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7 Carbohydrates In contrast to lipids and protein, which are the other two macro- nutrients in the diet, very little attention has been directed toward the study of carbohydrate intake and the occurrence of cancer. The principal carbohydrates in foods are sugars, starches, and cellulose. Evidence per- taining to sugars and starches is evaluated in this chapter. The data on cellulose are discussed under dietary fiber (Chapter 8~. EPIDEMIOLOGICAL EVIDENCE There is little epidemiological evidence to support a role for carbohydrates per se in the etiology of cancer. Fiber as a separate dietary component is discussed in Chapter 8. Armstrong and Doll (1975) correlated per capita intake of foods and specific nutrients with cancer incidence and mortality in 23 and 32 countries, respectively. They found a significant direct correlation between sugar intake and pancreatic cancer mortality (but not incidence) in women only. They also reported a weak association between liver cancer incidence and the intake of potatoes--a starch-rich vegetable. There are no reports of case-control studies that support either of these findings. Hems (1978) reported a study concerning the relationship of diet and breast cancer among women in 41 countries. He found that a high intake of refined sugar was one of the dietary components associated with increased incidence of breast cancer. This finding is consistent with findings in laboratory experiments. However, in an earlier study, Hems and Stuart (1975) found an inverse relationship between breast cancer incidence and another dietary carbohydrate--starch. Hakama and Saxen (1967) analyzed age- and sex-adjusted mortality rates for stomach cancer in 16 countries. They found a strong corre- lation (r = 0.75) with the per capita intake of cereal used as flour from 1934 to 1938. In a study of per capita food intake and cancer risk in 37 countries, Drasar and Irving (1973) observed a direct correlation between breast cancer and the intake of simple sugars. In a case-control study of gastric cancer, Modan et al. (1974) observed that high starch foods were consumed more frequently by cases than by controls. This finding has not been reported in other studies of gastric cancer. De Jong et al. (1974) studied cases of esophageal cancer and hospital controls in Singapore. Among their findings was a direct association between consumption of bread and potatoes (major sources of 123 7-1

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124 DIET, NUTRITION, AND CANCER dietary carbohydrates) and risk of esophageal cancer. Once again, other investigators who have studied cancer at this site have not observed a similar association. EXPERIMENTAL EVIDENCE There have also been only a few laboratory experiments to study the relationship between carbohydrates and cancer. These studies have gen- erally been conducted by varying the concentration of the test substance, e.g., starch, sucrose, dextrin, or glucose, in a basal diet. Often, little attention has been given to the differences in the caloric content of the control and experimental diets. Furthermore, the variation in carbohydrate content, resulting from attempts to "balance" diets on a weight basis, has generally been disregarded. A few recent studies have focused on the effects of long-term carbohydrate feeding on tumorigenesis. Sucrose The effects of long-term (more than 1 year) feeding or systemic administration of sucrose on spontaneously occurring tumors have been studied in both mice and rats. Roe et al. (1970) fed sucrose to mice at 10% by weight of the diet (~15 g/kg body weight [bw]), and Friedman et al. (1972) fed rats sucrose at 77% by weight of the diet (~40 g/kg bw). In neither study was there an increase in the incidence of tumors. Intraperitoneal or subcutaneous injections of sucrose given over vari- ous lengths of time (Nonaka, 1938; Takizawa, 1939; Zarattini, 1940) or systemic administration of 20% sucrose twice weekly for 2 years produced no evidence of carcinogenesis in either rats or mice (Hueper, 1965~. Hunter et al. (1978a) fed CFLP mice 20% sucrose in the diet for 2 years. The females, but not the males, exhibited a higher incidence of hepatocellular tumors. Parallel feeding studies by the same investiga- tors in which 20% sucrose diets were fed to male and female Sprague- Dawley (CD) rats for up to 1 year and to male and female beagle dogs for up to 2 years did not provide any evidence that sucrose contributed to tumorigenesis. This study has not been repeated. Hoehn and Carroll (1978) evaluated the effect of dietary carbohy- drates on chemically induced tumors in rats. After breast tumors were induced with 7,12-dimethylbenz~aJanthracene, rats were fed diets con- taining either refined sugar or complex starches. Significantly more breast tumors were observed in rats fed refined sugar than in those fed starch. Much more experimental work is required before a conclusion can be drawn about the relationship between sucrose and carcinogenesis. 7 - 2

