Alcohol and Cancer1

[CANCER RESEARCH (SUPPL.) 52. 2119s-2l23s, April I. 1992] Alcohol and Cancer1

William J. Blot2

Epidemiology and Biostatislics Program. National Cancer Institute, Bethesda, Maryland 20892

Abstract acterized and for which the most clues to mechanisms have arisen. Because cigarette smoking is a major determinant of Although ethanol has generally not been found to induce cancer in these cancers, and because drinkers of alcoholic beverages tend experimental animals, the consumption of alcoholic beverages has been to be smokers, smoking and drinking need be evaluated con linked to increased risks of several cancers in humans. Risks of oral, pharyngeal, laryngeal, esophageal, and liver cancer are elevated among currently. Table 2 shows the interaction between smoking and drinkers, typically in proportion to the amount consumed. Evidence drinking in the risk of oral and pharyngeal cancer, with data associating colorectal and breast cancer with alcohol drinking is sugges from a study of nearly 1100 patients with these cancers and tive but awaits confirmation. All types of alcoholic beverages seem to be 1300 control subjects that was conducted in the mid-1980s in implicated, pointing to an etiological role for ethanol or its metabolites. four areas of the United States (3). The large study size enabled The mechanisms, however, by which alcohol induces cancer in humans the most precise estimates available of the joint effects of are not clear. This review summarizes epidemiological studies of alcohol tobacco and alcohol on risk of any cancer. As indicated in Table and cancer, focusing primarily on characteristics of the association that 2, within each smoking category risks of oral and pharyngeal may provide clues to causal pathways. cancer tended to increase as alcohol intake increased. The smoking-adjusted RR (bottom row) rose to almost 9 for those Introduction who drank 30 or more drinks per week (i.e., averaging more than 4 per day), whereas the alcohol-adjusted RR (right column) Epidemiological studies have provided definitive evidence rose to over 4 among two-pack-a-day smokers. Drinking tended that the drinking of alcoholic beverages can induce cancer in to combine with smoking in a multiplicative fashion, so that humans (1). These investigations not only have identified can risks for heavy consumers of both products exceeded risks for cers associated with alcohol drinking but also have provided abstainers from both by 37-fold. clues to etiological mechanisms. This review describes the as The multiplicative interaction indicates that much of the sociations between alcohol and specific cancers in human pop effect of alcohol is via an enhancement of tobacco's effect on ulations and discusses potential pathways through which alco these tumors and that reduction in either one of the exposures holic beverages may cause cancer. will substantially reduce cancer incidence. Indeed, it is esti mated that approximately 75% of all oral and pharyngeal Materials and Methods cancers in the United States are caused by smoking and drink ing, with the bulk of these caused by the synergistic effect of Information on alcohol as a cause of cancer has come primarily from the two (3). Table 2 shows, however, that smoking is not a epidemiological observations. Both cohort studies, which ascertain necessary prerequisite for alcohol-induced cancer, because risks drinking habits of study participants and their subsequent mortality, and case-control studies, which focus on a particular cancer and the of oral and pharyngeal cancer rose with increasing alcohol intake in life-long nonsmokers (and also in exsmokers). Similar retrospective determination of prior alcohol consumption, have evalu ated cancer risks according to the amount and type of alcohol intake. effects were reported elsewhere (4). The strength of the trends Supporting evidence has come from studies correlating cancer rates at in nonsmokers suggests that alcohol drinking alone is sufficient the national, regional, local, or group level with average drinking to induce oral tumors. It is possible, however, that alcohol patterns for the group, although these descriptive investigations are interacts with other carcinogens in causing these cancers in generally more useful for raising rather than testing etiological hy tobacco abstainers. The issue is difficult to evaluate directly in potheses. The findings from these epidemiological investigations, cat epidemiological studies, because typically only few of the cancer egorized by type of cancer, are summarized below. patients are nonsmokers and subdividing this small group of nonsmokers into smaller categories of exposure to other risk Results factors is generally not feasible. Besides