In this chapter, the committee summarizes the role of dietary factors as they relate to the risks of various forms of cancer. Since the evidence regarding specific dietary constituents is discussed in detail in earlier chapters, it is only briefly summarized here. Some discussion of other risk factors for these cancers is included to put the role of diet in perspective. Epidemiologic data as well as supportive evidence from animal studies and from research on mechanisms of carcinogenesis are reviewed. Although the results of experiments in animals cannot be quantitatively extrapolated to humans, they provide evidence on the biologic plausibility of observed correlations between specific dietary constituents and cancer incidence or mortality in epidemiologic studies.
Trends in Cancer Incidence in the United States and the Role of Diet
Devesa et al. (1987) reviewed trends in the incidence of and mortality from specific forms of cancer in the white populations of five areas of the United States from 1947 to 1984. Overall trends were dominated by the well-known rise in lung cancer, clearly a direct result of exposure to tobacco smoke. The authors suggested that lung cancer rates in people with little or no exposure to tobacco smoke may also have increased, but the evidence is not conclusive. Large increases in incidence were also found for melanoma of the skin, cancer of the prostate and testis, and non-Hodgkin's lymphoma. Smaller increases were found for cancers of the liver, kidney, colon, urinary bladder, and breast. Major decreases in incidence were observed for cancer of the stomach and for invasive cancer of the cervix. The combined impact of improved detection standards, diagnostic ability, and reporting on the published cancer incidence rates could not be precisely measured. It is unlikely that these factors were of major importance, however, except possibly for cancers of the cervix and breast.
Some investigators have estimated the overall impact of diet on total cancer incidence and mortality. Such estimates are based on a combination of evidence regarding established relationships between dietary factors and cancer risk, the dramatic shifts in site-specific cancer rates among migrants to the United States, secular trends in cancer for which a dietary etiology is likely, supportive evidence from animal experiments, and lack of more persuasive alternative hypotheses. Doll and Peto (1981) estimated that approximately 35% (range, 10 to 70%) of all cancer mortality in the United States is related to diet, whereas Wynder and Gori (1977) estimated that 40% of cancer incidence among men and nearly 60% among women is related to diet. Because few
relationships between specific dietary components and cancer risk are well established, it is not possible to quantify the contribution of diet to individual cancers (and thus to total cancer rates) more precisely. Nevertheless, these estimates help to emphasize the importance of diet in the etiology and prevention of cancer in the United States today.
Evidence Associating Dietary Factors with Cancer at Specific Sites
The discussion in this section is presented by specific cancer sites because the dietary associations are not the same for all cancer types. See Chapters 6 through 17 for more detailed review of evidence by dietary components.
Correlation analyses have shown direct associations between consumption of alcoholic beverages and esophageal cancer in Western countries (Breslow and Enstrom, 1974; Chilvers et al., 1979; Hinds et al., 1980; Kolonel et al., 1980; Lyon et al., 1980; Schoenberg et al., 1971). Case-control and cohort studies have also provided consistent evidence of an association between alcohol consumption and risk of esophageal cancer (Hakulinen et al., 1974; Potter et al., 1981; Williams and Horn, 1977). Alcohol consumption appears to act synergistically with cigarette smoking to increase the risk. Wynder and Bross (1961) found that increases in the use of alcohol and tobacco were associated with an increased risk of squamous cell carcinoma of the esophagus and that alcohol and tobacco exert a multiplicative effect. Similar effects have been observed in Paris (Schwartz et al., 1962), Puerto Rico (Martinez, 1969), Brittany (Tuyns et al., 1977), and Normandy (Tuyns, 1983). Alcohol also seems to have an independent effect on cancer risk in the absence of smoking (Keller, 1980).
In correlation studies conducted in different parts of the world, investigators have found positive associations between esophageal cancer and several dietary factors, including (1) low intakes of lentils, green vegetables, fresh fruits, animal protein, vitamins A and C, riboflavin, nicotinic acid, magnesium, calcium, zinc, and molybdenum; (2) high intakes of pickles, pickled vegetables, and moldy foods containing N-nitroso compounds; and (3) consumption of very hot foods and beverages (de Jong et al., 1974; Hormozdiari et al., 1975; Joint Iran-IARC Study Group, 1977; Thurnham et al., 1982; van Rensburg, 1981; Yang, 1980; Zaridze et al., 1985). Many of these findings have been supported by the results of case-control studies (Cook-Mozaffari, 1979; de Jong et al., 1974; Mettlin et al., 1981). The reported associations are consistent with the general hypothesis that certain nutrient deficiencies, such as found in many high-risk populations, including heavy alcohol drinkers, might increase the susceptibility of the esophageal epithelium to neoplastic transformation (van Rensburg, 1981). In the esophageal epithelium of humans, for example, riboflavin deficiency causes lesions that may be precursors of cancer (Foy and Mbaya, 1977), although an intervention trial with riboflavin (and zinc and retinol) in a high-risk Chinese population failed to show any effect of these nutrients (Muñoz et al., 1985).
In summary, esophageal cancer is associated with the use of tobacco and alcohol individually, but especially with their combined use. Studies suggest that consumption of certain types of preserved foods increases risk and that several vitamins and minerals are protective against esophageal cancer, but the reasons for these relationships are not yet clearly established.
A high incidence of stomach cancer is found in South America, Japan, and other parts of Asia, but not in North America or Western Europe where the rates are low and still decreasing (Stukonis, 1978; Waterhouse et al., 1976). In the United States, stomach cancer rates are now among the lowest in the world, whereas in 1930, this was the leading cause of cancer death for men and the second leading cause in women (Page and Asire, 1985). Gastric cancer incidence has recently begun to decrease in Japan, and a gradual decline in incidence over several generations has been noted among Japanese migrants to Hawaii (Kolonel et al., 1980). It seems most likely that these trends are related to changes in food consumption patterns, since several dietary factors have been implicated in gastric cancer risk.