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Carbohydrates 125 Lactose Gershoff and McGandy (1981) studied the interaction of dietary lactose (49%) or sucrose (43%-55% total weight) with vitamin A deficiency in the production of primary urinary bladder calculi in male Charles River rats. A small percentage of rats fed lactose in a diet with sufficient vitamin A developed vesicle stones. Approximately 60% of the rats fed lactose in vitamin-A-deficient diets developed bladder calculi. The bladder walls in most of the affected rats were grossly hypertrophic and had focal areas of transitional cell hyperplasia. Histological changes consistent with grade I to II transitional cell carcinomas were observed in approximately 30% of the stone-containing bladders. It was not possi ble to discern whether the deficiency of vitamin A contributed directly to bladder tumors or indirectly via stone formation and subsequent physi Cal irritation of the bladder. Sucrose-fed rats with or without super- imposed vitamin A deficiency did not exhibit calculi or histological changes of the bladder. The authors remarked that this was the first study to demonstrate the production of tumors by diet without an exog- enous source of a carcinogen in animals not genetically predisposed to tumor formation. Glucose . A preliminary report by Ingram and Castleden (1981) implicated dietary glucose in the development of carcinogen-induced tumors in the large bowel. In this study, male Wistar rats were fed Milne's Standard Laboratory Diet and given drinking water ad libitum either with or without 1.6% glucose. Both groups were injected subcutaneously with 1,2-dimethylhydrazine to induce bowel tumors. There were no differences in the number of small bowel tumors observed in the two groups; however, the rats given the glucose solution developed approximately twice the number of large bowel tumors observed in those given the drinking water alone. These results are difficult to interpret because approximately 35% of the Milne Standard Laboratory Diet is composed of carbohydrates, and this diet was fed to both groups of animals. The contribution of this diet to blood glucose levels is considerably greater than that supplied by the 1.6% glucose-water drinking solution. Thus, there is a possibility that the observed results were an indirect effect of the glucose-water solution rather than a direct effect of glucose. Xylitol Xylitol is present in many natural foods (Washuttl et al., 1973~. Its sweetness is approximately equal to that of sucrose. In a 2-year feeding study, CFLP male and female mice were fed 0, 2%, 10%, or 20% xylitol in the diet for as long as 106 weeks (Hunter et al., 7 - 3

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126 DIET, NUTRITION, AND CANCER 1978b). In the mice fed the 10% or 20% xylitol diets, there was a re- duction in spontaneous hepatocellular tumors in the males, but not in the females. However, the males in these dietary groups had more crystalline bladder calculi and an associated increase in hyperplasia, metaplasia, and neoplasia of the transitional epithelium of the bladder than did the females fed similar diets, the control mice, or the mice fed 2% xylitol. Sprague-Dawley CD male and female rats were fed 2%, 5%, 10%, or 20% xylitol in the diet for 26 weeks without evidence of increased renal calculi or hepatocellular abnormalities at autopsy. However, the inci- dence of adrenal medullary hyperplasia was greater in rats fed 5%, 10%, or 20% xylitol than in the controls (Hunter et al., 1978b). In male and female beagle dogs fed 10% or 20% xylitol in their diets for 52 weeks, the single remarkable pathologic change was an increased liver weight at autopsy. This slight hepatomegaly was associated with hepatocyte en- largement and altered hepatocyte appearance in the periportal areas of the animals. The quantity of xylitol in the 20% diet approaches the LDso for xylitol in mice (Kieckebuch et al., 1961~. In rats, ingestion of 20% xylitol may exceed the maximum metabolic turnover rate as calculated from rates observed in humans (Bicker and Halmagyi, 1976~. SUMMARY Epidemiological Evidence The evidence concerning the role of carbohydrates in the development of cancer in humans is extremely limited. In one study, the intake of sugar was correlated with increased mortality from pancreatic cancer in women only, and the intake of potatoes was correlated with increased mortality from liver cancer in both sexes. In other studies, a high intake of refined sugar and a low intake of starch have been associated with an increased incidence of breast cancer. Frequent consumption of starch has been associated with a high incidence of gastric cancer in one case-control study and with esophageal cancer in another. However, the evidence is insufficient to permit any firm conclusions to be drawn. Experimental Evidence The data from the few laboratory experiments designed to study the role of carbohydrates in carcinogenesis are difficult to interpret because of generally poor experimental designs and because there is uncertainty about the actual carbohydrate content of the foods used in the test diets. A few recent studies suggest that dietary lactose combined with vitamin A deprivation and long-term feeding of high levels of sucrose and 7 - 4

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C~6aD ^ ~~ 127 xylitol may contribute to carcinogenesis. further study. CONCLUSION These observations require Thus, the evidence from both epidemiological and laboratory studies 18 too sparse to suggest a direct role for carbohydrates (possibly exclusive of fiber) in carcinogenesis. However, excessive carbohydrate consumption contributes to caloric excess, which 1u turn has been 1m- plicated as a modifier of carcinogenesis 7-5

