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6 Protein Dietary protein has often been associated with cancers of the breast, endometrium, prostate, colorectum, pancreas, and kidney. However, since the major dietary sources of protein (such as meat) contain a variety of other nutrients and nonnutritive components, the association of protein with cancer at these sites may not be direct but, rather, could reflect the action of another constituent concurrently present in protein-rich foods. EPIDEMIOLOGICAL EVIDENCE Armstrong and Doll (1975) examined incidence rates for 27 cancers in 23 countries and mortality rates for 14 cancers in 32 countries and correlated them with the per capita intake of a wide range of dietary constituents and other environmental factors. These investigators reported relationships between many of these variables. For example, the correlations of total protein and animal protein with total fat were 0.70 and 0.93, respectively, whereas correlations with the gross national product were 0.32 and 0.65. In a study that analyzed diet histories of more than 4,000 subjects, Kolonel et al. (1981) observed that the correlation between total protein and total fat consumption was 0.7. Breast Cancer In the study by Armstrong and Doll (1975) mentioned above, per capita intakes of total protein and animal protein were significantly correlated with the incidence of and mortality from breast cancer. In a similar study, Knox (1977) compared per capita intakes of individual foods and nutrients with the chief causes of mortality in 20 different countries: Canada, the United States, Japan, and 17 European countries. His results also indicated that there was a strong correlation between the per capita intake of animal protein and mortality from breast can- cer. Armstrong and Doll (1975) found that there was a stronger asso- ciation for animal protein than for total protein, and in both of these studies, the correlations of breast cancer with per capita total fat intake were generally as strong or stronger than those for animal protein. Hems (1978) correlated 1970-1971 mortality rates for breast cancer in 41 countries with per capita food intake for 1964-1966. He found a direct correlation with intake of protein, total fat, and calories from animal products, independent of other components of the diet. However, time-trend data for breast cancer mortality and per capita food intake 106 6-1

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Protein 107 in England and Wales supported the association with fat more strongly than the association with protein (Hems, 1980~. Gray et al. (1979) analyzed international incidence and mortality rates for breast cancer in relation to per capita intake of animal protein. They found a direct correlation, even after controlling for height, weight, and age at menarche. Gaskill et al. (1979) examined age-adjusted breast cancer mortality in relation to per capita intake for certain foods by state within the United States. Although they found a direct correlation between breast cancer mortality and per capita protein intake, this finding was not statistically significant after controlling for age at first marriage (as an indicator of age at first pregnancy). Kolonel et al. (1981) found a direct correlation between consumption of animal protein and the incidence of breast cancer in five different ethnic groups in Hawaii based on diet histories obtained by interview. Of three case-control studies of diet and breast cancer, signi- ficant direct associations with dietary fat only were found in two (Miller et al., 1978; Phillips, 1975), whereas direct associations with both animal fat and protein were found in the third (Lubin et al., 1981~. Large Bowel Cancer Gregor et al. (1969) reported a direct correlation between per capita intake of animal protein and mortality from intestinal cancer in 28 countries. Armstrong and Doll (1975) observed that per capita intake of total protein, animal protein, and total fat were all strong- ly correlated with the incidence of and mortality from colon and rectal cancer for both sexes. Their findings for cancer at these sites were similar to those for breast cancer (i.e., there were stronger correla- tions for total fat and for animal protein than for total protein). These authors also reported a strong association between the intake of eggs and cancer of the colon and rectum. This association was greater than that for total protein. In contrast to these direct correlations, gingham et al. (1979) found no significant association for intakes of animal protein in a study correlating the average intakes of foods, nutrients, and fiber in different regions of Great Britian with the regional pattern of mortality from colon and rectal cancers. Jain et al. (1980) reported the only case-control study of large bowel cancer in which protein was specifically examined. Although these investigators found a direct association between consumption of high levels of protein and risk of both colon and rectal cancer, they found a stronger association for saturated fat. The relationship of meat intake to risk of colorectal cancer has been examined in a number of studies, but protein intake per se was not 6 -2

