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Diet, Nutrition, and Cancer (1982)

Chapter: 10 Minerals

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Suggested Citation:"10 Minerals." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
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10 Minerals Very few epidemiological studies have been conducted to determine the relationship between minerals and the incidence of cancer in humans. This is due partly to the difficulty of identifying populations with significantly different intakes of the various minerals. In contrast, there have been numerous studies in laboratory animals. In these in- vestigations, the carcinogenic effects of many metals, administered at high doses to the animals parenterally, have been well established and have been reviewed extensively (Furst, 1979; Sunderman, 1977~. However, the results of these studies have shed little light on the potential carcinogenic risk posed by trace elements in the amounts occurring naturally in the diet of humans. Very few feeding studies have been conducted to test the carcino- genicity of trace elements in animals. The carcinogenic action of these elements is difficult to test in animals because some of them are toxic at levels that exceed dietary requirements, and because it is diffi- cult to control synergistic interactions of the element under investiga- tion with other elements that may contaminate air, diet, and drinking water. This chapter contains an evaluation of a few of those trace elements that are nutritionally significant and suspected of playing a role in carcinogenesis. The committee sought evidence primarily from those experiments in which the element was fed to the animal or from epidemiological reports of exposure through diet. Results obtained from laboratory experiments using other routes of exposure, or evidence from occupational exposure of humans, are described briefly when sufficient information about dietary exposure could not be found. The effects of both the deficiencies as well as excessive intakes of minerals are also discussed in this chapter. Schroeder and his associates investigated the carcinogenicity of trace elements in a series of large experiments extending over 15 years (Kanisawa and Schroeder, 1967; Schroeder and Mitchener, 1971a,b, 1972; Schroeder et al., 1964, 1965, 1968, 1970~. Animals were raised in an environment that permitted maximum control of trace element contamina- tion; they were fed one diet of known composition; and they were observed for their lifetime. The following elements were studied in at least 50 mice and/or rats per treatment: fluorine, titanium, vanadium, chromium, nickel, gallium, germanium, arsenic, selenium, yttrium, zirconium, nio- bium, rhodium, palladium, cadmium, indium, tin, antimony, tellurium, and lead. These elements were added to the drinking water at levels of 5 mg/liter, except for selenium (3 mg/liter) and tellurium (2 mg/liter). These levels (approximately 100 times greater than the concentrations present naturally in the diet) did not significantly affect growth and survival of the animals. The interpretation of these findings of no 162 10-1

Minerals 163 effects or minimally significant effects must be cautious, in view of the small number of animals used. Only rhodium and palladium (tested in mice only) showed any signs of carcinogenicity, but as Schroeder and Michener (1971a) stated, The results were at a minimally significant level of confidence. Further studies are needed to confirm these findings. Schroeder also reported that selenate, but not selenite, increased the incidence of spontaneous malignant mammary and subcutaneous tumors in rats after lifetime exposure (11 in 75 controls vs 20 in 73 selenate-fed animals). These results were not confirmed in similar studies in mice. (The effects of selenium on carcinogenesis are discussed in further detail below.) None of the remaining elements examined increased tumor incidence. A significant reduction in tumor incidence was observed in mice fed arsenic and cadmium and in mice and rats fed lead. SELENIUM Signs of chronic selenium toxicity in animals have been recognized for almost 700 years, but selenium was not identified as the responsible agent until the 1930's. Twenty years later, the economic importance of selenosis and selenium deficiency for animal producers became apparent. This discovery stimulated the mapping of selenium distribution in the soils, forages, and tissues of humans in several continents. Extreme differences of exposure were delineated, even within individual countries. This knowledge enabled investigators to make epidemiological correlations of diseases, including cancer, in humans and animals and to conduct lab- oratory experiments to test the resulting hypotheses (National Academy of Sciences, 1971~. Epidemiological Evidence Selenium has been reported as having a possible protective effect against cancer. Shamberger and colleagues correlated selenium levels in forage crops (grouped into high, medium, and low categories) with cancer mortality by state in the United States (Shamberger and Frost, 1969; Shamberger and Willis, 1971; Shamberger et al., 1976~. They found an inverse relationship in both males and females, especially for cancers of the gastrointestinal and genitourinary tracts. In other studies, Schrauzer and coworkers correlated per capita intake with cancer mortality rates in more than 20 countries (Schrauzer, 1976; Schrauzer et al., 1977a,b). The consumption estimates were based on international food disappearance data for major food sources (e.g., cereals, meat, and seafoods) to which the investigators attributed plausible mean selenium values. They found an inverse relationship between selenium intake and leukemia as well as with cancers of the colon, rectum, pancreas, breast, ovary, prostate, bladder, lung (males), and skin. Using-pooled blood samples from healthy donors in 19 U.S. states and 22 countries, they also correlated blood levels of selenium with corresponding cancer mortality rates. They found significant inverse relationships for most of these same sites. 10-2

164 DIET, NUTRITION, AND CANCER Shamberger et al. (1973) compared the blood selenium levels in more than 100 cancer patients with those in 48 normal subjects attend- ing a clinic. The levels in patients with gastrointestinal cancers and Hodgkin's disease were significantly lower than those in the normal subjects, but there were no differences between the normal subjects and patients with cancers at other sites, such as the breast. It is not clear from this study whether the observed difference in the selenium levels was the result or the cause of the cancers. Jansson _ al. (1975, 1978) examined cancer mortality rates in the United States by county. They compared the rates in the northeastern part of the country with corresponding levels of selenium in the water supply. In contrast to other investigators, they reported a direct correlation between mortality from colorectal cancer and selenium levels in the drinking water. Experimental Evidence Carcinogenicity. During the past 40 years selenium has been alter- nately described as a carcinogen and an anticarcinogen, on the basis of experiments on animals. Because studies conducted during the 1940's showed that high levels of selenium induced or enhanced tumor formation, the Food and Drug Administration until recently prohibited the enrichment of animal feeds with selenium, even in areas with established selenium deficiency. In contrast to the results of the earlier investigations, more recent studies by several independent investigators have established that dietary selenium has a protective effect against tumors induced by a variety of chemical carcinogens or at least one viral agent. A critical review of the experimental conditions suggests that the earlier studies demonstrating carcinogenic or promoting properties of selenium can be faulted on the basis of experimental design. Nelson et al. (1943) fed a 12% protein diet to 18 control rats and to 126 rats whose diet was enriched with selenium (5, hand 10 Agog) as seleniferous grain or selenides. Fifty-three of the test animals and 14 of the con- trols survived to an age of 1.5 to 2 years. The livers of the control rats were normal, but all animals fed the high selenium diet had liver cirrhosis. Of these, 11 had developed nonmetastasizing adenomas and the rest showed hyperplasia. These findings can be attributed to a combina- tion of two insults: the near toxic levels of selenium and the marginal protein content of the diet. Harr et al. (1967) investigated the effect of selenium on tumor formation in 1,437 rats fed a range of selenium levels for as long as 30 months. Eighty-eight rats were also fed 2-acetylaminofluorene (2-AAF) along with selenium. The experimental design also included a repetition of the earlier experiment by Nelson et al. (1943), i.e., a marginal pro- tein diet was supplemented with selenium as selenate at 0.5, 2.4, or 8 Agog. As expected, diets containing selenium in concentrations 10-3

Minerals 165 higher than 8 Agog were toxic and killed the rats within the first month. The rats fed the two lower levels survived for more than a year. Autopsies and histological examinations performed on 1,123 of the rats on various dietary treatments provided no evidence for a carcinogenic effect of selenium. Forty-three tumors occurred in 88 of the rats fed 50 or 100 ~g/g of AAF diet without added selenium; the rest of the autopsied animals exibited 20 neoplasms, randomly distributed, regardless of the level of dietary selenium. Although there were no hepatic tumors in any autopsied animals that did not receive the carcinogen, approximately half of the selenium-supplemented rats that survived for more than 9 months had hyperplastic lesions in the liver, whereas none occurred in the controls. In another series of studies, Volgarev and Tscherkes (1967) measured the effect of selenium in 200 rats, but they did not use a selenium- free control group. In the first experiment, 40 rats were fed selenium as selenate at 4.3 to 8.6 ~g/g of diet. All animals developed liver cirr- hosis, 10 had neoplastic tumors, 4 had precancerous lesions, and 9 were unaffected. In a second experiment, only 5 neoplasms were observed among 60 rats. The third experiment failed to produce any tumors in 100 animals. Schroeder and Mitchener (1971b, 1972) studied the effect of se- lenium supplementation (2 to 3 mg/liter in drinking water as selenate or selenite) in lifetime experiments with rats and mice. Neither form of selenium affected the incidence of tumors in mice, and selenite had no effect in rats. Specifically, no hepatic cirrhosis was observed. However, following an epidemic of pneumonia in the rat colonies, there were 30 tumors in 73 animals in the selenate group, but only 20 in 75 animals in the controls. Antitumorigenic Effects. A large accumulation of evidence indicates that supplementation of the diet or drinking water with selenium protects against tumors induced by a variety of chemical carcinogens and at least one viral agent (Table 10-1~. Although most investigators found that tumor incidence in the selenium-supplemented animals was approximately one-half that of the control animals, Schrauzer et al. (1978) reported that spontaneous breast tumors in female C3H mice were reduced from 82% in controls to 10% in the selenium-supplemented animals. In all but two of the experiments, comparisons were made between controls receiving diets with nutritionally adequate selenium levels and test animals fed diets supplemented with selenium levels 20 to 50 times higher than the animal's requirements. In the remaining two experiments, Barr et al. (1972) and Ip and Sinha (1981) used selenium-deficient diets and demon- strated beneficial effects of selenium supplementation at levels close to the physiological requirement. Of special nutritional importance is their finding that the incidence of tumors induced by 7,12-dimethyl- benz~ajanthracene (DMBA) was enhanced by diets high in polyunsaturated fatty acids and by dietary deficiency of selenium. Supplementation with physiological levels of selenium (0.1 ~g/g diet) resulted in protection against tumor formation (Ip and Sinha, 1981~. 10-4

