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L Alcohol Estimates of per capita alcoholic beverage intake based on taxes paid on alcohol purchases in various countries may be moderately or extremely low. This is partly because alcoholic beverages purchased either illegally or by special sanctions from U.S. government agencies escape taxation, and thus, inclusion in the tax records from which the estimates are drawn. Studies based on surveys are also prone to error because consumers tend to underestimate their alcohol intake (DeLuca, 1981). EPIDEMIOLOGICAL EVIDENCE Specific Alcoholic Beverages A number of reports implicate specific alcoholic beverages as risk factors for cancers at certain sites. Using data on per capita intake of various types of alcoholic beverages and standard mortality ratios in the 46 prefectures of Japan, Kono and Ikeda (1979) found only suggestive correlations for males between cancer of the esophagus and intake of both whiskey and shochu; cancer of the rectum and wine intake; and cancer of the prostate and shochu intake. There were no correlations for females. Cook (1971) and Collis et al. (1972) ascribed the high frequency of esophageal cancer in an African population to the consump- tion of an alcoholic beverage prepared from maize. In the Normandy region of France, people who consumed home-distilled apple brandy had an increased risk of esophageal cancer, compared to nondrinkers (Tuyns _ al., 1979~. Smoking enhanced this risk (Tuyns and Masse, 1973; Tuyns _ el., 1977~. In a very early study, Lamy (1910) reported an associa- tion between esophageal cancer and the consumption of absinthe by chronic alcoholics in France. In China, where earlier records indicated that esophageal cancer comprised approximately one-half of the gastrointesti- nal tract cancers, pai-kan, a strong alcoholic beverage, was cited as an etiological agent (Kwan, 1937; Wu and Loucks, 1951~. Recently, Hoey et al. (1981) reported that the consumption of alcohol (primarily red wine) increased the risk of adenocarcinoma of the stomach. In this study, which was conducted in Lyon, France, patients with gastric cancer consumed approximately 800 calories per day as alcohol compared to 400 calories per day for patients with other digestive diseases. In a multi-ethnic population living in Hawaii, a direct association was observed for beer consumption and eight cancer sites (including tongue/mouth, pharynx, larynx, esophagus, stomach, pancreas, lung, and kidney) (Hinds et al., 1980~. In the mainland United States, Breslow and Enstrom '1974) and Enstrom (1977) demonstrated a statistically signifi- cant association between per capita beer intake and colorectal cancer, 202 11-1

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A]coho] 203 especially rectal cancer. Wynder and Shigematsu (1967) reported that a group of 314 male colorectal cancer patients contained a significantly higher proportion of beer drinkers than did one control group, but there were no differences between the cases and a second control group. In a study of 166 male bowel cancer patients in Great Britain, Stocks (1957) demonstrated a significant association with beer drinking. Bjelke (1973) reported a dose-response relationship for the risk of colorectal cancer and the frequency of beer and liquor consumption in a prospective study of 12,000 middle-aged Norwegian men. Dean et al. (1979) also reported a direct association based on a cohort study in Dublin. Conversely, case- control studies of bowel cancer in Finland, Kansas, and Norway by Pernu (1960), Higginson (1966), and Bjelke (1971, 1973) showed no significant relationship with beer drinking. Similarly, no associations were ob- served in a correlational analysis by Hinds et al. (1980) or in a cohort study by Jensen (1979~. Using international data and estimates of ethanol intake from beer, wine, and distilled spirits, Vitale et al. (1981) demonstrated a corre- lation coefficient of 0.78 for beer drinking and colorectal cancer in 20 countries. Poor correlations were obtained for colon cancer and intake of total ethanol, distilled spirits, or wine. Thus, in certain populations throughout the world there appears to be an association between consumption of strong, locally prepared alcoholic beverages and esophageal cancer. There also appears to be a statistically significant association between beer drinking and colorectal cancers in certain countries but not in others. These associations with specific beverage types suggest that the effects may be due to intake of other contaminants in the beverages, rather than to consumption of ethanol per _- As noted above, epidemiological studies have linked the consumption of alcoholic beverages to the development of cancers at various sites. In an ideal study to examine this relationship, alcohol abusers and "moderate" drinkers should be studied separately. In the abusers, alcohol may play a modifying or contributing role in carcinogenesis by inducing nutritional deficiency diseases that, in turn, may interact in the process of carcinogenesis in the host. This effect of alcohol may be different in moderate drinkers. However, because it is difficult to determine alcohol intake with accuracy, the distinction between alcohol abuse and moderate drinking in the studies described below is to some extent arbitrary. Total Alcoholic Beverages An association between cancer at various sites and alcohol abuse has been recognized for some time. In France, Piquet and Tison (1937) observed that 95% of their patients with esophageal cancer were alcohol abusers. In a study of 4,000 French patients, Schwartz and colleagues 11-2