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108 DIET, NUTRITION, AND CANCER estimated in most of them. However, because meat is a major source of protein in the Western diet, findings in these studies may reflect associations with protein. Berg and Howell (1974) and Howell (1975) correlated international mortality rates for colon cancer with per capita intake data and found the strongest correlations for meat, especially beef. In a study by Armstrong and Doll (1975), the corre- lations were stronger for meat than for total protein and animal pro- tein. In studies of the relationship between certain foods and cancer of the large intestine, Knox (1977) reported the strongest correlations for eggs, followed by beef, sugar, beer, and pork. In contrast, time- trend data for per capita beef intake and colorectal cancer incidence and mortality in the United States showed no clear association (Enstrom, 1975). Haenszel et al. (1973) studied cases of large bowel cancer and hospital controls among Japanese in Hawaii. They found an associa- tion between cancer at this site and consumption of legumes, starches, and meats. The association was strongest for beef. A similar study among Japanese in Japan (Haenszel et al., 1980) did not reproduce these findings, nor did parallel case-control studies conducted in Norway and Minnesota (Bjelke, 1978) and at the Roswell Park Memorial Institute (Graham _ al., 1978~. All four of these case-control studies relied solely on frequency of consumption data for their assessments of dietary intake. A somewhat contradictory observation was reported by Hirayama (1981), whose large-scale cohort study in Japan indicated that there was a decrease in overall risk for cancer, including intestinal cancer, in association with daily intake of meat. Pancreatic Cancer Lea (1967) examined the relationship between per capita intake of foods and nutrients and cancer mortality resulting from up to 22 dif- ferent types of neoplasms in each of 33 countries. One of the findings was a strong direct correlation between intake of animal protein and pancreatic cancer. This result was reproduced by Armstrong and Doll (1975~. No case-control or cohort studies have confirmed this asso- ciation specifically; however, a study of pancreatic cancer cases and controls in Japan (Ishii et al., 1968), based on responses to a mailed questionnaire completed mostly by relatives of deceased cases, showed an association of the disease with consumption of high-meat diets by men. Hirayama (1977) reported a relative risk of 2.5 for daily meat intake and pancreatic cancer incidence in Japan in a cohort of 265,118 subjects followed prospectively. Since meat is a major source of protein in the diet, these findings offer tentative support for the results of correlation studies. 6 - 3

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Protein 109 Other Cancers l Armstrong and Doll (1975) found a strong correlation (correlation coefficient = 0.8) between animal protein and the incidence of renal cancer. However, in a subsequent case-control study, Armstrong et al. (1976) found no clear association between renal cancer and consumption frequencies for several foods containing animal protein (e.g., meat, poultry, seafood, eggs, milk, and cheese). The incidence of prostate cancer was significantly correlated with consumption of total and animal protein in the study by Kolonel _ al. (1981), whereas mortality from, but not the incidence of, prostate cancer was similarly correlated in the study by Armstrong and Doll (1975~. As noted in Chapter 5, Hirayama (1977) reported a sharp increase in the intake of animal protein in Japan since 1950. During this period, the incidence of prostate cancer in that country increased correspondingly. The intake of meat, especially beef, has also been correlated with mortality from prostate cancer (Armstrong and Doll, 1975; Howell, 1974). The incidence of endometrial cancer has also been significantly correlated with the intake of total protein (Armstrong and Doll, 1975; Kolonel _ al., 1981~. This finding may simply