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National Research Council (US) Committee on Diet and Health. Diet and Health: Implications for Reducing Chronic Disease Risk. Washington (DC): National Academies Press (US); 1989.

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Diet and Health: Implications for Reducing Chronic Disease Risk.

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14Trace 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 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 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).


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 (Benbassat 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 transformation 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, fortification, 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, 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.


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 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 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 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 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 prevalence 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 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.


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 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.


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.


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 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 (Patrono et al., 1984), but the significance of these animal experiments to human health has not yet been established.


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 highly sensitive to soil concentrations of selenium, leading to great variation in the selenium content of foods. Thus, estimates of consumption may not reliably reflect actual intake. This may account for the low correlations reported between individual estimates of dietary selenium and serum or hair levels (Goodwin et al., 1983; Thimaya and Ganapathy, 1982).

In summary, low selenium intakes or decreased selenium concentrations in blood or tissues are associated with increased risk of cancer in humans. It is not yet clear which cancers may be most affected by selenium, although respiratory and gastrointestinal tumors have been implicated most often. Nevertheless, because of inconsistencies in the findings regarding certain sites, such as the respiratory system (Menkes et al., 1986; Salonen et al., 1985a) and the skin (Clark et al., 1984; Salonen et al., 1984), and the lack of studies based on direct dietary assessment, a firm conclusion on the role of selenium in human cancer risk is not justified at present.

Animal Studies

Several feeding or drinking water studies conducted from the 1940s to the 1970s showed that high levels of selenium induced or enhanced tumor formation (Nelson et al., 1943; Schroeder and Mitchener, 1971; Volgarev and Tscherkes, 1967). Critical review, however, reveals serious drawbacks in the experimental designs, including such conditions as near toxic levels of selenium (5 µg/g and higher), low protein levels in the diet (12%), and a pneumonia epidemic in one of the rat colonies.

More recent animal studies demonstrate that under some conditions, elevated selenium intake protects against numerous types of chemically induced, spontaneous (presumably virally induced), and transplantable tumors in rats and mice (extensively reviewed by Ip, 1985, and Milner, 1985). The incidence of skin cancer induced in hairless mice by ultraviolet light could also be decreased by giving them drinking water containing high selenium concentrations (Overvad et al., 1985). In all these experiments, the amount of selenium given to the animals exceeded 0.25 mg/kg body weight—the level of dietary selenium considered by most investigators to be the upper limit for animal nutrition studies (Clark and Combs, 1986; Clark et al., 1984).

Relatively few experiments have been performed to investigate the effect of selenium deficiency on cancer in animals. Selenium deficiency increased the yield of mammary tumors induced by DMBA in rats fed diets with a high polyunsaturated fat content but not in rats fed diets with low levels of fat or high levels of saturated fat (Ip and Sinha, 1981). Pence and Buddingh (1985) observed that selenium deficiency had no influence on colon tumors induced in rats by DMH.

Some reports indicate that cancer incidence is reduced in animals deficient in dietary selenium. For example, Shamberger (1970) painted three groups of selenium-deficient mice with BaP. In the unsupplemented group, only 40% (14 of 35) developed papillomas. In another group, whose deficient diet was supplemented with selenium at 0.1 mg/kg diet as sodium selenite, 61% (22 of 36) developed papillomas. A higher level of selenium supplementation in a third group (1.0 mg/kg) resulted in a 24% (8 of 33) incidence of papillomas. In another study, Reddy and Tanaka (1986) showed that the incidence of colon tumors induced in male rats by azoxymethane was inhibited by selenium deficiency.

Under some conditions, high dietary selenium levels have little or no protective effect against tumors in animals (reviewed by Levander, 1987). Included in this category are certain chemically induced tumors of the trachea, forestomach, liver, small bowel, and pancreas. The reason for these negative results is unknown, but the data suggest that selenium may not protect against all forms of cancer.

Short-Term Tests

Selenium blocked the mutagenicity of malonaldehyde—a chemical shown to be mutagenic in the Ames Salmonella assay—in seven mutant strains used to detect various types of frameshift mutagens (Jacobs et al., 1977; Shamberger et al., 1978), but selenium itself was also shown to be a mutagen. For example, five selenium compounds noted for their ability to induce chromosome aberrations in cultured human leukocytes and for their reactivity with DNA by a rec-assay system yielded positive results. Damage to DNA was produced by selenites, but not by selenates (Lo et al., 1978; Nakamura et al., 1976). Nakamura also showed that selenates had the capacity to induce a small but significant DNA-repair synthesis.

Mechanisms of Action

A combination of different biochemical mechanisms may be involved in the expression of the various effects of selenium observed in different animal model tumor systems. These include protection against carcinogen-induced oxidative damage, changes in carcinogen metabolism, and cytotoxicity toward rapidly dividing cells (Combs and Clark, 1985).

The increased tumorigenicity of DMBA in selenium-deficient rats was seen only in animals subjected to the prooxidant stress of a diet with high levels of polyunsaturated fat (Ip and Sinha, 1981). The antitumorigenic effect of selenium in this system may involve its antioxidant function at nutritional levels (dietary selenium equal to or less than 0.1 mg/kg). The biochemical mechanism by which selenium deficiency protects against experimental cancer under some conditions may be related to the increase in non-selenium-dependent glutathione peroxidase activity that occurs in selenium-deficient animals. This enzymatic activity is now known to be due to the xenobiotic conjugating glutathione-S-transferases, certain subunits of which increase in rats made deficient in selenium (Mehlert and Diplock, 1985).

Ip and colleagues conducted a series of experiments to investigate the interaction of selenium with vitamin E in rats given DMBA and fed diets with high levels of polyunsaturated fat to provoke an oxidant stress (Ip, 1986). Vitamin E supplementation alone had no prophylactic effect, but high dietary levels potentiated the protective effect of selenium when fed during the postinitiation or the promotion phase. Moreover, vitamin E deficiency attenuated the anticarcinogenic efficacy of selenium. Although vitamin E was a much more effective antioxidant than selenium, as indicated by its suppression of systemic lipid peroxidation, it was inferior to selenium in terms of anticarcinogenic potency. These studies raise doubts about the hypothesis that high dietary levels of vitamin E and selenium protect against cancer by counteracting oxidant stress.

Thus, the anticarcinogenic effect of high dietary levels of selenium appears unrelated to its antioxidant role in glutathione peroxidase activity (Ip, 1986; Medina, 1986). Selenium is an effective chemopreventive agent when given during either the initiation or the promotion phase of chemical carcinogenesis, but effects of selenium on carcinogen metabolism or DNA-adduct formation do not seem to account for its inhibition of tumorigenesis (Ip, 1986). Elevations in the intracellular ratio of oxidized to reduced glutathione (GSSG/GSH) may account for the anti-proliferative effect of selenium by retarding all synthetic stages of the cell cycle (LeBoeuf et al., 1985). Selenodiglutathione (GSSeSG)—a reaction product of selenite and GSH—has been found to inhibit tumor growth (Vernie, 1984). This compound may interfere with certain aspects of protein biosynthesis. It has, however, been questioned whether the intracellular concentration of this metabolite could ever increase to levels high enough to inhibit protein synthesis (Combs and Clark, 1985).

In general, animal studies are contradictory concerning the effect of high levels of selenium on cancer and are confusing with regard to the relationship of selenium deficiency to cancer. Although some studies indicate that selenium deficiency enhances susceptibility to cancer, others suggest that deficiency inhibits it.


Copper is an essential nutrient that is widely distributed in food and water. In 1980, the National Research Council set the estimated safe and adequate daily dietary intake at 0.5 to 1.0 mg/day for infants, 1.0 to 2.5 mg/day for children, and 2.0 to 3.0 mg/day for those over 11 years of age (NRC, 1980). Pennington et al. (1984) estimated that men consumed a mean of 1.60 mg/day, based on data collected in 1981 and 1982. From data gathered from 1982 to 1984, Pennington et al. (1986) estimated that the mean intakes of 25- to 30-year-old women and men were 0.93 mg/day and 1.24 mg/day, respectively. Intakes of older women and men were lower (0.86 mg/day and 1.17 mg/ day, respectively). In 1985, the CSFII indicated that copper intakes averaged 0.8 mg/day for children 1 to 5 years old and 1.0 mg/day for women 19 to 50 years old, based on 4 nonconsecutive days of intake (USDA, 1987a). The mean intake for men 19 to 50 years old, based on 1 day's intake, was 1.6 mg/day. Schrauzer et al. (1977b) reported copper intakes in 28 countries varying from 1.6 to 3.3 mg/ day.

Cartwright and Wintrobe (1964) estimate that the healthy adult body contains 80 mg of copper. Individual tissues differ greatly in their susceptibility to variations in dietary copper intakes. Subnormal levels of dietary copper are reflected in subnormal blood copper concentrations. Elements such as zinc, cadmium, and iron depress copper absorption and can reduce plasma copper concentrations when ingested at high dietary levels. Copper also plays a key role in iron absorption and mobilization. Elevated plasma copper levels are characteristic of most acute and chronic infections.

Atherosclerotic Cardiovascular Diseases

Epidemiologic and Clinical Studies

The metabolism of copper is negatively influenced by zinc, and many researchers have used zinc-to-copper ratios to interpret their results. Klevay (1975, 1984) hypothesized that the major risk factor for CHD is a low ratio of copper to zinc. Although some data on the relationship of copper and zinc to established risk factors for CHD support the hypothesis, other data do not (Fischer and Collins, 1981; Klevay, 1975; Mertz, 1982).

Insufficient dietary copper leads to elevated blood lipid levels (hypercholesterolemia) and impaired heart function, including electrocardiographic anomalies, myocardial cellular atrophy, and fibrosis (Allen and Klevay, 1978; Klevay, 1980; Klevay and Viestenz, 1981). Electrocardiogram irregularities disappeared following copper supplementation in human subjects consuming a diet low in copper (Klevay, 1984). In a study by Reiser et al. (1985), subjects fed a diet low in copper (1.03 mg/day per 2,850 kcal) containing 20% fructose or starch exhibited heart-related abnormalities, including arrhythmias, and had to be removed from the study. These results confirm that copper is an essential trace element.

Animal Studies

Studies of low dietary copper levels in animals show degradation of heart muscle, including hypertrophy, degeneration of the muscle fibers, and chronic inflammation. The ventricular apex is the most severely affected. The hypertrophy and myopathy observed in animals consuming a low-copper diet are aggravated by sucrose or fructose ingestion (Fields, 1985).

Kopp et al. (1983) fed male weanling rats a copper-deficient diet for 49 days. In vivo cardiological assessment revealed irregularities, including electrocardiographic anomalies and gross pathology, reconfirming earlier studies (Klevay and Viestenz, 1981). Hypercholesterolemia was also observed. Microscopic examination of heart tissue revealed extensive disruption of mitochondrial fine structure and other changes. The authors concluded that these changes represent the appearance of a copper-dependent cardiomyopathy. Furthermore, they suggest that mitochondrial electron transport activity was inadequately sustained. Indeed, dietary copper deficiency has been shown to decrease cytochrome oxidase activity in cardiac and hepatic tissue (Kitano, 1980; O'Dell, 1976).


Epidemiologic and Clinical Studies

Both the absorption and the metabolism of copper are negatively influenced by zinc, and observed associations between copper and cancer or other chronic diseases may reflect the opposite effects of zinc. In many studies, therefore, investigators have reported zinc-to-copper ratios.

Epidemiologic evidence that dietary exposure to copper is etiologically related to cancer is not compelling. Blood levels of copper in pooled samples from healthy donors in 19 U.S. states were weakly but positively correlated with corresponding mortality rates from cancers of the breast, lung, thyroid, and intestine (Schrauzer et al., 1977b). Per-capita estimates of dietary copper in 27 countries were positively correlated with leukemia and cancers of the intestine, breast, and skin (Schrauzer et al., 1977b). In 12 districts of England and Wales, copper levels in the soil of vegetable gardens near houses in which people died from cancer differed little from the levels near houses in which people died from noncancer causes. However, higher zinc levels were associated with deaths from gastric cancer (but not other cancers). Thus, a lower copper-to-zinc ratio was associated with risk for this cancer (Stocks and Davies, 1964).

In many clinical reports, investigators have compared copper levels in tumor tissue or serum of cancer patients with levels in normal tissues from the same subjects or unmatched controls. These studies have generally associated higher copper levels with solid tumors at many sites, including the colorectum, pancreas, stomach, cervix, endometrium, ovary, prostate, and lung (Feustel et al., 1986; Gregoriadis et al., 1983; Jendryczko et al., 1986; Manousos et al., 1981; Margalioth et al., 1983; Schwartz, 1975; Sharma et al., 1984). The associations were sometimes shown to be specific for copper rather than for the other trace elements analyzed, such as magnesium, manganese, and zinc. In cancer patients, however, the abnormal copper levels may have been a consequence of the disease. This speculation is supported by the findings in some studies that copper levels increase with advancing stage or grade of the tumor, that the disease increases copper absorption, and that chemotherapy in lymphoma patients returns low serum copper levels to normal (Braganza et al., 1981; Fabris et al., 1985; Sharma et al., 1984).

Occupational studies of inhalation exposure to copper compounds offer little further evidence that copper may be carcinogenic in humans. Some investigators have reported increased mortality from cancers of the lung and gastrointestinal tract among workers in vineyards where Bordeaux mixture (a fungicide containing copper sulfate and lime) was sprayed and in copper mines or refineries (Logue et al., 1982; Newman et al., 1976; Pimentel and Menezes, 1977); however, the evidence is sparse, and other risk factors such as cigarette smoking have not been ruled out as being responsible for the associations.

Animal Studies

Several independent studies demonstrate that high levels of copper salts added to the diets of animals provide various degrees of protection against liver tumors induced by a variety of different carcinogens (Brada and Altman, 1977). Since these effects were obtained with extremely high concentrations of copper (from 0.3 to 0.6% copper acetate) in the diet and since similar effects were produced when manganese or nickel was substituted for copper (Yamane and Sakai, 1973), copper may have been acting as a nonspecific toxicant.

Carlton and Price (1973) studied the influence of a copper-deficient diet on carcinogenesis. Rats fed the deficient diets and given dimethylnitrosamine in drinking water or acetylaminofluorene in chow had a higher incidence of lung tumors than did copper-sufficient controls. However, copper deficiency had no effect on the initiation and progression of hepatomas.

Other Diseases

Epidemiologic Studies

Copper deficiency secondary to chronic diarrhea or inadequate diet has been associated with anemia, particularly in young children (Danks, 1980). This form of anemia is corrected by the addition of copper to the diet.

Excess exposure to copper, based on hepatic copper levels, has been implicated in a unique childhood cirrhosis of very young children in India (Pandit and Bhave, 1983). Epidemiologic observations in this population are consistent with the hypothesis that the children are exposed to copper in milk stored in brass vessels. However, it has not yet been demonstrated that the risk for this disease is lowered when alternative milk storage methods are adopted.

Copper-containing intrauterine devices have been used by women as contraceptives for several years in the United States. Copper may be lost from these devices and may be absorbed parenterally. No adverse long-term effects from this additional copper exposure have been reported (NRC, 1977c).


Chromium is an essential trace element needed for normal carbohydrate metabolism. The biologic function of chromium is closely associated with that of insulin. Most chromium-stimulated reactions are also insulin dependent. For example, chromium functions in carbohydrate and lipid metabolism as a potentiator of insulin action.

It has been difficult to determine the extent and importance of chromium deficiency in humans, partly because analytical techniques are not sufficiently sensitive. Glucose intolerance is usually one of the first signs of chromium deficiency. Among the heavy metals, chromium is the only one whose tissue levels continually decrease throughout life (Schroeder et al., 1962, 1970a). The chromium content of diets ranges from 5 to 150 µg/day in the United States to more than 200 µg/day in Japan (Pi-Sunyer and Offenbacher, 1984). The National Research Council (1980) has set 50 to 200 µg/day as a safe and adequate level for adolescents and adults and 10 to 120 µg for infants and children.

The richest sources of chromium include liver and other organ meats, brewer's yeast, whole grains, and nuts. Acidic foods promote chromium leaching from stainless steel cookware, but it has not been determined whether this is a nutritionally useful chromium source (Offenbacher and Pi-Sunyer, 1983). The amount of chromium in foods tends to decrease with processing (Schroeder, 1968). In general, chromium intake is about 50% of the suggested level (Anderson and Kozlovsky, 1985). This is exacerbated by increased chromium losses due to stress (Anderson, 1986). For example, urinary losses of chromium are usually elevated following physical injury and strenuous exercise (Anderson et al., 1982; Borel et al., 1984). Various forms of stress that affect glucose metabolism often also influence chromium metabolism. At present, it is unclear whether the estimated safe and adequate levels for chromium are unrealistically high.

Atherosclerotic Cardiovascular Diseases

Epidemiologic and Clinical Studies

An inverse association between chromium levels in drinking water and cardiovascular disease rates has been found in some populations (Punsar and Karvonen, 1979; Punsar et al., 1975; Voors, 1971) but not in others (Crawford et al., 1968; Sauer et al., 1971; Schroeder, 1966). In addition, inverse associations between chromium levels in serum or aortic tissue and atherosclerotic cardiovascular diseases have been reported (Mertz, 1982; Schroeder et al., 1970a; Simonoff et al., 1984a, 1984b), and chromium levels in hair samples from men with atherosclerotic cardiovascular diseases were lower than levels in normal controls (Cote et al., 1979).

Most other evidence regarding chromium and cardiovascular diseases pertains to its effects on established cardiovascular disease risk factors, particularly elevated serum cholesterol. As the trivalent ion in chromium chloride or glucose tolerance factor (GTF), chromium lowered serum total cholesterol and raised the HDL fraction in healthy participants in supplementation trials (Anderson, 1986; Riales and Albrink, 1981; Simonoff, 1984). Since elevated serum cholesterol and decreased HDL cholesterol are established risk factors for CHD, these findings offer indirect evidence for a beneficial effect of chromium. However, other trials show no effects of chromium supplementation on lipids or lipoproteins (Anderson et al., 1983; Rabinowitz et al., 1983; Uusitupa et al., 1984). These differences may be explained by the dose or the form (inorganic or organic) of chromium and perhaps by differing chromium status among subjects.

There is little evidence that chromium influences high blood pressure—another risk factor for CHD. Preliminary data from an international correlation study by the World Health Organization suggest that serum chromium levels are lower in hypertensive than in normal subjects (Masironi, 1974). A study of normotensive young adults yielded no correlation between hair chromium concentration and blood pressure (Medeiros et al., 1983), but this outcome cannot rule out an effect at elevated blood pressure levels.

In patients sustained on total parenteral nutrition without added chromium, symptoms such as impaired glucose tolerance, hyperglycemia, and relative insulin resistance were observed (Freund et al., 1979; Jeejeebhoy et al., 1977). These symptoms were reversed upon chromium repletion.

Animal Studies

Mertz and Schwarz (1955) reported that rats fed a low-chromium diet consisting of torula yeast had impaired glucose tolerance. Rats fed a chromium-poor diet had severely impaired glucide metabolism and a diabetes-like syndrome with elevated cholesterol levels (Schroeder, 1968). In another study, Schroeder et al. (1970a) noted increased serum cholesterol levels and the deposition of aortic plaques in rats fed a chromium-poor diet. They also observed that the feeding of chromium at normal levels prevented both the formation of plaques and the increase in serum cholesterol with age. Rats and monkeys fed a low-chromium diet develop glucose intolerance that can be reversed by administering inorganic chromium salts (Davidson and Blackwell, 1968; Mertz, 1979). In rabbits fed a high-cholesterol diet, subsequent intraperitoneal administration of 20 µg of potassium chromate per day led to a reduction in the size of aortic plaques and a decrease in aortic cholesterol concentrations (Abraham et al., 1980).

Several biochemical mechanisms might explain the postulated association between marginal chromium deficiency and cardiovascular diseases. As noted above, marginal chromium deficiency may lead to impaired glucose tolerance, high circulating insulin levels, and impaired lipid metabolism. Chromium supplementation may also lower plasma insulin levels or the response of plasma insulin to glucose (Offenbacher and Pi-Sunyer, 1980; Riales and Albrink, 1981; Uusitupa et al., 1984). These factors have been linked to the development of atherosclerotic cardiovascular diseases. Chromium may also play a role in the maintenance of normal serum lipids, either independently or through changes in glucose and insulin metabolism (Mertz, 1979).


Epidemiologic Studies

No epidemiologic studies have shown any increased cancer risk associated with dietary exposure to inorganic or organic chromium. However, occupational exposure by inhalation of hexavalent chromium has been causally related to lung cancer risk (Doll et al., 1981), but its possible association with gastrointestinal cancers has not been established (Doll et al., 1981; Sheffet et al., 1982). Occupational exposure to trivalent chromium, one of the biologically active forms, has not been associated with an increase in cancer risk (Axelsson et al., 1980).

Animal Studies

In a long-term study of rats exposed to a range of chromium-containing materials by the intrabronchial implantation technique, Levy and Venitt (1986) found that the incidence of squamous cell metaplasia increased in all rats exposed to chromium[VI] materials or to the reference carcinogen 20-methylcholanthrene, but not in those exposed to chromium[III] material.

In a study by Maruyama (1983), chromium chloride was more effective than dipotassium chromate in decreasing the hemoglobin level and red blood cell count of rats when administered to them in drinking water. Although other evidence suggests that chromium[VI] compounds are carcinogenic, no tumors were noted in this study.

Short-Term Tests

Potassium chromate induced invivo crosslinking of proteins to DNA in intact Novikoff ascite hepatoma cells (Wedrychowski et al., 1985) and induced lambda prophage in Escherichia coli WP2S (lambda) (Rossman et al., 1984); sodium chromate induced DNA lesions and breaks in the rat organ nuclei (Tsapakos et al., 1983); and chromate[VI] ions were found to be mutagenic in platelet incorporation and fluctuation assays (Arlauskas et al., 1985). Chromium[VI] compounds were mutagenic in Salmonella typhimurium strains, whereas chromium[III] compounds were inactive in all strains (Bennicelli et al., 1983). In other experiments, Warren et al. (1981) showed that chromium[III] can be genetically toxic.

Some salts of chromium[VI] promote the morphological transformation of hamster embryo cells exposed to organic carcinogens (Rivedal and Sanner, 1981) and induce forward mutations in the thymidine locus in L51784 mouse lymphoma cells (Oberly et al., 1982). Levis, Majone, and colleagues (Levis and Majone, 1979, 1981; Majone and Levis, 1979; Majone et al., 1983) studied the clastogenic effects of numerous chromium[II], [III], [IV], and [VI] compounds on cell cultures derived from several cell types and lymphocytes. They concluded that the state of oxidation is the most important parameter affecting the mutagenic activity of chromium compounds.


Clinical Studies

In several studies, chromium supplementation has been found to improve glucose tolerance (in hypo- as well as hyperglycemic subjects) and to lower blood insulin levels (Anderson, 1986; Riales and Albrink, 1981; Simonoff, 1984). However, other reports on chromium supplementation in diabetic subjects do not clearly show a beneficial effect on blood glucose or insulin levels (Anderson, 1986; Rabinowitz et al., 1983). Chromium supplementation of patients being treated for diabetes led to a great increase in HDL cholesterol (Mossop, 1983)—an effect also observed in nondiabetic subjects. It is not known whether the apparent chromium deficiency in some diabetic subjects is a consequence or an antecedent of the disease (Simonoff, 1984).

Animal Studies

The relationship between chromium and glucose/insulin response in animal studies is discussed above under Atherosclerotic Cardiovascular Diseases.


Iodine is an essential micronutrient and an integral component of thyroid hormones. In food and water, iodine occurs largely as inorganic iodide and is absorbed from all levels of the gastrointestinal tract.

Dietary deficiency of iodine is associated with enlargement of the thyroid gland and endemic goiter. This is rare in the United States at present, since the mean daily intake is estimated to be much higher than the RDA for all sex and age groups (Fisher and Carr, 1974; Pennington et al., 1986). High intakes are due to the use of iodine in disinfectants, the addition of iodate to dough conditioners, the use of iodophors in the dairy industry, the presence of iodine in alginates, and the use of iodized table salts. No adverse effects are known to result from the present level of iodine in the U.S. diet, but the National Research Council recommends that additional increased intakes should be of concern (NRC, 1980).


Epidemiologic Studies

Cancers of two sites, thyroid and breast, have been associated with dietary iodine. In neither instance, however, is the evidence compelling. Although rates of thyroid cancer in some areas with endemic goiter (i.e., with low iodine intake) have been observed to be higher than in nongoiter areas (Wahner et al., 1966), most investigators have found no correlation of regional thyroid cancer mortality rates with corresponding endemic goiter rates or with levels of dietary iodine (Clements, 1954; Pendergrast et al., 1961; Sambade et al., 1983). Furthermore, secular trend analyses in the United States (Pendergrast et al., 1961) and Switzerland (Hedinger, 1981) show no apparent decline in thyroid cancer following the introduction of iodized salt, despite dramatic reductions in endemic goiter rates.

