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14—
Trace Elements

Trace elements (or trace metals) are minerals present in living tissues in small amounts. Some of them  are known to be nutritionally essential, others may be essential (although the evidence is only suggestive or incomplete), and the remainder are considered to be nonessential. Trace elements function primarily as catalysts in enzyme systems; some metallic ions, such as iron and copper, participate in oxidation-reduction reactions in energy metabolism. Iron, as a constituent of hemoglobin and myoglobin, also plays a vital role in the transport of oxygen.

All trace elements are toxic if consumed at sufficiently high levels for long enough periods. The difference between toxic intakes and optimal intakes to meet physiological needs for essential trace elements is great for some elements but is much smaller for others.

This chapter is a summary of the role of the following essential trace elements in the etiology and prevention of chronic diseases: iron, zinc, fluoride, selenium, copper, chromium, iodine, manganese, and molybdenum. Also discussed are aluminum, cadmium, mercury, arsenic, and lead; these elements have not been demonstrated to be essential for humans but were reviewed by the committee because they are frequently ingested as contaminants in food or water. Interactions between the various trace elements are also briefly considered.

Epidemiologic data on the relationship between many of the trace elements and the incidence of diseases such as cancer, cardiovascular disease, and hypertension are incomplete. Most such studies have focused on cadmium, chromium, and selenium. Furthermore, most of the evidence is not related to dietary exposure but focuses, for example, on inhalation exposure in the workplace. Data from animal feeding experiments are also incomplete. The committee identifies such gaps in knowledge and suggests directions for research.

Evidence Associating Trace Elements with Chronic Diseases

Iron

Iron is present in all body cells. As a component of hemoglobin and myoglobin, it functions as a carrier of oxygen in the blood and muscles. Because of iron losses during menstruation, women in their reproductive years require higher iron intakes than men. Therefore, the Recommended Dietary Allowance (RDA) for women 11 to 50 years of age is 18 mg/day, but for men 19 years and older is only 10 mg/day. Women have difficulty achieving this high intake, because they generally have a relatively low caloric intake, and the usual U.S. diet provides only 6 to 7 mg of iron per 1,000 kcal. Since the need for iron is greater during periods of



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Page 367 14— Trace Elements Trace elements (or trace metals) are minerals present in living tissues in small amounts. Some of them  are known to be nutritionally essential, others may be essential (although the evidence is only suggestive or incomplete), and the remainder are considered to be nonessential. Trace elements function primarily as catalysts in enzyme systems; some metallic ions, such as iron and copper, participate in oxidation-reduction reactions in energy metabolism. Iron, as a constituent of hemoglobin and myoglobin, also plays a vital role in the transport of oxygen. All trace elements are toxic if consumed at sufficiently high levels for long enough periods. The difference between toxic intakes and optimal intakes to meet physiological needs for essential trace elements is great for some elements but is much smaller for others. This chapter is a summary of the role of the following essential trace elements in the etiology and prevention of chronic diseases: iron, zinc, fluoride, selenium, copper, chromium, iodine, manganese, and molybdenum. Also discussed are aluminum, cadmium, mercury, arsenic, and lead; these elements have not been demonstrated to be essential for humans but were reviewed by the committee because they are frequently ingested as contaminants in food or water. Interactions between the various trace elements are also briefly considered. Epidemiologic data on the relationship between many of the trace elements and the incidence of diseases such as cancer, cardiovascular disease, and hypertension are incomplete. Most such studies have focused on cadmium, chromium, and selenium. Furthermore, most of the evidence is not related to dietary exposure but focuses, for example, on inhalation exposure in the workplace. Data from animal feeding experiments are also incomplete. The committee identifies such gaps in knowledge and suggests directions for research. Evidence Associating Trace Elements with Chronic Diseases Iron Iron is present in all body cells. As a component of hemoglobin and myoglobin, it functions as a carrier of oxygen in the blood and muscles. Because of iron losses during menstruation, women in their reproductive years require higher iron intakes than men. Therefore, the Recommended Dietary Allowance (RDA) for women 11 to 50 years of age is 18 mg/day, but for men 19 years and older is only 10 mg/day. Women have difficulty achieving this high intake, because they generally have a relatively low caloric intake, and the usual U.S. diet provides only 6 to 7 mg of iron per 1,000 kcal. Since the need for iron is greater during periods of