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Minerals 167 Although these data indicate that selenium has an antitumorigenic effect, they provide no information on the mechanism of action or on the stage of tumor development during which selenium might exert its protec- tive action. In at least two studies, selenium was introduced only after the carcinogen was applied and led to a reduction in tumor incidence. Schrauzer _ al. (1978) stated that the selenium levels in the recipient animals do not influence the fate of transplanted tumor cells; others observed a strong reduction in the growth of inoculated Ehrlich ascites cells in recipient animals injected with high doses of selenium compounds for 3 weeks after the inoculation (Greeder and Milner, 1980~. Mutagenicity. In vitro studies have not shed much light on the mechanisms of action of selenium. On the one hand, selenium concentra- tions from 0.1 to 40 mM exert antimutagenic effects against a variety of mutagens In vitro, including the naturally occurring mutagen malonal- dehyde (Jacobs _ al., 1977; Shamberger et al., 1978~. On the other_ _ hand, similar concentrations of selenium have been reported to increase DNA fragmentation and chromosome aberrations in human and microbial cell cultures (Lo et al., 1978; Nakamuro et al., 1976~. These contrasting reports cannot be reconciled. Potential Mechanisms of Action. There are data suggesting that selenium _ vitro and in viva may decrease the activity of hydrox- ylating enzymes that activate procarcinogens and may increase a detoxi- fying enzyme--glucuronyl transferase (Griffin, 1979~. These results suggest that selenium acts during the early stages of initiation. The best known functions of selenium at nutritionally adequate, but not at excessive, levels are its role as a part of the enzyme glu- tathione peroxidase and its interaction with heavy metals. Glutathione peroxidase destroys hydroperoxides and lipoperoxides, thereby protecting the constituents of the cells against free radical damage. Ip and Sinha (1981) have shown that selenium, through its function in glutathione peroxidase, could well be involved in protecting against cancer induced by high intakes of fat, especially polyunsaturated fatty acids. Gluta- thione peroxidase activity in human blood increases with increasing selenium intakes, but reaches a plateau at intakes well below those customary in the United States (Thomson and Robinson, 1980~. Thus, if the antitumorigenic effect of selenium is mediated through its function in glutathione peroxidase, attempts to increase the enzyme activity by selenium supplementation, superimposed on an adequate diet in the United States, would not be successful. The second function of selenium is to protect against acute and chronic toxicity of certain heavy metals. Although selenium is known to interact with cadmium and mercury, the mechanism of action is not known. Selenium does not cause an increased elimination of the toxic elements, but, rather, an increased accumulation in some nontoxic form (National Academy of Sciences, 1971~. It is conceivable that carcinogenic effects of these, and perhaps other heavy metals, could be counteracted by selenium, in a manner similar to its protection against their general toxicity. 10-6

168 DIET, NUTRITION,AND CANCER Summary Epidemiological Evidence. The epidemiological evidence pertaining to the relationship between selenium and cancer is derived from a limited number of geographical correlation studies in which the risk of cancer was correlated with estimates of per capita selenium intake, with the selenium levels in blood specimens, or with selenium concentrations in water supplies. Although these studies generally demonstrated an in- verse relationship between the level of selenium and the risk of cancer, it is not clear whether this relationship applies to all cancer sites or only to specific cancer sites, such as those in the gastrointestinal tract. There are as yet no data from case-control or cohort studies. Experimental Studies. Numerous experiments in animals have demon- strated an antitumorigenic effect of selenium. The relevance of most of these studies to the risk of cancer for humans is not apparent since the levels of selenium used far exceeded dietary requirements and often bordered on levels that might be toxic. However, one experiment has demonstrated increased susceptibility to DMBA-induced tumors when se- lenium deficiency was aggravated by high dietary levels of polyunsatu- rated fatty acids, and protection by a physiological supplement of se- lenium (0.1 ~g/g) to the diet (Ip and Sinha, 1981~. The interpretation of these results is further complicated because of the varied protocols used in these experiments and the knowledge that selenium interacts with many other nutrients, such as heavy metals in the diet. The minimum requirement for selenium in mammalian species is 0.05 agog of diet, one-hundredth of the levels used in many studies of car- cinogenesis. A level of 4 or 5 Gig may not be acutely or even chroni- cally toxic when fed along with a well-balanced, nutritious diet, but it becomes chronically toxic when the quality of the diet is lowered, for example when the protein content is reduced. At least two experiments have demonstrated that selenium deficiency enhances carcinogenesis and that physiological amounts of selenium have a significant protective effect. The effectiveness of doses in the wide range between the nutritionally adequate and the higher, effective level used in many antitumorigenic studies has not yet been adequately investigated. The data on the mutagenicity of selenium compounds are also contradictory. However, these experiments provide sufficient evidence to suggest that the antitumorigenic effect of selenium should be investigated further. Recent data do not support the earlier reports that selenium per se is carcinogenic. Conclusion Both the epidemiological and laboratory studies suggest that selenium may offer some protection against the risk of cancer. However, firm conclusions cannot be drawn on the basis of the present limited evidence. Increasing the selenium intake to more than 200 ~g/day (the 10-7

Minerals 169 upper limit of the range of Safe and Adequate Daily Dietary Intakes published in the Recommended Dietary Allowances [National Academy of Sciences, 1980b]) by the use of supplements has not been shown to con- fer health benefits exceeding those derived from the consumption of a balanced diet. ZINC Zinc is an essential constituent of more than 100 enzymes and is essential for life. Through its function in nucleic acid polymerases, zinc plays a predominant role in nucleic acid metabolism, cell replica- tion, tissue repair, and growth (Prasad, 1978~. Severe zinc deficiency in humans has been known for 20 years; more moderate forms have been linked to protein-energy malnutrition. Marginal zinc deficiency is suspected to occur in a substantial number of infants and older children in the United States (Prasad, 1978~. Pronounced zinc deficiency in animals and humans results in depressed immune functions. Both tissue-mediated and humoral responses are affected. Golden _ al. (1978) have observed that impairment of delayed hypersensitivity reactions to Candida albicans antigen in malnourished children can be normalized by topically applied zinc preparations, but it is not known whether or to what degree immunocompetence is impaired by marginal zinc deficiency. Epidemiological Evidence There have been few epidemiological studies of the relationship between exposure to zinc and risk of cancer. Stocks and Davies (1964) correlated cancer mortality with the zinc and copper content of soil in 12 districts of England and Wales. They found higher zinc levels and higher ratios of zinc to copper in the soil of vegetable gardens near houses in which a death from gastric cancer had occurred than in the soil of gardens near houses in which there was a death attributed to another cause. The levels near houses with deaths from other cancers did not differ from those of the noncancer households. These analyses were made only when the deceased had resided in the same house for 10 or more years. Since the copper levels in soil varied little, the differences could be attributed to zinc. Schrauzer et al. (1977a,b) examined per capita food intake data in 27 countries. They found a direct correlation between estimated zinc intake and age-adjusted mortality from leukemia and cancers of the intestine, breast, prostate, and skin. Based on these findings and the inverse correlation between zinc and selenium concentrations in blood, they suggested that zinc increases cancer risk by its antagonism of selenium. Van Rensburg (1981) observed that wheat and corn are the primary dietary staples in many populations at high risk for esophageal cancer 10-8

170 DIET, NUTRITION, AND CANCER around the world. In contrast, the staples in low-risk populations include millet, cassava, yams, and peanuts. Since diets based on wheat and corn generally contain low concentrations of zinc, magnesium, nicotinic acid, and possibly riboflavin, he suggested that a deficiency of one or more of these micronutrients might be etiologically related to esophageal cancer. A number of investigators have examined the relationship between cancer and levels of zinc in blood and other body tissues. Schrauzer_ al. (1977b) found that mean zinc concentrations in pooled blood from healthy donors in 19 U.S. collection sites correlated directly with corresponding mortality rates from cancers of the large bowel, breast, ovary, lung, bladder, and oral cavity. Zinc and selenium levels in the blood were inversely correlated with each other. Strain et al. (1972) compared zinc and copper levels in the serum of patients with broncho- genic carcinoma and the levels in the serum of controls. Although zinc levels did not differ between the two groups, the copper levels were lower in the controls, resulting in higher ratios of zinc to copper in the cancer patients. On the other hand, Davies et al. (1968) reported that zinc levels in the plasma of bronchogenic carcinoma patients were lower than those of other cancer patients and lower than normal labora- tory values. et Lin_ al. (1977) examined serum, hair, and tissues from Chinese men in Hong Kong for levels of zinc and other minerals. They found that levels of zinc in serum and diseased esophageal tissue from esophageal cancer patients were much lower than those in other cancer patients and in normal subjects. Zinc levels in hair were lower in both cancer groups than in normal subjects. The serum of esophageal cancer patients also contained slightly elevated copper levels and much lower iron levels than the serum of normal sub jects . Gyorkey et al . (1967 ) reported that zinc concentrations in malignant prostatic tissue were lower than those in normal tissue, whereas benign hypertrophied prostatic tissue contained higher zinc levels. In all of these studies, the altered zinc levels may have followed, rather than preceded, the onset of the cancers. Experimental Evidence Experiments in animals have demonstrated both enhancing and retarding effects of zinc on tumor growth. Several reports suggest that a zinc deficiency strongly inhibits the growth of transplanted tumors in animals and prolongs survival time. The studies by Petering et al. (1967) with transplanted Walker 256 carcinoma in rats were confirmed by DeWys et al. (1970) and extended to other types of tumors, such as leukemias, Lewis lung carcinoma (DeWys and Pories, 1972), Ehrlich ascites tumor (Barr and Harris, 1973), P388 leukemia (Minkel et al., 1979), and plasmacy- toma TEP C-18 3 (Fenton et al., 1980~. The results of these studies are consistent with the knowledge that rapidly growing tumor cells require zinc for growth; however, they do not suggest zinc deficiency as a therapeutic modality because zinc deficiency by itself, with or with- out concomitant malignancies, results in death of the animals. 10 -9