There is evidence that exposure to iodine may have different effects on the main histological types of thyroid cancer. Williams et al. (1977) found higher rates of papillary carcinoma and a higher ratio of papillary-to-follicular carcinoma in the population of Iceland (high iodine intake) than in northeast Scotland (average iodine intake). Wahner et al. (1966) reported a lower ratio of papillary-to-follicular carcinoma in Cali, Colombia (a low-iodine area), compared with other areas of the world. In Switzerland, despite little evidence of a change in overall thyroid cancer incidence following the introduction of iodized table salt (as noted above), the relative frequency of papillary carcinoma increased and that of follicular carcinoma decreased substantially (Hedinger, 1981).

Thus, a high intake of dietary iodine may increase the risk for papillary carcinoma and decrease the risk for follicular carcinoma, whereas low iodine intake may have the opposite effects. Not all data support this hypothesis, however. For example, Sambade et al. (1983) found no significant difference in the ratio of papillary-to-follicular carcinoma between an area of high iodine intake and an area of endemic goiter in Portugal.

Breast cancer incidence in females may be influenced by abnormalities of thyroid function (Ito and Maruchi, 1975; Mittra et al., 1974). However, the role of dietary iodine in determining the risk for breast cancer is unclear. Bogardus and Finley (1961) found a direct correlation between mortality from breast cancer by state in the United States and corresponding prevalence rates of endemic goiter. Stadel (1976) suggested that a low iodine intake might be causally related not only to breast cancer but also to endometrial and ovarian cancers with which breast cancer is highly correlated. However, support for this hypothesis is lacking. For example, all three cancers are rare in sub-Saharan Africa, where iodine intake is low (Edington, 1976), and breast cancer incidence is high in Hawaii and Iceland, where iodine intake is high (Waterhouse et al., 1976).

Animal Studies

Aquino and Eskin (1972), Eskin et al. (1967), and Eskin (1977) reported that iodine deficiency produces hyperplastic changes in the breast tissue of female rats during puberty. The changes, aggravated by estrogen treatment, advanced to preneoplastic and neoplastic conditions and were reversible by supplementation with inorganic iodine. They were not reversed by thyroxine, which in higher doses increased the dysplastic changes. Eskin (1977) proposed that iodine deficiency itself rather than hypothyroidism was responsible for these effects. He demonstrated similar changes by blocking iodine uptake with perchlorate. Upon termination of the blockade or dietary iodine supplementation, most but not all the hyperplastic tissue changes returned to normal. Iodine-deficient prepubescent rats were also susceptible to early appearance of DMBA-induced mammary tumors, suggesting a carcinogenic effect of iodine deficiency (Eskin, 1977). Exposure of iodine-deficient animals to a carcinogen such as 2-acetylaminofluorene or to thyroid irradiation has been reported to increase yields of malignant thyroid tumors (Bieschowsky, 1944; Doniach, 1958).

Ohshima and Ward (1984) reported that rats injected intravenously with the carcinogen N-methyl-N-nitrosourea (MNU) and fed an iodine-deficient diet for 33 weeks had a significant increase in incidence of thyroid carcinoma of the follicular or papillary type, as well as diffuse pituitary thyrotropic hyperplasia, hypertrophy, and vacuolar degeneration. Thus, iodine-deficient diets seem to act as tumor promoters in this system.

Longer-term experiments have confirmed this observation. Ohshima and Ward (1986) reported that MNU-treated rats fed iodine-deficient diets for 52 weeks had increased thyroid gland weight and an increased incidence of both thyroid follicular cell carcinoma and diffuse pituitary thyrotropic hyperplasia, whereas rats fed an iodine-deficient diet alone (without MNU injection) had a lower incidence of thyroid follicular adenomas and a 10% increase of follicular carcinoma. This experiment shows that an iodine-deficient diet, in addition to being a potent promoter of thyroid tumors, can also be carcinogenic.

Endemic Goiter

Epidemiologic Studies

Dietary iodine deficiency is an established, but not exclusive, cause of endemic goiter in human populations (Stanbury and Hetzel, 1980). Endemic goiter is no longer a major public health problem in the United States and will not be considered further in this report; however, the disease still occurs throughout the world in developed as well as developing countries (European Thyroid Association, 1985; Stanbury and Hetzel, 1980).


Manganese functions both as a cofactor activating a large number of enzymes that form metal-enzyme complexes and as an integral part of certain metalloenzymes. It is also involved in the metabolism of biogenic amines and participates in the regulation of carbohydrate metabolism (Hurley and Keen, 1987).

Estimates of the human requirement for manganese are based on balance studies. Approximately 0.035 to 0.070 mg/kg body weight per day results in positive balance (McLeod and Robinson, 1972; Schlage and Wortberg, 1972). The daily dietary intake in the United States has been estimated to be between 2 and 4 mg (Kazantzis, 1981). The current safe and adequate intake is 0.5 to 1.0 mg/ day for infants, 1.0 to 3.0 mg/day for children up to 10 years of age, and 2.5 to 5.0 mg/day for adolescents and adults (NRC, 1980). The best sources of manganese are plant foods, especially cereals, which contain between 10 and 100 mg/kg (Kazantzis, 1981). Manganese toxicity has been observed in humans, but the route of exposure was inhalation in an occupational setting (Ulrich et al., 1979); dietary manganese appears to be nontoxic.


Epidemiologic and Clinical Studies

No studies have specifically addressed dietary exposure to manganese and cancer risk. In a clinical study, Gregoriadis et al. (1983) found no differences in the manganese content of cancerous tissue and adjacent normal tissue at various locations in the large bowel in patients with colorectal cancer.

Animal Studies

No toxic effects were observed in rhesus monkeys that had inhaled the combustion products of methylcyclopentadienyl manganese tricarbonyl, a product found in gasoline, in concentrations of 100 µg of manganese per cubic meter of air for up to 66 weeks (Cooper, 1984). Manganese chloride, given in a single injection to mice, enhanced cell-mediated cytotoxicity (Smialowicz et al., 1984), an effect apparently mediated by interferon.

In some instances, an anticarcinogenic role has been ascribed to manganese. In a study of an experimental tumor system, increased concentrations of manganese were found in malignant tissues, especially in the nuclear fraction of the cancerous cells (Ranade et al., 1979). The investigators suggest the use of transition metals (manganese, copper, and zinc) as markers of malignancy.

Short-Term Tests

Miyaki et al. (1979) reported that manganese was mutagenic in cultured V79 Chinese hamster cells. Hsi et al. (1979) found manganese to be mutagenic in the Chinese hamster ovary cell. Other researchers observed that manganese caused chromosome aberrations or possible transformations in several in vitro systems (DiPaolo and Casto, 1979; Umeda and Nishimura, 1979). The addition of soluble manganese salts altered the fidelity of DNA synthesis in vitro (Dube and Loeb, 1975; Sirover and Loeb, 1976, 1977; Van de Sande et al., 1982). Enhanced viral transformation of hamster embryo cells was demonstrated with manganese chloride (Casto et al., 1979). Manganese salts were comutagenic with ultraviolet exposure in Escherichia coli WP2 (Rossman and Molina, 1986). Mutagenesis was detected in the lacI gene of E. coli in cells grown in the presence of manganese (Zakour and Glickman, 1984). Manganese chloride induced lambda prophage in E. coli WP2S (lambda) (Rossman et al., 1984). Thus, various compounds of manganese have been found to be genotoxic and mutagenic in short-term tests.


Clinical Studies

A relationship between dietary manganese and carbohydrate metabolism in humans was suggested by Rubenstein et al. (1962). They described the case of a diabetic patient resistant to insulin therapy who responded to oral doses of manganese chloride (but not other trace elements) with a consistent drop in blood glucose levels.

Animal Studies

In laboratory animals, an essential role of manganese in carbohydrate metabolism was demonstrated by Everson and Shrader (1968), who found that guinea pigs born to manganese-deficient dams and fed manganese-deficient diets from birth to 60 days of age had abnormal glucose tolerance curves and decreased utilization of glucose. Histological examination showed that the deficient animals had hypertrophied pancreatic islet tissue with degranulated β-cells and an increased number of α-cells. All these signs of manganese deficiency were reversed following dietary manganese supplementation for 2 months. A similar observation was reported by Shani et al. (1972), who found that the sand rat, whose natural diet is high in manganese, developed an insulin-resistant diabetes when fed a commercial rat feed containing relatively low levels of manganese. The diabetic condition cleared up after the manganese-rich natural diet was reintroduced.

Baly et al. (1984) observed that the adult manganese-deficient offspring of manganese-deficient rats also had diabetic-like glucose tolerance curves, but that their plasma insulin levels were not commensurate with their high plasma glucose levels. Pancreatic manganese, insulin concentration, and insulin output from the perfused pancreas of these deficient rats were lower than in controls. Insulin synthesis as well as release was impaired by manganese deficiency, indicating a role for manganese in insulin biosynthesis, whereas pancreatic glucagon release was not affected by manganese deficiency (Baly et al., 1984).

Manganese deficiency may also help influence carbohydrate metabolism through effects on phosphoenolpyruvate carboxykinase, for which manganese is a cofactor, or pyruvate carboxylase, a manganese metalloenzyme. Baly et al. (1985) found that pyruvate carboxylase activity in the liver of adult manganese-deficient rats was normal in the fed state but lower than that of controls after they fasted for 48 hours.

Alzheimer's Disease

Markesbery et al. (1984) sampled the manganese content of tissue samples from various regions of the brain and found no differences between patients with Alzheimer's disease and a control group of nondemented adults. (This contrasts with the findings regarding another trace element, aluminum, described below. ) The manganese content of the control samples also showed no relationship to age.

Coronary Heart Disease

In male patients with and without CHD, as demonstrated by angiography, Manthey et al. (1981) found a progressive increase in serum manganese levels corresponding to the severity of the disease. The investigators reported a similar relationship for copper and an opposite relationship for magnesium. Serum manganese was also positively correlated with blood pressure. On the other hand, a comparison of drinking water sources in two regions of Finland with different rates of mortality from coronary heart disease in men showed no significant difference in the mean concentration of manganese, whereas differences were found for certain other trace elements, including copper and chromium (Punsar et al., 1975).


The requirement for molybdenum can only be estimated from balance studies (Golden et al., 1985). The estimated safe and adequate intake set by a committee of the National Research Council's Food and Nutrition Board is 0.15 to 0.5 mg for adults (NRC, 1980). High intakes of molybdenum (above 0.5 mg) can compromise copper balance (Nielsen and Mertz, 1984). Intakes of 10 to 15 mg/ day have been associated with gout in the Soviet Union (Koval'skii et al., 1961). Diet-induced molybdenum deficiency has been found in one patient on total parenteral nutrition (Abumrad et al., 1981). The role of molybdenum in animal and human nutrition has been reviewed by Hainline and Rajagopalan (1983).


Epidemiologic Studies

No epidemiologic reports have clearly associated molybdenum with cancer risk. However, the soil content of molybdenum (and other trace elements) has been inversely correlated with esophageal cancer mortality rates in high-risk areas for this cancer in China and Africa, and low molybdenum levels in water supplies have been correlated with excess esophageal cancer mortality in the United States (Lu and Lin, 1982; NRC, 1982). Supplementation of soil in the high-risk region of China has altered the chemical composition of locally produced grains and vegetables, but as yet there have been no reports of an associated reduction in esophageal cancer incidence or mortality.

Animal Studies

Luo et al. (1981, 1983) found that molybdenum supplementation tended to reduce the induction of tumors by gastric intubation of N-nitrososarcosine ethyl ester in the esophagus and forestomach of Sprague-Dawley rats. They also observed that 200 ppm concentrations of dietary tungsten countered the inhibitory effect of molybdenum at natural

dietary levels (Luo et al., 1983). Later, Wei et al. (1985) observed that molybdenum added to the drinking water inhibited mammary carcinoma induced in female rats by intravenous injection of N-methyl-N-nitrosourea (MNU) and that the effect was countered by tungsten.

Sprague-Dawley rats received either selenium as sodium selenite in drinking water, low or high doses of molybdenum as sodium molybdate in drinking water, or distilled, deionized water before being given methylbenzylnitrosamine intragastrically. Most rats on each regimen had precancerous lesions, and all had papillomas. Molybdenum was not observed to be a cocarcinogen (Bogden et al., 1986).

Molybdenum given intraperitoneally as molybdenum oxide was shown to induce a large increase in the number of lung adenomas in strain A mice (Stoner et al., 1976). These differing results cannot be reconciled at this time.

Other Diseases

Adding molybdenum to a diet containing sodium fluoride reduced dental caries in rats (Büttner, 1963).


Aluminum is the second most plentiful element in the earth's crust. Its concentrations in seawater and freshwater are usually quite low but are increasing in some surface waters because of acid rain.

Ingestion of aluminum in foods ranges from 3 to 5 mg/day (Gorsky et al., 1979; Greger and Baier, 1983). Dietary sources include aluminum used as a filler in pickles and cheese or as a major component of some types of baking powder. Aluminum is also leached from cooking utensils during preparation of acid foods. Drinking water is another source; the U.S. Environmental Protection Agency reported that some municipal waters contain as much as 2 to 4 mg/liter (Miller et al., 1984). Little of the ingested aluminum is actually absorbed, however, so that the total body content is extremely low and does not increase with age (Alfrey, 1986).


Epidemiologic Studies

Exposure to aluminum from food or water has not been associated with an increase in cancer risk for humans in any reports. In a few epidemiologic studies, workers in aluminum smelters were found to have an increased risk for cancer, particularly of the lung and bladder (Gibbs, 1985; Rockette and Arena, 1983; Simonato, 1981). In a case-control study of bladder cancer among aluminum smelter workers, the authors concluded that exposure to polycyclic aromatic hydrocarbons (PAHs), not aluminum, was probably the source of the increased risk (Thériault et al., 1984). At present, there is no reliable evidence that aluminum is carcinogenic in humans.

Animal Studies

Aluminum nitrilotriacetate was tested in male Wistar rats for nephrotoxicity and carcinogenicity (Ebina et al., 1986). No tumors developed. Thus, the authors suggest that aluminum is not related to renal carcinogenicity. In mice pretreated with aluminum, administration of dimethylnitrosamine by intraperitoneal injection once a week for 3 weeks resulted in a lower incidence of lung tumors than in untreated mice (Yamane et al., 1981). The incidence of lung tumors was also lower in groups pretreated with aluminum and then subjected to nitroquinoline oxide (Kobayashi et al., 1970).

Pigott et al. (1981) exposed rats to two types of alumina fibers by inhalation. They recorded minimal pulmonary reaction, supporting the contention that the alumina fibers were inert.

Short-Term Tests

Rat alveolar macrophages containing ingested aluminum oxide were incubated for 24 hours with dimethylbenzanthracene (DMBA) (Palmer and Creasia, 1984). The aluminum oxide did not act as a cocarcinogen with the DMBA.

Alzheimer's Disease

Epidemiologic and Clinical Studies

Incidence rates of Alzheimer's disease were positively correlated with the concentration of aluminum in county district water supplies in England and Wales (Martyn et al., 1989). In patients with Alzheimer's disease, higher levels of intracellular aluminum have been found in the neurofibrillary tangles of the hippocampal region than in other areas of the brain or in nonaffected control patients (Perl and Brody, 1980). Similar increases in neuronal aluminum have been found in members of the Chamorro population on Guam afflicted with amyotrophic lateral sclerosis or parkinsonian dementia (Garruto et al., 1984; Perl, 1985). In two other areas of the Pacific with similar neurological disorders (parts of southern Japan and New Guinea), the soil and water are rich in aluminum and poor in calcium and magnesium (Perl, 1985). This suggests that aluminum could be a common etiologic factor in several related neurological conditions.

However, present evidence does not exclude the possibility that the accumulation of aluminum in brain tissue is secondary to the degeneration in the affected neurons (Shore and Wyatt, 1983). Supporting this view is the finding that the use of aluminum-containing antacids by patients with Alzheimer's disease was not higher than in matched controls (Heyman et al., 1984), nor were there differences between patients and controls in serum, cerebrospinal fluid, or hair levels of aluminum (Shore and Wyatt, 1983). Furthermore, there are no reports of increased risks for Alzheimer's disease among workers in aluminum smelters (Perl, 1985).

Animal Studies

Troncoso et al. (1986) postulated that aluminum may produce damage by altering patterns of neurofilament phosphorylation, as has been recently observed in Alzheimer's disease. Antibodies against phosphorylated and nonphosphorylated neurofilament epitopes were used for immunocytochemical analysis of spinal cord sections from aluminum-treated rabbits. Proximal axons of affected motor neurons showed striking accumulations of immunoactivity of one phosphorylated epitope. This pathological finding was similar, but not identical, to the patterns observed in the neurofibrillary tangles in Alzheimer's disease. Benuck et al. (1985) have reported similar findings. De Boni (1985) reported that in cultured human cells, aluminum interacts with acidic nuclear proteins, decreases steroid binding, and produces a form of neurofibrillary degeneration.

The primary lesion in Alzheimer's disease is postulated to be an impaired permeability of the blood-brain barrier that allows neurotoxins such as aluminum to reach the central nervous system (Banks and Kastin, 1983; Crapper et al., 1980). Intraperitoneal injection of aluminum chloride into rats increased the permeability of the blood-brain barrier to certain peptides by 60 to 70% (Banks and Kastin, 1983). Direct injection of aluminum into the cerebrospinal fluid of cats resulted in a progressive encephalopathy with neurofibrillary degeneration and increased intranuclear aluminum content (Crapper et al., 1980).


Cadmium is known to be toxic at certain levels but may also have a physiological function (Schwarz, 1977). It is absent from the human body at birth and accumulates over the years to approximately 50 years of age (Underwood, 1977). The most recent data from a large-scale survey on the mean cadmium intake from food and water in the United States comes from the Food and Drug Administration's market-basket survey conducted during 1968-1974. These data indicate that the mean cadmium intake from birth to 50 years of age ranges from 26 to 38 µg/day, adjusted for calories and age (Mahaffey et al., 1975; Ryan et al., 1982). Most foodstuffs contain less than 0.05 mg of cadmium per kilogram, but considerably higher amounts may be found in certain types of seafood and in beef liver and kidney (Elinder, 1985).

Cadmium accumulates in the fiber-rich parts of plants and the cotyledon (Moldrup, 1984). The cadmium content of plants varies with the type of plant and soil characteristics, particularly pH. An extensive report on cadmium uptake by plants has been published (CAST, 1980), and the potential hazard of increasing cadmium levels in plants through crop fertilization is being comprehensively evaluated (Bingham, 1979; Ryan et al., 1982; Yost, 1979). In addition to diet, people may be exposed to cadmium through their occupation, household dust, or smoking (Elinder, 1985; Nordberg et al., 1985).


Epidemiologic Studies

The human health effects of exposure to cadmium have been extensively reviewed (Friberg et al., 1985b); however, few investigators have focused on exposure to cadmium in food and drinking water. Most of these studies have been based on ecologic correlations. Cadmium levels in drinking water supplies in the United States and Canada have been positively correlated with incidence or mortality rates of prostate and other cancers (Bako et al., 1982; Berg and Burbank, 1972). Similarly, per-capita cadmium intakes (based on food disappearance data) in more than 20 countries and cadmium levels in pooled blood samples in the United States have been positively correlated with cancers at several different sites (Schrauzer et al., 1977a,b). In a case-control study, Kolonel (1976) found a positive association between renal cancer and combined exposure to cadmium from diet, cigarette smoking, and occupation.

In contrast to these positive associations between cadmium intake and cancer risk, Inskip et al. (1982) found no evidence that mortality from cancer at any site was increased in a village with a high soil cadmium content in Britain, and Shigematsu (1984) found no difference in prostate cancer mortality between cadmium-polluted and control areas in Japan.

Prostate tissue levels of cadmium were higher in men with prostatic cancer than in men with benign prostatic hypertrophy (BPH) or normal prostates (Feustel et al., 1982), but such tissue differences may reflect a secondary accumulation of cadmium in malignant tissue. The increased cadmium levels found in lung tissue from patients with bronchogenic carcinoma (Gerhardsson et al., 1986) are undoubtedly a reflection of the association of this cancer with tobacco use, since cigarette smoke contains cadmium (IARC, 1976).

Although several studies of workers occupationally exposed to cadmium indicate increased risks for prostate cancer (Adams et al., 1969; Kipling and Waterhouse, 1967; Kjellström et al., 1979; Lemen et al., 1976; Potts, 1965), other reports, including updated analyses of some of the earlier studies, have not supported this association (Armstrong and Kazantzis, 1983; Kolonel and Winkelstein, 1977; Sorahan and Waterhouse, 1983; Thun et al., 1985).

Animal Studies

Subcutaneous injections of cadmium as sulfide, oxide, sulfate, or chloride induced sarcomas and Leydig cell tumors of (WI/Cbi) Wistar rats (Haddow et 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). Lung carcinomas were found in rats exposed to cadmium chloride aerosols (Takenaka et al., 1983). Exposure of experimental animals to soluble forms of cadmium causes renal, hepatic, pulmonary, hematopoietic, and testicular damage as well as chromosome aberrations and immunotoxicity (Friberg et al., 1979).

Intratracheal instillation of cadmium oxide at 75% of the LD50 caused mammary tumors in rats (Sanders and Mahaffey, 1984), whereas injection of cadmium chloride into the prostate induced tumors of the prostate (Scott and Aughey, 1978) or the pancreatic islet cells (Poirier et al., 1983).

No carcinogenic response has been observed in mice given cadmium at 5 mg/liter drinking water (Schroeder et al., 1964, 1965) or in rats fed cadmium chloride at concentrations up to 50 mg/g diet for 2 years (Löser, 1980).

Short-Term Tests

Various salts of cadmium decreased the fidelity of avian myeloblastosis virus AMV/DNA polymerase for replication of synthetic polynucleotide templates (Sirover and Loeb, 1976). Cadmium salts were mutagenic to Escherichia coli (Yagi and Nishioka, 1977) and Salmonella typhimurium and were positive in the Bacillus subtilis rec-assay (Nishioka, 1975). In vitro treatment of human lymphocytes with cadmium sulfide and cadmium[II] induced chromosome aberrations (Andersen, 1983; Shiraishi et al., 1972). Cadmium[II] induced the formation of morphologically altered colonies in Syrian hamster fetal cells (Casto et al., 1976; Rivedal and Sanner, 1981). Cadmium[II] also induced forward mutations in the thymidine kinase locus in certain strains of mouse lymphoma cells (Oberly et al., 1982). Other researchers found that cadmium[II] is not clastogenic (Ohno et al., 1982; Umeda and Nishimura, 1979). Short-term tests thus indicated that cadmium can be mutagenic and possibly clastogenic. The relationship of these data to human risk remains to be determined.


Epidemiologic Studies

There is little evidence on the relationship of dietary cadmium intake to hypertension in humans. Two studies based on samples of residents of two different communities in the United States indicated a positive correlation between cadmium in drinking water and blood pressure levels (Folsom and Prineas, 1982). In another study, conducted in the United Kingdom, mortality from hypertension was moderately increased among males but not among females in a village with high levels of cadmium in the soil (Inskip et al., 1982). In another, the prevalence of hypertension in areas of Japan where drinking water and rice are heavily contaminated with cadmium was not greater than in control areas (Shigematsu et al., 1979).

In several studies, the levels of cadmium in blood, hair, and renal tissue in normotensive and hypertensive subjects have been compared, but the findings have not been consistent (Adamska-Dyniewska et al., 1982; Beevers et al., 1980; Cummins et al., 1980; Ewers et al., 1985; Lener and Bibr, 1971; Medeiros and Pellum, 1984; Ostergaard, 1978). The results of these studies are difficult to interpret, however, because most investigators did not adequately address such concerns as the accumulation of cadmium in tissues with age, exposure to cadmium through smoking, the poor correlation of blood levels of cadmium with long-term exposure, and the possibility of artificially low cadmium levels in the tissues of hypertensive subjects secondary to renal damage and urinary loss of stores.

Most studies of occupational groups exposed to cadmium have shown no increase in mortality from hypertension (Armstrong and Kazantzis, 1983; Sorahan and Waterhouse, 1983; Thun et al., 1985). Cigarette smoking, an important source of exposure to cadmium (IARC, 1976), also was not associated with hypertension (Friedman et al., 1982).

