1

Introduction

TOBACCO HARM IN THE UNITED STATES

Smoking is the leading cause of preventable morbidity and mortality in the United States, contributing to approximately 443,000 premature deaths each year nationally (CDC, 2008). Cigarette smoking is the most common form of tobacco use; there are an estimated 46.6 million current adult smokers, and initial use of tobacco typically occurs in youth (CDC, 2010; HHS, 1994). Many of the approximately 1,000 adolescents who initiate smoking each day continue use to become regular adult smokers (SAMHSA, 2011).

Smoking-related disease causes more deaths than alcohol, illicit drug use, homicide, and suicide combined (Mokdad et al., 2004). In total, tobacco-related mortality amounts to approximately 5.1 million years of potential life lost per year (CDC, 2008). Lung cancer, ischemic heart disease, and chronic obstructive pulmonary disease (COPD) are the leading causes of smoking-attributable deaths (CDC, 2008). Smoking can also increase a person’s risk for stroke and other forms of cancers. A list of documented diseases and conditions that are caused by cigarette smoking can be found in Table 1-1. In total, cigarette smoking accounts for approximately 80 percent of deaths from COPD, and at least 30 percent of deaths due to cancers (CDC, 2008). Another 8.6 million smokers in the United States live with a smoking-attributable illness (CDC, 2009a). Smoking also imposes enormous costs on the U.S. health care system and economy, with an estimated $193 billion in losses due to health care costs and productivity losses per year (CDC, 2008).



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1 Introduction TOBACCO HARM IN THE UNITED STATES Smoking is the leading cause of preventable morbidity and mortality in the United States, contributing to approximately 443,000 premature deaths each year nationally (CDC, 2008). Cigarette smoking is the most common form of tobacco use; there are an estimated 46.6 million current adult smokers, and initial use of tobacco typically occurs in youth (CDC, 2010; HHS, 1994). Many of the approximately 1,000 adolescents who initiate smoking each day continue use to become regular adult smokers (SAMHSA, 2011). Smoking-related disease causes more deaths than alcohol, illicit drug use, homicide, and suicide combined (Mokdad et al., 2004). In total, tobacco-related mortality amounts to approximately 5.1 million years of potential life lost per year (CDC, 2008). Lung cancer, ischemic heart disease, and chronic obstructive pulmonary disease (COPD) are the lead - ing causes of smoking-attributable deaths (CDC, 2008). Smoking can also increase a person’s risk for stroke and other forms of cancers. A list of documented diseases and conditions that are caused by cigarette smok- ing can be found in Table 1-1. In total, cigarette smoking accounts for approximately 80 percent of deaths from COPD, and at least 30 percent of deaths due to cancers (CDC, 2008). Another 8.6 million smokers in the United States live with a smoking-attributable illness (CDC, 2009a). Smoking also imposes enormous costs on the U.S. health care system and economy, with an estimated $193 billion in losses due to health care costs and productivity losses per year (CDC, 2008). 21

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22 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS TABLE 1-1 Diseases and Conditions Caused by Active Cigarette Smokinga Disease Effects Tumor sites for which there is sufficient evidence: Malignant neoplasmsb • ral cavity O • ropharynx, nasopharynx, and hypopharynx O • esophagus (adenocarcinoma and squamous-cell carcinoma) O • tomach S • olorectum C • iver L • ancreas P • asal cavity and paranasal sinuses N • arynx L • ung L • terine cervix U • vary (mucinous) O • rinary bladder U • idney (body and pelvis) K • reter U • one marrow (myeloid leukaemia) B Tumor site for which there is limited evidence: • emale breast F Cardiovascular • oronary heart disease C diseases • erebrovascular disease C • therosclerosis A • ortic aneurysm A Respiratory • Chronic obstructive pulmonary disease (bronchitis, emphysema, diseases in chronic airway obstruction) adults • neumonia P • Premature onset of and an accelerated age-related decline in lung function • All major respiratory symptoms (e.g., coughing, phlegm, wheezing, dyspnea) • oor asthma control P Respiratory • mpaired lung growth I diseases in • Respiratory symptoms and asthma-related symptoms (e.g., wheezing) young people in childhood and adolescence • Early onset of lung function decline during late adolescence and early adulthood

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23 INTRODUCTION TABLE 1-1 Continued Disease Effects Reproductive • udden infant death syndrome S and perinatal • educed fertility in women R conditions • etal growth restriction F • ow birth weight L • remature rupture of the membranes P • lacenta previa P • lacental abruption P • reterm delivery and shortened gestation P • espiratory distress syndrome R Miscellaneous • ataracts C • ip fractures H • ow bone density L • eptic ulcer disease in persons who are Helicobacter pylori positive P • Diminished health status (i.e., increased absenteeism from work, increased use of medical care services) • Adverse surgical outcomes related to wound healing and respiratory complications SOURCE: a Modified from Giovino (2007). Reprinted from American Journal of Preventive Medicine, Vol 6, Supplement 1, Gary A. Giovino, The Tobacco Epidemic in the United States, S318-S326, Copyright 2007, with permission from Elsevier. b Data from Secretan et al. (2009). Cigarette smoking is harmful for nonusers as well. Secondhand smoke (also called environmental tobacco smoke, involuntary smoke, or passive smoke) is responsible for approximately 50,000 annual deaths, largely due to lung cancer, coronary heart disease, and sudden infant death syndrome (HHS, 2006). Other forms of tobacco use, such as smokeless tobacco products and cigars, also have harmful consequences. Smokeless tobacco use—primarily in the form of chewing tobacco and snuff—causes cancer of the oral cavity and pancreas and other oral health problems such as gum recession and leukoplakia (IARC, 2007). The United States faces particular challenges with youth smoking. Of the approximately 1 million people who start smoking regularly each year, 39.5 percent are under the age of 18 (SAMHSA, 2011). Like adult smokers, quit rates remain low in adolescent smokers (Mermelstein, 2003). It is estimated that 50 percent of those who start smoking in adolescence go on to smoke for 16 to 20 years (Pierce and Gilpin, 1996). Since the mid 1960s when smoking rates among adults in the United States peaked at more than 42 percent, efforts to reduce cigarette use have