reflect the high correlation between the occurrence of endometrial cancer and breast cancer, since the latter has also been associated with protein intake (see Chapter 16~. No case-control studies have been conducted to examine this association. EXPERIMENTAL EVIDENCE There is much less literature on results of laboratory studies to determine the relationship between cancer and dietary protein than has been published for certain other nutrients (e.g., fat). However, an inhibitory effect of selected amino acid deficiencies on tumor re- sponses in laboratory animals was claimed as early as 1936 (Voegtlin and Maver, 1936; Voegtlin and Thompson, 1936~. During the subsequent 30 years, further studies concentrated primarily on the effect of protein intake on experimental animal models. From the end of that period to the present, attention became increasingly focused on epidemiological studies. In general, animals fed minimum amounts of protein required for optimum growth have developed fewer tumors than comparable groups fed 2 to 3 times the minimum requirements. Unfortunately, a number of these earlier studies in animals are difficult to interpret for several reasons: several factors were being varied at the same time (Engel and Copeland, 1952a; Gilbert et al., 1958; Ross and Bras, 1965~; dietary levels of the carcinogen were different in the high and low dietary protein groups (Harris, 1947~; the total intake of food was less for animals fed very high levels of protein (Gilbert et al., 1958; 6 - 4

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110 DIET, NUTRITION,AND CANCER Tannenbaum and Silverstone, 1949), and tumor growth is known to be inhibited at lower food (and lower calorie) intake (Ross et al., 1970; Tannenbaum, 1945a,b); and a high dietary level of fat, which may have a tumor-enhancing effect, was present in the experimental diet (Ross and Bras, 1973~. Nonetheless, several of the earlier reports have pro- vided useful information either because they were well controlled or because they have been confirmed by other studies. When considering the effect of dietary protein, it is important to determine whether such an effect is specific for a particular amino acid or is a general effect of protein. In a well-controlled study, Silverstone and Tannenbaum (1951) reported that the spontaneous hepa- tomas in C3H mice were less frequent (measured as percent of tumor- bearing animals) in animals fed a 9% casein diet than in animals fed 18% or 45% casein diets. No significant difference in hepatomas was observed for the latter two dietary groups. All three diets were isocaloric and were fed to the mice at equivalent time intervals. In additional experiments, this effect of protein was still marked when the animals were fed diets that maintained their individual body weights. Therefore, the investigators concluded that the effect of protein was neither confounded with total food or caloric intake nor related to the change in body weight. Adding 9% gelatin to the 9% casein diet had little effect, whereas supplementation of that diet with methionine and cystine (which is present in relatively low levels in gelatin) increased the incidence of hepatomas to the level observed for the mice fed the 18% casein diet. Therefore, it is the excess of total protein or its adequacy as indicated by amino acid balance that generates the increased tumor response. The addition of gelatin may have resulted in extra total protein, but it did not compensate for the growth-limiting sulfur amino acids. In one experiment, the effects of an animal protein (casein) and a plant protein (isolated soy protein) were compared, but no significant difference in tumor incidence was noted (Carroll, 1975~. In earlier studies, Larsen and Heston (1945) found that cystine added to a low casein diet given to Strain A male mice increased the incidence of spontaneous pulmonary tumors from 28% to 54%. White and Andervont (1943) observed that female C3H mice fed a cystine-deficient casein diet exhibited no mammary gland tumors after 22 months, but almost all the animals quickly developed tumors after their diets were supplemented with cystine. Similarly, White and White (1944) observed that mammary tumors occurred in only 25% of C3H mice fed a lysine- deficient gliadin diet but in nearly all of the mice when the diet was supplemented with lysine. White et al. (1947) later showed that only cystine (but not lysine and tryptophan) was able to enhance the inci- dence of 3-methylcholanthrene-induced leukemia in casein-fed mice. Thus, it appears that tumor enhancement by dietary protein occurs only when there is amino acid balance, suggesting that the effect is not due to specific amino acids or to amino acid imbalance. 6-5