Animal Studies

Despite some evidence linking cadmium exposure to hypertension in animals, the mechanism of action is poorly understood. Doses insufficient to produce other signs of cadmium toxicity induced hypertension in animal models, whereas high doses chronically administered produced toxicity but no hypertension (Kopp et al., 1980, 1983; Perry et al., 1980; Schroeder et al., 1962). However, not all investigators were able to demonstrate cadmium-induced hypertension in feeding studies in rats and dogs (Eakin et al., 1980; Fingerle et al., 1982; Perry et al., 1980; Whanger, 1979). According to Perry and Kopp (1983), the presence of other elements such as selenium, copper, and zinc may have counteracted the hypertension-inducing action of cadmium. Talwar et al. (1985) demonstrated that cadmium produced a biphasic response in rats over time, i.e., an initial fall followed by a sustained increase in blood pressure. Cadmium-induced hypertension has also been associated with an increase in plasma noradrenalin (Revis et al., 1983).

Carmignani and Boscolo (1984) studied hemodynamics and cardiovascular reactivity to various physiological agonists in rats given cadmium. Cadmium exposure from the environment reduced the pressor effects of intravenous norepinephrine, angiotensin, and elevated doses of epinephrine, and also reduced the depressor effects of bradykinin. The exposed rats also had an increased vascular responsiveness to the β-adrenoceptor-stimulating effects of lower doses of epinephrine. That study suggests that cadmium affects several neurohumoral mechanisms that regulate cardiovascular function.

Renal Diseases

The kidney is the first organ affected by long-term exposure to cadmium. Severe renal cadmium poisoning may affect the glomerular filtration rate and cause tubular damage (Adams et al., 1969; Friberg et al., 1985a). It is unlikely that humans would ever encounter dietary exposures sufficiently high to produce these effects, except for an unusual contamination of foods.

Bone Diseases

Renal dysfunction secondary to long-term human exposure to high concentrations of cadmium in food or air may eventually lead to osteomalacia (Friberg et al. 1985b). Studies in rats show that under certain experimental conditions, cadmium can induce osteomalacia or osteoporosis (Kawamura et al., 1978; Nogawa et al., 1981; Takashima et al., 1980). A contributing factor may be the suppression of 1,25-dihydroxycholecalciferol by exposures to high levels of dietary cadmium (Lorentzon and Larsson, 1977). Chronic cadmium toxicosis was also reported to result in osteoporosis and nephrocalcinosis in horses (Gunson et al., 1982).


In nature, mercury is found mainly in low concentrations as sulfides in the earth's crust, except for rich focal deposits where it may also be present in metallic form. Soil levels of metallic mercury are low (Kazantzis, 1981). Methyl mercury, completely absorbed from the gastrointestinal tract as a lipid-soluble compound, readily accumulates in the brain. Its half-life in the body is estimated to be approximately 70 days (Chisolm, 1985).

Occupational exposure occurs most commonly through inhalation of metallic mercury vapor or of a variety of inorganic mercury compounds such as aerosols and alkyl mercurials. The provisional tolerable weekly intake established by the World Health Organization (WHO, 1972) is 0.3 mg of total mercury, of which not more than 0.2 mg should be present as methyl mercury.


Epidemiologic Studies

The major form of mercury in food is methyl mercury, which is ingested primarily through marine products. There is no epidemiologic evidence that such exposure is associated with cancer in humans. In a retrospective cohort analysis, occupational exposure to elemental mercury was not clearly associated with increased mortality from cancer at any site, although there was a small increase in deaths from renal cancer (Cragle et al., 1984).

Animal Studies

Mercuric chloride was reported to induce murine renal cell carcinoma in mice (Herr et al., 1981). Female Swiss mice were exposed to mercury concentrations of 1.0 to 2.0 µg/ml as methyl mercury in the drinking water. After 3 weeks all mice were given 1.5 mg/g of methyl mercury intraperitoneally per gram of body weight. Twelve weeks later, the incidence of pulmonary adenomas was significantly higher in the mice initially given the higher doses. Mercury at the levels given in the drinking water did not cause any clinical manifestations (Blakley, 1984).

Short-Term Tests

Mercuric chloride at acutely cytotoxic doses caused a rapid induction of DNA single-strand breaks in cultured Chinese hamster ovary cells (Cantoni and Costa, 1983) and inhibited the repair of these breaks, but the authors suggest that the compound was not severely mutagenic or carcinogenic.

Skerving et al. (1970) observed dose-related chromosome aberrations in the lymphocytes of people who consumed methyl mercury-contaminated fish. At blood methyl mercury levels of 100 µg/liter, they found an increase of aneuploidy, unstable chromosome-type aberrations, and cells with chromatid-type aberrations.

Other Diseases

Epidemiologic Studies

The primary organ affected by chronic exposure to inorganic or organic mercury is the brain, although renal damage may also occur (Berlin, 1979). In 1953 and 1965, in the Kumamoto and Niigata prefectures of Japan, respectively, severe poisoning occurred from the ingestion of fish heavily contaminated with methyl mercury. This disease, known as Minamata disease, is characterized by a spectrum of neurological symptoms and signs (Tsubaki and Irukayama, 1977). In a comparison of Minamata disease patients and residents of an unaffected area in Japan, a higher prevalence of hypertension was found in the patients, perhaps secondary to renal damage (Tsubaki and Irukayama, 1977). An occupational group exposed to elemental mercury had no evidence of increased mortality from nonmalignant diseases of the brain, kidney, liver, or lung (Cragle et al., 1984).


Schwarz (1977) postulated that arsenic is essential for growth in animals, and the evidence for essentiality of very low levels has grown considerably (Anke, 1986; Nielsen, 1982). Small amounts of this element are widely distributed 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 (e.g., the unintentional residue of the insecticides calcium arsenate or lead arsenate). Daily intakes of arsenic in the United States are estimated to range from 10 to 130 µg (Buchet et al., 1983).

Absorption, retention, and excretion of arsenic are influenced by the chemical form and the amount in which it is ingested. Rats, unlike other mammals, concentrate arsenic in their blood and appear unique in their metabolic management of arsenic (Dutkiewiez, 1977). Thus, experimental findings from rats may not be applicable to other species.

Atherosclerotic Cardiovascular Diseases

Epidemiologic Studies

Chronic exposure to arsenic through drinking water has been associated with peripheral vascular disease in Taiwan, Mexico, and Chile (NRC, 1977a; Tseng, 1977; Zaldivar and Ghai, 1980). Exposure of vintners, probably through consumption of contaminated wine as well as inhalation of dusts contaminated with arsenical insecticides, has also been associated with peripheral vascular disease (NRC, 1977a). However, exposure of U.S. populations in Alaska and Oregon to contaminated well water (at levels much lower than those found in Taiwan and Chile) was not associated with signs or symptoms of peripheral vascular disease (Harrington et al., 1978; Morton et al., 1976). Although excess mortality from cardiovascular, mainly cerebrovascular, diseases was found in a cohort of Swedish copper smelter workers exposed to arsenic, it was not possible to attribute the risk to arsenic exposure in particular (Wall, 1980).

Animal Studies

The committee did not find information regarding arsenic and cardiovascular diseases in animal models.


Epidemiologic Studies

Inorganic arsenic has been identified as a human carcinogen, associated with malignancies of the lung, skin, and possibly liver (Landrigan, 1981; NRC, 1977a; Pershagen, 1981). Because most epidemiologic studies of arsenic have been carried out in occupational settings, the potential carcinogenic effects of human exposure through food sources—particularly seafoods, which contain primarily organic arsenic (Pershagen, 1981)—have not been well studied. In Japan, population exposures to arsenic through food (powdered milk, soy sauce) and well-water contamination were not associated with the occurrence of cancers of the skin, lung, or other sites (Tsuchiya, 1977).

The primary source of ingested inorganic arsenic is drinking water. In areas where populations have high exposures through water sources, such as artesian wells in the southwest region of Taiwan, arsenic has been associated with nonmelanotic skin cancers and possibly with cancers of the lung, bladder, and liver (Chen et al., 1985, 1986; NRC, 1977a,b). Studies of exposed populations in the western United States were negative, possibly because the levels of exposure were much lower than in Taiwan (Calabrese, 1983; Harrington et al., 1978; Morton et al., 1976). Reports of increased risks for cancer of the skin, lung, and liver among vineyard workers in the Federal Republic of Germany and in France, who were exposed to arsenic through pesticide use, suggest that contaminated grapes or wine may be another potable source of exposure (NRC, 1982). However, these workers were exposed by inhalation as well as by ingestion. Thus, more research is necessary to establish the association as causal.

Smelter workers exposed to airborne inorganic arsenic are at increased risk for lung cancer (Lee-Feldstein, 1986; Pershagen et al., 1981; Wall, 1980). Medicinal use of arsenic, particularly as Fowler's solution (potassium arsenite), has been associated with nonmelanotic skin cancer and angiosarcomas of the liver in several case reports, but not in a follow-up study on 478 subjects treated with arsenic (Cuzick et al., 1982; Roat et al., 1982).

Animal Studies

Epidemiologic evidence of the carcinogenicity of arsenic in humans has not been confirmed in most animal studies (Furst, 1983; Leonard and Lauwerys, 1980; Pershagen, 1981). Several earlier long-term studies in rats and mice given arsenic or its salts in food or drinking water failed to show that it is either a carcinogen or a cocarcinogen (Baroni et al., 1963; Boutwell, 1963; Furst, 1977; Hueper and Payne, 1962).

Arsenic administered as arsenite at a level of 100 µg/liter drinking water for 15 months reduced mammary tumor incidence in female mice; however, once the tumors were established, arsenite enhanced their growth rate (Schrauzer and Ishmael, 1974). Shirachi et al. (1983) suggested that sodium arsenite increases the incidence of diethylnitrosamine-initiated renal tumors in rats by acting as a promoter.

Arsenic compounds were weakly carcinogenic in hamsters (Ishinihsi and Yamamoto, 1983). In dogs, a 2-year feeding study failed to show that sodium arsenite or arsenate was carcinogenic (Byron et al., 1967).

Short-Term Tests

Arsenic[III] yielded positive results in a Bacillus subtilis rec-assay (Nishioka, 1975). Later reports by Rossman and colleagues (Rossman, 1981a,b; Rossman et al. 1980) and Simonato (1981) indicate that arsenic[III] does not induce mutations in tryptophan auxotrophic strains of Escherichia coli. Tiedemann and Einbrodt (1982) reported negative results for arsenic[III] and [V] in the Ames Salmonella microsome assay. Arsenic[III] transformed Syrian hamster cells in vitro and enhanced the susceptibility of these cells to transformation by simian adenovirus (Casto et al., 1976). Larramendy et al. (1981) found that sodium arsenite elevates the sister chromatid exchange frequency from 11 to 19 in Syrian hamster cells.

Chromosome aberrations were found in leukocytes and fibroblasts in humans after exposure to arsenic compounds (Paton and Allison, 1972; Petres and Berger, 1972). Arsenic also appeared to enhance the clastogenic effect of cigarette smoking in lymphocytes of smelter workers (Nordenson et al., 1978).


Lead is not known to be essential to human nutrition. However, trace amounts of lead (29 ng/ g diet) have been reported to be essential in rats to maintain growth, reproduction, and hematopoiesis (Reichlmayr-Lais and Kirchgessner, 1981). Humans are exposed to oxides and salts of lead through various environmental sources, such as automobile exhausts, atmospheric dust, paint, or contaminated drinking water, food, and whiskey. Formerly, the main contributor was the lead that leached into canned foods (Chisolm, 1985), but the food canning industry has since converted from lead-soldered to lead-free cans. At present, the major source of lead exposure is likely to be dust particles from paint or the soil carried into homes.

The World Health Organization/Food and Agriculture Organization (WHO, 1978) recommended a permissible level of lead intake for adults up to 490 µg of lead per day or 7 µg/kg body weight per day. There is no comparable standard for infants and children. In metabolic balance studies, however, Ziegler et al. (1978) found that a daily lead intake exceeding 5 µg/kg per day is associated with positive lead balance in infants up to 24 months of age. Excess lead intakes by children (blood lead levels >20 µg/dl) have been associated with impairment of a variety of enzymatic and neurophysiological processes (Mahaffey et al., 1982; Otto et al., 1985; Piomelli et al., 1982).

Atherosclerotic Cardiovascular Diseases

Epidemiologic Studies

(See section on Hypertension, below.)

Animal Studies

Signs of cardiac disease are frequently observed as part of the syndrome of lead intoxication in animals. Neonatal animals are particularly susceptible to small doses of lead (Williams et al., 1983); rats given ≤1 µg of lead per milliliter of drinking water for 25 weeks developed ultrastructural changes in the cardiac mitochondria, including the loss of regular spacing and orientation of the cristae (Moore et al., 1975).


Epidemiologic Studies

There is little information on cancer risks associated with dietary exposure to lead, and the data are not specific. Berg and Burbank (1972) correlated the levels of lead and seven other trace elements in the water supplies of 10 regions of the United States with corresponding cancer mortality rates in the population. The levels of lead and several other elements were positively correlated with several malignancies, including gastrointestinal and hematopoietic cancers.

In an analysis of cancerous and surrounding noncancerous tissues taken from several locations in the large bowel of patients with colorectal cancer who had no special occupational exposures, Gregoriadis et al. (1983) found increased concentrations of lead (as well as nickel and copper, but not zinc or manganese) in the cancerous tissue; however, this trace metal accumulation could have been a consequence rather than a precursor of the cancers.

Most epidemiologic evidence pertaining to the possible carcinogenic effects of lead is based on occupational exposures. Studies of workers in smelters and plants producing or utilizing lead have generally shown no increase in mortality from cancer (Davies, 1984; Dingwall-Fordyce and Lane, 1963; Robinson, 1976; Selevan et al., 1985). However, in a follow-up study on two cohorts of workers exposed to lead (smelter and battery plant workers), the investigators observed increased mortality from cancers of the lung and stomach, but they did not control for cigarette smoking and other exposures that are potentially carcinogenic for these sites (Cooper et al., 1985). Evidence for an association between Wilms's tumor in children and possible occupational exposure to lead by the fathers has not been consistent (Kantor et al., 1979; Wilkins and Sinks, 1984a,b).

Animal Studies

Swiss mice fed 0.1% lead subacetate had a much higher frequency of renal tumors than did untreated controls (Van Esch and Kroes, 1969). In long-term feeding studies, the number of renal tumors in Wistar rats increased after treatment with lead acetate (Hass et al., 1967; Hiasa et al., 1983; Ito, 1973; Ito et al., 1971; Mao and Molnar, 1967; Van Esch and Kroes, 1969). Lead nitrate and lead powder were not carcinogenic when fed to Long Evans or Fischer rats (Furst et al., 1976; Schroeder et al., 1970b).

Rats fed lead at 2,600 ppm in their diet for 76 weeks had an 81% incidence of renal tumors, whereas those fed 2,600 ppm in combination with ethylurea and sodium nitrite had a 50% incidence of tumors (Koller et al., 1985). Lead did not appear to be syncarcinogenic to the activity of ethylnitrosourea—the carcinogen formed by oral exposure to ethylurea and sodium nitrite. The lead-induced renal neoplasms were histologically similar to those that occur spontaneously in humans and therefore may serve as an animal model to study human disease. Lead in the form of lead acetate was found to accelerate the onset and development of all renal lesions in rats exposed to N-(4'-fluoro-4-biphenyl)acetamide (Tanner and Lipsky, 1984). Lead acetate was also a promoter of 2-(ethylnitrosamino)ethanol-induced renal carcinomas in Fischer 344 rats (Shirai et al., 1984). Male rats were injected close to the prostate with either 50 µg of lead acetate, 50 µg of cadmium chloride, or 25 µg of both. After daily injections for 1 month, lead and cadmium exerted a synergistic effect on testicular damage and prostatic cytology. Although no tumor formation was observed in the prostate, tissue changes were suggestive of progressive precancerous changes (Fahim and Khare, 1980).

Short-Term Tests

Lead[II] reacted with phosphate groups of DNA bases to yield stable complexes (Sissoëff et al., 1976; Venugopal and Luckey, 1978). Lead chloride diminished the fidelity of DNA polymerase (Sirover and Loeb, 1976).

Lead acetate was negative in the Ames Salmonella assay test and in the Escherichia coli pol A assay for DNA-modifying effects (Rosenkranz and Poirier, 1979); in the host-mediated assay in Swiss Webster mice with Ames Salmonella strains and Saccharomyces cerevisiae D3 (Simmon, 1979); and in the Bacillus subtilis rec assay (Kada et al., 1980; Kanematsu et al., 1980; Nishioka, 1975). Long-term exposure to subtoxic doses of lead nitrate facilitated the induction of lambda prophage in E. coli WP2S (lambda) (Rossman et al., 1984).

There were more achromatic lesions in Chinese hamster ovary cells treated with lead acetate than in untreated controls (Bauchinger and Schmid, 1972). Morphological transformations of Syrian hamster embryo cells were observed after exposure to lead acetate (1 to 2.5 g/liter of medium), which produced fibrosarcomas (DiPaolo et al., 1978). Increased rates of sister chromatid exchanges were observed in human lymphocytes and macrophages exposed to lead[II] (Andersen, 1983). Lead increases misincorporation of nucleotide bases in the daughter strand of DNA that is synthesized in vitro from polynucleotide templates by microbial DNA polymerases (Zakour et al., 1981a,b).


Epidemiologic and Clinical Studies

Several studies of patients with hypertension have suggested a possible association with lead. In an area of Scotland with relatively high levels of lead in water supplies, blood lead levels of hypertensive patients were higher than those of normotensive controls (Beevers et al., 1980). Levels of lead (and of cadmium and zinc) in the hair of hypertensive black women in the United States were higher than corresponding levels in normotensive controls (Medeiros and Pellum, 1984). Batuman et al. (1983) studied patients with essential hypertension (some of whom had evidence of renal impairment) and controls and found higher lead levels in the patients, independent of renal impairment.

Data on the relationship of lead to blood pressure levels in primarily normotensive populations are conflicting. Weiss et al. (1986) and Pirkle et al. (1985) found positive correlations between blood lead levels and blood pressure among U.S. white males. Pirkle's study was based on NHANES II. In contrast, Pocock et al. (1984) found no correlation in a representative group of British men similar to the NHANES II sample. Similarly, there was no correlation between the lead content of drinking water and blood pressure levels in two areas of the United States and one area of Finland, but there was a modest correlation in another area of Finland (Calabrese and Tuthill, 1978; Punsar et al., 1975). Some of these conflicting results may be attributed to the exposure measures used, since blood levels of lead do not reflect the body burden (Batuman et al., 1983) and therefore may not be meaningful indicators of chronic exposure. Most occupational studies have shown no association between lead exposure and hypertension (Beevers et al., 1980; Lilis et al., 1984; Robinson, 1976; Selevan et al., 1985), but two of them suggest an increased risk (Cooper et al., 1985; Lilis et al., 1982).

Animal Studies

Hypertension was found in rat pups whose mothers were fed lead during gestation and lactation and was associated with defects in the renin-angiotensin system (Victery et al., 1982). Tarugi et al. (1982) reported lead-induced elevation of plasma lipoproteins and cholesterol esters in rats.

Renal Diseases

Epidemiologic and Clinical Studies

One plausible mechanism for the effect of lead on hypertension is through kidney damage and consequent impaired renal control of blood pressure. Although evidence of renal damage was not found in many of the reports cited (see section on Hypertension, above), slight degrees of impairment are likely to have been missed in most such studies (Meyer et al., 1984).

Animal Studies

Chronic exposures of rats to lead at 0.5 to 250 mg/g body weight per day for as long as 9 months resulted in pathological changes in the kidney, principally in the epithelium of the proximal convoluted tubules. These changes included intranuclear inclusion bodies, mitochondrial damage, tubular swelling, atrophy, fibrosis, and hyperuricemia. Renal lead levels of 5 mg/g were associated with a blood lead concentration of 11 µg/dl and with cytomegaly and karyomegaly in renal proximal tubule cells (Fowler et al., 1980).

Chronic Effects of Lead Exposure on Children

Debate persists regarding the blood lead level at which deficits in children's learning and behavior become apparent (Smith, 1985; Yule and Rutter, 1985). Several investigators concluded that blood lead levels persistently elevated above 60 µg/dl in preschool children carry a substantial risk of permanent central nervous system injury (DHSS, 1980; Rutter, 1980). However, a review of other studies by the U.S. Environmental Protection Agency (EPA) (Ernhart et al., 1981; Needleman et al., 1979) neither confirms nor refutes the hypothesis that low-level lead exposure causes permanent neuropsychological deficits in children (Marshall, 1983). The EPA in its proposed drinking water regulations has stated that fetal exposure at blood levels around 10 to 15 µl/dl appears to be associated with delays in early mental and physical development (EPA, 1988). The Centers for Disease Control established 25 µg/dl as the blood lead level above which medical intervention is necessary for children (CDC, 1985).

In a prospective cohort study assessing the relationship between prenatal and postnatal lead exposure and early cognitive development, Bellinger et al. (1987) found that the fetus may be adversely affected at maternal blood lead concentrations well below the CDC guideline of 25 µg/dl. They did not find that cognitive test scores were related to the postnatal blood lead levels of the infants.


Essential as well as nonessential trace elements have been implicated in the risk of certain chronic diseases in humans, but the evidence is weak in most instances. Some trace elements have been associated with an increased risk of cancer at certain sites, most notably chromium with lung cancer and arsenic with cancers of the lung and skin, but the evidence is based primarily on respiratory rather than dietary exposure. Animal data provide little support for these associations, and no conclusions regarding dietary intake of these elements and cancer risk are warranted at present. In several epidemiologic studies, selenium has been inversely associated with risk of cancer at several different sites, but the data are not entirely consistent and some animal studies do not show this inverse finding. The role of selenium in cancer etiology is unclear. The effects of zinc deficiency on tumor growth are also equivocal; however, zinc deprivation has been shown to alter immunocompetence in experimental animals as well as in humans.

The effects of dietary trace elements on cardiovascular disease risk are not well established. Some epidemiologic studies suggest that copper and chromium may be inversely associated and arsenic directly associated with these diseases or certain of their known risk factors, and some animal evidence supports the findings; however, the data are inconclusive.

Certain other associations of trace elements with chronic diseases have been established with certainty. The ingestion of fluoride in water is clearly associated with a reduction in dental caries. Dietary iodine deficiency is a cause of endemic goiter. Iron deficiency leads to the commonest form of anemia in the United States.

Most other reported relationships between trace elements and chronic diseases are much more weakly supported. Examples include positive associations of aluminum with Alzheimer's disease and of lead with hypertension.

Directions for Research

  • Interactions with Other Dietary Components Literature on the chronic effects resulting from the dietary exposure of humans to most trace elements is limited. Further research in this area could yield potentially important information, particularly on the interaction of these elements with other dietary and nondietary risk factors for conditions such as cancer, atherosclerotic cardiovascular diseases, and diabetes mellitus. Such research would be greatly facilitated by the identification of optimal markers of long-term dietary exposure to these elements.
  • Selenium and Cancer Selenium is being promoted to the public as a protective factor against cancer, despite inconclusive scientific evidence. Because there are some reports that selenium may enhance cancer risk at certain sites, it is important that the role of this trace element in human cancer be clarified through further epidemiologic and experimental study.
  • Nutritional Requirements There are still fundamental gaps in knowledge about nutritional requirements for trace elements, partly because assessment methods are poor. In particular, the development of better methods for determining zinc nutriture in individuals would permit a more adequate study of the relationship of this nutrient to health and disease.
  • Immune System The effects of certain trace elements, such as zinc and copper, on the immune system should be studied in order to offer plausible mechanisms for their associations with chronic diseases in humans.


