Tobacco Center of Regulatory Science: Improved Models to Inform Tobacco Product Regulation

Professor of Medicine

The UCSF Center for Tobacco Control Research and Education is home to one of 14 Tobacco Centers of Regulatory Science (TCORS) funded as part of a first-of-its-kind tobacco science regulatory program by the U.S. Food and Drug Administration and the National Institutes of Health.  CTCRE Director Professor Stanton Glantz  is Principal Investigator for this 4 year $20 million project.

The overarching theme of this Tobacco Center of Regulatory Science is the development of improved
models to inform tobacco product regulatory strategies that integrate 1) economic impacts of tobacco use on health costs, 2) risk perceptions, perceived acceptability, consumer responses to pro-tobacco marketing and anti-tobacco messages and other social determinants of tobacco use, and 3) rapid changes in risk due to tobacco use and secondhand smoke exposure as manifest in cardiovascular and pulmonary dysfunction.

This TCORS includes five full projects (one on economic models, two on behavioral models, and two on
cardiovascular and pulmonary disease models), two developmental projects (one on behavioral models and one on cardiovascular and pulmonary disease models), three Cores (Administrative, Informatics and
Analytics, and Biomarker), a postdoctoral training program and a process for selecting future developmental projects.

 The results will inform FDA regulation of the manufacture, distribution and marketing of tobacco products by providing an improved scientific framework in which to evaluate the likely effects of specific regulatory strategies by developing

1) improved economic models for analysis of proposed regulations that account for short-term as well as long-term effects of tobacco use,

2) better understanding of behavioral and social determinants of tobacco use (including perception of risk and decision making processes) to inform the economic models, regulation of marketing, and public education about risks of tobacco products, and

 3) functional biomarkers of acute cardiopulmonary responses to tobacco use and secondhand smoke that may predict future disease and also support development of improved economic models.

In particular, these improved economic models will integrate the rapid changes in risk due to reductions in cardiovascular and pulmonary diseases which would be expected to result from FDA regulatory decisions.

Stanton Glantz, PhD
Improved Models to Inform Tobacco Product Regulation

The overarching theme of this Tobacco Center of Regulatory Science <<Link this to the TCORS page>>  is the development of improved models to inform tobacco product regulatory strategies that integrate 1) economic impacts of tobacco use on health costs, 2) risk perceptions, perceived acceptability, consumer responses to pro-tobacco marketing and anti-tobacco messages and other social determinants of tobacco use, and 3) rapid changes in risk due to tobacco use and secondhand smoke exposure as manifest in cardiovascular and pulmonary dysfunction.

Wendy Max, PhD and Hai-Yen Sung, PhD
Project 1: The Impact of Changing Tobacco Product Use on Tobacco‐Related Disease and Healthcare Costs

An important component of any regulation of tobacco products the FDA issues is an economic analysis of the regulation. Models of the health-related economic costs of cigarette smoking have evolved and improved over the years, and current models take into account the complex relationship between smoking, health, and healthcare expenditures. However, there is a lack of research on healthcare costs attributable to the use of tobacco products other than cigarettes. It is important to have this information given the increased rates at which non-cigarette products are being used. To fill this gap, we propose to develop models to estimate the healthcare costs (i.e. healthcare expenditures) resulting from the use of different tobacco products, including cigars, moist snuff, chewing tobacco, menthol and non-menthol cigarettes, combinations of these products, and secondhand smoke exposure. Specifically, we plan to use individual level data from national surveys to 1) develop microeconomic models to estimate the healthcare costs attributable to the use of different tobacco products to determine whether the kind of product substantially affects costs and 2) develop microeconomic models to estimate the healthcare costs attributable to secondhand smoke exposure. These models will allow us to evaluate the impact of potential FDA regulations on healthcare costs through the projected changes in tobacco product use and secondhand smoke exposure using three alternative approaches (time series analysis with data from national surveys, longitudinal model analysis with the PATH data, and simulated changes in tobacco product use prevalence) and through incorporating mathematical simulation models of short-term risks of pulmonary and cardiovascular diseases. Our models will incorporate findings from other TCORS projects, including the impact of risk perception on use of different tobacco products  among young adults and older adults, and studies of the effects of tobacco products on lung injury and cardiovascular disease in the short-term. Having better models of the cost of smoking and models of costs associated with the use of other tobacco products will be useful for the regulation of tobacco products because policy analysis needs to consider the impact of regulations on tobacco consumption as well as costs.

