[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

Although ethanol has generally not been found to induce cancer inexperimental animals, the consumption of alcoholic beverages has beenlinked to increased risks of several cancers in humans. Risks of oral,pharyngeal, laryngeal, esophageal, and liver cancer are elevated amongdrinkers, typically in proportion to the amount consumed. Evidenceassociating colorectal and breast cancer with alcohol drinking is suggestive but awaits confirmation. All types of alcoholic beverages seem to beimplicated, pointing to an etiological role for ethanol or its metabolites.The mechanisms, however, by which alcohol induces cancer in humansare not clear. This review summarizes epidemiological studies of alcoholand cancer, focusing primarily on characteristics of the association thatmay provide clues to causal pathways.

Introduction

Epidemiological studies have provided definitive evidencethat the drinking of alcoholic beverages can induce cancer inhumans (1). These investigations not only have identified cancers associated with alcohol drinking but also have providedclues to etiological mechanisms. This review describes the associations between alcohol and specific cancers in human populations and discusses potential pathways through which alcoholic beverages may cause cancer.

Materials and Methods

Information on alcohol as a cause of cancer has come primarily fromepidemiological observations. Both cohort studies, which ascertaindrinking habits of study participants and their subsequent mortality,and case-control studies, which focus on a particular cancer and theretrospective determination of prior alcohol consumption, have evaluated cancer risks according to the amount and type of alcohol intake.Supporting evidence has come from studies correlating cancer rates atthe national, regional, local, or group level with average drinkingpatterns for the group, although these descriptive investigations aregenerally more useful for raising rather than testing etiological hypotheses. The findings from these epidemiological investigations, categorized by type of cancer, are summarized below.

Results

Total Cancer. Risks of cancer rise with increasing level ofconsumption of alcoholic beverages. Table 1 shows RR3 of

cancer (all types combined) according to daily intake, with a60% smoking-adjusted excess risk in the heaviest alcohol consumption category. The data, which are typical of several studiesof total cancer risk, are derived from the largest cohort studyof male drinkers, a 12-year follow-up of approximately 276,000American men (2). Risks, however, vary considerably by typeof cancer, as described below.

Oral and Pharyngeal Cancers. Among the strongest associations with alcohol intake are those found for oral and pharyngeal cancers. These are also among the cancers whose associations with alcohol consumption have been the most well char-

' Presented al "Nutrition and Cancer," the first conference of the InternationalConference Scries on Nutrition and Health Promotion. April 17-19, 1991,Atlanta, GA.

3To whom reprint requests should be addressed.1The abbreviation used is: RR. relative risk.

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acterized and for which the most clues to mechanisms havearisen. Because cigarette smoking is a major determinant ofthese cancers, and because drinkers of alcoholic beverages tendto be smokers, smoking and drinking need be evaluated concurrently. Table 2 shows the interaction between smoking anddrinking in the risk of oral and pharyngeal cancer, with datafrom a study of nearly 1100 patients with these cancers and1300 control subjects that was conducted in the mid-1980s infour areas of the United States (3). The large study size enabledthe most precise estimates available of the joint effects oftobacco and alcohol on risk of any cancer. As indicated in Table2, within each smoking category risks of oral and pharyngealcancer tended to increase as alcohol intake increased. Thesmoking-adjusted RR (bottom row) rose to almost 9 for thosewho drank 30 or more drinks per week (i.e., averaging morethan 4 per day), whereas the alcohol-adjusted RR (right column)rose to over 4 among two-pack-a-day smokers. Drinking tendedto combine with smoking in a multiplicative fashion, so thatrisks for heavy consumers of both products exceeded risks forabstainers from both by 37-fold.