  • Abraham, A.S., M. Sonnenblick, M. Eini, O. Shemesh, and A.P. Batt. 1980. The effect of chromium on established atherosclerotic plaques in rabbits. Am. J. Clin. Nutr. 33: 2294-2298. [PubMed: 7435408]
  • Abumrad, N.N., A.J. Schneider, D. Steel, and L.S. Rogers. 1981. Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate therapy. Am. J. Clin. Nutr. 34:2551-2559. [PubMed: 6795919]
  • Adams, R.G., J.F. Harrison, and P. Scott. 1969. The development of cadmium-induced proteinuria, impaired renal function and osteomalacia in alkaline battery workers. Q. J. Med. 38:425-443. [PubMed: 5355536]
  • Adamska-Dyniewska, H., T. Bala, H. Florczak, and B. Trojanowska. 1982. Blood cadmium in healthy subjects and in patients with cardiovascular diseases. Cor Vasa 24:441-447. [PubMed: 7184698]
  • Adler, A.L., B. Safai, Y.B. Wang, C. Menendez-Botet, and R.A. Good. 1981. Serum zinc levels in patients with basal-cell carcinoma. J. Dermatol. Surg. Oncol. 7:911-914. [PubMed: 7309978]
  • Alffram, P.A., J. Hernborg, and B.E.R. Nilsson. 1969. The influence of a high fluoride content in the drinking water on the bone mineral mass in man. Acta Orthop. Scand. 40: 137-142. [PubMed: 5365155]
  • Alfrey, A.C. 1986. Aluminum. Pp. 399-413 in W. Mertz, editor. , ed. Trace Elements in Human and Animal Nutrition, Vol. 2,5th ed. Academic Press, Orlando, Fla.
  • Allen, K.G.D., and L.M. Klevay. 1978. Cholesterolemia and cardiovascular abnormalities in rats caused by copper deficiency. Atherosclerosis 29:81-93. [PubMed: 629827]
  • Ammann, R.W., E. Müller, J. Bansky, G. Schüler, and W.H. Häcki. 1980. High incidence of extrahepatic carcinomas in idiopathic hemochromatosis. Scand. J. Gastroenterol. 15: 733-736. [PubMed: 6259710]
  • Andersen, O. 1983. Effects of coal combustion products and metal compounds on sister chromatid exchange in a macrophage cell line. Environ. Health Perspect. 47:239-253. [PMC free article: PMC1569383] [PubMed: 6337826]
  • Anderson, R.A. 1986. Chromium metabolism and its role in disease processes in man. Clin. Physiol. Biochem. 4:31-41. [PubMed: 3514054]
  • Anderson, R.A., and A.S. Kozlovsky. 1985. Chromium intake, absorption and excretion of subjects consuming self-selected diets. Am. J. Clin. Nutr. 41:1177-1183. [PubMed: 4003325]
  • Anderson, R.A., M.M. Polansky, N.A. Bryden, E.E. Raginski, K.Y. Patterson, and D.C. Reamer. 1982. Effect of exercise (running) on serum glucose, insulin, glucagon, and chromium excretion. Diabetes 31:212-216. [PubMed: 6759238]
  • Anderson, R.A., M.M. Polansky, N.A. Bryden, E.E. Roginski, W. Mertz, and W. Glinsmann. 1983. Chromium supplementation of human subjects: effects on glucose, insulin, and lipid variables. Metabolism 32:894-899. [PubMed: 6350814]
  • Anke, M. 1986. Arsenic. Pp. 347-372 in W. Mertz, editor. , ed. Trace Elements in Human and Animal Nutrition, Vol. 2,5th ed. Academic Press, Orlando, Fla.
  • Aquino, T.I., and B.A. Eskin. 1972. Rat breast structure in altered iodine metabolism. Arch. Pathol. 94:280-285. [PubMed: 5056923]
  • Arlauskas, A., R.S. Baker, A.M. Bonin, R.K. Tandon, P.T. Crisp, and J. Ellis. 1985. Mutagenicity of metal ions in bacteria. Environ. Res. 36:379-388. [PubMed: 3884331]
  • Armstrong, B.G., and G. Kazantzis. 1983. The mortality of cadmium workers. Lancet 1:1425-1427. [PubMed: 6134185]
  • Aro, A., G. Alfthan, S. Soimakallio, and E. Voutilainen. 1986. Se concentrations in serum and angiographically defined coronary artery disease are uncorrelated. Clin. Chem. 32:911-912. [PubMed: 3698299]
  • Atik, O.S. 1983. Zinc and senile osteoporosis. . Am. Geriatr. Soc. 31:790-791. [PubMed: 6655182]
  • Atukorala, S., T.K. Basu, J.W. Dickerson, D. Donaldson, and A. Sakula. 1979. Vitamin A, zinc and lung cancer. Br. J. Cancer 40:927-931. [PMC free article: PMC2010126] [PubMed: 575048]
  • Axelsson, G., R. Rylander, and A. Schmidt. 1980. Mortality and incidence of tumours among ferrochromium workers. Br. J. Ind. Med. 37:121-127. [PMC free article: PMC1008678] [PubMed: 7426462]
  • Bako, G., E.S. Smith, J. Hanson, and R. Dewar. 1982. The geographical distribution of high cadmium concentrations in the environment and prostate cancer in Alberta. Can. J. Public Health 73:92-94. [PubMed: 7104934]
  • Baly, D.L., D.L. Curry, C.L. Keen, and L.S. Hurley. 1984. Effect of manganese deficiency on insulin secretion and carbohydrate homeostasis in rats. J. Nutr. 114:1438-1446. [PubMed: 6379130]
  • Baly, D.L., C.L. Keen, and L.S. Hurley. 1985. Pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity in developing rats: effect of manganese deficiency. J. Nutr. 115:872-879. [PubMed: 4009297]
  • Banks, W.A., and A.J. Kastin. 1983. Aluminium increases permeability of the blood-brain barrier to labelled DSIP and beta-endorphin: possible implications for senile and dialysis dementia. Lancet 2:1227-1229. [PubMed: 6139573]
  • Barnhart, W.E., L.K. Hiller, G.J. Leonard, and S.E. Michaels. 1974. Dentifrice usage and ingestion among four age groups. J. Dent. Res. 53:1317-1322. [PubMed: 4529918]
  • Baroni, C., G.J. van Esch, and U. Saffiotti. 1963. Carcinogenesis tests of two inorganic arsenicals. Arch. Environ. Health 7:668-674. [PubMed: 14077213]
  • Barr, D.H., and J.W. Harris. 1973. Growth of the P388 leukemia as an ascites tumor in zinc-deficient mice. Proc. Soc. Exp. Biol. Med. 144:284-287. [PubMed: 4771572]
  • Batuman, V., E. Landy, J.K. Maesaka, and R.P. Wedeen. 1983. Contribution of lead to hypertension with renal impairment. N. Engl. J. Med. 309:17-21. [PubMed: 6406892]
  • Bauchinger, M., and E. Schmid. 1972. Chromosomenanalysen in Zellkulturen des chinesischen Hamsters nach Applikation von Bleiacetat. Mutat. Res. 14:95-100. [PubMed: 5062073]
  • Beach, R.S., M.E. Gershwin, and L.S. Hurley. 1979. Altered thymic structure and mitogen responsiveness in postnatally zinc-deprived mice. Dev. Comparat. Immunol. 3:725-738. [PubMed: 527749]
  • Beach, R.S., M.E. Gershwin, and L.S. Hurley. 1981. Dietary zinc modulation of Moloney sarcoma virus oncogenesis. Cancer Res. 41:552-559. [PubMed: 6256068]
  • Beevers, D.G., J.K. Cruickshank, W.B. Yeoman, G.F. Carter, A. Goldberg, and M.R. Moore. 1980. Blood-lead and cadmium in human hypertension. J. Environ. Pathol. Toxicol. 4:251-260. [PubMed: 7462903]
  • Bell, L.T., M. Branstrator, C. Roux, and L.S. Hurley. 1975. Chromosomal abnormalities in maternal and fetal tissues of magnesium- or zinc-deficient rats. Teratology 12:221-226. [PubMed: 1198329]
  • Bellinger, D., A. Leviton, C. Waternaux, H. Needleman, and M. Rabinowitz. 1987. Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. N. Engl. J. Med. 316:1037-1043. [PubMed: 3561456]
  • Benbassat, J., C. Hershko, R. Laskov, and M. Eliakim. 1981. Effect of iron deficiency on transplantable murine plasmacytoma. Nutr. Cancer 3:20-26. [PubMed: 7346786]
  • Bennicelli, C., A. Camoirano, S. Petruzelli, P. Zanacchi, and S. De Flora. 1983. High sensitivity of salmonella TA102 in detecting hexavalent chromium mutagenicity and its reversal by liver and lung preparations. Mutat. Res. 122:1-5. [PubMed: 6353220]
  • Benuck, M., K. Iqbal, H.M. Wisniewski, and A. Lajtha. 1985. Proteolytic activity in brains of rabbits treated with aluminum. Neurochem. Res. 10:729-736. [PubMed: 2993936]
  • Berg, J.W., and F. Burbank. 1972. Correlations between carcinogenic trace metals in water supplies and cancer mortality. Ann. N.Y. Acad. Sci. 199:249-264. [PubMed: 4506509]
  • Bergeron, R.J., R.R. Streiff, and G.T. Elliott. 1985. Influence of iron on in vivo proliferation and lethality of L1210 cells. J. Nutr. 115:369-374. [PubMed: 3973748]
  • Berlin, M. 1979. Mercury. Pp. 503-530 in L. Friberg, editor; , G.F. Nordberg, editor; , and V.B. Vouk, editor. , eds. Handbook on the Toxicology of Metals. Elsevier/North Holland Biomedical Press, Amsterdam.
  • Bernstein, D.S., N. Sadowsky, D.M. Hegsted, C.D. Guri, and F.J. Stare. 1966. Prevalence of osteoporosis in high- and low-fluoride areas in North Dakota. J. Am. Med. Assoc. 198:499-504. [PubMed: 5953273]
  • Bielschowsky, F. 1944. Tumors of the thyroid produced by 2-acetylaminofluorene and allylthiourea. Br. J. Exp. Pathol. 25:90-95.
  • Bingham, F.T. 1979. Bioavailability of CD to food crops in relation to heavy metal content to sludge-amended soil. Environ. Health Perspect. 28:39-43. [PMC free article: PMC1637513] [PubMed: 39746]
  • Blakley, B.R. 1984. Enhancement of urethan-induced adenoma formation in Swiss mice exposed to methylmercury. Can. J. Comp. Med. 48:299-302. [PMC free article: PMC1236066] [PubMed: 6478300]
  • Bogardus, G.M., and J.W. Finley. 1961. Breast cancer and thyroid disease. Surgery 49:461-468.
  • Bogden, J.D., H.R. Chung, F.W. Kemp, K. Holding, K.S. Bruening, and Y. Naveh. 1986. Effect of selenium and molybdenum on methylbenzylnitrosamine-induced esophageal lesions and tissue trace metals in the rat. J. Nutr. 116: 2432-2442. [PubMed: 3806240]
  • Böing, H., L. Martinez, R. Frentzel-Beyme, and U. Oltersdorf. 1985. Regional nutritional pattern and cancer mortality in the Federal Republic of Germany. Nutr. Cancer 7: 121-130. [PubMed: 4080563]
  • Bomford, A., and R. Williams. 1976. Long term results of venesection therapy in idiopathic haemochromatosis. Q. J. Med. 45:611-623. [PubMed: 188063]
  • Borel, J.S., T.C. Majerus, M.M. Polansky, P.B. Moser, and R.A. Anderson. 1984. Chromium intake and urinary chromium excretion of trauma patients. Biol. Trace Element Res. 6:317-326. [PubMed: 24264110]
  • Boutwell, R.K. 1963. A carcinogenicity evaluation of potassium arsenite and arsanilic acid. J. Agric. Food Chem. 11: 381-385.
  • Brada, Z., and N.H. Altman. 1977. The inhibitory effect of copper on ethionine carcinogenesis. Adv. Exp. Med. Biol. 91:193-206. [PubMed: 204168]
  • Braganza, J.M., H.J. Klass, M. Bell, and G. Sturniolo. 1981. Evidence of altered copper metabolism in patients with chronic pancreatitis. Clin. Sci. 60:303-310. [PubMed: 7237943]
  • Broghamer, W.L., K.P. McConnell, and A.J. Blotcky. 1976. Relationship between serum selenium levels and patients with carcinoma. Cancer 37:1384-1388. [PubMed: 1260658]
  • Broghamer, W.L., Jr., K.P. McConnell, M. Grimaldi, and A.J. Blotcky. 1978. Serum selenium and reticuloendothelial tumors. Cancer 41:1462-1466. [PubMed: 639004]
  • Brown, W.A.B., P.V. Christofferson, M. Massler, and M.B. Weiss. 1960. Postnatal tooth development in cattle. Am. J. Vet. Res. 21:7-34. [PubMed: 13805043]
  • Brown, W.E., editor; , and K.G. König, editor. , eds. 1977. Cariostatic mechanisms of fluorides. Caries Res. 11 Suppl. 1:1-327.
  • Brusick, D., F. Gletten, D.R. Jagannath, and U. Weeks. 1976. The mutagenic activity of ferrous sulfate for Salmonella typhimurium. Mutat. Res. 38:386-387.
  • Buchet, J.P., R. Lauwerys, A. Vandevoorde, and J.M. Pycke. 1983. Oral daily intake of cadmium, lead, manganese, copper, chromium, mercury, calcium, zinc and arsenic in Belgium: a duplicate meal study. Food Chem. Toxicol. 21: 19-24. [PubMed: 6681791]
  • Burt, B.A., S.A. Eklund, and W.J. Loesche. 1986. Dental benefits of limited exposure to fluoridated water in childhood. J. Dent. Res. 65:1322-1325. [PubMed: 3478391]
  • Büttner, W. 1963. Action of trace elements on the metabolism of fluoride. J. Dent. Res. 42:453-460. [PubMed: 14017437]
  • Byron, W.R., G.W. Bierbower, J.B. Brouwer, and W.H. Hansen. 1967. Pathologic changes in rats and dogs from two-year feeding of sodium arsenite or sodium arsenate. Toxicol. Appl. Pharmacol. 10:132-147. [PubMed: 6031922]
  • Calabrese, E.J. 1983. Role of epidemiologic studies in deriving drinking water standards for metals. Environ. Health Perspect. 52:99-106. [PMC free article: PMC1569334] [PubMed: 6653543]
  • Calabrese, E., and R.W. Tuthill. 1978. Elevated blood pressure levels and community drinking water characteristics. J. Environ. Sci. Health, Part A A13:781-802.
  • Calautti, P., G. Moschini, B.M. Stievano, L. Tomio, F. Calzavara, and G. Perona. 1980. Serum selenium levels in malignant lymphoproliferative diseases. Scand. J. Haematol. 24:63-66. [PubMed: 7367833]
  • Campbell, J.K., and C.F. Mills. 1974. Effects of dietary cadmium and zinc on rats maintained on diets low in copper. Proc. Nutr. Soc. 33:15A-16A. [PubMed: 4418680]
  • Campbell, J.K., and C.F. Mills. 1979. The toxicity of zinc to pregnant sheep. Environ. Res. 20:1-13. [PubMed: 499163]
  • Canfield, W.K., K.M. Hambidge, and LK. Johnson. 1984. Zinc nutriture in type I diabetes mellitus: relationship to growth measures and metabolic control. J. Pediatr. Gastroenterol. Nutr. 3:577-584. [PubMed: 6384460]
  • Cantoni, O., and M. Costa. 1983. Correlations of DNA strand breaks and their repair with cell survival following acute exposure to mercury (II) and x-rays. Mol. Pharmacol. 24:84-89. [PubMed: 6223207]
  • Carlton, W.W., and P.S. Price. 1973. Dietary copper and the induction of neoplasms in the rat by acetylaminofluorene and dimethylnitrosamine. Food Cosmet. Toxicol. 11:827-840. [PubMed: 4768879]
  • Carmignani, M., and P. Boscolo. 1984. Cardiovascular responsiveness to physiological agonists of male rats made hypertensive by long-term exposure to cadmium. Sci. Total Environ. 34:19-33. [PubMed: 6710136]
  • Cartwright, G.E., and M.M. Wintrobe. 1964. Copper metabolism in normal subjects. Am. J. Clin. Nutr. 14:224-232. [PubMed: 14142382]
  • CAST (Council for Agricultural Science and Technology). 1980. Effects of Sewage Sludge on the Cadmium and Zinc Content of Crops. Report No. 83. CAST, Ames, Iowa. 77 pp.
  • Casto, B.C., W.J. Pieczynski, R.L. Nelson, and J.A. DiPaolo. 1976. In vitro transformation and enhancement of viral transformation with metals. Proc. Am. Assoc. Cancer Res. 17:12.
  • Casto, B.C., J.D. Meyers, J.A. DiPaolo. 1979. Enhancement of viral transformation for evaluation of the carcinogenic or mutagenic potential of inorganic metal salts. Cancer Res. 39:193-198. [PubMed: 570089]
  • CDC (Centers for Disease Control). 1985. Preventing Lead Poisoning in Young Children. A Statement by the Centers for Disease Control, January 1985. Publ. No. 99-2230. Environmental Health Service Division, Bureau of State Services, Public Health Service, U.S. Department of Health and Human Services, Atlanta. 35 pp.
  • Charlton, R.W., and T.H. Bothwell. 1982. Definition, prevalence and prevention of iron deficiency. Clin. Haematol. 11:309-325. [PubMed: 7042153]
  • Chen, C.J., Y.C. Chuang, T.M. Lin, and H.Y. Wu. 1985. Malignant neoplasms among residents of a blackfoot diseaseendemic area in Taiwan: high-arsenic artesian well water and cancers. Cancer Res. 45:5895-5899. [PubMed: 4053060]
  • Chen, C.J., Y.C. Chuang, S.L. You, T.M. Lin, and H.Y. Wu. 1986. A retrospective study on malignant neoplasms of bladder, lung and liver in blackfoot disease endemic area in Taiwan. Br. J. Cancer 53:399-405. [PMC free article: PMC2001352] [PubMed: 3964542]
  • Chilvers, C. 1983. Cancer mortality and fluoridation of water supplies in 35 U.S. cities. Int. J. Epidemiol. 12:397-404. [PubMed: 6654558]
  • Chisolm, J.J., Jr. 1985. Pediatric exposures to lead, arsenic, cadmium, and methyl mercury. Pp. 229-262 in R.K. Chandra, editor. , ed. Trace Elements in Nutrition of Children. Raven Press, New York.
  • Clark, J.H., and J.S. Taylor. 1981. I.R. evidence for a strong hydrogen bond in the fluoride-uracil system. J. Chem. Soc. Commun. 41:466-468.
  • Clark, L.C. 1985. The epidemiology of selenium and cancer. Fed. Proc. 44:2584-2589. [PubMed: 3996614]
  • Clark, L.C., and G.F. Combs, Jr. 1986. Selenium compounds and the prevention of cancer: research needs and public health implications. J. Nutr. 116:170-173. [PubMed: 3511193]
  • Clark, L.C., G.F. Graham, R.G. Crounse, R. Grimson, B. Hulka, and C.M. Shy. 1984. Plasma selenium and skin neoplasms: a case-control study. Nutr. Cancer 6:3-21. [PubMed: 6545569]
  • Clements, F.W. 1954. The relationship of thyrotoxicosis and carcinoma of the thyroid to endemic goitre. Med. J. Aust. 2: 894-897. [PubMed: 13223082]
  • Clemmesen, J. 1983. The alleged association between artificial fluoridation of water supplies and cancer: a review. Bull. W.H.O. 61:871-883. [PMC free article: PMC2536164] [PubMed: 6360403]
  • Combs, G.F., Jr., and L.C. Clark. 1985. Can dietary selenium modify cancer risk? Nutr. Rev. 43:325-331. [PubMed: 3909013]
  • Cooper, W.C. 1984: The health implications of increased manganese in the environment resulting from the combustion of fuel additives: a review of the literature. J. Toxicol. Environ. Health 14:23-46. [PubMed: 6389893]
  • Cooper, W.C., O. Wong, and L. Kheifets. 1985. Mortality among employees of lead battery plants and lead-producing plants, 1947-1980. Scand. J. Work Environ. Health 11: 331-345. [PubMed: 4070998]
  • Cote, M., L. Munan, M. Gagne-Billon, A. Kelly, O. di Pietro, and D. Shapcott. 1979. Hair chromium concentration and arteriosclerotic heart disease. Pp. 223-228 in D. Shapcott, editor; and J. Hubert, editor. eds. Chromium in Nutrition and Metabolism: Developments in Nutrition and Metabolism, Vol. 2. Elsevier/North-Holland Biomedical Press, Amsterdam.
  • Cowgill, U.M. 1983. The distribution of selenium and cancer mortality in the continental United States. Biol. Trace Element Res. 5:345-361. [PubMed: 24263572]
  • Cragle, D.L., D.R. Hollis, J.R. Qualters, W.G. Tankersley, and S.A. Fry. 1984. A mortality study of men exposed to elemental mercury. J. Occup. Med. 26:817-821. [PubMed: 6502285]
  • Crapper, D.R., S. Quittkat, S.S. Krishnan, A.J. Dalton, and U. De Boni. 1980. Intranuclear aluminum content in Alzheimer's disease, dialysis encephalopathy, and experimental aluminum encephalopathy. Acta Neuropathol. 50: 19-24. [PubMed: 7376825]
  • Crawford, M.D., M.J. Gardner, and J.N. Morris. 1968. Mortality and hardness of local water supplies. Lancet 1: 827-831. [PubMed: 4171329]
  • Crenshaw, M.A., A. Wennberg, and J.W. Bawden. 1978. Flouride-binding by the organic matrix of developing bovine enamel. Arch. Oral Biol. 23:285-287. [PubMed: 278565]
  • Cummins, P.E., J. Dutton, C.J. Evans, W.D. Morgan, A. Sivyer, and P.C. Elwood. 1980. An invivo study of renal cadmium and hypertension. Eur. J. Clin. Invest. 10:459-461. [PubMed: 6788563]
  • Cuzick, J., S. Evans, M. Gillman, and D.A. Price Evans. 1982. Medicinal arsenic and internal malignancies. Br. J. Cancer 45:904-911. [PMC free article: PMC2011026] [PubMed: 6212076]
  • Dallman, P.R., M.A. Siimes, and A. Stekel. 1979. Iron Deficiency in Infancy and Childhood. A Report for the International Nutritional Anemia Consultive Group. The Nutrition Foundation, Washington, D.C. 49 pp.
  • Danks, D.M. 1980. Copper deficiency in humans. Ciba Found. Symp. 79:209-225. [PubMed: 6110526]
  • Davidson, I., and W. Blackwell. 1968. Changes in carbohydrate metabolism of squirrel monkeys with chromium dietary supplementation. Proc. Soc. Exp. Biol. Med. 127:66-70. [PubMed: 4967885]
  • Davies, I.J., M. Musa, and T.L. Dormandy. 1968. Measurements of plasma zinc. II. In malignant disease. J. Clin. Pathol. 21:363-365. [PMC free article: PMC473797] [PubMed: 5699076]
  • Davies, J.M. 1984. Lung cancer mortality among workers making lead chromate and zinc chromate pigments at three English factories. Br. J. Ind. Med. 41:158-169. [PMC free article: PMC1009277] [PubMed: 6722042]
  • Dean, H.T. 1936. Chronic endemic dental fluorosis (mottled enamel). J. Am. Med. Assoc. 107:1269-1273.
  • Dean, H.T., and E. Elvove. 1935. Studies on the minimal threshold of the dental sign of chronic endemic fluorosis (mottled enamel). Public Health Rep. 50:1719-1729.
  • De Boni, U. 1985. Cultured cells of the nervous system, including human neurones, in the study of the neurodegenerative disorder, Alzheimer's disease: an overview. Xenobiotica 15:643-647. [PubMed: 2866635]
  • DeWys, W., and W. Pories. 1972. Inhibition of a spectrum of animal tumors by dietary zinc deficiency. J. Natl. Cancer Inst. 48:375-381. [PubMed: 4652380]
  • DeWys, W., W.J. Pories, M.C. Richter, and W.H. Strain. 1970. Inhibition of Walker 256 carcinosarcoma growth by dietary zinc deficiency. Proc. Soc. Exp. Biol. Med. 135:17-22. [PubMed: 5475614]
  • DHSS (Department of Health and Social Security). 1980. Lead and Health: the Report of a DHSS Working Party on Lead in the Environment. Her Majesty's Stationary Office, London. 128 pp.
  • Dingwall-Fordyce, I., and R.E. Lane. 1963. A follow-up study of lead workers. Br. J. Ind. Med. 20:313-315. [PMC free article: PMC1038384] [PubMed: 14072623]
  • DiPaolo, J.A., and B.C. Casto. 1979. Quantitative studies on in vitro morphological transformation of Syrian hamster cells by inorganic metal salts. Cancer Res. 39:1008-1013. [PubMed: 427740]
  • DiPaolo, J.A., R.L. Nelson, and B.C. Casto. 1978. In vitro neoplastic transformation of Syrian hamster cells by lead acetate and its relevance to environmental carcinogenesis. Br. J. Cancer 38:452-455. [PMC free article: PMC2009741] [PubMed: 708578]