tobacco and alcohol, diet and nutrition are among Total Cancer. Risks of cancer rise with increasing level of consumption of alcoholic beverages. Table 1 shows RR3 of the factors most strongly associated with oral and pharyngeal cancer. Increased risks have been associated with nutritional cancer (all types combined) according to daily intake, with a deficiency, as in the Plummer Vinson syndrome of iron, ribo- 60% smoking-adjusted excess risk in the heaviest alcohol con flavin, and other vitamin deficiencies (5). Furthermore, within sumption category. The data, which are typical of several studies normal dietary ranges, risks typically increase as consumption of total cancer risk, are derived from the largest cohort study of male drinkers, a 12-year follow-up of approximately 276,000 of fresh fruits and vegetables decreases (6). Table 3 shows the joint effects of alcohol and fruit and vegetable intake on the American men (2). Risks, however, vary considerably by type oral and pharyngeal cancer risks of smokers in North Carolina of cancer, as described below. (7). Drinkers experienced increased risks in each fruit and Oral and Pharyngeal Cancers. Among the strongest associa vegetable category, with the highest risk for heavy drinkers who tions with alcohol intake are those found for oral and pharyn also had low fruit and vegetable intake. It thus appears that geal cancers. These are also among the cancers whose associa tions with alcohol consumption have been the most well char- drinking enhances the deleterious effect of poor nutrition. Al though Table 3 shows separate effects of alcohol and diet, it ' Presented al "Nutrition and Cancer," the first conference of the International may be that drinking contributes to increased risk through its Conference Scries on Nutrition and Health Promotion. April 17-19, 1991, lowering of nutritional status (by provision of nonnutritive Atlanta, GA. 3To whom reprint requests should be addressed. calories and deprivation of vitamins, minerals, and other 1The abbreviation used is: RR. relative risk. nutrients). 21 19s Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1992 American Association for Cancer Research. ALCOHOL AND CANCER

Table 1 Relative risks of total cancer mortality according to number of alcoholic is the predominant alcoholic beverage and intake is high, in drinks per day Data are from a cohort follow-up of 276.000 American men (2). creases in oral-cancer risk with increasing consumption also were reported (4). When spirits were classified as dark (such as of Alcohol intake cancer Confidence bourbon and scotch) or light (such as gin and vodka, which (drinks/day)None deaths4748 interval0.8- have fewer congeners) in one small American study, risks of hypopharyngeal cancer were higher in consumers of dark than <1 56.1 0.90.9 light alcohol (11). 2 1026 0.9- .1.3 3 458 1.11.31.5 1.0- The idea that ethanol may be the key ingredient responsible 4 345 1.2- .5 for the high rates of cancer in drinkers also was suggested by 5 178 1.3- .7 6+No. 441RRÂ°1.0 1.695% 1.5-.0.8 the observation that risk of oral cancer was increased in users Â°All risks relative to nondrinkers and adjusted for cigarette smoking. of mouthwash (12). The mouthwash association has been de tected in several studies, with the most recent (13) indicating that the excess risk may be limited to users of mouthwashes Table 2 Relative risks of oral and pharyngeal cancer in males according to amount of tobacco smoking and alcoholic beverage drinking high in alcohol content (Table 4). The link to mouthwash also RR suggests that alcohol may influence oral carcinogenesis via a topical rather than systemic route, because few persons swallow statusNonsmokerExsmokerl-19/dayforSmoking mouthwash. Esophageal Cancer. Like oral and pharyngeal cancer, esoph 20+yr20-39/day ageal cancer is strongly related to alcoholic-beverage consump yr40+/day for 20+ tion (1). Cohort and case-control studies around the world yrTotal1'<1"1.0Â°0.71.71.97.4\ff1-41.32.21.52.40.71.25-141.61.42.74.44.41.715-291.43.25.47.220.23.330+5.86.47.923.837.78.8Total*1.0e1.11.62.84.4for 20+ reveal significant increases in risk of this cancer with increasing Â°Number of drinks/week. alcohol intake. They also tend to show that alcohol combines 1Risks adjusted for alcohol intake. with smoking in a multiplicative fashion to enhance esophageal ' Reference category. Data from United States case-control study (3). d Risks adjusted for smoking. cancer risk. As indicated in Table 5, however, strong increases in risk with rising alcohol consumption have also been noted among nonsmokers, with > 10-fold elevations in heavy drinkers Table 3 Relative risks of oral and pharyngeal cancer among North Carolina in France (14). Similar