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24 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS made significant progress (CDC, 1999). The current prevalence of cigarette use is 20.6 percent among adults and 19.5 percent in youth (CDC, 2010). These tobacco control efforts have been recognized by the Centers for Disease Control and Prevention (CDC) as a major public health achieve - ment, both of the 20th century and of the first decade of the 21st century (CDC, 2011a). Despite this improvement in the past half-century, however, progress has stalled in recent years. After substantial declines in adult smoking rates through the 1980s and 1990s, the rate of U.S. adult smokers has remained relatively static, from 20.9 percent in 2004 to 20.6 percent in 2009 (CDC, 2010). This lack of continued progress is also seen in youth smoking rates. Between 1997 and 2003, smoking prevalence among high school students declined substantially from 36.4 percent to 21.9 percent; this decline slowed from a youth smoking rate of 21.9 percent in 2003 to 19.5 percent in 2009 (CDC, 2011a). Current disparities in tobacco use patterns are another cause for con - cern; trends in smoking show higher tobacco use rates among certain ethnic and racial minority groups, persons with low socioeconomic status, sexual minorities, and people in the South and Midwest of the United States (CDC, 2011b; HHS, 1998). In spite of the well-established health risks for smoking and other forms of tobacco use, some individuals still choose to use tobacco for a number of potentially desired effects or outcomes. These effects or out- comes may range from perceived social benefits (Halpern-Felsher et al., 2004), to discrete physiological effects (Vezina et al., 2007), or even the mere enjoyment of the flavor and aroma of tobacco. Although the ultimate deci- sion of whether the benefits outweigh the risks is up to the individual, the committee firmly maintains that the individual and public health hazards of tobacco use far outweigh any potentially desired effects of tobacco use. HARM REDUCTION The concept of harm reduction informs the public health rationale for permitting the development and potential marketing of modified risk tobacco products (MRTPs). The basic premise of harm reduction is the continuation of a potentially hazardous or dangerous behavior, with the aim of decreasing the potentially adverse consequences of these behaviors (Marlatt, 2002). The reduced risk can be for either participants or non - participants of the potentially harmful activity. Harm reduction is most typically associated with illicit substance use, including opioid substitu - tion therapies, needle exchange programs, and supervised injecting sites. Harm reduction strategies can incorporate a wide spectrum of individual tactics, from safer use, to managed use, to complete abstinence from the risk behavior. In the context of tobacco harm reduction, “a product is

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25 INTRODUCTION harm reducing if it lowers total tobacco-related mortality and morbidity, even though use of that product may involve continued exposure to tobacco-related toxicants” (IOM, 2001). Modification of the risk profiles of tobacco products is only one of several potential tactics to reduce the harm of tobacco. In addition to preventing initiation of tobacco use and promoting cessation of tobacco use, MRTPs with reduced risk profiles may potentially lessen the harm of tobacco for the substantial portion of U.S. smokers who are unable or unwilling to abstain. Of the 46 million adult smokers in the United States, an estimated 70 percent of smokers wish to quit completely, and approximately 45 percent of smokers attempt to quit each year (CDC, 2002, 2009b). However, only approximately 6 percent of the smokers who attempt to quit are successful for 1 month or more (HHS, 2000). Tobacco harm reduction efforts target users that are unwilling or unable to quit as one component of a comprehensive, multifaceted strategy to minimize the negative health effects of tobacco use. In 2001 the Institute of Medicine (IOM) specifically addressed the potential of tobacco harm reduction in Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction. The report articulated six principle conclusions: 1. For many diseases attributable to tobacco use, reducing risk of disease by reducing exposure to tobacco toxicants is feasible. 2. PREPs1 have not yet been evaluated comprehensively enough (including for a sufficient time) to provide a scientific basis for conclud- ing that they are associated with a reduced risk of disease compared to conventional tobacco use. 3. Surrogate biological markers that are associated with tobacco- related diseases could be used to offer guidance as to whether or not PREPs are likely to be risk-reducing. 4. Currently available PREPs have been or could be demonstrated to reduce exposure to some of the toxicants in most conventional tobacco products. 5. Regulation of all tobacco products, including conventional tobacco products as recommended in IOM (1994), as well as all other PREPs is a necessary precondition for assuring a scientific basis for judging the effects of using PREPs and for assuring that the health of the public is protected. 6. The public health impact of PREPs is unknown. They are poten- tially beneficial, but the net impact on population health could, in fact, be negative. 1 PREPs or potential reduced-exposure products are defined in Box 1-2.

