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Diet, Nutrition, and Cancer (1982)

Chapter: 5 Lipids (Fats and Cholesterol)

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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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Suggested Citation:"5 Lipids (Fats and Cholesterol)." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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5 Lipids (Fats and Cholesteroll EPIDEMIOLOGICAL EVIDENCE _ . Fats Of all the dietary factors that have been associated epidemiologi- cally with cancers of various sites, fat has probably been studied most thoroughly and produced the greatest frequency of direct associations. However, since dietary fat is highly correlated with the consumption of other nutrients that are present in the same foods, especially protein in Western diets, it is not always possible to attribute these associations to fat intake per se with absolute certainty. ~ _ Breast Cancer. Several international correlation studies have shown direct associations between per capita fat intake and breast cancer in- cidence or mortality (Armstrong and Doll, 1975; Carroll, 1975; Drasar and Irving, 1973; Gray et al., 1979; Hems, 1978; Knox, 1977~. In general, the correlations were higher for total fat than for the other dietary factors considered (e.g., animal protein, meat, specific fat components, and oils). Some of the similarities in the findings undoubtedly reflect the overlapping data sets used in these studies rather than reproduced results. In other correlation studies, intracountry data sets have been used to compare dietary fat intake and breast cancer. Gaskill et al. (1979) compared per capita intake of various foods by state within the United States with corresponding breast cancer mortality rates and found a significant direct correlation with fat intake when results from all states studied were combined. The correlation disappeared, however, when the southern states were excluded from the analysis or when they controlled for age at first marriage (as a reflection of age at first pregnancy) or median income. Their results suggested that dairy products as a class increased the risk of breast cancer. Hems (1980) noted that time trends for breast cancer mortality in England and Wales from 1911 to 1975 correlated best with corresponding per capita intake patterns for fat, sugar, and animal protein one decade earlier. In studies based on personal interview data, Kolonel et al. (1981) correlated individual consumption of fat with ethnic patterns of breast cancer incidence in Hawaii. These investigators found significant associations with total fat, with animal fat, and with both saturated and unsaturated fats. The findings of three case-control studies support a role for dietary fat in the risk for breast cancer. Phillips (1975) reported a direct association between frequency of consumption of high-fat foods and breast cancer in a study of 77 breast cancer cases and matched controls among 73 5-1

74 DIET, NUTRITION, AND CANCER Seventh-Day Adventists in California. Miller et al. (1978) also found a weak direct association, but no evidence of a dose response, between total fat consumption (based on quantitative dietary histories) and breast cancer in a study of 400 cases and 400 matched neighborhood controls in Canada. In the third case-control study, Lubin et al. (1981) found signifi- cant increasing trends in relative risk 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 _ al. (1978) compared the diets consumed by husbands of women with and without breast cancer. (The men were participants in a pro- spective cohort study of Japanese men in Hawaii.) These investigators reported a direct association between consumption of high fat diets by the husbands and breast cancer in their wives, who were assumed to have adhered to similar eating patterns. Prostate Cancer. Prostate cancer has also been associated epide- - miologically with fat intake. International data on mortality, but not incidence, indicate that there is a strong direct correlation of per capita total fat intake and cancer at this site (Armstrong and Doll, 1975~. Howell (1974) reported similar results from a study based on a rank correlation with mortality in 41 countries. In Hawaii, the inci- dence of prostate cancer in four ethnic groups was highly correlated with consumption of both animal and saturated fat (Kolonel et al., 1981~. In the mainland United States, Blair and Fraumeni (1978) corre- lated prostate cancer mortality by county with dietary variables. They observed that counties with a high risk for prostate cancer among whites had correspondingly high per capita fat intakes among the same population. Hirayama (1977) observed that one of the most notable dietary changes in Japan since 1950 is increased per capita fat intake and that this change parallels a striking increase in mortality from prostate cancer. Prostate cancer has been associated with dietary fat in two case- control studies. In an ongoing study based on 111 cases with prostate cancer and 111 matched hospital controls, Rotkin (1977) has found that the cases had consumed high fat foods with greater frequency than had the controls. Schuman et al. (1982) also reported a more frequent con- sumption of foods with high animal fat content by cases than by controls. Cancer of Other Reproductive Organs. Other reproductive organs for which there have been associations between dietary fat and cancer include the testes, corpus uteri, and ovary. Armstrong and Doll (1975) found direct correlations between per capita intake of total fat and incidence of cancer of the testes and corpus uteri and mortality from ovarian can- cer. Lingeman (1974) also correlated mortality from ovarian cancer with international data on fat intake. Kolonel et al. (1981) found a direct association between ethnic patterns of total, animal, saturated, and 5 - 2

Lipids (Fats and Cholesterop 75 unsaturated fat consumption in Hawaii and incidence of cancer of the corpus uteri. Gastrointestinal Tract Cancer. Dietary fat has also been associated - with cancer at several sites in the gastrointestinal tract. In only one case-control study, however, has an association of stomach cancer with dietary fat been suggested. In that study, Higginson (1966) reported more frequent consumption of fried foods and greater use of animal fats in cooking by gastric cancer cases than by controls. Graham et al. (1972) failed to confirm this finding in a subsequent study of 168 gas- tric cancer cases matched to hospital controls. Although time-trend data in Japan (Hirayama, 1977) and one inter- national correlation study (Lea, 1967) have shown associations of fat intake with pancreatic cancer, most epidemiological data pertain to cancers of the large bowel. Armstrong and Doll (1975) reported direct correlations between colon and rectal cancer incidence and mortality and per capita intake of total fat, based on international data. Knox (1977) also reported a strong correlation between mortality from cancer of the large intestine (excluding rectum) and per capita total fat intake, and only a slightly weaker correlation between mortality from rectal cancer and intake of total fat and animal fat. After reviewing their data from an earlier study, Enig et al. (1979) retracted their original suggestion that colon cancer was directly cor- related with intake of total, saturated, and vegetable fat, but not with animal fat. gingham et al. (1979) calculated average intakes of nutrients by populations in different regions of Great Britain. They found no sig- nificant association of fat intake with mortality from colon and rectal cancers. Lyon and Sorenson (1978) also reported little difference in fat intake between the population of Utah (with a low risk for colon cancer) and that of the United States as a whole. The contrast between the strong international correlations and the lack of associations within countries is striking. One possible expla- nation is that the regional food intake data within a country are based on means of individual consumption data and, thus, may be too uniform to demonstrate any strong association with risk of colon or rectal cancer. In contrast, the variation in fat intake among countries is much greater, thereby facilitating the demonstration of associations. MacLennan et al. (1978) compared the diets of adult men in two Scandi- navian populations with different risks for colon cancer (high risk for Danes in Copenhagen and low risk for Finns in Kuopio). These studies, which were based on food diaries, indicated that the consumption of fat was similar for both groups, but that there were differences in fiber intake (see Chapter 8~. Reddy et al. (1978) also studied this low risk Finnish population and compared their diets to those of a high risk population in New York. They too found no difference between groups in 5 - 3

