1 Department of Epidemiology, Boston University School of Public Health, Boston, MA.
2 Slone Epidemiology Center, Boston University, Boston, MA.
3 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA.
4 Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA.
5 Division of General Internal Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA.
Received for publication September 24, 2002; accepted for publication April 25, 2003.
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ABSTRACT |
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Blacks; case-control studies; lung neoplasms; menthol; smoking; Whites
Abbreviations: Abbreviations: CI, confidence interval; OR, odds ratio.
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INTRODUCTION |
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Menthol is a naturally occurring compound with topical cooling and anesthetic properties used in a wide range of products (13). Menthol cigarettes first appeared in the 1920s, but it was not until the mid-1950s that they came into widespread use (4, 5). Since 1973, menthol varieties have accounted for 2530 percent of all cigarettes sold in the United States (6). There are strong ethnic differences in the use of menthol cigarettes; more than 60 percent of Black smokers of both sexes use menthol brands compared with fewer than 25 percent of White smokers (711).
Lung cancer incidence is 50 percent higher among Black men than among White men (12). Although Black men are more likely to smoke, it does not appear that the excess occurrence of lung cancer can be fully explained by a higher prevalence of smoking (13, 14). The lung cancer rate among Black women is equal to that of White women despite the fact that they smoke fewer cigarettes (9, 10, 15). It has been suggested that smoking menthol cigarettes might increase lung cancer risk more than smoking nonmenthol cigarettes and might at least partly explain the observed disparities in lung cancer incidence (7, 16, 17).
Two main mechanisms have been offered to explain how menthol cigarettes could particularly elevate lung cancer risk. First, the products of menthol combustion might directly exert a carcinogenic effect on lung tissue (18). Alternatively, menthols cooling and anesthetic properties might permit larger puffs, deeper inhalation, or longer retention in the lungs, all of which would result in increased exposure to the carcinogenic elements in tobacco smoke (16, 19).
To our knowledge, there have been only three prior studies of the effect of menthol cigarettes on lung cancer risk (2022). Results have been ambiguous, with none showing an increased risk for women but two showing dose-related increases for men. Only one study published race-specific results, with no increases for either Whites or Blacks (22). Because studies conducted to date have not provided a clear answer concerning whether smoking menthol cigarettes increases the risk of lung cancer more than smoking nonmenthol cigarettes, we examined this question among long-term smokers in the Slone Epidemiology Center Case-Control Surveillance Study.
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MATERIALS AND METHODS |
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Subjects
The present analysis was restricted to subjects 4074 years of age who had no history of cancer, had smoked cigarettes for at least 20 years, and had been interviewed during the period 19812000. Cases had been diagnosed with lung cancer (confirmed by review of pathology reports) within the 12 months before their current hospital admission. Controls had been admitted for conditions judged to be unrelated to cigarette smoking. The most common control diagnoses included cancers or benign tumors of the breast, colon and rectum, prostate, and other non-tobacco-related sites (45 percent); diseases of the digestive (14 percent), genitourinary (10 percent), or musculoskeletal (7 percent) systems; and injury (13 percent). Respiratory or upper gastrointestinal conditions, regardless of etiology, were excluded. A total of 1,300 cases and 9,383 controls met the eligibility criteria.
Subjects were asked about their cigarette smoking history, including current smoking status, usual number of cigarettes smoked per day, total number of years of smoking, number of years since quitting, and information about the most recent brand and the brand used for the longest period of time, including name, characteristics (filter/nonfilter, menthol/nonmenthol), and number of years each brand was used. Responses to the questions about the most recent brand and brand smoked the longest were used to characterize use of menthol cigarettes. Because information was obtained on at most two brands (only one if the most recent and longest-smoked brand were the same), complete information on brand history was available for only 17 percent of subjects. We included in the study all subjects for whom brand information could be identified for at least 60 percent of the total duration of smoking; 513 cases (39 percent of those otherwise eligible) and 3,562 controls (38 percent) met this criterion.