The multiplicative interaction indicates that much of theeffect of alcohol is via an enhancement of tobacco's effect on

these tumors and that reduction in either one of the exposureswill substantially reduce cancer incidence. Indeed, it is estimated that approximately 75% of all oral and pharyngealcancers in the United States are caused by smoking and drinking, with the bulk of these caused by the synergistic effect ofthe two (3). Table 2 shows, however, that smoking is not anecessary prerequisite for alcohol-induced cancer, because risksof oral and pharyngeal cancer rose with increasing alcoholintake in life-long nonsmokers (and also in exsmokers). Similareffects were reported elsewhere (4). The strength of the trendsin nonsmokers suggests that alcohol drinking alone is sufficientto induce oral tumors. It is possible, however, that alcoholinteracts with other carcinogens in causing these cancers intobacco abstainers. The issue is difficult to evaluate directly inepidemiological studies, because typically only few of the cancerpatients are nonsmokers and subdividing this small group ofnonsmokers into smaller categories of exposure to other riskfactors is generally not feasible.

Besides tobacco and alcohol, diet and nutrition are amongthe factors most strongly associated with oral and pharyngealcancer. Increased risks have been associated with nutritionaldeficiency, as in the Plummer Vinson syndrome of iron, ribo-flavin, and other vitamin deficiencies (5). Furthermore, withinnormal dietary ranges, risks typically increase as consumptionof fresh fruits and vegetables decreases (6). Table 3 shows thejoint effects of alcohol and fruit and vegetable intake on theoral and pharyngeal cancer risks of smokers in North Carolina(7). Drinkers experienced increased risks in each fruit andvegetable category, with the highest risk for heavy drinkers whoalso had low fruit and vegetable intake. It thus appears thatdrinking enhances the deleterious effect of poor nutrition. Although Table 3 shows separate effects of alcohol and diet, itmay be that drinking contributes to increased risk through itslowering of nutritional status (by provision of nonnutritivecalories and deprivation of vitamins, minerals, and othernutrients).

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Table 1 Relative risks of total cancer mortality according to number of alcoholicdrinks per day

Data are from a cohort follow-up of 276.000 American men (2).

Alcohol intake(drinks/day)None

<123456+No.

ofcancerdeaths4748

56.11026458345178441RR°1.0

0.90.9

1.11.31.5

1.695%

Confidenceinterval0.8-

0.9-1.0-1.2-1.3-1.5-.0

.1.3

.5

.7

.8°All risks relative to nondrinkers and adjusted for cigarette smoking.

Table 2 Relative risks of oral and pharyngeal cancer in males according toamount of tobacco smoking and alcoholic beverage drinking

RR

SmokingstatusNonsmokerExsmokerl-19/dayfor

20+yr20-39/dayfor 20+yr40+/day

for 20+yrTotal1'<1"1.0°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*1.0e1.11.62.84.4

°Number of drinks/week.1Risks adjusted for alcohol intake.

' Reference category. Data from United States case-control study (3).d Risks adjusted for smoking.

Table 3 Relative risks of oral and pharyngeal cancer among North Carolinafemale smokers, according to alcohol and fruii and vegetable intake

Alcohol intake(ml/day)Nondrinker

<6060+>21°1.0*

2.44.4RR11-202.1

4.44.1<115.2

2.813.6

" Fruit and vegetable intake (sen ings/week).* Reference category. Data from Ref. 7.

Few studies have calculated risks of oral and pharyngeal orother cancers according to duration of drinking or years sincecessation of drinking. This information seems not to have beencollected in part because of difficulty in accurately identifyingexdrinkers and when they stopped consuming alcoholic beverages. Several cohort studies noted that total death rates forexdrinkers equal or exceed those of drinkers, but the excessseems mainly confined to cardiovascular disease and not cancermortality, probably because exdrinkers stopped drinking because of illness (8, 9). In a case-control study in Puerto Rico,risks of oral (and esophageal and laryngeal) cancer were lowerfor those who stopped drinking for 10 or more years, butchanges in smoking were not accounted for (10). The lack ofdata on the effects of alcohol according to the timing of exposure hinders evaluation of the stage at which alcohol influencescarcinogenesis. If it were known, for example, that risk of oralcancer dropped rapidly after cessation of drinking, as it doesafter cessation of smoking (3), then it could be inferred thatalcohol affects primarily a late or promotional stage in thecarcinogenic process.