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Page 368 rapid growth, children from infancy through adolescence, as well as pregnant women, may fail to consume sufficient iron to meet their needs. Iron absorption is affected by many factors. Heme iron is present in meats, poultry, and fish and is more efficiently absorbed than inorganic (nonheme) iron, which is found in plant as well as animal foods. Ascorbic acid facilitates the absorption of nonheme iron, but dietary fiber, phytates, and certain trace elements may diminish it. Food composition data provide no indicators concerning the efficiency with which the body absorbs iron from a given food. The publication Recommended Dietary Allowances (NRC, 1980) provides directions on how to calculate available iron. The availability of iron in the food supply has increased since 1909, chiefly because of the enrichment of flour and cereal products. The 1977-1978 Nationwide Food Consumption Survey (NFCS) indicates that on the average respondents of both sexes from 1 to 18 years old and females from 19 to 64 years old failed to meet their RDA for iron (USDA, 1984). The Continuing Survey of Food Intakes of Individuals (CSFII) conducted in 1985 and 1986 (USDA, 1987a,b) supports these findings. By itself, however, failure to meet the RDA is not an indicator of poor iron status. Using data from the National Health and Nutrition Examination Survey (NHANES II), conducted from  1976 to 1980, an expert scientific group of the Federation of American Societies for Experimental Biology (FASEB) assessed iron status (LSRO, 1984a). Five indicators in three different models were used in the assessment. A relatively high prevalence of impaired iron status was found in children 1 to 2 years old, males 11 to 14 years old, and females 25 to 44 years old. Among those whose incomes were below poverty level, impaired iron status was highest in children 1 to 5 years old and females 25 to 54 years old (LSRO, 1984a). Cancer Epidemiologic and Clinical Studies Iron deficiency is a risk factor for the Plummer-Vinson (Paterson-Kelly) syndrome, which was once common in parts of Sweden but has been almost eliminated through improved nutritional status, especially with regard to dietary iron and vitamins (Larsson et al., 1975; Wynder et al., 1957). This condition is associated with an increased risk for cancers of the upper alimentary tract, especially the esophagus and stomach, suggesting that the underlying iron deficiency might be one of the factors that contribute to the occurrence of these cancers. However, epidemiologic studies have not implicated low dietary iron intake per se as a risk factor for cancers at these sites (Schottenfeld and Fraumeni, 1982). In a correlation analysis of nutrition survey data and cancer mortality rates for 11 regions of the Federal Republic of Germany, Böing et al. (1985) found a positive association between estimated iron intake and mortality from colorectal and pancreatic cancer in men and from  gallbladder cancer in women. In a prospective cohort of 21,513 Chinese men in Taiwan, ferritin levels were considerably higher in men over age 50 who developed cancer, especially primary hepatocellular carcinoma (PHC), than in controls without cancer, whereas serum transferrin levels were lower in the men who developed cancer (excluding PHC) (Stevens et al., 1986). These findings probably reflect an association of cancer risk with increased body iron stores, although iron stores were not directly assessed. Occupational inhalation exposure to iron oxides has been associated with an increased risk for lung cancer in hematite miners and foundry workers (Kazantzis, 1981). In these occupational settings, however, there were other exposures to carcinogens, including ionizing radiation, polycyclic aromatic hydrocarbons (PAHs), and cigarette smoke. Thus, the increased cancer risk cannot be attributed specifically to iron (Doll, 1981; Kazantzis, 1981). Clinical studies of patients with idiopathic hemochromatosis, a condition that includes abnormal deposition of iron in the liver and frequently cirrhosis, show a highly increased risk for hepatocellular carcinoma (Ammann et al., 1980; Bomford and Williams, 1976; Strohmeyer et al., 1988). Overall, these studies in humans do not provide strong evidence for a role of iron  exposure, whether by diet or by other routes, in the etiology of human cancer. Animal Studies Iron-deficient rats given 1,2-dimethylhydrazine (DMH) developed neoplastic liver lesions within 4 months, compared to 6 months in an iron-sufficient group (Vitale et al., 1978). The authors noted that severe lack of iron appeared to promote carcinogenesis. The effect of iron deficiency on tumor growth and host survival was studied in BALB/c mice with transplanted Merwin Plasma Cell-II tumors (Ben-

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Page 369 bassat et al., 1981). Iron deficiency resulted in retardation of body growth and tumor growth in weanling mice, but not in adults. The reason for this difference in response was not determined. Mammary tumors induced by the intragastric administration of dimethylbenz[a]anthracene (DMBA) and fibrosarcomas induced by subcutaneous injections of methylcholanthrene (MCA) were studied in iron-deficient female Wistar rats (Webster, 1981). There was no difference in induction time, tumor site, total number of tumors, or incidence of metastases in the iron-deficient rats compared with controls. In this study, a lack of iron did not appear to inhibit carcinogenesis, as it did in the study by Benbassat et al. (1981). In a later study, albino iron-deficient rats were painted with 4NQO oral carcinogen and left untreated (Prime et al., 1986). These investigators also saw no difference in tumor development or epithelial dysplasia between the iron-deficient and iron-sufficient animals. Isolated perfused rabbit lung was used to investigate the effects of a cocarcinogen, ferric oxide, on the metabolism of benzo[a]pyrene (BaP) (Warshawsky et al., 1984). The data suggest that ferric oxide increased the production of dihydrodiols from BaP, which may be further metabolized to the ultimate carcinogenic forms. DBA-2 mice fed supplemental doses of iron (24 mg/kg body weight) and inoculated with L1210 cells eventually developed more tumor cells than did the controls. Animals treated at still higher levels of supplemental iron (250 mg/kg body weight) and inoculated with L1210 cells died sooner than untreated but inoculated controls (Bergeron et al., 1985). The authors concluded that high doses of supplemental iron may increase neoplastic proliferation or metastasis in vivo. Iron overload has frequently been associated with an enhanced incidence of malignancy in animals (Weinberg, 1983). In contrast to epidemiologic studies, animal studies suggest that depending on the conditions, iron can either enhance or inhibit tumor development. Reports disagree as to the effects of iron deficiency on tumor growth, and certain iron compounds may act as cocarcinogens. The route of administration, dose, and specific iron compound all seem to affect the outcome. Short-Term Tests Brusick et al. (1976) found that Fe[II] as iron sulfate induced reverse mutations in Salmonella typhimurium strains TA1537 and TA1538, with and without metabolic activation by the S9 fraction. In another study, 45 metal salts were evaluated for their capacity to induce morphological tranformation of Syrian hamster fetal cells in vivo. Iron was among the trace elements for which positive transformation assays were obtained (DiPaolo and Casto, 1979). Coronary Heart Disease Epidemiologic Studies The greater prevalence of iron deficiency among women, compared to men, has been proposed as an explanation for the lower coronary heart disease (CHD) rate among premenopausal women (Sullivan, 1986); however, no epidemiologic evidence supports this hypothesis. Iron-Deficiency Anemia Epidemiologic Studies Iron-deficiency anemia is the state in which the amount of iron in the body is less than that required for normal formation of hemoglobin, iron enzymes, and other functioning iron compounds. It is the most widespread nutritional deficiency in the world (Dallman et al., 1979) and is the major cause of anemia in Western countries. In the United States, however, the overall prevalence is low. NHANES II showed that the highest prevalence (9.3%) occurred among children 1 to 2 years old; next came women age 15 to 19 (7.2%) and 20 to 44 (6.3%). Men between the ages of 15 and 64 had a prevalence of less than 1% (LSRO, 1984a). Iron-deficiency anemia is usually due to inadequate iron nutriture in infants and small children and to blood loss or pregnancy in adults. The most frequent causes of anemia among older people are infections and chronic diseases—not iron deficiency. The prevalence of iron-deficiency anemia varies widely, depending on criteria for diagnosis (Charlton and Bothwell, 1982; Reeves et al., 1983); it can be affected by physiological, pathological, and nutritional factors. In some segments of the population, the amount of dietary iron has decreased with increases in caloric intake from fats and refined sugar. Where caloric intake has declined, iron intake has also declined. For example, iron-deficiency anemia occurs more commonly among women than among men, even in the absence of pathological blood loss. Women eat less food and are therefore able to absorb less iron, but their requirements for iron are greater because they lose iron through menstruation. Preventive approaches include iron supplementation, fortifica-

