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Diet, Nutrition, and Cancer (1982)

Chapter: 17 The Relationship of Diet to Cancer at Specific Sites

« Previous: 16 Cancer Incidence and Mortality
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

17 The Relationship of Diet to Cancer at Specific Sites To present more clearly what is known about the relationship between diet and cancer at specific sites, the committee has reassembled the epidemiological literature and summarized it by site: esophagus, stomach, colon and rectum, liver, pancreas, gallbladder, lung, urinary bladder, kidneys, breast, endometrium, ovary, and prostate. Since most of these data have already been discussed in earlier chapters on specific dietary constituents, the information contained in the following pages has been greatly condensed. The organization of this chapter reflects the design of most epidemiological studies, which generally examine cancer at spe- cific sites. ESOPHAGEAL CANCER The incidence of esophageal cancer varies widely among different regions of the world. A belt of particularly high risk runs from the Middle East (notably the Caspian littoral of Iran) through central Asia to China. Other regions of high risk are the eastern and southern areas of Africa, and France has unusually high rates, especially in Normandy and Brittany. Correlational analyses have shown direct associations of alcohol drinking with incidence of and mortality from esophageal cancer in some parts of the world. These studies were based on both estimated per capita intakes and dietary interview data in special population groups in Western countries (Breslow and Enstrom, 1974; Hinds et al., 1980; Kolonel et al., 1980; Lyon et al., 1980a,b; Schoenberg et al., 1971~. Chilvers et al. (1979) found a consistent relationship between mortality from esophageal cancer and total ethanol intake in England and Wales. Other investigators reported high correlations of esopha- geal cancer mortality with death rates from cirrhosis and alcoholism (Lipworth and Rice, 1979; Tuyns et al., 1979~. The results from a number of case-control studies have confirmed the association with alcohol. Various investigators have demonstrated a dose-response relationship after controlling for cigarette smoking (Keller, 1980; Martinez, 1969; Pattern et al., 1981; Tuyns et al., 1979; Williams and Horn, 1977; Wynder and Brass, 1961; Wynder and Stellman, 1977~. Schmidt and Popham (1981) found a significantly in- creased risk for esophageal cancer in a retrospective cohort study of male alcoholics. Smoking and alcohol appear to act synergistically to increase the risk for esophageal cancer as they do for cancers of the oral cavity and larynx (Rothman and Keller, 1972; Tuyns et al., 1977~. 17-1 391

392 DIET, NUTRITION, AND CANCER There has been no consistency in the type of alcoholic beverage most strongly associated with the risk of esophageal cancer. Some investi- gators found no specificity at all (Breslow and Enstrom, 1974; Williams and Horm, 1977~; some found a stronger association with hard liquor than with beer or wine (Pottern et al., 1981; Wynder and Bross, 1961~; and some reported a stronger association with beer (Hinds et al., 1980; Mettlin_ al., 1980~. Alcohol consumption cannot explain the pattern of esophageal cancer in Africa and Asia (Bradshaw and Schonland, 1974; Burrell, 1962; Collis _ al., 1971; Gatei et al., 1978; Higginson and Oettle, 1960; Joint Iran-International Agency for Research on Cancer Study Group, 1977; Yang, 1980~. Correlation studies have indicated that the intakes of pulses (e.g., lentils), green vegetables, fresh fruit, animal and fish protein, and the estimated intakes of vitamin A, vitamin C, and riboflavin, are lower in high risk regions of the Caspian littoral in Iran (Hormozdiari et al., 1975; Joint Iran-International Agency for Research on Cancer Study Group, 1977~. Similar studies in China have implicated low intakes of trace elements (particularly molybdenum), animal products, fat, fruits, vegetables, calcium, and riboflavin; high intakes of pickles, pickled vegetables, and moldy foods containing N-nitroso compounds (possibly produced by the fungal contaminants); and consumption of foods at very high temperatures (Coordinating Group for Research on Etiology of Esopha- geal Cancer in North China, 1975; Yang, 1980~. In Japan, Segi (1975) found a direct association between mortality from esophageal cancer and the intake of tea-cooked rice gruel. On the other hand, Stocks (1970) and Howell (1974) found no associations between international per capita food and beverage intakes and corresponding mortality rates for esophageal cancer. In view of the findings that nitrosamines and fungi contaminate some foods in China, it is notable that Marasas et al. (1979) found higher contamination levels of Fusarium mycotoxins in samples of corn (a dietary staple) from a high risk area for esophageal cancer in the African Repub- lic of Transkei, compared with levels in a low risk area. However, these mycotoxins, unlike aflatoxin, have not been shown to be carcinogenic. Furthermore, results of the studies in Iran indicated that there were no differences in aflatoxin (or nitrosamine) levels in foods in regions of high and low risk for esophageal cancer. A case-control study in Iran confirmed the inverse relationship be- tween esophageal cancer and consumption of fresh fruit and cooked vege- tables (Cook-Mozaffari, 1979; Cook-Mozaffari et al., 1979~. The authors concluded that the disease might be caused by opium use in combination with diets low in fresh fruit and vegetables. In a case-control study of white males in the United States, Mettlin et al. (1980) also found a statistically significant inverse relationship, including a dose-response gradient, between risk of esophageal cancer and frequency of consumption of fruits and vegetables. Similar inverse associations were found for indices of vitamin A and C intake, especially for vitamin C intake. In a case-control study among Chinese in Singapore, de Jong et al. (1974) 17-2

The Relationship of Diet to Cancer at Specific Sites 393 found that a significant decrease in risk for esophageal cancer among males was associated with consumption of bread, potatoes, and bananas. They also found a direct association with consumption of very hot bever- ages. Ziegler et al. (1981) examined the role of nutrition in the etiol- ogy of esophageal cancer among blacks in the United States. They found that nutrition in general was poorer among cases than controls, but they identified no specific nutrient deficiency as responsible for the effect, which appeared to be independent of ethanol consumption. Warwick and Harington (1973) reported that large quantities of grain, especially wheat and maize, are commonly consumed in most areas with high risk for esophageal cancer. This observation was recently extended by van Rensburg (1981), who examined esophageal cancer in- cidence and relative frequencies with which dietary staples were con- sumed in several populations, primarily in Africa and Asia. The low- risk populations consumed millet, cassava, yams, or peanuts; the high-risk populations consumed primarily wheat or corn, which provide diets relatively deficient in zinc, magnesium, nicotinic acid, and possibly riboflavin. He suggested that such nutritional deficiencies, which may also occur in abusers of alcohol, might increase suscepti- bility of the esophageal epithelium to neoplastic transformation. Thus, it is possible that a common mechanism is involved in the causation of esophageal cancer throughout the world. In summary, a number of dietary factors appear to be associated with the risk of esophageal cancer. An increased risk in some parts of the world is associated with alcohol drinking, especially in combination with cigarette smoke, high intakes of pickles and moldy foods possibly contain- ing mycotoxins or N-nitroso compounds, trace mineral deficiencies, and consumption of very hot beverages. Frequent consumption of fresh fruits and vegetables appears to be associated with a lower risk for esophageal cancer. STOMACH CANCER There is a high incidence rate of stomach cancer in Japan, in other parts of Asia, and in South America; but in North America and Europe, the incidence is low and is decreasing (Stukonis, 1978; Waterhouse et al., 1976~. In Japan, gastric cancer has been associated with chronic gastri- tis (Imai et al., 1971) and with the consumption of spiced and pickled foods (Haenszel _ al., 1976~. Surveys have shown that there is substantial variation in inci- dence among different areas of Colombia (Cuello et al., 1976~. These variations have been correlated with different levels of nitrate in the diet and drinking water (Correct et al., 1976; Tannenbaum et al., 1979~. Broitman _ al. (1981) studied iron-deficient patients in Medellin, Colombia, who exhibited lesions that were precursors to gastric cancer. They found that hypochlorhydria and achlorhydria associated with iron 17-3