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Protein 111 The effect of dietary protein on tumor incidence has been observed both with and without pretreatment with chemical carcinogens. That is, both spontaneous and chemically induced tumor responses may be influ- enced by the level of dietary protein. These two kinds of responses may not be distinct, since certain so-called spontaneous tumors may be related to the prior ingestion of, or other exposure to, some unknown initiator of carcinogenicity. For example, Newberne et al. (1966) speculated that the occasional high incidence of liver tumors observed in earlier studies may have been caused by aflatoxin contamination of peanut meal fed to animals. Because it is now known that corn products may be similarly contaminated, results of earlier studies using degermi nated corn grit diets should also be reevaluated, especially when an unexpectedly high incidence of liver tumors has been observed, as in the study of Engel and Copeland (1951~. Similarly, the appearance of some presumably spontaneous tumors may be due to the very potent mutagens produced in heated or cooked foods (Sugimura, 1979~. Spontaneous Tumors Ross and coworkers conducted extensive studies with large numbers of rats in order to examine the effects of diet on mortality patterns and lifespan (Ross and Bras, 1965, 1973; Ross et al., 1970~. They focused on the influence of total food, caloric, and protein intake on the appearance of a variety of tumors of unknown etiology. The total incidence of various types of tumors was directly related to the intake of calories, and the tumors appeared sooner when the caloric intake was high (Ross and Bras, 1965~. Because the rats developed many types of tumors, the investigators could not compare the effect of diet on specific types of tumors. The highest number of any tumor type for any one diet was 11--the number of fibrosarcomas observed among the 210 animals in the 30% casein diet group. The authors did note, however, that in two groups with identi- cal caloric intake, there were more tumors in the group with the higher protein intake. In these studies, only two of the four treatment groups differed in only one dietary variable--the ratio of casein to sucrose. The diet with the higher ratio contained 30% casein; the one with the lower ratio contained 8Z casein. All other comparisons among the treatment groups were confounded by two or more simultaneous variables. In a later study, Ross et al. (1970) reported that the prevalence of chromophobe adenomas of the anterior pituitary gland of male rats was directly related to the level of dietary protein (10%, 22%, or 51% casein). However, the tumor prevalence was 2.4% or less in each treat- ment group, which would seem to invalidate any such conclusions More- over, the simple composition of the diet used in these studies is now believed to be inadequate for studies of this type (Anonymous, 1977~. In their most recent study, Ross and Bras (1973) examined the effect 6 - 6

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112 DIET, NUTRITION, AND CANCER 10%, 22%, and 51% casein on the development of 58 types of tumors, none of which involved more than 10% of the rats. They found that protein had no effect on animals fed ad libitum, but that there were fewer tumor-bearing animals in groups fed the lower protein diets if the daily food intake was restricted to 6 g. In addition to the studies by Silverstone and Tannenbaum (1951) and White and Andervont (1943) described above, other reports that dietary protein affects "spontaneous" tumors are those of Slonaker (1931), White and White (1944), and Tannenbaum and Silverstone (1949~. Although Ross and Bras (1973) have interpreted the work of Slonaker (1931) as having demonstrated an inverse relationship between protein intake and tumor incidence (mammary gland and ovarian tumors in female rats and skin tumors in male rats), further inspection of Slonaker's report is necessary. Slonaker (1931) stated that the diets contained 10%, 14%, 18%, 22%, and 26% protein, but he did not describe the composition of the diets. Moreover, the numbers of tumor-bearing female animals were 5/20, 6/19, 5/17, 2/16, and 4/21 for the low to high protein groups, and the author, without providing histological evidence, concluded that the tumors "became cancer-like in appearance." For the males, skin cancers were found in 1/22, 1/21, 1/17, 0/14, and 0/13 animals for the low to high protein groups. Therefore, no firm conclusions can be drawn concerning the association of protein intake