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Page 370 tion, and alteration of eating habits, for example, increasing intake of nutrients and foods stimulating iron absorption (e.g., vitamin C, meat, and fish) or reducing intake of foods inhibiting iron absorption (e.g., phytates). Older, but still useful, methods for evaluating body iron stores include determination of the plasma iron level and iron-binding capacity. Measurement of serum ferritin and free erythrocyte protoporphyrin concentration provide a more accurate assessment of iron stores. Animal Studies Experimentally induced iron-deficiency anemia produced striking morphological changes in the hearts of rats. These changes were characterized by marked cellular hypertrophy together with distinct cellular degeneration and interstitial fibrosis (Rossi and Carillo, 1983). In other studies, Rossi and colleagues treated iron-deficient anemic rats with reserpine (Rossi and Carillo, 1982; Rossi et al., 1981). The hearts of anemic rats not given reserpine were marked by cardiac hypertrophy, as indicated by increases in both heart weight and size of muscle cells. The hearts of reserpine-treated animals were not enlarged. The researchers speculated that noradrenaline may play a key role in the cardiac hypertrophy of iron-deficiency anemia. Zinc Zinc, a constituent of more than 200 enzymes, plays an important role in nucleic acid metabolism, cell replication, tissue repair, and growth through its function in nucleic acid polymerases. These zinc-dependent enzymes include the potentially rate-limiting enzymes involved in DNA synthesis. Zinc also has many recognized and biologically important interactions with hormones and plays a role in production, storage, and secretion of individual hormones. Severe, moderate, and marginal zinc deficiencies have been reported in the United States (Hambidge et al., 1986). The richest sources of zinc are shellfish (especially oysters), beef, and other red meats. Poultry, eggs, hard cheeses, milk, yogurt, legumes, nuts, and whole-grain cereals are also good sources. Many dietary factors, including other minerals, phytates, and dietary fiber, may adversely affect zinc absorption (Hambidge et al., 1986). Food sources of zinc have changed since the turn of the century. Until the middle 1930s, people obtained about equal amounts of zinc from foods of animal and plant origin, but since 1960, people have obtained approximately 70% of food-supply zinc from animal foods. Zinc from animal sources appears to be better absorbed than that from plant sources. The 1980 RDA for zinc is 15 mg/day for people 11 years of age and older (NRC, 1980), but zinc available in the food supply amounts to only 12.3 mg per capita (see Table 3-5). Zinc intakes have been estimated in national surveys only since 1984. According to the 1985 NFCS, men and women 19 to 50 years of age consumed an average of 94 and 56% of their RDA, respectively, and children 1 to 5 years of age consumed 73% of their RDA of 10 mg/day (USDA 1986, 1987b). Data from NHANES II were evaluated by a FASEB group (LSRO, 1984b), which concluded that serum zinc levels are inadequate for assessing the nutritional status of zinc in individuals, but that low values may aid in identifying groups whose zinc status should be further investigated. Atherosclerotic Cardiovascular Diseases Epidemiologic and Clinical Studies On the basis of knowledge concerning the relationships of zinc and copper to several risk factors for CHD, including elevated serum cholesterol and hypertension, Klevay (1975) hypothesized that an excess of zinc relative to copper may underlie this disease. For example, supplementation of the diet of 12 adult men with more than 10 times the RDA of zinc for 5 weeks while they took in normal levels of copper led to a significant decrease in high-density-lipoprotein (HDL) cholesterol but no change in total cholesterol (Hooper et al., 1980). This hypothesis and the controversial evidence pertaining to it are discussed in the section on copper. Animal Studies The committee found no animal studies on the relationship between zinc and cardiovascular diseases. Cancer Epidemiologic and Clinical Studies Few epidemiologic studies have been conducted to examine the relationship between exposure to zinc, especially dietary zinc, and cancer risk. In correlation analyses, zinc levels in soil, food, or blood have been positively associated with several

