific nitrosamines, and polycyclic aromatic hydrocarbons. 2) Evaluate REALTIME design options in the clinical laboratory (Years 1 and 2). Two design options, placement of the smoke sampler and the percentage of smoke sampled, involve tradeoffs between accurate measurement of toxicant content and realistic smoker behavior. We propose two controlled clinical laboratory studies to inform design option choice, with Study 1 addressing sampler placement (bowl or mouthpiece) and Study 2 addressing percentage of smoke sampled (2, 5, or 10%). The preferred option maximizes realistic smoke toxicant analysis while minimizing effects on smoker behavior. 3) Evaluate REALTIME in the natural environment (years 4 and 5). REALTIME will be attached to WPs used by consenting individual and groups of WP cafi patrons. The study will demonstrate REALTIME's use in natural settings and examine the relationship between the number of WP users and tobacco temperature and WP smoke toxicant yield. In sum, the technology and methodology developed in this project will enable valid analysis of WP smoke toxicant content. This interdisciplinary project addresses an emerging public health threat and is directly relevant to the NIH mission and wholly responsive to PAR-08-212.

DESCRIPTION (provided by applicant): Tobacco use accounts for over 400,000 U.S deaths each year due to cardiovascular disorders, cancers, and other health problems. Much of this morbidity and mortality is attributable to the toxicants that cigarette smokers inhale like carcinogens, carbon monoxide (CO), and the dependence-producing drug nicotine. Cigar smoking is also linked to cancer and other health disorders, and cigar smoke contains many of the same toxicants as cigarette smoke. Unfortunately, unlike cigarette smoking, cigar smoking has not declined in recent years, especially among young adults who are the most frequent users of the cigarillo - a short, slender cigar comprised of a tobacco leaf wrapper, a reconstituted tobacco binder, and tobacco leaf filler. Cigarillos appeal to young consumers because of the availability of enticing flavors like grape, cherry, and vanilla, and the sweet aroma produced by cigarillos when smoked. Young adult use of cigarillos has also been spurred by perceptions of reduced harm of cigarillos compared to cigarettes. In fact, there is a widely-held belief that exposure to cigarillo smoke toxicants can be reduced by removing the reconstituted tobacco binder through a modification process known as hyping. Perhaps most concerning is the scientific community knows very little about the toxicant exposure and effects of cigarillos and its various forms of use (i.e., original or modified forms). Understanding cigarilo use involves a transdisciplinary approach that addresses cigarillo smoke toxicant yield, cigarillo user toxicant exposure, and the cardiovascular and subjective effects associated with cigarillo use directly. The specific aims of this proposal are to: (1) Compare the toxicant yield of original and modified cigarillos, (2) Investigate toxicant exposure and effects of original and modified cigarillos in the laboratory, and (3) Examine toxicant exposure and effect when participants smoke original or modified cigarillos in their natural environment. Notable is that similar information regarding the effects of cigarettes has been used to inform prevention and cessation interventions and to guide recent legislative efforts in tobacco control (i.e., Family Smoking Prevention and Tobacco Control Act, 2009). This project is consistent with NCI's Areas of Intensified Scientific Investigation (Connecting the Nation's Cancer Community: An Annual Plan and Budget Proposal for FY2011) to support the U.S. FDA's regulation of tobacco products by developing methods and measures for determining the impact of product ingredient changes. In this case, user-initiated modifications to reduce exposure to harmful ingredients in cigarillo smoke. This proposal uses a combination of newly-developed, analytical laboratory and clinical methods to address an emerging tobacco use phenomenon. PUBLIC HEALTH RELEVANCE: Public health experts call for us to remain vigilant and responsive to emerging trends in cigar use. Increasingly, young adults are smoking a type of cigar known as cigarillos, due to, in large part, the availability of enticing flavors and its flexbility as an easily modified product. A comprehensive clinical evaluation of cigarillos and their modified forms of use can help policymakers and healthcare providers address this emerging health threat in an informed manner.

Address; Attitude; Belief; Cigarette; Communities; Consultations; Data; design; Development; Electronics; Ensure; Evaluation; experience; flexibility; Funding; Goals; Grant; Health; Human; In Vitro; innovation; Internet; Lead; Leadership; Marketing; Measures; meetings; Methods; Mission; Modeling; Monitor; novel; Oral; Oral Tobacco; Peer Review; Performance; Pilot Projects; Population; Process; programs; Publications; Qualitative Methods; Regulation; Reporting; Research; Research Personnel; Research Proposals; Risk; Science; sound; success; symposium; System; Time; Tobacco; Tobacco Industry; tool; toxicant; United States National Institutes of Health; Universities; Virginia;