  • Doll, R., and L. Kinlen. 1977. Fluoridation of water and cancer mortality in the U.S.A. Lancet 1:1300-1302. [PubMed: 68395]
  • Doll, R., L. Fishbein, P. Infante, P. Landrigan, J.W. Lloyd, T.J. Mason, E. Mastromatteo, T. Norseth, G. Pershagen, U. Saffiotti, and R. Saracci. 1981. Problems of epidemiological evidence. Environ. Health Perspect. 40:11-20.
  • Doniach, I. 1958. Experimental induction of tumours of the thyroid by radiation. Br. Med. Bull. 14:181-183. [PubMed: 13536385]
  • Drinkard, C.R., M.A. Crenshaw, and J.W. Bawden. 1982. F Effect on protein/phosphorus in developing rat molar enamel. J. Dent. Res. (sp. iss.) 61:216.
  • Driscoll, W.S., S.B. Heifetz, and J.A. Brunelle. 1981. Caries-preventive effects of fluoride tablets in schoolchildren four years after discontinuation of treatments. J. Am. Dent. Assoc. 103:878-881. [PubMed: 6947007]
  • Dube, D.K., and L.A. Loeb. 1975. Manganese as a mutagenic agent during in vitro DNA synthesis. Biochem. Biophys. Res. Commun. 67:1041-1046. [PubMed: 173332]
  • Duncan, J.R., and I.E. Dreosti. 1975. Zinc intake, neoplastic DNA synthesis, and chemical carcinogenesis in rats and mice. J. Natl. Cancer Inst. 55:195-196. [PubMed: 169362]
  • Dunning, J.M. 1979. Water fluoridation. Pp. 377-414 in Principles of Dental Public Health, 3rd ed. Harvard University Press, Cambridge, Mass.
  • Dutkiewiez, T. 1977. Experimental studies on arsenic absorption routes in rats. Environ. Health Perspect. 19:173-176. [PMC free article: PMC1637393] [PubMed: 908295]
  • Eakin, D.J., L.A. Schroeder, P.D. Whanger, and P.H. Weswig. 1980. Cadmium and nickel influence on blood pressure, plasma renin, and tissue mineral concentrations. Am. J. Physiol. 238:E53-E61. [PubMed: 6986793]
  • Ebina, Y., S. Okada, S. Hamazaki, F. Ogino, J.L. Li, and O. Midorikawa. 1986. Nephrotoxicity and renal cell carcinoma after use of iron-and aluminum-nitrilotriacetate complexes in rats. J. Natl. Cancer Inst. 76:107-113. [PubMed: 3455733]
  • Edington, G.M. 1976. Dietary iodine and risk of breast, endometrial, and ovarian cancer. Lancet 1:1413-1414. [PubMed: 59054]
  • Elinder, C.G. 1985. Cadmium: uses, occurrence and intake. Pp. 23-64 in L. Friberg, editor; , C.G. Elinder, editor; , T. Kjellström, editor; , and G.F. Nordberg, editor. , eds. Cadmium and Health: A Toxicological and Epidemiological Appraisal, Vol. 1. Exposure, Dose, and Metabolism. CRC Press, Boca Raton, Fla.
  • Ellis, N.I., B. Lloyd, R.S. Lloyd, and B.E. Clayton. 1984. Selenium and vitamin E in relation to risk factors for coronary heart disease. J. Clin. Pathol. 37:200-206. [PMC free article: PMC498678] [PubMed: 6693579]
  • Emsley, J., D.J. Jones, J.M. Miller, R.E. Overill, and R.A. Waddilove. 1981. An unexpectedly strong hydrogen bond: ab initio calculations and spectroscopic studies of amidefluoride systems. J. Am. Chem. Soc. 103:24-28.
  • Emsley, J., D.J. Jones, and R.E. Overill. 1982. The uracil fluoride interaction Ab-initio calculations including solvation. J. Chem. Soc. Chem. Commun. (9):476-478.
  • EPA (Environmental Protection Agency). 1988. Proposed drinking water regulations. Fed. Reg. 53:31523.
  • Erickson, J.D. 1978. Mortality in selected cities with fluoridated and non-fluoridated water supplies. N. Engl. J. Med. 298:1112-1116. [PubMed: 643029]
  • Ericsson, S.Y. 1977. Cariostatic mechanisms of fluorides: clinical observations. Caries Res. 11 Suppl. 1:2-41. [PubMed: 11044]
  • Erkell, L.J., W. Ryd, and B. Hagmar. 1986. Effects of zinc on tumor transplantability. Invasion Metastasis 6:112-122. [PubMed: 3634763]
  • Ernhart, C.B., B. Landa, and N.B. Schell. 1981. Subclinical levels of lead and developmental deficit—a multivariate follow-up reassessment. Pediatrics 67:911-919. [PubMed: 7232055]
  • Eskin, B.A. 1977. Iodine and mammary cancer. Adv. Exp. Med. Biol. 91:293-304. [PubMed: 343535]
  • Eskin, B.A., D.G. Bartuska, M.R. Dunn, G. Jacob, and M.B. Dratman. 1967. Mammary gland dysplasia in iodine deficiency. J. Am. Med. Assoc. 200:691-695. [PubMed: 6071498]
  • European Thyroid Association. 1985. Report of the Subcommittee for the Study of Endemic Goitre and Iodine Deficiency. Goitre and iodine deficiency in Europe. Lancet 1: 1289-1293. [PubMed: 2860490]
  • Everson, G.J., and R.E. Shrader. 1968. Abnormal glucose tolerance in manganese-deficient guinea pigs. J. Nutr. 94: 89-94. [PubMed: 5638643]
  • Ewers, U., A. Brockhaus, R. Dolgner, I. Freier, E. Jermann, A. Bernard, R. Stiller-Winkler, R. Hahn, and N. Manojlovic. 1985. Environmental exposure to cadmium and renal function of elderly women living in cadmium-polluted areas of the Federal Republic of Germany. Int. Arch. Occup. Environ. Health 55:217-239. [PubMed: 3888850]
  • Fabris, C., R. Farini, G. Del Favero, G. Gurrieri, A. Piccoli, G.C. Sturniolo, A. Panucci, and R. Naccarato. 1985. Copper, zinc and copper/zinc ratio in chronic pancreatitis and pancreatic cancer. Clin. Biochem. 18:373-375. [PubMed: 4092355]
  • Fahim, M.S., and N.K. Khare. 1980. Effects of subtoxic levels of lead and cadmium on urogenital organs of male rats. Arch. Androl. 4:357-362. [PubMed: 7416856]
  • Fenton, M.R., J.P. Burke, F.D. Tursi, and F.P. Arena. 1980. Effect of a zinc-deficient diet on the growth of an IgM-secreting plasmacytoma (TEPC-183). J. Natl. Cancer Inst. 65:1271-1272. [PubMed: 6933272]
  • Fernandes, G., M. Nair, K. Onoe, T. Tanaka, R. Floyd, and R.A. Good. 1979. Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice. Proc. Natl. Acad. Sci. U.S.A. 76:457-461. [PMC free article: PMC382959] [PubMed: 311474]
  • Feustel, A., and R. Wennrich. 1984. Determination of the distribution of zinc and cadmium in cellular fractions of BPH, normal prostate and prostatic cancers of different histologies by atomic and laser absorption spectrometry in tissue slices. Urol. Res. 12:253-256. [PubMed: 6083653]
  • Feustel, A., and R. Wennrich. 1986. Zinc and cadmium plasma and erythrocyte levels in prostatic carcinoma, BPH, urological malignancies, and inflammations. Prostate 8:75-79. [PubMed: 2418432]
  • Feustel, A., R. Wennrich, D. Steiniger, and P. Klauss. 1982. Zinc and cadmium concentration in prostatic carcinoma of different histological grading in comparison to normal prostate tissue and adenofibromyomatosis (BPH). Urol. Res. 10: 301-303. [PubMed: 6186062]
  • Fields, M. 1985. Newer understanding of copper metabolism. Arch. Intern. Med. 6:91-98.
  • Fingerle, H., G. Fischer, and H.G. Classen. 1982. Failure to produce hypertension in rats by chronic exposure to cadmium. Food Chem. Toxicol. 20:301-306. [PubMed: 7201956]
  • Fischer, P.W., and M.W. Collins. 1981. Relationship between serum zinc and copper and risk factors associated with cardiovascular disease. Am. J. Clin. Nutr. 34:595-597. [PubMed: 7223710]
  • Fisher, K.D., and C.J. Carr. 1974. Iodine in Foods: Chemical Methodology and Sources of Iodine in the Human Diet. Life Sciences Research Office, Federation of American Societies for Experimental Biology, Bethesda, Md. 105 pp.
  • Folsom, A.R., and R.J. Prineas. 1982. Drinking water composition and blood pressure: a review of the epidemiology. Am. J. Epidemiol. 115:818-832. [PubMed: 7046430]
  • Forbes, G.B., and C.W. Woodruff. 1985. Pediatric Nutrition Handbook, 2nd ed. Committee on Nutrition, American Academy of Pediatrics, Elk Grove Village, III. 421 pp.
  • Fowler, B.A., C.A. Kimmel, J.S. Woods, E.E. McConnell, and L.D. Grant. 1980. Chronic low-level lead toxicity in the rat. III. An integrated assessment of long-term toxicity with special reference to the kidney. Toxicol. Appl. Pharmacol. 56:59-77. [PubMed: 7444967]
  • Freund, H., S. Atamian, and J. Fisher. 1979. Chromium deficiency during total parenteral nutrition. J. Am. Med. Assoc. 241:496-498. [PubMed: 104057]
  • Friberg, L., T. Kjellström, G. Nordberg, and G.M. Piscator. 1979. Cadmium. Pp. 355-381 in L. Friberg, editor; , G.F. Nordberg, editor; , and V.B. Vouk, editor. , eds. Handbook on the Toxicology of Metals. Elsevier/North-Holland Biomedical Press, Amsterdam.
  • Friberg, L., editor; , C.G. Elinder, editor; , T. Kjellström, editor; , and G.F. Nordberg, editor. , eds. 1985. a. Cadmium and Health: A Toxicological and Epidemiological Appraisal, Vol. 1. Exposure, Dose, and Metabolism. CRC Press, Boca Raton, Fla. 209 pp.
  • Friberg, L., editor; , C.G. Elinder, editor; , T. Kjellström, editor; , and G.F. Nordberg, editor. , eds. 1985. b. Cadmium and Health: A Toxicological and Epidemiological Appraisal, Vol. II. Effects and Response. CRC Press, Boca Raton, Fla. 307 pp.
  • Friedman, G.D., A.L. Klatsky, and A.B. Siegelaub. 1982. Alcohol, tobacco, and hypertension. Hypertension 4: III143-III150. [PubMed: 7049929]
  • Furst, A. 1977. Inorganic agents as carcinogens. Pp. 209-229 in H.F. Kraybill, editor; and M.A. Mehlman, editor. , eds. Environmental Cancer. Advances in Modern Toxicology, Vol. 3. Wiley, New York.
  • Furst, A. 1983. A new look at arsenic carcinogenesis. Pp. 151-165 in W.H. Lederer, editor; and R.J. Fensterheim, editor. , eds. Arsenic: Industrial Biomedical Environmental Perspectives. Van Nostrand Reinhold Co., New York.
  • Furst, A., M. Schlauder, and D.P. Sasmore. 1976. Tumorigenic activity of lead chromate. Cancer Res. 36:1779-1783. [PubMed: 1268834]
  • Gabrial, G.N., T.F. Schrager, and P.M. Newberne. 1982. Zinc deficiency, alcohol, and retinoid: association with esophageal cancer in rats. J. Natl. Cancer Inst. 68:785-789. [PubMed: 6951089]
  • Garruto, R.M., R. Fukatsu, R. Yanagihara, D.C. Gajdusek, G. Hook, and C.E Fiori. 1984. Imaging of calcium and aluminum in neurofibrillary tangle-bearing neurons in Parkinsonism-dementia of Guam. Proc. Natl. Acad. Sci. U.S.A. 81:1875-1879. [PMC free article: PMC345025] [PubMed: 6584922]
  • Gazdy, E, H. Csernyanszky, and T. Szilagyi. 1981. The effect of zinc ions (Zn+) on the procoagulent activity of PMN leukocytes. Acta Physiol. Acad. Sci. Hung. 57:29-35. [PubMed: 7282375]
  • Gerhardsson, L., D. Brune, G.F. Nordberg, and P.O. Wester. 1986. Distribution of cadmium, lead and zinc in lung, liver and kidney in long-term exposed smelter workers. Sci. Total Environ. 50:65-85. [PubMed: 3704626]
  • Gibbs, G.W. 1985. Mortality of aluminum reduction plant workers, 1950 through 1977. J. Occup. Med. 27:761-770. [PubMed: 4067680]
  • Gileva, E.A., E.G. Plotko, and E.Z. Gatiiatullina. 1972. Mutagenic activity of inorganic flourine compounds. Gig. Sanit. 37:9-12. [PubMed: 5020915]
  • Golden, M.H.N., B.E. Golden, P.S.E.G. Harland, and A.A. Jackson. 1978. Zinc and immunocompetence in protein-energy malnutrition. Lancet 1:1226-1228. [PubMed: 77993]
  • Golden, M.H.N., B.E. Golden, and F.I. Bennett. 1985. Relationship of trace element deficiencies to malnutrition. Pp. 185-207 in R.K. Chandra, editor. , ed. Trace Elements in Nutrition of Children. Raven Press, New York.
  • Goodwin, W.J., Jr., H.W. Lane, K. Bradford, M.V. Marshall, A.C. Griffin, H. Geopfert, and R.H. Jesse. 1983. Selenium and glutathione peroxidase levels in patients with epidermoid carcinoma of the oral cavity and oropharynx. Cancer 51:110-115. [PubMed: 6821799]
  • Gorsky, J.E., A.A. Dietz, H. Spencer, and D. Osis. 1979. Metabolic balance of aluminum studied in six men. Clin. Chem. 25:1739-1743. [PubMed: 476923]
  • Greenberg, S.R. 1982. Leucocyte response in young mice chronically exposed to fluorides. Fluoride 15:119-133.
  • Greger, J.L., and M.J. Baier. 1983. Excretion and retention of low or moderate levels of aluminum by human subjects. Food Chem. Toxicol. 21:473-476. [PubMed: 6684629]
  • Gregoriadis, G.C., N.S. Apostolidis, A.N. Romanos, and T.P. Paradellis. 1983. A comparative study of trace elements in normal and cancerous colorectal tissues. Cancer 52:508-519. [PubMed: 6861088]
  • 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. 31:745-759. [PubMed: 14069825]
  • 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. [PubMed: 14155788]
  • Gunn, S.A., T.C. Gould, and W.A.D. Anderson. 1967. Specific response of mesenchymal tissue to cancerigenesis by cadmium. Arch. Pathol. 83:493-499. [PubMed: 6024727]
  • Gunson, D.E., D.F. Kowalczyk, C.R. Shoop, and C.F. Ramberg, Jr. 1982. Environmental zinc and cadmium pollution associated with generalized osteochondrosis, osteoporosis, and nephrocalcinosis in horses. J. Am. Vet. Med. Assoc. 180:295-299. [PubMed: 7056680]
  • Guthrie, J. 1964. Histological effects of intra-testicular injections of cadmium chloride in domestic fowl. Br. J. Cancer 18:255-260. [PMC free article: PMC2071306] [PubMed: 14189680]
  • Györkey, F., K.W. Min, J.A. Huff, and P. Györkey. 1967. Zinc and magnesium in human prostate gland: normal, hyperplastic and neoplastic. Cancer Res. 27:1348-1353. [PubMed: 4167368]
  • 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. [PMC free article: PMC2071167] [PubMed: 14264930]
  • Hagan, T.L, M. Pasternack, and G.C. Scholz. 1954. Waterborne fluorides and mortality. Public Health Rep. 69:450-454. [PMC free article: PMC2024348] [PubMed: 13167266]
  • Hägglöf, B., G. Hallmans, G. Holmgren, J. Ludvigsson, and S. Falkmer. 1983. Prospective and retrospective studies of zinc concentrations in serum, blood clots, hair and urine in young patients with insulin-dependent diabetes mellitus. Acta Endocrinol. 102:88-95. [PubMed: 6337453]
  • Hainline, B.E., and K.V. Rajagopalan. 1983. Molybdenum in animal and human health. Pp 150-166 in J. Rose, editor. , ed. Trace Elements in Health: A Review of Current Issues. Butterworths, London.
  • Hallmans, G., and F. Lithner. 1980. Early changes in zinc and copper metabolism in rats with alloxan diabetes of short duration after local traumatization with heat. Upsala J. Med. Sci. 85:59-66. [PubMed: 7385460]
  • Hambidge, K.M., C.E. Casey, and N.F. Krebs. 1986. Zinc. Pp. 1-137 in W. Mertz, editor. , ed. Trace Elements in Human and Animal Nutrition, Vol. 2,5th ed. Academic Press, Orlando, Fla.
  • Hanson, T., and B. Roos. 1978. Effect of combined therapy with sodium fluoride, calcium, and vitamin D on the lumbar spine in osteoporosis. Am. J. Roentgenol., Radium Ther. Nucl. Med. 126:1294-1297. [PubMed: 179414]
  • Harrington, J.M., J.P. Middaugh, D.L. Morse, and J. Housworth. 1978. A survey of a population exposed to high concentrations of arsenic in well water in Fairbanks, Alaska. Am. J. Epidemiol. 108:377-385. [PubMed: 727207]
  • 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., editor. , ed. Renal Neoplasia. J. & A. Churchill Ltd., London.
  • Hedinger, C. 1981. Geographic pathology of thyroid diseases. Pathol. Res. Pract. 171:285-292. [PubMed: 6895108]
  • Henrikson, P.A., L. Lutwak, L. Krook, R. Skogerboe, F. Kallfelz, L.F. Bélanger, J.R. Marier, B.E. Sheffy, B. Romanus, and C. Hirsch. 1970. Fluoride and nutritional osteoporosis: physicochemical data on bones from an experimental study in dogs. J. Nutr. 100:631-642. [PubMed: 5453360]
  • Herr, H.W., E.L. Kleinert, and W.F. Whitmore, Jr. 1981. Mercury-induced necrosis of murine renal cell carcinoma. J. Surg. Oncol. 18:95-99. [PubMed: 6457222]
  • Heyman, A., W.E. Wilkinson, J.A. Stafford, M.J. Helms, A.H. Sigmon, and T. Weinberg. 1984. Alzheimer's disesase: a study of epidemiological aspects. Ann. Neurol. 15: 335-341. [PubMed: 6742780]
  • Hiasa, Y., M. Ohshima, Y. Kitahori, T. Fujita, T. Yuasa, and A. Miyashiro. 1983. Basic lead acetate: promoting effect on the development of renal tubular cell tumors in rats treated with N-ethyl-N-hydroxyethylnitrosamine. J. Natl. Cancer Inst. 70:761-765. [PubMed: 6572762]
  • Hill, G.M., ER. Miller, P.A. Whetter, and D.E. Ullney. 1983. Concentration of minerals in tissues of pigs from dams fed different levels of dietary zinc. J. Anim. Sci. 57:130-138. [PubMed: 6885655]
  • Hoekstra, W.G. 1975. Biochemical function of selenium and its relation to vitamin E. Fed. Proc. 34:2083-2089. [PubMed: 1100437]
  • Hooper, P.L, L. Visconti, P.J. Garry, and G.E. Johnson. 1980. Zinc lowers high-density lipoprotein-cholesterol levels. J. Am. Med. Assoc. 244:1960-1961. [PubMed: 7420708]
  • Hoover, R.N., F.W. McKay, and J.F. Fraumeni, Jr. 1976. Fluoridated drinking water and the occurrence of cancer. J. Nad. Cancer Inst. 57:757-768. [PubMed: 1003528]
  • Hoover, R.L, R. Folger, W.A. Haering, B.R. Ware, and M.J. Karnovsky. 1980. Adhesion of leukocytes to endothelium: roles of divalent cations, surface charge, chemotactic agents and substrate. J. Cell Sci. 45:73-86. [PubMed: 7462350]
  • Hsi, A., N.P. Johnson, J. San Sebastian, J.P. O'Neill, R.O. Rahn, and N.L. Forbes. 1979. Quantitative mammalian cell mutagenesis and a study of mutagenic potential of metallic compounds. Pp. 55-69 in Kharasch, editor. , ed. Trace Metals in Health and Disease. Raven Press, New York.
  • Hueper, W.C., and W.W. Payne. 1962. Experimental studies in metal carcinogenesis: chromium, nickel, iron, arsenic. Arch. Environ. Health 5:445-462. [PubMed: 13955488]
  • Hurley, L.S. 1981. Teratogenic aspects of manganese, zinc, and copper nutrition. Physiol. Rev. 61:249-295. [PubMed: 7012858]
  • Hurley, L.S., and C.L. Keen. 1987. Manganese. Pp. 185-223 in W. Mertz, editor. , ed. Trace Elements in Human and Animal Nutrition, Vol. I. Academic Press, New York.
  • IARC (International Agency for Research on Cancer). 1976. Cadmium and cadmium compounds. Pp. 39-74 in IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, Vol. 11. Cadmium, Nickel, Some Epoxides, Miscellaneous Industrial Chemicals and General Considerations on Volatile Anaesthetics. IARC, Lyon, France. [PubMed: 992654]
  • IARC (International Agency for Research on Cancer). 1982. a. Inorganic fluorides used in drinking-water and dental preparations. Pp. 237-303 in IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 27. Some Aromatic Amines, Anthraquinones and Nitroso Compounds, and Inorganic Fluorides Used in Drinking-Water and Dental Preparations. IARC, Lyon, France. [PubMed: 6955259]
  • IARC (International Agency for Research on Cancer). 1982. b. Iron dextran complex (group 3). Pp. 145-146 in IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Human, Suppl. 4. Chemical, Industrial Processes and Industries Associated with Cancer in Humans. IARC, Lyon, France.
  • Inskip, H., V. Beral, and M. McDowall. 1982. Mortality of Shipham residents: 40-year follow-up. Lancet 1:896-899. [PubMed: 6122112]
  • Ip, C. 1985. Selenium inhibition of chemical carcinogenesis. Fed. Proc. 44:2573-2578. [PubMed: 3922798]
  • Ip, C. 1986. The chemopreventive role of selenium in carcinogenesis. Adv. Exp. Med. Biol. 206:431-447. [PubMed: 3591532]
  • Ip, C., and D.K. Sinha. 1981. Enhancement of mammary tumorigenesis by dietary selenium deficiency in rats with high polyunsaturated fat intake. Cancer Res. 41:31-34. [PubMed: 6778606]
  • Ishinihsi, N., and A. Yamamoto. 1983. Discrepancy between epidemiological evidence and animal experimental result. Sangyo Ika Daigaku Zasshi J. UOEH, Suppl. 5:109-116. [PubMed: 6679661]
  • Ito, K., and N. Maruchi. 1975. Breast cancer in patients with Hashimoto's thyroiditis. Lancet 2:1119-1121. [PubMed: 53602]
  • Ito, N. 1973. Experimental studies on tumors of the urinary system of rats induced by chemical carcinogens. Acta Pathol. Jpn. 23:87-109. [PubMed: 4800583]
  • Ito, N., Y. Hiasa, Y. Kamakoto, S. Makiura, and S. Sugihara. 1971. Histopathological analysis of kidney tumors in rats induced by chemical carcinogens. Gann 62:435-444. [PubMed: 4334633]
  • Ivey, J.L, and D.J. Baylink. 1981. Postmenopausal osteoporosis: proposed roles of defective coupling and estrogen deficiency. Metab. Bone Dis. Relat. Res. 3:3-7. [PubMed: 7266364]
  • Jacobs, M.M., T.S. Matney, and A.C. Griffin. 1977. Inhibitory effects of selenium on the mutagenicity of 2-acetylaminofluorene (AAF) and AAF derivatives. Cancer Lett. 2: 319-322. [PubMed: 324608]
  • Jagiello, G., and J.S. Lin. 1974. Sodium fluoride as potential mutagen in mammalian eggs. Arch. Environ. Health 29: 230-235. [PubMed: 4472310]
  • Jeejeebhoy, K.N., R.C. Chu, E.B. Marliss, G.R. Greenberg, and A. Bruce-Robertson. 1977. Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am. J. Clin. Nutr. 30:531-538. [PubMed: 192066]
  • Jendryczko, A., M. Crozdz, J. Tomala, and K. Magner. 1986. Copper and zinc concentrations, and superoxide dismutase activities in malignant and nonmalignant tissues of female reproductive organs. Neoplasma 33:239-244. [PubMed: 3713926]
  • Jenkins, G.N. 1978. Fluoride. Pp. 466-500 in The Physiology and Biochemistry of the Mouth, 4th ed. Blackwell Scientific Publications, Oxford.
  • Jowsey, J. 1979. The long-term treatment of osteoporosis with fluoride, calcium, and vitamin D. Pp. 123-134 in U.S. Barzel, editor. , ed. Osteoporosis II. Grune & Stratton, New York.
  • Kada, T., K. Hirano, and Y. Shirasu. 1980. Screening of environmental chemical mutagens by the rec-assay system with Bacillus subtilis . Pp. 149-173 in F.J. de Serres, editor; and A. Hollaender, editor. , eds. Chemical Mutagens: Principles and Methods for Their Detection, Vol. 6. Plenum Press, New York.