with tumor appear- ance. Tannenbaum and Silverstone (1949) described a study in which diets containing from 9% to 45% protein were fed ad libitum to an inbred strain of mice. The incidence of spontaneous hepatomas in the animals fed 9% casein diets was 11/44; in the animals fed 18% casein diets, it was 28/46. However, no significant effect on either the incidence or the average time of appearance was observed for the spontaneous mammary tumors. Chemically Induced Tumors More studies have been conducted to determine the relationship of dietary protein to chemically induced tumors than to spontaneous tumors. When aflatoxin is fed with varying levels of protein, the inci- dence of liver tumors is depressed at lower protein intakes. Madbavan and Gopalan (1968) incubated weanling or young rats with aflatoxin and then fed them either 5% or 20% casein diets for 1 year. They observed that the incidence of hepatomas in the two groups was 0/12 and 15/30, respectively. These data summarize results from experi- ments that used different protocols. Wells et al. (1976) fed diets containing 8%, 22Z, or 30Z casein with 1.7 m ~ kg aflatoxin B1 (AFB1) to male weanling rats for 3 months, then the same diets without AFB1 for as long as 1 year. Hepatomas were found in 0/16, 6/9, and 8/10 rats, respectively. This finding confirmed the results 6-7

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Protein 113 of Madhavan and Gopalan (1968~. Similarly, Temcharoen et al. (1978) fed male rats an equal mixture of aflatoxin B1 and G1 along with diets containing either 5% casein or 20% casein for 33 weeks. They found 4/47 hepatoma-bearing animals in the low protein group and 7/49 in the higher protein group, which is not in accord with their con- clusion that "in animals fed a low-protein diet, aflatoxin induced extensive . . . carcinogenic effects." In contrast to the incidence of hepatomas, the incidence of cystic lesions, cholangiofibrosis, cirrhosis, and hyperplastic nodules was higher among the animals fed the low protein diets. This appears to be in agreement with the ob- servations of other investigators that the effect of the level of dietary protein on aflatoxin-induced hepatotoxicity is the opposite of its effect on aflatoxin-induced carcinogenesis (Madhavan and Gopalan, 1965, 1968). The effect of dietary protein on the emergence of precancerous lesions is not clear from these studies. Madhavan and Gopalan (1968) reported fewer "preneoplastic lesions" in the animals fed the low pro- tein diet. But Temcharoen _ al. (1978) observed more "hyperplastic nodules" and other lesions in the low protein groups, suggesting that their study might have been confounded by the simultaneous appearance of toxic and carcinogenic lesions. Madhavan and Gopalan (1968) administered aflatoxin early in their studies and then discontinued further administration; Temcharoen _ al. (1978) appeared to have administered the toxin throughout the study, although this was not explicitly stated. Part of the confusion about the association of low protein intake and the hepatocarcinogenicity of aflatoxin results from the use of the terms hepatotoxicity and hepatocarcinogenesis. These effects are different, and have been used without definition in some reports. Each of the studies cited above (i.e., Madhavan and Gopalan, 1968; Temcharoen et al., 1978; Wells et al., 1976) is singularly inconclusive, but collectively they support the hypothesis that a high protein diet enhances aflatoxin-induced hepatocarcinogenesis. Morris _ al. (1948) found that more tumors of a greater variety appeared in rats treated with N-acetyl-2-aminofluorene (2-AAF) and fed synthetic diets containing 18% and 24% casein than in similarly treated animals fed diets containing 12% casein. Engel and Copeland (1952b) observed that dietary protein did not affect 2-AAF-induced tumors in rats fed ad libitum with diets containing 9% to 27% casein. There was, however, a highly significant reduction in the incidence of mammary tumors in rats fed diets containing 40% to 60% casein. When the 9% and 60% protein diets were pair-fed, i.e., fed to two matched groups, the incidence of mammary tumors was 80% and 12%, respectively. Ad libitum feeding of the 60% protein diet, however, overcame some of the inhibi- tion (77% incidence), indicating inhibition of tumorigenesis by very high protein diets can be overcome by increasing food intake. Harris (1947) concluded that protein had no effect on carcinogenesis induced either by 2-AAF or by aminofluorene (AF), which was applied to the 6 - 8