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Page 371 different cancers (Schrauzer et al., 1977a,b; Stocks and Davies, 1964). In an effort to identify etiologic factors for esophageal cancer in the very-high-risk area of Linxian in Hunan Province, China, blood and hair samples from a random sample of 58 men and 53 women who had undergone esophagoscopy with biopsy were analyzed for zinc, riboflavin, and vitamin A components (Thurnham et al., 1982). Zinc levels in plasma and hair were not significantly different between subjects with normal histology and those with lesions presumed to be precusors of cancer (e.g., esophagitis, dysplasia, acanthosis). No differences in zinc levels in blood and hair were found in another study of a similar random sample from a low-risk area in Shandong Province (Thurnham et al., 1985). Dietary zinc was assessed in only one case-control study of cancer. Kolonel et al. (1988) found that patients with prostate cancer who were 70 years old and older ingested more zinc (from supplements but not from food) prior to the onset of cancer than did matched population controls. Occupational studies of workers exposed to zinc by inhalation (usually in the presence of other trace elements such as copper, lead, arsenic, and chromium) have not implicated zinc as a risk factor for cancer (Gerhardsson et al., 1986). In many clinical studies, serum or tissue levels of zinc in cancer patients have been compared with those in controls. In most of these studies, sample sizes were small; controls were not well matched to the cases, even on age; and potential confounding factors were not considered in the analyses. The results have been mixed. In studies of patients with cancers at several different sites, investigators have found both decreased serum zinc levels in patients (Atukorala et al., 1979; Davies et al., 1968; Lin et al., 1977; Mellow et al., 1983; Sharma et al., 1984; Whelan et al., 1983) and higher zinc levels in the patients (Adler et al., 1981) compared to controls. In other studies, no differences were found between patients and controls (Feustel and Wennrich, 1986; Manousos et al., 1981; Smith et al., 1971; Strain et al., 1972; Thurnham et al., 1982). In many of these studies, serum copper levels were also measured; they were generally and consistently higher in the patients than in the controls, leading to lowered zinc-to-copper ratios. The possibility that the zinc findings in these studies were a consequence rather than a cause of the cancers is suggested by the observation of Sharma et al. (1984), who reported that the depressed serum zinc levels in lymphoma patients returned to normal following chemotherapy. The prostate normally contains the highest concentrations of zinc in the body and is therefore of great interest in studies of zinc and cancer (Hambidge et al., 1986). In several studies, investigators have compared zinc levels in prostate tissue from healthy subjects and from patients with benign prostatic hypertrophy (BPH) and cancer. Zinc concentrations were lowest in carcinomatous tissue, highest in BPH tissue, and intermediate in normal tissue (Feustel and Wennrich, 1984; Feustel et al., 1982; Györkey et al., 1967). Zinc interacts with other trace elements and is an antagonist to copper (Mertz, 1982) (see discussion below under Zinc-Copper Interactions). Zinc also interacts with vitamin A  (Solomons and Russell, 1980). Thus, the findings on zinc in human studies could reflect fundamental relationships between other nutrients and the diseases of interest. In general, however, human studies provide no evidence that zinc intake plays an important role in the etiology of cancer. Animal Studies Investigators have reported both enhancing and retarding effects of zinc on tumor growth in animals. Several have suggested that a zinc-deficient diet strongly inhibits the growth of transplanted tumors and prolongs survival (Barr and Harris, 1973; Beach et al., 1981; DeWys and Pories, 1972; DeWys et al., 1970; Fenton et al., 1980; Mills et al., 1984; Minkel et al., 1979). These findings suggest that rapidly growing tumor cells require zinc for growth. Zinc deficiency is not recommended as a therapeutic modality, however, because serious zinc deficiency, with or without concomitant malignancies, is itself lethal. In contrast to transplanted tumors, chemically induced carcinogenesis appears to be enhanced by zinc deficiency. For example, Gabrial et al. (1982) observed that the incidence of esophageal tumors induced by nitrosomethylbenzylamine was much higher in zinc-deficient rats than in control rats. Still other studies indicate that a zinc intake well above nutritional requirements suppresses the carcinogenesis of dimethylbenzylamine in Syrian hamsters (Poswillo and Cohen, 1971) and of azo dyes in rats (Duncan and Dreosti, 1975). On the other hand, Schrauzer (1979) demonstrated that high concentrations of zinc (200 mg/ liter) in the drinking water of C3H mice countered the protective effect of selenium against

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Page 372 spontaneous mammary carcinoma and resulted in a great increase in tumor growth. The two different effects of zinc deficiency on carcinogenesis were elucidated in a study by Beach et al. (1981) in which BALB/c mice were fed diets containing four levels of zinc beginning at 6, 3, 1, and 0 weeks before injection of Moloney sarcoma virus (MSV). Mice fed marginal and moderately zinc-deficient diets had greater sarcoma growth than did control mice, whereas those fed a diet severely deficient in zinc had a lower incidence of and smaller sarcomas. Feeding low-zinc diets for 6 weeks before MSV injection caused fewer sarcomas to be initiated and slower progression of the tumors. After sufficient severity and duration of zinc deprivation, mice also had a longer tumor latency and shorter tumor regression time. These apparently contradictory effects of zinc deficiency—the enhancement of tumor growth at some levels and the inhibition of growth at others—may indicate that there are two different mechanisms of action (Beach et al., 1981). Zinc deprivation has been shown to alter many facets of immunocompetence in experimental animals (Beach et al., 1979; Fernandes et al., 1979) as well as in humans (Golden et al., 1978). Thus, alterations in host immunologic function through zinc deprivation may contribute to changes in host-tumor interactions. However, zinc is also known to influence many aspects of host and tumor metabolism, including nucleic acid and protein synthesis, and tissues in the phase of rapid growth are most severely affected by zinc deprivation (Hurley, 1981). Thus, zinc is also necessary for tumor growth. Altered DNA synthesis by neoplastic tissue contributes to the inhibition of tumor growth in zinc-deficient animals. Zinc deficiency also causes chromosome aberrations in pregnant and fetal rats (Bell et al., 1975). It is difficult to assess the relative roles of host immune responsiveness and the interaction of host and tumor metabolism. Nevertheless, it appears that the influence of zinc nutrition on carcinogenesis reflects, at least in part, the interaction of the host and tumor. In contrast to human studies, studies in animals show that zinc can either enhance or inhibit tumor growth, perhaps by its effects on host immunocompetence, as stated above, or on nucleic acid synthesis. Short-Term Tests Zinc can affect both the tumor cell and the host, interfering with mechanisms that may be important for metastasis. It also promotes the adhesion of leukocytes to the endothelium (Hoover et al., 1980) and inhibits the procoagulant activity of polymorphonuclear leukocytes (Gazdy et al., 1981). Erkell et al. (1986) observed that preincubating B16 tumor cells in 0.1 M zinc caused a dramatic decrease in their intravenous transplantability. They postulated that this may be due to an impairment of cell adhesion. Other Diseases Epidemiologic and Clinical Studies The relationship between diabetes and zinc metabolism has been the subject of recent research. In humans, hyperzincuria is frequently found in diabetics. This condition is not entirely reversed following insulin treatment and does not seem to be compensated for by increased intestinal absorption (Kinlaw et al., 1983; Hallmans and Lithner, 1980; Levine et al., 1983). The increased loss of urinary zinc in diabetics is positively related to glycosuria (McNair et al., 1981; Pidduck et al., 1970). Stunted growth observed in many diabetic children suggests that the diabetes-induced change in zinc metabolism could be functionally important (Canfield et al., 1984). It is possible that the teratogenicity of diabetes may be due in part to the induction of zinc deficiency in the embryo or fetus. The observation that the offspring of diabetic rats have low zinc concentrations in their livers, compared to controls, supports this suggestion (Uriu-Hare et al., 1985). Although there is considerable evidence that abnormal zinc metabolism occurs in diabetics, the role of zinc, if any, in the etiology of diabetes is unknown. In a study of children with diabetes mellitus (Hägglöf et al., 1983), hair zinc levels were found to be normal, whereas serum  levels were lower and urinary levels were higher than in controls. The serum levels, but not the urinary levels, returned to normal after the diabetes was treated with insulin, suggesting that these two parameters reflect different metabolic processes or defects. Since zinc is part of the mineral content of bone, it might play a role in osteoporosis; however, there was no difference in the zinc content of bone samples taken from the iliac crest of 88 subjects with normal mineral status and 50 subjects with osteoporosis. Variations in zinc concentrations were best predicted by the copper and fluoride content of the bone (Lappalainen et al., 1982). An opposite finding was reported in a small study