Dineros 171 The results of these studies contradict reports indicating that zinc deficiency enhances chemically induced carcinogenesis. For example, Fang et al. (1978) observed that the incidence of esophageal tumors induced by n~trosomethylbenzylamine (NMBA) was significantly higher in zinc-defi- cient rats than in control rats. The intragastric incubation of NMBA in a dose of 48 ~g/g body weight resulted in a 15% incidence of carcinoma in control rats fed ad libitum and a 43% incidence in rats maintained on zinc-deficient diets. In two consecutive experiments, lowering the dose of NMBA to 34 ~g/g body weight produced no cancer in the control rats, but 83% and 33Z in the zinc-deficient animals. In contrast, some studies have indicated that zinc intake greatly exceeding nutritional requirements suppresses carcinogenesis induced by DMBA in Syrian hamsters (Poswillo and Cohen, 1971) or by azo dyes in rats (Duncan and Dreosti, 1975~. But Schrauzer (1979) demonstrated that high concentrations of zinc (200 ma/ liter) in the drinking water of C3H mice countered the protective effect of selenium against spontaneous mammary carcinoma and resulted in a significant increase in tumor growth. These contradictory reports are not easily reconciled. Perhaps there are two different mechanisms of action by which zinc influences two dif- ferent phases of carcinogenesis: Zinc, perhaps through its effect on the immune system, may be protective during the early phases of transforma- tion, whereas the demonstrated role of zinc in cell proliferation may explain the protective effect of zinc deficiency against the growth of established tumors. Furthermore, numerous interactions of zinc with other trace elements, such as selenium, are incompletely understood. Thus, the evidence is insufficient to determine the answer to an impor- tant question: Does marginal zinc deficiency, believed to be widespread, especially among children, present a risk for or provide protection against carcinogenesis? Summary Epidemiological Evidence. There are few epidemiological data con- - cerning dietary zinc and cancer. Some studies have suggested that higher levels of dietary zinc are associated with an increase in the incidence of cancer at several different sites, including the breast and stomach, and other studies have reported lower levels of zinc in the serum and tissue of patients with esophageal, bronchogenic, and other cancers, compared to corresponding levels in controls. However, the possibility that the lower serum and tissue levels resulted from the cancer itself has not been ruled out. Experimental Evidence. Experiments in animals have shown that zinc can either enhance or retard the growth of tumors. Zinc deficiency appears to retard the growth of transplanted tumors, whereas it enhances the incidence of some chemically induced cancers. In some experiments, dietary zinc exceeding nutritional requirements has been shown to sup- press chemically induced tumors in rats and hamsters, but when given in 10-10

172 DIET, NUTRITION, AND CANCER drinking water it counteracts the protective effect of selenium in mice. These data are insufficient to explain the effects of zinc and of inter- actions between zinc and other minerals on tumorigenesis. Conclusion The epidemiological evidence concerning zinc is too sparse and the results of laboratory experiments too contradictory to permit any con- clusion to be drawn. In view of the important nutritional role of zinc and of its many interactions with other minerals involved in carcino- genesis, additional research is warranted to resolve the contradictory results. IRON Epidemiological Evidence Iron deficiency has been associated with cancers of the upper ali- mentary tract including the esophagus and stomach. In epidemiological studies conducted in Sweden, iron deficiency was associated with Plummer-Vinson (Paterson-Kelly) syndrome, which in turn was associated with increased risk for cancer of the upper alimentary tract (Larsson et _., 1975; Wynder et al., 1957~. Improved nutrition, especially with_ regard to iron and vitamins in the diet, has been associated with the virtual elimination of new cases of Plummer-Vinson disease in areas of Sweden where it had formerly been highly endemic (Larsson et al., 1975~. Broitman _ al. (1981) studied iron-deficient patients with ante- cedent lesions of gastric carcinoma in an area of Colombia with high risk for this cancer. They found that hypochlorhydria and achlorhydria, which are associated with chronic atrophic gastritis resulting from iron deficiency, permitted bacterial colonization of the stomach. The investi- gators postulated that these bacteria could reduce ingested nitrate to nitrite, leading to the formation of nitrosamines that are carcinogenic in the stomach of laboratory animals, and are suspected of being carcin- ogenic in humans. A similar mechanism was suggested by Ruddell et al. (1978) to explain the increased risk of gastric cancer in patients with · . — pernlclous anemia. There have been no epidemiological reports of cancer associated with increased dietary intake of iron, although heavy inhalation exposure to high levels of iron oxide has been related to increased risk for lung and laryngeal cancers in miners of iron ore, metal workers, and workers in iron foundries (Cole and Goldman, 1975~. In addition, sarcomata have developed in patients at sites of injection of iron-dextran solutions (MacKinnon and Bancewicz, 1973; Robinson _ al., 1960), and many clinical reports have associated hemochromatosis with an increased risk for 10-11

Minerals 173 hepatomas and possibly other hepatic and extrahepatic cancers (Armann et al., 1980; Scott and Theologides, 1974; Steinherz et al., 1976; Sussman _ al., 1974~. - Experimental Evidence Mild iron deficiency appeared to protect mice from the hepatocellu- lar and porphyria toxicity due to 2, 3,7, 8-tetrachlorodibenzo-p-dioxin (TODD) (Sweeney et al., 1979~. It is not known if such protection might extend to the teratogenic or possible carcinogenic action of TODD. Rats made severely deficient in iron through manipulation of their diet became anemic and developed fatty livers (Vitale et al., 1978), but they were devoid of any neoplastic lesions. However, in the same study, iron- deficient rats given 1,2-dimethylhydrazine developed neoplastic lesions in their livers within 4 months, as compared to 6 months in the iron- sufficient group. The authors concluded that severe lack of iron appeared to function as a cocarcinogen (Vitale et al., 1978~. Brusick et al. (1976) found that Fe(II) as iron sulfate induced reverse mutaTLons in Salmonella typhimurium strains TA1537 and TA1538 with the S9 fraction of various species. Weak mutagenic activity was also observed in nonactivated suspensions. Summary Epidemiological Evidence. Iron deficiency has been related to an increase in the risk of Plummer-Vinson syndrome, which is associated with upper alimentary tract cancer. Some evidence suggests that iron deficiency may be related to gastric cancer, also through an indirect mechanism. Although epidemiological and clinical reports have suggested that heavy exposure to iron by inhalation increases the risk of cancer, there is no evidence pertaining to the effect of high levels of dietary iron on the risk of cancer in humans. Experimental Evidence. The evidence from experiments in animals is limited. In one study, dietary deficiency of iron was associated with an earlier onset of chemically induced tumors in rats. These data are not sufficient to clarify the role of iron in carcinogenesis. Conclusion The data are not sufficient for a firm conclusion to be drawn about the role of iron in carcinogenesis. COPPER Copper is an essential nutrient that is widely distributed in foods. Public water supplies may be an additional source of copper. The intake 10-12

174 DIET, NUTRITION, AND CANCER of copper in 28 countries has been reported by Schrauzer et al. (1977b) to vary between 1.6 and 3.3 mg/day. However, more recent studies indi- cate that the average copper intake for U.S. adults is m1 mg/day (Holder _ al., 1979; Klevay et al., 1979~. Epidemiological Evidence Schrauzer et al. (1977b) used pooled blood samples from healthy donors in 19 U.S. states to correlate blood levels of copper with corresponding cancer mortality rates. They found weak direct associa- tions for cancers of the intestine, breast, lung, and thyroid. From reported average concentrations of copper in major food items and inter- national food disappearance data, they were also able to correlate per capita intake of copper with cancer mortality rates in 27 countries. In this portion of their study, they found direct associations for leukemia and cancers of the intestine, breast, and skin. These investigators proposed that the mechanism for the apparent carcinogenicity of copper might involve selenium antagonism, since large doses of copper produce symptoms of selenium deficiency in animals (Jensen, 1975~. The possibility that dietary exposure to copper, through the copper content of either foods or cookware, may play an etiologic role in gas- tric carcinogenesis is raised by the experiments of Endo et al. (1977), who found that the copper ion may be involved in conversion of creatine and creatinine to methylguanidine, a precursor of methylnitrosoguanidine. However, no epidemiological data on the relationship of gastric cancer and dietary copper have been reported. In a number of clinical studies, levels of copper in the serum and tissues of cancer patients were found to be higher than normal labora- tory values and higher than levels in healthy subjects or in noncancerous tissues (Schwartz, 1975~. However, the possibility that these levels are the consequence, rather than the cause, of the disease cannot be ruled out. Indeed, many of these reports indicate that changes in copper levels may be effected by therapy or by different stages and activity of the disease. Inhalation of copper has been suggested as a possible cause of hepatic angiosarcoma as well as pulmonary adenocarcinoma and alveolar cell carcinoma in workers who sprayed vineyards with a fungicide called the Bordeaux mixture (copper sulfate plus lime) (Pimentel and Menezes, 1977~. An increased risk for bronchogenic carcinoma has also been reported for copper miners in cases where exposure to radiation was dismissed as a likely cause (Newman et al., 1976~. Thus, although some data suggest that copper is carcinogenic in humans, very little epidemiological evidence implicates dietary sources per _. 10-13