394 DIET, NUTRITION, AND CANCER deficiency permitted bacterial colonization of the stomach. Reduction of dietary nitrate to nitrite, and subsequent endogenous synthesis of N-nitroso compounds from nitrite, could thus be mediated by the gastric flora. Ruddell et al. (1978) suggested a similar mechanism to explain the increased risk for gastric cancer in patients with pernicious anemia. An association between gastric cancer and high concentrations of nitrate in drinking water was suggested by Hill et al. (1973), who ob- served that mortality rates for stomach cancer were higher in Worksop, England, where the water supply contained higher concentrations of nitrate, than in nine control towns. However, Davies (1980) pointed out that Worksop was a coal-mining town, been associated with coal-mining regions ~ for coal mining and socioeconomic status abolished the excess mortality from stomach cancer in males in Worksop and reduced it markedly in females. ~ , ~ and that stomach cancer has in Great Britain. Adiustment In Chile, exposure of the general population to high concentrations of nitrate in drinking water or in food appeared to be associated with high rates of stomach cancer (Armijo and Coulsen, 1975; Zaldivar, 1977~. However, although nitrate levels were significantly higher in the urine of schoolchildren from two areas of central Chile with high mortality from stomach cancer than they were in the urine of schoolchildren from a northern, low risk area, levels of nitrate were also significantly higher in vegetables obtained from the low risk area (Armijo et al., 1981). Dungal (1966) observed that large quantities of smoked foods (e.g., mutton and trout) were consumed in high incidence areas of Iceland and that there was a lower incidence of stomach cancer in sailors than in farmers in Iceland. He noted that sailors often stock food obtained at foreign ports; thus, their diet contains a higher proportion of fresh food. Choi et al. (1971) showed that the mortality from gastric cancer among Icelanders in Manitoba was twice as high as that among people born in Manitoba. A dietary survey showed that the people born in Iceland had consumed high levels of smoked and pickled foods. Hakama and Saxen (1967) analyzed age- and sex-adjusted mortality rates for stomach cancer in 16 countries. They found a strong corre- lation (r = 0.75) with the per capita intake of cereals used for flour during 1934-1938. In the United States, counties with high mortality from stomach cancer tend to be concentrated in Minnesota, Wisconsin, and the upper peninsula of Michigan (Mason et al., 1975~. Kriebel and Jowett (1979) pointed out that although high rates in migrants from Northern Europe may explain part of this increased mortality, the rates are dispropor- tionately high. They suggested that native-born Americans have shared the increased risk of the migrants, possibly by adopting the "high-risk" diet of the foreign-born residents. 17-4

The Relationship of Diet to Cancer at Specific Sites 395 Over several generations, there has been a gradual decline in the incidence of stomach cancer in Japanese migrants to the United States (Kolonel et al., 1980), suggesting that the risk factors for this cancer exert their effect early in life. Data from several countries indicate that there is a strong correla- tion between mortality from gastric cancer and cerebrovascular disease. Joossens and Geboers (1981) suggested that both diseases are related to salt intake. However, the use of salt to preserve food is often accom- panied by the use of nitrate for the same purpose (Weisburger et al., 1980~. Furthermore, Okamura and Matsuhisa (1965) found no correlation between the salt content of salted fish and the death rate from gastric cancer in Japan. In a number of case-control studies, investigators have attempted to define more specifically the role of diet and other factors in the etiology of gastric cancer. Acheson and Doll (1964) and Wynder et al. (1963) found no association with dietary factors. In another study, however, Meinsma (1964) observed that cases had eaten more bacon and less citrus fruits (and, thus, less ascorbic acid) than had the con- trols. Higginson (1966) found that cases had also consumed fried foods more frequently, especially bacon drippings and animal fats used for cooking. Hirayama (1967) reported that the daily consumption of milk was less frequent and the daily use of salted foods was more frequent among cases. Graham et al. (1972) observed that a low risk of gastric cancer was associated with the consumption of raw lettuce, tomatoes, carrots, coleslaw, and red cabbage and that there was a dose-response relationship for these food items. Haenszel et al. (1972) studied Japanese living in Hawaii. Migrants (Issei) continued to display an increased risk in Hawaii, but the Nisei offspring, who adhered to Western-style diets, did not. There were ele- vated risks for both Issei and Nisei users of pickled vegetables and dried/salted fish. Low risks were associated with the consumption of several Western vegetables, many of which are eaten raw. Using a simi- lar protocol, Haenszel et al. (1976) showed that farmers in Japan, representing the lower socioeconomic class, had the highest risk for gastric cancer. A lower risk was found for those whose diet included more frequent use of lettuce and celery. Modan et al. (1974) reported that starches were consumed more frequently by gastric cancer patients than by controls. B. jelke ( 19 78) f ound an inverse relationship between s tomach cancer and consumption of vegetables and vitamin C, especially in younger pa- tients and among women. He also reported preliminary findings from a prospective study, showing a reduced risk for those with a high consump- tion of vegetables in Norway, but not in Minnesota. The Norwegian study also suggested that frequent use of salted fish may be associated with a high risk of stomach cancer. In a large cohort study conducted in Japan, Hirayama (1977) reported that a protective effect against gastric cancer was associated with the 17-5

396 DIET, NUTRITION, AND CANCER consumption of two glasses of milk daily and that there was an increased risk in cigarette smokers. Nonsmokers who ate green or yellow vegetables also had a lower risk of stomach cancer. Weisburger and Rainer! (1975) suggested that gastric cancer in humans may result from the in viva nitrosation in the stomach of as yet unknown substrates, with the production of alkylnitrosamides. They postulated that exposure to reducing agents such as ascorbic acid may interfere with the endogenous production of N-nitroso compounds by the reaction of dietary nitrite with amine s or amides (Weisburger et al., 1980~. Such a mechanism could explain the protective effect of green or yellow vegetables, raw lettuce, and other vitamin-C-containing vegetables. In summary, studies in migrants to the United States suggest that gastric cancer is related in part to dietary factors that exert their influence early in life. The factors increasing risk may include fre- quent consumption of smoked food (which in some parts of the world leads to increased exposure to polycyclic aromatic hydrocarbons) and frequent ingestion of salt-pickled foods or foods containing nitrate and nitrite (which may result in subsequent in viva production of nitrosa- mines) and other carcinogens produced in food by preservation treatments and cooking. Protective factors may include consumption of milk, raw green or yellow vegetables, especially lettuce, and other foods contain- ing vitamin C. COLON AND RECTAL CANCER Haenszel (1961) reported that the rates of colon and rectal cancer in migrants from Italy, Norway, Poland, and the Soviet Union more closely resembled those in the host country (the United States) than those in their country of origin, in contrast to the findings for stomach cancer. Haenszel and Dawson (1965) observed that mortality for cancer of the colon and rectum was higher in urban regions in the United States. Urban-born people who migrate to rural areas acquire the lower mortality of the rural areas; the reverse occurs for those who migrate from rural to urban areas. Mortality is higher in the North than in the South for long-term residents of these regions. De Jong _ al. (1972) found that in areas of high and intermediate risk there is a decreasing incidence from the ascending colon to the descending colon and a sharp increase at the sigmoid colon. Rectal cancer rates are generally higher than those for the sigmoid. In low incidence areas, there may be a low rate for sigmoid cancers. Berg and Howell (1974) reviewed international mortality from cancer of the bowel from 1952 to 1953 and from 1966 to 1967. The highest death rates were reported in Scotland, but these rates were falling, as were those for England and Wales. The rates for whites in the United States 17-6

The Relationship of Diet to Cancer at Specific Sites 397 appeared to be stable, but those for the Federal Republic of Germany, Italy, and Japan were rising. The investigators interpreted differences between colon and rectal cancer rates as indicating that, although much of rectal cancer is caused by the same factors that cause colon cancer, there is a second set of factors that affect rectal cancers alone. Lee '1976) found that death rates from large bowel cancer in Japan have risen rapidly since World War II and that colon cancer has increased at a greater rate than rectal cancer. In Japan, each successive birth cohort had an increased rate of colon cancer, whereas those in the United States did not. Haenszel et al. (1975) investigated the incidence of large-bowel cancer in Call, Colombia in relation to place of residence, by census tract. They found that the upper socioeconomic classes were at higher risk. Lynch _ al. (1975) also reported a greater frequency of colon cancer in patients living in census tracts with higher average incomes. Similarly, Teppo et al. (1980) found a higher incidence of colon cancer in higher socioeconomic areas of Finland. Studies of the international incidence of and mortality from large bowel cancer in relation to dietary variables strongly support an association of colon cancer and, to a lesser extent, rectal cancer with total dietary fat (Armstrong and Doll, 1975; Wynder, 1975~. Irving and Drasar (1973) failed to find a correlation between cancer of the colon and the per capita intake of various fiber-containing foods. In studies of mortality rates for colon cancer, Berg and Howell (1974) and Howell (1975) reported that the highest correlations were found for per capita meat intake, and that the highest was for beef. However, Enstrom (1975) pointed out that the trends in per capita beef and fat intake in the United States do not correlate with trends in incidence of and mortality from colorectal cancer. Jansson_ al. (1978) correlated the selenium concentration in water samples from the eastern part of the United States with the incidence of colorectal cancer. They found a strong, direct relationship between the selenium content of water and colorectal cancer and observed that the mean mortality rate increased with increasing levels of selenium in the drinking water. Other studies, however, have shown an inverse correla- tion between the intake of selenium and colon cancer (Schrauzer et al., 1977a,b; also see the section on selenium in Chapter 10~. Lui _ al. (1979) evaluated food disappearance data for 1954-1965 and data on mortality from colon cancer for 1967-1973 from 20 industrialized countries. They found that the per capita intakes of total fat, satu- rated fat, monounsaturated fat, and cholesterol were directly correlated and that fiber intake was inversely correlated with mortality from colon cancer. The correlation of dietary cholesterol with colon cancer was highly significant and remained so when they controlled for fat or fiber. However, the correlations of fat or of fiber with colon cancer mortality were no longer significant when they controlled for cholesterol. 17-7

