PRELIMINARY SCIENTIFIC EVALUATION OF THE POSSIBLE PUBLIC HEALTH EFFECTS OF MENTHOL VERSUS NONMENTHOL CIGARETTES Food and Drug Administration 1 TABLE OF CONTENTS I. Executive Summary..................................................................................................... 3 II. Science Reviews .......................................................................................................... 7 A. Smoke Chemistry and Nonclinical Toxicology................................................. 8 B. Physiology.................................... ................................................................... 22 C. Biomarkers ...................................................................................................... 37 D. Patterns of Use ................................................................................................ 53 E. Marketing and Consumer Perception of Risk.................................................. 66 F. Initiation and Progression to Regular Use ....................................................... 90 G. Dependence...................................................................................................... 106 H. Cessation ......................................................................................................... 124 I. Disease Risk..................................................................................................... 138 2 I. Executive Summary Menthol is widely used in consumer and medicinal products and has long been used in cigarettes, often as a flavor-characterizing additive. In medical products, menthol is regulated as a drug with restrictions on allowable doses and use. There are no product standards for menthol when used in cigarettes. Approximately one-fourth of all cigarettes sold in the United States are menthol (Giovino, 2004). The vast majority (88%) of adult smokers in the United States start to smoke before age 18 (U.S. Department of Health and Human Services, 2012). Thus, youth and young adulthood appear to be a critical age-span for initiation of cigarette smoking, and research suggests that menthol cigarettes may have an impact on initiation rates that differ from nonmenthol cigarettes. Further, the impact of menthol cigarettes on dependence, cessation, and health risks has been the topic of scientific inquiry and intense debate. The Federal Food, Drug, and Cosmetic Act (FD&C Act) (Section 907 (e)) requires FDA’s Tobacco Products Scientific Advisory Committee (TPSAC) to submit a report and recommendation to the Secretary of Health and Human Services (HHS) on the impact of the use of menthol in cigarettes on public health – including use among children, women, African Americans, Hispanics, and other racial or ethnic minorities – by March 23, 2011. In March 2010, TPSAC began its process of reviewing the available evidence as well as soliciting and receiving valuable input from researchers, tobacco industry representatives, consultants to the tobacco industry, representatives of the public health sector, and others. On July 21, 2011, TPSAC voted on its final report and recommendations on menthol, which concluded “removal of menthol cigarettes from the marketplace would benefit public health in the United States.” TPSAC noted that a variety of options were available for FDA to consider, and they made no specific suggestions for follow-up by FDA should the agency decide it should pursue this recommendation. In addition, the non-voting industry representatives of TPSAC submitted a separate document reflecting the industry perspective. That document acknowledged the inherent risks of all tobacco products, including those that have menthol as a characterizing flavor, and raised the possibility of countervailing effects, including potential risks of contraband menthol products, should a ban be imposed. Independently, FDA has undertaken a thorough review of the available science concerning menthol cigarettes. To accomplish this task, FDA weighed the collective body of evidence for the impact of the use of menthol in cigarettes on public health. One of the first considerations in weighing the value of a particular study was the relevance of the information to the consumption of menthol cigarettes in the United States. Findings that were replicated in different studies, especially different types of studies, were given greater weight. FDA also considered the source of information, the type of study, and the quality of study methods and data. In drawing conclusions, more consideration was given to peer-reviewed studies, studies in humans, and studies that were appropriately powered and designed. In this process, FDA evaluated the peer- reviewed literature, industry submissions and other materials provided to TPSAC, and performed or commissioned additional analyses in an attempt to fill in and inform some of the gaps in the literature. 3 In making its assessment, FDA used a “weight of scientific evidence” approach. Studies were evaluated to determine the strength of both negative and positive associations of menthol in cigarettes with the impact under consideration. Scientific determinations fell into one of five categories, where x is the impact under consideration: The weight of evidence supports the conclusion that menthol in cigarettes is associated with x The weight of evidence supports the conclusion that menthol in cigarettes is likely associated with x The weight of evidence supports the conclusion that menthol in cigarettes is likely not associated with x The weight of evidence supports the conclusion that menthol in cigarettes is not associated with x The evidence is not sufficient to support a conclusion of an association of menthol in cigarettes with x The purpose of this evaluation was to determine whether there are independent associations between menthol in cigarettes and various outcomes of interest. In doing so, FDA evaluated the weight of evidence, taking into account potential threats to validity, such as bias or confounding, and whether the findings were generalizable to the U.S. population The evaluations were not an attempt to establish causality. In reviewing the science of menthol smoking, FDA divided the scientific evidence into the following broad categories: Smoke Chemistry and Nonclinical Toxicology: This review assessed information on in vitro and in vivo studies, as well as studies that examined menthol alone or tobacco smoke from menthol cigarettes. Two particular areas of interest were the comparison of menthol to nonmenthol cigarettes and whether the addition of menthol impacted the presence and levels of harmful and potential harmful constituents in the smoke. The studies examined did not show increased toxicity in menthol cigarettes compared to the already-toxic nonmenthol cigarettes. From the available studies, the weight of evidence supports the conclusion that, from a nonclinical toxicity standpoint, menthol in cigarettes is not associated with increased or decreased smoke toxicity. Physiology: FDA considered information on menthol’s effect on cooling, desensitization, anesthesia, and potential effect on nicotine and tobacco specific nitrosamines (TSNAs). FDA reviewed both in vitro and in vivo studies in human and animal models. In addition, analysts reviewed studies looking at the effect of menthol on smoking topography. There are some in vivo and in vitro studies that show menthol has cooling, desensitizating, and proanalgesic effects. Menthol acts primarily through receptors on sensory nerves. From the available studies, the weight of evidence supports the conclusion that menthol in cigarettes is likely associated with altered physiological responses to tobacco smoke. Biomarkers: FDA analyzed studies measuring biomarkers of exposure in smokers of menthol and nonmenthol cigarettes. Biomarkers included levels of smoke constituents or their metabolites in exhaled air, saliva, blood, and urine such as expired carbon monoxide (CO) and plasma carboxyhemoglobin (COHb) for levels of CO exposure; cotinine (main nicotine 4 metabolite) and other nicotine equivalents in plasma and urine for exposure to nicotine. Some studies show that smoking menthol cigarettes modulates the exposure or metabolism of nicotine and tobacco-specific nitrosamines (TSNAs), while other studies fail to show a significant association. From the available studies, the weight of evidence supports the conclusion that menthol in cigarettes is likely not associated with increased or decreased levels of biomarkers of exposure. Patterns of Use: FDA reviewed scientific literature focusing on the general trends and patterns in menthol smoking. Articles reporting data on national estimates or very large representative populations were given highest priority in order to draw estimations of patterns of use that would be applicable and generalizable for the U.S. population overall. Data support that a majority of African American smokers smoke menthol cigarettes, but other minority groups are also more likely to smoke menthol cigarettes as compared to Whites. Further, younger populations have the highest rate of smoking menthol cigarettes, and female smokers are more likely to smoke menthol cigarettes than male smokers. Also, the use of menthol cigarettes is associated with lower socioeconomic status (SES). From the available studies, the weight of evidence supports the conclusion that menthol in cigarettes is associated with particular patterns of smoking. Marketing and Consumer Perception of risk: FDA reviewed studies of brand