We increased the number of eligible subjects by making certain inferences about periods of unknown brand history. The market share of menthol cigarettes was only 3 percent prior to 1956 (5); therefore, subjects who we could determine had some period of unknown brand history prior to 1956 could reasonably be assumed to have smoked nonmenthol cigarettes during that time. Addition of this inferred time increased the number of subjects for whom menthol status could be identified for at least 60 percent of total smoking duration to 661 cases (51 percent of those otherwise eligible) and 4,228 controls (45 percent). The preferential addition of cases mainly reflected the fact that they were older on average than controls (mean ages: 58.1 and 55.2 years, respectively), which increased the number of years of smoking prior to 1956 during which brand history could be inferred.
We classified subjects into three categories according to the number of years they smoked menthol cigarettes (0, 115, >15). We also created a proportional measure of exposure, calculated as the number of years that menthol cigarettes were used divided by the total duration for which brand information was known (0 percent, 149 percent, 50100 percent). We excluded the 3 years prior to admission in calculating exposure because smoking habits during this period would not be expected to have an impact on the occurrence of lung cancer.
Analysis
We excluded two cases and 52 controls whose race was other than White or Black and 16 cases and 66 controls for whom values for any of the other covariates were missing, leaving 643 cases and 4,110 controls for analysis. We fit unconditional logistic regression models with all covariates entered as indicator terms. Demographic factors included sex, age (5-year groups), and race. Smoking-related characteristics included duration (10-year groups), number of cigarettes smoked per day (<5, 514, 1524, 2534, 3544, 45), number of years since quitting (02, 35, 610, 1120,
21), and number of years of smoking filter cigarettes as a percentage of the duration of time for which brand information was known (<10 percent, 1025 percent, 2550 percent, 5075 percent, 7590 percent,
90 percent).
Because lung cancer was a priority diagnosis for surveillance in the earlier years of the study, 75 percent of cases were interviewed during 19811986, while controls were more evenly distributed throughout the study period. Since the proportion of subjects who were long-term menthol smokers increased during the later period of the study because of the increased availability and popularity of menthol cigarettes beginning in the 1950s, we also controlled for time period of interview (19811986, 19871993, 19941996, 19972000) to correct for any bias introduced by differential ascertainment of cases and controls over the course of the study. Adjustment for educational attainment and geographic area had no impact on the overall estimates, and these factors were not included in the final model.
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RESULTS |
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In separate analyses of men, women, Blacks, and Whites, long-term use of menthol cigarettes was not associated with an increase in lung cancer relative to exclusive use of nonmenthol cigarettes (table 3). Odds ratios were 1.0 or below in all groups except Blacks, for whom the odds ratio was 1.21 (95 percent CI: 0.64, 2.26).
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DISCUSSION |
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Our findings are similar to those of Kabat and Hebert (20), who found no increased risk associated with smoking menthol cigarettes for men or women. Two studies did report increases for men, but the estimates for women were substantially below 1.0 (21, 22). The only known study besides ours to present race-specific results also found no increases for Blacks or Whites (22).
The lack of clear-cut evidence from epidemiologic studies regarding the effect of menthol cigarettes is mirrored by inconsistent and ambiguous findings from laboratory and experimental studies. One set of investigators reported that combustion of menthol produced carcinogenic benzpyrenes (18), but a second study using radioactive labeling did not detect menthol-derived benzpyrenes in tobacco smoke (24). Menthol has also been hypothesized to affect smoking topography in a manner that increases the dose of cigarette smoke delivered to the lungs. However, contrary to expectation, most experimental studies indicate that smoking menthol cigarettes is not associated with an increase in puff volume or frequency, with some studies actually finding decreases in these measures (2529). On the other hand, a number of studies have also found that menthol cigarettes appear to produce a greater boost in nicotine and carbon monoxide levels than nonmenthol cigarettes (2527, 30). Although neither of these substances is itself carcinogenic, this finding suggests the possibility that menthol could also potentiate the uptake of carcinogenic constituents of cigarette smoke.