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Page 373 of 10 male patients with senile osteoporosis and 12 male controls with degenerative osteoarthritis of the hip joint; the zinc concentrations in serum and bone tissue from the head of the femur were much lower in the patients with osteoporosis (Atik, 1983). Zinc-Copper Interactions Excessive intakes of zinc interfere with the absorption and utilization of iron and copper in animals. Campbell and Mills (1974) fed diets with a low or marginal copper content to weanling rats and found that 300 µg of additional zinc per gram of diet reduced plasma ceruloplasmin activity; more zinc, up to 1,000 µg, caused growth depression, hair depigmentation, and depressed copper levels in the liver. In sows, the addition of 5,000 µg of zinc per gram of diet increased zinc and depressed copper concentrations in plasma and liver (Hill et al., 1983). In sheep, increases in dietary zinc also result in copper deficiency, which is manifested by reduced plasma levels of copper, ceruloplasmin, and amine oxidase (Campbell and Mills, 1979). An antagonistic effect of dietary zinc on copper concentrations in maternal and fetal tissues was observed in pregnant rats fed diets with various levels of copper and zinc (Reinstein et al., 1984). The authors concluded that in zinc-deficient diets, the high copper-to-zinc ratio potentiates the teratogenic effects of zinc deficiency. In humans, prolonged use of oral zinc supplements, even at relatively modest levels, may have adverse clinical consequences. For example, copper deficiency, evidenced by microcytic anemia, neutropenia, and decreased levels of plasma copper and ceruloplasmin, was found in a man who had been taking 150 mg of zinc daily for 2 years (Prasad et al., 1978). Fluoride Fluoride is an integral part of the food chain. Kumpulainen and Koivistoinen (1977) reported that the measured fluoride content of the diet is three times higher in communities with fluoridated water than in those where the water is not fluoridated. Singer and Ophaug (1979) found that the fluoride content of dry cereals is strongly influenced by the fluoride content of the water in which they were processed. They also reported that baby foods contain high levels of fluoride (Singer and Ophaug, 1979). Fluoride is also consumed unintentionally from two major sources: products containing mechanically boned meat and fluoridated dentifrices. The highest daily average consumption (equivalent to 0.3 mg of fluoride) is reported for children under the age of 5 (Barnhart et al., 1974). The interaction of fluoride with other dietary ions could influence its bioavailability. Aluminum-containing antacids cause a negative fluoride balance by markedly increasing fluoride excretion (Spencer and Kramer, 1985; Spencer et al., 1981). For infants not drinking fluoridated water, and for those receiving human or cow milk (both low in fluoride) rather than infant formula, fluoride supplements of 0.25 mg/day are advised (Forbes and Woodruff, 1985). Fluoride could be involved in the growth and maintenance of a normal skeleton (see below and Chapter 23, Osteoporosis). Modest accumulations of fluoride in the bone mineral complex result in increased bone crystallinity and decreased solubility. The net result is the formation of a more stable mineral system that is less susceptible to bone resorption (Spencer and Kramer, 1985). Dental Caries Epidemiologic Studies Fluoride therapy has been used since 1949 to prevent dental caries (Dunning, 1979). In the late 1930s, large-scale epidemiologic studies first elucidated the relationship between fluoride in water supplies and reduced prevalance of dental caries (Brown and König, 1977; Dean, 1936; Dean and Elvove, 1935; Levine, 1976). More recently, Burt et al. (1986) determined that children who have lived for a few years in a community with optimal water fluoride have a 30 to 40%  lower caries incidence than children who have lived continuously in low-fluoride communities. Similar reductions in dental caries incidence were observed by Driscoll et al. (1981). For fluoride, there is a narrow range of safe and adequate intake and therefore much concern among health activists about its potential toxicity. The level of fluoride commonly maintained in municipal water supplies is 1 part per million (ppm). At 2 ppm, such undesirable effects as dental fluorosis (i.e., mottling of teeth) have been observed (Pollack and Kravitz, 1985). A fluoride concentration of 4 ppm has been associated with an increased incidence of caries (Ericsson, 1977; Jenkins, 1978). Although the increased consumption of dietary sugars has led to increases in dental caries prevalence internationally (Taylor, 1980; Yassin and