Several correlation and case-control studies have shown positive associations between gastric cancer and the consumption of dried, salted fish, smoked fish, or pickled vegetables (e.g., Dungal, 1966; Haenszel et al., 1976; Hirayama, 1967; Joossens and Geboers, 1987; Risch et al., 1985). These foods contain high concentrations of salt,
nitrates, and nitrites. Other investigators have reported associations between gastric cancer and nitrate levels in the drinking water supplies of populations in such settings as Chile (Armijo and Coulson, 1975; Zaldivar, 1977), Colombia (Correa et al., 1976; Tannenbaum et al., 1979), and England (Hill et al., 1973). In a case-control study in Canada, Risch et al. (1985) found a significant association between nitrite consumption and stomach cancer risk. The above findings support a hypothesis that gastric cancer is related to the reduction of nitrates to nitrites in the stomach and the subsequent formation of N-nitroso compounds (NRC, 1981). A high intake of salt might facilitate this process either by irritating the gastric mucosa, which is then more susceptible to carcinogenic transformation, or by inducing atrophic gastritis, leading to colonization of the stomach with bacteria that can nitrosate dietary precursors to form nitrosamines (Correa et al., 1976). Chronic gastritis has been associated with gastric cancer risk in Japan (Imai et al., 1971).
A second major dietary association with stomach cancer has been a protective effect of fresh fruits, vegetables, and vitamins, especially vitamin C. Several case-control and correlation studies have shown this inverse relationship (Bjelke, 1978; Correa et al., 1985; Graham et al., 1972; Haenszel and Correa, 1975; Higginson, 1966; Kolonel et al., 1981; Risch et al., 1985), which is consistent with the ability of ascorbic acid to inhibit the formation of carcinogenic N-nitroso compounds (Mirvish et al., 1972).
Evidence relating certain other dietary components to stomach cancer risk is uncertain because of an inadequate replication of results. This evidence includes a direct association with carbohydrates and high-starch foods in two studies (Modan et al., 1974; Risch et al., 1985), a direct association with fried foods (Higginson, 1966), an inverse association with milk (Hirayama, 1977), and an inverse association with dietary fiber (Modan et al., 1974; Risch et al., 1985). Some studies suggest that stomach cancer risk is increased by alcoholic beverage consumption (Correa et al., 1985; Hoey et al., 1981), but others do not suggest it (Acheson and Doll, 1964; Graham et al., 1972; Haenszel et al., 1972; Tuyns et al., 1982).
In summary, stomach cancer is associated with diets comprising large amounts of salt-preserved foods (that possibly contain precursors of nitrosamines) and low levels of fresh fruits and vegetables (acting as possible inhibitors of nitrosamine formation). Dietary shifts away from this pattern could explain the great decline in stomach cancer mortality in the United States over the past 50 years, but the evidence is not conclusive.
International data show a strong correlation between the incidence of colorectal cancer and cancers of the breast, endometrium, ovary, and, to a lesser extent, prostate. Within the United States, mortality from colorectal cancer is higher in the north and in urban areas than in other parts of the country (Haenszel and Dawson, 1965). Although the incidence of and mortality from this cancer have been relatively stable over the past 30 to 40 years, there has been a recent decline in mortality among females and possibly the beginning of a decline among males. In epidemiologic studies, the risk of colorectal cancer has been associated with the fat and fiber content of the diet, but other dietary constituents have also been implicated.
Several correlation and case-control studies demonstrate positive associations between the risk for colorectal (primarily colon) cancer and dietary fat (Armstrong and Doll, 1975; Carroll and Khor, 1975; Dales et al., 1979; Drasar and Irving, 1973; Graham et al., 1988; Howe et al., 1986; McKeown-Eyssen and Bright-See, 1984; Miller et al., 1983; Pickle et al., 1984; Wynder, 1975). In several other studies, positive associations have been found between meat consumption and this cancer (Haenszel et al., 1973; Hirayama, 1979; Howell, 1975; Knox, 1977; Manousos et al., 1983; Pickle et al., 1984). Conversely, many other studies have shown no relationship between fat or meat intake and colorectal cancer (e.g., Enstrom, 1975; Graham et al., 1978; Haenszel et al., 1980; Kinlen, 1982; Lyon and Sorenson, 1978; Modan et al., 1975). The studies not showing a positive correlation usually included narrow ranges of fat intake. In general, the data suggest that if this association is real, saturated rather than unsaturated fatty acids are responsible.
Two other major dietary componentsprotein and calorieshave been positively associated with colorectal cancer risk in some studies (Armstrong and Doll, 1975; Carroll and Khor, 1975; Gregor et al., 1969; Jain et al., 1980; Kune et al., 1987; Lyon et al., 1987; Macquart-Moulin et al., 1986; Potter and McMichael, 1986; Thind, 1986) but not in all (Bingham et al., 1979; International Agency for Research on Cancer Intestinal Microecology Group, 1977; Jensen et al., 1982; Tuyns et al., 1987). Since it is not possible to separate
clearly the effects of these variables in epidemiologic analyses, it remains possible that dietary fats are not the only relevant factor. Two recent case-control studies in Europe suggest that monounsaturated fatty acids may actually have a protective effect against colorectal cancer (Macquart-Moulin et al., 1986; Tuyns et al., 1987), but this finding needs further confirmation.
Few studies have examined the relationship between dietary cholesterol and colorectal cancer, but one correlation study (Liu et al., 1979) and one case-control study (Jain et al., 1980) did show a positive effect. Furthermore, the correlation of high levels of meat consumption with colorectal cancer implies a positive association with dietary cholesterol. Reports that very low serum cholesterol levels are associated with an increased risk of colon cancer in some male cohorts have not been reproduced in a substantial number of similar cohorts; in some of these studies, the association has appeared to be due to undiagnosed colon cancer in the early years of observation (McMichael et al., 1984). A relationship of diet to these low levels of serum cholesterol has not been established, and present evidence does not support a causal relationship between low serum cholesterol and colon cancer.
The data relating dietary fiber to colorectal cancer are equivocal. Although several case-control and correlation studies have shown inverse relationships between the intake of high-fiber foods and colon cancer risk (Bjelke, 1978; Dales et al., 1979; Modan et al., 1975; Phillips, 1975), these foods (vegetables to a large extent) are rich sources of other nutritive and nonnutritive constituents with potential cancer-inhibiting properties. Thus, the observed effects cannot be attributed to fiber per se. The results of the few studies that attempted to assess the intake of fiber itself have also not been consistent. Some correlation and case-control studies (Bingham et al., 1985; Bjelke, 1978; Jensen et al., 1982; Kune et al., 1987; MacLennan et al., 1978; Malhotra, 1977; McKeown-Eyssen and Bright-See, 1984) support the hypothesis of a protective effect from dietary fiber, whereas other studies (Howe et al., 1986; Potter and McMichael, 1986; Smith et al., 1985) do not. The study by Potter and McMichael (1986) even suggests a direct association among females.