76 DIET, NUTRITION, AND CANCER total fat intake, but noted that a higher proportion of total fat was consumed as dairy products by the Finns and as meat by the New Yorkers. This observation raises the possibility that the source as well as the quantity of dietary fat may be relevant. In a case-control study conducted in parallel with the study on breast cancer (described above), Phillips (1975) found a direct asso- ciation between colon cancer and the frequent consumption of high-fat foods by Seventh-Day Adventists. In a study of cases and hospital con- trols among blacks in California, Dales et al. (1978) observed a direct association between risk of colon cancer and frequent consumption of foods high in saturated fat. The association was strongest for those who consumed diets high in saturated fat and low in fiber content. Total fat consumption, estimated from frequency data, was also reported to be higher among large bowel cancer cases than among controls in a study conducted in Puerto Rico (Martinez et al., 1979~. Dietary histories were used to estimate nutrient intake in a case- control study conducted by Jain et al. (1980) in Canada. They reported a direct association (including a dose response) between risk of both colon and rectal cancer and consumption of fat, especially saturated fat. The elevated risks persisted after adjustment for other nutrients in the diet. Several reports on meat consumption are relevant to this discussion since meat can be an important source of dietary fat, especially satu- rated fat. Berg and Howell (1974) and Howell (1975) reported a high correlation between colon cancer mortality and meat intake (particularly beef), based on international per capita intake data. In Hawaii,investi- gators reported a direct association between frequency of meat, especially beef, consumption and large bowel cancer among Japanese cases and hospital controls (Haenszel et al., 1973~. This finding was not reproduced in studies conducted in Buffalo, New York (Graham et al., 1978) and in Japan (Haenszel et al., 1980), nor in parallel cohorts followed prospectively in Minnesota and Norway (Bjelke, 1978~. Furthermore, Enstrom (1975) has noted that trends in beef intake in the United States do not correlate with trends in the incidence of and mortality from colorectal cancer. Meat consumption has also been associated with pancreatic cancer. In a case-control study conducted in Japan, Ishii et al. (1968) found a direct association between meat consumption by men and mortality from pancreatic cancer. Their findings were based on responses to mailed questionnaires, most of which were completed by relatives of deceased cases. Hirayama (1977) reported a relative risk of 2.5 for daily meat intake and incidence of pancreatic cancer in a prospective cohort study of 265,118 Japanese. Summary. The results from a substantial number of epidemiological studies have indicated an association between dietary fat and cancers of the gastrointestinal tract (especially the large bowel) and of endocrine target organs (especially the breast and prostate). Some studies of

Lipids (Fats and Cholesterol) 77 large bowel cancer were conducted on groups of relatively homogeneous populations, and some were not specifically designed to test the hypothe- sis that fat consumption is associated with colon cancer. The studies designed specifically to test this hypothesis (e.g., Dales et al., 1978; Jain et al., 1980) tended to show the most striking direct associations, especial ~ when the possible confounding effects of dietary fiber were considered. The evidence for cancer of the breast and prostate is more consistent than that for large bowel cancer. The results of the most thorough case-control study of breast cancer yet reported (Miller et al., 1978) were only weakly positive, however, partly reflecting the fact that recent food consumption was measured rather than dietary intake patterns earlier in life, which may have been the more relevant exposure period. (Studies of changing breast cancer incidence among Japanese migrants to the United States and their descendants, for example, suggest that early-life exposures are important determinants of breast cancer risk.) Cholesterol High-fat diets have been associated with atherosclerosis--a condition that has also been associated with elevated serum cholesterol levels. Therefore, there has been interest in studying the relationship of serum cholesterol levels as well as cholesterol intake to the incidence of can- cer. Most of the studies described below were designed to examine the association between cholesterol and cardiovascular disease, and were not specifically intended to measure cancer incidence or mortality. However, the opportunity provided by these long-term studies of cardiovascular disease in which serum cholesterol levels of the subjects were determined at the beginning of the study has resulted in a number of different re- ports on observed associations. Using per capita food intake data from 20 industrialized nations and simple correlation analysis, Liu et al. (1979) showed that there was a strong direct correlation between per capita intake of total fat and cholesterol and the mortality rate for colon cancer, but that there was an inverse correlation for fiber intake. Cross-classification showed a highly significant association for cholesterol, but not for fat or fiber. These investigators suggested that the data support a causal relationship between dietary cholesterol and colon cancer. Pearce and Dayton (1971) conducted an 8-year clinical trial in which groups of 422 and 424 men were fed a conventional diet or one containing high levels of polyunsaturated fat (to lower cholesterol levels), respec- tively. Incidence of cancer deaths in the groups on the experimental diet was higher. In a similar experiment conducted in Finland, Miettinen _ al. (1972) also found more carcinomas in the test group. A study group, convened to examine cancer incidence in men from five controlled trials of cholesterol-lowering diets, found little difference in relative risks (Ederer et al.. 1971). _ _ _ ~ _ 5-5 ad;