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128 DIET, NUTRITION, AND CANCER REFERENCES Armstrong, B., and R. Doll. 1975. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practice. Int. J. Cancer 15:617-631. Bickel, H., and M. Halmagyi. 1976. Requirement and utilization of carbohydrates and alcohol. Pp. 66-79 in F. W. Ahnefeld, C. Burri, W. Dick, and M. Halmagyi, eds. Parenteral Nutrition. Springer-Verlag, Berlin, Heidelberg, and New York. de Jong, U. W., N. Breslow, J. G. E. Hong, M. Sridharan, and K. Shanmugaratnam. 1974. Aetiological factors in oesophageal cancer in Singapore Chinese. Int. J. Cancer 13:291-303. Drasar, B., and D. Irving. 1973. Environmental factors and cancer of the colon and breast. Br. J. Cancer 27:167-172. Friedman, L., H. L. Richardson, M. E. Richardson, E. J. Lethco, W. C. Wallace, and F. M. Sauro. 1972. Toxic response of rats to cycla- mates in chow and semisynthetic diets. J. Natl. Cancer Inst. 49:751-764. Gershoff, S. N., and R. B. McGandy. 1981. The effects of vitamin A- deficient diets containing lactose in producing bladder calculi and tumors in rats. Am. J. Clin. Nutr. 34 :483~89. Hakama, M., and E. A. Saxen. 1967. Cereal consumption and gastric cancer. Int. J. Cancer 2:265-268. Hems, G. 1978. The contribution of diet and childbearing to breast- cancer rates. Br. J. Cancer 37:974-982. Hems, G., and A. Stuart. 1975. Breast cancer rates in populations of single women. Br. J. Cancer 31:118-123. Hoehn, S. K., and K. K. Carroll. 1978. Effects of dietary carbohy- drate on the incidence of mammary tumors induced in rats by 7,12- dimethylbenz~a janthracene. Nutr. Cancer 1:27-30. Hueper, W. C. 1965. Are sugars carcinogens? An experimental study. Cancer Res. 25:44004 3. Hunter, B., C. Graham, R. Heywood, D. E. Prentice, F. J. C. Roe, and D. N. Noakes. 1978a. Tumorigenicity and Carcinogenicity Study with Xylitol in Long-Term Dietary Administration to Mice (Final report). Huntingdon Research Centre, Huntingdon, Cambridgeshire, England. Volumes 20-23 of Xylitol. F. Hoffman La Roche Company, Ltd., Basel, Switzerland. 1500 pp. 7 - 6

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Carbohydrates 129 Hunter, B., J. Colley, A. E. Street, R. Heywood, D. E. Prentice, and G. Magnusson. 1978b. Xylitol Tumorigenicity and Toxicity Study in Long-Term Dietary Administration to Rats (Final Report). Huntingdon Research Centre, Huntingdon, Cambridgeshire, England. Volumes 11-14 of Xylitol. F. Hoffman La Roche Company, Ltd., Basel, Switzerland. 2225 pp. Ingram, D. M., and W. M. Castleden. 1981. Glucose increases experi- mentally induced colorectal cancer: A preliminary report. Nutr. Cancer 2:150-152. Kieckebuch, W., W. Gzeim, and K. Lang. 1961. [In German.] Die Verwertbarkeit van Xylit als Nahrungskohlenhydrat und seine Vertraglichkeit. Klin. Wochenschr. 39:447-448. Modan, B., F. Lubin, V. Barrell, R. A. Greenberg, M. Modan, and S. Graham. 1974. The role of starches in the etiology of gastric cancer. Cancer 34:2087-2092. Nonaka, T. 1938. [In Japanese; English Title.] The occurrence of sub- cutaneous sarcomas in the rat after repeated injections of glucose solution. Gann 32:234-235. Roe, F. J. C., L. S. Levy, and R. L. Carter. 1970. Feeding studies on sodium cyclamate, saccharin and sucrose for carcinogenic and tumour- promoting activity. Food Cosmet. Toxicol. 8:135-145. Takizawa, N. 1939. [In Japanese; German Title.] Uber die Erzeugung des Maussarkoms durch die subcutane Injektion der konzentrierten Zuckerlosung. (II. Mitteilung.) Gann 33:193-195. Washuttl, J., D. Reiderer, and E. Bancher. 1973. A qualitative and quantitative study of sugar-alcohols in several foods. J. Food Sci. 38:1262-1263. Zarattini, A. 1940. [In Italian.] Sulla produzione sperimentale del sarcoma nei ratti mediante somministrazione paraenterale di glucosio. Tumori 26:77-84. 7 - 7