Certain other dietary components have been associated with colorectal cancer in some studies. A few investigators reported inverse relationships with the intake of vitamin A or with the consumption of vegetables that were not necessarily high in fiber content (Bjelke, 1978; Macquart-Moulin et al., 1986; Phillips, 1975). Although some studies show protective effects of vitamin C and calcium (Garland et al., 1985; Macquart-Moulin et al., 1986; Potter and McMichael, 1986), others do not (Heilbrun et al., 1986; Jain et al., 1980; Tuyns et al., 1987).
Several case-control and cohort studies suggest an association between alcohol intake and colorectal cancer, especially with rectal cancer (Bjelke, 1978; Dean et al., 1979; Kabat et al., 1986; -Kune et al., 1987; Pollack et al., 1984; Tuyns et al., 1982). In some studies, colorectal cancer was associated with the consumption of alcoholic beverages in general. In others, there was an association with beer consumption specifically. Other studies did not find this relationship with alcohol (Dales et al., 1979; Graham et al., 1978; Jensen, 1979; Miller et al., 1983; Modan et al., 1975).
In summary, the data on diet and colorectal cancer are inconsistent, perhaps because of differences in the populations studied or in the dietary methodology used to assess intake. In general, increased risk of colorectal cancer appears to be associated with a dietary pattern consisting of a high fat intake (particularly saturated fats) and low vegetable intake. It is not clear whether dietary fiber per se is protective or whether the apparent protective effects in some studies are due to other food constituents such as vitamin C or calcium. Colorectal cancer risk may be increased by the consumption of alcoholic beverages, especially beer.
Primary liver cancer is relatively rare in the United States and most Western countries, but it is common in sub-Saharan Africa and Southeast Asia, where it is associated primarily with exposure to hepatitis B virus infection in early life and with consumption of foods contaminated with aflatoxins. Limited evidence links liver cancer to other possible dietary risk factors, including pyrrolizidine alkaloids, safrole, and cycasin (Anthony, 1977).
In Africa, liver cancer incidence and mortality by geographic area or among different population groups have been correlated with aflatoxin contamination of foodstuffs (Alpert et al., 1971; Peers et al., 1976; van Rensburg et al., 1974). Similar geographic correlations have been found in China (Armstrong, 1980), Thailand (Shank et al., 1972a,b; Wogan, 1975), Taiwan (Tung and Ling, 1968), and in a case-control study in the Philippines (Bulatao-Jayme et al., 1982).
Numerous reports have documented a high correlation between primary liver cancer and infection with hepatitis B virus, which has a worldwide distribution similar to that of aflatoxins (Chien et al., 1981). This association was confirmed in a large prospective cohort in Taiwan (Beasley et al., 1981).
Alcohol has been suggested as an etiologic agent for liver cancer in Western countries. Although liver cancer is associated with cirrhosis of the liver, which is in turn associated with heavy alcohol consumption, direct epidemiologic evidence linking alcohol to primary liver cancer is limited. Some studies show an association (Hakulinen et al., 1974; Inaba et al., 1984; Jensen, 1979; Yu et al., 1983), and others do not (Monson and Lyon, 1975; Nicholls et al., 1974; Pell and D'Alonzo, 1973; Robinette et al., 1979; Schmidt and de Lint, 1972; Trichopoulos et al., 1987).
In summary, liver cancer risk is most clearly associated with early-life infection with hepatitis B virus. Aflatoxins are also an etiologic factor, possibly in association with hepatitis B virus infection, in the high-risk areas of Africa and Southeast Asia. In Western countries, some studies show an association between heavy alcohol consumption and this cancer.
An increasing trend in the incidence of pancreatic cancer in the United States over the past 20 to 30 years now appears to be stabilizing. In general, pancreatic cancer occurs more commonly in higher socioeconomic groups and is most clearly associated with cigarette smoking as a risk factor (DHEW, 1979). Pancreatic cancer has been associated with meat consumption in some studies (Hirayama, 1977; Ishii et al., 1968; Mack et al., 1986) but not in others (Gold et al., 1985; Norell et al., 1986). In a case-control study conducted in Boston, MacMahon et al. (1981) found a dose-response relationship between pancreatic cancer and coffee consumption, but in a subsequent study by some of the same authors (Hsieh et al., 1986), other case-control studies (Gold et al., 1985; Mack et al., 1986; Norell et al., 1986; Wynder et al., 1983), and large cohort studies in the United States (Whittemore et al., 1983) and Norway (Heuch et al., 1983), no consistent evidence was found to support this association. Some studies have related cancer of the pancreas to alcohol consumption (Blot et al., 1978; Burch and Ansari, 1968; Cubilla and Fitzgerald, 1978; Dorken, 1964), but most have noteven among alcoholics (Hakulinen et al., 1974; MacMahon et al., 1981; Monson and Lyon, 1975; Tuyns et al., 1982; Williams and Horm, 1977; Wynder et al., 1973).
In summary, only cigarette smoking has been clearly established as a major risk factor for pancreatic cancer.
In most technologically advanced countries, lung cancer is the leading cause of death from cancer among men, and it is rapidly approaching this status among women (Miller, 1980). The most important causal factor is cigarette smoking (DHEW, 1979). Lung cancer risk in males is clearly increased by certain occupational exposures (e.g., to asbestos, nickel, chromate, gamma-radiation), several of which have been shown to interact synergistically with smoking (Fraumeni, 1975). In females, cigarette smoking appears to be the only major contributor to lung cancer incidence in most Western countries. Although most studies of dietary factors and lung cancer have controlled for cigarette smoking, possible interactions between tobacco and dietary factors have received little attention.