Bonnie Halpern-Felsher, PhD and Pam Ling, MD
Project 2:  The Role of Risk and Benefit Perceptions in Tobacco Control and Product Usage

Tobacco companies have developed and implemented advertising and marketing efforts to reduce
perceptions of harm associated with tobacco use, increase perceptions that tobacco is socially acceptable, and encourage and sustain use of tobacco. Many marketing strategies have particularly focused on adolescents and young adults. There are gaps in the science concerning 1) how perceptions influence tobacco use among adolescents and young adults, including changes in patterns of tobacco use from initiation to regular use, cessation, relapse, product switching, or dual use; 2) the role of pro- and anti-tobacco messages on perceptions of new tobacco products such as e-cigarettes, cigarillos, smokeless tobacco, snus, dissolvables, compressed tobacco, and emerging products that come on the market during the course of this research; and 3) the specific mechanisms by which marketing messages change tobacco-related perceptions, perceived acceptability of the product, and tobacco use behaviors. Prospective, longitudinal studies using frequent assessments and comprehensive measures of tobacco use, perceptions and marketing are needed to provide specific scientific evidence about how marketing shapes decisions to use and stop using different tobacco products. This information will inform FDA regulation of the marketing and promotion of conventional, new, and emerging tobacco products. This study will fill gaps in the science base by developing and testing a comprehensive model concerning the relationships among pro- and anti-tobacco marketing messages, perceptions of tobacco risks and benefits, perceived product acceptability, and patterns of tobacco use among adolescents and young adults. We will address these gaps and develop and test our model by using a longitudinal cohort design with a sample of 1,000 ninth graders followed through high school and another sample of 1,000 twelfth graders followed into young adulthood to 1) determine adolescents’ and young adults’ perceptions of risk for disease, addiction, and death; acceptability; and benefits of using conventional, new, and emerging tobacco products that come on the market during the course of this research; 2) determine the predictive relationships among perceptions of tobacco-related risks, benefits, and acceptability of tobacco products, and the onset, continuation, cessation, relapse, switching, and dual use of tobacco products; and 3) identify contextual factors (exposure to pro-tobacco media, anti-tobacco media, warning labels, and smoking images in the media and on the Internet) that influence perceptions of risks, benefits, acceptability, and subsequent tobacco use.

Margaret Walsh, EdD, Neal Benowitz, MD, and  Stuart Gansky, DrPH, MS
Project 3:  Tobacco Use among Rural High School Males and Associated Nicotine and Carcinogen Exposure