Increased risks of oral and pharyngeal cancer have beenassociated with nearly all types of alcoholic beverages, suggesting a role for common ingredients, particularly ethanol. Therehave been differences in the magnitude of risk, however, withdifferent types of beverages. In the large national study of oraland pharyngeal cancer, risks associated with equivalentamounts of hard liquor and beer were nearly equal and exceededthose for wine, which were elevated only in the heaviest consumption categories (3). In areas of northern Italy where wine

is the predominant alcoholic beverage and intake is high, increases in oral-cancer risk with increasing consumption alsowere reported (4). When spirits were classified as dark (such asbourbon and scotch) or light (such as gin and vodka, whichhave fewer congeners) in one small American study, risks ofhypopharyngeal cancer were higher in consumers of dark thanlight alcohol (11).

The idea that ethanol may be the key ingredient responsiblefor the high rates of cancer in drinkers also was suggested bythe observation that risk of oral cancer was increased in usersof mouthwash (12). The mouthwash association has been detected in several studies, with the most recent (13) indicatingthat the excess risk may be limited to users of mouthwasheshigh in alcohol content (Table 4). The link to mouthwash alsosuggests that alcohol may influence oral carcinogenesis via atopical rather than systemic route, because few persons swallowmouthwash.

Esophageal Cancer. Like oral and pharyngeal cancer, esophageal cancer is strongly related to alcoholic-beverage consumption (1). Cohort and case-control studies around the worldreveal significant increases in risk of this cancer with increasingalcohol intake. They also tend to show that alcohol combineswith smoking in a multiplicative fashion to enhance esophagealcancer risk. As indicated in Table 5, however, strong increasesin risk with rising alcohol consumption have also been notedamong nonsmokers, with > 10-fold elevations in heavy drinkersin France (14). Similar to the situation for oral cancer, alcoholalso appears to worsen the effect of poor nutrition, and viceversa. Table 6 shows risks of esophageal cancer according tothe cross-classification of dietary status and alcohol intake froma case-control study in Washington DC. (15). Risks rose asalcohol intake increased and nutritional status decreased, with

Table 4 Relative risks of oral and pharyngeal cancer associated with use ofmouthwashes with low and high alcohol content

Data are from Ref. 13.

MouthwashusedNone

Low-alcohol"High-alcohol*

Mixed typesRR1.0

0.71.61.5Males95%

Confidenceinterval0.4-1.1

1.1-2.31.1-2.1RR1.0

0.81.92.0Females95%

Confidenceinterval0.4-1.5

1.1-3.31.3-3.1

" Less than 25% ethanol.* 25% or more ethanol.

Table 5 Relative risks of esophageal cancer among nonsmokers in Normandy,France, according to level of alcohol intake

Data are from Ref. 14.

Ethanol intake(ml/day)0-4041-80

81-120121+RRMales1.0(7)

3.8(15)10.2(9)

101.0(8)(no.

of cases)Females1.0(25)

5.6 (8)11.0(3)

Table 6 Relative risks of esophageal cancer according to nutritional status andlevel of alcohol drinking

Data are from a case-control study in Washington. DC (15).

Alcohol intake(ml/day)

RR

High" Moderate Low

0-179180+

1.0*

2.71.74.1

3.08.0

' Nutritional status, defined by usual adulthood intake of fruits, vegetables,

and other foods.* Reference category.

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Table 7 Relative risks oflaryngeal cancer in western Canada hy anatomicsubsite, according to alcoholic bererage intake

Data are from Ref. 19.

Alcohol intake(Huidoz/wk)<1

1-45-910-20

20+Extrinsic

larynx1.0

1.72.65.16.4Intrinsic

larynx1.01.1

0.72.02.2

a nearly constant ratio of the effect of alcohol across nutritioncategories, consistent with a multiplicative interaction betweenthe two.