A prospective study in Norway showed that dietary vitamin A was inversely associated with lung cancer (Bjelke, 1975; Kvale et al., 1983). This result was supported by hospital-based studies in the United States (Mettlin and Graham, 1979) and in the United Kingdom (Gregor et al., 1980). Other studies (Byers et al., 1987; Hinds et al., 1984; Samet et al., 1985; Shekelle et al., 1981; Ziegler et al., 1984) suggest that the relevant dietary constituent may be b-carotene rather than retinol. This is consistent with several reports of an inverse association between lung cancer and the frequency of eating green or yellow vegetables (Hirayama, 1979; MacLennan et al., 1977). In prospective studies (Menkes et al., 1986; Nomura et al., 1985), the concentration of b-carotene in serum was inversely associated with the risk of lung cancer. Early reports of a similar inverse association for serum retinol were not confirmed by subsequent studies (Friedman et al., 1986; Kark et al., 1981; Menkes et al., 1986; Peleg et al., 1984; Salonen et al., 1985; Wald et al., 1980, 1986). No effect of dietary vitamin C on lung cancer risk has been found (Byers et al., 1987; Hinds et al., 1984; Kvale et al., 1983; Mettlin et al., 1981). Dietary fats (Byers et al., 1987; Wynder et al., 1987) and dietary cholesterol (Hinds et al., 1983) have been positively associated with lung cancer risk.
In summary, the main causal factor for lung cancer is cigarette smoke. Occupational exposures
to asbestos, nickel, radiation, and other agents also increase risk, and some of these have been shown to interact synergistically with smoking. Frequent consumption of green and yellow vegetables (leading to a high intake of b-carotene and other constituents in such foods) appears to be protective against lung cancer.
Breast cancer is a common cause of death among U.S. women. This cancer is more common in Caucasians than in other racial groups, although rates have been rising among blacks, Hispanics, and women of Asian origin. Descriptive epidemiologic studies suggest that some aspects of lifestyle are related to the incidence of breast cancer. For example, breast cancer incidence among Japanese migrant women in Hawaii is much higher than that in Japan and is even higher in their daughters born in Hawaii (Kolonel et al., 1980).
Breast cancer risks are closely correlated with hormonal activity, and diet might be a major contributing factor through its effects on hormonal pathways and levels (MacMahon et al., 1973). A role of dietary factors is supported by descriptive epidemiologic studies, correlation studies, case-control and cohort studies, and evaluations of nutrition-mediated risk factors.
Correlation studies provide evidence of a direct association between breast cancer mortality and the intake of calories, fats, and specific sources of dietary fats, such as milk and beef (Armstrong and Doll, 1975; Carroll and Khor, 1975; Gaskill et al., 1979). Some studies show an inverse correlation between the intake of carbohydrates or fiber and the risk of breast cancer (Adelcreutz et al., 1982; Lubin et al., 1986).
Several case-control studies associate breast cancer risk with dietary constituents, especially fats. Lubin et al. (1981) and Phillips (1975) reported an association between the frequency of consumption of high-fat foods and breast cancer. Miller et al. (1978) found a positive association with total fat consumption in pre- and postmenopausal women and weaker associations with saturated fats and cholesterol in the premenopausal women, the strongest association relating to saturated fat intake (Howe, 1985). A similar association with dietary saturated fats was found by Hirohata et al. (1987). Lubin et al. (1986) reported an increased risk of breast cancer among women who consumed a diet containing high levels of fats and animal protein and low levels of fiber; Hislop et al. (1986) found a positive association with intake of fat-containing foods, especially whole milk and beef; and Talamini et al. (1984) associated moderately increased risks with indices of fat intake. However, not all studies show these relationships (Graham et al., 1982; Hirohata et al., 1985; Willett et al., 1987a).
Several studies relate alcohol consumption to the risk of breast cancer in women (Begg et al., 1983; Byers and Funch, 1982; Hiatt and Bawol, 1984; Lê et al., 1986; Schatzkin et al., 1987; Willett et al., 1987b). However, it is unlikely that this association, even if established as causal, could account for a substantial fraction of the female breast cancer incidence in most populations.
Certain nutrition-mediated factors, notably body weight, height, and obesity (as reflected by body mass indices), have also been associated with breast cancer risk, primarily among postmenopausal women (de Waard et al., 1977; Lubin et al., 1985; Paffenbarger et al., 1980; Talamini et al., 1984). Height may be the best of these measures for predicting breast cancer risk (de Waard et al., 1977), but most studies show that the strongest association is with body mass index. However, these anthropometric measures have not been associated with risk in all populations (Kolonel et al., 1986).
In summary, breast cancer risk has been associated with the high-calorie Western diet, and dietary fat is the nutrient for which the data are strongest. However, the evidence is not conclusive, and other dietary factors may also be involved. Alcohol consumption may also be a risk factor for this cancer.
Endometrial cancer has been correlated with cancers of the breast, ovary, colon, and rectum (Miller, 1978). It tends to be more common in the United States than in other parts of the world and is more frequent in Caucasian women of higher socioeconomic status. The only well-established cause for this cancer is the use of exogenous estrogens at the high dosages commonly prescribed some years ago. Both noninsulin-dependent diabetes mellitus (NIDDM) and hypertension have been associated with this cancer (Elwood et al., 1977; La Vecchia et al., 1986). An association between endometrial cancer risk and excess weight was reported in several studies (Elwood et al., 1977; Henderson et al., 1983; Jensen, 1986; La Vecchia et al., 1986; Lew and Garfinkel, 1979; Wynder et al., 1966), and a hormonal mechanism has been postulated for this association (Henderson et al.,
1982). A protective effect of fiber has been reported (La Vecchia et al., 1986) but not confirmed.
In summary, endometrial cancer can be caused by exogenous estrogen hormones and is associated with obesity, hypertension, and NIDDM. Possible dietary risk factors for this cancer have not been established.
Ovarian cancer is more common in the United States and other Western countries than in Asia, and it occurs more frequently in countries where breast, colon, and endometrial cancers tend to occur. It tends to be more common in higher socioeconomic groups and less frequent in women who use oral contraceptives (Casagrande et al., 1979; Cramer et al., 1982; Nasca et al., 1984; Weiss et al., 1981).