78 DIET, NUTRITION, AND CANCER In other studies, clofibrate, a hypolipidemic agent, or a placebo was administered to more than 10,000 volunteers between 30 to 54 years of age whose serum cholesterol levels were in the top fertile (committee on Prin- ciple Investigators, 1978~. The total mortality from causes other than ischemic heart disease was substantially higher in the clofibrate group: there was a disproportionately large number of neoplasms of the gastroin- testinal tract and a few more neoplasms in the respiratory tract. How- ever, there were too few cancer deaths to demonstrate a statisticially significant difference among the test groups. In another study of the relationship between colon cancer and serum cholesterol, Rose _ al. (1974) observed that the initial levels of serum cholesterol in colon cancer patients were lower than expected. They also reported that serum cholesterol levels were higher in patients with cancer of the stomach, pancreas, liver, bile ducts, and rectum than in the con- trols. Bjelke (1974) reported a similar correlation between colon cancer and low levels of serum cholesterol. Nydegger and Butler (1972) examined total serum cholesterol levels in 186 controls and 122 subjects with malignant tumors. Their data also generally showed lower cholesterol levels in the cancer patients. Beaglehole et al. (1980) studied the relationship between serum cholesterol concentration and mortality in New Zealand Maoris over a period of 11 years. They found significant inverse relationships be- tween serum cholesterol concentrations and cancer mortality. In a 7.5-year follow-up study of London civil servants, Rose and Shipley (1980) observed that mortality from cancer at all sites was associated with a progressive decline in plasma cholesterol levels. These investigators grouped cancer deaths into those that occurred less than 2 years after the subjects entered the study and those that occurred from 2 to 7.5 years afterward. For the group in which deaths occurred within 2 years, the age-adjusted mortality rate for those with the lowest plasma cholesterol levels was more than double the rate for those with the highest levels. However, cancer deaths among those followed for longer than 2 years occurred at the same rate, regardless of plasma cholesterol level at entry into the study. The investigators concluded that the decline in cholesterol levels was probably a meta- bolic consequence of cancer, which, while unsuspected, was present when the subjects entered the study. In more than 5,000 subjects studied for 24 years in the Framingham Heart Study (Williams et al., 1981), an inverse relationship between serum cholesterol levels and cancer of the colon and other sites was ob- served in men but not in women. Kark et al. (1980) related serum cholesterol levels to cancer inci- dence in more than 3,000 individuals followed for as long as 14 years in Evans County, Georgia. Patients diagnosed as having cancer at any site at least 1 year following entry into the study had had entry serum cho- lesterol levels significantly lower than those in the noncancer patients. 5 - 6

Lipids (Fats and Cholestero1) 79 This association was the same for black and white females and for black and white males, but was stronger in males of both races. The possibility that the presence of cancer may have been responsible for the lower serum cholesterol levels was investigated. Patients were categorized into three groups, depending on when evidence of cancer was first observed after entry into the study: within 1 year, from 1 to 6 years, and from 7 to 13 years. Initial serum cholesterol levels were higher in the first group than in the other two groups, but no differences were noted between the latter groups. Kark and colleagues also observed little difference in cholesterol levels in cases and controls when various cancer sites were grouped together. However, they did report low serum cholesterol levels in lung cancer- patients, whereas Stamler et al. (1968) observed that serum cholesterol levels were higher in lung cancer cases than in controls. A study conducted in Norway indicated that there was no over- all relationship between serum cholesterol levels and total cancer inci- dence (Westlund and Nicolaysen, 1972~. In the Honolulu Heart Study, 598 deaths were observed in 7,961 men whose cholesterol levels had been determined and who were followed for 9 years (Kagan et al., 1981~. The baseline serum cholesterol levels were directly associated with mortality from coronary heart disease but in- versely associated with total cancer mortality, mortality from cancers of the esophagus, colon, liver, and lung, and malignancies of the lymphatic and hematopoietic systems. In Yugoslavia, Kozarevic et al. (1981) related baseline serum choles- terol levels to mortality in 11,121 males over a 7-year period. The in- verse association between cancer deaths and serum cholesterol levels was not statistically significant. In the Puerto Rico Heart Health Programme, 9,824 men were followed for 8 years (Garcia-Palmieri et al., 1981~. Serum cholesterol levels mea- sured at the first examination were found to vary inversely with subse- quent mortality from cancer. Peterson _ al. (1981) followed 10,000 men in Sweden for a mean of 2.5 years. They found that deaths from neoplastic disease and other noncoronary heart disease peaked at low levels of serum cholesterol. In contrast, serum cholesterol was not associated with overall risk of death from cancer in three epidemiological studies of Chicago men (Dyer et al., 1981~. When cancer deaths were evaluated by site, there was a significant inverse association between serum cholesterol and deaths from sarcoma, leukemia, and Hodgkin's disease in the nearly 2,000 men studied for 17 years, but not for deaths from lung cancer, colorectal cancer, cancer of the oral cavity, pancreatic cancer, or all other can- cers combined. There was, however, a suggestion of a direct association for breast cancer in women. These studies have been assessed by Lilienfeld (1981) and by others, who concluded that the observed inverse correlations do not substantiate 5 - 7

80 DIET, NUTRITION, AND CANCER any direct cause-and-effect relationship between low blood cholesterol levels and cancer. Only one case-control study has specifically evaluated serum choles- terol levels in cases of colon cancer and matched controls (Miller et _., 1981~. In 133 pairs matched by age and sex, serum cholesterol levels were lower for cases than for controls. However, following stratification by tumor stage, significant differences in cholesterol levels persisted only between cases with advanced tumors and controls. Furthermore, only women, not men, had significantly lower serum choles- terol levels with advancing disease. The lack of an association in early disease supports the concept that low serum cholesterol levels observed in colon cancer patients may be the result of a metabolic change accom- panying tumor growth and may not necessarily precede tumor formation. Miller et al. (1978) studied the association of dietary levels of cholesterol and breast cancer. They found no significant differences in estimated cholesterol consumption between cases and controls. In another case-control study, the same group found that cholesterol intake for males with rectal cancer and females with colon and rectal cancer was higher than for controls (Jain et al., 1980~. Although the relative risk for dietary cholesterol was significant at higher intakes for all male and female cases, compared to all controls, it was substantially less than the estimates of risk for other nutrients associated with intake of fat, especially saturated fat. There is an apparent conflict in the evidence, i.e., that an in- creased risk of cancer of the colon and other sites has been associated not only with dietary cholesterol (and simultaneous intake of other, possibly more relevant lipid components) but also with very low serum cholesterol levels. A possible explanation might be that a high intake of dietary fat (and/or cholesterol) by persons whose metabolism maintains low serum cholesterol results in reduced biosynthesis of cholesterol and a high rate of excretion for cholesterol breakdown products in the intestine (tin and Connor, 1980~. These breakdown products could serve as substrates for the intraluminal production of carcinogens by intes- tinal bacteria (Hill et al., 1971~. However, in metabolic studies con- ducted in hospital wails, low serum cholesterol is usually accompanied by excretion of low levels of bile acid. This observation is not compatible with the mechanisms normally proposed for the carcinogenic effect of dietary lipids. In summary, data pertaining to the association between serum cholesterol levels and total cancer incidence and mortality are incon- sistent. An inverse correlation between serum cholesterol levels and colon cancer in men has been noted in some studies, but not in all. It is not clear whether lower than normal serum cholesterol levels are the cause, or whether they reflect the metabolic consequences, of cancer. Thus, the data are inconclusive and do not point to a causal relationship between low cholesterol levels and risk of colon cancer. However, since 5 - 8