398 DIET, NUTRITION, AND CANCER gingham et al. (1979) related the average intake of foods, nutrients, and dietary fiber in Great Britain to the regional pattern of death from colon and rectal cancer. They found that intakes of the pentosan frac- tion of total dietary fiber and of vegetables other than potatoes were inversely correlated with death rates for colon cancer. The possible importance of dietary cholesterol (and/or dietary fat) is supported by the correlations of mortality from colon cancer with mortality from coronary heart disease in different countries (Rose et al., 1974), correlations with large-bowel cancer among different social classes in Call, Colombia (Haenszel et al., 1975), and for cancer of the colon and rectum together and individually within 34 health-planning subdivisions in the Commonwealth of Massachusetts (Lipworth and Rice, 1979~. Stemmermann et al. (1979) noted the high rate of colon cancer among Japanese who migrated to Hawaii and observed that myocardial infarction, severe atherosclerosis, diverticulosis, and polyposis of the colon also occurred more frequently in this population, compared to Japanese living in Japan. In studies of cancer incidence in Seventh-Day Adventists, Phillips and colleagues reported that a lacto-ovovegetarian diet had a protec- tive effect against colon cancer (Phillips, 1975; Phillips et al., 1980a,b). The findings among Mormons in Utah (Lyon and Sorenson, 1978; Lyon et al., 1976, 1980a,b) and in California (Enstrom, 1980) confirmed that this group had a lower incidence of colon cancer than the U.S. average, but were less clear with respect to the impact of dietary fac- tors. In a preliminary dietary survey, Lyon and Sorenson (1978) found little difference in meat, fat, and fiber intake by the population of Utah and by the general U.S. population. Malhotra (1977) suggested that the virtual absence of colon cancer among Punjabis from northern India is due to their diet, which is rich in roughage, cellulose, vegetable fiber, and short-chain fatty acids contained in fermented milk products. MacLennan et _ . (1978) evaluated the diets consumed by adult men from Kuopio, Finland and compared them with the diets consumed by a similar sample from Copenhagen, Denmark, where the incidence of colon cancer is 4 times higher. They found that the high incidence group consumed more refined wheat breads, meats (especially pork), and beer, but less potatoes and milk than did the low incidence group in Finland. The estimated consumption of fat was similar, but the consumption of fiber was higher in the low incidence group. Reddy _ al. (1978) studied the dietary patterns and fecal constit- uents of a high risk group in New York and the low risk group in rural Kuopio. The average daily intake of dietary fat and protein was the same in the two groups, but a greater proportion of fat came from dairy products in Kuopio and from meat in New York. The daily stool output and fecal fiber excretion were also greater in Kuopio, where there was a high dietary intake of cereal products rich in fiber. 17-8

The Relationship of Diet to Cancer at Specific Sites 399 These investigators found more mutagenic activity in the stools from New York subjects who were not Seventh-Day Adventists than in the stools obtained from subjects in Kuopio, who had a similar fat but a higher fiber intake (Ready et al., 1980~. However, they found no mu- tagenic activity in the stools from vegetarian Seventh-Day Adventist volunteers from New York, who had a lower average fat intake than the other two groups, but an intermediate level of fiber intake. A number of case-control studies have been conducted to examine the relationship between diet and cancer of the large bowel. Wynder and Shigematsu (1967) could not identify environmental factors that differed significantly between cases and controls. A study of Japanese patients with bowel cancer and hospital controls in Hawaii indicated that there was a higher risk for persons who regularly ate Western-style meals (Haenszel _ al., 1973~. Control for beef produced the largest downward displacement in estimated risks for other dietary variables. In Japan, a study conducted with similar methodology did not replicate these find- ings (Haenszel et al., 1980~; however, reduced risk was associated with consumption of cabbage. Modan _ al. (1975) found that fiber-containing foods were con- sumed less frequently by cases of colon cancer than by controls, but there were no differences for cases with rectal cancer. They also observed no differences in consumption of fat-containing foods by either cancer group or the controls. Parallel studies in Norway and Minnesota indicated that there was a slightly lower consumption of cereal products, milk, and coffee by colorectal cancer cases, compared to controls, and several vegetables were eaten less frequently by the cases (Bjelke, 1978~. The cases also had lower indices for consumption of vitamin A and crude fiber, both of which are associated with vegetable intake. In the United States, Phillips (1975) found that consumption of beef, lamb, and fish, and the heavy use of dairy products other than milk and other high-fat foods, were directly associated with the risk of colon cancer, and that there was a slight inverse association with the consumption of milk, vegeta- ble protein products, and green leafy vegetables. Dales _ al. (1979) reported that foods with at least 0.5% fiber content were consumed less frequently by colon cancer cases than by the controls, and that there was a consistent dose-response relation- ship. Cases tended to have eaten foods with at least 5% saturated fat more often than controls. Significantly more cases than controls re- ported a high saturated fat, low fiber food consumption pattern. Graham et al. (1978) reported that a decreased risk of colon cancer was associated with frequent ingestion of vegetables, especially cabbage, Brussels sprouts, and broccoli. Decreased risk of rectal cancer was associated only with frequent ingestion of raw vegetables and cabbage. 17-9

400 DIET, NUTRITION, AND CANCER However, Martinez et al. (1979) reported that cases had consumed signif- icantly higher quantiELes of meats, cereals, total fats, total residue, and fiber. Jain _ al. (1980) observed that an increased risk of both colon and rectal cancer was associated with elevated consumption of calories, total fat, total protein, saturated fat, oleic acid, and cholesterol, but that there was no association with consumption of crude fiber, vitamin C, and linoleic acid. The highest risk was found for saturated fat consumption, and there was evidence of a dose-response relationship. The only cohort studies that have yet provided data on dietary vari- ables are the ongoing parallel studies in Norway and Minnesota (Bjelke, 1978~. These studies indicate that there is a reduced risk of colorectal cancer in the Minnesota subjects who have a high index of vegetable con- sumption. No such effect has been observed in Norway, but the number of cases in that country is small. Most information on the association between colon cancer and choles- terol levels has been derived from epidemiological studies and interven- tion trials to determine risk for cardiovascular disease. The findings have been conflicting, and it is not certain whether reported increases in risk of cancer (especially colon cancer) at low serum cholesterol levels reflect a causal association (Feinleib, 1981; Lilienfeld, 1981~. Rectal cancer has been associated with intake of beer in some stud- ies (Breslow and Enstrom 1974; Dean et al., 1979; Enstrom, 1977; Stocks, 1957), but not in all studies (Jensen, 1979; Schmidt and Popham, 1981~. McMichael _ al. (1979) suggested that there is a better correlation be- tween trends in mortality from rectal cancer and changes in beer intake than has been found for saturated fat. Wynder and Shigematsu (1967) showed that the proportion of beer drinkers among male colorectal cancer patients was significantly higher than in one control group, but not in a second control group. In a prospective study conducted by Bjelke (1973), there was a dose-response relationship between the risk of colorectal cancer and the frequency of beer and liquor consumption. The gradient was steeper for beer consump- tion. Conversely, case-control studies of intestinal cancer in Finland, Kansas, and Norway (Bjelke, 1971, 1973; Higginson, 1966; Pernu, 1960) indicated that there was no significant relationship with beer drinking. Vitale _ al. (1981) reported a correlation coefficient of 0.78 between alcohol consumed as beer and colon cancer in 20 countries. There were poor correlations for colon cancer and the intake of total ethanol, distilled spirits, or wine. In summary, three hypotheses appear to be supported by data of vari- ous strengths obtained from epidemiological studies of both colon and 17-10

The Relationship of Diet to Cancer at Specific Sites 401 and rectal cancer: (1) a causal association with total, and perhaps satu- rated, fat; (2) a protective effect of dietary fiber; and (3) a protective effect of cruciferous vegetables. The diverse results concerning the im- portance of fat and fiber may be partly due to differences in the degrees of precision in the dietary methodology used in the various studies. The possible role of alcohol in the induction of rectal cancer requires fur- ther study. LIVER CANCER Primary liver cancer is relatively uncommon in the United States and most Western countries, but it is a major form of cancer in sub-Saharan Africa and Southeast Asia. Several different dietary agents have been reported as possible hepatic carcinogens, including alcohol, aflatoxin, safrole, pyrrolizidine alkaloids, and cycasin (Anthony, 1977~. Oettle (1965) suggested that the geographic distribution of liver cancer in Africa could be explained by differing levels of exposure to aflatoxin in the diet. In a number of studies, aflatoxin contamination of foodstuffs has been correlated with liver cancer incidence and mor- tality by geographic area or for different population groups in Africa (Alpert et al., 1971; Keen and Martin, 1971; Peers and Linsell, 1973; Peers _ al., 1976; van Rensburg et al., 1974~. Similar correlations_ _ have been found in Thailand,-China, and Taiwan, which also have high rates of liver cancer (Armstrong, 1980; Shank et al., 1972a,b; Tung and Ling, 1968; Wogan, 1975~. There is a strong correlation between the estimated levels of aflatoxin ingestion and liver cancer rates in these various studies, and no populations with documented high levels of afla- toxin ingestion have low rates of liver cancer (Linsell and Peers, 1977~. Numerous reports (e.g., Chien et al., 1981) have also documented a high correlation between primary liver cancer and exposure to hepatitis B viral infection, which has a worldwide distribution similar to that of aflatoxin. Many investigators believe that although primary liver cancer could be initiated by aflatoxin, there is a higher probability that liver cancer develops in individuals exposed to the hepatitis B virus. In Guam and Okinawa, which have high rates of liver cancer, the ingestion of cycasin (a toxic substance contained in cycad nuts) has been proposed as an etiologic factor. However, in a descriptive study conducted in the Miyako Islands of Okinawa, investigators found no correlation between mortality from hepatoma and the ingestion of cycad nuts (Hirono _ al., 1970~. Alcohol is the main dietary factor that has been suggested as an etiologic agent for liver cancer in Western, low-risk countries, al- though Armstrong and Doll (1975) reported a weak correlation between liver cancer incidence (but not mortality) and per capita intake of 17-11