Risks of esophageal cancer have tended to be somewhathigher for drinkers of hard liquor than beer or wine, but risingtrends in risk have been noted with increasing consumption ofeach beverage category (1). In some areas of the world, particular alcoholic beverages have been linked to unusually highlevels of esophageal cancer risk. In coastal South Carolina,which for several decades has led the nation in death rates fromesophageal cancer, nearly 90% of interviewed black patientsreported they were regular consumers of moonshine whiskeys(16). Home-brewed rum has been implicated along with otheralcoholic beverages in the high rates of upper-digestive-tractcancers in Puerto Rico (10). In Southern Brazil, strong increases in risk of esophageal cancer have been linked to thedrinking of cachaca, a distilled spirit from sugarcane (17). Oneof the most striking links between a particular beverage andcancer is seen in northern France, where extraordinarily highrisks of esophageal cancer were documented in drinkers ofCalvados and other local apple brandies (18). The variations inrisk based on beverage type suggest that, in addition to ethanol,congeners or other ingredients in beverages may play an etio-logical role.

Laryngeal Cancer. Alcohol is a strong determinant of cancerof the larynx, with the risk profile being quite similar to thatseen for cancers of the oral cavity, pharynx, and esophagus (1).Risk of alcohol-induced laryngeal cancer, however, appears tovary by anatomic subsite. Table 7, using data from a case-control study in western Canada (19), shows that alcohol exertsa greater effect on cancers of the extrinsic than the intrinsiclarynx. Similar differentials were reported in France, Spain,and Italy (20) and provide additional evidence that alcohol mayact through topical exposure.

Liver Cancer. Alcohol is recognized as a cause of primaryliver cancer (1). Deaths from liver cancer were reported to beincreased by about 50% in alcoholics, with increases of this orslightly higher magnitude also noted in case-control studies ofthis cancer (1). Epidemiological studies have provided limiteddata on interrelationships between alcohol and other risk factors for liver cancer, but some interactive effects with smoking(a weak liver carcinogen) and hepatitis B virus (a strong livercarcinogen) were reported (21, 22). Alcohol's effect on liver

cancer may be through its induction of cirrhosis and other liverdamage, which in some cases may predispose patients to hepatictumor development.

Alcohol's influence on the liver may potentially be more

important for cancer in organs other than the liver than in theliver itself. Continued alcohol drinking can elevate levels ofliver enzymes, including cytochrome P-450, which in turn cancatalyze the metabolism of xenobiotics (23. 24). Alcohol canalso alter the liver's ability to detoxify compounds with carcin

ogenic potential. This influence on metabolism has been hypothesized to influence formation of tumors at extrahepatic

sites. For example, liver enzymes that normally metabolicallydeactivate diethylnitrosamine, an esophageal carcinogen in animals, are impaired with alcohol intake (25). With first-passclearance altered in drinkers, the nitrosamine may more readilytarget the susceptible esophagus. Alcohol also tends to depletethe liver's vitamin A stores and consequently may affect blood

and tissue levels of retinol and its metabolites, compounds thathave been shown to influence several types of chemically induced cancer in animals (26, 27).

Breast Cancer. In the past decade, more than one-dozenepidemiological investigations have found increased risks ofbreast cancer associated with the drinking of alcoholic beverages(1, 28-31). Dose-response trends have generally been evident.The trends are remarkable because excess risks often wereapparent at relatively low levels of consumption. Table 8 displays RR of breast cancer according to alcoholic beverage intakefrom a 4-year follow-up of nearly 90,000 nurses (28). Significantincreases in breast cancer were associated with consumptionlevels as low as three to nine drinks per week. Adjustment forknown breast-cancer risk factors did not substantially affect thefindings. Similarly, a 12-year follow-up of >500,000 women bythe American Cancer Society, which recorded 599 breast-cancerdeaths in drinkers and 2,334 in nondrinkers, revealed an approximate 20% increase in risk among women consuming onealcoholic drink per day, rising to a 70% increase among thoseconsuming five or more per day (29). In a combination of datafrom six case-control studies conducted outside the UnitedStates, however, a significant excess risk of breast cancer wasevident only in women drinking more than three drinks per day(31). In some studies, the effect of alcohol was most pronouncedwhen intake occurred at young ages (32). The consistent findings and generally similar dose-response trends in these andother studies suggest that alcohol intake may be causally relatedto breast cancer. The magnitude of the association is not large,so that confounding by other risk factors could play a role, butmost investigations controlled for the known causes of thiscancer.