Lipids (Fats and Cholesterop Sl they do suggest that low serum cholesterol levels may be a clue to some unknown factor, possibly something that is transported in the low density lipoprotein fraction of serum, these data and future findings should be examined carefully. RELATIONSHIP OF FECAL STEROID EXCRETION TO BOWEL CARCINOGENESIS The possibility that metabolites in the colon could provide a clue to the presence of malignancy has stimulated a number of investigators to study the level and spectrum of steroids in the feces of populations at low or high risk for colon cancer, as well as of animals fed colon car- cinogens together with various dietary regimens. The amounts of neutral and acidic fecal steroids correspond to the level of fat intake. How- ever, studies of the ratios of primary to secondary bile acids or the ratio of cholesterol to its metabolic products (i.e., coprostanol and coprostanone) have revealed no significant differences among the popula- tions studied (Moskovitz et al., i979; Mower et al., 1979; Reddy, 1979~. Recent comparisons of high risk and low risk populations, e.g., three socioeconomic groups in Hong Kong (Hill et al., 1979) and Finns and New Yorkers (Ready, 1979), suggest that the concentration of bile acids is elevated in feces of the groups that are at higher risk. Pioneering efforts by Hill and his colleagues (1971) pointed to an association between rates of mortality from colon cancer and fecal excretion of bile acids as well as the fecal degradation of cholesterol and its metabolizes. They revived an earlier concept, based on struc- tural and steric similarities, that bile acids might be transformed to the carcinogen 3-methylcholanthrene by anaerobic gut bacteria. In the studies leading to these earlier theories, deoxycholic acid was converted chemically to 3~ethylcholanthrene by Wieland and Dane (1933) and by Cook and Haslewood (1933~. Later, Fieser and Newman (1935) derived the same carcinogen from cholic acid. The chemical steps used in these studies were all reactions known to occur naturally, i.e., oxidation, hydrogena- tion, cyclization, and dehydrogenation, although laboratory conditions for the synthesis did not reproduce normally encountered biological conditions. Through the efforts of Hill, Reddy, Mastromarino, Narisawa, Nigro, their coworkers, and others, the concept has evolved that fecal bile acids and metabolizes of cholesterol may function as cocarcinogens, carcinogens, or promoters in tumorigenesis of the large bowel (Hill et al., 1971; Mastromarino et al., 1976; Narisawa et al., 1974; Nigro et al., 1973; Reddy and Wynder, 1973; Reddy et al., 1977a). To date, how- ever, no active carcinogen derived from bile acids has been isolated from human or animal feces. Reddy_al. (1977a) demonstrated that a fourfold increase in dietary fat (from 5% to 20%) given to rats increased the 24-hour fecal excretion 5 - 9

82 DIET, NUTRITION, AND CANCER of neutral and acid sterols by 30% to 40% (based on body weight). Bac- terial conversion of primary to secondary bile acids occurred more exten- sively in rats fed the high fat diet than in those fed the low fat diet. The possibility that bile acids may have tumor-promoting effects is supported to some extent by the finding that bile acids affect cell ki- netics in the intestinal epithelium. Diversion of biliary and pancrea- tic secretions from the intestine decreases DNA synthesis and cell pro- liferation (Fry and Staffeldt, 1964; Ranken et al., 1971; Roy et al., 1975), whereas the administration of secondary bile acids increases cell proliferation in liver bile ducts and the biliary tract epithelium (Bagheri _ al., 1978~. Inhibition of DNA synthesis and cell prolifer- ation has also been observed in the rat colon following biliary diversion (Deschner and Raicht, 1979~. Possible promotional effects of bile acids on bowel tumorigenesis were suggested in studies initiated by Narisawa et al. (1974) and com- pleted, with a large sampling of bile acids, by Redly and colleagues (see review by Reddy _ al., 1980~. In these studies, N-methyl-N'- nitro-N-nitrosoguanidine (MNNG), which is a direct-acting carcinogen, was administered intrarectally to conventional or germfree rats for 2 weeks. During the subsequent 16 weeks, 20 mg doses of sodium cholate, sodium chenodeoxycholate, or sodium lithocholate in 0.5 ml of peanut oil were administered intrarectally to rats 3 times a week. No tumors were detected in the control groups. The total number of large bowel tumors in each of the conventional and germfree rats given intrarectal instilla- tions of bile salts was greater than in rats given MNNG without bile salts. These data also suggest that gut microflora was not required for the effect of bile acids to be manifested. In this study, the quantity of bile salts administered intrarectally was approximately 20 to 60 times higher than that normally excreted in the feces during a 24-hour period. Perhaps more importantly, the instillations at levels of approximately 100 mM were at least 10 times higher than the normal concentrations of these salts within the lumen of the bowel. Palmer (1979) observed that bile salts interact readily with mem- branes from artificial liposomes, bacteria, and mammalian cells. The well-studied cytotoxic effects of bile salts are invariably preceded by alterations in membrane permeability in red blood cells, in a variety of tissues, and in mucosal cells of both the large and the small intestine (Dawson and Isselbacher, 1960; Dietschy, 1967; Hoffman, 1967~. In one study, the effects of these salts upon permeability (and presumably cytotoxicity) in the gut were minimized when conjugated bile salts were added to the unconjugated bile salts in sufficiently high concentrations (Low-Beer _ al., 1970~. Thus, it cannot be determined whether the effects of intrarectally instilled unconjugated bile salts demonstrated classic tumor promotional activity or resulted from nonspecific damage and repair activity associated with increased cellular proliferation of the colonic mucosa induced by the high intraluminal concentration of the salts. 5-10