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114 DIET, NUTRITION, AND CANCER skin. In the 2-AAF-treated rats, reduction in the total incidence of tumors from 65% to 45% in males and from 80% to 70% in females resulted from a modest reduction in dietary casein from 20% to 13%. In animals receiving the low protein diet, the incidence of liver tumors was de- pressed from 50% to 30% in males and frown 207 to 0 in females. Walters and Roe (1964) injected nice within 24 hours of birth with 9,10-dimethyl-1,2-benzanthracene (DMBA) and then fed them diets con- taining either 25% or between 10% and 15% casein. The animals fed the higher level of casein developed significantly snore lung tumors. In contrast, other reports showed that a reduction of the protein content of the diet enhanced the formation of DMBA-induced hepato~nas (Elson, 1958; Miller et al., 1941; Silverstone, 1948) and mammary tumors (Clinton _ al., 1979) in rats. Clinton et al. (1979) studied the effect of dietary protein levels on the incidence of DMBA-induced mam- mary tumors in rats and observed that the effect of protein depended on whether the dietary treatment occurred before or after the ad~ninistra- tion of the carcinogen. Topping and Visek (1976) studied the effect of dietary protein on the induction of adenocarcinomas of the small and large intestines of rats by 1,2-dimethylhydrazine. They observed that the tumors were larger and more numerous in the rats fed diets containing 15% and 22.5% protein than in those given 7.5Z protein diets. Moreover, the 22.5% protein diets also caused an earlier appearance of keratin-producing papillomas of the sebaceous glands of the external ear. Shay et al. (1964) studied the effect of dietary protein on tu~nori- genesis induced by 3-~nethylcholanthrene. They observed an increase in mammary adenocarcinomas in pretreated rats fed high levels of protein (27% to 64% casein). In an earlier study, White et al. (1947) reported that a high protein diet enhanced 3-methylcholanthrene-induced leukemia In mice. Extensive studies have been undertaken to determine the mechanism by which dietary protein alters AFBl-induced tu~norigenesis. A low protein intake depresses the mixed-function oxygenate (Mgbodile and Campbell, 1972) responsible for AFB1 ~netabolis~n as well as the in viva formation of AFB1-DNA covalent adducts (Preston et al., 1976~. Although Campbell (1979) suggested that modification of AFB metabolism was responsible for the effect of dietary protein on AFB1 tu~norigenicity, more recent studies indicate that the effect of dietary protein on events occurring after initiation may be more important. For example, the development of Y-gluta~nyl transpeptidase hepatocellu- ular foci, which is an excellent early indicator of hepatocarcinogenesis (Tsuda et al., 1980), is greatly depressed in rats fed a 57 casein diet compared to rats fed a 20% casein diet, both given after the ad~ninis- tration of AFB1 is completed (Appleton and Campbell, 1981~. This postinitiation effect of the low protein diet was even capable of over- coming the potential carcinogenic effects of a higher AFB1-DNA adduct 6-9

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Protein 115 level, which had been established by feeding high levels of protein during AFB1 administration. Tumor Transplantation Studies Low protein diets have also been associated with the general inhibition of the growth of transplanted tumors. Haley and Williamson (1960) implanted HAD-1 tumors into rats fed a diet with no protein and rats fed a 20% casein control diet. They observed that the resultant tumors were smaller in the no protein diet group. Earlier, Babson (1954) had found that increasing dietary casein from 0 to 18% increased tumor growth rates in rats implanted either with the Sarcoma R-1 tumor or the Flexner-Jobling carcinosarcoma. According to Devik et al. (1950), there was a prolonged inflammatory reaction to the implantation of the Walker carcinosarcoma 256 and incomplete connective tissue encapsulation in animals fed 5% casein diets, compared to animals fed 20% casein diets. White and Belkin (1945) studied the effect of low protein diets on the "take" of implanted mammary carcinoma 15091a. Although the number of takes was higher (16/31) in the protein-deficient group than in the adequate dietary protein group (10/31), the growth rate at 3 weeks was only 74% of the rate for the higher protein diet. These tumor implan- tation studies were later summarized by White (1961~. The mechanism for the inhibition of tumor growth by low protein diets is not known. Jose and Good (1973) have proposed that the cellu- lar immune response may be involved. This response is enhanced through a deficiency of blocking serum antibody production at low