In interpreting the results of this study, it is important to consider factors that might have obscured an association between smoking menthol cigarettes and lung cancer. The most potentially serious limitation was the substantial proportion of missing data on menthol cigarette use because of the incomplete reporting of brands over subjects smoking histories. We compared the percentages of cases and controls who had sufficient information to be eligible for analysis within strata of demographic and smoking-related characteristics and found little evidence for bias due to missing data; any differences between cases and controls were minor and nonsystematic. We were able to modestly reduce the amount of missing data by making the reasonable assumption that brands used prior to 1956 were almost certainly not mentholated. We evaluated the impact of the remaining missing data by creating measures of years of menthol cigarette use that used different assumptions about the distribution of missing cigarette brand information and by restricting analyses to subjects for whom information on menthol cigarettes was complete. In neither instance did we find any evidence for an increased risk for menthol relative to nonmenthol cigarettes. Nevertheless, we cannot rule out the possibility that the apparent lack of association between menthol cigarette use and lung cancer is due to the large amount of missing data in our study.
Another important concern is imprecise information on the use of menthol cigarettes obtained by patient self-report. Although all studies of menthol cigarettes and lung cancer have relied on recall, each used a different method to ascertain menthol cigarette use, including lifetime brand history (20), identity of usual brand (21), or a global query about menthol cigarette use as a proportion of lifetime number of cigarettes smoked (22). In our study, subjects were asked to report the brand they smoked currently or most recently and the brand they had smoked for the longest period of time.
Information is limited regarding the validity of reporting of menthol cigarette use. However, the level of agreement between self-report and Universal Product Code (UPC) information read directly from the cigarette pack has been shown to be 98 percent for current brand (31), while, in one small study, agreement was 84 percent for recall of a brand reported by participants in smoking cessation programs 7 years earlier. The level of agreement may have been underestimated because, in some cases, the brand was not one customarily smoked by the participants but rather was expressly adopted as part of a smoking cessation strategy (32).
On the basis of the above information, it is likely that smokers in our study were able to report menthol cigarette use with a high degree of accuracy since they were being asked only about brands they currently smoked or had used over a period of many years (median duration of use of usual brand, 20 years). However, the trade-off inherent in obtaining greater accuracy by inquiring about only current/last and usual brand was an increase in missing data for varying proportions of smoking history.
Absent repeated ascertainment of current brand in prospective studies, future studies of cigarette brand effects will continue to have to rely on subject recall. Appropriately designed validation studies would help evaluate accuracy of recall of past brands. It would also be useful to evaluate the strengths and weaknesses of different measurement approaches and determine whether any are clearly superior.
Another concern in our study is the possibility of residual confounding. Control for confounding factors resulted in large increases from the crude to the adjusted odds ratios. Much of this confounding can be attributed to the fact that menthol cigarettes were introduced later than nonmenthol cigarettes; therefore, smokers of menthol cigarettes were younger and smoked for fewer years on average. In addition, because menthol cigarettes are almost invariably filtered, long-term menthol smokers were much more likely to have smoked filter cigarettes for most of their smoking history. The use of filter cigarettes has been associated with decreases in lung cancer risk relative to nonfilter cigarettes, including in a previous study in this same population (3335). Menthol smokers in our study also smoked fewer cigarettes per day, a finding also reported by Sidney et al. (16). All of these factors would have acted to negatively confound any estimate of the effect of smoking menthol cigarettes on the occurrence of lung cancer. Although we were able to adjust for all of these measures, some residual confounding may have remained that most likely biased the estimate downward.
There were also certain potential confounders, primarily low levels of fruit and vegetable consumption and occupational exposure to lung carcinogens, for which we had no information. However, restricting the study to long-term smokers who differed only in the type of cigarette they smoked decreased the likelihood of substantial confounding. Although smokers are known to both have poorer diets (3638) and work in occupations with a greater possibility of exposure to lung carcinogens (39, 40), substantial differences between smokers of menthol and nonmenthol cigarettes are less likely. Carpenter et al. (22) did control for fruit and vegetable consumption and for occupational exposure and found that doing so had no effect on the association between menthol cigarette smoking and lung cancer risk.