Lipids (Fats and Cholesterol) 83 Cohen and associates studied the effect of bile acid on colon tumors induced by nitrosomethylurea (NMU) by feeding rats lab chow pellets with and without added bile acid. They observed that 0.2% cholic acid (Cohen et al., 1978), but not chenodeoxycholic acid (Raicht et al., 1975), in- creased the number of NMU-induced colon tumors, as compared to the num- ber of tumors in rats fed nonsupplemented pellets. In the dimethylhydra- zine (DMH) model, no effect on colon tumorigenesis was observed in rats fed 0.3% cholic acid in a semisynthetic diet (Broitman, 1981~. Evidence that increased quantities of bile acids in the colonic lumen were associated with an increase in azoxymethane (AOM)-induced colon tumorigenesis in rats was provided by Chomchai et al. (1974~. Williamson et al. (1979) showed that bile initiated prompt ileal hyperplasia in rats following intestinal resection with diversion of the pancreatic and bil- iarv ducts to the terminal ileum, i.e., pancreatobiliary diversion. Feeding cholestyramine to rats given AOM for tumor induction increased the average number of tumors in the large bowel but not in the small bowel (Nigro et al., 1973, 1977~. Vahouny et al. (1981) demonstrated that in- tralumina i nfusion of 165 AM of chol~c, deoxycholic, and chenodeoxycholic acids 1:1:1 twice daily for 5 days resulted in severe topological changes in the colonic mucosa. Thus, the enhancement of tumorigenesis observed at high concentra- tions of bile acids may be related to nonspecific effects of tissue injury. Tumor-enhancing effects of nonspecific injury have been attrib- uted to increased cellular proliferation, which accompanies inflammation and repair (Ryser, 1971~. EXPERIMENTAL EVIDENCE - The first demonstration that dietary fat could influence tumorigene- sis was reported by Watson and Mellanby (1930~. Most of these studies were conducted by increasing the level of dietary fat, which also led to an increase in the total intake of calories. Addition of 12.5% to 25.0% butter to a basal (3% fat) diet given to coal-tar-treated mice increased the incidence of skin tumors from 34% to 57%. Similarly, Lavik and Baumann (1941, 1943), who administered 3-methylcholanthrene topically to mice found that a basal diet, when supplemented with 15% fat (shortening), increased the yield of skin tumors from 12% to 83%. Fat was especially effective when fed 6 to 12 weeks after treatment with a carcinogen. Com- paring diets containing 10% corn oil, 10% coconut oil, or 10% lard for their ability to enhance tumors, these investigators observed a minor effect of unsaturation: the incidence of tumors at 5 months was 33% (for control diets), 61% (for added lard diets), 66% (for added coconut oil diets), and 76% (for added corn oil diets). Mammary Tumors Tannenbaum (1942) demonstrated that dietary fat enhanced the develop- ment of either chemically or spontaneously induced mammary tumors in mice. 5-11

84 DIET, NUTRITION, AND CANCER The incidence of spontaneous tumors was greater when the high fat diets were instituted at 24 weeks of age than when they were fed beginning at 38 weeks. Tannenbaum and Silverstone (1957) noted that tumor incidence was greater in obese mice than in normal mice and that caloric restric- tion inhibited mammary tumorigenesis in normal mice. This was also observed by Waxier and colleagues, who induced obesity in mice with gold thioglucose and observed that spontaneous mammary carcinomas developed more quickly in obese mice than in controls (Waxier, 1954; Waxier et al., 195 3~. After reducing the weight of the obese mice below that of con- trols (which were also treated with gold thioglucose) by limiting their dietary intake, they observed a decrease in mammary tumors compared to controls. The effects of caloric restriction on reducing the incidence of chemically induced tumors can be negated by increasing the dose of the carcinogen (King et al., 1949; Tannenbaum and Silverstone, 1957; White, 1961; White et al., 1944~. By feeding mice isocaloric high and low fat diets, Tannenbaum (1942) provided evidence that fat, rather than calories per se, was responsible for enhancing tumorigenesis. This observation differed from the findings of Lavik and Baumann (1943), who reported that the caloric content of the diet had a greater effect than the level of fat on the induction of skin tumors in mice by 3-methylcholanthrene. These earlier studies have been comprehensively reviewed by Tannenbaum (1959), Tannenbaum and Silverstone (1957), and Carroll and Khor (1975~. In 1970, Carroll and Khor again pointed out that the level of dietary fat was as important as the amount of 7,12-dimethylbenz~aJanthracene (DMBA) administered to induce breast cancer. They studied the effect of both high and low doses of the carcinogen fed to rats in corn oil. At the low dose (1 mg), rats fed a 20% corn oil diet exhibited more tumors and a shorter latent period, but no difference in the number of tumors per tumor-bearing rat, as compared to rats fed a 0.5% corn oil diet. When the dose of DMBA was increased to 2.5 ma, the high fat diet in- creased tumor incidence and the number of tumors, but did not alter the latent period. The quality or type of lipid was also shown to be an important factor in the induction of breast cancer by DMBA (Carroll and Khor, 1971~. The incidence of tumors at this site was uniformly high with all dietary fats tested at a level of 20% in the diet, but the number of tumors per group and per tumor-bearing rat was proportionally greater in the rats fed un- saturated fats. Furthermore, it was apparent that the yield of tumors per group was also influenced by the level of essential fatty acid-- linoleic acid--present in the fat. Groups of rats fed tallow or coconut oil (which are inadequate sources of linoleate) had significantly fewer tumors than groups fed polyunsaturated fats (which are adequate sources of linoleate). Because the enhancement of breast tumorigenesis by high fat diets was observed when the diets were fed after tumor initiation by DMBA, the investigators concluded that dietary fat exerted its effect during the promotional phase (Carroll, 1980~. As the dose of carcinogen was increased, the promotional effect of high fat diets became stronger. There is a limit to the promotional effects of dietary fats, however, 5-12

Lipids (Fats and Cholestero1) 85 since diets containing fat at levels greater than 20% were no more effective than those containing 20%. The enhancement of DMBA-induced mammary tumorigenesis in rodents by high fat diets (especially those containing polyunsaturated fats) has been observed by a number of investigators (Carroll and Khor, 1971; Hopkins and West, 1976; Ip, 1980; King et al., 1979~. More recently, Carroll and coworkers found that saturated fat was as effective as polyunsaturated fat in enhancing tumorigenesis when a small quantity of polyunsaturated fat (3% sunflower seed oil) was added to the saturated fat (17% coconut oil) (Carroll, 1975; Carroll and Hopkins, 1979; Hopkins and Carroll, 1979~. They also learned that the polyunsaturated fat used must provide sufficient amounts of essential fatty acids and that the diet must contain high levels of total fat to increase the yield of breast tumors. Whether these two requirements are interrelated is not certain. But studies in rats have shown that essential fatty acid metabolism and accumulation of polyunsaturated fat in tissues is influenced by dietary fat (Mohrhauer and Holman, 1967; Peifer and Holman, 1959). Providing support for an association between dietary fat and DMBA- induced breast cancer are findings from studies in rats with the known breast carcinogen NMU. Chan et al. (1977) observed a significant re- duction in the latent period for the development of NMU-induced breast tumors in female Fischer 344 rats fed high fat diets compared to rats fed low fat diets. However, unlike the studies using the DMBA model of breast carcinogenesis, high fat diets increased only the incidence and not the multiplicity of NMU-induced breast tumors. In a study of the relationship of dietary fat levels to x-ray-induced and NMU-induced mammary carcinogenesis, Silverman et al. (1980) reported similar effects. The incidence and multiplicity of breast tumors induced by 350 reds of total body irradiation were increased in Sprague-Dawley rats fed a calorie-controlled, 20% lard diet, compared to rats fed a 5% lard diet. The high fat diet increased the multiplicity of NMU-induced tumors, but not the incidence. Both the level and the quality of dietary fat appear to influence the growth rate of DMBA-induced breast tumors, according to studies by McCay et al. (1980~. Rats fed a diet containing a high level of polyunsaturated fat (20Z corn oil) exhibited an average tumor growth rate that was con- siderably greater than that for rats fed a diet containing high levels of saturated fat (18% coconut oil and 2% linoleic acid). In animals fed a low fat diet (2% linoleic acid), the average tumor growth rate was mark- edly lower than the rates for the other two groups. Thus, the tumor growth rate appears to be determined in part by the total dietary fat and in part by the polyunsaturated fat content. Therefore, a given dose of DMBA could produce a similar number of initiated cells in the mammary gland, independent of the dietary regimen used, and the number of tumors that are palpable within a fixed time would depend on the growth rate of the initiated clones. Consequently, if a higher level of total dietary 5-13