402 DIET, NUTRITION, AND CANCER potatoes in more than 20 countries. Interest in alcohol as a causal factor for primary liver cancer was generated by reports of hepatomas occurring at increased rates in cirrhotic patients with histories of heavy alcohol use and by other reports of high rates of alcoholic cirrhosis in he patoma patients (Lee, 1966; Purtilo and Gottlieb, 1973~. However, the cirrhosis usually associated with liver cancer is the macronodular form, which is characteristically associated with hepatitis B viral infection (Anthony, 1977~. Furthermore, ethanol itself has not been shown to be carcinogenic in animals (Vitale and Gottlieb, 1975~. Most descriptive epidemiological data do not support the association between alcohol intake and risk of liver cancer. Esophageal cancer has been linked to alcohol consumption; however, the incidence rates for esophageal cancer in various countries have been significantly correlated with liver cancer in men, but not in women (Miller, 1981~. Despite dif- ferences in alcohol consumption between Mormons and non-Mormons in Utah and between Issei and Nisei Japanese in Hawaii, both groups in Utah and both in Hawaii have similar incidence rates for liver cancer (Kolonel et al., 1980; Lyon et al., 1976, 1980a,b). There is also no significant correlation between ethnic patterns of liver cancer incidence in Hawaii and alcohol consumption (Hinds et al., 1980~. There have been few analytical studies of the relationship between alcohol and liver cancer. In a proportional mortality analysis, Monson and Lyon (1975) found no increase in deaths from liver cancer among alcoholics admitted to mental hospitals in Massachusetts. Conversely, Hakulinen _ al. (1974) found that liver cancer cases in two alcohol abuser populations in Finland exceeded the number expected, based on data in the Finnish Cancer Registry. In a retrospective cohort study of male alcoholics in Ontario, Canada, Schmidt and Popham (1981) observed that liver cancer deaths were 2 times higher than expected, based on the general population of Ontario, but the numbers were small and the differ- ence was not statistically significant. In summary high intake of foods contaminated with aflatoxin is asso- ciated with liver cancer in high incidence areas of the world, i.e., Asia and Africa. Chronic infection with hepatitis B virus, which has the same geographic distribution as aflatoxin contamination, has been proposed as a primary etiologic factor in liver cancer. The evidence that excessive alcohol consumption may indirectly contribute to the development of some types of liver cancer is extremely tenuous. PANCREATIC CANCER The per capita intake of several foods has been associated with pan- creatic cancer incidence and mortality in a number of international studies. Analyses of mortality data have produced direct associations with intake of fats and oils, sugar, animal protein, eggs, milk, and coffee (Armstrong and Doll, 1975; Lea, 1967; Stocks, 1970; Wynder et al., 17-12

The Relationship of Diet to Cancer at Specific Sites 403 1973~. From incidence data, there was a direct correlation only with per capita intake of eggs (Armstrong and Doll, 197S). In a correlation analysis by county in the United States, Blot et al. (1978) found that there was a direct association with alcohol intake. In contrast, Hinds _ al. (1980) reported that pancreatic cancer incidence in five ethnic groups in Hawaii correlated directly with beer consumption, after con- trolling for cigarette smoking and consumption of other types of alco- holic beverages. This finding was in agreement with the observation of Kolonel _ al. (1980) that pancreatic cancer incidence rates are the same for migrant and native-born Japanese groups in Hawaii, which have similar rates for beer consumption but not for total alcohol consumption. Lyon _ al. (1980a,b) observed that non-Mormons in Utah have higher incidence rates of pancreatic cancer than do Mormons, who drink less alcohol, tea, and coffee. Reports of several case-control studies have indicated an associa- tion between diet and pancreatic cancer. Based on data obtained from relatives of cases and controls, who responded to a mailed questionnaire, Burch and Ansari (1968) found a direct association between pancreatic cancer and chronic alcoholism. Using a similar design, Ishii et al. (1968) found direct associations with alcohol and meat consumption (men only) and an inverse association with vegetable intake. Lin and Kessler (1981) reported that the consumption of wine by female cases was greater than that of controls, a finding not observed in the males. In contrast, Wynder et al. (1973) and MacMahon et al. (1981) found no association between pancreatic cancer and alcohol consumption. Wynder et al. (1973) did find a direct association with early-onset diabetes in women, and MacMahon et al. (1981) reported a direct association with coffee con- sumption and a dose-response gradient for women only. Lin and Kessler (1981) also noted a greater consumption of decaffeinated coffee by cases than by controls. Two cohort studies have reproduced the association of pancreatic cancer with diabetes in women, which was observed in the case-control study of Wynder _ al. (1973) and in the correlational analyses of Blot _ al. (1978). After studying a cohort of diabetics for 29 years, Kessler (1970) found excess deaths from pancreatic cancer, despite fewer overall cancer deaths than expected. Armstrong et al. (1976b) also fol- lowed a cohort of diabetics and found a slight increase in mortality from pancreatic cancer (although not statistically significant) and an overall decrease in mortality from all cancers. Hirayama (1977) reported a rela- tive risk of 2.5 for daily meat consumption and pancreatic cancer in a cohort study conducted in Japan, thereby reproducing a similar finding in the case-control study of Ishii et al. (1968~. In summary, there is limited evidence that certain dietary factors (e.g., the intake of alcohol, coffee, and meat) are associated with an elevated risk for cancer of the pancreas. 17-13

404 DIET, NUTRITION, AND CANCER GALLBLADDER CANCER There is a high incidence of gallbladder cancer in Latin America, Japan, and Southeast Asia for both sexes--but it is higher for females than for males (Waterhouse et al., 1976~. Cancer at this site is rela- tively uncommon among blacks and whites in the United States, but occurs more frequently among North American Indians and Mexican-American females. It has also been associated with gallstones, obesity, and type IV hyper- lipoproteinemia (Fraumeni, 1975a). Among the dietary risk factors that have been postulated are both high calorie and high fat diets. However, the uniformly poor correlation of gallbladder cancer with other cancers associated with high fat diets appears to militate against high fat diets as a causal factor. No case-control study of dietary factors and cancer of this site has been reported. The evidence for a dietary etiology of this cancer is therefore in- direct and rather weak at this time, other than an association with obes- ity and, therefore, possibly an excess of calories. LUNG CANCER Lung cancer is the most prevalent cancer in men in most technically advanced countries, and it is rapidly approaching this level in women (Miller, 1980; Waterhouse et al., 1976~. The most important causal fac- tor is cigarette smoking (Surgeon General, 1979~. Occupational exposures contribute substantially to the incidence in males (Fraumeni, 1975b). In women, cigarette smoking probably accounts for more than one-half of the cases (Surgeon General, 1980~. Bjelke (1975) conducted a prospective study of 8,278 Norwegian men who responded to a mailed questionnaire designed to determine the associ- ation between vitamin A intake and lung cancer. As a result of observa- tions made during a 5-year follow-up of this group, Bjelke was one of the first to suggest a relationship between vitamin A intake and cancer at this site. He found that the relative risk for lung cancer was 2.5 times higher for current and former smokers in the low vitamin A intake group than for those in the high intake group. Subsequently, a number of other investigators studied this associa- tion. Basu et al. (1976) and Sakula (1976) found that levels of vitamin A in the plasma of bronchial carcinoma patients were lower than those in the serum of controls. MacLennan _ al. (1977) studied the relationship between consumption of dark green, leafy vegetables rich in vitamin A precursors and the risk of lung cancer in Chinese female cases and con- trols in Singapore. They found a relative risk of 2.2 for low indices of vegetable intake. Smith and Jick (1978) assessed the frequency with which preparations containing vitamin A were used by newly diagnosed lung cancer patients and patients with nonmalignant conditions. They found an inverse association among men, but not among women. Mettlin et al. (1979) 17-14