Cramer et al. (1984) found that women with ovarian cancer consumed much greater amounts of animal fat and considerably less vegetable fat than did control subjects, whereas Byers et al. (1983) found no association. Weight and height, which in part reflect diet, were weakly but positively associated with ovarian cancer in one case-control study (Tzonou et al., 1984), but not in others (Annegers et al., 1979; Byers et al., 1983; Hildreth et al., 1981). Two case-control studies showed an association between coffee drinking and increased risk of ovarian cancer (La Vecchia et al., 1984; Trichopoulos et al., 1981), but a third study failed to detect this association (Byers et al., 1983); this matter remains unresolved.
In summary, ovarian cancer has been inversely related to oral contraceptive use, but no dietary associations have been established.
Bladder cancer is more common in the United States than in many other parts of the world. It occurs more frequently in men than in women and in people of lower socioeconomic status. Bladder cancer risk is increased among cigarette smokers and among certain occupational groups exposed to certain chemicals, notably b-naphthylamine and benzidine.
One cohort study showed a statistically significant association between coffee drinking and death from bladder cancer (Snowdon and Phillips, 1984), and several case-control studies found that coffee was associated with elevated risks among males (Mettlin and Graham, 1979) and females (Cole, 1971; Fraumeni et al., 1971; Howe et al., 1980; Simon et al., 1975). Other studies found only a weak association with coffee (Hartge et al., 1983; Marrett et al., 1983; Rebelakos et al., 1985), and several found no evidence of an association (Jacobson et al., 1986; Jensen et al., 1986; Morrison et al., 1982; Nomura et al., 1986; Ohno et al., 1985). Since the relative risks in most of the positive studies were low (<2.0) and few studies showed a dose-response relationship, this association is unlikely to be causal. Residual confounding by cigarette smoking may explain the apparent effect.
Conflicting findings have been reported for nonnutritive sweeteners and bladder cancer (see Chapter 17). Overall, however, it appears that use of such sweeteners does not measurably increase the risk of bladder cancer (Howe et al., in press).
There is limited epidemiologic evidence pertaining to the association of other dietary exposures with bladder cancer. Armstrong and Doll (1975) found a direct association of bladder cancer mortality with per-capita intake of fats and oils, particularly among women, but this association has not been confirmed in other studies. One case-control study (Mettlin and Graham, 1979) suggested an inverse association with carrots, milk, and an index of vitamin A intake, whereas another (Risch et al., 1988) showed no evidence of a protective effect of retinol or b-carotene, but an increased risk from consumption of dietary cholesterol. Although a direct association between beer intake and bladder cancer mortality in men was reported in a correlation study (Breslow and Enstrom, 1974), this finding has not been confirmed in case-control studies (Brownson et al., 1987; Thomas et al., 1983).
In summary, bladder cancer risk is clearly related to the use of cigarettes and to certain occupational exposures, such as benzidine and b-naphthylamine. Its relationship to dietary factors is less clear. Possible associations with coffee drinking, artificial sweetener use, and alcoholic beverage consumption have not been confirmed.
Cancer of the prostate is common in the United States, and rates among black males are especially high. This cancer is relatively rare in males under 45 years. International incidence and mortality data generally show a positive correlation of prostate cancer with cancers of several other sites associated with diet, including cancers of the breast, corpus uteri, and colon (Berg, 1975; Howell, 1974; Wynder et al., 1971). Certain popula-
tions provide interesting exceptions, however: Mormons in Utah have high prostate but relatively low breast cancer incidence rates, whereas the native Polynesians of Hawaii have low prostate but high breast cancer incidence rates (Kolonel, 1980; Lyon et al., 1976).
Although male hormones appear to contribute to the risk for this disease, little is known about the etiology of prostate cancer. Some investigators have suggested a causal relationship to aspects of sexual behavior or to a venereally transmitted virus, but no convincing evidence supports these hypotheses (Mandel and Schuman, 1980; Ross et al., 1983).
Three dietary components appear to be related to this disease: fats, vitamin A, and the trace element cadmium. Several inter- and intracountry analyses show positive correlations between mortality from prostate cancer and per-capita intake of total fat (Armstrong and Doll, 1975; Blair and Fraumeni, 1978; Howell, 1974). These findings have been confirmed in several analytical studies showing an association of prostate cancer with the intake of high-fat foods (Rotkin, 1977; Schuman et al., 1982; Snowdon et al., 1984), as well as intake of fats per se (Graham et al., 1983; Heshmat et al., 1985; Kolonel et al., 1988).
Although studies of certain other cancers suggest that vitamin A (particularly b-carotene) may be a protective factor, case-control studies of prostate cancer have tended to identify vitamin A as a risk factor, especially among men age 70 years and older (Graham et al., 1983; Heshmat et al., 1985; Kolonel et al., 1987). In the study by Kolonel et al. (1987), the effect was specific for carotenes, not for retinol. A few studies based on food frequency data suggest inverse associations with the intake of some carotene-containing vegetables (Ross et al., 1983; Schuman et al., 1982).
Occupational exposure to cadmium has been associated with an increased risk for prostate cancer, but the evidence is not consistent (Friberg et al., 1986). The evidence regarding dietary cadmium is also equivocal. Some geographic analyses of estimated per-capita intakes or levels in drinking water or soil showed positive associations (Bako et al., 1982; Berg and Burbank, 1972; Schrauzer et al., 1977), whereas others did not (Inskip et al., 1982; Shigematsu, 1984). In one case-control study, Kolonel and Winkelstein (1977) found no effect of cadmium from dietary sources. Cadmium levels in prostate tissue of men with prostate cancer were higher than in men with benign prostatic hypertrophy or normal prostate glands (Feustel and Wennrich, 1986; Feustel et al., 1982).
Increased weight or obesity has been positively associated with prostate cancer (Lew and Garfinkel, 1979; Snowdon et al., 1984; Talamini et al., 1986), but not in all studies (Kolonel et al., 1988).
In summary, prostate cancer risk appears to be higher in men consuming high-fat diets. A possible direct association with dietary vitamin A (notably carotenes) needs further confirmation. The effect of exposure to cadmium, either occupational or dietary, is not established.
Animal models have been used extensively to study the effects of different dietary components on carcinogens. By using defined diets in such studies, it is possible to distinguish among the effects of different dietary constituents and to study mechanisms of actionboth of which are difficult to accomplish in studies of humans. For this reason, and because there are no animal models for some cancer sites of importance in humans, this section is organized by dietary constituent rather than by cancer site.