to the situation for oral cancer, alcohol female smokers, according to alcohol and fruii and vegetable intake also appears to worsen the effect of poor nutrition, and vice Alcohol intake versa. Table 6 shows risks of esophageal cancer according to (ml/day)Nondrinker the cross-classification of dietary status and alcohol intake from a case-control study in Washington DC. (15). Risks rose as <60 2.4 4.4 2.8 alcohol intake increased and nutritional status decreased, with 60+>21Â°1.0* 4.4RR11-202.1 4.1<115.2 13.6 " Fruit and vegetable intake (sen ings/week). * Reference category. Data from Ref. 7. Table 4 Relative risks of oral and pharyngeal cancer associated with use of mouthwashes with low and high alcohol content Data are from Ref. 13. Few studies have calculated risks of oral and pharyngeal or other cancers according to duration of drinking or years since cessation of drinking. This information seems not to have been Mouthwash Confidence Confidence usedNone interval0.4-1.1 interval0.4-1.5 collected in part because of difficulty in accurately identifying exdrinkers and when they stopped consuming alcoholic bever Low-alcohol" 0.7 0.8 ages. Several cohort studies noted that total death rates for High-alcohol* 1.6 1.1-2.3 1.92.0Females95%1.1-3.3 1.1-2.1RR1.0 exdrinkers equal or exceed those of drinkers, but the excess Mixed typesRR1.0 1.5Males95% 1.3-3.1 " Less than 25% ethanol. seems mainly confined to cardiovascular disease and not cancer * 25% or more ethanol. mortality, probably because exdrinkers stopped drinking be cause of illness (8, 9). In a case-control study in Puerto Rico, Table 5 Relative risks of esophageal cancer among nonsmokers in Normandy, risks of oral (and esophageal and laryngeal) cancer were lower France, according to level of alcohol intake for those who stopped drinking for 10 or more years, but Data are from Ref. 14. changes in smoking were not accounted for (10). The lack of of cases)Females1.0(25) data on the effects of alcohol according to the timing of expo Ethanol intake sure hinders evaluation of the stage at which alcohol influences (ml/day)0-4041-80 carcinogenesis. If it were known, for example, that risk of oral 3.8(15) 5.6 (8) cancer dropped rapidly after cessation of drinking, as it does 81-120 10.2(9) 11.0(3) after cessation of smoking (3), then it could be inferred that 121+RRMales1.0(7) 101.0(8)(no. alcohol affects primarily a late or promotional stage in the carcinogenic process. Table 6 Relative risks of esophageal cancer according to nutritional status and Increased risks of oral and pharyngeal cancer have been level of alcohol drinking associated with nearly all types of alcoholic beverages, suggest Data are from a case-control study in Washington. DC (15). ing a role for common ingredients, particularly ethanol. There RR Alcohol intake have been differences in the magnitude of risk, however, with High" different types of beverages. In the large national study of oral (ml/day) Moderate Low 1.0* and pharyngeal cancer, risks associated with equivalent 0-179 1.7 3.0 180+ 2.7 4.1 8.0 amounts of hard liquor and beer were nearly equal and exceeded ' Nutritional status, defined by usual adulthood intake of fruits, vegetables, those for wine, which were elevated only in the heaviest con and other foods. sumption categories (3). In areas of northern Italy where wine * Reference category. 2120s

Table 7 Relative risks oflaryngeal cancer in western Canada hy anatomic sites. For example, liver enzymes that normally metabolically subsite, according to alcoholic bererage intake deactivate diethylnitrosamine, an esophageal carcinogen in an Data are from Ref. 19. imals, are impaired with alcohol intake (25). With first-pass Alcohol intake (Huidoz/wk)<1 larynx1.0 larynx1.01.1 clearance altered in drinkers, the nitrosamine may more readily target the susceptible esophagus. Alcohol also tends to deplete the liver's vitamin A stores and consequently may affect blood 1-45-910-20 1.7 2.6 0.7 and tissue levels of retinol and its metabolites, compounds that 5.16.4Intrinsic 2.0 20+Extrinsic 2.2 have been shown to influence several types of chemically in duced cancer in animals (26, 27). Breast Cancer. In the past decade, more than one-dozen a nearly constant ratio of the effect of alcohol across nutrition epidemiological investigations have found increased risks of categories, consistent with a multiplicative interaction between breast cancer associated with the drinking of alcoholic beverages the two. (1, 28-31). Dose-response trends have generally been evident. Risks of esophageal cancer have tended to be somewhat The trends are remarkable because excess risks often were higher for drinkers of hard liquor than beer or wine, but rising apparent at relatively low