 
Unlike smoking, conventional smokeless tobacco (ST) use (moist snuff, known as dip and chewing tobacco) among US high school students is much higher among males (13%) than females (2%) and is especially high in rural areas. Among rural high school male athletes and smokers, smokeless tobacco use ranges from 18% to 42%. In 2005, ST manufacturers spent over $250M on marketing, including “new” ST products such as dissolvable films, compressed tobacco (e.g. tablets and toothpick-like sticks), and snus products, modeled after Swedish snus, a relatively low-tobacco carcinogen and high-nicotine-content moist snuff. Between 2006 and 2008, Reynolds American and Philip Morris/Altria bought ST companies and started aggressively promoting new ST line extensions of their flagship Camel and Marlboro cigarette brands (e.g. Camel Snus, Camel Orbs and Camel Sticks, and Marlboro Snus). Expanded promotion of conventional, new, and emerging ST products may encourage increased ST use and dual use with cigarettes among adolescent males. No data exist on the addictive potential or nicotine and carcinogen exposure in adolescents using new ST products alone, or in dual use with cigarettes. We propose a clustered longitudinal observational study of adolescent male athletes to better understand cognitive and social determinants of conventional and new ST product use, their dual use with cigarettes, and the impact of exposure to ST marketing and anti-tobacco messages (e.g. graphic warning labels) on risk and benefit perceptions, change in ST use status (experimentation, initiation, relapse, switching, and cessation) and actual exposure to nicotine and carcinogens over time in rural high school males. Specifically, we propose to 1) measure patterns and determinants of conventional and new ST product use and dual use with cigarettes over time; 2) measure tobacco marketing and anti-tobacco message exposure and their association with ST use, perceived risks and benefits of use, and future expectations of conventional and new ST product use and dual use with cigarettes over time; 3) evaluate nicotine and carcinogen exposure and their association with the rate of nicotine metabolism in conventional and new ST product users, and users of multiple forms of tobacco; and 4) identify factors in addition to product type and brand that predict nicotine and carcinogen exposure (e.g. measures of risk and benefit perception and nicotine metabolism rate).

Carolyn Calfee, MD and Michael Matthay, MD
Project 4: Quantification and Biomarkers of Short‐Term Pulmonary Effects of Tobacco Smoke Exposure:  Infection‐Related Acute Lung Injury

The health consequences of smoking are primarily perceived to be cancer, cardiovascular disease, and chronic pulmonary disease, but acute pulmonary consequences of exposure to cigarette smoke are likely to be as or more important with respect to overall morbidity and mortality from smoking. However, there has been little research on smoking and acute lung injury (ALI), a common cause of acute respiratory failure in critically ill patients. Cigarette smoking and secondhand smoke exposure are associated with a nearly threefold increase in the odds of developing ALI after severe blunt trauma, but the effects of cigarette smoke exposure on susceptibility to infection-associated ALI, the most common type of ALI, are unknown. This project will increase our understanding of the adverse health consequences of tobacco use by quantifying the increased susceptibility to infection-related ALI. Understanding the impact of smoking and secondhand smoke exposure on infection-related ALI will have major implications for the regulation of tobacco products because of the large immediate cost burden of ALI and the potentially rapid impact of changes in cigarette smoke exposure on the incidence of ALI and its associated mortality burden and costs. We hypothesize that cigarette smoke exposure before infection primes patients to develop acute respiratory failure from ALI. We will leverage the infrastructure of our ongoing prospective cohort of critically ill patients with severe infection
and our experience with animal models of ALI and cigarette smoke exposure to 1) quantify the strength, dose-response curve, and time course of the association between cigarette smoke exposure, as  measured by validated biomarkers, and the development of ALI in patients admitted to the hospital with severe infection; 2) test the effects of cigarette smoke exposure and varying nicotine content on the development of infection-related ALI in mouse models, with a focus on identifying plasma biomarkers of tobacco-related lung epithelial or endothelial injury that can then be tested in critically ill patients; and 3) validate the association between biomarkers of tobacco-related lung epithelial and endothelial injury and the development of ALI in critically ill human subjects with severe infection. The results of this project will inform more accurate models of the economic and public health effects of cigarette smoke exposure. This project will also identify biomarkers of tobacco-related lung injury that can be used in future studies of toxicity and take the critical first steps towards determining which constituents of tobacco smoke promote lung injury, including studies of the roles of nicotine and acrolein in tobacco smoke toxicity, with important regulatory implications.