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Page 374 Low, 1975), World Health Organization data indicate that caries is decreasing in Western countries and  increasing in developing  countries (WHO, 1988). Reports from the National Institute of Dental Research (NIDR) substantiate this observation (NIDR, 1981). The decline in caries incidence in the United States has been attributed primarily to the widespread use of fluoride in many forms (Dunning, 1979; Newbrun, 1975; Shaw, 1954), to improved oral hygiene, and to the increased use of antibiotics. The role of fluoride in dental caries is discussed more fully in Chapter 26. Animal Studies Developing teeth are extremely sensitive to fluoride. Abnormalities in permanent dentition are the most obvious signs of excessive fluoride ingestion. The tooth becomes mottled, perhaps with hypoplasia (thin enamel), and is subject to more rapid wear and possible erosion of the enamel (NRC, 1971). Brown et al. (1960) established that developing incisors in cattle are vulnerable up to 30 months of age. Shupe et al. (1962) fed young dairy heifers various levels of fluoride for 7.5 years. They reported that dental and bone lesions were correlated with the amount of fluoride ingested, the amount of fluoride in the bone, the age of the cow, and the duration of exposure. Milk production in cows given a higher level of fluoride was reduced. Fluoride concentrations appear to be higher during the matrix-forming secretory stage of enamel formation than in the rapidly mineralizing maturation stage. An in vitro study by Crenshaw et al. (1978) suggests that selective binding of fluoride by newly synthesized matrix proteins may in large measure account for the enhanced uptake. Drinkard et al. (1982) found that fluoride also delays deposition of the matrix proteins in rat molars during the secretory stage of enamel development. It has not been established, however, whether these fluoride-protein interactions contribute to the fluoride-induced changes in enamel crystallinity. Cancer Epidemiologic Studies Epidemiologic studies have focused on the health effects of fluoride in public water supplies—the major source of fluoride for most people. Early reports found no association between fluoride and mortality in communities with and without naturally high fluoride levels in their water supplies (Hagan et al., 1954; Nixon and Carpenter, 1974), which led the way to the introduction of water fluoridation in many communities. In the 1970s, attention was abruptly redirected to the possibility of an increased risk for cancer by a well-publicized analysis of cancer mortality rates in 10 fluoridated and 10 nonfluoridated cities in the United States (Yiamouyiannis and Burk, 1977). Although these investigators claimed that cancer mortality was higher in the fluoridated cities, their analysis failed to include necessary and routine adjustments for such demographic differences among populations as age, sex, and racial composition. Subsequently, different investigators reanalyzed in a more appropriate fashion the same data, as well as more comprehensive data sets in the United States, and all concluded that there was no evidence of an increased risk for mortality from cancer overall or at any specific site (Chilvers, 1983; Doll and Kinlen, 1977; Erickson, 1978; Hoover et al., 1976; Kinlen and Doll, 1981; Oldham and Newell, 1977; Rogot et al., 1978; Taves, 1979). Similar ecological studies have been conducted in Great Britain, Canada, Australia, New Zealand, Austria, and Norway, and all have yielded negative results. These studies have been exhaustively reviewed in several recent reports (Clemmesen, 1983; IARC, 1982a,b; Knox, 1985; NRC, 1977b). Short-Term Tests Fluoride-induced chromosome changes have been repeatedly demonstrated in mammalian cells. For example, Mukherjee and Sobels (1968) showed that both irradiated and fluoride-treated sperm  cells had more chromosome aberrations than did controls. Jagiello and Lin (1974) found that in vitro exposure to sodium fluoride sharply reduced the percentage of cow and ewe oocytes undergoing meiotic division. In cells of bone and testes of mice, the number of chromosome breaks and abnormalities increased with increasing fluoride levels in drinking water (Mohamed and Weitzenkamp-Chandler, 1976). Similar mutagenic effects and dose responses were observed when bone cells of white rats were exposed to inorganic fluoride (Gileva et al., 1972; Voroshilin et al., 1975). In general, fluoride interacts with DNA and RNA and alters biologic activity in mammalian cells (Clark and Taylor, 1981; Emsley et al., 1981, 1982; Greenberg, 1982). Tsutsui et al. (1984) produced anaplastic fibrosarcomas by treating hamster embryo cells with