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204 DIET, NUTRITION, AND CANCER showed a significant correlation between mean daily alcohol consumption and frequency of cancers of the tongue, hypopharynx, and larynx (Schwartz, 1966; Schwartz et al., 1962, 1966~. A large majority of the individuals with cancers at these sites were heavy drinkers. In a Finnish male cohort study, chronic alcoholics were found to have excess morbidity from cancers of the pharynx, esophagus, and lung (Hakulinen et al., 1974~. On the basis of a literature survey, the World Health Organization (1964) con- cluded that excessive consumption of alcoholic beverages was associated with cancer of the mouth, larynx, and esophagus. Case-control studies conducted in the United States have established that excessive consumption of alcoholic beverages increases the risk of incurring cancer of the oral cavity, excluding the lip, glottis and supraglottic region, larynx, and esophagus (Bross and Coombs, 1976; Burch et al., 1981; Graham et al., 1977; Kaminonkowski and Fleshier, 1965; Keller and Terris, 1965; Keller et al., 1977; Moore, 1965; Rothman and Keller, 1972; Schottenfeld, 1979; Schottenfeld _ al., 1974; Vincent and Marchetta, 1963; Wynder and Bross, 1961; Wynder et al., 1957a). Salient features of the earlier studies have been summarized by Keller et al. (1977) in a report prepared for the U.S. Congress. Excessive alcohol consumption has also been linked with the develop- ment of hepatomas (MacDonald, 1956~. Purtilo and Gottlieb (1973) noted that by far the greatest number of hepatomas were hepatocellular carcino- mas, which were found in 72% of the hepatoma patients studied. Approxi- mately one-half of the 98 patients in this series were alcohol abusers. The investigators suggested that chronic alcoholism contributed to the development of hepatomas by inducing cirrhosis. Keen and Martin (1971) suggested that aflatoxin consumed by African patients induced hepatomas indirectly by first inducing cirrhosis. Vogel and his associates (1970) found hepatitis-associated antigen (HAA) in African patients with hepato- mas. Hepatitis B antigenemia has been frequently associated with hepato- cellular carcinomas (Sherlock et al., 1970; Vogel et al., 1970; Wu and Lam, 1979~. In general, hepatomas are found in individuals with cirrho- sis. Thus, agents such as alcohol, hepatitis antigen, and aflatoxin, which result in hepatic injury leading to cirrhosis, may contribute to the development of hepatomas through this pathway. A number of etiolo- gies have been proposed for the development of carcinomas through the hepatocellular regeneration that accompanies cirrhosis (Lieber et al., 1979). There is a substantial amount of experimental evidence indicating that aflatoxin is a carcinogen as well as a hepatotoxin (Rogers and Newberne, 1971), but there is no direct evidence that hepatitis B virus is oncogenic. (See Chapter 12 for a discussion of primary liver cancer associated with exposure to hepatitis B viral infection.) No adequate studies have been conducted to determine whether alcohol per se is carcinogenic or cocarcinogenic in the develoment of hepatomas in the absence of cirrhosis. Lieber et al. (1979) reported that a small number of alcohol abu- sers developed hepatocellular carcinomas in the absence of cirrhosis. 11-3

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AIcoho] 205 Although other investigators (e.g., Keller, 1978) reported similar findings, Lieber and colleagues suggested that the numbers were too small to ascertain if the tumor incidence was significantly greater in alcohol abusers than in moderate drinkers or nondrinkers. Additional studies are required to evaluate fully the role of ethanol in hepatocarcinogenesis. Other sites in the digestive tract where cancer has also been asso- ciated with alcohol abuse include the gastric cardia (MacDonald, 1972) and the pancreas (Burch and Ansari, 1968~. Synergism Between Alcohol and Smoking Alcohol consumers (especially abusers) are, more often than not, smokers. Flamant _ al. (1964), assessing both variables, stressed the interaction between alcohol consumption and smoking for cancers of the oral cavity and the esophagus. Studies completed since then have con- firmed these findings supporting an interactive role between tobacco and alcohol in tumorigenesis of the oral cavity, the larynx, and esophagus (Burch et al., 1981; Keller and Terris, 1965; Martinez, 1970; Pattern et al., 1981, Rothman and Keller, 1972; Wapnick et al., 1972~. Avoidance of tobacco and alcohol by males could effect a marked reduction of these cancers (Rothman, 1980; Rothman and Keller, 1972~. Flamant et al. (1964) suggested that alcohol abuse may be more important than smoking in the development of esophageal cancer, but smoking is more closely allied to cancers of the mouth and pharynx. It is difficult to ascertain if moderate or heavy consumption of alcohol (other than the beverages specified above) enhances the risk of oral and upper respiratory tract cancer in nonsmokers. Synergistic effects of alcohol and smoking have been observed in smokers consuming 45 ml or more of ethanol per day (Schottenfeld, 1979~. Cancer sites correlating with past ethanol consumption more strongly than with ex- posure to tobacco include the floor of the mouth, supraglottic region, hypopharynx, and esophagus (Omerovic, 1976; Spala jkovic, 1976; Stevens, 1979~. Since alcohol consumption involves direct exposure of the sites, Kissin (1975) suggested that ethanol exerts a direct local effect rather than a systemic one. Geographic, ethnic, and dietary factors may also be of some consequence in esophageal cancer (Pothe and Voigtsberger, 1976; Sadeghi et al., 1977; Schwartz et al., 1966; Steiner, 1956~. A case- control study conducted by Graham et al. (1977) introduced still another variable. These investigators reported that the interaction of tobacco and alcohol in cancers of the oral cavity was apparent only in individuals with clinical evidence of inadequate dentition. McCoy et al. (1979) noted that excessive ethanol consumption and exposure to tobacco may act synergistically to affect the risk of cancer of the upper alimentary and respiratory tracts. The much lower incidence of cancer at these sites in nondrinkers and nonsmokers suggested to these 11-4