Academia; addiction; Alcohols; Area; authority; base; career; career development; Clinic; Collaborations; cost; Data Analyses; Data Collection; Development; Educational process of instructing; Enrollment; Evaluation; evidence base; experience; Faculty; Fellowship Program; Government; graduate student; Grant; Health Psychology; Industry; Institutes; interest; International; Laws; Learning; Manuscripts; meetings; Mentors; Methods; Mission; Paper; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Play; Postdoctoral Fellow; pre-doctoral; Preparation; programs; Public Health; Recording of previous events; Regulation; Reporting; Research; Research Methodology; Research Personnel; Research Project Grants; Research Training; Role; Science; Scientist; Series; Students; Substance abuse problem; Sum; Tobacco; Training; Training and Education; Training Programs; Training Support; United States National Institutes of Health; Vision; Work; Writing;

Adverse effects; Adverse event; Attitude; base; Behavior; Belief; Categories; Cigarette; Cigarette Smoker; Cluster Analysis; Complement; Confidence Intervals; Consumption; Data; Data Sources; Dose; Electronics; Elements; Evaluation; Goals; Human; Individual; innovation; Internet; Liquid substance; Maps; Marketing; Methods; Modeling; Motivation; Nicotine; novel; Pattern; population based; Prevalence; Procedures; Process; Qualitative Methods; Randomized Controlled Trials; Recording of previous events; Recruitment Activity; Regulation; Research; response; Risk; Sampling; Science; Smoking; Sorting - Cell Movement; Source; Staging; Subgroup; Sum; Surveys; Text; Tobacco; Tobacco use; tool; Variant; Work;

Abstinence; Address; Adverse event; Air; base; Biochemical; Biological Markers; blind; Blood Pressure; Breathing; Carbon Monoxide; carcinogenicity; Cigarette; Cigarette Smoker; cigarette smoking; Cotinine; Data; Devices; Disease; disorder risk; Dose; Effectiveness; Electronic cigarette; Evaluation; Exhalation; Exposure to; Eye; Glutathione; Goals; Health; Heart; Heart Rate; Hematocrit procedure; Hemoglobin; Human; indexing; interest; Lipoproteins; Measures; Methods; Modeling; Monitor; Nausea; Nicotine; Nitrosamines; novel; Outcome Measure; Oxidative Stress; Participant; Persons; Pharyngeal structure; Placebo Effect; Placebos; Propylene Glycols; pulmonary function; Qualitative Methods; Randomized Controlled Trials; Recruitment Activity; Regulation; Reporting; Research; Risk; Role; Safety; Science; Self Administration; Smoke; Spirometry; standard measure; Symptoms; System; Telephone; Text; Tobacco; tobacco abstinence; Tobacco use; tool; toxicant; Toxicant exposure; Urine; Xerostomia;

Abstinence; base; Behavior; behavior influence; Behavioral; behavioral response; Cigarette; Cigarette Smoker; Data; Dose; Effectiveness; Electronic cigarette; Evaluation; experience; Goals; Human; Inhalators; innovation; Investigation; Laboratory Study; Learning; Liquid substance; Marketing; Measurement; Measures; Methodology; Methods; Modeling; Nicotine; Nicotine Inhaler; novel; Participant; Pharmacologic Substance; Physiological; Population; post-market; Procedures; Qualitative Methods; Randomized Controlled Trials; Recording of previous events; Regulation; Risk; Safety; Science; Smoking; Study Subject; success; Sum; Symptoms; Technology; Testing; Therapeutic; Time; Tobacco; tobacco abstinence; tool; toxicant; Toxicant exposure;

Affect; analytical tool; base; Behavior; behavior influence; Blood; Breathing; Chemicals; Data; design; disorder risk; Dose; Effectiveness; Electronic cigarette; Engineering; Evaluation; experience; Goals; hookah; Human; innovation; Life; Liquid substance; Marketing; mathematical model; Measurement; Measures; Methods; Modeling; Nicotine; novel; Physiological; post-market; pre-clinical; Qualitative Methods; Randomized Controlled Trials; Regulation; research clinical testing; Risk; Safety; Science; screening; Smoking; Sum; Testing; Tobacco; tobacco tar; tool; toxicant; Toxicant exposure; Work;