Minerals 175 Experimental Evidence Several independent studies have demonstrated that high levels of copper salts added to the diets of animals provided various degrees of protection against chemically induced liver tumors. The effects ranged from a prolongation of the induction time to partial or complete protec- tion against tumor formation. These studies, in which a variety of different carcinogens were used, have been reviewed by Brada and Altman (1978~. Since these effects were obtained with extremely high concentra- tions of copper (from 0.3% to 0.6% copper acetate in the diet) and since similar effects have been produced when manganese or nickel were sub- stituted for copper (Yamane and Sakai, 1973), the action of copper may be pharmacologic, perhaps toxic in nature and nonspecific. There is no experimental evidence that the copper levels in animal tissues influence their susceptibility to carcinogens. Summary Epidemiological Evidence. Although there are some data from clinical and epidemiological studies concerning the association of copper with neoplasia in humans, there is little evidence pertaining to the role of dietary copper in the etiology of human cancer. Experimental Evidence. Experiments in animals have indicated that pharmacological doses of copper appear to protect against chemically induced tumors, but there are no studies to indicate whether the nutri- tional copper status of animals influences their susceptibility to cancer. Conclusion The evidence does not permit any conclusion to be drawn about the role of dietary copper in carcinogenesis. IODINE Iodine is an essential micronutrient in the diet and is an integral component of thyroid hormones. Dietary deficiency of iodine is associated with enlargement of the thyroid gland and endemic goiter, but this does not occur commonly in the United States. The mean daily intake of iodine in the United States is estimated to range from approximately 60 to 680 ~g/day. Even the lower level is adequate to meet the minimum daily requirements of 50 fig, and many diets furnish iodine in excess of the Recommended Dietary Allowance of 150 fig (Fisher and Carr, 1974~. The ionization of table salt, the use of iodine in disinfectants, and the addition of iodate to dough conditioners have contributed to the drastic reduction in iodine deficiency in the United States. Together, these sources can also result in high intakes of iodine, which are considered excessive by some nutritionists. 10-14

176 DIET, NUTRITION, AND CANCER Epidemiological Evidence Wahner _ al. (1966) concluded that thyroid cancer occurred more frequently in Call, Colombia (an area of endemic goiter) than in New York State or Puerto Rico. Their analysis was based on published data from the United States and on a large autopsy series conducted by the authors in Colombia. Although papillary carcinoma was the type of cancer found most frequently in their series, the relative proportion of follicular carcinomas was high compared with other areas of the world. Williams et al. (1977) compared the incidence and histologic types of thyroid cancer In two contrasting populations: Icelanders with high iodide diets and Scot s from northeast Scotland with normal levels of dietary iodide. Based on a pathological review of all surgical thyroid specimens in these areas, the investigators were able to determine the histology-specific incidence rates of thyroid cancer. Their results indicated that the incidence of papillary carcinoma and the ratio of papillary to follicular carcinomas were higher in Iceland than in Scotland. They concluded that high intake of iodide was associated only with the papillary type of thyroid cancer, and suggested that low levels of dietary iodide may increase the risk for follicular carcinoma of the thyroid. In studies that have not distinguished histologic types of thyroid cancer, investigators have tended to find no associations with exposure to iodine. Clements (1954) found no difference between observed and expected deaths from thyroid cancer by state in Australia, despite the fact that iodine intakes varied and endemic goiter was particularly prevalent in Tasmania. Pendergrast et al. (1961) compared thyroid can- cer mortality rates by state in the United States with corresponding prevalence rates of endemic goiter and found no association between the two diseases. They also examined secular trends in mortality from these two diseases and observed that there had been a decline in endemic goiter rates but not in thyroid cancer rates in the United States during the previous 30-year period. Mortality data, used in both of these studies, can be quite misleading for thyroid cancer and other cancers that have very high survival rates. A second type of cancer associated with iodine deficiency is breast cancer in females. In an analysis similar to that of Pendergrast et al. (1961) for thyroid cancer, Bogardus and Finley (1961) compared mortality rates for this cancer by state in the United States with the prevalence of endemic goiter. They found a direct association between the two dis- eases. Commenting on this observation, Stadel (1976) noted that breast cancer in females is highly correlated with endometrial and ovarian cancers and hypothesized that low iodine intake may be etiologically related to all three cancers. However, the results of many other stud- ies do not support this association. Edington (1976) reported conflict- ing data obtained in sub-Saharan Africa, where these three cancers are rare despite very low levels of dietary iodine. In Hawaii and Iceland, iodine intake is high, but there are also high incidence rates for breast cancer (Waterhouse et al., 1976~. 10-15

Minerals 177 Experimental Evidence Eskin et al. (1967) and Aquino and Eskin (1972) reported that iodine deficiency produces hyperplastic changes in the breast tissue of female rats during puberty. Because of the epidemiological correlations indi- cating a higher incidence of mammary carcinoma in areas with endemic goiter, Eskin (1978) studied the influence of iodine deficiency, per se, on mammary tissue when the thyroid was maintained in a normal state. Deficiency resulted in dysplastic changes of the epithelium, which were aggravated by estrogen treatment and advanced to preneoplastic and neo- plastic conditions. These changes were reversible by supplementation with inorganic iodine but not thyroxine which, in higher doses, increased the dysplastic changes. Eskin proposed that iodine deficiency itself rather than hypothyroidism was responsible for these effects and demon- strated similar changes by blocking iodine uptake with perchlorate. Upon termination of the blockade or dietary iodine supplementation, most but not all of the hyperplastic tissue changes returned to normal. The iodine-deficient prepubescent rats were also susceptible to earlier appearance of DMBA-induced mammary tumors, suggesting a cocarcinogenic effect of iodine deficiency. Eskin _ al. (1976) also demonstrated that the ratios of DNA to RNA in the breast of iodine-deficient rats were much higher than those for control rats. In addition, observed alterations in the estrogen receptor protein may suggest that mammary tumorigenesis may be stimulated in the presence of estrogen and higher physiological levels of its receptor, as observed in iodine deficiency. Exposure of iodine-deficient animals to a carcinogen such as 2-acetylaminofluorene (2-AAF) or to thyroid irra- diation has been reported to result in increased yields of malignant thyroid tumors (Bielchowsky, 1944; Doniach, 1958~. Summary Epidemiological Evidence. Although studies that focused on mortality from thyroid cancer showed no association of the disease with dietary iodine, a large series of autopsies from Colombia and a study of cancer incidence in Iceland and Scotland, based on histology-specific analyses, suggested that the risk of follicular thyroid carcinoma may be increased in iodine-deficient populations. In the Iceland/Scotland study, investi- gators also found a higher incidence of papillary carcinoma in the popula- tion with high dietary iodine intake. However, the relationship between iodine and thyroid cancer should be studied further before firm conclu- sions can be drawn. Epidemiological studies provide no clear evidence that the risk of cancers of the breast, ovary, and endometrium are related to dietary iodine deficiency. Experimental Evidence. Experimentally induced iodine deficiency seems to predispose rats to the development of preneoplastic and neo- plastic lesions in mammary tissue and to reduce the induction time of chemically induced mammary and thyroid tumorse 10-16

178 DIET, NUTRITION, AND CANCER Conclusion = Although limited epidemiological and laboratory evidence suggests that iodine deficiency is associated with an increased risk for thyroid cancer in humans, the evidence is not conclusive. MOLYBDENUM Epidemiolo~ical Evidence A few reports have indirectly implicated molybdenum deficiency in the etiology of cancer, especially cancer of the esophagus. In China, the Coordinating Group for Research on Etiology of Esophageal Cancer in North China (1975) and Yang (1980) reported that correlation analyses by county have shown an inverse association of esophageal cancer with the levels of molybdenum and a variety of other minerals in the soil. Molybdenum levels in hair were low in areas at high risk for this cancer. Low levels of molybdenum in the soil have also been observed in a region of Africa with high mortality rates from esophageal cancer (Burrell et al., 1966~. Fur- thermore, low levels of molybdenum in water supplies have been correlated with excess esophageal cancer mortality in the United States (Berg et _., 1973~. In areas of China at high risk for esophageal cancer, supplementation of the soil with ammonium molybdate has been observed to increase the molybdenum and ascorbic acid content of locally produced grains and vegetables and to decrease their nitrate and nitrite concentration (Luo _ al., 1981~. The investigators have proposed that high ascorbic acid and decreased nitrate and nitrite content of vegetables and grains could decrease the high incidence of esophageal cancer in these areas. Experimental Evidence Luo _ al. (1981) studied the effect of molybdenum supplementation on the induction of tumors by N-nitrososarcosine in the esophagus and fore- stomach of Sprague-Dawley rats. They observed that tumor incidence in the group supplemented with molybdenum (2 mg/liter drinking water) was lower than that in the control group, whose diet contained a molybdenum concentration of 26 ~g/kg diet. Molybdenum in the form of molybdenum oxide was shown to induce a significant increase in the number of lung adenomas in Strain A mice (Stoner _ al., 1976~. Molybdenum as potassium molybdate and ammonium molybdate was positive in Bacillus subtilus rec assay (Nishioka, 1975~. Nishioka (1975) also noted the mutagenicity of ammonium molybdate in Escherchia colt. 10-17