levels of consumption. Table 8 dis trends in risk have been noted with increasing consumption of plays RR of breast cancer according to alcoholic beverage intake each beverage category (1). In some areas of the world, partic from a 4-year follow-up of nearly 90,000 nurses (28). Significant ular alcoholic beverages have been linked to unusually high increases in breast cancer were associated with consumption levels of esophageal cancer risk. In coastal South Carolina, levels as low as three to nine drinks per week. Adjustment for which for several decades has led the nation in death rates from known breast-cancer risk factors did not substantially affect the esophageal cancer, nearly 90% of interviewed black patients findings. Similarly, a 12-year follow-up of >500,000 women by reported they were regular consumers of moonshine whiskeys the American Cancer Society, which recorded 599 breast-cancer (16). Home-brewed rum has been implicated along with other deaths in drinkers and 2,334 in nondrinkers, revealed an ap alcoholic beverages in the high rates of upper-digestive-tract proximate 20% increase in risk among women consuming one cancers in Puerto Rico (10). In Southern Brazil, strong in alcoholic drink per day, rising to a 70% increase among those creases in risk of esophageal cancer have been linked to the consuming five or more per day (29). In a combination of data drinking of cachaca, a distilled spirit from sugarcane (17). One from six case-control studies conducted outside the United of the most striking links between a particular beverage and States, however, a significant excess risk of breast cancer was cancer is seen in northern France, where extraordinarily high evident only in women drinking more than three drinks per day risks of esophageal cancer were documented in drinkers of (31). In some studies, the effect of alcohol was most pronounced Calvados and other local apple brandies (18). The variations in when intake occurred at young ages (32). The consistent find risk based on beverage type suggest that, in addition to ethanol, ings and generally similar dose-response trends in these and congeners or other ingredients in beverages may play an etio- other studies suggest that alcohol intake may be causally related logical role. to breast cancer. The magnitude of the association is not large, Laryngeal Cancer. Alcohol is a strong determinant of cancer so that confounding by other risk factors could play a role, but of the larynx, with the risk profile being quite similar to that most investigations controlled for the known causes of this seen for cancers of the oral cavity, pharynx, and esophagus (1). cancer. Risk of alcohol-induced laryngeal cancer, however, appears to If the association between alcohol and breast cancer is causal, vary by anatomic subsite. Table 7, using data from a case- the mechanisms are not clear. Ethanol, however, was reported control study in western Canada (19), shows that alcohol exerts to alter hormonal status in experimental animals, including a greater effect on cancers of the extrinsic than the intrinsic disturbing the menstrual cycle and decreasing luteinizing hor larynx. Similar differentials were reported in France, Spain, mone levels (33). In humans, alcohol abuse can lead to early and Italy (20) and provide additional evidence that alcohol may menopause (a protective factor for breast cancer) and increased act through topical exposure. levels of estrogens, prolactin, and other hormones (potential Liver Cancer. Alcohol is recognized as a cause of primary breast-cancer risk factors) (33). It seems likely that more mod liver cancer (1). Deaths from liver cancer were reported to be erate doses of alcohol would have more subtle effects but increased by about 50% in alcoholics, with increases of this or perhaps could modify hormonal status or other factors enough slightly higher magnitude also noted in case-control studies of to result in the small increases in breast-cancer risk observed. this cancer (1). Epidemiological studies have provided limited Colon and Rectal Cancers. Several cohort and case-control data on interrelationships between alcohol and other risk fac studies suggest that the risk of large-bowel cancer, particularly tors for liver cancer, but some interactive effects with smoking rectal cancer, may be increased with the consumption of alco (a weak liver carcinogen) and hepatitis B virus (a strong liver holic beverages. In four of nine cohort and six of nine case- carcinogen) were reported (21, 22). Alcohol's effect on liver control studies reviewed by the International Agency for Re cancer may be through its induction of cirrhosis and other liver search on Cancer, significant increases in rectal cancer risk were damage, which in some cases may predispose patients to hepatic tumor development. Alcohol's influence on the liver may potentially be more Table 8 Relative risks of breast cancer hy level of alcohol intake Data are from a prospective 4-year follow-up of 90,000 American nurses (28). important for cancer in organs other than the liver than in the Alcohol of liver itself. Continued alcohol drinking can elevate levels of intake breast cancer Confidence liver enzymes, including cytochrome P-450, which in turn can (drinks/wk)None cases171 interval0.8-1.3 catalyze the metabolism of xenobiotics (23. 