Animal studies relating diet to carcinogenesis have been largely concerned with effects of dietary fats (Ip et al., 1986a; NRC, 1982). Tumors of the skin, mammary gland, colon, and pancreas develop more readily in animals fed high-fat diets than in those fed low-fat diets. Recent studies of treatment with carcinogens have been conducted in rats and, to a lesser extent, in mice and a few other species. Dietary fats appear to act primarily during the promotion stage of carcinogenesis, but the exact mechanism of action is not known and may depend on the tumor site (see Chapter 7).
Polyunsaturated vegetable oils promote tumorigenesis more effectively than saturated fats, apparently because of a requirement for w-6 essential fatty acids, but a high level of dietary fats is also required for maximum effect (Ip, 1987). Fish oils, whose polyunsaturated fatty acids belong mainly to the w-3 family, do not promote and may inhibit tumorigenesis at high levels of intake. However, a relatively large amount of fish oil is required to counteract the promoting effect of polyunsaturated vegetable oils (Cave and Jurkowski, 1987; O'Connor et al., 1987). Other types of fatty acids, including monounsaturated, medium-chain saturated, and trans fatty acids, do not appear to have
specific promoting effects on carcinogenesis in animals (Cohen et al., 1986a,b; Ip et al., 1986b).
The fact that high-fat diets promote carcinogenesis in animals more effectively than low-fat diets supports the positive correlation between dietary fats and cancer incidence and mortality shown by epidemiologic data for different countries (Armstrong and Doll, 1975; Carroll and Khor, 1975) and in several case-control studies and suggests a causal relationship (see Chapter 7 for a detailed discussion). The consumption of monounsaturated fats in the form of olive oil has been suggested as a reason for the relatively low cancer rates in Mediterranean countries where fat intake is nevertheless quite high (Cohen, 1987).
The mechanism of action of dietary fats has been studied most extensively as it relates to mammary cancer (Welsch, 1987). This is reviewed in Chapter 7 and is summarized only briefly here. Although hormonal mechanisms are clearly important for breast cancer development, early suggestions that dietary fats might work through a hormonal mechanism now seem unlikely. Several other putative mechanisms relate to the requirement for w-6 essential fatty acids. Evidence that the promoting effect can be prevented by prostaglandin synthesis inhibitors and that fish oils containing w-3 fatty acids do not promote carcinogenesis suggest that prostaglandins may be involved. However, not all prostaglandin synthesis inhibitors counteract the promoting effect (Carter et al., 1987), and the extreme susceptibility of the w-3 fatty acids in fish oil to oxidation may give rise to products other than prostaglandins that act as inhibitors of carcinogenesis (Carroll, in press).
Polyunsaturated fatty acids are characteristic components of the phospholipids of cellular membranes and are supplied entirely by the diet. Thus, dietary fats have the potential to alter the fatty acid composition of membrane phospholipids, thereby changing the fluidity of cell membranes and affecting other properties that could influence the potential for cellular growth, for example, immune responses, intercellular communication mediated by gap junctions, and responsiveness to growth factors such as protein kinase C (Welsch, 1987).
As indicated in Chapter 7, cancer mortality is positively correlated with total dietary fats but not with polyunsaturated fats. Why, then, is a high level of total dietary fat necessary for cancer promotion in animals in addition to the requirement for polyunsaturated fats? The promotional effect may result from the increased intake of energy from high-fat, high-calorie diets. Recent studies indicate that caloric restriction may inhibit carcinogenesis in animals even when the diet is high in fats (Klurfeld et al., 1987; Pariza and Boutwell, 1987), but it has not been demonstrated conclusively that excessive energy intake per se promotes carcinogenesis (see Chapter 6).
Different mechanisms may be involved in the promotion of carcinogenesis at specific sites. For example, dietary fats may enhance colon cancer by increasing the colonic concentration of secondary bile acids that act as tumor promoters (see Chapter 7).
Dietary animal protein tends to be associated with dietary fat. In humans, therefore, animal protein and fats are correlated similarly with cancer incidence and mortality. The greater emphasis on dietary fat is due in part to the consistency of the evidence that high-fat diets are associated with increased tumor incidence and tumor yield in animal models; however, effects of dietary protein have also been investigated in a substantial number of experiments in animals (NRC, 1982; see also Chapter 8).
Diets with a low protein content have usually been found to suppress carcinogenesis, and a tumor-enhancing effect is generally observed at protein levels of 20 to 25%. Higher levels produce no further enhancement and may be inhibitory, possibly because of decreased food intake (NRC, 1982; Visek, 1986). Dietary protein appears to enhance tumorigenesis only when there is amino acid balance. Thus, the effect is not due to specific amino acids or to amino acid imbalance (NRC, 1982). It was at first suggested that the effects of dietary protein on hepatomas were due to a modification in aflatoxin B metabolism, but later studies suggest that effects occurring after initiation may be important (Appleton and Campbell, 1983; Campbell, 1983). Other studies show that the effect of dietary protein is so marked that the development of preneoplastic lesions is chiefly determined by protein intake, regardless of the level of aflatoxins consumed (Dunaif and Campbell, 1987). Low-protein diets are associated with inhibition of the growth of transplanted tumors, perhaps in conjunction with cellular immune function (see Chapter 8).
There have been relatively few studies of dietary carbohydrates in relation to carcinogenesis, but
there is some evidence that rats fed sucrose or dextrose develop mammary tumors more readily than those fed lactose, starches, or dextrin (NRC, 1982; see also Chapter 9). This is of interest in connection with epidemiologic data suggesting a weak correlation between dietary sugar and breast cancer incidence and mortality.
The role of dietary fiber has been investigated in animals primarily in relation to colon cancer. The original hypothesis was that dietary fiber inhibits colon carcinogenesis by adsorption or dilution of potential carcinogens or promoters in the colon or by decreasing colonic transit time, thereby reducing the length of exposure. Experimental studies have given variable results, however. Some types of fiber inhibit carcinogenesis, whereas others actually increase the yield of colon cancers (NRC, 1982; see also Chapter 10).