Minerals 179 Summary Epidemiological Evidence. In a few studies, investigators have found an inverse correlation between molybdenum levels in the soil and water and the risk of esophageal cancer, especially in China. Supple- mentation of molybdenum-deficient soil in high risk areas of China has been observed to increase the ascorbic acid content and lower the ni- trate content of locally grown plants and grains, and is therefore being considered as a means of reducing the risk of esophageal cancer. Experimental Evidence. Data from one report of laboratory experi- ments suggest that molybdenum supplementation of the diet may reduce the incidence of nitrosamine-induced tumors of the esophagus and forestomach. Conclusion The epidemiological and laboratory evidence is too meager to assess the validity of the associations suggested by the studies summarized above. CADMIUM Regarded only as a toxic substance for many years, cadmium is now beginning to be recognized as an element with a possible physiological function (Schwarz, 1977~. Market Basket Surveys conducted by the Food and Drug Administration indicate that the per capita intake of cadmium in the United States ranged from 26 to 61 ~g/day during 1968-1974 (Mahaffey et al., 1975~. The tolerable weekly intake for cadmium established by a FAD/WHO Expert Committee is from 400 to 500 ~g/week (World Health Organization, 1972~. Epidemiological Evidence In a correlation analysis based on cancer mortality by state and trace element content of the water supplies in 10 river basins of the United States, Berg and Burbank (1972) found direct associations be- tween cadmium levels and mortality from myeloma, lymphoma, and cancers at several other sites, including the mouth and pharynx, the esophagus, the large intestine, the larynx, the lung, the breast (female), and the bladder. Four other trace elements (arsenic, beryllium, nickel, and lead) were also directly associated with cancer, but chromium, cobalt, and iron were not. Schrauzer _ al. (1977a,b) correlated estimated per capita cad- mium intakes with cancer mortality rates in 27 countries. They found significant direct associations with leukemia and cancers of the intestine, female breast, uterus, prostate, and skin, and an inverse 10-18

180 DIET, NUTRITION, AND CANCER association with liver cancer. A similar analysis, based on the cad- mium concentration in pooled blood samples and cancer mortality in 19 U.S. states, yielded significant direct correlations for uterine cancer and stomach cancer in females. Schrauzer and colleagues suggested that cadmium may act as a selenium antagonist to prevent its uptake and lower its physiological activity as an anticarcinogen. Kolonel (1976) reported the results of a case-control study in which the combined exposure to cadmium from three sources (diet, cigarette smoking, and workplace) was associated with increased risk for renal cancer. In studies based on occupational exposure (Adams et al., 1969; Kipling and Waterhouse, 1967; Lemen et al., 1976; Potts, 176557 investigators have observed associations between exposure to cadmium and prostate cancer. However, the main source of exposure to cadmium for the general population is diet (Friberg et al., 1974), and a case-control study of prostate cancer that included dietary as well as occupational exposure (Kolonel and Winkelstein, 1977) failed to confirm this association between cadmium and prostate cancer. Experimental Evidence Carcinogenicity. Except for one long-term study in which Schroeder et al. (1964, 1965) observed no carcinogenic effect in mice given cad- mium at 5 mg/liter drinking water, no studies have been conducted in laboratory animals to determine the effect of dietary cadmium on carcinogenicity. Intramuscular injection of cadmium powder induced sarcomas in hooded rats (Heath et al., 1962~. Subcutaneous injections of cadmium sulfide, cadmium oxide, cadmium sulfate, or cadmium chloride induced sarcomas and Leydig cell tumors in Wistar rats of the Chester Beatty strain (WI/Cbi) (Haddow _ al., 1964; Kazantzis and Hanbury, 1966; Roe et al., 1964~. Intratesticularly administered cadmium chloride also induced teratomas in White Leghorn cockerels (Guthrie, 1964) and sarcomas in Wistar rats and albino mice (Gunn et al., 1963, 1964, 1967~. Mutagenicity and Related Tests. Sirover and Loeb (1976) found that various salts of cadmium decreased the fidelity of avian myeloblastosis virus (AMV)/DNA polymerase for replication of synthetic polynucleotide templates. Cadmium salts were mutagenic to Escherichia cold (Yagi and Nishioka, 1977) and positive in rec assay in Bacillus subtilis (Nishioka, 1975~. Shiraishi _ al. (1972) found that in vitro treatment of human_ lymphocytes with cadmium sulfide induced chromosome aberrations. Casto _ al. (1976) reported that cadmium (II) induced the formation of morpho- logically altered colonies in Syrian hamster fetal cells. Summary Epidemiological Evidence. The effect of dietary cadmium on cancer has been examined in only a few epidemiological studies. The results of 10-19

Dineros 181 three studies suggested that ingestion of cadmium in food or drinking water is associated with an increased risk of cancer, but another study did not confirm these findings. Occupational exposure to cadmium has been associated with an increase in the risk of renal and prostate cancer. Experimental Evidence. Data from one laboratory experiment suggest that cadmium given in drinking water is not carcinogenic in mice, whereas intramuscular and subcutaneous injections of cadmium salts induce cancer in rats and mice. Some salts of cadmium induce mutations in bacteria and chromosome aberrations in human lymphocytes in culture. The implications of the latter findings for the effect of dietary exposure to cadmium are not clear. Conclusion The evidence from epidemiological and laboratory studies does not permit any fits conclusions to be drawn about the effects of dietary exposure to cadmium. ARSENIC Arsenic is considered to be an essential element for growth in animals (Schwarz, 19771. Small amounts of this element are widely dis- tributed throughout the soils and waters of the world, and trace amounts occur in foods (especially seafood) and in some meats and vegetables. Arsenic may be present in food as a contaminant or as the unintentional residue of calcium arsenate or lead arsenate, which are used as insecti- cides, particularly on fruits and potatoes. A Market Basket Survey of 28 cities conducted by the Food and Drug Administration (FDA) during 1969- 1970 revealed that arsenic levels in dairy products were less than 0.1 mg/kg, but ranged from 0.1 to 2.6 mg/kg in meat, fish, and poultry (Corneliussen, 1972~. In the most recent published survey (for FY 1977), arsenic was detected in 45 of 300 (15%) food composites in amounts rang- ing between 0.02 and 0.83 mg/kg (U.S. Food and Drug Administration, 1980~. In one study of selected trace elements in 727 samples of U.S. surface waters, the concentration of arsenic ranged from <10 to 1,100 g/liter (Durum et al., 1971~. In river waters, the median concentration of arsenic was less than 10 ~g/liter. The daily intake of arsenic in the United States was reported to average 63 ~g/day between 1965 and 1970, 10 ~g/day in 1973, and 21 ~g/day in 1974 (Mahaffey et al., 1975~. Because of the variations in individual susceptibility to the tox- icity of arsenic and differences in toxicity of the various chemical forms of arsenic, it is difficult to estimate the average tolerable level for arsenic. No provisional tolerable daily intake has been established for arsenic by the World Health Organization. 10-20

182 DIET, NUTRITION, AND CANCER Epidemiological Evidence Most of the epidemiological evidence for the carcinogenicity of arsenic has been obtained in studies of lung cancer among workers occupationally exposed to inorganic arsenic by inhalation. In addition, several clinical reports have recorded observations of an unexpectedly high frequency of skin cancer among patients treated with inorganic arsenic drugs (e.g., Fowler's solution). Neither of these sources of exposure is dietary. Water supplies may contain arsenic, and the consumption of contami- nated water has also been associated with an increased risk for skin cancer in certain regions of the world. For example, studies in Taiwan have shown a direct relationship between the arsenic content of well water and the prevalence of skin cancer in the population drinking the water (Tseng, 1977; Tseng et al., 1968~. Epidemiological literature on cancer risk associated with occupa- tional, medicinal, and drinking water sources of exposure to arsenic has been reviewed in publications by the International Agency for Research on Cancer (1973, 1980a) and the National Academy of Sciences (1977a,b; 1980a). The occurrence of cancers of the skin, lung, and liver (hemangioendo- theliomas) in association with clinical evidence of chronic arsenism has been reported among vineyard workers in the Federal Republic of Germany and in France (Gary et al., 1963; Latarjet et al., 1964; Roth, 1957a,b). The workers had been exposed to arsenic both from inhalation of arsenical pesticides and from ingestion of contaminated wine. These reports suggest the possibility that a carcinogenic risk resulted from the ingestion of the wine. On the other hand, Nelson et al. (1973) found no increased risk for total cancer mortality or for lung cancer specifically in a cohort of residents in the State of Washington who had consumed apples from orchards treated with lead arsenate sprays. (There was also no increase among the workers who applied the sprays.) Moreover, ingestion of arsenic-contaminated foods in Japan, including powdered milk and soy sauce, has not been associated with any increased occurrence of cancer (Tsuchiya, 1977~. Experimental Evidence Carcinogenicity. Hueper and Payne (1962) exposed rats and C57BL mice from the age of 2 months to 15 months to a 0.0004% solution of arsenic in 127 aqueous ethanol through drinking water. the incidence of tumors in the treated group was no greater than that in the untreated controls. The tumor incidence in Swiss mice receiving 0.01% was similar to that of the control mice (Baron) _ al., 19633. In another study, Rockland all- purpose mice fed potassium arsenite at 169 Agog diet for 48 weeks and also exposed to this chemical by skin painting failed to develop more tumors than did the control animals (Boutwell, 1963~. 10-2 1