If the association between alcohol and breast cancer is causal,the mechanisms are not clear. Ethanol, however, was reportedto alter hormonal status in experimental animals, includingdisturbing the menstrual cycle and decreasing luteinizing hormone levels (33). In humans, alcohol abuse can lead to earlymenopause (a protective factor for breast cancer) and increasedlevels of estrogens, prolactin, and other hormones (potentialbreast-cancer risk factors) (33). It seems likely that more moderate doses of alcohol would have more subtle effects butperhaps could modify hormonal status or other factors enoughto result in the small increases in breast-cancer risk observed.

Colon and Rectal Cancers. Several cohort and case-controlstudies suggest that the risk of large-bowel cancer, particularlyrectal cancer, may be increased with the consumption of alcoholic beverages. In four of nine cohort and six of nine case-control studies reviewed by the International Agency for Research on Cancer, significant increases in rectal cancer risk were

Table 8 Relative risks of breast cancer hy level of alcohol intakeData are from a prospective 4-year follow-up of 90,000 American nurses (28).

Alcoholintake

(drinks/wk)None

<11-23-910+No.

ofbreast cancer

cases171

6698

139127RR1.0

1.00.91.31.695%

Confidenceinterval0.8-1.3

0.7-1.21.0-1.61.3-2.0

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found in drinkers, particularly beer drinkers (1). In a recentfollow-up of 106,000 members of a prepaid health plan inOakland, CA, which adjusted for several potential risk factors,the RR of subsequent rectal cancer (cancers occurring morethan 6 months after ascertainment of alcohol intake) reached4.1 and of colon cancer reached 1.9 in those who drank threeor more drinks per day (34). Inconsistencies across studies andsmall numbers of observations, however, preclude inferring atthis time that alcohol intake causes large-bowel cancer, so thatdiscussion of etiological mechanisms is premature.

Other Cancers. Although there have been some reports ofalcohol-related stomach, pancreas, lung, bladder, and othertumors, the overall evidence suggests that alcohol is not a riskfactor for these cancers ( 1).

Discussion

The epidemiológica! observations from around the worldleave little doubt that drinking alcoholic beverages can causecancer. How intake influences cancer risk, however, is not clear.Few clues to mechanisms have come from bioassays, becauseneither alcoholic beverages nor ethanol have been shown toinduce cancer in experimental animals. In its review of nearly20 experiments in mice, rats, and hamsters administered alcohol orally, an International Agency for Research on Cancerworking group noted that most failed to reveal significant orpositive associations, but the numbers of animals were oftensmall and the durations of exposure often short (1). In somestudies, however, ethanol was reported to increase the incidenceof esophageal carcinomas induced by /V-nitrosodiethylamineand /V-nitrosodipropylamine and of liver cancers induced byvinyl chloride (35-37). In another experiment, chronic consumption of alcohol by rats fed a methyl-deficient diet enhancednitrosamine-induced liver carcinogenesis (38). Furthermore,acetaldehyde, the major intermediary metabolite of ethanol, isa recognized animal carcinogen, causing nasal and laryngealcarcinomas after inhalation and enhancing the incidence ofbenzo(a)pyrene-induced lung tumors (39).

The absence of carcinogenic effect of alcohol in most studiesin experimental animals has precluded their generation of leadsto mechanisms of alcohol-induced cancer. Studies of noncarcin-ogenic effects of alcohol in experimental situations and inhumans, however, provide some clues. When combined withthe epidemiological observations described earlier, some support can be found for each of the following hypotheses regardingpossible mechanistic pathways through which alcohol drinkingmay cause cancer. Alcohol (or alcoholic beverages) may

1. Contain congeners and other contaminants that may becarcinogenic. Several substances known or thought to causecancer in humans have been detected in alcoholic beverages.Included are /V-nitroso compounds (found in some beers), my-cotoxins (found in some wines and south African maize beer),urethan (found at high levels in certain fruit brandies), tannins(found in wines), inorganic arsenic and other pesticide residues,and asbestos filtration products (1, 40, 41). In addition, alcoholic beverages may contain additives, such as flavoring agentsand preservatives, and natural products, such as aldehydes,acrolein, phenols, and ketones, that may influence the carcinogenic process.