86 DIET, NUTRITION, AND CANCER fat or of polyunsaturated fat accelerated clonal growth, the number of tumors reaching palpable size within a fixed time would be greater. Growth of transplantable tumors is also influenced by dietary fat. A transplantable mammary adenocarcinoma developed much more readily in host mice fed a high level of polyunsaturated fat than in mice fed an equivalent level of saturated fat (Hopkins and West, 1977~. In a study by Abraham and Rao (1976), as little as 1.0% corn oil added to the diet stimulated the growth of a transplantable mammary tumor in mice. By using inhibitors of prostaglandin biosynthesis, these investigators concluded that this effect was related to the level of essential fatty acids, rather than to synthesis of prostaglandin. Pure linoleic acid in the diet at 0.1% was as effective as 15% corn oil in enhancing the growth of a transplantable mammary adenocarcinoma (Hillyard and Abraham, 1979~. In studies of cell cultures with and without added polyunsaturated fat, Kidwell _ al. (1978) and Wicha et al. (1979) demonstrated that polyun-_ _ saturated fat enhanced the growth of both normal and neoplastic mammary epithelial cells from rats. Corwin et al. (1979) measured the tumori- genicity of Kirsten sarcoma virus-transformed murine cell line, AK3T3, which was grown in delipidized tissue culture media. Its tumorigenicity (incidence of tumors following implantation of a constant number of cells) in BALB/c mice was compared to that in a conventional line of FK3T3 cells maintained in a complete tissue culture medium. Although sarcomas in general are not responsive to diet, an increase in tumorigenicity was observed with AK3T3 cells as the level of dietary polyunsaturated fats was increased from 4% to 8%, whereas an opposite effect on tumorigenicity was noted with the FK3T3 cells. Thus, lipid supply In vitro affected the expression of the transformed phenotype of a transplantable tumor. This, in turn, altered the response of the tumor to dietary lipids in the host. Rogers (1975) and Newberne and Zeiger (1978) observed that the effects of a high fat diet on breast carcinogenesis could be modified when the diet was marginal in lipotrope (choline and methionine) content. In Sprague-Dawley rats given 2-acetylaminofluorene (AAF) or DMBA to induce breast tumors, the tumor incidence was lower and death from the tumors occurred later in marginally lipotrope-deficient rats than in controls. Hepatic and Pancreatic Cancer When administered to Fischer rats, which are resistant to breast cancer, AAF induced hepatic carcinomas (Newberne and Zeiger, 1978~. Under these conditions, a high fat diet that was marginally deficient in lipotropes significantly increased the incidence of hepatic carcino- mas, as compared to the incidence in rats fed a high fat diet with adequate lipotropes. Thus, the effect of marginal lipotrope deficiency on the relationship between dietary fat and carcinogen-induced tumori- genesis appeared to differ from one target organ to another. An increase in dietary fat increased the incidence of AAF-induced hepatomas in male rats (Sugai et al., 1962~. Farber (1973) suggested 5-14

Lipids (Fats and Cholesterol) 87 that chronic feeding of AAF resulted in the cloning of hepatic cells with resistance to AAF toxicity. Hyperplastic nodules that result from the regenerative activity of such clones ultimately progress to form hepato- mas. McCay et al. (1980) studied the influence of dietary fat in the early stages of hyperplastic nodule formation and during the later stages of hepatoma development. Hyperplastic nodules formed from AAF more frequently and the latent period was shorter in rats fed a low fat diet (2% linoleic acid) than in rats fed diets with high saturated fat (18% coconut oil and 2% linoleic acid) or with a high polyunsaturated fat con- tent (20% corn oil). In contrast, there was a 100% incidence of hepatomas in the rats fed the high polyunsaturated fat diet, a 20% incidence in those fed the low fat diet, and high mortality among those fed the high saturated fat diet because of the excessive toxicity of M F under these conditions. These studies illustrate the differing effects of dietary fat upon the various stages of hepatoma development. Dietary lipids also modify aflatoxin-Bl-induced liver tumors in rats (Newberne et al., 1979~. When beef fat was fed to rats, the number of tumors induced was the same, regardless of whether the beef fat was fed only after induction (51%) or both before and after induction (53%~. Feeding of polyunsaturated fat (corn oil) before and after induction resulted in a 100% tumor yield, but when the oil was fed only after tumor induction, the yield was 66%. The authors concluded that unsaturated fats increase the tumor yield more effectively than do saturated fats, but that this effect may occur during the initiation or early promotional phase of hepatic carcinogenesis. Dietary fat may modify the incidence of pancreatic adenocarcinomas induced in rats by azaserine (Longnecker et al., 1981; Roebuck et al., 1981~. In Lewis rats fed diets containing either 20% corn oil or 20% safflower oil, the number of pancreatic neoplasms was higher than in animals fed the same percentage of saturated fat. The animals fed the control diet (5% corn oil) and treated with azaserine exhibited the same incidence and numbers of pancreatic neoplasms as did animals fed an 18% saturated fat diet. Compared to controls, there was a marked increase in hepatocellular carcinomas in rats given azaserine but maintained on a lipotrope-deficient diet. Intestinal Cancer A variety of compounds that are carcinogenic in the bowel have been used in a number of animal models to study the effect of dietary fat on tumorigenesis at that site. Nigro et al. (1975) demonstrated that Sprague-Dawley rats treated with AOM developed more intestinal tumors and more metastatic lesions when fed a diet containing 35% beef fat than when fed regular chow. Since the caloric density of the beef fat diet was significantly greater than that of the laboratory chow, it is diffi- cult to sort out the effect of calories from that of fat on tumori- genesis. Nevertheless, the report provided a model for studying diet- responsive intestinal tumorigenesis. 5-15