Minerals 183 In rats exposed daily to 10 mg of lead arsenate or calcium arsenate for 2 years, there was no increase in the incidence of tumors (Fairhall and Miller, 1941~. Byron _ al. (1967) similarly reported no evidence of carcinogenicity in a 2-year study in which Osborne-Mendel rats were fed sodium arsenite (which provided arsenic at 0-250 Agog diet) or sodium arsenate (which provided arsenic at O to 440 Agog diet). In dogs, sodium arsenite or sodium arsenate fed at levels of 5, 25, 50, and 125 Agog diet for 2 years produced no increase in the incidence of tumors (Byron et al., 1967~. Cocarcinogenicity. Arsenic has also been evaluated as a cocarcinogen, l but the results were negative when tested in combination with urethane, DMBA, and _-nitrosodiethylamine (Furst, 1977~. Mutagenicity. Rossman _ al. (1977) reported that sodium arsenite significantly decreased the survival of wild type Escherichia cold (WP) after irradiation, suggesting that it inhibits one or more steps in the postreplication DNA repair pathways. Arsenic (III) yielded positive results in Bacillus subtilis rec assay (Nishioka, 1975~. It has also _. been shown to transform Syrian hamster cells in vitro and to enhance the susceptibility of these cells to transformation by simian adenovirus (Casto et al., 1976~. Chromosome breakage in leukocytes of humans exposed to arsenic com- pounds was reported by Petres and Berger (1972) and Petres and Hundeiker (19683. Analysis of lymphocytes from exposed patients indicated that frequent chromosome aberrations occurred even decades after the last exposure (Petres et al., 1970, 1977~. Paton and Allison (1972) reported that sodium arsenite and acetylarsan induced chromosome aberrations in diploid fibroblasts of humans. Nordenson _ al. (1978) reported that exposure to arsenic com- bined with cigarette smoking significantly enhanced the incidence of chromosome aberrations in the lymphocytes of smelter workers, compared to the incidence for nonsmoking smelter workers exposed to arsenic alone. The authors speculated that the chromosome aberrations may have been initiated by smoking or by some other agent in the workplace en- vironment, and that exposure to arsenic may have inhibited their repair. Summary and Conclusions Arsenic is unique among the various agents covered in this report in that it has been associated with cancer in humans but not in laboratory animals. Epidemiological Evidence. There is good evidence that drinking water . . , heavily contaminated with arsenic increases the risk of skin cancer in humans in some parts of the world, and some evidence that the risk of lung cancer is increased by inhaling arsenic in occupational settings. 10-22

184 DIET, NUTRITION,AND CANCER However, the reported epidemiological studies do not provide sufficient information to determine the effects of the normally low levels of dietary arsenic on cancer risk. Experimental Evidence. Arsenic does not appear to induce tumors in laboratory animals despite extensive testing in animals of various spe- cies. It is possible that humans are more sensitive to the carcinogenic effects of arsenic and that the appropriate animal species, strain, dosage schedule, compound, or the route of exposure have not yet been identified. LEAD Although a requirement for trace amounts of lead (29 ng/g diet) has recently been demonstrated in rats for the maintenance of growth, reproduction, and hemopoiesis (Reichlmayr-Lais and Kirchgessner, 1981), it is not known to be essential to human nutrition. Humans are exposed to oxides and salts of lead through various environmental sources such as automobile exhausts, atmospheric dust, drinking water, food, and paint, all of which contribute to the total body burden of lead. The dietary intake of lead in the United States was estimated to be 60 ~g/person/day in 1973 and 19 ~g/day in 1974 (Mahaffey et al., 1975~. Epidemiological Evidence Berg and Burbank (1972) correlated the levels of eight trace ele- ments in the water supplies of 10 major river basins in the United States with corresponding cancer mortality rates for white and nonwhite males and females. There were significant correlations for five of the eight elements. Among these was lead, which was directly correlated with cancers of the stomach, small intestine, large intestine, ovary, and kidney, as well as with myeloma, all lymphomas, and all leukemias. Nelson _ al. (1973) found no increased risk for cancer mortality in a population that consumed apples from orchards treated with lead arsenate spray; thus, neither lead nor arsenic in this form was implicated as a carcinogen. Occupational exposure to lead has not been conclusively associated with any form of cancer. Most studies have shown no association (Dingwall-Fordyce and Lane, 1963; Robinson, 1976), although the results of the study by Cooper and Gaffey (1975) can be interpreted as either demonstrating or not demonstrating a relationship, depending on the method of analysis used (International Agency for Research on Cancer, 1980b; Kang et al., 1980~. Experimental Evidence Carcinogenicity. The number of renal tumors that developed in Swiss mice fed 0.1Z lead subacetate was significantly higher than that observed 10-23

Minerals 185 in untreated controls (Van Esch and Kroes, 1969~. There were also signif- icantly more renal tumors in Wistar rats fed lead acetate, as compared to controls (Mao and Molnar, 1967; Shakerin and Paloucek, 1965; Van Esch et al., 1962; Zawirska and Medras, 1968~. Lead nitrate and lead powder were found not to be carcinogenic when fed to Long Evans and Fischer rats, respectively (Furst et al., 1976; Schroeder et al., 1970~. In several other feeding studies, the majority of rats developed renal tumors; however, these studies did not include concurrent untreated control animals (Boyland et al., 1962; Bass et al., 1967; Ito, 1973; Ito et al., 1971). Mutagenicity. Lead (II) reacted with phosphate groups of DNA bases to yield stable complexes (Venugopal and Luckey, 1978; Sissoeff et al., 1976). Sirover and Loeb (1976) reported that 4 mM lead chloride diminished the fidelity of DNA polymerase. Lead acetate was found to be negative in the Ames test and E. cold pal A assay for DNA-modifying effects (Rosenkranz and Poirier, T9793 ; in the host-mediated assay in Swiss Webster mice with Ames Salmonella strains and Saccharomyces cerevisiae D3 as indicator organisms (Simmon et al., 1979~; in the mitotic recombination assay with Saccharomyces cerev~siae D3 (Simmon, 1979~; and in the Bacillus subtilis rec assay (Kada _ al., 1980; Nishioka, 1975~. Bone marrow cells from rats treated with 1% lead acetate in drinking water had more chromatic gaps, fragments, deletions, and translocations than did the same cells from controls (Teodorescu and Calugaru, 1972~. Bauchinger and Schmid (1972) reported that there were more achromatic lesions in Chinese hamster ovary cells treated with 1 mM lead acetate than in untreated controls. Morphological transformations of Syrian hamster embryo cells were observed after exposure to lead acetate (1-2.5 g/liter medium), which produced fibrosarcomas in Syrian hamsters (DiPaolo _ al., 1978~. Lead acetate (10-2 mM) induced achromatic lesions and chromatic and isochromatid breaks (Beck and Obe, 1974), but not sister chromatic exchanges in leukocytes from humans (Beck and Obe, 1975~. Summary Epidemiological Evidence. There is very little epidemiological evidence linking dietary lead to the risk of cancer in humans. The only study that correlated lead levels in drinking water supplies and cancer mortality suggested that lead increased the risk of cancer. Exposure to lead in industrial settings has not been clearly associated with an increased risk for any form of cancer. Experimental Evidence. The ingestion of high levels of lead compounds induces renal tumors in mice and rats. 10-24

186 DIET, NUTRITION, AND CANCER Conclusion On the basis of experiments in animals, it would seem that exposure to large amounts of some compounds of lead may pose a carcinogenic risk to humans. However, there is little direct epidemiological evidence to support this conclusion. 10-25

