Possible effects on smokers of cigarette mentholation: A review of the evidence relating to key research questions

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Abstract

Menthol (2-isopropyl-5-methyl-cyclohexan-1-ol) is used in food, pharmaceutical, and tobacco products. Despite its long usage history and GRAS status, scientific literature on effects of cigarette mentholation is limited. Because African-American men have high lung cancer rates and predominantly smoke mentholated cigarettes, and because menthol’s cooling effect might affect puffing and smoke inhalation, possible adverse effects of cigarette mentholation have been suggested. We review the evidence on the effects of mentholation on smokers, and we also identify areas for further study. Five large epidemiological studies provide no evidence that cigarette mentholation increases lung cancer risk. Mentholation cannot explain the higher risk for lung cancer in African-American male smokers, who also predominantly smoke mentholated cigarettes. Limited data on other cancers also suggest no risk from mentholation. The scientific literature suggests that cigarette mentholation does not increase puff number or puff volume of smoked cigarettes, and has little or no effect on heart rate, blood pressure, uptake of carbon monoxide, tar intake or retention, or blood cotinine concentration. Mentholation has little effect on other smoke constituents, and no apparent effect on nicotine absorption, airway patency and smoking initiation, dependency or cessation. Any toxicological effects of cigarette mentholation on adult smokers are probably quite limited.

Introduction

Tobacco companies routinely use food flavorings and other ingredients in complex mixtures that enhance the natural tobacco character of the smoke. Apart from uses such as moisture retention and humidification, these ingredients contribute unique sensory and flavor characteristics that in part differentiate brands and styles of cigarettes. Most ingredients added have been thoroughly evaluated toxicologically for use as flavors in food by regulatory agencies such as the FAO/WHO expert committee on flavor additives, the Council of Europe and the Food and Drug Administration, and by the Flavor and Extract Manufacturer’s Association (FEMA). Many of these ingredients are considered to be “Generally-Recognized-As-Safe” (GRAS) as determined by FEMA for their intended use in food as a flavor, flavor enhancer, and taste modifier. The certifications mentioned above do not apply to ingredients that are modified by, for example pyrolysis, as is the case for cigarettes. Importantly, this does not appear to be the case for menthol (see below), so the above reviews are probably valid.

Menthol is a naturally occurring compound obtained commercially from the Mentha piperata (peppermint) and M. arvensis plants and by extraction from other natural sources such as citronella java oil, Spanish pennyroyal oil, eucalyptus oil as well as other plant sources (Galeotti et al., 2002, Bedoukian, 1986). Synthetic processes are also used to produce d,l-menthol (the racemate) found in many commercial products. Use of menthol in food, pharmaceuticals and tobacco has been reported for more than 50 years (Eccles, 1994). It is used pharmaceutically as an antipruritic, antiseptic and cooling compound, in the symptomatic treatment of digestive disorders due to its carminative, antispastic and choleretic properties, and externally in broncholytic and secretolytic preparations, and is also used as a flavoring in toothpaste and oral hygiene products (Galeotti et al., 2002). Menthol activates transient receptor potential melastatin 8 (TRPM8), an ion channel also activated by cold, voltage, and phosphatidylinositol-4,5-bisphosphate (PIP2) (Bandell et al., 2006). Studies conducted by NTP showed that menthol was not carcinogenic in animals when dosed by the oral route ((National Cancer Institute, 1979). Nor was it mutagenic in a battery of genotoxicity assays (Speijers, 1999, Murthy et al., 1991).

Menthol is used in cigarettes to give attributes of mint and “coolness” to the smoke, and is viewed as pleasurable to the smokers who prefer mentholated cigarettes. In the United States nearly 25% of Caucasian and 70–80% of African-American male and female smokers choose menthol-flavored cigarettes (Cummings et al., 1987, Pickworth et al., 2002, Castro, 2004, Sutton and Robinson, 2004).

Although the toxicological properties of menthol are well described and the available results generally support its use in pharmaceuticals and foods, the clinical effects of applying menthol to cigarettes are less well understood. It has been suggested that mentholation of the cigarette may increase smoke exposure by affecting smoking behavior and topography, increase cigarette dependency, increase the cigarettes’ nicotine “impact”, increase exposure to toxic smoke constituents, increase the number of cigarettes smoked, and increase disease risk, so helping to explain differences in risk between Caucasians and African-Americans, along with numerous other possible adverse effects (Henningfield et al., 2003). Claims have also been made that menthol added to cigarettes may “anesthetize” the respiratory tract, allowing for increased intake of smoke.

Our objective is to review the published scientific literature on menthol and mentholated cigarettes and summarize relevant results to clarify knowledge about potential effects of cigarette mentholation on the smoker and to identify areas where more study is needed.

Section snippets

Does mentholation of cigarettes affect other smoke constituents?

It has been suggested that mentholation may increase the hazards of smoking, as menthol can pyrolyze during smoking, possibly increasing exposure to known toxic smoke constituents (Hébert, 2004).