  • Kanematsu, N., M. Hara, and T. Kada. 1980. Rec assay and mutagenicity studies on metal compounds. Mutat. Res. 77: 109-116. [PubMed: 6769036]
  • Kanis, J.A., and P.J. Meunier. 1984. Should we use fluoride to treat osteoporosis? A review. Q. J. Med. 53:145-164. [PubMed: 6379725]
  • 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. [PMC free article: PMC1051966] [PubMed: 231629]
  • 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. [PubMed: 202886]
  • Kazantzis, G. 1981. Role of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium in carcinogenesis. Environ. Health Perspect. 40:143-161. [PMC free article: PMC1568837] [PubMed: 7023929]
  • 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. [PMC free article: PMC2008064] [PubMed: 5936680]
  • Kinlaw, W.B., A.S. Levine, J.E. Morley, S.E. Silvis, and C.J. McClain. 1983. Abnormal zinc metabolism in type II diabetes mellitus. Am. J. Med. 75:273-277. [PubMed: 6881179]
  • Kinlen, L., and R. Doll. 1981. Fluoridation of water supplies and cancer mortality. III. A re-examination of mortality in cities in the USA. J. Epidemiol. Community Health 35: 239-244. [PMC free article: PMC1052170] [PubMed: 7338697]
  • Kipling, M.D., and J.A.H. Waterhouse. 1967. Cadmium and prostatic carcinoma. Lancet 1:730-731.
  • Kitano, S. 1980. Membrane and contractile properties of rat vascular tissue in copper-deficient conditions. Circ. Res. 46: 681-689. [PubMed: 7363417]
  • Kjellström, T., L. Friberg, and B. Rahnster. 1979. Mortality and cancer morbidity among cadmium-exposed workers. Environ. Health Perspect. 29:199-204. [PMC free article: PMC1637490] [PubMed: 488034]
  • Klevay, LM. 1975. Coronary heart disease: the zinc/copper hypothesis. Am. J. Clin. Nutr. 28:764-774. [PubMed: 1146731]
  • Klevay, L.M. 1980. Interactions of copper and zinc in cardiovascular disease. Ann. N.Y. Acad. Sci. 355:140-151. [PubMed: 6940471]
  • Klevay, L.M. 1984. The role of copper, zinc, and other chemical elements in ischemic heart disease. Pp. 129-157 in O.M. Rennert, editor; and W.Y. Chan, editor. , eds. Metabolism of Trace Metals in Man, Vol 1. Developmental Aspects. CRC Press, Boca Raton, Fla.
  • Klevay, L.M., and K.E. Viestenz. 1981. Abnormal electrocardiograms in rats deficient in copper. Am. J. Physiol. 240: H185-H189. [PubMed: 7468813]
  • Knox, E.G., editor. , ed. 1985. Fluoridation of Water and Cancer A Review of the Epidemiological Evidence. Report of the Working Party on the Fluoridation of Water and Cancer. Her Majesty's Stationary Office, London. 115 pp.
  • Kobayashi, N., H. Katsuki, and Y. Yamane. 1970. Inhibitory effect of aluminum on the development of experimental lung tumor in mice induced by 4-nitroquinone 1-oxide. Gann 61: 239-244. [PubMed: 5455322]
  • Kok, F.J., A.M. de Bruijn, A. Hofman, R. Vermeeren, and H.A. Valkenburg. 1987. a. Is serum selenium a risk factor for cancer in men only? Am. J. Epidemiol. 125:12-16. [PubMed: 3788940]
  • Kok, F., A.M. de Bruijn, R. Vermeeren, A. Hofman, A. van Laar, M. de Bruin, R.J. Hermus, and H.A. Valkenburg. 1987. b. Serum selenium, vitamin antioxidants, and cardiovascular mortality: a 9-year follow-up study in the Netherlands. Am. J. Clin. Nurr. 45:462-468. [PubMed: 3812345]
  • Koller, LD., N.I. Kerkvliet, and J.H. Exon. 1985. Neoplasia induced in male rats fed lead acetate, ethyl urea, and sodium nitrite. Toxicol. Pathol. 13:50-57. [PubMed: 4035262]
  • Kolonel, L.N. 1976. Association of cadmium with renal cancer. Cancer 37:1782-1787. [PubMed: 769938]
  • Kolonel, L.N., and W. Winkelstein, Jr. 1977. Cadmium and prostatic carcinoma. Lancet 2:566-567. [PubMed: 95781]
  • Kolonel, L.N., C.N. Yoshigama, and J.H. Hankin. 1988. Diet and prostatic cancer: a case-control study in Hawaii. Am. J. Epidemiol. 127:999-1012. [PubMed: 3358418]
  • Kopp, S.J., T. Glonek, M. Erlanger, E.F. Perry, M. Barany, and H.M. Perry, Jr. 1980. Altered metabolism and function of rat heart following chronic low level cadmium/lead feeding. J. Mol. Cell Cardiol. 12:1407-1425. [PubMed: 7205958]
  • Kopp, S.J., L.M. Klevay, and J.M. Feliksik. 1983. Physiological and metabolic characterization of a cardiomyopathy induced by chronic copper deficiency. Am. J. Physiol. 245: H855-H866. [PubMed: 6638205]
  • Koval'skii, V.V., G.A. Iarovaia, and D.M. Shmavonian. 1961. Modification of human and animal purine metabolism in conditions of various molybdenum bio-geochemical areas. Zh. Obshch. Biol. 22:179-191. [PubMed: 13753620]
  • Kumpulainen, J., and P. Koivistoinen. 1977. Fluorine in foods. Residue Rev. 68:37-57. [PubMed: 337435]
  • Landrigan, P.J. 1981. Arsenic—state of the art. Am. J. Ind. Med. 2:5-14. [PubMed: 6295141]
  • Lappalainen, R., M. Knuuttila, S. Lammi, EM. Alhava, and H. Olkkonen. 1982. Zn and Cu content in human cancellous bone. Acta Orthop. Scand. 53:51-55. [PubMed: 7064680]
  • Larramendy, M.L., N.C. Popescu, and J.A. DiPaolo. 1981. Induction by inorganic metal salts of sister chromatid exchanges and chromosome aberrations in human and Syrian hamster cell strains. Environ. Mutagen 3:597-606.
  • Larsson, L.G., A. Sandström, and P. Westling. 1975. Relationship of Plummer-Vinson disease to cancer of the upper alimentary tract in Sweden. Cancer Res. 35:3308-3316. [PubMed: 1192404]
  • LeBoeuf, R.A., B.A. Laishes, and W.G. Hoekstra. 1985. Effects of selenium on cell proliferation in rat liver and mammalian cells as indicated by cytokinetic and biochemical analysis. Cancer Res. 45:5496-5504. [PubMed: 4053023]
  • Lee-Feldstein, A. 1986. Cumulative exposure to arsenic and its relationship to respiratory cancer among copper smelter employees. J. Occup. Med. 28:296-302. [PubMed: 3701479]
  • Lemen, R.A., J.S. Lee, J.K. Wagoner, and H.P. Blejer. 1976. Cancer mortality among cadmium production workers. Ann. N.Y. Acad. Sci. 271:273-279. [PubMed: 1069514]
  • Lener, J., and B. Bibr. 1971. Cadmium and hypertension. Lancet 1:970. [PubMed: 4103345]
  • Leonard, A., and R.R. Lauwerys. 1980. Carcinogenicity, mutagenicity, and teratogenicity of arsenic. Mutat. Res. 75: 49-62. [PubMed: 6987506]
  • Leone, N.C., E.F. Geever, and N.C. Moran. 1956. Acute and subacute toxicity studies of sodium fluoride in animals. Public Health Rep. 71:459-467. [PMC free article: PMC2030974] [PubMed: 13323211]
  • Levander, O.A. 1987. A global view of selenium nutrition. Annu. Rev. Nutr. 7:227-250. [PubMed: 3300734]
  • Levander, O.A., editor; , and L. Cheng, editor. , eds. 1980. Micronutrient interactions: vitamins, minerals, and hazardous elements. Ann. of N.Y. Acad. Sci. 355:1-372.
  • Levine, R.S. 1976. The action of fluoride in caries prevention. A review of current concepts. Br. Dent. J. 140:9-14. [PubMed: 1061590]
  • Levine, A.S., C.J. McClain, B.S. Handwerger, D.M. Brown, and J.E. Morley. 1983. Tissue zinc status of genetically diabetic and streptozotocin-induced diabetic mice. Am. J. Clin. Nutr. 37:382-386. [PubMed: 6219574]
  • Levis, A.G., and F. Majone. 1979. Cytotoxic and clastogenic effects of soluble chromium compounds on mammalian cell cultures. Br. J. Cancer 40:523-533. [PMC free article: PMC2010087] [PubMed: 497104]
  • Levis, A.G., and F. Majone. 1981. Cytotoxic and clastogenic effects of soluble and insoluble compounds containing hexavalent and trivalent chromium. Br. J. Cancer. 44:219-235. [PMC free article: PMC2010749] [PubMed: 7272188]
  • Levy, LS., and S. Venitt. 1986. Carcinogenicity and mutagenicity of chromium compounds: the association between bronchial metaplasia and neoplasia. Carcinogenesis 7:8318-35. [PubMed: 3698209]
  • Lilis, R., J.A. Valciukas, S. Kon, L. Sarkosi, C. Campbell, and I.J. Selikoff. 1982. Assessment of lead health hazards in a body shop of an automobile assembly plant. Am. J. Ind. Med. 3:33-51. [PubMed: 7124742]
  • Lilis, R., J.A. Valciukas, J.P. Weber, J. Malkin, and I.J. Selikoff. 1984. Epidemiologic study of renal function in copper smelter workers. Environ. Health Perspect. 54:181-192. [PMC free article: PMC1568152] [PubMed: 6376092]
  • Lin, H.J., W.C. Chan, Y.Y. Fong, and P.M. Newberne. 1977. Zinc levels in serum, hair and tumors from patients with esophageal cancer. Nutr. Rep. Int. 15:634-643.
  • Lo, L.W., J. Koropatnick, and H.F. Stich. 1978. The mutagenicity and cytotoxicity of selenite, ''activated" selenite and selenate for normal and DNA repair-deficient human fibroblasts. Mutat. Res. 49:305-312. [PubMed: 634305]
  • Logue, J.N., M.D. Koontz, and M.A. Hattwick. 1982. A historical prospective mortality study of workers in copper and zinc refineries. J. Occup. Med. 24:398-408. [PubMed: 7086554]
  • Lorentzon, R., and S.E. Larsson. 1977. Vitamin D metabolism in adult rats at low and normal calcium intake and the effect of cadmium exposure. Clin. Sci. Mol. Med. 53:439-446. [PubMed: 589928]
  • Löser, E. 1980. A 2 year oral carcinogenicity study with cadmium on rats. Cancer Lett. 9:191-198. [PubMed: 7226151]
  • LSRO (Life Sciences Research Office). 1984. a. Assessment of the Iron Nutritional Status of the U.S. Population Based on Data Collected in the Second National Health and Nutrition Examination Survey, 1976-1980. Federation of American Societies for Experimental Biology, Bethesda, Md: 120 pp.
  • LSRO (Life Sciences Research Office). 1984. b. Assessment of the Zinc Nutritional Status of the U.S. Population Based on Data Collected in the Second National Health and Nutrition Examination Survey, 1976-1980. Federation of American Societies for Experimental Biology, Bethesda, Md. 82 pp.
  • Lu, F.C., R.S. Grewal, W.B. Rice, R.C.B. Graham, and M.G. Allmark. 1965. Acute toxicity of sodium fluoride for rhesus monkeys and other laboratory animals. Acta Pharmacol. Toxicol. 22:99-106. [PubMed: 14284200]
  • Lu, S.H., and P. Lin, 1982. Recent research on the etiology of esophageal cancer in China. Z. Gastroenterol. 20:361-367. [PubMed: 7051590]
  • 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. 40:928.
  • Luo, X.M., H.J. Wei, and S.P. Yang. 1983. Inhibitory effects of molybdenum on esophageal and forestomach carcinogenesis in rats. J. Natl. Cancer Inst. 71:75-80. [PubMed: 6575213]
  • Mahaffey, K.R., P.E. Corneliussen, C.F. Jelinek, and 3.A. Fiorino. 1975. Heavy metal exposure from foods. Environ. Health Perspect. 12:63-69. [PMC free article: PMC1475014] [PubMed: 1227862]
  • Mahaffey, K.R., J.F. Rosen, R.W. Chesney, J.T. Peeler, C.M. Smith, and H.F. DeLuca. 1982. Association between age, blood lead concentration, and serum 1,25-dihydroxycholecalciferol levels in children. Am. J. Clin. Nutr. 35: 1327-1331. [PubMed: 6896257]
  • Majone, F., and A.G. Levis. 1979. Chromosome aberrations and sister-chromatid exchanges in Chinese hamster cells treated in vivo with hexavalent chromium compounds. Mutat. Res. 67:231-238. [PubMed: 481449]
  • Majone, F., A. Montaldi, F. Ronchese, A. DeRossi, L. Chieco-Bianchi, and A.G. Levis. 1983. Sister-chromatid exchanges induced in vivo and in vitro by chemical carcinogens in mouse lymphocytes carrying endogenous Maloney leukemia virus. Carcinogenesis 4:33-37. [PubMed: 6821887]
  • Manousos, O., D. Trichopoulos, A. Koutselinis, C. Papadimitriou, and X. Zavitsanos. 1981. Epidemiologic characteristics and trace elements in pancreatic cancer in Greece. Cancer Detect. Prev. 4:439-442. [PubMed: 7349806]
  • Manthey, J., M. Stoeppler, W. Morgenstern, E. Nüssel, D. Opherk, A. Weintraut, H. Wesch, and W. Kübler. 1981. Magnesium and trace metals: risk factors for coronary heart disease? Association between blood levels and angiographic findings. Circulation 64:722-729. [PubMed: 7273372]
  • 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. [PMC free article: PMC1965304] [PubMed: 4225664]
  • Margalioth, E.J., J.G. Schenker, and M. Chevion. 1983. Copper and zinc levels in normal and malignant tissues. Cancer 52:868-872. [PubMed: 6871828]
  • Markesbery, W.R., W.D. Ehmann, T.I. Hossain, and M. Alauddin. 1984. Brain manganese concentrations in human aging and Alzheimer's disease. Neurotoxicology 5:49-57. [PubMed: 6538949]
  • Marshall, E. 1983. EPA faults classic lead poisoning study. A review questions a study linking lead in teeth with low IQ scores: EPA finds other grounds for regulation. Science 222: 906-907. [PubMed: 6688887]
  • Martyn, C.N., D.J.P. Barker, C. Osmond, E.C. Harris, J.A. Edwardson, and R.F. Lacey. 1989. Geographical relation between Alzheimer's disease and aluminium in drinking water. Lancet 1:59-62. [PubMed: 2562879]
  • Maruyama, Y. 1983. The health effect of mice given oral administration of trivalent and hexavalent chromium over a long-term. Gifu Daigaku Igakubu Kiyo 31:25-46.
  • Masironi, R., editor. , ed. 1974. Trace Elements in Relation to Cardiovascular Diseases; Status of the Joint WHO/IAEA Research Programme. WHO Offset Publ. No. 5. World Health Organization, Geneva. 45 pp.
  • Masironi, R., and R. Parr. 1976. Selenium and cardiovascular diseases: preliminary results of the WHO/IAEA joint research programme. Pp. 316-325 in Proceedings of the Symposium on Selenium-Tellurium in the Environment. Industrial Health Foundation, Pittsburgh.
  • McConnell, K.P., W.L. Broghamer, Jr., A.J. Blotcky, and O.J. Hurt. 1975. Selenium levels in human blood and tissues in health and disease. J. Nutr. 105:1026-1031. [PubMed: 1142009]
  • McConnell, K.P., R.M. Jager, K.I. Bland, and A.J. Blotcky. 1980. The relationship of dietary selenium and breast cancer. J. Surg. Oncol. 15:67-70. [PubMed: 6252392]
  • McLeod, B.E., and M.F. Robinson. 1972. Dietary intake of manganese by New Zealand infants during the first six months of life. Br. J. Nutr. 229-232. [PubMed: 5066770]
  • McNair, P., S. Kiilerich, C. Christiansen, M.S. Christensen, S. Madsbad, and I. Transbol. 1981. Hyperzincuria in insulin treated diabetes mellitus—its relation to glucose homeostasis and insulin administration. Clin. Chem. Acta 112: 343-348. [PubMed: 7016379]
  • Medeiros, D.M., and L.K. Pellum. 1984. Elevation of cadmium, lead, and zinc in the hair of adult black female hypertensives. Bull. Environ. Contam. Toxicol. 32:525-532. [PubMed: 6733298]
  • Medeiros, D.M., L.K. Pellum, and B.J. Brown. 1983. The association of selected hair minerals and anthropometric factors with blood pressure in a normotensive adult population. Nutr. Res. 3:51-60.
  • Medina, D. 1986. Mechanisms of selenium inhibition of tumorigenesis. Adv. Exp. Med. Biol. 206:465-472. [PubMed: 3591534]
  • Mehlert, A., and A.T. Diplock. 1985. The glutathione S-transferases in selenium and vitamin E deficiency. Biochem. J. 227:823-831. [PMC free article: PMC1144911] [PubMed: 4004801]
  • Mellow, M.H., E.A. Layne, T.O. Lipman, M. Kaushik, C. Hostetler, and J.C. Smith, Jr. 1983. Plasma zinc and vitamin A in human squamous carcinoma of the esophagus. Cancer 51:1615-1620. [PubMed: 6831364]
  • Menkes, M.S., G.W. Comstock, J.P. Vuilleumier, K.J. Helsing, A.A. Rider, and R. Brookmeyer. 1986. Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer. N. Engl. J. Med. 315:1250-1254. [PubMed: 3773937]
  • Mertz, W. 1979. Chromium—an overview. Pp. 1-14 in D. Shapcott, editor; and J. Hubert, editor. , eds. Chromium and Metabolism. Elsevier; / North-Holland, Amsterdam.
  • Mertz, W. 1982. Trace minerals and atherosclerosis. Fed. Proc. 41:2807-2812. [PubMed: 6749552]
  • Mertz, W., and K. Schwarz. 1955. Impaired intravenous glucose tolerance as an early sign of dietary necrotic liver degeneration. Arch. Biochem. Biophys. 58:504-506. [PubMed: 13269145]
  • Meyer, B.R., A. Fischbein, K. Rosenman, Y. Lerman, D.E. Drayer, and M.M. Reidenberg. 1984. Increased urinary enzyme excretion in workers exposed to nephrotoxic chemicals. Am. J. Med. 76:989-998. [PubMed: 6731470]
  • Miettinen, T.A., G. Alfthan, J.K. Huttunen, J. Pikkarainen, V. Naukkarinen, S. Mattila, and T. Kumlin. 1983. Serum selenium concentration related to myocardial infarction and fatty acid content of serum lipids. Br. Med. J. 287:517-519. [PMC free article: PMC1548429] [PubMed: 6411201]
  • Miller, G.W., M.N. Egyed, and J.L. Shupe. 1977. Alkaline phosphatase activity, fluoride citric acid, calcium, and phosphorus content in bones of cows with osteoporosis. Fluoride 10:76-82.
  • Miller, R.G., F.C. Kopfler, K.C. Kelty, J.A. Stober, and N.S. Ulmer. 1984. The occurrence of aluminum in drinking water. J. Am. Water Works Assoc. 77:84-91.
  • Mills, B.J., W.L. Broghamer, P.J. Higgins, and R.D. Lindeman. 1984. Inhibition of tumor growth by zinc depletion in rats. J. Nutr. 114:746-752. [PubMed: 6716177]
  • 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. [PubMed: 445445]
  • Mittra, I., J.L. Hayward, and A.S. McNeilly. 1974. Hypothalamic-pituitary-prolactin axis in breast cancer. Lancet 1: 885-889. [PubMed: 4133416]
  • Miyake, M., N. Akamatsu, T. Ono, and H. Koyama. 1979. Mutagenicity of metal cations in cultured cells from Chinese hamster. Mutat. Res. 68:259-263. [PubMed: 514305]
  • Mohamed, A.H., and M.E.W. Chandler. 1976. Cytological effects of sodium fluoride on mitotic and meiotic chromosomes of mice. Presented at American Chemical Society, 172nd National Meeting, San Francisco, August 29-September. 3 pp.
  • Moldrup, A.M. 1984. Cadmium in Foods With a Special Emphasis on Cadmium in Grain Products. Ph.D. thesis, University of Copenhagen.
  • Moore, J.A., R. Noiva, and I.C. Wells. 1984. Selenium concentrations in plasma of patients with arteriographically defined coronary atherosclerosis. Clin. Chem. 30:1171-1173. [PubMed: 6733902]
  • Moore, M.R., P.A. Meredith, A. Goldberg, K.E. Crr, P.G. Toner, and T.D.V. Lawrie. 1975. Cardiac effects of lead in drinking water of rats. Clin. Sci. Mol. Med. 49:337-341. [PubMed: 1192693]
  • Morton, W., G. Starr, D. Pohl, J. Stoner, S. Wagner, and D. Weswig. 1976. Skin cancer and water arsenic in Lane County, Oregon. Cancer 37:2523-2532. [PubMed: 1260732]
  • Mossop, R.T. 1983. Effects of chromium III on fasting blood glucose, cholesterol and cholesterol HDL levels in diabetics. Cent. Afr. J. Med. 29:80-82. [PubMed: 6883494]
  • Mukherjee, R.W., and F.H. Sobels. 1968. The effects of sodium fluoride and iodoacetamide on mutation induction by x-irradiation in mature spermatozoa of Drosophila. Mutat. Res. 6:217-225. [PubMed: 5714160]
  • Nakamuro, K., K. Yoshikawa, Y. Sayato, H. Kurata, M. Tonomura, and A. Tonomura. 1976. Studies on selenium-related compounds. V. Cytogenetic effect and reactivity with DNA. Mutat. Res. 40:177-183. [PubMed: 8704]
  • Needleman, H.L., C. Gunnoe, A. Leviton, R. Reed, H. Peresie, C. Maher, and P. Barrett. 1979. Deficits in psychological and classroom performance of children with elevated dentine lead levels. N. Engl. J. Med. 300:689-695. [PubMed: 763299]
  • Nelson, A.A., O.G. Fitzhugh, and H.O. Calvery. 1943. Liver tumors following cirrhosis caused by selenium in rats. Cancer Res. 3:230-236.
  • Newbrun, E., editor. , ed. 1975. Fluorides and Dental Caries, 2nd ed: Contemporary Concepts for Practitioners and Students. C.C. Thomas, Springfield, Ill. 181 pp.
  • Newman, J.A., V.E. Archer, G. Saccomanno, M. Kuschner, O. 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. [PubMed: 187098]
  • NIDR (National Institute of Dental Research). 1981. The Prevalence of Dental Caries in United States Children: 1979-1980. NIH Publ. No. 82-2245. National Caries Program, National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Bethesda, Md. 159 pp.
  • Nielsen, F.H. 1982. Possible future implications of nickel, arsenic, silicon, vanadium, and other ultratrace elements in human nutrition. Pp. 379-404 in A.S. Prasad, editor. , ed. Clinical, Biochemical, and Nutritional Aspects of Trace Elements: Current Topics in Nutrition and Disease, Vol. 6. Alan R. Liss, New York.
  • Nielsen, F.H., and W. Mertz. 1984. Other trace elements. Pp. 607-618 in R.E. Olson, editor; , H.P. Broquist, editor; , C.O. Chichester, editor; , W.J. Darby, editor; , A.C. Kolbye, Jr., editor; , and R.M. Stalvey, editor. , eds. Nutrition Reviews' Present Knowledge in Nutrition. The Nutrition Foundation, Washington, D.C.
  • Nishioka, H. 1975. Mutagenic activities of metal compounds in bacteria. Mutat. Res. 31:185-189. [PubMed: 805366]
  • Nixon, J.M., and R.G. Carpenter. 1974. Mortality in areas containing natural fluoride in their water supplies, taking account of socioenvironmental factors and water hardness. Lancet 2:1068-1071. [PubMed: 4138117]
  • Nogawa, K., E. Kobayashi, and F. Konishi. 1981. Comparison of bone lesions in chronic cadmium intoxication and vitamin D deficiency. Environ. Res. 24:233-249.
  • Nordberg, G.F., T. Kjellström, and M. Nordberg. 1985. Kinetics and metabolism. Pp. 103-178 in L. Friberg, editor; , C.G. Elinder, editor; , T. Kjellström, editor; , and G.F. Nordberg, editor. , eds. Cadmium and Health: A Toxicological and Epidemiological Appraisal, Vol. 1. Exposure, Dose, and Metabolism. CRC Press, Boca Raton, Fla.