levels of protein intake. An Evaluation of the Data from Animal Studies The relationship of dietary protein to the carcinogenic process does not appear to be straightforward. Levels of protein ranging from those somewhat below the minimum required for optimum growth (approxi- mately 5% of the diet) up to those generally consumed by mammals (15% to 20%) have been studied most extensively. In many studies in animals, diets with low protein (near or below the requirement for optimum growth) have generally been shown to suppress the carcinogenic process and the subsequent growth and development of tumors. The only apparent exception to this effect is the increase in DMBA-induced tumor yield in animals fed low protein diets. Although there is generally a tumor- enhancing effect from 20% to 25% dietary protein, higher levels appear either to produce no further enhancement or, in fact, to inhibit tumor- igenesis (Appleton and Campbell, 1981; Engel and Copeland, 1952b; Ross and Bras, 1973; Ross et al., 1970; Saxton et al., 1948; Tannenbaum and Silverstone, 1949; Topping and Visek, 1976; Wells et al., 1976~. It is not clear whether the general inhibition or the absence of effect on 6-10

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116 DIET, NUTRITION, AND CANCER tumorigenesis at very high levels of dietary protein is due to a reduced intake of food and total calories or whether it is due to other adverse effects, e.g., renal toxicity due to high levels of protein. SUMMARY En idling al Phi r~ 1 Pvi H - nor Epidemiological studies have suggested possible associations between high levels of dietary protein and increased risk of cancers at a number of different sites. However, the literature on protein is much more limited than the literature concerning fats and cancer. In addition, because of the very high correlation between fat and protein intake in Western diets, and the more consistent and often stronger association of these cancers with fat intake, it seems more likely that dietary fat is the more active component. Nevertheless, the evi- dence does not completely preclude an independent effect of protein. Experimental Evidence In laboratory experiments, the relationship of dietary protein to carcinogenesis appears to depend upon the level of protein intake. In most studies, carcinogenesis was suppressed by diets containing levels of protein at or below the minimum required for optimum growth. Chemically induced carcinogenesis appears to be enhanced as protein intake is increased up to 2 or 3 times the normal requirement; however, higher levels of protein begin to inhibit carcinogenesis. There is some evidence to suggest that protein may affect the initiation phase of carcinogenesis and/or the subsequent growth and development of the tumor. CONCLUSION Thus, evidence from both epidemiological and laboratory studies suggests that protein intake may be associated with an increased risk of cancers of certain sites. Because of the relative paucity of data on protein compared to fat, and the strong correlation between intakes of fat and protein in the Western diet, the committee is unable to arrive at a firm conclusion about an independent effect of protein. 6-11

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REFERENCES Protein 117 Anonymous. 1977. Report of the American Institute of Nutrition, Ad Hoc Committee on Standards for Nutritional Studies. J. Nutr. 107:1340-1348. Appleton, B. S., and T. C. Campbell. 1981. Effects of dietary protein level and phenobarbital (PB) on aflatoxin (AFBl)-induced hepatic y-glutamyl transpeptidase (GOT) in the rat. Fed. Proc. Fed. Am. Soc. Exp. Biol. 40:842. Abstract 3477. Armstrong, B., and R. Doll. 1975. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int. J. Cancer 15:617-631. Armstrong, B., A. Garrod, and R. Doll. 1976. A retrospective study of renal cancer with special reference to coffee and animal protein consumption. Br. J. Cancer 33:127-136. Babson, A. L. 1954. Some host-t~nor relationships with respect to nitrogen. Cancer Res. 14:89-93. Berg, J. W., and M. A. Howell. 1974. The geographic pathology of bowel cancer. Cancer 34:805-814. gingham, S., D. R. R. Williams, T. J. Cole, and W. P. T. James. 1979. Dietary fibre and regional large-bowel cancer mortality in Britain. Br. J. Cancer 40:456-463. Bjelke, E. 1978. Dietary factors and the epidemiology of cancer of the stomach and large bowel. Aktuel. Ernaehrungsmed. Klin. Prax. Suppl. 2:10-17. Campbell, T. C. 1979. Influence of nutrition on metabolism of carcinogens. Adv. Nutr. Res. 2:29-55. Carroll, K. K. 1975. Experimental evidence of dietary factors and hormone-dependent cancers. Cancer Res. 35:3374-3383. Clinton, S. K., C. R. Truex, and W. J. Visek. 1979. Dietary protein, aryl hydrocarbon hydroxylase and chemical carcinogenesis in rats. J. Nutr. 109:55-62. Devik, F., L. A. Elson, P. C. Koller, and L. F. Lamerton. 1950. Influence of diet on Walker rat carcinoma 256, and its response to X-radiation--Cytological and histological investigations. Br. J. Cancer 4:298-314. Elson, L. A. 1958. Some dynamic aspects of chemical carcinogenesis. Br. Med. Bull. 14:161-164. 6-12