2. Generate metabolites that are carcinogenic to humans. Themajor metabolite of ethanol is acetaldehyde, a recognized animal carcinogen and teratogen, which may have a similar effecton humans (39).

3. Act as a solvent, increasing penetration of other carcino

gens into target tissues. The strong increases in risk of cancersin tissues that are topically exposed (e.g., mouth, throat, esophagus, and extrinsic larynx) to alcohol and the strong interactiveeffects with tobacco are consistent with this hypothesis.

4. Reduce intake and bioavailability of nutrients that mayinhibit cancer and enhance nutritional deficiencies that increaserisk of cancer. For heavy drinkers the percentage of caloriesderived from alcohol can be substantial. In one survey of middle-class males, for those who consumed the equivalent of about2.5 or more drinks per day alcohol contributed 24% of allcalories and intake of protein and several nutrients (especiallyvitamins A and C) was significantly decreased (42). In somecases, the deprivations may lead to nutritional deficiencies thatmay alter epithelial cell chemistry and function, increasingsusceptibility to carcinogens. Via its hepatic effect, alcohol maylimit the delivery to cells of nutrients that may be protectivebecause of antioxidant or other properties. In rats, ethanol wasreported to enhance trachea! metaplasia induced by vitamin Adeficiency (43). Alcohol may also induce methyl deficiencies,which have been shown to cause liver cancer in experimentalanimals, and enhance the tumorigenic effect of methyl-deficientdiets (38, 44). The hypomethylating environment induced byalcohol may be due to the effects of alcohol on enzyme activities,because acetaldehyde, even at relatively low concentrations, hasbeen reported to inhibit DNA methyltransferase activity (45).

5. Inhibit the detoxification of carcinogenic compounds.Heavy alcohol consumption can induce cirrhosis and other liverdamage. Experimental studies suggest that, through its effectson the liver, alcohol may block hepatic inactivation of tobacco-related and other carcinogens and modify the liver's clearance

function, increasing exposure to compounds such as JV-nitro-sodiethylamine in other organs (24, 46).

6. Catalyze the metabolic activation of some compounds intocarcinogens. Chronic alcohol intake can induce enzyme (including cytochrome P450) activities that enhance the metabolicactivation of compounds into carcinogens (23, 46-48). Forexample, ethanol influences enzymes that catalyze the metabolism of tobacco-specific nitrosamines, possibly contributing tothe interactive effects of tobacco and alcohol on risk of upperaerodigestive tract cancers (49).

7. Affect hormonal status, increasing the risk of hormone-related cancers. Alcohol may influence the level, function, andmetabolism of hormones (33), resulting in increased exposureto estrogens and other compounds in susceptible target organs(e.g., breast).

8. Increase cellular exposure to oxidants. Alcohol may influence activation or inactivation of carcinogens at the cellularlevel in target tissues (e.g., mouth and throat). Ethanol has beenreported to result in elevated tissue exposure to oxidants, thusincreasing the risk of DNA damage and malignant transformation (50).

9. Suppress immune function. Alcohol, through its effect onnutritional status, liver disease, and perhaps other body functions, may decrease immune response (51), although increasedrisks of lymphoma, the tumor most closely associated withdepressed immune function (52), have not been reported indrinkers.

Additional laboratory and epidemiological research on theeffects of alcohol consumption may help clarify the mechanism(or, more likely, mechanisms) by which alcohol causes cancerin humans. On the basis of existing evidence, however, it isclear that the most direct avenue to reducing the cancer burdenassociated with drinking is to reduce the level of intake ofalcoholic beverages. Because a substantial portion of alcohol-

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induced oral, esophageal, laryngeal, and hepatic cancers (thetumors most strongly related to alcohol) result from heavydrinking, reductions to moderate levels should help to considerably lower the risk of these cancers while further studies seekto determine causal pathways.

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