Peter Ganz, MD, and Suzaynn Schick, PhD
Project 5: Cardiovascular Assessment of the Effects of Tobacco and Nicotine-Delivery Products

Cigarette smoking continues to be a major cause of cardiovascular disease (CVD). In contrast, the cardiovascular risks of other tobacco products in common use (smokeless tobacco) and new tobacco products (e-cigarettes) are not adequately understood. The FDA will need information about the cardiovascular safety of these products to inform their regulatory  decisions. While long-term clinical outcome studies that investigate the cardiovascular risks of tobacco products would be optimal, they take too long to provide the data that the FDA needs now. Disturbances in the function of vascular endothelium (the lining of arteries, which plays an important role in regulating vascular function), in the activation of the autonomic nervous system and increased inflammation, oxidative stress and propensity to thrombosis (clotting) are key mechanisms in the progression of CVD and provide useful and validated biomarkers of CVD risk. These biomarkers form the basis for our model to assess the CVD risks of tobacco product use and secondhand smoke exposure. We will conduct controlled, short-term exposures of human subjects to test products that provide a wide range of nicotine, particle and other cardiovascular toxin concentrations to determine how these components associated with tobacco use adversely affect cardiovascular risk. Specifically, we will 1) determine the relative contributions of nicotine and combustion products to the cardiovascular risk of active cigarette smoking; 2) determine which cardiovascular risk biomarkers are affected by exposure to low concentrations of secondhand smoke; 3) determine the cardiovascular risk of smokeless tobacco use; and 4) determine the cardiovascular risk of electronic cigarettes and the respective contributions of nicotine and electronic cigarette vapor. By quantifying and comparing the immediate effects of 4 different kinds of tobacco products on the cardiovascular system, Project 5 will validate a sensitive and practical panel of physiological and molecular biomarkers that predict cardiovascular disease and will be of great use in premarket human testing of tobacco products.

Janine Cataldo, PhD, RN
Developmental Project 1: Risk and Benefit Perceptions in the Use of Conventional and Emerging Tobacco Products among Older Smokers

The absolute negative health burden from smoking is greatest for adults over age 55. Older adults (>45) are growing in number and are the least likely to quit of any age group, perhaps because they underestimate both the risks for smoking and the benefits of cessation.  While quitting smoking by age 50 halves the risk of lung cancer, and almost immediately decreases cardiovascular risk, older adults are often unaware of these benefits.  A primary reason for these misperceptions is the tobacco industry’s heavy targeting and promotional efforts directed at older smokers for both conventional and emerging tobacco products.  Tobacco industry marketing exposure distorts perceptions about the availability, use, and risks of tobacco.  Currently, there is an increase in tobacco industry advertising to encourage cigarette smokers to use smokeless tobacco and e-cigarettes in no-smoking areas and as an aid to decrease smoking.  While these  messages are likely to appeal strongly to older smokers,  most research on tobacco marketing, risk perception and smoking behavior has been done with adolescents and young adults. This developmental project will elucidate older adults’ risk perceptions of conventional, new and emerging tobacco products, and e-cigarettes, how these perceptions are affected by pro- and anti-tobacco messages, and how these perceptions affect tobacco use behaviors. The results will be important first steps to characterize the tobacco consumer decision making model as it applies to older adults, an important group with distinct motivations, influences, and economic impact.

Matthew Springer, PhD
Developmental Project 2: Development of a Low-Level Continuous Smoke Exposure System

This  project will lay the groundwork for important studies with relevance to FDA tobacco product regulation, including the FDA’s regulatory responsibility to consider effects of exposure to tobacco products on bystanders. We will do so by improving an existing cigarette smoke exposure system
to produce stable sidestream smoke at levels approximating real-world secondhand smoke (SHS) exposures. We developed methodology in living rats using ultrasound to measure flow-mediated dilation (FMD), an established human indicator of cardiovascular health that reflects vasodilation of an artery in response to changes in blood flow and is impaired by smoke in humans.  Rat studies have advantages over human studies of minimal inter-subject variability and the availability of tissues for analysis, yet our FMD approach still enables the same integrative physiology of human studies. We have used our current smoke exposure system, which delivers low but changing SHS concentrations, to show that even one minute of SHS exposure impairs FMD in rats. However, the decay in smoke concentration during the exposure period complicates interpretation of the dose-response. Improving our system to generate SHS at continuous stable levels will allow collection of better data to characterize the dose-response between SHS exposure and FMD, a functional biomarker, to assess cardiovascular toxicity of different inhaled tobacco products.