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26 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS In the report, the IOM also suggests a research agenda for evaluat- ing the potential for harm reduction of PREPs (IOM, 2001). Since the publication of Clearing the Smoke, significant advances have been made in the science of evaluating tobacco products (Carter et al., 2009; Cohen et al., 2009; Hatsukami et al., 2005, 2006, 2007, 2009; O’Connor et al., 2009; Shields, 2002). Also, in following the report’s conclusion that harm reduc - ing products might be possible, tobacco companies have developed a large number of PREPs. Several products remain on the market; however, no products have been proven to reduce harm or risk. HISTORY OF TOBACCO REGULATION IN THE UNITED STATES The Family Smoking Prevention and Tobacco Control Act of 2009 (FSPTCA)2 grants the Food and Drug Administration (FDA) broad author- ity to regulate the manufacturing, distribution, and marketing of tobacco products. This law marks an important turning point in the history of tobacco control in the United States. In fewer than 70 years, the profile of tobacco has changed from that of a popular luxury item associated with athletes, movie stars, and celebrities to that of a highly regulated public health hazard. However, despite decades of heightened concern and pub- lic awareness, smoking is still the leading cause of preventable death in the United States. Modern tobacco control began in the 1940s and 1950s with scientific and public health authorities establishing through emerging evidence that smoking causes disease. Prior to the 1940s, little existing evidence linked tobacco use to disease. As late as the 1950s, certain cigarettes were still mar- keted with explicitly positive health claims. The 2001 IOM report chronicled the early health claims of tobacco manufacturers in response to the health concerns of smokers (IOM, 2001). Evidence collected in the 1940s and 1950s confirmed the link between smoking and lung cancer. Landmark publications from Richard Doll and Austin Hill, and from Ernst Wynder and Evarts Ambrose Graham, pro- vided convincing evidence that smoking caused lung cancer (Doll and Hill, 1950, 1956; Wynder and Graham, 1950). In 1962, a report from the Royal College of Physicians of London reaffirmed findings that smoking significantly increased the risk of death from lung and heart disease (Royal College of Physicians, 1962). In 1964, the Surgeon General released a report that authoritatively linked smoking to lung cancer, cardiovascular disease, and emphysema (U.S. Public Health Service, 1964). 2 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat. 1776 (June 22, 2009).

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27 INTRODUCTION In addition to authoritatively linking smoking to disease, the Royal College of Physicians and the Surgeon General reports also directed the evidence to policy makers and the public with recommendations to reduce the harm of smoking. The Royal College report specifically recom- mended preventive measures including filtration of smoke, modifications of tobacco, and discouragement of smoking. The report also made specific recommendations for government action, including public education, taxation, and restrictions on advertisement and smoking in public places. In response to the Surgeon General’s report, which stated that “ciga- rette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial action” (U.S. Public Health Service, 1964), Congress passed the Federal Cigarette Labeling and Advertising Act of 1965 requiring that the statement “Caution: cigarette smoking may be hazardous to your health” be placed on every cigarette package. In 1970, Congress strengthened the regulation through the Public Health Cigarette Smoking Act, which banned cigarette advertisements on any medium of electronic communication subject to the jurisdiction of the Federal Trade Commission. In total between 1965 and 2000, Congress passed six pieces of legislation to address the harm of tobacco use, including • the Federal Cigarette Labeling and Advertising Act of 1965;3 • the Public Health Cigarette Smoking Act of 1970;4 • the Alcohol and Drug Abuse Amendments of 1983;5 • the Comprehensive Smoking Education Act of 1984;6 • the Comprehensive Smokeless Tobacco Health Education Act of 1986;7 and • the Alcohol, Drug Abuse, and Mental Health Administration Reor- ganization Act of 1992.8 Additional smoking-related regulations and interventions have fol- lowed, with the recognition of secondhand smoke as a serious public health hazard (IOM, 2010), including the restriction of smoking in govern- ment facilities and on all commercial U.S. airline flights. (See Table 1-2 for 3 Federal Cigarette Labeling and Advertising Act of 1965 , Public Law 89-92, 79 Stat. 282 (July 27, 1965). 4 Public Health Cigarette Smoking Act of 1970, Public Law 91-222, 84 Stat. 87 (April 1, 1970). 5 Alcohol and Drug Abuse Amendments of 1983, Public Law 98-24, 97 Stat. 175 (April 26, 1983). 6 Comprehensive Smoking Education Act of 1984, Public Law 98-474, 98 Stat. 2200, 98th Congress (October 12, 1984). 7 Comprehensive Smokeless Tobacco Health Education Act of 1986 , Public Law 99-252, 100 Stat. 30, 99th Congress (February 27, 1986). 8 Alcohol, Drug Abuse, and Mental Health Administration Reorganization Act of 1992 , Public Law 102-321, 106 Stat. 323, 102nd Congress (July 10, 1992).