Extensive studies in animals show that retinoids can prevent cancer at such sites as the skin, mammary gland, and bladder, although no effect or even increased susceptibility has been reported in several instances. There is also some evidence that carotenoids can decrease the incidence of tumors in laboratory animals (see Chapter 11). Retinoids induce cell differentiation and may act directly on nonneoplastic cells to suppress malignant transformation. They also counteract the effects of phorbol esters and inhibit the proliferative effects of growth factors. Investigators have sought novel synthetic retinoids because the naturally occurring compounds are quite toxic at doses that inhibit carcinogenesis.
The antioxidant properties of vitamin E have stimulated interest in its possible anticarcinogenic properties, but experiments have yielded largely negative results. These studies, and research showing that vitamin K may have some effects on tumorigenesis in animals, are discussed in Chapter II.
Most of the water-soluble vitamins have been investigated in relation to cancer in animals (see Chapter 12). Vitamin C may prevent carcinogenesis by preventing the formation of N-nitroso compounds or by enhancing cellular immunity, but experiments to test its effects in tumor models have produced variable results (Glatthaar et al., 1986). Esophageal cancer has been associated with riboflavin deficiency in humans, and experiments in animals have provided some supporting evidence (Rivlin, 1986). Rats fed diets deficient in lipotropes (choline, methionine, folate) are prone to develop liver tumors (Ghoshal et al., 1986; Newberne, 1986), perhaps because the deficient diet increases the initiating potency of carcinogens or serves as a promoter. Possible mechanisms include hypomethylation of DNA and alterations in membrane phospholipids, leading to structural and functional changes in membranes and increased peroxidation of membrane lipids (Shinozuka et al., 1986).
Selenium inhibits virally and chemically induced tumors as well as transplanted tumors in animals and is effective during both initiation and proliferative phases of tumorigenesis (Ip, 1985, 1986; Milner, 1985, 1986). Various mechanisms for this inhibitory effect have been proposed. Selenium may prevent the activation of carcinogens such as dimethylbenzanthracene (DMBA) and may modify RNA transcription or translation (Milner, 1986). Its effect on the in vivo activation of aflatoxin B1 to form covalent DNA adducts is equivocal (Chen et al., 1982a,b). The main function of selenium is to induce and maintain the enzyme glutathione peroxidase, which prevents cellular damage by catabolizing organic peroxides, but this function does not seem to be responsible for its chemopreventive effects (Medina, 1986). Other possible mechanisms of action include inhibition of DNA synthesis and enhancement of immune responses (Ip, 1985).
Dietary zinc deficiency has not been associated with an increased incidence of esophageal carcinoma in humans (see Chapter 14). In animals, zinc deficiency increases the incidence of esophageal carcinoma induced by methylbenzylnitrosamine (MBN), which requires metabolic activation. Zinc acts as a noncompetitive inhibitor of cytochrome P450 activity, and zinc deficiency activates the cytochrome P450-dependent metabolism of MBN, which may explain how zinc deficiency enhances the carcinogenic potential of this compound (Barch and Iannaccone, 1986). On the other hand, zinc is required for growth of both normal and neoplastic tissues, and zinc deficiency reduces the incidence of tumors induced in animals by 3-methylcholanthrene and 4-nitroquinoline-N-oxide (Barch and Iannaccone, 1986). Zinc deficiency affects immunocompetence and influences many other aspects of metabolism, including nucleic acid and protein synthesis.
Testicular tumors have been induced by direct injection of zinc. Excessive dietary zinc can sometimes enhance carcinogenesis, perhaps because it is required for synthesis of DNA, but in other animal models, excess zinc inhibits tumor formation. Other studies reviewed in Chapter 14 also demonstrate that zinc deficiency can either enhance or inhibit tumor growth, indicating that different mechanisms are involved. The role of zinc in carcinogenesis is complex and poorly defined (Kasprzak and Waalkes, 1986).
In rats fed an iodine-deficient diet, follicular adenomas of the thyroid develop by 12 months and follicular carcinomas by 18 months, probably because the iodine deficiency causes chronic hypersecretion of thyroid-stimulating hormone. Iodine deficiency, goitrogenic compounds, and thyroid toxins all act as potent tumor promoters in animals. These findings are not consistent with the weight of epidemiologic evidence, which does not show increased risk of thyroid cancer associated with goiter or living in iodine-deficient areas (see Chapter 14).
Some elements, such as iron and molybdenum, have been shown to enhance or inhibit cancer in different experiments. Others, such as chromium, manganese, and cadmium, were found to be mutagenic in short-term assays. In general, the relevance of these trace element studies to cancer in humans is not clear (see also Chapter 14).
Salt has been implicated as a promoter of gastric cancer (Joossens and Geboers, 1987). Some experiments in animals indicate that dietary salt facilitates both initiation and promotion of gastric cancer (Takahashi, 1986; Takahashi et al., 1983). It may act by irritating and possibly damaging the gastric mucosa. (See Chapter 15 for further discussion of salt.)
Dietary calcium has been reported to increase the incidence of tumors in some animals (Kasprzak and Waalkes, 1986), whereas other studies focused on its possible protective effects in colon carcinogenesis (Bruce, 1987; Newmark et al., 1984). Calcium may bind bile acids and fatty acids, thereby preventing them from acting as tumor promoters, but in experiments on azoxymethane-induced colon tumors, rats fed a high-calcium diet developed more tumors than did those fed a low-calcium diet (Bull et al., 1987). On the other hand, Appleton et al. (1987) reported that calcium supplementation reduces colonic crypt-cell production rates and prevents the increase in intestinal tumor yields produced by enterectomy in rats treated with azoxymethane. Pence and Buddingh (1987) also reported that supplemental calcium or vitamin D3 inhibits the promotion by dietary fats of intestinal cancer induced in rats by 1,2-dimethylhydrazine. Furthermore, there is evidence that dietary calcium can reduce the yield of mammary tumors induced in rats by DMBA (Jacobson et al., 1987).