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194 DIET, NUTRITION, AND CANCER Lo, L. W., J. Koropatrick, and H. T. Stich. 1978. The mutagenicity and cytotoxicity of selenite and selenate for normal and DNA repair- deficient human fibroblasts. Mutat. Res. 49:305-312. Luo, X. M., H. J. Wei, G. G. Hu, A. L. Shang, Y. Y. Liu, S. M. Lu, and S. P. Yang. 1981. Molybdenum and esophageal cancer in China. Fed. Proc. Fed. Am. Sac. Exp. Biol. 40:928. Abstract 3962. MacKinnon, A. E., and J. Bancewicz. 1973. Sarcoma after injection of intramuscular iron. Br. Med. J. 2:277-279. Mahaffey, K. R., P. E. Corneliussen, C. F. Jelinek, and T. A. Fiorino. 1975. Heavy metal exposure from foods. Environ. Health Perspect. 12:63-69. Mao, P., and J. J. Molnar. 1967. The fine structure and histochemistry of lead-induced renal tumors in rats. Am. J. Pathol. 50:571-603. Medina, D., and F. Shepherd. 1980. Selenium-mediated inhibition of mouse mammary tumorigenesis. Cancer Lett. 8:241-245. Minkel, D. T., P. J. Dolhun, B. L. Calhoun, L. A. Saryan, and D. H. Petering. 1979. Zinc deficiency and growth of Ehrlich ascites tumor. Cancer Res. 39:2451-2456. Nakamuro, K., K. Yoshikawa, Y. Sayato, H. Kurata, M. Tonomura, and A. Tonomura. 1976. Studies on selenium-related compounds. V. Cyto- genetic effect and reactivity with DNA. Mutat. Res. 40:177-183. National Academy of Sciences. 1971. Selenium in Nutrition. A report of the Subcommittee on Selenium, Committee on Animal Nutrition. National Academy of Sciences, Washington, D.C. 79 pp. National Academy of Sciences. 1977a. Arsenic. A report of the Com- mittee on Medical and Biologic Effects of Environmental Pollutants. National Academy of Sciences, Washington, D.C. 332 pp. National Academy of Sciences. 1977b. Drinking Water and Health. A report of the Safe Drinking Water Committee, National Academy of Sciences, Washington, D.C. 939 pp. National Academy of Sciences. 1980a. Drinking Water and Health, Volume 2. A report of the Safe Drinking Water Committee. National Academy Press, Washington, D.C. 393 pp. National Academy of Sciences. 1980b. Pp. 162-163 in Recommended Dietary Allowances, 9th edition. A report of the Food and Nutrition Board. National AcademY of Sciences, Washington, D.C. 10-3 3

Minerals 19S Nelson, A. A., 0. G. Fitzhugh, and H. 0. Calvery. 1943. Liver tumors following cirrhosis caused by selenium in rats. Cancer Res. 3:230-236. Nelson, W. C., M. H. Lykins, J. Mackey, V. A. Newill, J. F. Finklea, and D. I. Hammer. 1973. Mortality among orchard workers exposed to lead arsenate spray: A cohort study. J. Chronic Dis. 26:105-118. Newman, J. A., V. E. Archer, G. Saccomanno, M. Kuschner, 0. Auerbach, R. D. Grondahl, and J. C. Wilson. 1976. Histologic types of bronchogenic carcinoma among members of copper-mining and smelting communities. Ann. N. Y. Acad. Sci. 271:260-268. Nishioka, H. 1975. Mutagenic activities of metal compounds in bacteria. Mutat. Res. 31:185-189. Nordenson, I., G. Beckman, L. Beckman, and S. Nordstrom. 1978. Occu- pational and environmental risks in and around a smelter in northern Sweden. II. Chromosomal aberrations in workers exposed to arsenic. Hereditas 88:4 7-50. Paton, G. R., and A. C. Allison. 1972. Chromosome damage in human cell cultures induced by metal salts. Mutat. Res. 16:332-336. Pendergrast, W. J., B. K. Milmore, and S. C. Marcus. 1961. Thyroid cancer and thyrotoxicosis in the United States: Their relation to endemic goiter. J. Chronic Dis. 13:22-38. Petering, H. G., H. H. Buskirk, and J. A. Crim. 1961. The effect of dietary mineral supplements of the rat on the antitumor activity of 3-ethoxy-2-oxobutyraldehyde bis~thiosemicarbazone). Cancer Res. 27:1115-1121. Petres, J., and A. Berger. 1972. [In German; English Summary.] The effect of inorganic arsenic on DNA-synthesis of human lymphocytes ~n vitro. Arch. De~atol. Forsch. 242:343-352. Petres, J., and M. Hundeiker. 1968. [In German; English Summary.] "Chromosome pulverization" induced in vitro in cell cultures by sodium diarsenate. Arch. Klin. Exp. Dermatol. 231:366-370. Petres, J., K. Schmid-Ullrich, and U. Wolf. 1970. [In Ge`=an.] Chromosomenaberrationen an menschlichen Lymphozyten bei chronischen Arsenschaden. Dtsch. Med. Wochenschr. 95:79-80. Petres, J., D. Baron, and M. Hagedorn. 1977. Effects of arsenic cell metabolism and cell proliferation: Cytogenetic and biochemical studies. Environ. Health Perspect. 19:223-227. 10-34

196 DIET, NUTRITION, AND CANCER Pimentel, J. C., and A. P. Menezes. 1977. Liver disease in vineyard sprayers. Gastroenterology 72:275-283. Poswillo, D. E., and B. Cohen. 1971. Inhibition of carcinogenesis by dietary zinc. Nature 231:447-448. Potts, C. L. 1965. Cadmium proteinuria--the health of battery workers exposed to cadmium oxide dust. Ann. Occup. Hyg. 8:55-61. Prasad, A. S. 1978. Trace Elements and Iron in Human Metabolism. Plenum Publishing Corp., New York and London. 392 pp. Reichlmayr-Lais, A. M., and M. Kirchgessner. 1981. [In German; English Summary.] Essentiality of lead for growth and metabolism. Z. Tierphysiol. Tierernaehr. Futtermittelkd. 46:1-8. Robinson, C. E. G., D. N. Bell, and J. H. Sturdy. 1960. Possible association of malignant neoplasm with iron-dextran injection. Br. Med. J. 2:648-650. Robinson, T. R. 1976. The health of long service tetraethyl lead workers. J. Occup. Med. 18:31-40. Roe, F. J. C., C. E Dukes, K. M. Cameron, R. C. B. Pugh, and B. C. V. Mitchley. 1964. Cadmium neoplasia: Testicular atrophy and Leydig cell hyperplasia and neoplasia in rats and mice following the subcutaneous injection of cadmium salts. Br. J. Cancer 18:674-681. Rosenkranz, H. S., and L. A. Poirier. 1979. Evaluation of the muta- genicity and DNA Modifying activity of carcinogens and noncarcino- gens in microbial systems. J. Natl. Cancer Inst. 62:873-892. Rossman, T. G., M. S. Meyn, and W. Troll. 1977. Effects of arsenite on DNA repair in Escherichia coli. Environ. Health Perspect. 19:229-233. Roth, F. 1957a. [In German.] Uber die Spatfolgen des chronischen Arsenismus der Moselwinzer. Dtsch. Med. Wochenschr. 82:211-217. Roth, F. 1957b. [In German; English Summary.] Arsen-Leber-Tumoren (Hamangioendotheliom). Z. Krebsforsch. 61:468-503. Ruddell, W. S. J., E. S. Bone, M. J. Hill, and C. L. Walters. 1978. Pathogenesis of gastric cancer in pernicious anaemia. Lancet 1:52; 523. Schrauzer, G. N. 1976. Selenium and cancer: A review. Bioinorg. Chem. 5:27S-281. 10-3 5

Minerals 197 Schrauzer, G. N. 1979. Trace elements in carcinogenesis. Pp. 219-244 in H. H. Draper, ed. Advances in Nutritional Research, Volume 2. Plenum Publishing Corp., New York and London. Schrauzer, G. N., D. A. White, and C. J. Schneider. 1977a. Cancer mortality correlation studies--III. Statistical associations with dietary selenium intakes. Bioinorg. Chem. 7:23-34. Schrauzer, G. N., D. A. White, and C. J. Schneider. 1977b. Cancer mortality correlation studies--IV. Associations with dietary intakes and blood levels of certain trace elements, notably Se-antagonists. Bioinorg. Chem. 7:35-56. Schrauzer, G. N., D. A. White, and C. J. Schneider. 1978. Selenium and cancer: Effects of selenium and of the diet on the genesis of spontaneous mammary tumors in virgin inbred female C3H/St mice. Bioinorg. Chem. 8:387-396. Schroeder, H. A., and M. Mitchener. 1971a. Scandium, chromium (VI), gallium, yttrium, rhodium, palladium, indium in mice: Effects on growth and life span. J. Nutr. 101:14 31-14 38. Schroeder, H. A., and M. Mitchener. 1971b. Selenium and tellurium in rats: Effects on growth, survival, and tumors. J. Nutr. 101:1531-1540. Schroeder, H. A., and M. Mitchener. 1972. Selenium and tellurium in mice: Effects on growth, survival and tumors. Arch. Environ. Health 24 :66-71. Schroeder, H. A., J. J. Balassa, and W. H. Vinton, Jr. 1964. Chro- mium, lead, cadmium, nickel and titanium in mice: Effect on mortality, tumors and tissue levels. J. Nutr. 83:239-250. Schroeder, H. A., J. J. Balassa, and W. H. Vinton, Jr. 1965. Chromium, cadmium and lead in rats: Effects on life span, tumors and tissue levels. J. Nutr. 86:51-66. Schroeder, H. A., M. Mitchener, J. J. Balassa, M. Kanisawa, and A. P. Nason. 1968. Zirconium, niobium, antimony and fluorine in mice: Effect on growth, survival and tissue levels. J. Nutr. 95:95-101. Schroeder, H. A., M. Mitchener, and A. P. Nason. 1970. Zirconium, niobium, antimony, vanadium and lead in rats: Life term studies. J. Nutr. 100:59-68. Schwartz, M. K. 1975. Role of trace elements in cancer. Cancer Res. 35:3481-3487. 10-36