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28 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS TABLE 1-2 Summary of Milestones in Decreasing Indoor Tobacco Smoke in the United States Year Event 1971 The Surgeon General proposes a federal smoking ban in public places. 1972 The first report of the Surgeon General to identify secondhand smoke as posing a health risk is released. 1973 Arizona becomes the first state to restrict smoking in several public places. The Civil Aeronautics Board requires no-smoking sections on all commercial airline flights. 1974 Connecticut passes the first state law to apply smoking restrictions in restaurants. 1975 Minnesota passes a statewide law restricting smoking in public places. 1977 Berkeley, California, becomes the first community to limit smoking in restaurants and other public places. 1983 San Francisco passes a law to place private workplaces under smoking restrictions. 1986 A report of the Surgeon General focuses entirely on the health consequences of involuntary smoking, proclaiming secondhand smoke a cause of lung cancer in healthy nonsmokers. The National Research Council issues a report on the health consequences of involuntary smoking. Americans for Nonsmokers’ Rights becomes a national group; it had formed as the California Group Against Smoking Pollution. 1987 The U.S. Department of Health and Human Services establishes a smoke-free environment in all its buildings, affecting 120,000 employees nationwide. Minnesota passes a law requiring all hospitals in the state to prohibit smoking by 1990. A Gallup poll finds, for the first time, that a majority (55 percent) of U.S. adults favor a complete ban on smoking in all public places. 1988 A congressionally mandated smoking ban takes effect on all domestic airline flights of 2 hours or less. New York City’s ordinance for clean indoor air takes effect; the ordinance bans or severely limits smoking in various public places and affects 7 million people. California implements a statewide ban on smoking aboard all commercial intrastate airplanes, trains, and buses. 1990 A congressionally mandated smoking ban takes effect on all domestic airline flights of 6 hours or less. The U.S. Environmental Protection Agency (EPA) issues a draft risk assessment of secondhand smoke.

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29 INTRODUCTION TABLE 1-2 Continued Year Event 1991 The National Institute for Occupational Safety and Health issues a bulletin recommending that secondhand smoke be reduced to the lowest feasible concentration in the workplace. 1992 Hospitals applying to the Joint Commission on Accreditation of Healthcare Organizations for accreditation are required to develop a policy prohibiting smoking by patients, visitors, employees, volunteers, and medical staff. The EPA releases its report classifying secondhand smoke as a group A carcinogen (known to be harmful to humans), placing secondhand smoke in the same category as asbestos, benzene, and radon. 1993 Los Angeles passes a ban on smoking in all restaurants. The U.S. Postal Service eliminates smoking in all facilities. Congress enacts a smoke- free policy for Special Supplemental Food Program for Women, Infants, and Children clinics. A working group of 16 state Attorneys General releases recommendations for establishing smoke-free policies in fast-food restaurants. Vermont bans smoking in all public buildings and in many private buildings open to the public. 1994 The U.S. Department of Defense prohibits smoking in all indoor military facilities. The Occupational Safety and Health Administration proposes a rule that would ban smoking in most U.S. workplaces. San Francisco passes a ban on smoking in all restaurants and workplaces. The Pro-Children Act requires persons who provide federally funded children’s services to prohibit smoking in their facilities. Utah enacts a law restricting smoking in most workplaces. 1995 New York City passes a comprehensive ordinance effectively banning smoking in most workplaces. Maryland enacts a smoke-free policy for all workplaces except hotels, bars, some restaurants, and private clubs. California passes comprehensive legislation that prohibits smoking in most enclosed workplaces. Vermont’s smoking ban is extended to include restaurants, bars, hotels, and motels except establishments holding a cabaret license. 1996 The U.S. Department of Transportation reports that about 80 percent of nonstop scheduled U.S. airline flights between the United States and foreign points will be smoke free by June 1, 1996. 1997 President Clinton signs an executive order establishing a smoke-free environment for federal employees and all members of the public visiting federally owned facilities. The California EPA issues a report determining that secondhand smoke is a toxic air contaminant. Settlement is reached in the class-action lawsuit brought by flight attendants exposed to secondhand smoke. continued

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30 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS TABLE 1-2 Continued Year Event 1998 The U.S. Senate ends smoking in the Senate’s public spaces. California law takes effect banning smoking in bars that do not have a separately ventilated smoking area. The Minnesota tobacco-document depository is created as a result of a tobacco-industry settlement with Minnesota and Blue Cross and Blue Shield of Minnesota. U.S. tobacco companies are required to maintain a public depository to house more than 32 million pages of previously secret internal tobacco industry documents. 2000 The New Jersey Supreme Court strikes down a local clean-indoor-air ordinance adopted by the city of Princeton on the grounds that state law preempts local smoking restrictions. A congressionally mandated smoking ban takes effect on all international flights departing from or arriving in the United States. 2002 New York City holds its first hearing on an indoor smoking ban that would include all bars and restaurants. The amended Clean Indoor Air Act enacted by the state of New York (Public Health Law, Article 13-E), which took effect July 24, 2003, prohibits smoking in virtually all workplaces, including restaurants and bars. The Michigan Supreme Court refuses to hear an appeal of lower-court rulings striking down a local clean-indoor- air ordinance enacted by the city of Marquette on the grounds that state law preempts local communities from adopting smoking restrictions in restaurants and bars that are more stringent than the state standard. Delaware enacts a comprehensive smoke-free law and repeals a preemption provision precluding communities from adopting local smoking restrictions that are more stringent than state law. Florida voters approve a ballot measure that amends the state constitution to require most workplaces and public places—with some exceptions, such as bars—to be smoke free. 2003 Dozens of U.S. airports—including airline clubs, passenger terminals, and nonpublic work areas—are designated as smoke free. Connecticut and New York enact comprehensive smoke-free laws. Maine enacts a law requiring bars, pool halls, and bingo venues to be smoke free. State supreme courts in Iowa and New Hampshire strike down local smoke-free ordinances, ruling that they are preempted by state law. 2004 Massachusetts and Rhode Island enact comprehensive smoke-free laws. The International Agency for Research on Cancer issues a new monograph identifying secondhand smoke as “carcinogenic to humans.” 2005 North Dakota, Vermont, Montana, and Washington enact 100 percent smoke-free workplace and/or restaurant and/or bar regulations. 2006 New Jersey, Colorado, Hawaii, Ohio, and Nevada enact 100 percent smoke- free workplace and/or restaurant and/or bar regulations. 2007 Louisiana, Arizona, New Mexico, New Hampshire, and Minnesota enact 100 percent smoke-free workplace and/or restaurant and/or bar regulations.