Restricting the study to long-term smokers also minimized concerns about control selection bias. Although smokers may be overrepresented among hospitalized controls even when diseases known to be caused by smoking are excluded, it is doubtful that the type of cigarette smoked has an important impact on the likelihood of hospitalization. We also used a variety of control diagnoses to minimize the potential for bias in case any individual condition was in fact related to exposure (41). Furthermore, odds ratios for the association of menthol cigarette use with lung cancer were very similar whether the control series was limited to patients with other cancers or patients with noncancer conditions.
Our study, in common with other studies conducted to date, was designed to address whether smoking menthol cigarettes increased the risk of lung cancer given that the comparison condition was smoking nonmenthol cigarettes. Alternatively, it is possible that smoking menthol cigarettes increases the risk of lung cancer not through any direct mechanism but by discouraging cessation, that is, by causing some people to continue to smoke who otherwise would have quit had they been using nonmenthol cigarettes. However, two recent studies indicated that smokers of menthol cigarettes are as likely to quit as smokers of nonmenthol cigarettes (31, 42).
In summary, our results do not support the hypothesis that smoking menthol cigarettes increases the risk of lung cancer more than does smoking nonmenthol cigarettes. However, owing to methodological and sample size limitations in our study and previous studies, the possibility of a modest increase in risk associated with smoking menthol cigarettes cannot be excluded. A small increase could translate to a substantial number of additional cases and partially explain the increased lung cancer incidence among Blacks. The reasons for using menthol cigarettes may vary among different groups of smokers in ways that affect smoking topography, patterns of use, and effective dose. In particular, if menthol does potentiate nicotine absorption, lower-income smokers (who are more likely to be Black) might use menthol cigarettes as a more efficient way of obtaining nicotine and consequently may smoke in a manner that increases their exposure compared with other groups of smokers. Studies that include larger numbers of Black smokers, careful documentation of lifetime smoking history, and information on smoking topography and/or dose would help clarify the effect of use of menthol cigarettes.
The higher incidence of lung cancer among Blacks is an important public health concern, but the causes remain largely unexplained. In addition to the possible role of menthol cigarettes, other hypotheses include historically higher smoking rates (43), other differences in exposure to tobacco smoke (e.g., higher-tar cigarettes) (16, 44), differences in metabolism of carcinogenic compounds in tobacco smoke (9, 45), and greater exposure to other causes of lung cancer, such as diet, occupation, or environmental tobacco smoke (4648). Although the possibility that differential use of menthol cigarettes contributes to racial differences in lung cancer incidence cannot be ruled out based on the results of studies to date, it will also be important to pursue other possible explanations for the disproportionate burden of lung cancer in Blacks.
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ACKNOWLEDGMENTS |
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The following hospitals participated in this studyNew York: Brookhaven Memorial Hospital, Lenox Hill Hospital, Memorial Sloan-Kettering Cancer Center, and New York Hospital; Philadelphia, Pennsylvania: American Oncologic Hospital, Crozier Chester Medical Center, Hahnemann University Hospital, Hospital of the Medical College of Pennsylvania, Hospital of the University of Pennsylvania, Lankenau Hospital, Montgomery Hospital, Pennsylvania Hospital, Presbyterian Hospital, and Thomas Jefferson University Hospital; Massachusetts: Beth Israel Hospital, Brigham and Womens Hospital, Massachusetts General Hospital, Mount Auburn Hospital, New England Medical Center, Newton-Wellesley Hospital, Sancta Maria Hospital, and University Hospital; Maryland: Greater Baltimore Medical Center, Johns Hopkins Hospital, Mercy Medical Center, and University of Maryland Hospital.
The authors thank the many physicians who allowed their patients to be interviewed; the nurse-interviewers who collected the data; Marguerite Angeloni, who coordinated data collection; Leonard Gaetano, who was responsible for data management; and Dr. Samuel Shapiro, founder of the Case-Control Surveillance Study, and Dr. Steven Stellman for their helpful review and advice.
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NOTES |
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REFERENCES |
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