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206 DIET, NUTRITION, AND CANCER researchers that excessive alcohol consumption may augment other process- es such as impaired nutritional status, which may be associated with the development of cancer at these sites. Estimated ethanol intake, independent of smoking, was associated with a modest, but increased risk for cancers of the upper respiratory tract (McCoy and Wynder, 1979; Rothman and Keller, 1972~. Williams and Horm (1977) also observed that ethanol increased the risk for cancers at this site when they controlled for smoking. A number of other reports have indicated that there is a dose response between consumption of ethanol (independent of the type of alcoholic beverage) and the risk of upper respiratory tract cancer (Williams and Horm, 1977; Wynder and Stellman, 1977; Wynder _ al., 1957b). In general, these studies focused on mod- erate to heavy consumers of ethanol. Reports by Rothman (1980) and by Burch et al. (1981) indicate that the risk for cancers of the oral cavity is slightly increased in smokers reporting low to moderate consumption of ethanol (i.e., >12 to 45 ml, or approximately 70 to 270 calories daily). However, because consumers tend to underreport their ethanol intake (DeLuca, 1981), it is difficult to interpret these findings. Effect of Nutritional Status Malnutrition may play a key role in the development of cancers of the head and neck in alcohol abusers (Kissin and Kaley, 1974~. These indi- viduals frequently suffer from malnutrition because they often consume from 25% to 50% (or more) of their daily calories as alcohol. In the absence of chronic alcoholism and smoking, malnutrition or nutritional imbalance have been found frequently in individuals with cancer of the oral cavity and respiratory tract (Kissin and Kaley, 1974~. For exam- ple, an association between Plummer-Vinson (also called Paterson-Kelly) syndrome and iron deficiency with esophageal cancer has been observed in Swedish women (Wynder and Fryer, 1958; Wynder and Klein, 1965~. Since the early 1950's, dietary supplementation with iron and vitamins has markedly reduced the incidence of Plummer-Vinson syndrome as well as esophageal cancer (Larsson et al., 1975~. Esophageal cancer in Iran (Kmet and Mahboubi, 1972), Sweden (Jacobsson, 1961), and Puerto Rico (Martinez, 1970) is more frequent among the malnourished. Experi- mentallY induced deficiency of lipotropes, riboflavin, vitamin A, or enhance carcino~en-induced tumors in labora- zinc have been shown to ~ tory animals (Newberne and McConnell, 1980~. EXPERIMENTAL EVIDENCE Postulated Mechanisms of Action in Carcinogenesis Possible mechanisms through which alcohol might contribute to the risk of cancer of the head and neck are: alcohol acting as a carcinogen, 11-5

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Alcohol 207 cocarcinogen, or promoter; alcohol acting as a solvent facilitating transport of carcinogens across membranes; induction of microsomal enzymes by alcohol leading to activation and/or metabolism of car- cinogens; alcohol as a source of putative carcinogenic contaminants in alcoholic beverages; alcohol-related nutritional deficiencies; and alcohol abuse associated with immunosuppression. These have been dis- cussed by Kissin and Kaley (1974), Vitale and Gottlieb (1975), McCoy and Wynder (1979), Lieber et al. (1979), Schottenfeld (1979), and Vitale _ al. (1981~. There are only a few experimental data to indicate that alcohol can act either as a carcinogen or cocarcinogen or that its solvent properties facilitate the transport of carcinogens across cell mem- branes. The relationship of alcohol-induced immunosuppression to tumorigenesis in animals has not been explored, and the role of alco- hol-related nutritional deficiencies to carcinogenesis in animals is only in the preliminary stages of investigation. Alcohol and Induction of Microsomal Enzymes The chronic feeding of ethanol to laboratory animals can increase the activity of the hepatic microsomal enzymes responsible for bioacti- vation of procarcinogens (Rubin et al., 1970~. Polycyclic hydrocarbons, e.g., benzotaipyrene, were activated to a greater extent when rats were fed ethanol than when they were fed a control diet (Seitz et al., 1978~. In contrast, Capel et al. (1978) reported a decrease in benzota~pyrene- hydroxylase activity following chronic administration of ethanol. McCoy _ al. (1979) demonstrated that ethanol fed to hamsters for 28 days in- creased the hydroxylation rates of two cyclic nitrosamines, N-nitroso- pyrrolidine and N-nitrosonornicotine, which are found in mainstream and sidestream tobacco smoke. Enhanced mutagenicity of these hydroxylated compounds was assessed with the Ames test. The enhanced activation of both nitrosamines by ethanol provides some experimental evidence for the synergistic effect of chronic alcohol abuse and smoking in the induction of head and neck cancers. Microsomal activation of tobacco pyrolysate has been observed in the rat lung, and activation of benzotaipyrene occurs in cultures of small bowel tissue. The metabolic activation of these procarcinogens was increased in tissues chronically exposed to ethanol by injection (McCoy et al., 1979~. Occurrence of Putative Carcinogens in Alcoholic Beverages Certain congeners of alcoholic beverages, e.g., nitrosamines (Li jinsky and Epstein, 1970) and fusel oil (Giber et al. , 1968), have been demonstrated to produce tumors of the stomach and esophagus in laboratory animals. Other putative carcinogens found in alcoholic beverages include polycyclic hydrocarbons, such as phenanthrene, fluoranthrene' benzanthracene, benzotaipyrene, and chrysene (Goff and 11-6