24). Alcohol can also alter the liver's ability to detoxify compounds with carcin <1 66 1.0 1-2 98 0.9 0.7-1.2 ogenic potential. This influence on metabolism has been hy 3-9 139127RR1.0 1.31.695% 1.0-1.6 pothesized to influence formation of tumors at extrahepatic 10+No. 1.3-2.0 2121s

found in drinkers, particularly beer drinkers (1). In a recent gens into target tissues. The strong increases in risk of cancers follow-up of 106,000 members of a prepaid health plan in in tissues that are topically exposed (e.g., mouth, throat, esoph Oakland, CA, which adjusted for several potential risk factors, agus, and extrinsic larynx) to alcohol and the strong interactive the RR of subsequent rectal cancer (cancers occurring more effects with tobacco are consistent with this hypothesis. than 6 months after ascertainment of alcohol intake) reached 4. Reduce intake and bioavailability of nutrients that may 4.1 and of colon cancer reached 1.9 in those who drank three inhibit cancer and enhance nutritional deficiencies that increase or more drinks per day (34). Inconsistencies across studies and risk of cancer. For heavy drinkers the percentage of calories small numbers of observations, however, preclude inferring at derived from alcohol can be substantial. In one survey of middle- this time that alcohol intake causes large-bowel cancer, so that class males, for those who consumed the equivalent of about discussion of etiological mechanisms is premature. 2.5 or more drinks per day alcohol contributed 24% of all Other Cancers. Although there have been some reports of calories and intake of protein and several nutrients (especially alcohol-related stomach, pancreas, lung, bladder, and other vitamins A and C) was significantly decreased (42). In some tumors, the overall evidence suggests that alcohol is not a risk cases, the deprivations may lead to nutritional deficiencies that factor for these cancers (1). may alter epithelial cell chemistry and function, increasing susceptibility to carcinogens. Via its hepatic effect, alcohol may Discussion limit the delivery to cells of nutrients that may be protective because of antioxidant or other properties. In rats, ethanol was The epidemiolÃ³gica! observations from around the world reported to enhance trachea! metaplasia induced by vitamin A leave little doubt that drinking alcoholic beverages can cause deficiency (43). Alcohol may also induce methyl deficiencies, cancer. How intake influences cancer risk, however, is not clear. which have been shown to cause liver cancer in experimental Few clues to mechanisms have come from bioassays, because animals, and enhance the tumorigenic effect of methyl-deficient neither alcoholic beverages nor ethanol have been shown to diets (38, 44). The hypomethylating environment induced by induce cancer in experimental animals. In its review of nearly alcohol may be due to the effects of alcohol on enzyme activities, 20 experiments in mice, rats, and hamsters administered alco because acetaldehyde, even at relatively low concentrations, has hol orally, an International Agency for Research on Cancer been reported to inhibit DNA methyltransferase activity (45). working group noted that most failed to reveal significant or 5. Inhibit the detoxification of carcinogenic compounds. positive associations, but the numbers of animals were often Heavy alcohol consumption can induce cirrhosis and other liver small and the durations of exposure often short (1). In some damage. Experimental studies suggest that, through its effects studies, however, ethanol was reported to increase the incidence on the liver, alcohol may block hepatic inactivation of tobacco- of esophageal carcinomas induced by /V-nitrosodiethylamine related and other carcinogens and modify the liver's clearance and /V-nitrosodipropylamine and of liver cancers induced by function, increasing exposure to compounds such as JV-nitro- vinyl chloride (35-37). In another experiment, chronic con sodiethylamine in other organs (24, 46). sumption of alcohol by rats fed a methyl-deficient diet enhanced 6. Catalyze the metabolic activation of some compounds into nitrosamine-induced liver carcinogenesis (38). Furthermore, carcinogens. Chronic alcohol intake can induce enzyme (includ acetaldehyde, the major intermediary metabolite of ethanol, is ing cytochrome P450) activities that enhance the metabolic a recognized animal carcinogen, causing nasal and laryngeal activation of compounds into carcinogens (23, 46-48). For carcinomas after inhalation and enhancing the incidence of example, ethanol influences enzymes that catalyze the metab benzo(a)pyrene-induced lung tumors (39). olism of tobacco-specific nitrosamines, possibly contributing to The absence of carcinogenic effect of alcohol in most studies the interactive effects of tobacco and alcohol on risk of upper in experimental animals has precluded their generation of leads aerodigestive tract cancers (49). to mechanisms of alcohol-induced cancer. Studies of noncarcin- 7. Affect hormonal status, increasing the risk of hormone- ogenic effects of alcohol in experimental situations and in related cancers. Alcohol may influence the level, function, and humans, however, provide some clues. When combined with metabolism of hormones (33), resulting in increased exposure the epidemiological observations described earlier, some sup to estrogens and other compounds in susceptible target organs port can be found for each of the following hypotheses regarding (e.g., breast). possible mechanistic pathways through which alcohol drinking 8. Increase cellular exposure to oxidants. Alcohol may influ may cause cancer. Alcohol (or alcoholic beverages) may ence activation or inactivation of carcinogens at the cellular 1. Contain congeners and other contaminants that may be level in target tissues (e.g., mouth and throat). Ethanol has been carcinogenic. Several substances known or thought to cause reported to result in elevated tissue exposure to oxidants, thus cancer in humans have been detected in alcoholic beverages. increasing the risk of DNA damage and malignant transfor Included are /V-nitroso compounds (found in some beers), my- mation (50). cotoxins (found in some wines and south African maize beer), 9. Suppress immune function. Alcohol, through its effect on urethan (found at high levels in certain fruit brandies), tannins nutritional status, liver disease, and perhaps other body func (found in wines), inorganic arsenic and other pesticide residues, tions, may decrease immune response (51), although increased and asbestos filtration products (1, 40, 41). In addition, alco risks of lymphoma, the tumor most closely associated with holic beverages may contain additives, such as flavoring agents depressed immune function (52), have not been reported in and preservatives, and natural products, such as aldehydes, drinkers. acrolein, phenols, and ketones, that may influence the carcin Additional laboratory and epidemiological research on the ogenic process. effects of alcohol consumption may help clarify the mechanism 2. Generate metabolites that are carcinogenic to humans. The (or, more likely, mechanisms) by which alcohol causes cancer major metabolite of ethanol is acetaldehyde, a recognized ani in humans. On the basis of existing evidence, however, it is mal carcinogen and teratogen, which may have a similar effect clear that the most direct avenue to reducing the cancer burden on humans (39). associated with drinking is to reduce the level of intake of 3. Act as a solvent, increasing penetration of other carcino alcoholic beverages. Because a substantial portion of alcohol- 2122s

Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1992 American Association for Cancer Research. ALCOHOL AND CANCER induced oral, esophageal, laryngeal, and hepatic cancers (the 25. Swann. P. F.. Coe, A. M.. and Mace. R. Ethanol and dimcthylnitrosamine and diethylnitrosamine metabolism and disposition in the rat: possible rele tumors most strongly related to alcohol) result from heavy vance to the influence of ethanol on human cancer incidence. Carcinogenesis drinking, reductions to moderate levels should help to consid (Land.). IS: 1337-1343. 1984. 26. Leo. M. A., Lowe, N., and Lieber, C. S. Potentiation of ethanol-induced erably lower the risk of these cancers while further studies seek hepatic vitamin A depletion by phÃ©nobarbitaland butylated hydroxytoluene. to determine causal pathways. J. Nutr., // 7: 70-76, 1987. 27. Sporn, M. B., and Roberts, A. B. Role of retinoids in differentiation and carcinogenesis. J. Nail. Cancer Inst.. 73: 1381-1386. 1984. References 28. Colditz, G. A prospective assessment of moderate alcohol intake and major chronic diseases. Ann. Epidemiol., /: 167-177. 1990. 29. Garfinkel, L., Boffetta. P.. and Stellman, S. Alcohol and breast cancer: a 1. International Agency for Research on Cancer. Alcohol Drinking. 1ARC cohort study. Prev. Med., 17: 686-693. 