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31 INTRODUCTION TABLE 1-2 Continued Year Event 2008 Illinois, Maryland, Iowa, and Pennsylvania enact 100 percent smoke-free workplace and/or restaurant and/or bar regulations. 2009 Oregon and Nebraska enact 100 percent smoke-free workplace and/or restaurant and/or bar regulations. 2010 Wisconsin, Michigan, North Carolina, and Kansas enact 100 percent smoke- free workplace and/or restaurant and/or bar regulations. As of Across the United States, 21,875 municipalities are covered by a 100 percent Oct. 7, smoke-free provision in workplaces and/or restaurants and/or bars by a 2011 state, commonwealth, or local law; this represents 79.6 percent of the U.S. population. The District of Columbia and 39 states have local laws in effect that require 100 percent smoke-free workplaces and/or restaurants and/or bars. SOURCE: Derived from IOM (2010) with additional information from the American Non - smokers’ Rights Foundation (2011) and the Robert Wood Johnson Foundation (2011). a summary of significant milestones in addressing indoor tobacco smoke exposure in the United States.) In 1996, 13 years before the passage of the FSPTCA, the FDA unsuc- cessfully attempted to assert regulatory authority over tobacco. The FDA argued that tobacco products fell within its purview, claiming that nicotine is a drug, and that cigarettes and smokeless tobacco are combina- tion products that consist of the drug (nicotine) and device components intended to deliver nicotine to the body.9 Based on this framework, the FDA issued a regulation that included • prohibiting the sale of tobacco products to individuals under age 18; • prohibiting free samples and the sale of tobacco products through vending machines and self-service displays, except in facilities that ensure that no person under age 18 is present; • restricting advertising exposed to children and adolescents to black-and-white, text-only displays; • prohibiting billboards and outdoor advertising within 1,000 feet of schools and public playgrounds; • prohibiting the sale or distribution of brand identified promotional nontobacco items; and • prohibiting sponsorship of sporting and other events in the name of a product. 9 61 Federal Register 44396-45318; 21 CFR Parts 801, 803, 804, 807, 820, and 897.

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34 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS products (IOM, 2001). In 2007, an IOM report gave extensive and detailed recommendations for federal regulation, including the specific recom - mendation that “Congress should confer upon the FDA broad regula- tory authority over the manufacture, distribution, marketing, and use of tobacco products” (IOM, 2007). FSPTCA OVERVIEW The FSPTCA codified the recommendation from the 2007 IOM report, amending the Food, Drug and Cosmetic Act (FD&C Act) to grant the FDA broad authority to regulate tobacco products. Under the FSPTCA, a tobacco product is defined as “any product made or derived from tobacco that is intended for human consumption, including any compo- nent, part, or accessory of a tobacco product (except for raw materials other than tobacco used in manufacturing a component, part, or accessory of a tobacco product).” Under Section 301 of the FD&C Act, any adulter- ated or misbranded product is prohibited from being introduced into interstate commerce. Chapter IX articulates the definitions of adulterated or misbranded tobacco products. Among other things, Chapter IX gives the FDA authority to regulate the sale, distribution, labeling, and advertis- ing of tobacco products, to set product standards, and to require reporting and disclosure of tobacco product ingredients and components. SECTION 911 This report provides advice to the FDA on the minimum scientific standards for studies on MRTPs. Under Section 911 of the FSPTCA, the FDA is required to develop regulations or guidance, in consultation with the IOM, on the evidence that product sponsors should submit in filing an application to market an MRTP. This committee and the report adopt the definitions used in the legislation (see Box 1-2) and also take into account the regulatory framework established by the act in making any conclu - sions or recommendations. Pursuant to the FSPTCA, no MRTP may be marketed without an order for sale from the Secretary of the U.S. Department of Health and Human Services (HHS). Under the FSPTCA, an MRTP is defined as any tobacco product that is sold or distributed for use to reduce harm or the risk of tobacco-related disease. The FSPTCA also specifies that a product will be categorized as an MRTP, and therefore be regulated under Section 911, if any labeling or advertising represents implicitly or explicitly that a product is reduced in risk or harm, or is free of or contains a reduced amount of a substance. Furthermore, any action that a tobacco product sponsor takes directed toward consumers through the media that would