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208 DIET, NUTRITION, AND CANCER Fine, 1979; Masuda _ al., 1966), and asbestos fibers, which often leach from filters into wines (Bignon et al., 1977; Gaudichet et al., 1978), beer (Bile s and Emerson, 1968), and gin (Wehman and Plantholt, 1974~. SUMMARY AND CONCLUSIONS The effects of alcohol consumption on cancer incidence have been studied in human populations. In some countries, including the United States, excessive beer drinking has been associated with an increased risk of colorectal cancer, especially rectal cancer. This observation has not been confirmed in most case-control or cohort studies. There is limited evidence that excessive alcohol consumption contributes to hepatic injury and cirrhosis, which in turn may lead to the formation of hepatomas. Excessive consumption of alcoholic beverages by smokers appears to act synergistically in increasing the risk for cancer of the mouth, larynx, esophagus, and the respiratory tract. 11-7

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Alcohol 209 REFERENCES Bignon, J., M. Bientz, G. Bonnaud, and P. Sebastien. 1977. [In French.] Letter to the Editor: Evaluation numerique des fibres d'amiante dans des echantillons de vies. Nouv. Presse Med. 6:1148- 1149. Biles, B., and T. R. Emerson. 1968. Examination of fibres in beer. Nature 219:93-94. Bjelke, E. 1971. Case-control study of cancer of the stomach, colon, and rectum. Pp. 320-334 in R. L. Clark, R. C. Cumley, J. E. McCay, and M. M a Copeland, eds. Oncology 1970. Volume 5: A. Environ- mental Causes. B. Epidemiology and Demography. C. Cancer Educa- tion. Yearbook Medical Publishers, Chicago. Bjelke, E. 1973. Epidemiologic Studies of Cancer of the Stomach, Colon, and Rectum; With Special Emphasis on the Role of Diet, Volumes I-IV. Ph.D. Thesis, University of Minnesota. 1,746 pp. Breslow, N. E., and J. E. Enstrom. 1974. Geographic correlations between cancer mortality rates and alcohol-tobacco consumption in the United States. J. Natl. Cancer Inst. 53:631-639. Brass, I. D. J., and J. Coombs. 1976. Early onset of oral cancer among women who drink and smoke. Oncology 33:136-139. Burch, G. E., and A. Ansari. 1968. Chronic alcoholism and carcinoma of the pancreas: A correlative hypothesis. Arch. Intern. Med. 122:273-275. Burch, J. D., G. R. Howe, A. B. Miller, and R. Semenciw. 1981. To- bacco, alcohol, asbestos, and nickel in the etiology of cancer of the larynx: A case-control study. J. Natl. Cancer Inst. 67:1219-1224. Capel, I. D., M. Jenner, M. H. Pinnock, H. M. Dorrell, and D. C. Williams. 1978. The effect of chronic ethanol intake on the growth and spread of some murine tumors. Oncology 35:224-226. Collis, C. H., P. J. Cook, J. K. Foreman, and J. F. Palframan. 1972. Letter to the Editor: Cancer of the oesophagus and alcoholic drinks in East Africa. Lancet 1:441. Cook, P. 1971. Cancer of the oesophagus in Africa: A summary and evaluation of the evidence for the frequency of occurrence, and a 11-8

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210 DIET, NUTRITION, AND CANCER preliminary indication of the possible association with the con- sumption of alcoholic drinks made from maize. Br. J. Cancer 25: 853-880. Dean, G., R. MacLennan, H. McLaughlin, and E. Shelly. 1979. Causes of death of blue-collar workers at a Dublin brewery, 1954-1973. Br. J. Cancer 40: 581-589. DeLuca, J. R., ed. 1981. Fourth Special Report to the U.S. Congress on Alcohol and Health. National Institute on Alcohol Abuse and Alcoholism, Public Health Service, U.S. Department of Health and Human Services, Rockville, Md. 206 pp. Enstrom, J. E. 1977. Colorectal cancer and beer drinking. Br. J. Cancer 35: 674-683. Flamant, R., O. Lasserre, P. Lazar, J. Leguerinais, P. Denoix, and D. Schwartz. 1964. Differences in sex ratio according to cancer site and possible relationship with use of tobacco and alcohol:- Review of 65,000 cases. J. Natl. Cancer Inst. 32: 1309-1316. audichet, A., P. Sebastien, G. Dufour, G. Bonnaud, M. Bientz, J. Bignon, and J. Puisais. 1978. Asbestos fibers in wines: Relation to filtration process. J. Environ. Pathol. Toxicol. 2: 417-425. Gibel, W., G. P. Wildner, and K. Lobs. 1968. [In German; English Summary.] Cancerogenic and hepatotoxic effects of fusel oil. Arch. Geschwulstforsch. 32:115-125. Goff, E. U., and D. H. Fine. 1979. Analysis of volatile N-nitros- amines in alcoholic beverages. Food Cosmet. Toxicol. 17 :569-573. Graham, S., H. Dayal, T. Rohrer, M. Swanson, H. Sultz, D. Shedd, and S. Fischman. 19 77. Dentition, diet, tobacco, and alcohol in the epidemiology of oral cancer. J. Natl. Cancer Inst. 59:1611-1618. Hakulinen, F., L. Lehtimaki, M. Lehtonen, and L. Teppo. 1974. Cancer morbidity among two male cohorts with increased alcohol consumption in Finland. J. Natl. Cancer Inst. 52: 1711-1714. Higginson, J. 1966. Etiological factors in gastrointestinal cancer in man. J. Natl. Cancer Inst. 37: 527-545. Hinds, M. W., L. N. Kolonel, J. Lee, and T. Hirohata. 1980. Associa- tions between cancer incidence and alcohol/cigarette consumption among five ethnic groups in Hawaii. Br. J. Cancer 41:929-940. 11-9