  • Nordenson, I., G. Beckman, L. Beckman, and S. Nordström. 1978. Occupational and environmental risks in and around a smelter in northern Sweden. II. Chromosomal aberrations in workers exposed to arsenic. Hereditas 88:47-50. [PubMed: 649424]
  • NRC (National Research Council). 1971. Fluorides. Report of the Committee on Biologic Effects of Atmospheric Pollutants. National Academy of Sciences, Washington, D.C. 295 pp.
  • NRC (National Research Council). 1977. a. Arsenic. Report of the Committee on Medical and Biologic Effects of Environmental Pollutants, Division of Medical Sciences, Assembly of Life Sciences. National Academy of Sciences, Washington, D.C. 332 pp.
  • NRC (National Research Council). 1977. b. Drinking Water and Health, Vol. 1. Report of the Safe Drinking Water Committee, Advisory Center on Toxicology, Assembly of Life Sciences, National Academy of Sciences, Washington, D.C. 939 pp.
  • NRC (National Research Council). 1977. c. Medical and Biological Effects of Environmental Pollutants: Copper. Report of the Committee on Medical and Biologic Effects of Environmental Pollutants, Division of Medical Sciences, Assembly of Life Sciences, National Academy of Sciences, Washington, D.C. 115 pp.
  • NRC (National Research Council). 1980. Magnesium. Pp. 134-136 in Recommended Dietary Allowances, 9th ed. Report of the Committee on Dietary Allowances, Food and Nutrition Board, Division of Biological Sciences, Assembly of Life Sciences. National Academy Press, Washington, D.C.
  • NRC (National Research Council). 1982. Diet, Nutrition, and Cancer. Report of the Committee on Diet, Nutrition, and Cancer, Assembly of Life Sciences. National Academy Press, Washington, D.C. 478 pp.
  • NRC (National Research Council). 1983. Selenium in Nutrition, rev. ed. Report of the Subcommittee on Selenium, Committee on Animal Nutrition, Board on Agriculture. National Academy Press, Washington, D.C. 174 pp.
  • Oberly, T.J., C.E. Piper, and D.S. McDonald. 1982. Mutagenicity of metal salts in the C51784 mouse lymphoma assay. J. Toxicol. Environ. Health 9:367-376. [PubMed: 7097791]
  • O'Dell, B.L 1976. Biochemistry of copper. Med. Clin. North Am. 60:687-703. [PubMed: 5635]
  • Offenbacher, E.G., and F.X. Pi-Sunyer. 1980. Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids. Diabetes 29:919-925. [PubMed: 7000589]
  • Offenbacher, E.G., and F.X. Pi-Sunyer. 1983. Temperature and pH effects on the release of chromium from stainless steel into water and fruit juices. J. Agric. Food Chem. 31: 89-92. [PubMed: 6826924]
  • Ohno, H., F. Hanaoka, and M.A. Yamada. 1982. Inducibility of sister chromatid exchanges by heavy metal ions. Mutat. Res. 104:141-145. [PubMed: 7078567]
  • Ohshima, M., and J.M. Ward. 1984. Promotion of Nmethyl-N-nitrosourea-induced thyroid tumors by iodine deficiency in F344/NCr rats. J. Natl. Cancer Inst. 73:289-296. [PubMed: 6588234]
  • Ohshima, M., and J.M. Ward. 1986. Dietary iodine deficiency as a tumor promoter and carcinogen in male F344/NCr rats. Cancer Res. 46:877-883. [PubMed: 3940650]
  • Oldham, P.D., and D.J. Newell. 1977. Fluoridation of water supplies and cancer-a possible association? Appl. Statist. 26:125-135.
  • Oster, O., M. Drexler, J. Schenk, T. Meinertz, W. Kasper, C.J. Schuster, and W. Prellwitz. 1986. The serum selenium concentration of patients with acute myocardial infarction. Ann. Clin. Res. 18:36-42. [PubMed: 3717871]
  • Ostergaard, K. 1978. Renal cadmium concentration in relation to smoking habits and blood pressure. Acta Med. Scand. 203:379-383. [PubMed: 665303]
  • Otto, D., G. Robinson, S. Baumann, S. Schoeder, P. Mushak, D. Kleinbaum, and L. Boone. 1985. 5-year followup study of children with low-to-moderate lead absorption: electrophysiological evaluation. Environ. Res. 38:168-186. [PubMed: 4076105]
  • Overvad, K., E.B. Thorling, P. Bjerring, and P. Ebbesen. 1985. Selenium inhibits UV-light-induced skin carcinogenesis in hairless mice. Cancer Lett. 27:163-170. [PubMed: 4005828]
  • Palmer, W.G., and D.A. Creasia. 1984. Metabolism of 7,12-dimethylbenz(a)anthracene by alveolar macrophages containing ingested ferric oxide, aluminum oxide or carbon particles. J. Environ. Pathol. Toxicol. Oncol. 5:261-270. [PubMed: 6440976]
  • Pandit, A.N., and S.A. Bhave. 1983. Cooper and Indian childhood cirrhosis. Indian Pediatr. 20:893-899. [PubMed: 6676301]
  • Paton, G.R., and A.C. Allison. 1972. Chromosome damage in human cell cultures induced by metal salts. Mutat. Res. 16:332-336. [PubMed: 5078138]
  • Patrono, C., F.E Preston, and J. Vermylen. 1984. Platelet and vascular arachidonic acid metabolites: can they help detect a tendency towards thrombosis? Br. J. Haematol. 57: 209-212. [PubMed: 6428446]
  • Pence, B.C., and F. Buddingh. 1985. Effect of dietary selenium deficiency on incidence and size of 1,2-dimethylhydrazine-induced colon tumors in rats. J. Nutr. 115:1196-1202. [PubMed: 4032067]
  • 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. [PubMed: 13734092]
  • Pennington, J.A., D.B. Wilson, RF. Newell, B.F. Harland, R.D. Johnson, and J.E. Vanderveen. 1984. Selected minerals in foods surveys, 1974 to 1981/82. J. Am. Diet. Assoc. 84:771-780. [PubMed: 6736504]
  • Pennington, J.A., D.E. Young, D.B. Wilson, R.D. Johnson, and J.E. Vanderveen. 1986. Mineral content of foods and total diets: the Selected Minerals in Foods Survey, 1982 to 1984. J. Am. Diet. Assoc. 86:876-891. [PubMed: 3722652]
  • Perl, D.P. 1985. Relationship of aluminum to Alzheimer's disease. Environ. Health Perspect. 63:149-153. [PMC free article: PMC1568482] [PubMed: 4076080]
  • Perl, D.P., and A.R. Brody. 1980. Alzheimer's disease: x-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons. Science 208:297-299. [PubMed: 7367858]
  • Perry, H.M., Jr., and S.J. Kopp. 1983. Does cadmium contribute to human hypertension. Sci. Total Environ. 26:223-232. [PubMed: 6344213]
  • Perry, H.M., Jr., E.F. Perry, and M.W. Erlanger. 1980. Possible influence of heavy metals in cardiovascular disease: introduction and overview. J. Environ. Pathol. Toxicol. 4:195-203. [PubMed: 7007556]
  • Pershagen, G. 1981. The carcinogenicity of arsenic. Environ. Health Perspect. 40:93-100. [PMC free article: PMC1568809] [PubMed: 7023936]
  • Pershagen, G., S. Wall, A. Taube, and L. Linnman. 1981. On the interaction between occupational arsenic exposure and smoking and its relationship to lung cancer. Scand. J. Work Environ. Health 7:302-309. [PubMed: 7347915]
  • Petres, J., and A. Berger. 1972. The effect of inorganic arsenic on DNA-synthesis of human lymphocytes in vitro. Arch. Dermatol. Forsch. 242:343-352. [PubMed: 5021577]
  • Pidduck, H.G., P.J. Wren, and D.A. Evans. 1970. Hyperzincuria of diabetes mellitus and possible genetical implications of this observation. Diabetes 19:240-247. [PubMed: 5437978]
  • Pigott, G.H., B.A. Gaskell, and J. Ishmael. 1981. Effects of long term inhalation of alumina fibres in rats. Br. J. Exp. Pathol. 62:323-331. [PMC free article: PMC2041697] [PubMed: 7248173]
  • Pimentel, J.C., and A.P. Menezes. 1977. Liver disease in vineyard sprayers. Gastroenterology 72:275-283. [PubMed: 556610]
  • Piomelli, S., C. Seaman, D. Zullow, A. Curran, and B. Davidow. 1982. Threshold for lead damage to heme synthesis in urban children. Proc. Natl. Acad. Sci. U.S.A. 79: 3335-3339. [PMC free article: PMC346410] [PubMed: 6954483]
  • Pirkle, J.L., J. Schwartz, J.R. Landis, and W.R. Harlan. 1985. The relationship between blood lead levels and blood pressure and its cardiovascular risk implications. Am. J. Epidemiol. 121:246-258. [PubMed: 4014119]
  • Pi-Sunyer, F.X., and E.G. Offenbacher. 1984. Chromium. Pp. 571-586 in R.E. Olson, editor; , H.P. Broquist, editor; , C.O. Chichester, editor; , W.J. Darby, editor; , A.C. Kolbye, Jr., editor; , and RM. Stalvey, editor. , eds. Nutrition Reviews' Present Knowledge in Nutrition. Nutrition Foundation, Washington, D.C.
  • Pocock, S.J., A.G. Shaper, D. Ashby, T. Delves, and T.P. Whitehead. 1984. Blood lead concentration, blood pressure, and renal function. Br. Med. J. 289:872-874. [PMC free article: PMC1443446] [PubMed: 6434118]
  • Poirier, LA., K.S. Kasprzak, K.L. Hoover, and M.L. Wenk. 1983. Effects of calcium and magnesium acetates on the carcinogenicity of cadmium chloride in Wistar rats. Cancer Res. 43:4575-4581. [PubMed: 6883316]
  • Pollack, R.L, editor; , and E. Kravitz, editor. , eds. 1985. Nutrition in Oral Health and Disease. Lea & Febiger, Philadelphia. 483 pp.
  • Poswillo, D.E., and B. Cohen. 1971. Inhibition of carcinogenesis by dietary zinc. Nature 231:447-448. [PubMed: 4931600]
  • Potts, C.L. 1965. Cadmium proteinuria—the health of battery workers exposed to cadmium oxide dust. Ann. Occup. Hyg. 8:55-61. [PubMed: 14287870]
  • Power, G.R., and J.D. Gay. 1986. Sodium fluoride in the treatment of osteoporosis. Clin. Invest. Med. 9:41-43. [PubMed: 3955920]
  • Prasad, A.S., G.J. Brewer, E.B. Schoomaker, and P. Rabbani. 1978. Hypocupremia induced by zinc therapy in adults. J. Am. Med. Assoc. 240:2166-2168. [PubMed: 359844]
  • Prime, S.S., D.G. MacDonald, D.R. Sawyer, and J. Rennie. 1986. The effect of iron deficiency on early oral carcinogenesis in the rat. J. Oral Pathol. 15:265-267. [PubMed: 3091792]
  • Punsar, S., and M.J. Karvonen. 1979. Drinking water quality and sudden death: observations from west and east Finland. Cardiology 64:24-34. [PubMed: 758986]
  • Punsar, S., O. Erametsa, M.J. Karvonen, A. Ryhanen, P. Hilska, and H. Vornamo. 1975. Coronary heart disease and drinking water. A search in two Finnish male cohorts for epidemiologic evidence of a water factor. J. Chronic Dis. 28: 259-287. [PubMed: 1141423]
  • Rabinowitz, M.B., H.C. Gonick, S.R. Levin, and M.B. Davidson. 1983. Effects of chromium and yeast supplements on carbohydrate and lipid metabolism in diabetic men. Diabetes Care 6:319-327. [PubMed: 6352208]
  • Ranade, S.S., S. Shah, and P. Haria. 1979. Transition metals in an experimental tumor system. Experientia 35:460-461. [PubMed: 437022]
  • Reddy, B.S., and T. Tanaka. 1986. Interactions of selenium deficiency, vitamin E, polyunsaturated fat, and saturated fat on azoxymethane-induced colon carcinogenesis in small F344 rats. J. Natl. Cancer Inst. 76:1157-1162. [PubMed: 3458951]
  • Reeves, J.D., E. Vichinsky, J. Addiego, Jr., and B.H. Lubin. 1983. Iron deficiency in health and disease. Adv. Pediatr. 30:281-320. [PubMed: 6369941]
  • Reichlmayr-Lais, A.M., and M. Kirchgessner. 1981. Essentiality of lead for growth and metabolism. Z. Tierphysiol. Tieremahr. Futtermittelkd. 46:1-8. [PubMed: 7303950]
  • Reinstein, N.H., B. Lönnerdal, C.L. Keen, and L.S. Hurley. 1984. Zinc-copper interactions in the pregnant rat: fetal outcome and maternal and fetal zinc, copper and iron. J. Nutr. 114:1266-1279. [PubMed: 6737088]
  • Reiser, S., J.C. Smith, W. Mertz, J.T. Holbrook, D.J. Scholfield, A.S. Powell, W.K. Canfield, and J.J. Canary. 1985. Indices of copper status in humans consuming a typical American diet containing either fructose or starch. Am. J. Clin. Nutr. 42:242-253. [PubMed: 4025196]
  • Revis, N.W., T.C. Major, and C.Y. Horton. 1983. The response of the adrenergic system in the cadmium induced hypertension. J. Am. Coll. Toxicol. 2:165.
  • Riales, R., and M.J. Albrink. 1981. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men. Am. J. Clin. Nutr. 34:2670-2678. [PubMed: 7032273]
  • Riggs, B.L., S.F. Hodgson, D.L. Hoffman, P.J. Kelly, K.A. Johnson, and D. Taves. 1980. Treatment of primary osteoporosis with fluoride and calcium. Clinical tolerance and fracture occurrence. J. Am. Med. Assoc. 243:446-449. [PubMed: 7351765]
  • Riggs, B.L, E. Seeman, S.F. Hodgson, D.R. Taves, and W.M. O'Fallon. 1982. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. Comparison with conventional therapy. N. Engl. J. Med. 306:446-450. [PubMed: 6276746]
  • Rivedal, E., and T. Sanner. 1981. Metal salts as promotes of in vitro morphological transformation of hamster embryo initiated by benzoapyrene. Cancer Res. 41:2950-2958. [PubMed: 6265071]
  • Roat, J.W., A. Wald, H. Mendelow, and K.I. Pataki. 1982. Hepatic angiosarcoma associated with short-term arsenic ingestion. Am. J. Med. 73:933-936. [PubMed: 6890767]
  • Robinson, M.F., P.J. Godfrey, C.D. Thomson, H.M. Rea, and A.M. van Rij. 1979. Blood selenium and glutathione peroxidase activity in normal subjects and in surgical patients with and without cancer in New Zealand. Am. J. Clin. Nutr. 32:1477-1485. [PubMed: 110128]
  • Robinson, T.R. 1976. The health of long service tetraethyl lead workers. J. Occup. Med. 18:31-40. [PubMed: 1249656]
  • Rockette, H.E., and V.C. Arena. 1983. Mortality studies of aluminum reduction plant workers potroom and carbon department. J. Occup. Med. 25:549-557. [PubMed: 6886861]
  • 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. [PMC free article: PMC2071181] [PubMed: 14264931]
  • Rogot, E., A.R. Sharrett, M. Feinleib, and RR. Fabsitz. 1978. Trends in urban mortality in relation to fluoridation status. Am. J. Epidemiol. 107:104-112. [PubMed: 623093]
  • Rosenkranz, H.S., and L.A. Poirier. 1979. Evaluation of the mutagenicity and DNA-modifying activity of carcinogens and noncarcinogens in microbial systems. J. Natl. Cancer Inst. 62:873-892. [PubMed: 372656]
  • Rossi, M.A., and S.V. Carillo. 1983. Electron microscopic study on the cardiac hypertrophy induced by iron deficiency anaemia in the rat. Br. J. Exp. Pathol. 64:373-387. [PMC free article: PMC2040798] [PubMed: 6225450]
  • Rossi, M.A., S.V. Carillo, and J.S. Oliveira. 1981. The effect of iron deficiency anemia in the rat on catecholamine levels and heart morphology. Cardiovasc. Res. 15:313-319. [PubMed: 6457688]
  • Rossman, T.G. 1981. a. Effect of metals on mutagenesis and DNA repair. Environ. Health Perspect. 40:187-195. [PMC free article: PMC1568811] [PubMed: 7274183]
  • Rossman, T.G. 1981. b. Enhancement of UV-mutagenesis by low concentrations of arsenite in E. coli. Mutat. Res. 91: 207-211. [PubMed: 7017398]
  • Rossman, T.G., and M. Molina. 1986. The genetic toxicology of metal compounds. II. Enhancement of ultraviolet light-induced mutagenesis in Escherichia coli WP2. Environ. Mutagen 8:263-271. [PubMed: 3516673]
  • Rossman, T.G., D. Stone, M. Molina, and W. Troll. 1980. Absence of arsenite mutagenicity in E. coli and Chinese hamster cells. Environ. Mutagen 2:371-379. [PubMed: 6459229]
  • Rossman, T.G., M. Molina, and L.W. Meyer. 1984. The genetic toxicology of metal compounds. I. Induction of lambda prophage in E. coli WP2s (lambda). Environ. Mutagen 6:59-69. [PubMed: 6229401]
  • Rubenstein, A.H., N.W. Levin, and G.A. Elliott. 1962. Manganese-induced hypoglycemia. Lancet 2:1348-1351. [PubMed: 13982963]
  • Rutter, M. 1980. Raised lead levels and impaired cognitive/ behavioral functioning: a review of the evidence. Dev. Med. Child. Neurol. Suppl. 42:1-36. [PubMed: 6929768]
  • Ryan, J.A., H.R. Pahren, and J.B. Lucas. 1982. Controlling cadmium in the human food chain: a review and rationale based on health effects. Environ. Res. 28:251-302. [PubMed: 6288368]
  • Salonen, J.T., G. Alfthan, J.K. Huttunen, J. Pikkarainen, and P. Puska. 1982. Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 2:175-179. [PubMed: 6123886]
  • Salonen, J.T., G. Alfthan, J.K. Huttunen, and P. Puska. 1984. Association between serum selenium and the risk of cancer. Am. J. Epidemiol. 120:342-349. [PubMed: 6475911]
  • Salonen, J.T., R. Salonen, R. Lappeteläinen, P.H. Mäenpää, G. Alfthan, and P. Puska. 1985. a. Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data. Br. Med. J. 290:417-420. [PMC free article: PMC1417771] [PubMed: 3918611]
  • Salonen, J.T., R. Salonen, I. Penttilä, J. Herranen, M. Jauhiainen, M. Kantola, R. Lappeteläinen, P.H. Mäenpää, G. Alfthan, and P. Puska. 1985. b. Serum fatty acids, apolipoproteins, selenium and vitamin antioxidants and the risk of death from coronary artery disease. Am. J. Cardiol. 56:226-231. [PubMed: 2992263]
  • Sambade, M.C., V.S. Gonçalves, M. Dias, and M.A. Sobrinho-Simoes. 1983. High relative frequency of thyroid papillary carcinoma in Northern Portugal. Cancer 51:1754-1759. [PubMed: 6831371]
  • Sanders, C.L, and J.A. Mahaffey. 1984. Carcinogenicity of single and multiple intratracheal instillations of cadmium oxide in the rat. Environ. Res. 33:227-233. [PubMed: 6692809]
  • Sauer, H.I., D.W. Parke, and M. Neill. 1971. Associations between drinking water and death rates. Pp. 318-325 in D.D. Hemphill, editor. , ed. Trace Substances in Environmental Health. University of Missouri Press, Columbia, Mo.
  • Schlage, C., and B. Wortberg. 1972. Manganese in the diet of healthy preschool and school children. Acta Paediatr. Scand. 61:648-652. [PubMed: 5080643]
  • Schoene, N.W., V.C. Morris, and O.A. Levander. 1986. Altered arachidonic acid metabolism in platelets and aortas from selenium-deficient rats. Nutr. Res. 6:75-83.
  • Schottenfeld, D., editor; , and J.F. Fraumeni, Jr., editor. , eds. 1982. Cancer Epidemiology and Prevention. W.B. Saunders, Philadelphia. 1173 pp.
  • Schrauzer, G.N. 1979. Trace elements in carcinogenesis. Pp. 219-244 in H.H. Draper, editor. , ed. Advances in Nutritional Research, Vol. 2. Plenum Press, New York.
  • Schrauzer, G.N., and D. Ishmael. 1974. Effects of selenium and of arsenic on the genesis of spontaneous mammary tumors in inbred C3H mice. Ann. Clin. Lab. Sci. 4:441-447. [PubMed: 4473954]
  • Schrauzer, G.N., D.A. White, and C.J. Schneider. 1977. a. Cancer mortality correlation studies. 111. Statistical associations with dietary selenium intakes. Bioinorg. Chem. 7:23-34. [PubMed: 856291]
  • Schrauzer, G.N., D.A. White, and C.J. Schneider. 1977. b. Cancer mortality correlation studies. IV. Associations with dietary intakes and blood levels of certain trace elements, notably Se-antagonists. Bioinorg. Chem. 7:35-56. [PubMed: 856292]
  • Schrauzer, G.N., T. Molenaar, S. Mead, K. Kuehn, H. Yamamoto, and E. Araki. 1985. Selenium in the blood of Japanese and American women with and without breast cancer and fibrocystic disease. Jpn. J. Cancer Res. 76:374-377. [PubMed: 3924710]
  • Schroeder, H.A. 1966. Municipal drinking water and cardiovascular death rates. J. Am. Med. Assoc. 195:125-129.
  • Schroeder, H.A. 1968. The role of chromium in mammalian nutrition. Am. J. Clin. Nutr. 21:230-244. [PubMed: 5642900]
  • Schroeder, H.A., and M. Mitchener. 1971. Selenium and tellurium in rats: effect on growth, survival and tumors. J. Nutr. 101:1531-1540. [PubMed: 5124041]
  • Schroeder, H.A., J.J. Balassa, and I.H. Tipton. 1962. Abnormal trace metals in man. J. Chronic Dis. 15:941-964. [PubMed: 13987070]
  • Schroeder, H.A., J.J. Balassa, and W.H. Vinton, Jr. 1964. Chromium, lead, cadmium, nickel and titanium in mice: effect on mortality, tumors and tissue levels. J. Nutr. 83: 239-250. [PubMed: 14191424]
  • 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. [PubMed: 14291684]
  • Schroeder, H.A., A.P. Nason, and I.H. Tipton. 1970. a. Chromium deficiency as a factor in artherosclerosis. J. Chronic Dis. 23:123-142. [PubMed: 5455353]
  • Schroeder, H.A., M. Mitchener, and A.P. Nason. 1970. b. Zirconium, niobium, antimony, vanadium and lead in rats: life term studies. J. Nutr. 100:59-68. [PubMed: 5412131]
  • Schwartz, M.K. 1975. Role of trace elements in cancer. Cancer Res. 35:3481-3487. [PubMed: 1104155]
  • Schwarz, K. 1977. Essentiality versus toxicity of metals. Pp. 3-22 in S.S. Brown, editor. , ed. Clinical Chemistry and Chemical Toxicology of Metals. Elsevier/North-Holland Biomedical Press, Amsterdam.
  • Scott, R., and E. Aughey. 1978. Methyl cholanthrene and cadmium induced changes in rat prostate. Br. J. Urol. 50: 25-28. [PubMed: 630198]
  • Selevan, S.G., P.J. Landrigan, F.B. Stem, and J.H. Jones. 1985. Mortality of lead smelter workers. Am. J. Epidemiol. 122:673-683. [PubMed: 4025307]
  • Shamberger, R.J. 1970. Relationship of selenium to cancer. I. Inhibitory effect of selenium on carcinogenesis. J. Natl. Cancer Inst. 44:931-936. [PubMed: 11515060]
  • Shamberger, R.J., and D.V. Frost. 1969. Possible protective effect of selenium against human cancer. Can. Med. Assoc. J. 100:682. [PMC free article: PMC1945904] [PubMed: 5776446]
  • Shamberger, R.J., and C.E. Willis. 1971. Selenium distribution and human cancer mortality. Crit. Rev. Clin. Lab. Sci. 2:211-221. [PubMed: 4950948]
  • 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. [PubMed: 4703775]
  • 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. [PubMed: 973735]
  • Shamberger, R.J., K.D. Beaman, C.L. Corlett, and B.L. Kasten. 1978. Effect of selenium and other antioxidants on the mutagenicity of malonaldehye. Fed. Proc. 37:261.
