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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

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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

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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

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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

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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

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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

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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

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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

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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

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Minerals 191 Golden, M. H. N., B. E. Golden, P. S. E. Harland, and A. A. Jackson. 1978. Zinc and immunocompetence in protein-energy malnutrition. Lancet 1:1226-1227. Greeder, G. A., and J. A. Milner. 1980. Factors influencing the inhibitory effect of selenium on mice inoculated with Ehrlich ascites tumor cells. Science 209:825-827. Griffin, A. C. 1979. Role of selenium in the chemoprevention of cancer. Adv. Cancer Res. 29:419-442. Gunn, S. A., T. C. Gould, and W. A. D. Anderson. 1963. Cadmium- induced interstitial cell tumors in rats and mice and their prevention by zinc. J. Natl. Cancer Inst. 31:74 5-759. Gunn, S. A., T. C. Gould, and W. A. D. Anderson. 1964. Effect of zinc on cancerogenesis by cadmium. Proc. Soc. Exp. Biol. Med. 115 :653-657. Gunn, S. A., T. C. Gould, and W. A. D. Anderson. 1967. Specific response of mesenchymal tissue in cancerigenesis by cadmium. Arch. Pathol. 83:493-499. Guthrie, J. 1964. Histological effects of intra-testicular injections of cadmium chloride in domestic fowl. Br. J. Cancer 18:255-260. Gyorkey, F., K. W. Min. J. A. Huff, and P. Gyorkey. 1967. Zinc and magnesium in human prostate gland: Normal, hyperplastic and neoplastic. Cancer Res. 27:1348-1353. Haddow, A., F. J. C. Roe, C. E. Dukes, and B. C. V. Mitchley. 1964. Cadmium neoplasia: Sarcomata at the site of injection of cadmium sulphate in rats and mice. Br. J. Cancer 18:667-673. Harr, J. R., J. F. Bone, I. J. Tinsley, P. H. Weswig, and R. S. Yamamoto. 1967. Selenium toxicity in rats. II. Histopathology. Pp. 153-178 in O. H. Muth, ed. Symposium: Selenium in Biomedi- cine. First International Symposium. AVI Publishing Co., Westport, Conn. Harr, J. R., J. H. Exon, P. D. Whanger, and P. H. Weswig. 1972. Effect of dietary selenium on N-2-fluorenyl-acetamide(FAA)-induced cancer in vitamin E supplemented, selenium depleted rats. Clin. Toxicol. 5 :187-194. Hass, G. M., J. H. McDonald, R. Oyasu, H. A. Battifora, and J. T. Paloucek. 1967. Renal neoplasia induced by combinations of dietary lead subacetate and N-2-fluorenylacetamide. Pp. 377-412 in J. S. King, Jr., ed. Renal Neoplasia. Little, Brown Co., Boston. 10-30

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