The Relationship of Diet to Cancer at Specific Sites 405 found a dose-response relationship for lung cancer up to risk ratios of 2.4 for heavy smoking men with a low index of vitamin A consumption. Shekelle et al. (1981) studied a prospective cohort of 1,954 men in Chicago. After 19 years of followup, they found a significant inverse association between lung cancer incidence and the intake of carotene, after adjustment for cigarette smoking. In contrast, lung cancer was not significantly associated with the intake of preformed vitamin A. In summary, there is evidence that low dietary levels of foods con- taining vitamin A and/or vitamin A precursors (e.g., 6-carotene) are associated with increased risk of lung cancer, especially among heavy smokers. Because the indices of vitamin A intake in these studies were derived from foods that also contain other natural inhibitors of carcino- genesis, it is also possible that dietary constituents other than pre- formed vitamin A or carotene are the relevant risk-reducing factors. BLADDER CANCER Most of the epidemiological literature on the association between diet and bladder cancer pertains to coffee and nonnutritive sweeteners. In both correlation and case-control studies, direct associations have been found between coffee consumption and bladder cancer (C. T. Miller et al., 1978; Simon et al., 1975; Wynder and Goldsmith, 1977~; however, in most of the case-control studies, investigators failed to find a dose- response gradient. In other epidemiological studies, no association at all was found between coffee consumption and bladder cancer. These studies are reviewed in Chapter 12. There are similarly conflicting findings in the epidemiological literature on nonnutritive sweetener use and bladder cancer. Both corre- lational data and observations in studies of diabetics have failed to implicate nonnutritive sweetener use in the etiology of bladder cancer (Armstrong _ al., 1976b; Kessler, 1970~. In some case-control studies, investigators found an association; in others, they did not. With the exception of a study by Howe et al. (1977), direct associations were observed only in very select, low-risk subgroups, e.g., nonsmoking women without occupational exposure to bladder carcinogens (Hoover and Strasser, 1980~. These studies are discussed in detail in Chapter 14. The epidemiological literature pertaining to the association of other dietary exposures and bladder cancer is much more limited. In an analysis based on international data, Armstrong and Doll (1975) found a direct association of bladder cancer mortality, but not incidence, with per capita intake of fats and oils, particularly in women. In another cor- 17-15

406 DIET, NUTRITION, AND CANCER relation study, based on data by state in the United States, there was a direct association between beer intake and bladder cancer mortality in men (Breslow and Enstrom, 1974~. In a report of a case-control study, Mettlin and Graham (1979) ob- served that there was an inverse association between bladder cancer and an index of vitamin A intake as well as with consumption of carrots and milk. In another case-control study, Howe et al. (1980) found a direct association between bladder cancer and consumption of coffee and no association with consumption of tea, alcohol, soft drinks, fiddlehead greens (related to bracken fern, which is a bladder carcinogen in cattle), or meats preserved with nitrite (such as hams and sausages). Nitrosa- mines (presumably formed from precursors of dietary origin) have been found in the urine of patients with urinary tract infections (Hicks et _., 1977; Radomski et al., 1978~. In summary, bladder cancer has frequently been associated with cof- fee consumption, although the relationship does not appear to be causal. The use of nonnutritive sweeteners (primarily saccharin) does not appear to be a significant risk factor, except perhaps in some very select low risk groups. A possible inverse association with an index of vitamin A intake has been reported in one study. RENAL CANCER The epidemiological data on dietary factors related to renal cancer are meager. International incidence and mortality data have shown cor- relations of renal cancer with per capita intake of coffee, milk, meat, total fat, and animal protein (Armstrong and Doll, 1975; Shennan, 1973~. In a correlation study of ethnic-specific incidence rates for renal cancer with corresponding intakes of alcohol based on representative interview data, Hinds _ al. (1980) found a direct association for beer consumption, but not for the consumption of wine or hard liquor. A similar direct correlation for beer intake and renal cancer was reported by Breslow and Ens tram (1974), who compared mortality data and per capi- ta alcohol intake by state in the United States. These associations have not been reproduced in case-control studies of renal cancer. In a case-control study by Wynder et al. (1974), there were no differences for coffee drinking or alcohol consumption; however, they did report that the relative weight of female (but not male) cases 2 years bef ore the onset of illness was greater than that of the con- trols. Armstrong et al. (1976a) also found no direct associations with the frequency of intake of coffee, tea, alcohol, chocolate, or the major food sources of animal protein. Kolonel (1976) observed a direct asso- ciation between renal cancer and combined exposure to cadmium from three sources: diet, cigarette smoking, and occupational setting. 17-16

The Relationship of Diet to Cancer at Specific Sites 407 BREAST CANCER Breast cancer is the commonest cause of death from cancer among women in North America. In the United States, it is the cause of more deaths than any other cause among women between the ages of 40 and 44. It Is known that cancer at this site is associated with hormonal activi- ty, but diet has also been suspected as a major cause (MacMahon et al., 1973). Several types of studies have provided evidence supporting the importance of dietary factors in breast cancer: descriptive epidemio- logical studies, correlation studies, evaluations of nutrition-mediated risk factors, and case-control studies. Additional evidence for an association has been provided in reports of studies in laboratory animals, which are discussed in Chapter 5. The evidence from descriptive epidemiological studies suggests that cultural factors or lifestyle, especially diet, are influential in the etiology of breast cancer. For example, the incidence of breast cancer among premenopausal Japanese-American women living in California is now almost as high as that for Caucasian women (Dunn, 1977~; whereas the incidence of cancer among them was similar to that in Japan when they first migrated. Moolgavkar et al. (1980) have shown that changes in cancer incidence for certain populations can be related to changes in lifestyle of successive birth cohorts. The second type of evidence has been provided by studies correlating breast cancer incidence and mortality with per capita intake of total fat and other nutrients in different countries (Armstrong and Doll, 1975; Carroll, 1975; Drasar and Irving, 1973; Hems, 1978; Knox, 1977), including Japan (Hirayama, 1977) and the United States (Enig et al., 1978; Kolonel et al., 1981~. Gaskill et al. (1979) found a direct cor- relation between breast cancer mortality and intake of milk, table fats, beef, calories, protein, and fat, and an inverse correlation with intake of eggs. Milk and egg intake remained significantly associated (directly and inversely, respectively) with breast cancer when the investigators controlled for age at first marriage. The third type of evidence is derived from evaluating certain, prob- ably nutrition-mediated, factors that affect the risk of breast cancer. These factors include weight, height, body mass (which is dependent on height and weight) (de Waard 1975; de Waard and Baanders-van Halewijn, 1974; de Waard et al., 1977), and age at menarche (MacMahon et al., 1973; Miller, 1978~. Women who experienced menarche at an early age, especially before the age of 12, were at higher risk. Evidence that body weight and food intake are related to early onset of estrus in rats (Frisch et al., 1975) supports the hypothesis that the rat's body must contain a minimum amount of fat for estrus to occur. This also appears 17-17

DIET, NUTRITION, AND CANCER to be essential for menarche in women (Frisch and McArthur, 1974~; how- ever, not all studies of these factors have confirmed these findings (Miller, 1981), perhaps reflecting the overriding importance of other variables more directly related to nutrition. Gray et al. (1979) evaluated the effect of per capita intake of total fat and animal protein on international incidence and mortality rates for breast cancer, while controlling for height, weight, and age at menarche. They found that a significant effect of the dietary vari- ables persisted after controlling for the other factors. Case-control or cohort studies should provide the most conclusive evidence. Thus far, no cohort studies have been reported. Of the three case-control studies that have been reported, one involved 77 breast cancer cases and 77 controls (Phillips, 1975~. In this study, five categories of foods were associated with breast cancer: fried foods, fried potatoes, hard fat used for frying, dairy products (except milk), and white bread. The relative risks ranged from 1.6 to 2.6. In the case-control study of 400 cases and 400 neighborhood controls reported by A. B. Miller et al. (1978), the mean nutrient consumption was estimated from dietary histories for six nutrients. In the premeno- pausal group, the strongest association was found for total fat con- sumption. There were weaker associations for saturated fat and choles- terol. When the effect of each nutrient was controlled for the effect of the others, the association for total fat consumption became stronger, whereas the association for saturated fat and cholesterol diminished. In the postmenopausal group, the only consistent finding was an associa- tion for total fat consumption. The risk ratios were low (1.6 for total fat in premenopausal women and 1.5 for postmenopausal women), and there was no evidence of a dose-response relationship. In the third case-control study, which involved 577 cases and 826 controls, Lubin et al. (1981) found that relative risk increased signif- icantly with more frequent consumption of beef and other red meat, pork, and sweet desserts. Analysis of computed mean daily nutrient intake supported a link between breast cancer and consumption of animal fat and protein. Nomura et al. (1978) compared the diet of Japanese men whose wives had developed breast cancer with the diets of other Japanese men who had participated in the Japan-Hawaii Cancer Study. They assumed that the diets of the husbands and wives were similar. Their results indicated that the husbands of the cases consumed more beef or other meat, butter/ margarine/cheese, corn, and wieners, and that they ate less Japanese foods than did the control group. In summary, information derived from a number of different types of studies support the association of diet, especially high fat diets, with 17-18