88 DIET, NUTRITION, AND CANCER Reddy et al. (1974) used DMH to induce tumors of the colon (and, to a lesser extent, small intestine) in rats fed 5% or 20% lard or corn oil diets. Rats fed the 5% corn oil diets had a greater tumor incidence and higher average number of tumors per animal than those fed the 5% lard diet. Tumor incidence and multiplicity increased with the higher levels of dietary fat. However, rats fed the 20% fat diets exhibited essentially the same incidence and multiplicity of tumors whether the fat was polyun- saturated or saturated. In a repeat study with animals maintained on these diets for two generations before tumor induction with DMH, findings were essentially the same (Ready et al., 1977a). Measurements indicated that there were no differences in the quantities of diet consumed daily among all the dietary groups. Since the caloric density of low and high fat diets differed, rats eating the high fat diets consumed, in addition to more fat, approximately 20% more calories. In a study by Broitman et al. (1977), atherogenic diets containing 5: or 20% coconut oil were fed to rats given DMH to induce tumors of the bowel. These investigators also observed that rats fed the 20% saturated fat diet had a greater incidence and multiplicity of tumors than those fed the 5% saturated fat diet. However, they pointed out that rats fed the low fat diet consumed fewer calories, gained much less weight, and thus received less of the carcinogen than did rats fed the high fat diets. Studies with a number of strains of rats and various carcinogens have illustrated that intestinal t~'morigenesis is enhanced as the quan- tity of dietary fat is increased. Bansal et al. (1978), using Wistar Furth rats and DMH for tumor induction, noted that rats fed 30% lard developed more large bowel tumors than did those fed a low fat standard diet. To induce colon tumorigenesis in Fischer 344 rats, Reddy and associates (1977b, 1980) administered DMH or methylazoxymethanol (HAM) acetate systemically on a weight basis or gave the animals constant intrarectal doses of 2',3-dimethyl-4-aminobiphenyl (DMAB) or NMU. These investigators demonstrated that the tumor incidence in rats fed 20% beef fat was greater than that in those fed 5% beef fat, irrespec- tive of the carcinogen used to induce the intestinal tumors. Since the routes of metabolic activation for some of these carcinogens differ, it is more likely that the effects of increased levels of dietary fat were manifested following activation of the carcinogen, rather than during the various steps leading to activation. Promoting effects of dietary fat were suggested by studies in which high fat diets increased the frequency of small and large bowel tumors when fed to rats after administration of AOM but not before or during administration of the carcinogen (Bull et al., 1979~. The high fat diet (30% beef fat) used in these studies had a caloric density that was approximately 34% greater than the low fat diet (5% beef fat), and was considered by the authors to be responsible for the differences in weight gains between groups fed the high and low fat diets. 5-16

Lipids (Fats and Cholestero]J X9 Cruse et al. (1978) suggested that dietary cholesterol may be cocarcinogenic. Rats given DMH and fed a diet of liquid Vivonex (an amino acid hydrolysate) with added cholesterol had shorter lifespans, decreased time to tumor appearance, and more colonic tumors per rat than did the animals fed Vivonex alone. Because these dietary regimens are so different from those consumed by humans, the applicability of these find- ings to human health is not clear. Broitman et al. (1977) studied effects of serum cholesterol levels on DMH-induced tumorigenesis in the bowel. Sprague-Dawley rats were fed isocaloric cholesterol-containing diets supplemented with either 20Z coconut oil to promote hypercholesterolemia and vascular lipidosis or 20% safflower oil to maintain lower serum cholesterol levels and, presumably, to shunt cholesterol through the gut. Rats fed the 20% polyunsaturated fat diet experienced less vascular lipidosis but developed more bowel tumors than did rats fed the saturated fat diet. It could not be ascer- tained from these studies whether the enhanced bowel tumorigenesis was due to the polyunsaturated fat per se or whether the effects were related to its hypocholesterolemic action. Reddy and Watanabe (1979) observed that the intrarectal administration of cholesterol, cholesterol-5,6- epoxide, or cholestane-3,5,6-triol did not exert or lead to any tumor- promoting activity in rats given MNNG to induce bowel tumors. The number of DMH-induced intestinal tumors was greater in rats fed diets marginally deficient in the lipotropes choline and methionine than in rats fed high fat diets with adequate amounts of lipotropes (Rogers and Newberne, 1973~. To date, an active carcinogen derived from bile acids has not been isolated from human or animal feces. The proposed mechanisms for the action of bile acids on bowel tumorigenesis are discussed earlier in this chapter. SUMMARY . Epidemioloeical Evidence Fats. There is some epidemiological evidence for an association between dietary fat and cancer at a number of sites, but most of the evi- dence pertains to three sites: the breast, the prostate, and the large bowel. In various populations, both the high incidence of and mortality from breast cancer have been shown to correlate strongly with higher per capita fat intake; the few case-control studies conducted have also shown this association with dietary fat. Like breast cancer, increased risk of large bowel cancer has been associated with higher fat intake in both correlation and case-control studies. The data on prostate cancer are more limited, but they too suggest that an increased risk is related to high levels of dietary fat. In general, it is not possible to identify specific components of fat as being clearly responsible for the observed effects, although total fat and saturated fat have been associated most frequently. 5-17

90 DIET, NUTRITION, AND CANCER The epidemiological data are not entirely consistent. For example, the magnitude of the association of fat with breast cancer appears greater in the correlation data than in the case-control data. This may reflect the fact that recent dietary intake was assessed in the case- control studies, whereas dietary patterns much earlier in life may have had a greater influence on breast cancer risk. Furthermore, some studies of large bowel cancer did not show an association with dietary fat, possi- bly because they either focused on relatively homogeneous populations or were not specifically designed to test the hypothesis that fat intake is associated with cancer. Indeed, the studies designed specifically to test this hypothesis tended to show the most striking direct correlations, especially when the possible confounding effects of dietary fiber were taken into consideration. Cholesterol. The relationship between dietary cholesterol and cancer in humans is not yet clear. Many studies of serum cholesterol levels and cancer mortality have indicated that there is an inverse association with colon cancer in males, but the evidence is inconsistent and is not suffi- cient to establish a causal relationship. Furthermore, other explanations for the observations are possible. For example, low serum levels could be the result rather than the cause of the cancer. Relationship of Fecal Steroid Excretion to Bowel Carcinogenesis In most reports on the association of dietary fat and bowel carcino- genesis, it is generally assumed that dietary fat acts as a promoter. To date, this effect has been examined in only one report, which suggested that high lipid diets may promote bowel tumorigenesis. High fat diets increased tumor yields more effectively than low fat diets when fed after the administration of a bowel carcinogen but not before. It is not clear if the effects observed were related to consumption of lipids or calories. Increasing the quantity of dietary fat fed to rats increases the total quantity of bile acids and neutral sterols excreted in the feces. There is no evidence that bile acids or neutral sterols per se can be converted In viva to carcinogens or cocarcinogens by the fecal flora under any dietary conditions. Regardless of the carcinogen used to initiate bowel tumors, expo- sures of the colonic lumen to a direct flow of bile, resin-bound salts, or direct intrarectal instillation of bile salts have been consistently associated with a higher number of tumors than in control animals. Colonic tissue damage may result from exposure to the abnormally high quantities and/or concentrations of bile salts used in these studies. Thus, it is not possible to determine whether the enhancing effect of bile salts on colon tumorigenesis is promotion or the result of nonspecific tissue injury. 5-18