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35 INTRODUCTION be reasonably expected to result in consumers believing a product is reduced in risk or exposure, or contains a reduced amount of a substance, renders the product subject to regulation under Section 911. A product must also obtain FDA approval to market or advertise the product using descriptors such as light, low, mild, or other similar descriptors. Smokeless tobacco products are not considered an MRTP solely because they use the word smokeless or other similar descriptors; if the smokeless tobacco product sponsor wishes to make additional modified risk claims, then the product must first apply for this claim. A product that is intended for tobacco cessation that is regulated by Chapter V of the FD&C Act cannot be considered an MRTP (for further detail, see Box 1-2). To obtain an order for the sale of any new product, or for a new modified risk claim on an existing product, the manufacturer is required to submit an application to the FDA, which must include comprehensive documentation about the intended advertising and labeling, conditions of use, formulation, all documents relating to the product’s effect on health, and information on how consumers actually use the product. Under the FSPTCA the Secretary may only issue an order for the sale of an MRTP if the Secretary finds that the product that is the sub- ject of the application meets one of two public health standards: either (1) an empirically demonstrated Modified Risk claim or (2) a Special Rule for Certain Products claim, specifying a reduced exposure product. The determination of whether an order is granted under either the Modified Risk standard or the Special Rule for Certain Products must be based on scientific evidence submitted by the applicant. To issue an order pursuant to the Modified Risk standard, the Secre- tary must find that the applicant has demonstrated that the product, as actually used by consumers, will (1) significantly reduce harm and the risk of tobacco-related disease to individual tobacco users and (2) benefit the health of the population as a whole, taking into account both users and nonusers of the product. Under the Modified Risk standard, the orders expire after a time specified within the order. Under the Special Rule for Certain Products, the Secretary may issue an order for the sale of a reduced-exposure product for which there is inadequate long-term epidemiologic data to support a finding under the Modified Risk standard. The specific conditions that must be met for approval under the Special Rule for Certain Products are outlined in Section 911(g)(2). Orders granted under the Special Rule for Certain Products cannot last longer than 5 years. The law also specifies public health considerations that the Secretary must take into account when evaluating whether to issue an order, either under the Modified Risk standard or the Special Rule for Certain Prod- ucts. These considerations are outlined in Section 911(g)(4) and include

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36 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS BOX 1-2 Definitions and Historical Comparisons Definition of MRTP from FSPTCA Section 911, Subsection (b), “Definitions”: (1) MODIFIED RISK TOBACCO PRODUCT- The term “modified risk tobacco product” means any tobacco product that is sold or distributed for use to reduce harm or the risk of tobacco-related disease associated with commer- cially arketed tobacco products. m (2) SOLD OR DISTRIBUTED- (A) IN GENERAL- With respect to a tobacco product, the term “sold or distrib- uted for use to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products” means a tobacco product— (i) the label, labeling, or advertising of which represents explicitly or implicitly that— (I) the tobacco product presents a lower risk of tobacco-related dis- ease or is less harmful than one or more other commercially mar- keted tobacco products; (II) the tobacco product or its smoke contains a reduced level of a substance or presents a reduced exposure to a substance; or (III) the tobacco product or its smoke does not contain or is free of a substance; (ii) the label, labeling, or advertising of which uses the descriptors “light,” “mild,” or “low” or similar descriptors; or (iii) the tobacco product manufacturer of which has taken any action directed to consumers through the media or otherwise, other than by means of the tobacco product’s label, labeling, or advertising, after the date of enactment of the Family Smoking Prevention and Tobacco Con- trol Act, respecting the product that would be reasonably expected to result in consumers believing that the tobacco product or its smoke may present a lower risk of disease or is less harmful than one or more com- mercially marketed tobacco products, or presents a reduced exposure to, or does not contain or is free of, a substance or substances. (B) LIMITATION- No tobacco product shall be considered to be “sold or dis- tributed for use to reduce harm or the risk of tobacco-related disease associ- ated with commercially marketed tobacco products,” except as escribed d in subparagraph (A). (C) SMOKELESS TOBACCO PRODUCT- No smokeless tobacco product shall be considered to be “sold or distributed for use to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products” solely because its label, labeling, or advertising uses the following phrases to describe such product and its use: “smokeless

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37 INTRODUCTION tobacco,” “smokeless tobacco product,” “not consumed by smoking,” “does not produce smoke,” “smokefree,” “smoke-free,” “without smoke,” “no smoke,” or “not smoke.”* From Subsection (c), “Tobacco Dependence Products”: A product that is intended to be used for the treatment of tobacco dependence, including smoking cessation, is not a modified risk tobacco product under this section if it has been approved as a drug or device by the Food and Drug A dministration and is subject to the requirements of Chapter V. From Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction: The etymology of the term “Potential reduced-exposure products” or “PREP”: Many tobacco and cigarette-like products have been introduced in the distant and recent past that do, under measurement systems such as the smoking machine, result in decreased emission of some toxicants compared to conventional prod- ucts. These products could, therefore, potentially, results in reduced exposure to toxicants. The committee uses “potentially,” because whether exposure to tobacco toxicants is reduced depends on the user’s behavior, such as frequency and intensity of use. Reduced exposure, however, does not necessarily assure reduced risk to the user or reduced harm to the population. Therefore, and in order to avoid misinterpretation, the committee will use the generic phrase “potential reduced-exposure products,” or PREPs, when discussing modified tobacco products, cigarette-like products (whether tobacco containing or not) developed for their tobacco harm reduction potential (IOM, 2001). Comparison of “PREPs” and “MRTPs”: The term PREPs is not used by the committee and will not be included in this report. The term “PREPs” was coined in Clearing the Smoke to describe a cat- egory of products that theoretically could be used for tobacco harm reduction. While the term “PREPs” has been adopted within the academic literature fol- lowing Clearing the Smoke, the passing of the FSPTCA has created a statutory definition that relates to PREPs. PREPs might be understood as a category of potential MRTPs that have not yet been shown to reduce exposure or risk. The task of this committee is essentially to advise the FDA in identifying scientific standards for studies to produce evidence showing that a PREP actually does reduce exposure, harm to users, and can protect public health. An MRTP may be thought of as a PREP that has been validated according to standards set in the FSPTCA and by the judgment of the FDA. * It should be noted that some products, including some existing smokeless tobacco products, may be marketed without an order if they do not make a reduced risk or exposure claim. Products that do not make a claim or representation of reduced risk or exposure are not subject to regulation under section 911, and are not addressed in this report.