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Alcohol 211 Hoey, J., C. Montvernay, and R. Lambert. 1981. Wine and tobacco: Risk factors for gastric cancer in France. Am. J. Epidemiol. 113:668-674. Jacobsson, F. 1961. The Paterson-Kelly (Plummer-Vinson) syndrome and carcinoma of the cervical oesophagus. Pp. 53-60 in N. C. Tanner and D. W. Smithers, eds. Neoplastic Disease at Various Sites, Volume 4. Tumors of the Esophagus. E. and S. Livingstone, Ltd., Edinburgh and London. Jensen, 0. M. 1979. Cancer morbidity and causes of death among Danish brewery workers. Int. J. Cancer 23 :454063. Kamionkowski, M. D., and B. Fleshier. 1965. The role of alcoholic intake in esophageal carcinoma. Am. J. Med. Sci. 249 :696-700. Keen, P., and P. Martin. 1971. Is aflatoxin carcinogenic in man? The evidence in Swaziland. Trap. Geogr. Med. 23 :44-53. Keller, A. Z. 1978. Liver cirrhosis, tobacco, alcohol and cancer among blacks. J. Natl. Med. Assoc. 70 :575-579. Keller, A. Z., and M. Terris. 1965. The association of alcohol and tobacco with cancer of the mouth and pharynx. Am. J. Public Health 55:1578-1585. Keller, M., D. M. Promisel, D. Spiegler, L. Light, and M. N. Davies, eds. 1977. Alcohol and cancer. Pp. 53-67 in Second Special Report to the U.S. Congress on Alcohol and Health. Public Health Service, Department of Health, Education, and Welfare, Rockville, Md. Kissin, B. 1975. Epidemiologic investigations of possible biological interactions of alcohol and cancer of the head and neck. Ann. N.Y. Acad. Sci. 252:374-377. Kissin, B., and M. M. Kaley. 1974. Alcohol and cancer. Pp. 481-511 in B. Kissin and H. Begleiter, eds. The Biology of Alcoholism. Volume 3. Clinical Pathology. Plenum Press, New York and London. Kmet, J., and E. Mahboubi. 1972. Esophageal cancer in the Caspian littoral of Iran: Initial studies. Science 175:846-853. Kono, S., and M. Ikeda. 1979. Correlation between cancer mortality and alcoholic beverage in Japan. Br. J. Cancer 40:449-455. Kwan, K. W. 1937. Carcinoma of the esophagus. A statistical study. Chin. Med. J. (Peking) 52:237-254. 11-10

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212 DIET, NUTRITION, AND CANCER Lamy, L. 1910. [In French.] Etude de statistique clinique de 134 cas de cancer de l'oesophage et du cardia. Arch. Mall Appar. Dig. Mall Nutr. 4 :451~7S. Larsson, L.-G., A. Sandstrom, and P. Westling. 1975. Relationship of Pl~mmer-Vinson disease to cancer of the upper alimentary tract in Sweden. Cancer Res. 35:3308-3316. Lieber, C. S., H. K. Seitz, A. J. Garro, and T. M. Warner. 1979. Alcohol-related diseases and carcinogenesis. Cancer Res. 39:2863-2886. Lijinsky, W., and S. S. Epstein. 1970. Nitrosamines as environmental carcinogens. Nature 225:21-23. MacDonald, R. A. 1956. Cirrhosis and primary carcinoma of the liver: Changes in their occurrence at the Boston City Hospital, 1897-1954. N. Engl. J. Med. 255:1179-1183. MacDonald, W. C. 1972. Clinical and pathological features of adeno- carcinoma of the gastric cardia. Cancer 29:724-732. Martinez, I. 1970. Retrospective and prospective study of carcinoma of the esophagus, mouth, and pharynx in Puerto Rico. Boll Asoc. Med. P. R. 62:170-178. Masuda, Y., K. Mori, T. Hirohata, and M. Kuratsune. 1966. Carcino- genesis in the esophagus. III. Polycyclic aromatic hydrocarbons and phenols in whisky. Gann 57:549-557. McCoy, G. D., and E. L. Wynder. 1979. Etiological and preventive implications in alcohol carcinogenesis. Cancer Res. 39:2844-2850. McCoy, G. D., C. B. Chen, S. S. Hecht, and E. C. McCoy. 1979. Enhanced metabolism and mutagenesis of nitrosopyrrolidine in liver fractions isolated from chronic ethanol-consuming hamsters. Cancer Res. 39:793-796. Moore, C. 1965. Smoking and cancer of the mouth, pharynx, and larynx. J. Am. Med. Assoc. 191:283-286. Newberne, P. M., and R. G. McConnell. 1980. Nutrient deficiencies in cancer causation. J. Environ. Pathol. Toxicol. 3~4~:323-356. Omerovic, V. H. 1976. [In Serbo-Croatian; English Summary.] Kronicni alkololizam: Njegova korelacija sa karcinomom oro-farinska. Med. Arh. 30:19-21. 11-11