The Relationship of Diet to Cancer at Specific Sites 409 breast cancer. The association is weak, if examined for individuals rather than for populations. One explanation for this may be that the effect of diet takes place early in life and is indirect, possibly in- fluencing cancer risk by its effects on hormones (Miller and Bulbrook, 1980). ENDOlIE: TRIAL CANCER Endometrial (uterine) cancer has been correlated with other cancers that are associated with dietary factors (e.g., cancers of the breast, ovary, colon, and rectum) (Miller, 1981) and has been associated with higher socioeconomic status. In correlation studies, it has been asso- ciated primarily with high per capita intake of total fat (Armstrong and Doll, 1975~. Two indirect indicators of the effect of nutrition have been evalu- ated in case-control studies. In two such studies, an association was found with obesity (Elwood et al., 1977; Wynder et al., 1966), although the excess risk appeared to be restricted to the most obese group. In one of these studies, Elwood et al. (1977) observed no association with height. Thus far, there have been no case-control studies directly comparing the effects of diet on cases of endometrial cancer and con- trols. In summary, the evidence for an association between endometrial cancer and diet is indirect. It is derived mainly from the similarity between the occurrence of this disease and cancer of the breast and colon. The recent dramatic increases in the incidence of endometrial cancer have been clearly related to the use of exogenous estrogens at the time of menopause (Jick et al., 1980~; they do not appear to be related to any factor in the diet. OVARIAN CANCER The evidence associating dietary factors, especially high fat diets, and ovarian cancer is largely indirect. It includes both international and national correlations between incidence of and mortality from ovari- an cancer and other diet-associated cancers, especially cancers of the breast and colon (Miller, 1981), and the correlation of dietary varia- bles, especially per capita intake of total fat, with incidence of and mortality from ovarian cancer (Armstrong and Doll, 1975; Lingeman, 1974~. In one case-control study, Annegers et al. (1979) observed that obesity is not a risk factor for ovarian cancer, and in another, Hildreth et al. (1981) found no effect of height or weight. No case- control studies evaluating dietary variables directly have yet been reported. There is, however, a greater than expected risk of second 17-19

410 DIET, NUTRITION, AND CANCER primary cancers of the corpus uteri, colon, and breast in patients with ovarian cancer (Reimer _ al., 1978~. This supports the hypothesis that there are common etiological factors for these sites. PROSTATE CANCER Several investigators have correlated dietary intake data with inci- dence of and mortality from prostate cancer. Stocks (1970) reported a direct correlation of prostate cancer mortality with per capita coffee intake in 20 countries. In a similar analysis, Armstrong and Doll (1975) found a significant direct correlation of prostate cancer mor- tality, but not incidence, with the per capita intake of total fat and the intake of fats and oils. They noted a high intercorrelation of coffee and fat consumption in their data, which they believed could explain the association with coffee drinking reported by Stocks. Howell (1974) found a high direct correlation between mortality from prostate cancer in 41 countries and per capita intake of fats, milk, and meats (especially beef), and an inverse correlation with intake of rice. Blair and Fraumeni (1978) observed that U.S. counties with the highest prostate cancer mortality among whites were those with greater per capi- ta intake of high fat foods (e.g., beef products, milk products, fats and oils, pork, and eggs). A correlational analysis based on dietary data obtained from individual interviews in Hawaii indicated that there was a significant association between incidence of prostate cancer in five ethnic groups and the consumption of animal fat and protein (Kolonel et al., 1981~. Furthermore, it has been observed that both prostate cancer incidence and fat intake are higher among Japanese in Hawaii than in Japan (Kato et al., 1973; Waterhouse et al., 1976~. These observations are further supported by international incidence and mortality data indicating that there are significant correlations of prostate cancer with cancers of other sites associated with diet, in- cluding cancer of the breast, corpus uteri, and colon (Berg, 1975; Howell, 1974; Wynder et al., 1971~. However, there are important excep- tions. For example, the Mormons in Utah have high prostate but low breast cancer incidence rates, and the native Hawaiians have low pros- tate but high breast cancer incidence rates (Kolonel, 1980; Lyon et al., 1976). There have been few case-control studies of prostate cancer and diet. Rotkin (1977), in an interim report, observed that high fat foods (including beef, pork, eggs, cheeses, milk, creams, and butter/margarine) were consumed more frequently by cases than by matched hospital controls. Schuman _ al. (1982) reproduced this finding in a study conducted in Minnesota. They also reported that the consumption of foods rich in vitamin A (e.g., liver) or its precursors (e.g., carrots) were lower for cases than for controls. Kolonel and Winkelstein (1977) found no difference between cases and controls in exposure to cadmium from 17- 20

The Relationship of Diet to Cancer at Specific Sites 411 dietary sources. This lack of association is interesting in light of reports indicating that there are direct associations between prostate cancer and exposure to cadmium in occupational groups (Adams et al., 1969; Kipling and Waterhouse, 1967; Lemen et al., 1976; Potts, 1965), and the knowledge that diet is the main source of exposure to cadmium for the general population (bribers et al., 1974~. After a 10-year follow-up of a cohort of 122,261 Japanese men aged 40 years and older, Hirayama (1979) found an inverse association between daily intake of green or yellow vegetables and mortality from prostate cancer. Hirayama (1977) also reported that prostate cancer occurred at a lower rate among vegetarian men in this cohort. In summary, the incidence of prostate cancer is correlated with other cancers associated with diet, e.g., breast cancer. There is good evidence that an increased risk of prostate cancer is associated with certain dietary factors, especially the intake of high fat and high protein foods, which usually occur together in the diet. There is some evidence that foods rich in vitamin A or its precursors and vegetarian diets are associated with a lower risk. 17-21

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420 DIET, NUTRITION, AND CANCER Keen, P., and P. Martin. 1971. Is aflatoxin carcinogenic in man? The evidence in Swaziland. Trop. Geogr. Med. 23:44-53. Keller, A. Z. 1980. The epidemiology of esophageal cancer in the west. Prev. Med. 9: 607-612. Kessler, I. I. 19 70. Cancer mortality among diabetics. J. Natl. Cancer Inst. 44: 673-68 6. Kipling, M. D., and J. A. H. Waterhouse. 1967. Letter to the Editor: Cadmium and prostatic carcinoma. Lancet 1: 730-7 31. Knox, E. G. 1977. Foods and diseases. Br. J. Prev. Soc. Med. 31: 71-80. Kolonel, L. N. 197 6. Association of cadmium with renal cancer. Cancer 37 :1782-1787. Kolonel, L. N. 1980. Cancer patterns of four ethnic groups in Hawaii. J. Natl. Cancer Inst. 65 :1127-1139. Kolonel, L. N., and W. Winkelstein, Jr. 1977. Letter to the Editor: Cadmium and prostatic carcinoma. Lancet 2: 566-567. Kolonel, L. N., M. W. Hinds, and J. H. Hankin. 1980. Cancer patterns among migrant and native-born Japanese in Hawaii in relation to smoking, drinking, and dietary habits. Pp. 327-340 in H. V. Gelboin, M. MacMahon, T. Matsushima, T. Sugimura, S. Takayama, and H. Takebe, eds. Genetic and Environmental Factors in Experimental and Human Cancer. Japan Scientific Societies Press, Tokyo. Kolonel, L. N., J. H. Hankin, J. Lee, S. Y. Chu, A. M. Y. Nomura, and M. W. Hinds. 1981. Nutrient intakes in relation to cancer incident in Hawaii. Br. J. Cancer 44: 332-339. Kriebel, D., and D. Jowett. 1979. Stomach cancer mortality in the north central states: High risk is not limited to the foreign-born. Nutr. Cancer 1~2~: 8-12. Lea, A. J. 1967. Neoplasms and environmental factors. Ann. R. Coll. Surg. Engl. 41: 432-438. Lee, F. I. 1966. Cirrhosis and hepatoma in alcoholics. 5ut 7: 77-85. Lee, J. A. H. 197 6. Recent trends of large bowel cancer in Japan compared to United States and England and Wales. Int. J. Epidemiol. 5: 18 7-19 4. 17-30 ~e