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38 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS the health risks to individual current users, the likelihood that users will quit or that nonusers will start using the product, and the risks compared to cessation products. If an order is approved, product sponsors are required to comply with certain conditions for marketing, as well as requirements to conduct post- market surveillance and studies of the product to determine the impact of the order on consumer perception, behavior, and health. Results of the postmarket surveillance and studies must be submitted to the Secretary annually. Additionally, the Secretary can withdraw authorization, after an opportunity for hearing, if the product sponsors either fail to fulfill their obligations under the law, or if new evidence demonstrates that market - ing of the product is not consistent with protecting the public’s health. COMPARISON OF REGULATORY FRAMEWORKS The statutory framework established by the FSPTCA for regulation of MRTPs shares certain similarities with the existing regulatory frameworks for pharmaceuticals, biologics, and devices. For instance, the power of the FDA to inspect facilities and records, to require record keeping and reporting of data on health effects, and to require good manufacturing practices are generally consistent. In particular, all potential MRTPs must undergo a premarket approval process similar to new drugs and high-risk devices. However, tobacco products, including MRTPs, are fundamentally different than other products regulated by the FDA: tobacco products are inherently hazardous, addictive products. As a result, there are sev- eral significant differences in the regulatory standards and requirements established by the FSPTCA that are worth mention. First, the standard to issue an order for the marketing of an MRTP is a public health standard. According to the FSPTCA, the Secretary’s actions regarding tobacco products, such as setting product standards or restricting sales of certain products and advertising, must be based on a finding that the action is “appropriate for the protection of public health.” In Section 911 the law specifies that the Secretary must take into account the effect of the product on nonusers when evaluating whether to issue an order for the sale of an MRTP.12 The law also requires the Secretary take into account the increased or decreased likelihood of tobacco users quitting and nonusers initiating, and the risks and benefits compared to other smoking cessation products. This public health standard is a significant departure from the stan- dards for drugs and devices. Generally, to obtain approval, drugs and devices must be shown to be “safe and effective” for the individual 12 911(g)(1)(b) and 911(g)(2)(B)(4).

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39 INTRODUCTION research participant or consumer. In contrast, MRTPs are potentially haz - ardous to the user and are never truly “safe” or “effective” in the sense that the product will improve the health of the user. The rationale for issuing an order for the sale of an MRTP is not that the products are safe and may improve health for individual users, but rather, that marketing the products may reduce the overall negative health effects in a popula - tion. To obtain an order to sell an MRTP, an MRTP candidate sponsor must demonstrate to the FDA that the overall burden of tobacco-related disease and death will be lower with the MRTP on the market than if it were not on the market. Second, product sponsors are required as a condition of obtaining an order to market an MRTP to conduct postmarket studies and surveillance, and to report the data to the FDA annually. In contrast, at this point in time, drug and device manufacturers are generally not required to con- duct postmarket studies of their products as an obligatory condition of approval. Third, orders for the marketing of an MRTP must expire, and manu- facturers must reapply for additional orders to allow for the ongoing sale of a product. MRTPs granted orders to market under the Special Rule for Certain Products are given a maximum of 5 years, while the terms of the orders granted under the Modified Risk standard are unspecified by the law. Following the expiration of an order, MRTP sponsors may obtain a renewal based on the filing of a new application. In contrast, drug and device sponsors do not have to reapply and essentially repeat the pre- market approval process after a specified period of time. BURDEN OF PROOF The Secretary’s decisions on whether an action will be appropriate for the protection of public health must be based on scientific evidence. According to the FSPTCA, a determination to allow for the marketing of an MRTP can be based on scientific evidence submitted by the product sponsor and on other scientific evidence made available to the Secretary. The committee maintains that the burden of proof rests on the appli- cant. That is, the product sponsor that is applying for an order to market an MRTP bears the responsibility of producing evidence in support of an application, including the evidence necessary to demonstrate that an order is appropriate for the protection of public health. Without evidence, the Secretary cannot determine that issuing an order for the sale of an MRTP is appropriate for the protection of public health.