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The Role of Nonnutnt:ive Dietary Constituents 223 TABLE B-2 Use of Some Food Additives (Nutritive and Nonnutritive) in the United Statesa Category Thickeners/ stabilizers (hydrocolloids) Flavors and enhancers Emulsifiers (surfactants) Approximate Quantity (million kg/year) 195 - 215 132 - 145 123 - 136 Acidulants 82 - 91 Chemical leavening agents 80 - 91 Colors 36 - 39 Humectants 27 - 32 Nutritional supplements (vitamins) Preservatives Enzymes Dietary sweeteners (nonnutritive) Antioxidants Sugar Other aAdapted from Jorgenson, 1980. bData from U.S. Department of Agriculture B-7 25 - 30 23 - 27 ' 12 '2.3 2.3 - 3.6 9,000 '91 , 1980.

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224 DIET, NUTRITION, AND CANCER THE CARCINOGENICITY OF FOOD ADDITIVES AND CONTAMINANTS - Both additives and contaminants have been studied within the United States and abroad. During the past two decades, these studies have produced an immense body of literature on the health effects of food additives. For example, the Select Committee on GRAS Substances (SCOGS) has published 118 reports on 415 GRAS substances (Fisher and Allison, 1981), and the Flavor and Extracts Manufacturing Association (FEMA) has compiled approximately 70 reports (Oser and Ford, 1979), which contain the opinions of an FEMA expert committee on about 1,650 flavoring ingre- dients used in foods. Since 1958 the FAD/WHO Joint Expert Committee on Food Additives has prepared annual reports concerning the toxicity of several hundred additives (World Health Organization, 1958-1980~. The International Agency for Research on Cancer (1972-1981) has published 24 monographs, many of which evaluate the carcinogenic risk of selected additives to humans. Before the 1970's, most reports concerned with the safety of additives were based on data from tests of acute or subchronic toxicity. These reports documented the general health effects of food ingredients, but did not necessarily contain comments on carcinogenicity, although they did identify substances found to be carcinogenic. More chronic feeding studies have been conducted during the past decade. However, the majority of food additives approved for use have not been tested specifically for carcinogenicity or mutagenicity. Table B-3 summarizes the classes of chemicals tested from 1953 to 1973 in the National Cancer Institute Carcinogenesis Bioassay Program (National Cancer Institute, 1975~. Very few epidemiological studies have been conducted to study the effect of food additives. This is probably because of the difficulty of identifying populations with significantly different exposures to specific additives, and because of lack of sensitivity of epidemiological techniques to measure the effects of exposure to low levels of chemicals. Eighty-three of the 415 GRAS substances reviewed by SCOGS have been tested by long-term feeding studies, but very few of these studies were designed to test for carcinogenicity. A total of 513 GRAS substances have been tested for mutagenicity and/or by long-term feeding studies. Because SCOGS was restricted to evaluating each substance only for its use as a GRAS substance, the determination of safety for many of the compounds is based on one specific use of the compound. For example, caffeine was evaluated for its use as an additive in cola beverages only, not for total exposure from all dietary sources, such as from coffee and tea (Fisher and Allison, 1981~. Flavoring ingredients have been assessed by FEMA to determine their safety for specific uses (Oser and Ford, 1979~; however, not all ingre- dients have been tested for mutagenicity and carcinogenicity. Because several food-coloring agents are suspected or known carcinogens, the 30 or more compounds currently approved for this use in the United States have been studied extensively for carcinogenicity. Many pesti- cides, heavy metals, and industrial chemicals have also been examined B-8

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The Role of Nonnutnhve Dietary Constituents 225 TABLE B-3 Categories of Compounds Bioassayed for Carcinogenicity Between 1953 and 1973a Category - Pharmaceuticals Pesticides Industrial chemicals (organic) Metallic compounds Natural food products Food chemicals Tobacco ingredients Environmental agents (general) Miscellaneous (structural analogues, multiple uses) aData from National Cancer Institute, 1975. Percent of Total Bioassayed 20 e8 17.4 15 e2 6~7 5~7 1~6 0.8 0.2 31.6 100.0 specifically for carcinogenicity and/or mutagenicity. Although many naturally occurring contaminants have also been tested for mutagenicity and a few for carcinogenicity, much less emphasis has generally been placed on this class of substances. Table B-4 lists examples of suspected or proven carcinogens in each category of food ingredients. With the exception of saccharin, any direct food additive known to cause cancer in animals or humans has been banned from use in foods. For known carcinogens in some classes of additives, especially contaminants of natural origin, the FDA establishes tolerable levels. However, for residues of pesticides, the Environmental Protection Agency establishes limits (Acceptable Daily Intakes) (U.S. Department of Health and Human Services, 1980~. B-9