  • Shani, J., Z. Ahronson, F.G. Sulman, W. Mertz, G. Frenkel, and P.F. Kraicer. 1972. Insulin-potentiating effect of salt bush (Atriplex halimus) ashes. Isr. J. Med. Sci. 8:757-758 . [PubMed: 5065909]
  • Sharma, V.P., V. Parikh, and L.M. Bhandari. 1984. Serum copper and zinc levels in patients with solid tumours. Indian J. Cancer 21:1-6. [PubMed: 6510939]
  • Shaw, J.H., editor. , ed. 1954. Fluoridation as a Public Health Measure. American Association for the Advancement of Science, Washington, D.C. 240 pp.
  • Sheffet, A., I. Thind, A.M. Miller, and D.B. Louria. 1982. Cancer mortality in a pigment plant utilizing lead and zinc chromates. Arch. Environ. Health 37:44-52. [PubMed: 7059230]
  • Shigematsu, I. 1984. The epidemiological approach to cadmium pollution in Japan. Ann. Acad. Med. Singapore: 13: 231-236. [PubMed: 6497320]
  • Shigematsu, I., M. Minowa, T. Yoshida, and K. Miyamoto. 1979. Recent results of health examinations on the general population in cadmium-polluted and control areas in Japan. Environ. Health Perspect. 28:205-210. [PMC free article: PMC1637532] [PubMed: 226356]
  • Shirachi, D.Y., M.G. Johansen, J.P. McGowan, and S.H. Tu. 1983. Tumorigenic effect of sodium arsenite in rat kidney. Proc. West. Pharmacol. Soc. 26:413-415. [PubMed: 6688469]
  • Shirai, T., M. Ohshima, A. Masuda, S. Tamano, and N. Ito. 1984. Promotion of 2-(ethylnitrosamino)ethanol-induced renal carcinogenesis in rats by nephrotoxic compounds: positive responses with folic acid, basic lead acetate, and N-(3,5-dichlorophenyl)succinimide but not with 2,3-dibromo-l-propanol phosphate. J. Natl. Cancer Inst. 72:477-482. [PubMed: 6582330]
  • 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.
  • Shore, D., and R.J. Wyatt. 1983. Aluminum and Alzheimer's disease. J. Nerv. Ment. Dis. 171:553-558. [PubMed: 6350535]
  • Shupe, J.L, M.L. Miner, D.A. Greenwood, L.E. Harris, and G.E. Stoddard. 1962. The effect of fluorine on dairy cattle. II. Clinical and pathologic effects. Am. J. Vet. Res. 24.964-979. [PubMed: 14080528]
  • 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. [PubMed: 372658]
  • Simonato, L 1981. Carcinogenic risk in the aluminum production industry: an epidemiological overview. Med. Lav. 72:266-276. [PubMed: 7335001]
  • Simonoff, M. 1984. Chromium deficiency and cardiovascular risk. Cardiovasc. Res. 18:591-596. [PubMed: 6386156]
  • Simonoff, M., Y. Llabador, G.N. Simonoff, P. Besse, and C. Conri. 1984. a. Cineangiographically determined coronary artery disease and plasma chromium level for 150 subjects. Nucl. Instrum. Methods 231:368-372.
  • Simonoff, M., Y. Llabador, C. Hamon, P.A. MacKenzie, and G.N. Simonoff. 1984. b. Low plasma chromium in patients with coronary artery and heart diseases. Biol. Trace Element Res. 26:431-439. [PubMed: 24264180]
  • Singer, L., and R. Ophaug. 1979. Total fluoride intake of infants. Pediatrics 63:460-466. [PubMed: 582065]
  • 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. [PubMed: 1006310]
  • Sirover, M.A., and L.A. Loeb. 1977. On the fidelity of DNA replication: effect of metal activators during synthesis with avian myeloblastosis virus DNA polymerase. J. Biol. Chem. 252:3606-3610. [PubMed: 863897]
  • Sissoëff, I., J. Grisvard, and E. Guillë. 1976. Studies on metal ions-DNA interactions: specific behaviour of reiterative DNA sequences. Prog. Biophys. Mol. Biol. 31:165-199. [PubMed: 185659]
  • Skerving, S., K. Hansson, and J. Lindsten. 1970. Chromosome breakerage in humans exposed to methyl mercury through fish consumption. Arch. Environ. Health 21:133-139. [PubMed: 5464308]
  • Smialowicz, R.J., R.R. Rogers, M.M. Riddle, R.W. Luebke, D.G. Rowe, and R.J. Garner. 1984. Manganese chloride enhances murine cell-mediated cytotoxicity: effects on natural killer cells. J. Immunopharmacol. 6:1-23. [PubMed: 6206161]
  • Smith, J.C., Jr., H.H. Hansen, M.P. Howard, LD. McBean, and J.A. Halsted. 1971. Plasma-zinc concentration in patients with bronchogenic cancer. Lancet 2:13-23. [PubMed: 4143573]
  • Smith, M. 1985. Recent work on low level exposure and its impact on behavior, intelligence, and learning: a review. J. Am. Acad. Child. Psychiatry 24:24-32. [PubMed: 3881503]
  • Solomons, N.W., and R.M. Russell. 1980. The interaction of vitamin A and zinc: implications for human nutrition. Am. J. Clin. Nurr. 33:2031-2040. [PubMed: 6774607]
  • Sorahan, T., and J.A. Waterhouse. 1983. Mortality study of nickel-cadmium battery workers by the method of regression models in life tables. Br. J. Ind. Med. 40:293-300. [PMC free article: PMC1069325] [PubMed: 6871118]
  • Spencer, H., and L. Kramer. 1985. Osteoporosis: calcium, fluoride, and aluminum interactions. J. Am. Col. Nutr. 4: 121-128. [PubMed: 3886758]
  • Spencer, H., L Kramer, C. Norris, and E. Wiatrowski. 1981. Effect of aluminum hydroxide on plasma fluoride and fluoride excretion during a high fluoride intake in man. Toxicol. Appl. Pharmacol. 58:140-144. [PubMed: 7233433]
  • Stadel, B.V. 1976. Dietary iodine and risk of breast, endometrial, and ovarian cancer. Lancet 1:890-891. [PubMed: 58152]
  • Stanbury, J.B., editor; , and B.S. Hetzel, editor. , eds. 1980. Endemic Goiter and Endemic Cretinism: Iodine Nutrition in Health and Disease. Wiley, New York. 606 pp.
  • Stevens, R.G., R.P. Beasley, and B.S. Blumberg. 1986. Iron-binding proteins and risk of cancer in Taiwan. J. Natl. Cancer Inst. 76:605-610. [PubMed: 3007843]
  • 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. [PMC free article: PMC2071249] [PubMed: 14154229]
  • Stoner, G.D., M.B. Shimkin, M.C. Troxell, T.L. Thompson, and LS. Terry. 1976. Test for carcinogenicity of metallic compounds by the pulmonary tumor response in strain A mice. Cancer Res. 36:1744-1747. [PubMed: 1268831]
  • Strain, W.H., E.G. Mansour, A. Flynn, W.J. Pories, A.J. Tomaro, and O.A. Hill, Jr. 1972. Plasma-zinc concentration in patients with bronchogenic cancer. Lancet 1:1021-1022. [PubMed: 4112349]
  • Strohmeyer, G., C. Niederau, and W. Stremmel. 1988. Survival and causes of death in hemochromatosis: observations in 163 patients. Ann. N.Y. Acad. Sci. 526:245-257. [PubMed: 3389643]
  • Sullivan, J.L. 1986. Sex, iron, and heart disease. Lancet 2: 1162. [PubMed: 2877310]
  • Sundström, H., E. Yrjänheikki, and A. Kauppila. 1984. Low serum selenium concentration in patients with cervical or endometrial cancer. Int. J. Gynaecol. Obstet. 22:35-40. [PubMed: 6144589]
  • Takashima, M., S. Moriwaki, and Y. Itokawa. 1980. Osteomalacic change induced by long-term administration of cadmium to rats. Toxicol. Appl. Pharmacol. 54:223-228. [PubMed: 7423488]
  • Takenaka, S., H. Oldiges, H. Koenig, D. Hochrainer, and G. Oberdoerster. 1983. Carcinogenicity of cadmium chloride aerosols in W-rats. J. Natl. Cancer Inst. 70:367-371. [PubMed: 6571943]
  • Talwar, S.J., S. Qadry, K.K. Pillai, and R.G. Arora. 1985. Cadmium zinc antagonism in the hypertensive rat (abstract 004). Indian J. Pharm. 17 suppl. 1.
  • Tanner, D.C., and M.M. Lipsky. 1984. Effect of lead acetate on N-(4'-fluoro-4-biphenyl)acetamide-induced renal carcinogenesis in the rat. Carcinogenesis 5:1109-1113. [PubMed: 6467501]
  • Tarugi, P., S. Calandra, P. Borella, and G.F. Vivoli. 1982. Heavy metals and experimental atherosclerosis. Effect of lead intoxication on rabbit plasma lipoproteins. Atherosclerosis 45:221-234. [PubMed: 7159495]
  • Taves, D.R. 1979. Claims of harm from fluoridation. Pp. 295-321 in E. Johansen, editor; , D.R. Taves, editor; , and T.O. Olsen, editor. , eds. Continuing Evaluation of the Use of Fluorides. Westview Press, Boulder, Colo.
  • Taylor, C. 1980. Oral health status in primary school children in two areas of Papua New Guinea 1979: primary results. J. Dent. Res. 59:1773.
  • Thériault, G., C. Tremblay, S. Cordier, and S. Gingras. 1984. Bladder cancer in the aluminum industry. Lancet 1: 947-950. [PubMed: 6143877]
  • Thimaya, S., and S.N. Ganapathy. 1982. Selenium in human hair in relation to age, diet, pathological condition and serum levels. Sci. Total Environ. 24:41-49. [PubMed: 7112093]
  • Thun, M.J., T.M. Schnorr, A.B. Smith, W.E. Halperin, and R.A. Lemen. 1985. Mortality among a cohort of U.S. cadmium production workers—an update. J. Natl. Cancer Inst. 74:325-333. [PubMed: 3856046]
  • Thurnham, D.I., P. Rathakette, K.M. Hambidge, N. Munoz, and M. Crespi. 1982. Riboflavin, vitamin A and zinc status in Chinese subjects in a high-risk area for esophageal cancer in China. Hum. Nutr. Clin. Nutr. 36:337-349. [PubMed: 7174357]
  • Thurnham, D.I., S.F. Zheng, N. Munoz, M. Crespi, A. Grassi, K.M. Hambidge, and T.F Chai. 1985. Comparison of riboflavin, vitamin A, and zinc status of Chinese populations at high and low risk for esophageal cancer. Nutr. Cancer 7:131-143. [PubMed: 3878498]
  • Tiedemann, G., and H.J. Einbrodt. 1982. Mutagen reaction of inorganic arsenic compounds. Wiss. Umwelt. 3:170-173.
  • Troncoso, J.C., N.H. Sternberger, L.A. Sternberger, P.N. Hoffman, and D.L. Price. 1986. Immunocytochemical studies of neurofilament antigens in the neurofibrillary pathology induced by aluminum. Brain Res. 364:295-300. [PubMed: 3512034]
  • Tsapakos, M.J., T.H. Hampton, and K.E. Wetterhahn. 1983. Chromium(VI)-induced DNA lesions and chromium distribution in rat kidney, liver, and lung. Cancer Res. 43:5662-5667. [PubMed: 6640521]
  • Tseng, W.P. 1977. Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic. Environ. Health Perspect. 19:109-119. [PMC free article: PMC1637425] [PubMed: 908285]
  • Tsubaki, T., editor; , and K. Irukayama, editor. , eds. 1977. Minamata Disease: Methylmercury Poisoning in Minamata and Niigata, Japan. Elsevier Scientific Publishing Co., New York. 317 pp.
  • Tsuchiya, K. 1977. Various effects of arsenic in Japan depending on type of exposure. Environ. Health Perspect. 19:35-42. [PMC free article: PMC1637385] [PubMed: 561692]
  • Tsutsui, T., N. Suzuki, and M. Ohmori. 1984. Sodium fluoride induced morphological and neoplastic transformation, chromosome aberrations, sister chromatid exchanges and unscheduled DNA synthesis in cultured Syrian hamster embryo cells. Cancer Res. 44:938-941. [PubMed: 6692416]
  • Ulrich, C.E., W. Rinehart, and W. Busey. 1979. Evaluation of the chronic inhalation toxicity of a manganese oxide aerosol. 1. Introduction, experimental design and aerosol generation methods. Am. Ind. Hyg. Assoc. J. 40:238-244. [PubMed: 91319]
  • Umeda, M., and M. Nishimura. 1979. Inducibility of chromosomal aberrations by metal compounds in cultured mammalian cells. Mutat. Res. 67:221-229. [PubMed: 481448]
  • Underwood, E.J. 1977. Trace Elements in Human and Animal Nutrition, 4th ed. Academic Press, New York. 545 pp.
  • Uriu-Hare, J.Y., J.S. Stern, G.M. Reaven, and C.L Keen. 1985. The effect of maternal diabetes on trace element status and fetal development in the rat. Diabetes 34:1031-1040. [PubMed: 4043553]
  • USDA (U.S. Department of Agriculture). 1984. Nationwide Food Consumption Survey. Nutrient Intakes: Individuals in 48 States, Year 1977-78. Report No. 1-2. Consumer Nutrition Division, Human Nutrition Information Service, Hyattsville, Md. 439 pp.
  • USDA (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals. Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service, Hyattsville, Md. 94 pp.
  • USDA (U.S. Department of Agriculture). 1987. a. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals. Women 19-50 Years and Their Children 1-5 Years, 1 Day, 1986. Report No. 86-1. Nutrition Monitoring Division, Human Nutrition Information Service, Hyattsville, Md. 98 pp.
  • USDA (U.S. Department of Agriculture). 1987. b. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals. Women 19-50 Years and Their Children 1-5 Years, 4 Days, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service, Hyattsville, Md. 182 pp.
  • Uusitupa, M.I.J., J.T. Kumpulainen, E. Voutilainen, K. Hersio, H. Sarlund, P.K. Pyorala, P.E. Kovistoinen, and J.T. Lehto. 1984. Effect of inorganic chromium supplementation on glucose tolerance, insulin response, and serum lipids in noninsulin-dependent diabetics. Am. J. Clin. Nutr. 38:404-410. [PubMed: 6351586]
  • Van de Sande, J., L.P. McIntosh, and T.M. Jovin. 1982. Mn and other transition metals at low concentration induce the right-to-left helical transformation poly(dG-dC). Eur. Mol. Biol. Org. J. 1:777-782. [PMC free article: PMC553109] [PubMed: 7188360]
  • 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. [PMC free article: PMC2008495] [PubMed: 5367336]
  • Venugopal, B., and T.D. Luckey. 1978. Lead. Pp. 185-195 in Metal Toxicity in Mammals, 2. Chemical Toxicity of Metals and Metalloids. Plenum Press, New York.
  • Vernie, LN. 1984. Selenium in carcinogenesis. Biochim. Biophys. Acta 738:203-217. [PubMed: 6440591]
  • Victery, W., A.J. Vander, J.M. Shulak, P. Schoeps, and S. Julius. 1982. Lead, hypertension, and the renin-angiotensin system in rats. J. Lab. Clin. Med. 99:354-362. [PubMed: 7057062]
  • Virtamo, J., E. Valkeila, G. Alfthan, S. Punsar, J.K. Huttunen, and M.J. Karvonen. 1985. Serum selenium and the risk of coronary heart disease and stroke. Am. J. Epidemiol. 122:276-282. [PubMed: 4014210]
  • 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. [PubMed: 605850]
  • Volgarev, M.N., and L.A. Tscherkes. 1967. Further studies in tissue changes associated with sodium selenate. Pp. 179-184 in O.H. Muth, editor; , I.E. Oldfield, editor; , and P.H. Weswig, editor. , eds. Symposium: Selenium in Biomedicine. First International Symposium, Oregon State University, 1966. AVI Publishing Co., Westport, Conn.
  • Voors, A.W. 1971. Minerals in the municipal water and atherosclerotic heart death. Am. J. Epidemiol. 93:259-266. [PubMed: 5550342]
  • Voroshilin, S.I., E.G. Plotko, and V.I. Nikiforova. 1975. Mutagennoe deistvie ftoristogo vodoroda na zhivonykh. Tsitol. Genet. 9:42-44. [PubMed: 1167265]
  • Wahner, H.W., C. Cuello, P. Correa, LF. Uribe, and E. Gaitan. 1966. Thyroid carcinoma in an endemic goiter area, Cali, Colombia. Am. J. Med. 40:58-66. [PubMed: 5900688]
  • Wall, S. 1980. Survival and mortality pattern among Swedish smelter workers. Int. J. Epidemiol. 9:73-87. [PubMed: 7419333]
  • Warren, G., P. Schultz, D. Bancroft, K. Bennett, E.H. Abbott, and S. Rogers. 1981. Mutagenicity of a series of hexacoordinate chromium (III) compounds. Mutat. Res. 90: 111-118. [PubMed: 7035934]
  • Warshawsky, D., E. Bingham, and R.W. Niemeier. 1984. The effects of a cocarcinogen, ferric oxide, on the metabolism of benzo[a]pyrene in the isolated perfused lung. J. Toxicol. Environ. Health 14:191-209. [PubMed: 6438343]
  • Waterhouse, J., editor; , C. Muir, editor; , P. Correa, editor; , and J. Powell, editor. , eds. 1976. Cancer Incidence in Five Continents, Vol. 3. IARC Scientific Publ. No. 15. International Agency for Research on Cancer, Lyon, France.
  • Webster, D.J. 1981. Tumour induction by carcinogens in iron deficient rats. Anticancer Res. 1:293-294. [PubMed: 6808888]
  • Wedrychowski, A., W.S. Ward, W.N. Schmidt, and LS. Hnilica. 1985. Chromium-induced cross-linking of nuclear proteins and DNA. J. Biol. Chem. 260:7150-7155. [PubMed: 3997861]
  • Wei, H.J., X.M. Luo, and S.P. Yang. 1985. Effects of molybdenum and tungsten on mammary carcinogenesis in SD rats. J. Nat. Cancer Inst. 74:469-473. [PubMed: 3856053]
  • Weinberg, E.D. 1983. Iron in neoplastic disease. Nutr. Cancer 4:223-233. [PubMed: 6302639]
  • Weiss, S.T., A. Muñoz, A. Stein, D. Sparrow, and F.E. Speizer. 1986. The relationship of blood lead to blood pressure in a longitudinal study of working men. Am. J. Epidemiol. 123:800-808. [PubMed: 3485920]
  • Westermarck, T. 1977. Selenium content of tissues in Finnish infants and adults with various diseases, and studies on the effects of selenium supplementation in neuronal ceroid lipofuscinosis patients. Acta Pharmacol. Toxicol. 41:121-128. [PubMed: 579051]
  • Whanger, P.D. 1979. Cadmium effects in rats on tissue iron, selenium, and blood pressure: blood and hair cadmium in some Oregon residents. Environ. Health Perspect. 28:115-121. [PMC free article: PMC1637503] [PubMed: 488028]
  • Whelan, P., B.E. Walker, and J. Kelleher. 1983. Zinc, vitamin A and prostatic cancer. Br. J. Urol. 55:525-528. [PubMed: 6194843]
  • WHO (World Health Organization). 1972. Evaluation of Certain Food Additives and the Contaminants Mercury, Lead, and Cadmium. Sixteenth Report of the Joint FAO/ WHO Expert Committee on Food Additives. Technical Report Series No. 505. World Health Organization, Geneva. 32 pp.
  • WHO (World Health Organization). 1978. Evaluation of Certain Food Additives and Contaminants. Twenty-Second Report of the Joint FAO/WHO Expert Committee on Food Additives. Technical Reports Series No. 631. World Health Organization, Geneva. 39 pp. [PubMed: 107662]
  • WHO (World Health Organization). 1988. The Work of WHO 1986-1987. Biennial Report of the Director General to the World Health Assembly and to the United Nations. World Health Organization, Geneva. 250 pp.
  • Wilkins, J.R., III, and T.H. Sinks, Jr. 1984. a. Occupational exposures among fathers of children with Wilms' tumor. J. Occup. Med. 26:427-435. [PubMed: 6330324]
  • Wilkins, J.R., III, and T.H. Sinks, Jr. 1984. b. Paternal occupation and Wilms' tumour in offspring. J. Epidemiol. Community Health 38:7-11. [PMC free article: PMC1052307] [PubMed: 6323612]
  • Willett, W.C., B.F. Polk, J.S. Morris, M.J. Stampfer, S. Pressel, B. Rosner, J.O. Taylor, K. Schneider, and C.G. Hames. 1983. Prediagnostic serum selenium and the risk of cancer. Lancet 2:130-134. [PubMed: 6134981]
  • Williams, B.J., M.R. Hejtmancik, and M. Abreu. 1983. Cardiac effects of lead. Fed. Proc. 42:2989-2993. [PubMed: 6352336]
  • 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. [PubMed: 832237]
  • 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. [PubMed: 13460941]
  • 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. [PubMed: 4205229]
  • Yamane, Y., K. Sakai, M. Ohtawa, N. Murata, T. Yarita, and G. Ide. 1981. Suppressive effect of aluminum chloride administration on mouse lung carcinogenesis by dimethylnitrosamine. Gann 72:992-996. [PubMed: 7341344]
  • Yang, G.Q., J.S. Chen, Z.M. Wen, K.Y. Ge, LZ. Zhu, X.C. Chen, and X.S. Chen. 1984. The role of selenium in Keshan disease. Adv. Nutr. Res. 6:203-231. [PubMed: 6507187]
  • Yang, G.Q., P.C. Qian, L.Z. Zhu, J.H. Huang, S.J. Liu, M.D. Lu, and LZ. Gu. 1987. Human selenium requirement in China. Pp. 589-607 in G.F. Combs, Jr., editor; , O.A. Levander, editor; , J.E. Spallholz, editor; , and J.E. Oldfield, editor. , eds. Selenium in Biology and Medicine. Van Nostrand Reinhold Co., New York.
  • Yang, J.G., J. Morrison-Plummer, and R.F. Burk. 1987. Purification and quantitation of a rat plasma selenoprotein distinct from glutathione perioxidase using monoclonal antibodies. J. Biol. Chem. 262:13372-13375. [PubMed: 3654615]
  • Yassin, I., and T. Low. 1975. Caries prevalence in different racial groups of schoolchildren in West Malaysia. Community Dent. Oral Epidemiol. 3:179-183. [PubMed: 1056826]
  • Yiamouyiannis, J., and D. Burk. 1977. Fluoridation and cancer. age-dependence of cancer mortality related to artificial fluoridation. Fluoride 10:102-125.
  • Yost, K.J. 1979. Some aspects of cadmium flow in the U.S. Environ. Health Perspect. 28:5-16. [PMC free article: PMC1637512] [PubMed: 488047]
  • Yu, S.Y., Y.J. Chu, X.L. Gong, and C. Hou. 1985. Regional variation of cancer mortality incidence and its relation to selenium levels in China. Biol. Trace Element Res. 7:21-29. [PubMed: 24258872]
  • Yule, W., and M. Rutter. 1985. Effect of lead on children's behavior and cognitive performance: a critical review. Pp. 211-259 in K.R. Mahaffey, editor. , ed. Dietary and Environmental Lead: Human Health Effects. Topics in Environmental Health, Vol. 7. Elsevier Press, Amsterdam.
  • Zakour, R.A., and B.W. Glickman. 1984. Metal-induced mutagenesis in the lacI gene of Escherichia coli. Mutat. Res. 126:9-18. [PubMed: 6366534]
  • Zakour, R.A., T.A. Kunkel, and L.A. Loeb. 1981. a. Metal-induced infidelity of DNA synthesis. Environ. Health Perspect. 40:197-205. [PMC free article: PMC1568814] [PubMed: 7274184]
  • Zakour, R.A., L.K. Tkeshelashvili, C.W. Shearman, R.M. Koplitz, and L.A. Loeb. 1981. b. Metal-induced infidelity of DNA synthesis. J. Cancer Res. Clin. Oncol. 99:187-196. [PubMed: 7251634]
  • Zaldivar, R., and G.L. Ghai. 1980. Clinical epidemiological studies on endemic chronic arsenic poisoning in children and adults, including observations on children with high- and low-intake of dietary arsenic. Zentralbl. Bakteriol. B 170:409-421. [PubMed: 7424281]
  • Ziegler, E.E., B.B. Edwards, R.L. Jensen, K.R. Mahaffey, and S.J. Fomon. 1978. Absorption and retention of lead by infants. Pediatr. Res. 12:29-34. [PubMed: 643372]
Copyright © 1989 by the National Academy of Sciences.
Bookshelf ID: NBK218751


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