Lipids (Fats and Cholesterol) 91 Although most of the data suggest that dietary fat has promoting activity, there is little or no knowledge concerning the specific mecha- nisms involved in tumor promotion. Furthermore, there is not enough evidence to warrant the complete exclusion of an effect on initiation. Experimental Evidence Mammary Tumors. In studies of breast cancer, the influence of lipid nutriture on tumorigenesis follows a consistent pattern, regardless of whether the tumors are chemically induced, occur spontaneously, or result from tumor cell implantation. Increasing the level of dietary fat from 5% to 20Z increases the yield and/or incidence of chemically induced breast tumors, depending on the carcinogen used. Breast tumorigenesis is enhanced when high fat diets are fed after, but not before, tumor initiation. This is consis- tent with the concept that dietary fat exerts a promoting effect on tumorigenesis rather than an effect at the initiation stage. At low doses of the carcinogen, high fat diets decrease the latent period and increase tumor incidence. At high doses of carcinogen, high fat diets increase the incidence and numbers of tumors, but have no effect on latency. In a few studies using isocaloric diets, various levels of dietary fat have been administered. It is possible that enhanced tumorigenesis, associated with increasing levels of dietary fat, may be related to a nonspecific increase in caloric intake. Mammary tumorigenesis is en- hanced by obesity and is inhibited by restriction of total food intake. Diets containing 20% polyunsaturated fat enhance tumorigenesis more effectively than saturated fat, provided that it serves as an adequate source of essential fatty acids. Supplementation of a high saturated fat diet with 3% polyunsaturated fat provides the same tumor-enhancing effects as a 20% polyunsaturated fat diet. Thus, the possible promoting effects of high-lipid diets on breast carcinogenesis depend upon the total quantity of fat in the diet (with the maximum effect achieved at 20%) and sufficient polyunsaturated fat to serve as an adequate source of essential fatty acids. Lipid requirements for enhanced growth of transplantable breast adenocarcinomas are essentially the same as those described above. Limited data on normal and neoplastic rat mammary epithelial cells in cell culture also indicate that essential fatty acids are required for maximal cell growth. Hepatic and Pancreatic Cancer. Increasing dietary lipids increases the incidence of carcinogen-induced hepatomas. Differing effects of the quality and quantity of dietary fat depend upon the stage of hepatoma development at the time of exposure. Hepatic tumorigenesis, unlike breast carcinogenesis, is enhanced by lipotrope deficiency. Limited data 5-19

92 DIET, NUTRITION, AND CANCER indicate that the tumor yield of hepatomas and pancreatic neoplasms is increased more effectively by polyunsaturated fat than by saturated fat. Intestinal Cancer. Increasing the quantity of dietary fat (generally from 570 to 20%) increases the incidence and yield of bowel tumors induced by a variety of carcinogens, including DMH, AOM, MAM acetate, DMAB, MNNG, and NMU. Data on the association of dietary lipids and tumorigenesis are more consistent for the large bowel than for the small intestine. Studies comparing the effects of high and low dietary fat on tumorigenesis in the bowel rarely used isocaloric diets or pair-feeding studies. Consequently, it is equally possible that the tumor-enhancing effect of high fat diets at this site may be related to increased consumption of calories. At dietary fat levels of 5%, polyunsaturated fat appears to have a greater tumor-enhancing effect than does the equivalent level of saturated fat. At 20% dietary fat levels, there is no clear difference between the effects of polyunsaturated fat and saturated fat on bowel tumorigenesis. General Summation of Experimental Evidence. In summary, numerous experiments on animals have shown that dietary lipid influences tumori- genesis in the breast and the colon. Its effects on the liver and the pancreas have been studied in a few experiments. An increase in total dietary fat from 5% to 20% of the weight of the diet (i.e., approximately 10% to 40% of total calories) is associated with a higher tumor incidence in each of these tissues; conversely, animals consuming low fat diets have a lower tumor incidence. When total fat intake is low, polyun- unsaturated fats appear to be more effective than saturated fat in enhancing tumorigenesis; however, the effect of polyunsaturated fats becomes less prominent as total dietary fat is increased to 20% of the diet. Dietary fat appears to affect tumor promotion rather than tumor initiation, although an effect on initiation cannot be excluded. The specific mechanism involved in tumor promotion is not known, although some evidence suggests that colon cancer is associated with enhanced secretion of certain bile steroids and bile acids. Experimental data on cholesterol and cancer risk are too limited to permit any inferences to be drawn. CONCLUSIONS1 The committee concluded that of all the dietary components it studied, the combined epidemiological and experimental evidence is most The Committee on Diet, Nutrition, and Cancer judged the evidence asso- ciating high fat intake with increased cancer risk to be sufficient to recommend that consumption of fat be reduced (see Chapter 1~. Two years ago, the Food and Nutrition Board stated in its report Toward Healthful Diets (National Academy of Sciences, 1980) that there is no basis for making recommendations to modify the proportions of these macronutrients [e.g., fat] in the American diet at this time. 5-20

Lipids (Fats and Cholestero]) 93 suggestive for a causal relationship between fat intake and the occur- rence of cancer. Both epidemiological studies and experiments in animals provide convincing evidence that increasing the intake of total fat in- creases the incidence of cancer at certain sites, particularly the breast and colon, and, conversely, that the risk is lower with lower intakes of fat. Data from studies in animals suggest that when total fat intake is low, polyunsaturated fats are more effective than saturated fats in enhancing tumorigenesis, whereas the data on humans do not permit a clear distinction to be made between the effects of different components of fat In general, however, the evidence from epidemiological and laboratory studies is consistent. 5-21 .

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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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