As noted earlier, there has been increasing regulatory interest in the possible contribution of additives to the carcinogenicity of cigarettes, both in the United States and Europe. In principle, menthol is by far the easiest to study, as brand names clearly identify whether or not the cigarette is mentholated, and smokers will be well aware anyway whether the cigarettes they are smoking are mentholated. Also mentholated cigarettes are quite widely smoked, particularly in the United States, especially in Black people who have a much greater preference for them than do White people (see Table ).
While menthol itself has been widely used for many years and experimental studies provide no reason for concern that it is genotoxic or carcinogenic [7
], there is a suggestion that its acute effects on the mouth, nose and respiratory system [6
] may affect how smoke from cigarettes is inhaled [10
]. Coupled with evidence in the United States that Black males have markedly higher lung cancer rates than do White males (see Table ), despite Black people smoking less heavily and tending to start smoking later in life than do White people (see e.g. Table ), it is often suggested (e.g. [17
]) that mentholation of cigarettes may increase the risk of lung cancer.
The main objective of this paper is to investigate this possibility by a direct epidemiological comparison of risk in mentholated and non-mentholated cigarette smokers. However, it should be noted that various other pieces of evidence argue against this possibility. First, data from a number of studies (see e.g. [9
]) provide no convincing evidence that mentholation increases puffing, inhalation or tobacco smoke uptake. Also, Black females have similar lung cancer rates (see Table ) to White females, despite the preference for mentholated cigarettes in Black people being at least as great in females as in males (see Table ). It should also be noted that, as described in the Background section, there are other differences in smoking characteristics between Black and White people, with Black people being more likely to be current smokers, less likely to quit, tending to choose higher tar cigarettes and having higher cotinine levels. Other differences between Black and White people may also be relevant, for example in body mass index, access to health care and metabolism.
Although mentholated cigarettes have assumed an important place in the United States cigarette market over the last 50 years, and the number of published epidemiological studies of smoking and lung cancer is extremely large, relatively few publications provide information comparing risk in smokers according to use of mentholated cigarettes.
While only eight relevant studies were identified, and two of the papers reporting on this relationship [83
] did not have mentholation as a central interest and one [84
] was published only as an abstract, the data available to study effects of mentholation seem quite good. The studies are reasonably large, involving in total some 1200 lung cancers in mentholated cigarette smokers and are of standard designs analysed by standard methods. Cases are generally histopathologically confirmed, with selection of controls unlikely to cause relevant bias. All the studies take age, gender, race and other aspects of smoking into account in their analyses, with some adjustment for other potential confounding variables such as education and body mass index.
Nevertheless, the studies have limitations. These include failure to present results by histological type (except in one study [68
]), failure to adjust for occupation or diet, and failure to report results by length of use of mentholated cigarettes in the later published studies [56
] - important as the earlier studies [51
] had insufficient subjects who smoked mentholated cigarettes for a long time. One would like to be able to compare subjects who smoked only mentholated or only non-mentholated cigarettes for 30 years or more.
Another issue is the extent and reliability of the data on lifetime use of mentholated cigarettes. Some studies only collected or analyzed information on brand currently smoked [51
] or on a few brands smoked during lifetime [53
], and some studies collecting data on names of brands smoked and whether the brand was mentholated [51
] seemed not to cross-check this information. The reliability of statements on brands smoked years ago is in any case questionable [89
The analyses presented are typically adjusted for smoking habits, such as daily cigarette consumption and duration of smoking. This is an attempt to compare mentholated and non-mentholated cigarette smokers with an equivalent smoking history. None of the analyses have attempted to account for the possibility that switching from non-mentholated to mentholated cigarettes might be associated with changes in cigarette consumption.
The combined data from the eight studies are not at all suggestive of any effect of mentholation on lung cancer risk. Meta-analysis of adjusted RRs for ever use give a combined estimate of 0.93 (95% CI 0.84-1.02), with individual estimates showing remarkably little heterogeneity, varying only from 0.81 to 1.12. The same is true for long-term use, where the combined estimate of 0.95 (0.80-1.13) is again based on consistent individual estimates, varying from 0.88 to 1.10. There is also no evidence of an increase in males or females separately, in Black or White people separately or in estimates for ever smokers, current smokers or former smokers. Limited data on risk by age and by histological type of lung cancer also suggest no effect of mentholation. There is a question as to the validity of adjustment for aspects of smoking habits that might be affected by use of mentholated cigarettes, but the estimates that are adjusted only for non-smoking variables tend to be lower. Overall the data, taken as a whole, could hardly be more indicative of a lack of relationship.
For mentholation to explain the increased lung cancer risk in Black compared to White males of some 30-35% would require a relative risk of about 1.7 to 1.8. The excess risk, therefore, cannot possibly be explained by the much greater preference of Black people for mentholated cigarettes.