The Relationship of Diet to Cancer at Specific Sites 421 Lemen, R. A., J. S. Lee, J. K. Wagoner, and H. P. Blejer. 1976. Cancer mortality among cadmium production workers. Ann. N. Y. Acad. Sci. 271:273-279. Lilienfeld, A. M. 1981. The Humean fog: Cancer and cholesterol. An. J. Epidemiol. 114:1-4. Lin, R. S., and I. I. Kessler. 1981. A multifactorial model for pancre- atic cancer in man: Epidemiologic evidence. J. Am. Med. Assoc. 245: 147-152. Lingeman, C. H. 1974. Etiology of cancer of the human ovary: A review. J. Natl. Cancer Inst. 53:1603-1618. Linsell, C. A., and F. G. Peers. 1977. Aflatoxin and liver cell cancer. Trans. R. Soc. Trop. Med. Hyg. 71:471-473. Lipworth, L. L., and C. A. Rice. 1979. Correlations in mortality data involving cancers of the colorectum esophagus. Cancer 43:1927-1933. Lubin, J. H., W. J. Blot, and P. E. Burns. 1981. Breast cancer follow- ing high dietary fat and protein consumption. Am. J. Epidemiol. 114:422. Abstract. Lui, K., D. Moss, V. Persky, J. Stamler, D. Garside, and I. Soltero. 1979. Dietary cholesterol, fat, and fibre, and colon-cancer mortality. An analysis of international data. Lancet 2:782-785. Lynch, H. T., H. Guirgis, J. Lynch, F. D. Brodkey, and H. Magee. 1975. Cancer of the colon: Socioecohomic variables in a community. Am. Epidemiol. 102:119-127. Lyon, J. L., and A. W. Sorenson. 1978. Colon cancer in a low-risk population. Am. J. Clin. Nutr. 31:S227-S230. Lyon, J. L., M. R. Klauber, J. W. Gardner, and C. R. Smart. 1976. Cancer incidence in Mormons and non-Mor~ons in Utah, 1966-1970. N. Engl. J. Med. 294:129-133. Lyon, J. L., J. W. Gardner, and D. W. West. 1980a. Cancer risk and lifestyle: Cancer among Mormons (1967-1975~. Pp. 273-290 in H. V. Gelboin, B. MacMahon, T. Flatsushima, T. Sugimura, S. Takayama, and H. Takebe, eds. Genetic and Environmental Factors in Experimental and Human Cancer. Japan Scientific Societies Press, Tokyo. , . Lyon, J. L., J. W. Gardner, and D. W. West. 1980b. Cancer risk and life-style: Cancer among Mormons from 1967-1975. Pp. 3-28 in J. Cairns, J. L. Lyon, and M. Skolnick, eds. Cancer Incidence in Defined 17-3 1

422 DIET, NUTRITION, AND CANCER Populations. Banbury Report 4. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. MacLennan, R., J. Da Costa, N. E. Day, C. H. Law, Y. K. Ng, and K. Shan- mugaratnam. 197 7. Risk factors for lung cancer in Singapore Chinese, a population with high female incidence rates. Int. J. Cancer 20:854-860. MacLennan, R., O. M. Jensen, J. Mosbech, and H. Vuori. 1978. Diet, transit time, stool weight, and colon cancer in two Scandinavian populations. Am. J. Clin. Nutr. 31:S239-S242. MacMahon, B., P. Cole, and J. Brown. 1973. Etiology of human breast cancer: A review. J. Natl. Cancer Inst. 50:21-42. MacMahon, B., S. Yen, D. Trichopoulos, K. Warren, and G. Nardi. 1981. Coffee and cancer of the pancreas. N. Engl. J. Med. 304:630-633. Malhotra, S. L. 1977. Dietary factors in a study of cancer colon from cancer registry, with special reference to the role of saliva, milk and fermented milk products and vegetable fibre. Med. Hypotheses 3:122-126. Marasas, W. F. O., S. J. van Rensburg, and C. J. Mirocha. 1979. Inci- dence of Fusarium species and the mycotoxins, deoxynivalenol and zearalenone, in corn produced in esophageal cancer areas in Transkei. J. Agric. Food Chem. 27:1108-1112. Martinez, I. 1969. Factors associated with cancer of the esophagus, mouth and pharynx in Puerto Rico. J. Natl. Cancer Inst. 42:1069- 1094. Martinez, I. , R. Torres, Z. Frias, J. R. Colon, and M. Fernandez. 1979. Factors associated with adenocarcinomas of the large bowel in Puerto Rico. Pp. 45-52 in J. M. Birch, ed. Advances in Medical Oncology, Research and Education. Volume 3: Epidemiology. Pergamon Press, Oxford, New York, Toronto, Sydney, Paris, and Frankfurt. Mason, T. J., F. W. McKay, R. Hoover, W. J. Blot, and J. F. Fraumeni, Jr. 1975. Atlas of Cancer Mortality for U.S. Counties: 1950-1969. DHEW Publication No. (NIH) 75-780. U.S. Department of Health, Education, and Welfare, Washington, D.C. 102 pp. McMichael, A. J., J. D. Potter, and B. S. Hetzel. 1979. Time trends in colo-rectal cancer mortality in relation to food and alcohol consump- tion: United States, United Kingdom, Australia and New Zealand. Int. J. Epidemiol. 8:295-303. Meinsma, L. 1964. [In Dutch; English Summary.] Nutrition and Cancer. Voeding 25:357-365.

The Relationship of Diet to Cancer at Specific Sites 423 Mettlin, C., and S. Graham. 1979. Dietary risk factors in human bladder cancer. Am. J. Epidemiol. 110:255-263. Mettlin, C., S. Graham, and M. Swanson. 1979. Vitamin A and lung cancer. J. Natl. Cancer Inst. 62:1435-1438. Mettlin, C., S. Graham, R. Priore, J. Marshall, and M. Swanson. 1980. Diet and cancer of the esophagus. Nutr. Cancer 2:143-147. Miller, A. B. 1978. An overview of hormone-associated cancers. Cancer Res. 38:3985-3990. Miller, A. B. 1980. Epidemiology and etiology of lung cancer. Pp. 9-26 in H. H. Hansen and M. R,brth, eds. Lung Cancer, 1980. Excerpta Med- ica, Amsterdam, Oxford, and Princeton. Miller, A. B. 1981. Epidemiology of gastrointestinal cancer. Compr. Therapy 7~8~:53-58. Miller, A. B., and R. D. Bulbrook. 1980. The epidemiology and etiology of breast cancer. N. Engl. J. Med. 303:1246-1248. Miller, A. B., A. Kelly, N. W. Choi, V. Matthews, R. W. Morgan, L. Munan, J. D. Burch, J. Feather, G. R. Howe, and M. Jain. 1978. A study of diet and breast cancer. Am. J. Epidemiol. 107:499-509. Miller, C. T., C. I. Neutel, R. C. Nair, L. D. Marrett, J. M. Last, and W. E. Collins. 1978. Relative importance of risk factors in bladder carcinogenesis. J. Chronic Dis. 31:51-56. Modan, B., F. Lubin, V. Barrell, R. A. Greenberg, M. Modan, and S. Graham. 1974. The role of starches in the etiology of gastric cancer. Cancer 34:2087-2092. Modan, B., V. Barrell, F. Lubin, M. Modan, R. A. Greenberg, and S. Graham. 1975. Low-fiber intake as an etiologic factor in cancer of the colon. J. Natl. Cancer Inst. 55:15-18. Monson, R. R., and J. L. Lyon. 1975. Proportional mortality among alcoholics. Cancer 36:1077-1079. Moolgavkar, S. H., N. E. Day, and R. G. Stevens. 1980. Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. J. Natl. Cancer Inst. 65:559-569. Nomura, A., B. E. Henderson, and J. Lee. 1978. Breast cancer and diet among the Japanese in Hawaii. Am. J. Clin. Nutr. 31:2020-2025. 17-33

424 DIET, NUTRITION, AND CANCER Oettle, A. G. 1965. The aetiology of primary carcinoma of the liver in in Africa: A critical appraisal of previous ideas with an outline of the mycotoxin hypothesis. S. Afr. Med. J. 39:817-825. Okamura, T., and F. Matsuhisa. 1965. [In Japanese; English Summary.] Fluorine and other related components of Japanese foods. V. Fluorine and salt contents of miso and other foods rich in salt, and their geographical correlation with mortality from gastric cancer. Eiyo To Shokuryo 18~4~:253-257. Peers, F. G., and C. A. Linsell. 1973. Dietary aflatoxins and liver cancer--a population based study in Kenya. Br. J. Cancer 27:473- 484. Peers, F. G., G. A. Gilman, and C. A. Linsell. 1976. Dietary aflatoxins and human liver cancer. A study in Swaziland. Int. J. Cancer 17:167- 176. Pernu, J. 1960. An epidemiological study on cancer of the digestive organs and respiratory system. A study based on 7078 cases. Ann. Med. Intern. Penn. Suppl. 33:1-137. Phillips, R. L. 1975. Role of life-style and dietary habits in risk of cancer among Seventh-Day Adventists. Cancer Res. 35:3513-3522. Phillips, R. L., J. W. Kuzma, and T. M. Lotz. 1980a. Cancer mortality among comparable members versus nonmembers of the Seventh-Day Adven- tist Church. Pp. 93-102 in J. Cairns, J. L. Lyon and M. Skolnick, eds. Cancer Incidence in Defined Populations. Banbury Report 4. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. Phillips, R. L., J. W. Kuzma, W. L. Beeson, and T. Lotz. 1980b. In- fluence of selection versus lifestyle on risk of fatal cancer and cardiovascular disease among Seventh-Day Adventists. Am. J. Epidemiol. 112:296-314. Pottern, L. M., L. E. Morris, W. J. Blot, R. G. Ziegler, and J. F. Fraumeni, Jr. 1981. Esophageal cancer among black men in Washington, D.C. I. Alcohol, tobacco, and other risk factors. J. Natl. Cancer Inst. 67:777-783. Potts, C. L. 1965. Cadium proteinuria--The health of battery workers workers exposed to cadmium oxide dust. Ann. Occup. Hyg. 8:55-59. Purtilo, D. T., and L. S. Gottlieb. 1973. Cirrhosis and hepatoma occurring at Boston City Hospital (1917-1968~. Cancer 32:458-462. 17-34