Nonnutritive Dietary Components
Animal studies of some of the constituents of coffee and tea, such as caffeine, phenolic compounds, and tannic acid, have yielded mixed results about the ability of these constituents to produce tumorigenesis (see Chapter 17). Nonnutritive sweeteners have been the subject of several long-term studies in animal cancer models. Two-generation studies have provided evidence of a positive association between dietary saccharin and bladder cancer in rats, and saccharin was also shown to have tumor-promoting and cocarcinogenic potential for bladder cancer induced in rats by other chemicals. Cyclamate does not appear to be carcinogenic in rats (NRC, 1985), but it may enhance the carcinogenic effect of other substances on the bladder. Aspartame has not been implicated as a bladder carcinogen, and there is conflicting evidence with regard to its effects on brain neoplasms in animals (see Chapter 17).
There is no conclusive evidence that nitrates or nitrites are carcinogenic in animals, but nitrites may interact with other dietary components to produce N-nitroso compounds (NRC, 1981). These compounds require metabolic activation to be mutagenic or carcinogenic, but can then induce a variety of tumors; however, there are large differences in the susceptibility of different species and different tissues (Lijinsky, 1986). The formation of N-nitroso compounds can be enhanced by a variety of ions present in food, especially thiocyanate and iodine, but can be prevented by other dietary components, including ascorbic acid and a-tocopherol.
Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)food additives that are widely used as preservatives and antioxidantshave been studied extensively in animal cancer models. BHA can induce tumors of the forestomach, but can also inhibit the activity of a variety of carcinogens (see Chapter 17), perhaps by preferential enhancement of hepatic detoxifying mechanisms. Unlike other antioxidants, however, BHT administered after carcinogens may increase the number of tumors.
Other nonnutritive components of foods studied for their cancer potential in animals are polychlorinated biphenyls, polybrominated biphenyls, polycyclic aromatic hydrocarbons, diethylstilbestrol, and various food colors (see Chapter 17). In addition to studies involving feeding trials of animals, many of these compounds have been investigated in short-term tests for genotoxicity and mutagenesis (Chapter 17). Positive results are frequently obtained, but Ames et al. (1987) emphasize that naturally occurring components of the diet often have mutagenic properties. Because these components may be associated with protective substances, it is difficult to assess the relative risks of these various mutagenic compounds in the overall context of human cancer.
Although the contribution of diet to the total incidence of and mortality from cancer in the United States cannot be determined with certainty, it seems reasonable that approximately one-third of all cancer mortality may be related to diet. Over the past 30 years, the incidence of cancer at some sites associated with diet (e.g., breast, colon, prostate) has increased modestly, whereas for other sites (most notably the stomach), it has decreased substantially.
Cancers of the gastrointestinal tract have been positively associated in epidemiologic studies with a variety of dietary exposures, e.g., esophageal cancer with alcohol consumption (particularly combined with tobacco use), stomach cancer with a high intake of foods preserved with salt, colorectal cancer with dietary fats and alcoholic beverages (particularly beer), and liver cancer with aflatoxin-contaminated foods and possibly heavy alcohol consumption (but most strongly with hepatitis B virus infection). Inverse associations with some of these cancers have been noted for other dietary components, e.g., fresh fruits and vegetables (possibly reflecting vitamin C intake) with stomach cancer, and a high intake of vegetables (possibly reflecting intake of certain vitamins, components of fiber, or nonnutritive constituents) with colorectal cancer.
Cancers of the lung and bladder are most clearly associated with exposure to cigarette tobacco and certain industrial chemicals. Foods of plant origin, especially fruits, and green and yellow vegetables, rich in b-carotene (and other carotenoids) appear to exert a protective effect against lung cancer, but this effect could be due to some other constituent of these foods.
Cancers of the breast and prostate have been positively associated with dietary fats. Animal experiments support this positive association, but the epidemiologic evidence is not totally consistent. Alcohol consumption may also be a risk factor for breast cancer. Cancer of the endometrium is clearly associated with obesity, but no specific dietary risk factors for this cancer have been established.
Many of these epidemiologic associations are supported by evidence from experiments in animals. For example, high-fat diets clearly promote mammary and colon carcinogenesis in animals, whereas retinoids and selenium can inhibit experimentally induced tumors at several sites. Nitrites have been shown to interact with other dietary components to produce carcinogenic N-nitroso compounds. However, data on the carcinogenicity of most components of the human diet are quite limited. Although one or more mechanisms have been proposed for the carcinogenic effects of specific dietary factors, the exact mechanisms of carcinogenesis in humans are not yet established for any diet-related cancer.
Directions for Research
· Methodology Although a considerable amount of research is being focused on the relationship of dietary constituents to cancer, few associations have been established with certainty. Progress in this field could be greatly facilitated by methodological improvements in several areas. For example, innovative methods for dietary assessment in population samples, including the identification of meaningful and practical biologic markers of exposure, might yield more reliable estimates of intake and less inconsistency among studies. Improvement is also needed in the quality and comprehensiveness of the food composition data bases used in this research, for example, those used to estimate the vitamin A and fiber content of foods.
·Intervention Trials To date, epidemiologic studies on diet and cancer in humans have been largely observational, i.e., intercountry comparisons, studies on migrants, or case-control and cohort studies. Although some findings are supported by animal studies, the results of such studies cannot be quantitatively extrapolated to humans. Furthermore, there are not always suitable animal models. Thus, to obtain definitive information on the role of diet and cancer in humans, it would be desirable to conduct intervention trials in which diets are modified in specific ways and the subjects
are monitored for sufficient time to determine the impact on the incidence of cancer in a number of different sites. Such trials should be planned carefully on the basis of epidemiologic and experimental evidence; efforts should be made to identify the best study populations and the modifications in dietary patterns that most warrant investigation. Although intervention trials are likely to be very expensive, the magnitude of the health problem and the lack of satisfactory treatments for many major types of cancer warrant such an investment of human and financial resources.
· Genetic Determinants The role of genetic factors, particularly as they modify individual responses to environmental (dietary) exposures, has not been studied much. Research in this area might clarify some of the poorly understood relationships between dietary components and cancer.
· Quantitative Relationships The quantitative nature of the relationship between food constituents and cancer risk is as yet little understood. Such information will be necessary if the public is to be given more precise dietary recommendations than are currently possible.
· Mechanisms of Action Mechanisms of action for most dietary factors that affect cancer risk in humans are not completely understood. Elucidation of these mechanisms would help to establish the causal nature of some diet-cancer associations, but this information is not essential to the formulation of policy.
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