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228 DIET, NUTRITION, AND CANCER ASSESSMENT OF EFFECTS ON HUMAN HEALTH - Lack of adequate data on a large number of substances precludes a comprehensive assessment of the risk to humans exposed to food additives and contaminants. Therefore, Chapters 12, 13, 14, and 15 contain examples of nonnutritive substances selected from Table B-4 to illustrate the car- cinogenic potential of this vast group of substances. The selection of these examples was determined by the extent to which humans are exposed through the general diet and the reliability of the data pertaining to these exposures. Any assessment of the health effects of food additives and contami- nants must take into consideration not only the extent to which humans are exposed through the average diet, but also the wide range of exposure for subgroups of the population, the wide range in the carcinogenic potency of these compounds, and the potential for synergistic and/or antagonistic effects of the numerous compounds that are present in the average diet. B-12

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The Role of NonnutA~ve Dietary Constituents 229 REFERENCES Cater, D. B. 1961. The carcinogenic action of carrageenin in rats. Br. J. Cancer 15:607-614. Code of Federal Regulations. 1981. Title 21, Parts 1-99, 100-169, and 170-199. Office of the Federal Register, National Archives and Records Service, General Services Administration, Washington, D. C. Dickens, F., and H. E. H. Jones. 1961. Carcinogenic activity of a series of reactive lactones and related substances. Br. J. Cancer 15:85-100. Feron, V. J., C. F. M. Hendriksen, A. J. Speek, H. P. Til, and B. J. Spit. 1981. Lifespan oral toxicity study of vinyl chloride in rats. Food Cosmet. Toxicol. 19:317-333. Fisher, K. D., and R. G. Allison. 1981. Food Additives as Candidates for Carcinogenicity Testing. Paper prepared for the Committee on Diet, Nutrition, and Cancer for its meeting of February 17-18, 1981. National Academy of Sciences, Washington, D. C. 36 pp. [unpublished]. Gross, M. A., W. I. Jones, E. L. Cook, and C. C. Boone. 1967. Carcino- genicity of oil of calamus. Proc. Am. Assoc. Cancer Res. 8:24. Abstract 93. Hirono, I., H. Mori, M. Haga, M. Fujii, K. Yamada, Y. Hirata, H. Takanashi, E. Uchida, S. Hosaka, I. Ueno, T. Matsushima, K. Umezawa, and A. Shirai. 1979. Edible plants containing carcino- genic pyrrolizidine alkaloids in Japan. Pp. 79-87 in E. C. Miller, J. A. Miller, I. Hirono, T. Sugimura, and S. Takayama, eds. Nat- urally Occurring Carcinogens-Mutagens and Modulators of Carcino- genesis. Japan Scientific Societies Press, Tokyo; University Park Press, Baltimore, Md. Hunter, B., J. Colley, A. E. Street, R. Heywood, D. E. Prentice, and G. Magnusson. 1978a. Xylitol Tumorigenicity and Toxicity Study in Long-Term Dietary Administration To Rats (Final Report). Huntingdon Research Centre, Huntingdon, Cambridgeshire, England. Volumes 11-14 of Xylitol. F. Hoffman La Roche Company, Ltd., Basel, Switzerland. 2250 pp. Hunter, B., C. Graham, R. Heywood, D. E. Prentice, F. J. C. Roe, and D. N. Noakes. 1978b. Tumorigenicity and Carcinogenicity Study with Xylitol in Long-Term Dietary Administration to Mice (Final Report). Huntingdon Research Centre, Huntingdon, Cambridgeshire, England. Volumes 20-23 of Xylitol. F. Hoffman La Roche Company, Ltd., Basel, Switzerland. 1500 pp. B-13

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230 DIET, NUTRITION, AND CANCER International Agency for Research on Cancer. 1973. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 3. Certain Polycyclic Aromatic Hydrocarbons and Heterocyclic Compounds. International Agency for Research on Cancer, Lyon, France. 271 pp. International Agency for Research on Cancer. 1974a. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 5. Some Organochlorine Pesticides. International Agency for Re- search on Cancer, Lyon, France. 241 pp. International Agency for Research on Cancer. 1974b. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 7. Some Anti-Thyroid and Related Substances, Nitrofurans and Industrial Chemicals. International Agency for Research on Cancer, Lyon, France. 326 pp. International Agency for Research on Cancer. 1975. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 8. Some Aromatic Azo Compounds. International Agency for Research on Cancer, Lyon, France. 357 pp. International Agency for Research on Cancer. 1976a. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 10. Some Naturally Occurring Substances. International Agency for Research on Cancer, Lyon, France. 353 pp. International Agency for Research on Cancer. 1976b. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 12. Some Carbamates, Thiocarbamates and Carbazides. International Agency for Research on Cancer, Lyon, France. 282 pp. International Agency for Research on Cancer. 1977. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 13. Some Miscellaneous Pharmaceutical Substances. International Agency for Research on Cancer, Lyon, France. 255 pp. International Agency for Research on Cancer. 1978a. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 16. Some Aromatic Amines and Related Nitro Compounds--Hair Dyes, Colouring Agents and Miscellaneous Industrial Chemicals. International Agency for Research on Cancer, Lyon, France. 400 pp. International Agency for Research on Cancer. 1978b. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volume 18. Polychlorinated Biphenyls and Polybrominated Biphenyls. International Agency for Research on Cancer, Lyon, France. 140 pp. International Agency for Research on Cancer. 1979a. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. Volume 20. Some Halogenated Hydrocarbons. International Agency for Research on Cancer, Lyon, France. 609 pp. B-14