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40 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS COMMITTEE CHARGE AND STATEMENT OF TASK Origin of Task In Section 911(l)(2) of the FSPTCA, Congress specifies that regulations and guidance on the scientific evidence required for the assessment and review of applications for a modified risk claim for a tobacco product must be developed in consultation with the IOM. The law states: The regulations or guidance issued under paragraph (1) shall be devel- oped in consultation with the Institute of Medicine, and with input of other appropriate scientific and medical experts, on the design and con - duct of such studies and surveillance. Statement of Task Pursuant to the legislation, the FDA Center for Tobacco Products (CTP) engaged the IOM to advise the agency. In discussing the scope of the report, the CTP and the IOM agreed that the committee would address premarket and postmarket studies in support of MRTPs and that postmarket surveillance would be excluded from the report to maintain appropriate focus and depth within the study time frame (see Box 1-3). Scope of Task The committee’s interpretation of the task was informed by the text of the legislation and by input from the project sponsor in a public meeting. The law specifically states that regulation or guidance shall be developed in consultation with the IOM on both the design and conduct of studies. As such, the committee found authority to address issues not only concerning research methods and scientific standards, but also research conduct and governance. The CTP also provided direction about the task to the committee during an open session of the first committee meeting. In a presentation BOX 1-3 Statement of Task The Institute of Medicine will establish a committee of 15 public health and medical experts to advise the Food and Drug Administration on the minimum standards for scientific studies to support the marketing of modified risk tobacco products and for post market studies of approved products.

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41 INTRODUCTION to the committee, CTP Director Dr. Lawrence Deyton, emphasized that the committee should advise the CTP on the “types and characteristics” of evidence needed to evaluate an application for an order to market an MRTP. The director also specifically reminded the committee that it must take into account the population health regulatory standard described in the law. Finally, Dr. Deyton described tasks that he regarded as out - side the committee’s charge. Specifically, he indicated that he did not expect the committee to • assess the evidence for any particular product; • opine on whether any tobacco product or class of products is a potential candidate for modified risk determination; • offer regulatory principles; • define or recommend a conceptual or regulatory framework for modified risk assessment; and • define terms from the act, such as “reasonably likely” or “measur- able and substantial reduction.” The statutory mandate and the limits articulated by the sponsor pre - sented a challenge to the committee. On the one hand, the law clearly placed the conduct of scientific studies within the scope of the IOM’s task; on the other hand, the director indicated that the committee should not address regulatory principles. Furthermore, the state of tobacco sci- ence and regulation was well developed, with a significant existing body of literature on the evaluation and regulation of tobacco. As such, the committee concluded it would be inefficient and unproductive to sim - ply reiterate basic scientific principles and review existing literature on tobacco. Accordingly, the committee sought to provide insight and direc- tion to the CTP without usurping the judgments that should be left to the agency and the Secretary. COMMITTEE PROCESS With this task in mind, the IOM convened a committee of 15 experts. The committee conducted five meetings between February and September 2011. During these meetings, committee members heard from a wide vari- ety of experts and stakeholders, including individuals representing the tobacco industry, researchers, public health experts and advocates, and government. The committee also extensively reviewed literature includ - ing original peer-reviewed research articles and published reports. In the course of deliberations, the committee commissioned work from and consulted with external experts to gain additional expertise.

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42 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS OVERVIEW OF THE REPORT This report is organized into six chapters. Chapter 2 discusses the standards for governance and the conduct of studies that are necessary to produce reliable and credible data to support a tobacco product’s applica- tion for a modified risk claim. Chapters 3 through 5 then address the types and designs of studies available to assess these products’ impact on an individual’s health and on the population’s health. Chapter 3 discusses studies on the health effects of the products, such as product composi - tion, biomarkers, preclinical studies, clinical studies, and epidemiologic studies. Chapter 4 reviews the research methods to study the addictive potential of the product. This information provides evidence on the impli- cations for human behavior patterns and public health risks. Chapter 5 outlines the standards for studies needed to address both consumer and nonconsumer risk perceptions and communication surrounding modi - fied products. Issues of participant recruitment, measurement, and data analysis are also detailed in Chapter 5. In the final chapter, Chapter 6, the committee discusses the integration of these various classes of evi - dence required for informed decision making by the FDA. The commit - tee presents its overarching findings and recommendations at the end of Chapter 6. REFERENCES American Nonsmokers’ Rights Foundation. 2011. Overview list—how many smokefree laws? http://no-smoke.org/pdf/mediaordlist.pdf (accessed October 17, 2011). Carter, L. P., M. L. Stitzer, J. E. Henningfield, R. J. O’Connor, K. M. Cummings, and D. K. Hatsukami. 2009. Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiology, Biomarkers & Prevention 18(12):3241- 3262. CDC (Centers for Disease Control and Prevention). 1999. Tobacco use—United States, 1990– 1999. Morbidity and Mortality Weekly Report 48(43):986-993. CDC. 2002. Cigarette smoking among adults—United States, 2000. Morbidity and Mortality Weekly Report 51(29):642. CDC. 2008. Smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 2000–2004. Morbidity and Mortality Weekly Report 57(45):1226-1228. CDC. 2009a. Tobacco use: Targeting the nation’s leading killer—at a glance 2009. National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Department of Health and Human Services. CDC. 2009b. Cigarette smoking among adults and trends in smoking cessation—United States, 2008. Morbidity and Mortality Weekly Report 58(44):1227-1232. CDC. 2010. Vital signs: Current cigarette smoking among adults aged ≥ 18 years—United States, 2009. Morbidity and Mortality Weekly Report 59(35):1135-1140. CDC. 2011a. Ten great public health achievements—United States, 2001–2010. Morbidity and Mortality Weekly Report 60(19):619-623. CDC. 2011b. Cigarette smoking—United States, 1965–2008. Morbidity and Mortality Weekly Report 60(1):109-113.

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