1988. Monographs on the Evaluation of the Carcinogenic Risk to Humans, Vol. 30. Longnecker. M. P., Berlin. J. A.. Orza, M. J., and Chalmers, T. C. A meta- 44. Lyon. France: IARC. 1988. analysis of alcohol consumption in relation to breast cancer. JAMA, 260: 2. Buffetta. P.. and Garfinkel. L. Alcohol drinking and mortality among men 652-656. 1988. enrolled in an American Cancer Society prospective study. Epidemiology, /: 342-348. 1990. 31. Howe, G., Rohan. T., Decarli, A.. Iscovich, J., Kaldor. J.. Katsouyanni, K., Marubini, E., Miller. A.. Riboli. E., Tomolo. P.. and Trichopoulos. D. The 3. Blot, W. J., McLaughlin. J. K.. VVinn.D. M.. Austin, D. F.. Greenberg. R. association between alcohol and breast cancer risk: evidence from the com S.. Preston-Martin. S., Bernstein. L.. Schoenberg, J.. Stemhagen. A., and bined analysis of six dietary case-control studies. Int. J. Cancer, 47: 707- Fraumeni. J. F. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res.. 48: 3282-3287. 1988. 710. 1991. 32. Harvey. E. B., Schairer, C., Brinton. L. A., Hoover, R. N., and Fraumeni, J. 4. Talamini, R., Franceschi. S., Barra. S., and LaVecchia, C. The role of alcohol F. Alcohol consumption and breast cancer. J. Nati. Cancer Inst., 78: 657- in oral and pharyngeal cancer in non-smokers, and of tobacco in non-drinkers. Int. J. Cancer. 46: 391-393. 1990. 661. 1987. 33. Gavaler, J. S., and VanThicl. D. H. Reproductive consequences of alcohol 5. Wynder. E. L.. Hultberg. S.. Jacobsson. F.. and Bross. I. J. Environmental abuse: males and females compared and contrasted. MutÃ¢t.Res., 186: 269- factors in cancer of the upper alimentary tract: Swedish study with special 277, 1987. reference to Plummer-Vinson (Patterson-Kelly) syndrome. Cancer (Phila.). 34. Klatsky. A. L.. Armstrong. M. A., Friedman, G. D., and Hiatt, R. A. The 10: 470-487. 1957. relations of alcoholic beverage use to colon and rectal cancer. Am. J. Epide 6. McLaughlin. J. K., Gridley. G.. Block, G.. Winn. D. M., Preston-Martin. S.. miol., 128: 1007-1015. 1988. Schoenberg. J. B., Greenber, R. S.. Stemhagen. A.. Austin. D. F., Ershow. 35. Griciute. L., Castegnaro. M., and Bereziat. J. C. Influence of ethyl alcohol A. G.. Blot, \V. J., and Fraumeni. J. F. Dietary factors in oral and pharyngeal on the carcinogenic activity of iV-nitrosodi-n-propylamine. In: H. Bartsch, cancer. J. Nail. Cancer Inst., 80: 1237-1245. 1988. M. Castegnaro, I. O'Neill, and M. Okaka (eds.), iV-Nitroso Compounds: 7. Ziegler, R. G. Alcohol-nutrient interactions in cancer etiology. Cancer Occurrence and Biological Effects, IARC Scientific Publication 41, pp. 643- (Phila.). 58: 1942-1948. 1986. 648. Lyon, France: IARC. 1982. 8. Kono, S.. Ikeda, M.. Tokudome, S., Nishizumi. M.. and Kuratsune. M. 36. Griciute. L., Castegnaro. M., and Bereziat, J. C. Influence of ethyl alcohol Alcohol and mortality: a cohort study of male Japanese physicians. Int. J. on carcinogenesis induced with A'-nitrosodimethydamine. In: M. Borzsonyo, Epidemiol., IS: 527-532, 1986. N. Day. K. Lapis, and H. Yamasaki (eds.). Models, Mechanismsand Etiology 9. Shaper, A. G., Wannamethee. G., and Walker, M. Alcohol and mortality in of Tumor Production, IARC Scientific Publication 56, pp. 413-417. Lyon, British men: explaining the U-shaped curve. Lancet, 2: 1267-1273. 1988. France: IARC. 1984. 10. Martinez. I. Factors associated with cancer of the esophagus, mouth, and 37. Radike. M. J., Stemmer, K. L., and Bingham. E. Effect of ethanol on vinyl pharynx in Puerto Rico. J. Nail. Cancer Inst.. 42: 1069-1094. 1969. chloride carcinogenesis. Environ. Health Perspect.. 41: 59-62, 1981. 11. Rothman. K. J., Cann. C. I., and Fried, M. P. Carcinogenicity of dark liquor. 38. Pasta. E. A., Markell. N., and Dorado, R. D. Chronic alcoholism enhances Am. J. Public Health, 79: 1516-1520, 1989. hepatocarcinogcnicity of diethylnitrosamine in rats fed a marginally methyl- 12. Wynder, E. L., Kabat. G., Rosenberg. S., and Levenstein, M. Oral cancer deficient diet. Hepatology, 5: 1120-1125. 1985. and mouthwash use. J. Nati. Cancer Inst.. 70: 255-260. 1988. 39. International Agency for Research on Cancer. Ally! Compounds, Aldehydes, 13. Winn, D. M., Blot, W. J.. McLaughlin, J. K., Austin, D. F., Greenberg. R. Epoxides and Peroxides, IARC Monographs on the Evaluation of the Car S.. Preston-Martin. S.. Schoenberg. J.. and Fraumeni, J. F. Mouthwash use cinogenic Risk of Chemicals to Humans, Vol 36. Lyon. France: IARC, 1985. and oral conditions in the risk of oral and pharyngeal cancer. Cancer Res., 40. Walker. E. A., Castegnaro, M., Garren, L., Toussant. G., and Kowalski, B. 51: 3044-3047, 1991. Intake of volatile nitrosamines from consumption of alcohols. J. Nati. Cancer 14. Tuyns, A. J. Oesophageal cancer in non-smoking drinkers and in non- Inst.. 69:947-951, 1979. drinking smokers. Int. J. Cancer. 