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118 DIET, NUTRITION, AND CANCER Engel, R. W., and D. H. Copeland. 1951. Influence of diet on the relative incidence of eye, mammary, ear-duct, and liver tumors in rats fed 2-acetylaminofluorene. Cancer Res. 11:180-183. Engel, R. W., and D. H. Copeland. 1952a. Protective action of stock diets against the cancer-inducing action of 2-acetylaminofluorene in rats. Cancer Res. 12:211-215. Engel, R. W., and D. H. Copeland. 1952b. The influence of dietary casein level on tumor induction with 2-acetylaminofluorene. Cancer Res. 12:905-908. Enstrom, J. E. 1975. Colorectal cancer and consumption of beef and fat. Br. J. Cancer 32:432-439. Gaskill, S. P., W. L. McGuire, C. K. Osborne, and M. P. Stern. 1979. Breast cancer mortality and diet in the United States. Cancer Res. 39:3628-3637. Gilbert, C., J. Gillman, P. Loustalot, and W. Lutz. 1958. The modifying influence of diet and the physical environment on spontaneous tumour frequency in rats. Br. J. Cancer 12:565-593. Graham, S., H. Dayal, M. Swanson, A. Mittelman, and G. Wilkinson. 1978. Diet in the epidemiology of cancer of the colon and rectum. J. Natl. Cancer Inst. 61:709-714. Gray, G. E., M. C. Pike, and B. E. Henderson. 1979. Breast-cancer incidence and mortality rates in different countries in relation to known risk factors and dietary practices. Br. J. Cancer 39:1-7. Gregor, O., R. Toman, and F. Prutova. 1969. Gastrointestinal cancer and nutrition. Gut 10:1031-1034. Haenszel, W., J. W. Berg, M. Segi, M. Kurihara, and F. B. Locke. 1973. Large-bowel cancer in Hawaiian Japanese. J. Natl. Cancer Inst. 51:1765-1779. Haenszel, W., F. B. Locke, and M. Segi. 1980. A case-control study of large bowel cancer in Japan. J. Natl. Cancer Inst. 64:17-22. Haley, H. B., and M. B. Williamson. 1960. Growth of tumors in experimental wounds. Proc. Am. Assoc. Cancer Res. 3:116. Abstract 99. Harris, P. N. 1947. Production of tumors in rats by 2-aminofluorene and 2-acetylaminofluorene: Failure of liver extract and of dietary protein level to influence liver tumor production. Cancer Res. 7:88-94. 6-13

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120 DIET, NUTRITION, AND CANCER Lea, A. J. 1967. Neoplasms and environmental factors. Ann. R. Coll. Surg. Engl. 41:432-438. Lubin, J. H., W. J. Blot, and P. E. Burns. 1981. Breast cancer following high dietary fat and protein consumption. Am. J. Epidemiol. 114:422. Abstract. Madhavan, T. V., and C. Gopalan. 1965. Effect of dietary protein on aflatoxin liver injury in weanling rats. Arch. Pathol. 80:123-126. Madhavan, T. V., and C. Gopalan. 1968. The effect of dietary protein on carcinogenesis of aflatoxin. Arch. Pathol. 85:133-137. Mgbodile, M. U. K., and T. C. Campbell. 1972. Effect of protein deprivation of male weanling rats on the kinetics of hepatic microsomal enzyme activity. J. Nutr. 102:53-60. Miller, A. B., A. Kelly, N. W. Choi, V. Matthews, R. W. Morgan, L. Munan, J. D. Burch, J. Feather, G. R. Howe, and M. Jain. 1978. A study of diet and breast cancer. Am. J. Epidemiol. 107:499-509. Miller, J. A., D. L. Miner, H. P. Rusch, and C. A. Baumann. 1941. Diet and hepatic tumor formation. Cancer Res. 1:699-708. Morris, H. P., B. B. Westfall, C. S. Dubnik, and T. B. Dunn. 1948. Some observations on carcinogenicity, distribution and metabolism of N-acetyl-2-aminofluorene in the rat. Cancer Res. 8:390. Abstract. Newberne, P. M., D. H. Harrington, and G. N. Wogan. 1966. Effects of cirrhosis and other liver insults on the induction of liver tumors by aflatoxin in rats. Lab. Invest. 15:962-969. Phillips, R. L. 1975. Role of life-style and dietary habits in risk of cancer among Seventh-Day Adventists. Cancer Res. 35:3513-3522. Preston, R. S., J. R. Hayes, and T. C. Campbell. 1976. The effect of protein deficiency on the in vivo binding of aflatoxin B1 to rat liver macromolecules. Life Sci. 19:1191-1197. Ross, M. H., and G. Bras. 1965. Tumor incidence patterns and nutrition in the rat. J. Nutr. 87:245-260. Ross, M. H., and G. Bras. 1973. Influence of protein under- and overnutrition on spontaneous tumor prevalence in the rat. J. Nutr. 103:944-963. 6-15

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