198 DIET, NUTRITION, AND CANCER Schwarz, K. 1977. Essentiality versus toxicity of metals. Pp. 3-22 in S. S. Brown, ed. Clinical Chemistry and Chemical Toxicology of Metals. Elsevier/North-Holland Biomedical Press, Amsterdam, New York, and Oxford. Scott, D., and A. Theologides. 1974. Hepatoma, erythrocytosis and increased serum er~ythropoietin developing in long-standing hemo- chromatosis. Am. J. Gastroenterol. 61:206-211. Shakerin, M., and J. Paloucek. 1965. Intranuclear inclusions and renal tumors in rats fed lead subacetate. Lab. Invest. 14:592. Abstract. Shamberger, R. J. 1970. Relation of selenium to cancer. I. Inhi- bitory effect of selenium on carcinogenesis. J. Natl. Cancer Inst. 44:931-936. Shamberger, R. J., and D. V. Frost. 1969. Letter to the Editor: Possible protective effect of selenium against human cancer. Can. Med. Assoc. J. 100:682. Shamberger, R. J., and C. E. Willis. 1971. Selenium distribution and human cancer mortality. CRC Crit. Rev. Clin. Lab. Sci. 2:211-221. Shamberger, R. J., E. Rukovena, A. K. Longfield, S. A. Tytko, S. Deodhar, and C. E. Willis. 1973. Antioxidants and cancer. I. Selenium in the blood of normals and cancer patients. J. Natl. Cancer Inst. 50:863-870. Shamberger, R. J., S. A. Tytko, and C. E. Willis. 1976. Antioxidants and cancer. Part VI. Selenium and age-adjusted human cancer mortality. Arch. Environ. Health 31:231-235. Shamberger, R. J., K. D. Beaman, C. L. Corlett, and B. L. Kasten. 1978. Effect of selenium and other antioxidants on the mutagenicity of malonaldehyde. Fed. Proc. Fed. Am. Sac. Exp. Biol. 37:261. Abstract 265. Shiraishi, Y., H. Kurahashi, and T. H. Yosida. 1972. Chromosomal aberrations in cultured human leukocytes induced by cadmium sulfide. Proc. Jpn. Acad. 48:133-137. Simmon, V. F. 1979. In vitro assays for recombinogenic activity of chemical carcinogens and related compounds with Saccharomyces cerevisiae D3. J. Natl. Cancer Inst. 62:901-909. Simmon, V. F., H. S. Rosenkranz, E. Zeiger, and L. A. Poirier. 1979. Mutagenic activity of chemical carcinogens and related compounds in the intraperitoneal host-mediated assay. J. Natl. Cancer Inst. 62:911-918. 10-37

Minerals 199 Sirover, M. A., and L. A. Loeb. 1976. Infidelity of DNA synthesis In vitro: Screening for potential metal mutagens or carcinogens. Science 194:1434-1436. Sissoeff, I., J. Grisvard, and E. Guille. 1976. Studies on metal ions-DNA interactions: Specific behaviour of reiterative DNA sequences. Prog. Biophys. Mol. Biol. 31:165-199. Stadel, B. V. 1976. Dietary iodine and risk of breast, endometrial, and ovarian cancer. Lancet 1:890-891. Steinherz, P. G., V. C. Canale, and D. R. Miller. 1976. Hepatocellular carcinoma, transfusion-induced hemochromatosis and congenital hypo- plastic anemia (Blackfan-Diamond Syndrome). Am. J. Med. 60:1032- 1035. Stocks, P., and R. I. Davies. 1964. Zinc and copper content of soils associated with the incidence of cancer of the stomach and other organs. Br. J. Cancer 18:14-24. Stoner, G. D., M. B. Shimkin, M. C. Troxell, T. L. Thompson, and L. S. Terry. 1976. Test for carcinogenicity of metallic compounds by the pulmonary tumor response in strain A mice. Cancer Res. 36:1744-1747 Strain, W. H., E. G. Mansour, A. Flynn, W. J. Pories, A. J. Tomaro, and 0. A. Hill, Jr. 1972. Letter to the Editor: Plasma-zinc concentration in patients with bronchogenic cancer. Lancet 1:1021-1022. Sunderman, F. W., Jr. 1977. Metal carcinogenesis. Pp. 257-295 in R. A. Coyer and M. A. Mehlman, eds. Toxicology of Trace Elements. Hemisphere Publishing Corporation, Washington and London. Sussman, E. B., I. Nydick, and G. F. Gray. 1974. Hemangioendothelial sarcoma of the liver and hemochromatosis. Arch. Pathol. 97:39-42. Sweeney, G. D., K. G. Jones, F. M. Cole, D. Basford, and F. Krestynski. 1979. Iron deficiency prevents liver toxicity of 2,3,7,8-tetra- chlorodibenzo-p-dioxin. Science 204:332-335. Teodorescu, F., and A. Calugaru. 1972. [In Romanian; French Summary.] Modificdri cromozomiale produse ~n celulele maduvei osoase la goblanul alb ~n urma intoxicatiel cu acetat de plumb. Stud. Cercet. Biol. Seria Zool. 24:451-457. Thompson, H. J., and P. J. Becci. 1980. Selenium inhibition of N methyl-N-nitrosourea-induced mammary carcinogenesis in the rat. J. Natl. Cancer Inst. 65:1299-1301. 10-38

200 DIET, NUTRITION, AND CANCER Thomson, C. D., and M. F. Robinson. 1980. Selenium in human health and disease with emphasis on those aspects peculiar to New Zealand. Am. J. Clin. Nutr. 33:303-323. Tseng, W. P. 1977. Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic. Environ. Health Perspect. 19:109-119. Tseng, W. P., H. M. Chu, S. W. How, J. M. Fang, C. S. Lin, and S. Yeh. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl. Cancer Inst. 40:453-463. Tsuchiya, K. 1977. Various effects of arsenic in Japan depending on the type of exposure. Environ. Health Perspect. 19:35-42. U.S. Food and Drug Administration. 1980. Compliance Program Report of Findings, FY 1977. Total Diet Studies (Adult, 7320.73~. Bureau of Foods, Food and Drug Administration, Washington, D.C. [33] pp. Van Esch, G. J., and R. Kroes. 1969. The induction of renal tumours by feeding basic lead acetate to mice and hamsters. Br. J. Cancer 23:765-771. Van Esch, G. J., H. Van Genderen, and H. H. Vink. 1962. The incidence of renal tumours by feeding of basic lead acetate to rats. Br. J. Cancer 16:289-297. van Rensburg, S. J. 1981. Epidemiologic and dietary evidence for a specific nutritional predisposition to esophageal cancer. J. Natl. Cancer Inst. 67:243-251. Venugopal, B., and T. D. Luckey. 1978. Lead. Pp. 185-19S in Metal Toxicity in Mammals--2. Chemical Toxicity of Metals and Metalloids. Plenum Press, New York and London. Vitale, J. J., S. A. Broitman, E. Vavrousek-Jakuba, P. W. Rodday, and L. S. Gottlieb. 1978. The effects of iron deficiency and the quality and quantity of fat on chemically induced cancer. Adv. Exp. Med. Biol. 91:229-242. Volgarev, M. N., and L. A. Tscherkes. 1967. Further studies in tissue changes associated with sodium selenate. Pp. 179-184 in 0. H. Muth, ed. Symposium: Selenium in Biomedicine. First International Symposium. AVI Publishing Co., Westport, Conn. Wahner, H. W., C. Cuello, P. Correa, L. F. Uribe, and E. Gaitan. 1966. Thyroid carcinoma in an endemic goiter area, Cali, Colombia. Am. J. Med. 40:58-66. 10-39

Dineros 201 Waterhouse, J., C. Muir, P. Correa, and J. Powell, eds. 1976. Cancer Incidence in Five Continents, Volume 3. IARC Scientific Publica- tions No. 15. International Agency for Research on Cancer, Lyon, France. Williams, E. D., I. Doniach, O. Bjarnason, and W. Michie. 1977. Thyroid cancer in an iodide rich area. A histopathological study. Cancer 39:215-222. World Health Organization. 1972. Evaluation of certain food additives and the contaminants mercury, lead, and cadmium. Sixteenth Report of the Joint FAD/WHO Expert Committee on Food Additives. W.H.O. Tech. Rep. Ser. 505:1-32. Wynder, E. L., S. Hultberg, F. Jacobsson, and I. J. Bross. 1957. Environmental factors in cancer of the upper alimentary tract: A Swedish study with special reference to Plummer-Vinson (Paterson- Kelly) syndrome. Cancer 10:470-487. Yagi, T., and H. Nishioka. 1977. DNA damage and its degradation by metal compounds. Sci. Eng. Rev. Doshisha Univ. 18:63-70. Yamane, Y., and K. Sakai. 1973. Suppressive effect of concurrent administration of metal salts on carcinogenesis by 3' methyl-4- (dimethylamino~azobenzene, and the effect of these metals on aminoazo dye metabolism during carcinogenesis. Gann 64:563-573. Yang, C. S. 1980. Research on esophageal cancer in China: A review. Cancer Res. 40:2633-2644. Zawirska, B., and K. Medras. 1968. [In German.] Tumoren und Stor- ungen des Porphyrinstoffweschels bei Ratten mit chronischer experi- menteller Bleiintoxikation. Zentralbl. Allg. Pathol. Pathol. Anat. 111:1-12. 10-40

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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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