32: 443-444, 1983. 41. Schlatter, J.. and Lutz, W. K. The carcinogenic potential of ethyl carbamate 15. Ziegler. R. G.. Morris, L. E., Blot. W. J.. Pottern. L. M.. Hoover. R.. and (urethane): risk assessment at human dietary levels. Food Chem. Toxicol., Fraumeni, J. F. Esophageal cancer among black men in Washington. D.C. 28: 205-211. 1990. II. Role of nutrition. J. Nati. Cancer Inst.. 67: 1199-1206. 1981. 42. Hillers. V. N., and Masscy, L. K. Interrelationships of moderate and high 16. Brown. L. M.. Blot, W. J., Schuman, S. H., Smith, V., Ershow, A., Marks, alcohol consumption with diet and health status. Am. J. Clin. Nutr., 41: 356-362, 1985. R.. and Fraumeni, J. F. Environmental factors and high risk of esophageal cancer among men in coastal South Carolina. J. Nati. Cancer Inst., 80: 1620- 43. Mak. K.. Leo. M.. and Lieber, C. Potentiation by ethanol consumption of 1625. 1988. trachea! squamous metaplasia caused by vitamin A deficiency. J. Nail. Cancer Inst.. 79: 1001-1010. 1987. 17. Victoria, C. G., MuÃ±oz,N.. Day, N. E.. Barcelosl. B., Peccin, D., and Braga, N. Hot beverages and esophageal cancer in southern Brazil: a case-control 44. Mikol. Y. B., Hoover, K. L., Creasia, D., and Poirier, L. Hepatocarcinoge- study. Int. J. Cancer, 39: 710-716, 1987. nesis in rats fed methyl-deficient, amino-acid defined diets. Carcinogenesis (Lond.), 4: 1619-1629, 1983. 18. Tuyns, A. G.. Pequignol. G.. and Abbatucci. J. S. Oesophageal cancer and alcohol consumption: importance of type of beverage. Int. J. Cancer. 23: 45. Garro, A. J., McBeth. D. L.. Lima. V.. and Lieber, C. S. Ethanol consumption 443-447. 1979. inhibits fetal DNA methylation in mice: implications for fetal alcohol syn drome. Alcoholism Clin. Exp. Res.. IS: 395-398, 1991. 19. Elwood, J. M., Pearson, J. C. G.. Skippen. D. H.. and Jackson, S. M. 46. Driver, H. E., and Swann, P. F. Alcohol and human cancer. Anticancer Res., Alcohol, smoking, social and occupational factors in the aetiology of cancer 7:309-320, 1987. of the oral cavity, pharynx, and larynx. Int. J. Cancer, 34: 603-612, 1984. 47. Park, S. S., Ko. L, Patten, C.. Yang, C. S., and Gelboin. H. V. Monoclonal 20. Tuyns, A. F., Esteve, J.. Raymond. L.. Berrino. F.. Benhamou, E.. Blanche!. antibodies to ethanol induced cytochrome P-450 that inhibit aniline and F.. Boffetta. P., Crosignani. P.. DelMoral. A.. Lehman. W., Merletti. F., nitrosamine metabolism. Biochem. Pharmacol.. 35: 2855-2858, 1986. Pequignol. G., Riboli. E.. Sancho-Garnier. H.. Terracini. B.. Zubiri, A., and 48. Murphy, S. E., and Hecht, S. S. Effects of chronic ethanol consumption on Cancer,Zubiri. L. 41:483-491, Cancer of the 1988. larynx/hypopharynx, " tobacco and alcohol. Int. J. benzo[a]pyrene metabolism and glutiathione-5-transferase activities in Syr ian golden hamster cheek pouch and liver. Cancer Res., 46: 141-146, 1986. 21. Yu. M. C.. Mack, T., Hanisch. R.. Peters, R. L.. Henderson, B. E., and Pike, 49. Castonguay, A., Rivenson, A., Trushin, N., Reinhardt, J.. Stathopoulos, S., M. C. Hepatitis, alcohol consumption, cigarette smoking and hepatoccllular Weiss. C., Reiss. B., and Hecht. S. Effects of chronic ethanol consumption carcinoma in Los Angeles. Cancer Res.. 43:6077-6079. 1983. on the metabolism and Carcinogenicity of A'-nitrosonornicotine in F344 rats. 22. Oshima, A., Tsukuma. H., Hiyama. T., Fujimoto. I.. Yamano, H.. and Cancer Res., 44: 2285-2290, 1984. Tanaka. M. Followup study of HBsAg-positive blood donors with special 50. Shaw, S., Rubin. K. P., and Lieber, C. S. Depressed hepatic glutathione and reference to effect of drinking and smoking on development of liver cancer. increased diene conjugates in alcoholic liver disease: evidence of lipid per- Int. J. Cancer, 34: 775-779. 1984. oxidation. Dig. Dis. Sci., 28: 585-589. 1983. 23. McCoy, G. D.. and Wynder, E. L. Enologica! and preventive implications in 51. Palmer. D. L. Alcohol consumption and cellular immunocompctence. Laryn alcohol carcinogenesis. Cancer Res.. 39: 2844-2850, 1979. goscope. Â«A:13-17. 1978. 24. Song, B., Gelboin, H., Park. S. S.. Yang, C. S.. and Gonzales. F. J. Comple 52. Greene. M. H. Non-Hodgkins lymphomas and mycoses fungoides. In: D. mentary DNA and protein sequences of ethanol-inducible rat and human Schottenfeld and J. Fraumeni (eds.). Cancer Epidemiology and Prevention, cytochrome P-450s. J. Biol. Chem.. 261: I6684-I6697. 1987. pp. 754-778. Philadelphia: Saunders. 1982.

2123s

William J. Blot

Cancer Res 1992;52:2119s-2123s.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/52/7_Supplement/2119s

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/52/7_Supplement/2119s. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.