The Relationship of Diet to Cancer at Specific Sites 425 Radomski, J. L., D. Greenwald, W. L. Hearn, N. L. Block, and F. M. Woods. 1978. Nitrosamine formation in bladder infections and role in the etiology of bladder cancer. J. Ural. 120:48-50. Reddy, B. S., A. R. Hedges, K. Laskso, and E. L. Wynder. 1978. Metabolic epidemiology of large bowel cancer. Fecal bulk and constituents of high-risk North American and low-risk Finnish population. Cancer 42:2832-2838. Reddy, B. S., C. Sharma, L. Darby, K. Laakso, and E. L. Wynder. 1980. Metabolic epidemiology of large bowel cancer. Fecal mutagens in high- and low-risk population for colon cancer. A preliminary report. Mutat. Res. 72:511-522. Reimer, R. R., R. Hoover, J. F. Fraumeni, Jr., and R. C. Young. 1978. Second primary neoplasms following ovarian cancer. J. Natl. Cancer Inst. 61:1195-1197. Rose, G., H. Blackburn, A. Keys, H. L. Taylor, W. B. Kannel, 0. Paul, D. D. Reid, and J. Stamler. 1974. Colon cancer and blood-cholesterol. Lancet 1:181-183. Rothman, K., and A. Keller. 1972. The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. J. Chronic Dis. 25:711-716. Rotkin, I. D. 1977. Studies in the epidemiology of prostatic cancer: Expanded sampling. Cancer Treat. Rep. 61:173-180. Ruddell, W. S. J., E. S. Bone, M. J. Hill, and C. L. Walters. 1978. Pathogenesis of gastric cancer in pernicious anaemia. Lancet 1:521-523. Sakula, A. 1976. Letter to the Editor: Vitamin A and lung cancer. Br. Med. J. 2:298. Schmidt, W., and R. E. Popham. 1981. The role of drinking and smoking in mortality from cancer and other causes in male alcoholics. Cancer 47:1031-1041. Schoenberg, B. S., J. C. Bailar III, and J. F. Fraumeni, Jr. 1971. Certain mortality patterns of esophageal cancer in the United States, 1930-67. J. Natl. Cancer Inst. 46:63-73. Schrauzer, G. N., D. A. White, and C. J. Schneider. 1977a. Cancer mortality correlation studies.--III. Statistical associations with dietary selenium intakes. Bioinorg. Chem. 7:23-34. 17-35

426 DIET, NUTRITION, AND CANCER Schrauzer, G. N., D. A. White, and C. J. Schneider. 1977b. Cancer mortality correlation studies.--IV. Associations with dietary intakes and blood levels of certain trace elements, notably Se-antagonists. Bioinorg. Chem. 7:35-56. Schuman, L. M., J. S. Handel, A. Radke, U. Seal, and F. Halberg. 1982. Some selected features of the epidemiology of prostatic cancer: Minneapolis-St. Paul, Minnesota case control study, 1976-1979. Pp. 345-354 in K. Magnus, ed. Trends in Cancer Incidence: Causes and Practical Implications. Hemisphere Publishing Corp., Washington, New York, and London. Segi, M. 1975. Tea-gruel as a possible factor for cancer of the esophagus. Gann 66:199-202. Shank, R. C., J. E. Gordon, G. N. Wogan, A. Nondasuta, and B. Subhamani. 1972a. Dietary aflatoxins and human liver cancer. III. Field survey of rural Thai families for ingested aflatoxins. Food Cosmet. Toxicol. 10:71-84. Shank, R. C., N. Bhamarapravati, J. E. Gordon, and G. N. Wogan. 1972b. Dietary aflatoxins and human liver cancer. IV. Incidence of primary liver cancer in two municipal populations of Thailand. Food Cosmet. Toxicol. 10:171-179. Shekelle, R. B., M. Lepper, S. Liu, C. Maliza, W. J. Raynor, Jr., A. H. Rossof, 0. Paul, A. M. Shryock, and J. Stamler. 1981. Dieta~y vitamin A and risk of cancer in the Western Electric study. Lancet 2:1185-1190. Shennan, D. H. 1973. Letter to the Editor: Renal carcinoma and coffee consumption in 16 countries. Br. J. Cancer 28:473-474. Simon, D., S. Yen, and P. Cole. 1975. Coffee drinking and cancer of the lower urinary tract. J. Natl. Cancer Inst. 54:587-591. Smith, P. G., and H. Jick. 1978. Cancers among users of preparations containing vitamin A. Cancer 42:808-811. Stemmermann, G. N., M. Mandel, and H. F. Mower. 1979. Colon cancer: Its precursors and companions in Hawaii Japanese. Natl. Cancer Inst. Monogr. 53:175-179. Stocks, P. 1957. Cancer incidence in North Wales and Liverpool region in relation to habits and environment. British Empire Cancer Campaign, Thirty Fifth Annual Report, Supplement to Part II. Cancer Research Campaign, London. 156 pp. 17-36

The Re~ahon ship of Diet to Cancer at Specific Sites 427 Stocks, P. 1970. Cancer mortality in relation to national consumption of cigarettes, solid fuel, tea and coffee. Br. J. Cancer 24:215-225. Stukonis, M. K. 1978. Cancer Incidence Cumulative Rates--International Comparison Based on Data from Cancer Incidence in Five Continents . IARC Technical Report No. 78/002. International Agency for Research on Cancer, Lyon, France. 54 pp. Surgeon General. 1979. Smoking and Health. A Report of the Surgeon General. U.S. Department of Health, Education, and Welfare, Washington, D.C. 1222 pp. Surgeon General. 1980. The Health Consequences of Smoking for Women. A Report of the Surgeon General. U.S. Department of Health, Edu- cation and Welfare, Washington, D.C. 359 pp. Tannenbaum, S. R., D. Moran, W. Rand, C. Cuello, and P. Correa. 1979. Gastric cancer in Colombia. IV. Nitrite and other ions in gastric contents of residents from a high-risk region. J. Natl. Cancer Inst. 62:9-12. Teppo, L., E. Pukkala, M. Hakama, T. Hakulinen, A. Herva, and E. Saxen. 1980. Way of life and cancer incidence in Finland. A municipality- based ecological analysis. Scand. J. Soc. Med. Suppl. 19:1-84. Tung, T. C., and K. H. Ling. 1968. Study on aflatoxin of foodstuffs in Taiwan. J. Vitaminol. 14 (Suppl.~: 48-52. Tuyns, A. J., G. Pequinot, and 0. M. Jensen. 1977. [In French; English Summary.] Oesophageal cancer in Ille-et-Vilaine in relation to levels of alcohol and tobacco consumption: Multiplicative risks. Bull. Cancer 64045-60. Tuyns, A. J., G. Pequignot, and J. S. Abbatucci. 1979. Oesophageal can- cer and alcohol consumption: Importance of type of beverage. Int. J. Cancer 23:443-447. van Rensburg, S. J. 1981. Epidemiologic and dietary evidence for a spe- cific nutritional predisposition to esophageal cancer. J. Natl. Can- cer Inst. 67:243-251. van Rensburg, S. J., J. J. van der Watt, I. F. H. Purchase, L. P. Coutinho, and R. Markham. 1974. Primary liver cancer rate and aflatoxin intake in a high cancer area. S. Afr. Med. J. 48:2508a-2508d. Vitale, J. J., and L. S. Gottlieb. 1975. Alcohol and alcohol-related deficiencies as carcinogens. Cancer Res. 3S: 3336-3338. 17-37

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The Relationship of Diet to Cancer at Specific Sites 429 Wynder, E. L., G. C. Escher, and N. Mantel. 1966. An epidemio- logical investigation of cancer of the endometrium. Cancer 19:489- 520. Wynder, E. L., K. Mabuchi, and W. F. Whitmore, Jr. 1971. of cancer of the prostate. Cancer 28:344-360. Epidemiology Wynder, E. L., K. Mabuchi, N. Maruchi, and J. G. Fortner. 1973. Epidemiology of cancer of the pancreas. J. Natl. Cancer Inst. 50:645-667. Wynder, E. L., K. Mabuchi, and W. F. Whitmore, Jr. 1974. Epidemi- ology of adenocarcinoma of the kidney. J. Natl. Cancer Inst. 53:1619-16 By. Yang, C. S. 1980. Research on esophageal cancer in China: A review. Cancer Res. 40:2633-2644. Zaldivar, R. 1977. Nitrate fertilizers as environmental pollutants: Positive correlations between nitrates (NaNO3 and KNO3) used per unit area and stomach cancer mortality rates. Experientia 33:264- 265. Ziegler, R. G., L. E. Morris, W. J. Blot, L. M. Pattern, R. Hoover, and J. F. Fraumeni, Jr. 1981. Esophageal cancer among black men in Washington, D.C. II. Role of nutrition. J. Natl. Cancer Inst. 67:1199-1206. 17-39

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Based on a thorough review of the scientific evidence, this book provides the most authoritative assessment yet of the relationship between dietary and nutritional factors and the incidence of cancer. It provides interim dietary guidelines that are likely to reduce the risk of cancer as well as ensure good nutrition.

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