DESCRIPTION (provided by applicant): The U.S. tobacco marketplace is changing fast, and regulatory science lags far behind. The FDA can alter this dynamic, but needs the tools to do so. One necessary tool is a model for evaluating all types of modified risk tobacco products (MRTPs): novel tobacco products marketed with the claim that they reduce harm or risk associated with conventional products. There are few demonstrated models for predicting tobacco product harm or risk, which demands an understanding of MRTP constituents using analytic lab methods, toxicant exposure and abuse liability using human lab methods, longer-term effects using randomized control trial (RCT) methods, and attitudes, beliefs, and perceived effects using quantitative and qualitative methods. The overarching goal of the Center for the Study of Tobacco Products is to demonstrate empirically an integrated, iterative MRTP evaluation model that uses all of these methods to inform tobacco product regulation across all product types (combustible, oral, or vapor). The Center unites NIH-funded scientist/educators from multiple disciplines to demonstrate the transdisciplinary MRTP evaluation model. We begin with an evaluation of electronic cigarettes (EClGs), novel tobacco products that are marketed now and increasingly popular. EClGs offer an opportunity to demonstrate how the model we propose can inform regulatory policy. To meet the Center's overarching goal we describe four integrated, multi-year projects that aim to: 1) Examine factors that influence MRTP nicotine and toxicant yield; 2) Compare short-term effects of MRTPs to other products in the human lab; 3) Characterize effects of real-world MRTP use in the natural environment using RCT methods; and 4) Study the influence MRTP use and misuse on user attitudes, beliefs, and perceived effects using qualitative and quantitative methods. An Administrative Core will facilitate financia and managerial processes, provide data management and biostatistical support, co-ordinate communication within and across centers, and interface with scientists and policymakers. A Training and Education Core will develop a course on transdisciplinary methods for evaluating products and will support up to 4 pre-doctoral and 4 postdoctoral appointees. Finally, a pilot research program will solicit and fund innovative projects from our Virginia-wide network of scientists and respond to emerging products of any type. The Center is thus structured to address FDA needs and operate collaboratively. Overall, this Center will provide the expertise, innovation, infrastructure, and information necessary for the sustained success of FDA's mandate to regulate novel tobacco products, including MRTPs. RELEVANCE: This Center is designed to inform tobacco regulatory science and thereby contribute to public health. The four projects will answer important questions about electronic cigarettes while giving the Food and Drug Administration an empirical demonstration of a transdisciplinary, integrated, iterative, MRTP evaluation model. The Center thus provides FDA necessary scientific tools to ensure that only those novel tobacco products that have positive public health effects are marketed.

Address; Benchmarking; Collaborations; Communication; Communities; data management; Databases; Decision Making; design; Discipline; Educational Activities; Educational process of instructing; Electronic cigarette; Ensure; Evaluation; experience; Fostering; Funding; Goals; Institutional Review Boards; interdisciplinary collaboration; Internet; investigator training; Knowledge; Lead; Leadership; meetings; Methods; Modeling; Monitor; Nicotine; novel; Participant; Pattern; Process; programs; Progress Reports; Proliferating; Protocols documentation; Public Health; Public Policy; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Research Training; Resource Sharing; Science; Scientist; screening; Secure; Series; sharing data; Structure; success; Sum; symposium; Techniques; Tobacco; Toxicant exposure; Training; United States National Institutes of Health; Work;

Project Summary. The Center for the Study of Tobacco Products (CSTP) aims to build upon previous successful work on tobacco product evaluation by moving to an integrative theme of impact analysis. The rationale for this effort is that it will provide a transdisciplinary model with which empirical data from several domains can help FDA to predict the extent to which potential tobacco product regulation is likely to meet the mandated ?public health standard?. The CSTP?s vision is to provide tools that can be used to guide regulation development so that, by the time a regulation goes into effect, validated methods have been used to test it, refine it, and generate data showing that its health-promoting effects are maximized and that any harmful, unintended consequences are minimized. To realize this vision, the CSTP builds on an existing team of scientists and educators from multiple disciplines to conduct hypothesis-driven research and test population- level predictions. A Center with a complex collaborative and transdisciplinary research vision requires a strong administrative structure to support it. Thus, the specific aims of the Administrative Core are to: (1) facilitate financial and managerial processes, (2) establish mechanisms for evaluation of progress (3) foster intra-, inter-, and extra-Center collaboration, (4) disseminate results to FDA, NIH, and other scientists and policymakers (5) provide centralized recruitment, data management, biostatistical, and participant protections support, and (6) respond rapidly to regulatory needs. In sum, the Administrative Core will continue to serve and strengthen the CSTP by reducing management burden; tracking benchmarks of project and Center success; integrating investigators, appointees, and non-center scientists into CSTP activities; ensuring knowledge transfer to the public, scientific, and decision-making communities; providing recruitment support and biostatistical expertise; and responding rapidly to FDA needs. The Administrative Core is led by a team with a proven track record in transdisciplinary collaboration, project management, reporting, communication and dissemination.