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Page 375 fluoride concentrations ranging from 75 to 125 ppm and later injecting the cells into newborn Syrian hamsters. The dose levels used in these experiments were much higher than those to which humans are normally exposed; it is not known what results would be observed at lower doses. Hypertension and Cardiac Effects Epidemiologic Studies The committee found no studies in humans that examine possible effects of fluoride on hypertension or cardiac function. Animal Studies Fluoride has caused a decrease in blood pressure and induced cardiac changes in several studies in animals. For example, Leone et al. (1956) subjected dogs to intravenous infusion of fluoride at doses of 20 and 30.6 mg/kg body weight. There was a dose-related depression of the respiratory rate and a conversion to atrioventricular nodal or ventricular rhythm with terminal ventricular fibrillation. Lu et al. (1965) observed the same response in monkeys. Osteoporosis Epidemiologic and Clinical Studies The use of fluoride to reverse or delay the progression of osteoporosis and hence to reduce the risk of fractures has been reviewed by Kanis and Meunier (1984). Methodological limitations and inconsistencies in results of the various studies prevented firm  conclusions from  being drawn (Kanis and Meunier, 1984). Fluoride may actually increase the risk of femoral fractures at the same time that it decreases the risk of vertebral fractures in some patients (Power and Gay, 1986). Riggs et al. (1982) reported a decrease in the rate of spinal fracture associated with the use of fluoride. However, it is unclear as to whether vertebral fractures are reduced among lifelong residents of areas with highly fluoridated drinking water (Alffram et al., 1969; Bernstein et al., 1966). Reports of effects of fluoride therapy on bone mass are reasonably consistent. Trabecular bone volume is increased in patients given fluoride (Hanson and Roos, 1978; Ivey and Baylink, 1981; Jowsey, 1979). Other studies show that trabecular bone mass increases in only 60%  of patients receiving fluoride therapy (Riggs et al., 1980, 1982). It is not possible to predict which patients will respond favorably to fluoride, because the factors influencing the response have not been identified. Many questions regarding the use of fluoride to reduce osteoporosis and fractures remain unanswered. Animal Studies Miller et al. (1977) reported that the bones of cows with osteoporosis resulting from environmental exposure to fluoride had higher calcium levels and a somewhat lower phosphorus content than the bones of cows not exposed to fluoride. Henrikson et al. (1970) studied the ash of osteoporotic bones from dogs and found that fluoride caused a slight decrease in the calcium content and an increase in phosphorus. The mineral mass also increased with increasing dietary fluoride, but there was no improvement in the degree of osteoporosis. These studies suggest that fluoride may indirectly affect osteoporosis by increasing bone mineral mass; however, the data on calcium are inconsistent, and it is not certain if dogs are an appropriate model for osteoporosis. Selenium In the 1950s, recognition of the economic importance of selenium deficiency in food animals led to the mapping of selenium distributions in the soils, forages, and blood of humans in several continents. Extreme differences in exposure were found, even within countries. This knowledge enabled investigators to make epidemiologic correlations of diseases in humans and animals and to conduct laboratory experiments to test hypotheses. In 1980, a committee of the National Research Council set the estimated safe and adequate daily intake of selenium at 10 to 40 µg/day for infants, 20 to 200 µg/day for children, and 50 to 200 µg/ day for those over 11 years of age (NRC, 1980). Studies based on saturation of plasma glutathione peroxidase activity suggest that the selenium requirement of Chinese men is about 40 µg/day (G. Q. Yang et al., 1987). After adjusting for differences in body weight and incorporating a safety factor, a dietary recommendation of 70 and 55 µg/ day can be calculated for North American men and women, respectively (Levander, 1987). The average dietary selenium intake for U.S. men was 108 µg/day between 1974 and mid-1982 (Pennington et al., 1984). At present, the only well-characterized biochemical function for selenium in mammals is its role in the peroxide-destroying enzyme glutathione

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Page 376 peroxidase (Hoekstra, 1975). However, other selenium-containing proteins in mammals have been described (J. G. Yang et al., 1987). Selenium is also known to participate in several important metabolic interactions with a variety of hazardous elements such as mercury, cadmium, and arsenic, which may be important to public health (Levander and Cheng, 1980). Atherosclerotic Cardiovascular Diseases Epidemiologic and Clinical Studies Several reports on the relationship of serum selenium to the risk of cardiovascular diseases have been published by investigators in Finland—a country with reportedly low selenium intakes. In two prospective cohorts, Salonen et al. (1982, 1985b) found that selenium levels were lower in the serum of subjects who died from cardiovascular diseases, including CHD specifically, than in control subjects matched on daily tobacco consumption and other risk factors for CHD. In two other Finish cohort studies (Miettinen et al., 1983; Virtamo et al., 1985), investigators found no association of serum selenium with CHD, although Virtamo et al. (1985) did find an inverse association with cardiovascular diseases generally and possibly with stroke. In a similar analysis of a large cohort in the Netherlands, where selenium intake is higher than in Finland, Kok et al. (1987b) found no significant association between serum selenium level and mortality from CHD or stroke, although the findings for stroke suggested an inverse association. Thus, the results of these cohort studies are equivocal. The inconsistencies in findings could reflect, in part, such methodological concerns as reliance on single serum measurements or the possibility of a threshold in serum selenium level above which there is no associated risk of cardiovascular diseases. The observation that regional variations in mean serum levels of selenium within Finland do not correlate inversely with CHD mortality suggests that selenium is unlikely to be a major determinant of risk for this disease (Virtamo et al., 1985). Ellis et al. (1984) studied the relationship of blood selenium  levels to smoking and alcohol consumption in healthy male volunteers. They found much lower selenium levels in the whole blood and serum  of cigarette smokers than of nonsmokers, independent of alcohol use. In addition, selenium was not associated with other risk factors for CHD (including blood pressure, serum total and HDL cholesterol, and obesity). Whether the lower selenium concentration in smokers was a metabolic consequence of smoking or was secondary to differences in the dietary patterns of smokers could not be determined from this study. Clinical studies based on tissue and serum concentrations of selenium generally show no association between coronary artery disease or hypertension and selenium levels (Aro et al., 1986; Masironi and Parr, 1976; Shamberger et al., 1978; Westermarck, 1977), although a few investigators reported inverse associations (Moore et al., 1984; Oster et al., 1986). A cardiomyopathy (degeneration of the heart muscle), known as Keshan disease, primarily affects young children and women during reproductive years in certain regions of China where the soil levels of selenium  are low. The poor soil content is reflected in the very low selenium levels in locally grown cereals, which can explain why mean selenium levels in blood, urine, and hair are substantially lower in the affected areas than in other parts of China. Trials in children given diets supplemented with sodium selenite provided convincing evidence that selenium deficiency is a major etiologic factor in this disease. These findings are reviewed and discussed by Yang et al. (1984). Since most cardiovascular mortality in Western countries occurs in adults and results from disease of the coronary arteries, not the myocardium, the observations on Keshan disease do not implicate selenium  deficiency as a likely risk factor for cardiovascular diseases in the United States, and its role in the etiology of atherosclerotic cardiovascular diseases remains uncertain. Animal Studies Cardiomyopathy has been observed in several species of animals fed diets deficient in both vitamin E and selenium (NRC, 1983). Although selenium deficiency clearly is involved in impaired heart function under these conditions, this disease should not be confused with the diseases of coronary arteries prevalent in the West. No animal model suggestive of a role for selenium in human cardiovascular diseases has been developed; however, biochemical studies show that the production of thromboxane by platelets is increased and biosynthesis of prostacyclin by aortic tissue is decreased in selenium-deficient rats (Schoene et al., 1986). Alterations in the thromboxane-to-prostacyclin ratio in vivo might influence the course of human cardiovascular diseases