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The Role of NonnutAhve Dietary Constituents 231 International Agency For Research on Cancer. 1979b. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volume 21, Sex Hormones (II). International Agency for Research on Cancer, Lyon, France. 583 pp. International Agency for Research on Cancer. 1980. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volume 22, Some Non-Nutritive Sweetening Agents. International Agency for Research on Cancer, Lyon, France. 208 pp. Jorgensen, D. J. 1980. The need of additives in industry. Pp. 652-677 in H. D. Graham, ed. The Safety of Foods. Second edition. AVI Publishing Company, Westport, Conn. Kraybill, H. F. 1976. Food chemicals and food additives. Pp. 245-318 in P. M. Newberne, ed. Trace Substances and Health: A Handbook. Part 1. Marcel Dekker, New York and Basel. Merrill, R. A. 1978. Regulating carcinogens in food: A Legislator Is guide to the food safety provisions of the Federal Food, Drug, and Cosmetic Act. Mich. Law Rev. 77:171-250. National Academy of Sciences. 1972. A Comprehensive Survey of Industry on the Use of Food Chemicals Generally Recognized as Safe (GRAS) (Comprehensive GRAS Survey). A report prepared by the Subcommittee on Review of GRAS List--Phase II. National Academy of Sciences, Washington, D.C. 41 pp. National Academy of Sciences. 1973. The Use of Chemicals in Food Production, Processing, Storage, and Distribution. A report prepared by the Committee on Food Protection, Food and Nutrition Board. National Academy of Sciences, Washington, D.C. 34 pp. National Academy of Sciences. 1978. 1975 Resurvey of the Annual Poundage of Food Chemicals Generally Recognized as Safe (GRAS). Committee on GRAS List Survey--Phase III. National Academy of Sciences, Washington, D.C. 23 pp. National Academy of Sciences. 1979. The 1977 Survey of Industry on the Use of Food Additives. Volume 1, Description of the Survey; Volume 2, Summarized Data; Volume 3, Estimates of Daily Intake. Food and Nutrition Board, National Academy of Sciences, Washington, D.C. 2,135 pp. Available from the National Technical Information Service, Springfield, Va. as Publication No. PB 80-113418. National Academy of Sciences. 1981. The Health Effects of Nitrate, Nitrite, and N-Nitroso Compounds. Part 1 of a 2-Part Study by the Committee on Nitrite and Alternative Curing Agents in Food. National Academy Press, Washington, D.C. 544 pp. B-15

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232 DIET, NUTRITION, AND CANCER National Cancer Institute. 1975. Survey of Compounds Which Have Been Tested for Carcinogenic Activity. 1972-1973 Volume. National Institutes of Health, U.S. Department of Health, Education, and Welfare, Bethesda, Md. 1638 pp. National Cancer Institute. 1979. Bioassay of Methyl Parathion for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 157. DREW Publication No. (NIH) 79-1713. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 112 pp. National Science Foundation. 1973. Chemicals and Health. Report of the Panel on Chemicals and Health of the President's Science Advisory Committee, September 1973. Science and Technology Policy Office, National Science Foundation, Washington, D.C. 211 pp. Norris, J. M. 1977. Status Report on the 2 Year Study Incorporating Acrylonitrile in the Drinking Water of Rats. Health and Environ- mental Research, The Dow Chemical Company, Midland, Mich. t14] pp. (unpublished). Oser, B. L., and R. A. Ford. 1979. Recent progress in the considera- tion of flavoring ingredients under the food additives amendment. 12. GRAS substances. Food ~echnol. 33~7~:65-73. Roberts, H. R. 1981. Food safety in perspective. Pp. 1-13 in H. R. Roberts, ed. Food Safety. John Wiley & Sons, New York. U.S. Department of Agriculture. 1980. Sugar and Sweetener Report 5~8~: 1-54. U.S. Department of Health and Human Services. 1980. Food and Drug Administration Acts. Federal Food, Drug, and Cosmetic Act, as Amended January 1980; Public Health Service Act, Biological Products; Radiation Control for Health and Safety Act; Fair Packaging and Labeling Act. HHS Publication No. (FDA) 80-1051. Food and Drug Administration, U.S. Department of Health and Human Services, Rockville, Md. 169 pp. U.S. Department of Health, Education, and Welfare. 1981. Toxicological Principles and Procedures for Direct Food Additive Cyclic Review U.S. Department of Health, Education, and Welfare, Washington, D.C. (unpublished) U.S. Food and Drug Administration. 1980. Compliance Program Report of Findings. FY 77 Total Diet Studies--Adult (7320.73~. Bureau of Foods, Food and Drug Administration, Washington, D.C. [33] pp. B-16

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The Role of Nonnutritive Dietary Constituents 233 U.S. Food and Drug Administration. 1981. Consumers participate in FDA's priority setting process. FDA Consumer Update 18:1-3. Witschi, H. P., P. J. Hakkinen, and J. P. Kehrer. 1981. Modification of lung tumor development in A/J mice. Toxicology 21:37-45. World Health Organization. 1958-1980. Reports of the Joint FAD/WHO Expert Committee on Food Additives. World Health Organization Technical Report Series (Twenty-four reports to date). World Health Organization, Geneva, Switzerland. World Health Organization. 1980. Evaluation of Certain Food Additives. Twenty-Third Report of the Joint FAD/WHO Expert Committee on Food Additives. WHO Tech. Rep. Ser. 648:1-45. B-17