ABSTRACT Since their introduction to the United States (US), the prevalence of electronic cigarettes (ECIGs) has risen markedly. In 2016, rates of use among high school students was estimated to be 11% and 3.2% among adults. There is considerable heterogeneity in ECIGs, but common to most is that they use an electrically-powered heater to aerosolize a liquid usually (though not always) containing nicotine, a solvent (e.g., propylene glycol and/or vegetable glycerin), and flavorants. The power (Watts=V2/?) of the ECIG device, which is based on the device?s operating voltage (V) and heater resistance (Ohms or ?), is a major determinant of how much nicotine or other toxicants are aerosolized. Recent population based surveys are providing insight into ECIG use patterns, but there are significant gaps in our understanding of ECIG behavioral and health effects. Many surveys are producing mixed results with respect to whether or not ECIGs aid in smoking cessation efforts or if there are potential harmful health effects of ECIG use. Heterogeneity in ECIG products that include low power disposable devices, higher power modular devices, and newer ?pod mods? such as JUUL, leads to difficulty in assessing device characteristics with self-report surveys and may contribute to these mixed and inconclusive findings. Recent data from our group shows that users of ECIGs are not able to report the power of their device accurately. As noted in RFA-OD-18-003, studies are needed to determine ?how product design characteristics (and changes in those characteristics) impact constituent exposures and toxicities from tobacco products.? The premise of this application rests on a growing consensus in the field that in order to inform policy, regulation, and the public health impact of ECIG use, researchers must improve methods to quantify ECIG device characteristics and how much ECIG liquid is ingested. In order to advance research in this area, we propose the development of a novel tool to assess ECIG power objectively in real-world settings. We propose adapting a method being used in the field of dietary assessment whereby pictures of food are evaluated to measure food intake and the nutritional quality of the diet. We will apply this methodology to assess ECIG device characteristics and liquids. Using an iterative design and evaluation process, we will develop a smartphone app (SmartVape) designed for an ECIG user to capture an image of their device and their liquid(s). On a back-end server, an operator will be able to compare these images to an image-based product registry with known data on device characteristics and ECIG liquid nicotine content. The result will be the ability to assess accurately the ECIG device being used and the amount of liquids being consumed over a discrete period of time. With this information, we will be able to estimate nicotine intake more accurately from ECIGs in real-world settings. Successful completion of the aims will move the field forward significantly as it would provide a feasible and objective method for assessing heterogeneity in ECIG device characteristics in surveillance research and offer an innovative method to remotely quantify ECIG liquid intake, both of which are barriers that hinder our understanding of the toxicity of ECIG use.

Project Summary. The Center for the Study of Tobacco Products (CSTP) has developed a model for evaluating novel tobacco products using, as exemplars, electronic cigarettes (ECIGs) that heat a liquid that often contains nicotine, forming an aerosol that users inhale. Now, CSTP leverages its methodological and ECIG expertise to pivot from product evaluation to an integrative theme of impact analysis. FDA tobacco regulation must protect public health, though regulations may also have unintended consequences that cause harm. For example, limiting ECIG liquid nicotine content, as in the European Union, can drive use of higher power ECIGs that aerosolize more liquid, leading users to inhale more nicotine and other toxicants. Other potential ECIG regulations involve constraining amount of nicotine emitted/unit time (nicotine ?flux?) that may influence product toxicity and abuse liability, or reducing flavor availability that may lead users to mix their own flavored liquids. If FDA could predict a potential regulation?s effects, then refinements before the regulation is issued might maximize its health-promoting effects and minimize unintended consequences. Methods exist for assessing a regulation?s effects once it is in place, but few data-driven models predict impact beforehand. Any such model must draw from several domains to assess how a potential regulation might change product toxicity, user behavior, and addiction/abuse liability. Also, the model must demonstrate the extent to which predictions about potential regulatory effects describe actual population-level outcomes. CSTP addresses this issue with this application: Projects 1-3 will test hypotheses and generate predictions regarding the impact of three potential ECIG regulations (i.e., limit nicotine, constrain flux, reduce flavor availability); Project 4 will test these predictions at the population level. CSTP?s vision is to provide tools to guide regulation development so that, by the time a regulation goes into effect, validated methods have tested it, refined it, and generated data showing that its health-promoting effects are maximized and unintended consequences minimized. The team (Drs. Eissenberg, Breland, Shihadeh, Cobb, Barnes, Cohen, Fagan) will complete 4 integrated projects that aim to: predict product toxicity, predict user behavior, predict abuse liability, and assess potential regulation impact. A Contextual Knowledge Core uses mixed methods to ensure Projects 1-4 reflect the real world. A Career Enhancement Core conducts a tobacco regulatory science course, supports pre- and post- doctoral appointees, and pilot projects. An Administrative Core supports financial/managerial processes, biostatistical needs, receives input from an External Advisory Board, and interfaces with FDA, NIH, and others. Overall, CSTP?s integrative theme of impact analysis draws on the team?s expertise in tobacco product toxicity, user behavior, and abuse liability. We seek to provide FDA with hypothesis-driven data regarding advanced generation ECIGs and test predictions about some potential regulations now, while developing a model that can be used to shape, refine, and predict the effects of many potential regulatory actions in the future.