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Page 377 (Patrono et al., 1984), but the significance of these animal experiments to human health has not yet been established. Cancer Epidemiologic Studies Many correlation studies suggest that a deficiency of dietary selenium might increase the risk of cancer in humans (Clark, 1985; Cowgill, 1983; Shamberger and Frost, 1969; Shamberger and Willis, 1971; Shamberger et al., 1976). These studies correlated selenium levels in forage crops with corresponding cancer mortality rates by geographic area (states, counties, or cities in the United States) and found an inverse relationship with cancers of several different sites (including the lung, colon, rectum, bladder, esophagus, pancreas, female breast, ovary, and cervix). In the report by Clark  (1985),  liver  and  stomach  cancers, Hodgkin's disease, and leukemia were positively associated. Schrauzer and colleagues (1977a) estimated per-capita selenium intakes for more than 20 countries on the basis of food disappearance data and found an inverse association between consumption levels and mortality from leukemia and certain other cancers. In other geographic correlation studies, investigators have found inverse associations between pooled blood selenium levels and total cancer mortality as well as mortality from cancer at various sites (Schrauzer et al., 1977a,b; Yu et al., 1985). Many investigators have compared blood selenium levels in cancer patients with corresponding levels in controls (Broghamer et al., 1976, 1978; Calautti et al., 1980; Clark et al., 1984; Goodwin et al., 1983; McConnell et al., 1975, 1980; Robinson et al., 1979; Schrauzer et al., 1985; Shamberger et al., 1973; Sundström et al., 1984; Thimaya and Ganapathy, 1982). In general, these investigators found lower selenium levels in patients than in controls for all cancers combined, and for cancers of selected sites, but the findings are not entirely consistent among the different reports. These studies are limited by the generally small sample sizes, the failure to adjust for other risk factors, and the possibility that the selenium levels were a consequence, not an antecedent, of the cancers. The issue of cause and effect is best addressed in prospective studies that determine selenium exposure before clinical manifestations of the cancer are observed. In five cohort studies conducted in Finland, the Netherlands, and the United States, investigators analyzed stored prediagnostic serum from cancer cases and a group of matched controls (Kok et al., 1987b; Menkes et al., 1986; Salonen et al., 1984, 1985a; Willett et al., 1983). In the two investigations conducted in Finland, significantly lower selenium levels were found in patients than in controls for all cancers combined (Salonen et al., 1984, 1985a). In the more recent study, Salonen et al. (1985a) reported that the risk was restricted to men, particularly smokers. In the Netherlands, Kok et al. (1987a) also found lower selenium intake to be significantly associated with increased mortality from cancer among men only. In the United States, Willett et al. (1983) reported the same inverse association to be limited to smokers, males, and blacks (whose levels were lower than those of the whites in the study). Analyses by specific site in these studies were based on very few cases, but did suggest that cancers of the respiratory and gastrointestinal tracts are influenced most strongly by selenium. The report of Menkes et al. (1986) contrasts with the others. In their analysis of prediagnostic serum from lung cancer cases and matched controls, these investigators found a positive association between selenium level and cancer risk, especially for squamous cell carcinomas. This finding is consistent with the results of a case-control study by Goodwin et al. (1983), who found higher selenium concentrations in the plasma of patients with cancers of the oral cavity and oropharynx than in controls. Although the analysis of selenium in the prediagnostic serum of subjects in prospective cohorts has the advantage of precise measurement and the proper temporal relationship to the disease, the results could still be misleading for several reasons: Single serum measurements may not accurately represent long-term mean levels; serum selenium levels may only be markers of the intake of other more directly related components of the food sources of selenium; and the relevant determination may actually be tissue rather than blood concentrations of selenium. An additional complexity in these studies is the interaction of selenium with other micronutrients, including certain antioxidant vitamins and possibly other trace metals. Willett et al. (1983) found that selenium-associated risk was enhanced by low serum retinol and low vitamin E levels, whereas Salonen et al. (1985a) also found enhancement by low levels of vitamin E but not of retinol. It is particularly difficult to assess selenium intake from dietary histories, because plants are

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Kanematsu, N., M. Hara, and T. Kada. 1980. Rec assay and mutagenicity studies on metal compounds. Mutat. Res. 77: 109-116. Kanis, J.A., and P.J. Meunier. 1984. Should we use fluoride to treat osteoporosis? A review. Q. J. Med. 53:145-164. Kantor, A.F., M.G. Curnen, J.W. Meigs, and J.T. Flannery. 1979. Occupations of fathers of patients with Wilms's tumour. J. Epidemiol. Community Health 33:253-256. Kawamura, J., O. Yoshida, K. Nishino, and Y. Itokawa. 1978. Disturbances in kidney functions and calcium and phosphate metabolism in cadmium poisoned rats. Nephron 20: 101-110. Kazantzis, G. 1981. Role of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium in carcinogenesis. Environ. Health Perspect. 40:143-161. Kazantzis, G., and W.J. Hanbury. 1966. The induction of sarcoma in the rat by cadmium sulphide and by cadmium oxide. Br. J. Cancer 20:190-199. Kinlaw, W.B., A.S. Levine, J.E. Morley, S.E. Silvis, and C.J. McClain. 1983. 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