Schmeltz and Schlotzhauer (1968) investigated the fate of a racemic mixture of d,l-menthol in a horizontal quartz tube packed with quartz chips under a stream of dry nitrogen at 860 ± 5 °C. They reported that pyrolysis resulted in the thermal degradation of menthol to yield phenols, benzene, toluene,

Does mentholation affect absorption of nicotine?

Hébert (2004) asked whether menthol speeds absorption of nicotine in the mouth and lungs. Currently no publications in the scientific literature demonstrate such effects from menthol in cigarette smoke. However, numerous investigators have reported that, in some animal models, l-menthol and other substituted terpenes like thiomenthol enhance dermal absorption of pharmaceutical agents. The epidermal skin is covered with a keratinized stratified squamous layer of cells covered by the stratum

Does mentholation affect the metabolism and clearance of nicotine and other smoke constituents?

The mammalian metabolism and elimination of menthol and its metabolites is well described (Gordon et al., 1987, Jackson et al., 1988, Madyastha and Srivatsan, 1988, Yamaguchi et al., 1994, Green and Tephly, 1998). Menthol is metabolized into glucuronide conjugates or oxidized into various polyalcohols or carboxylic acids. These oxidized metabolites are then eliminated either unchanged (some via the enterohepatic circulation) or as glucuronide conjugates in the urine or feces. In man,

Does cigarette mentholation affect smoking behavior?

Various studies have investigated possible effects of cigarette mentholation on smoking behavior and topography. These studies are first described, starting with the cross-sectional studies and going on to the experimental studies, after which the results are summarized.

Gardner et al. (1984) determined serum thiocyanate (SCN) concentrations in 130 young healthy persons. Seventy subjects were non-smokers, 12 were smokers of mentholated cigarettes, and 48 of non-mentholated cigarettes. Multiple

Does menthol impact upon airway patency?

There is some evidence that pure menthol decreases inflammation/irritation and bronchoconstriction in the respiratory tract, possibly explained by its action on “cold” receptors and/or bronchial smooth muscle (Sant’Ambrogio et al., 1995). Thus, menthol may induce smooth muscle relaxation (Wright et al., 1997), so increasing airway caliber and potentially airflow. Whether these effects occur at the concentrations of menthol found in cigarette smoke is unknown. Moreover, data obtained through the

Does cigarette mentholation affect initiation, dependency, and cessation?

Mentholation of tobacco may have effects on “determinants of exposure” (Henningfield and Djordjevic, 2004, Hébert, 2004). Specifically, these determinants may include an earlier age at initiation of the smoking habit, an increased dependence, and a reduced rate of cessation (Hyland et al., 2002). The three may be inter-related (Moolchan, 2004).

The possibility of menthol affecting age of initiation has been raised (Henningfield and Djordjevic, 2004). Our literature review revealed little

Does mentholation increase the risk of lung cancer in smokers?

Five relatively large epidemiological US studies comparing lung cancer risk in mentholated and non-mentholated cigarettes have been conducted. These are described first, after which the results are summarized.

Kabat and Hebert (1991) reported results based on the American Health Foundation multi-center case-control study. The analyses described were based on current cigarette smokers (defined as subjects who had smoked within the year preceding diagnosis) interviewed between 1985 and 1990 in

Does mentholation explain the higher risk of lung cancer in African-Americans?

In the USA, African-American men have substantially higher age-specific lung cancer rates than do Caucasian men. Based on mortality data presented by the US Surgeon General, 1998, rates in African-Americans were higher by 6% in 1960, 22% in 1970, 41% in 1980 and 54% in 1990. Also, the proportion of cigarette smokers smoking mentholated brands is much higher for African-Americans than Caucasians. For example, data for 2004 from the National Household Survey on Drug Abuse (US Department of Health

Does mentholation increase the risk of other diseases?

The American Health Foundation study which reported results for lung cancer (Kabat and Hebert, 1991) has also reported results for current smokers for some other smoking-related cancers.

Analyses on esophageal cancer (Hébert and Kabat, 1989) were based on 303 cases and 453 age-matched controls. After adjustment for education, religion, alcohol consumption and race, mentholated cigarette smoking was not associated with an increased risk in males (odds ratios 0.50, CI 0.23–1.07 for <10 years and

Summary

Menthol has a long history of use in food and pharmaceuticals and has been used in tobacco since the 1920s. Many clinical and non-clinical studies have addressed the toxicological properties of menthol, but the literature on the potential clinical effects of mentholation of cigarettes is much more limited. Because of the higher lung cancer risk in African-American men in the USA and the much higher preference for mentholated cigarettes in African-American smokers, and because of concern that

Acknowledgments

The authors are grateful to Drs. Martin Unverdorben, Andrew Livermore and Edward Sanders, who helped with the preliminary interpretation and literature gathering, as well as Dr. Richard Carchman for his helpful suggestions and insights during the writing and review of this paper. Dr. Werley co-authored this manuscript in his capacity as an employee of Philip Morris USA Inc. (“PM USA”). PM USA provides all employees who publish peer reviewed journal articles a nominal award in recognition of

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