Trace elements là gì

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


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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 sầu or incomplete), và the remainder are considered lớn be nonessential. Trace elements function primarily as catalysts in enzyme systems; some metallic ions, such as iron và copper, participate in oxidation-reduction reactions in energy metabolism. Iron, as a constituent of hemoglobin và myoglobin, also plays a vital role in the transport of oxygene.

All trace elements are toxic if consumed at sufficiently high levels for long enough periods. The difference between toxic intakes & optimal intakes lớn 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, zinh, fluoride, selenium, copper, chromium, iodine, manganese, & molybdenum. Also discussed are aluminum, cadmium, mercury, arsenic, & 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.

Epidemiosúc tích data on the relationship between many of the trace elements & the incidence of diseases such as cancer, cardiovascular disease, and hypertension are incomplete. Most such studies have sầu focused on cadmium, chromium, và selenium. Furthermore, most of the evidence is not related to lớn 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 và suggests directions for research.


Evidence Associating Trace Elements with Chronic Diseases


Iron

Iron is present in all toàn thân cells. As a component of hemoglobin và myoglobin, it functions as a carrier of oxyren in the blood & 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 sầu difficulty achieving this high intake, because they generally have sầu a relatively low caloric intake, & the usual U.S. diet provides only 6 khổng lồ 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 lớn meet their needs.

Iron absorption is affected by many factors. Heme iron is present in meats, poultry, & 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, & certain trace elements may diminish it. Food composition data provide no indicators concerning the efficiency with which the body toàn thân absorbs iron from a given food. The publication Recommended Dietary Allowances (NRC, 1980) provides directions on how to lớn calculate available iron.

The availability of iron in the food supply has increased since 1909, chiefly because of the enrichment of flour & cereal products. The 1977-1978 Nationwide Food Consumption Survey (NFCS) indicates that on the average respondents of both sexes from 1 to lớn 18 years old và females from 19 to 64 years old failed khổng lồ 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 và Nutrition Examination Survey (NHANES II), conducted from 1976 lớn 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, & females 25 to 44 years old. Among mỏi those whose incomes were below poverty màn chơi, impaired iron status was highest in children 1 to 5 years old and females 25 to lớn 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 khổng lồ dietary iron & 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 khổng lồ the occurrence of these cancers. However, epidemioxúc tích và ngắn gọn studies have not implicated low dietary iron intake per se as a risk factor for cancers at these sites (Schottenfeld và Fraumeni, 1982).

In a correlation analysis of nutrition survey data và cancer mortality rates for 11 regions of the Federal Republic of Germany, Böing et al. (1985) found a positive sầu association between estimated iron intake & mortality from colorectal and pancreatic cancer in men & from gallbladder cancer in women. In a prospective sầu 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 toàn thân 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 & foundry workers (Kazantzis, 1981). In these occupational settings, however, there were other exposures to lớn carcinogens, including ionizing radiation, polycyclic aromatic hydrocarbons (PAHs), and cigarette smoke. Thus, the increased cancer risk cannot be attributed specifically lớn 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 & 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 lớn 6 months in an iron-sufficient group (Vitale et al., 1978). The authors noted that severe lack of iron appeared to lớn promote carcinogenesis.

The effect of iron deficiency on tumor growth & 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 toàn thân growth & 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) & 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 laông chồng of iron did not appear lớn 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 carcinoren and left untreated (Prime et al., 1986). These investigators also saw no difference in tumor development or epithelial dysplasia between the iron-deficient & iron-sufficient animals.

Isolated perfused rabbit lung was used lớn investigate the effects of a cocarcinogen, ferric oxide, on the metabolism of benzopyrene (BaP) (Warshawsky et al., 1984). The data suggest that ferric oxide increased the production of dihydrodiols from BaPhường, which may be further metabolized lớn the ultimate carcinogenic forms. DBA-2 mice fed supplemental doses of iron (24 mg/kilogam toàn thân weight) và 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 toàn thân weight) & 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 lớn epidemioxúc tích và ngắn gọn 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, & certain iron compounds may act as cocarcinogens. The route of administration, dose, và specific iron compound all seem to affect the outcome.


Short-Term Tests

Brusiông chồng et al. (1976) found that Fe as iron sulfate induced reverse mutations in Salmonella typhimurium strains TA1537 và TA1538, with and without metabolic activation by the S9 fraction. In another study, 45 metal salts were evaluated for their capađô thị to lớn induce morphological transformation of Syrian hamster fetal cells in vivo. Iron was aước ao the trace elements for which positive sầu transformation assays were obtained (DiPaolo & Caskhổng lồ, 1979).


Epidemioxúc tích và ngắn gọn Studies

The greater prevalence of iron deficiency among mỏi women, compared to men, has been proposed as an explanation for the lower coronary heart disease (CHD) rate ahy vọng premenopausal women (Sullivan, 1986); however, no epidemiologic evidence supports this hypothesis.


Epidemiolô ghích Studies

Iron-deficiency anemia is the state in which the amount of iron in the toàn thân 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) & 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 amuốn children 1 to lớn 2 years old; next came women age 15 lớn 19 (7.2%) và đôi mươi lớn 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 và small children và khổng lồ blood loss or pregnancy in adults. The most frequent causes of anemia aước ao older people are infections and chronic diseases—not iron deficiency. The prevalence of iron-deficiency anemia varies widely, depending on criteria for diagnosis (Charlton và 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 & refined sugar. Where caloric intake has declined, iron intake has also declined. For example, iron-deficiency anemia occurs more commonly aước ao women than among muốn men, even in the absence of pathological blood loss. Women eat less food and are therefore able to lớn absorb less iron, but their requirements for iron are greater because they thua trận iron through menstruation. Preventive approaches include iron supplementation, fortification, & alteration of eating habits, for example, increasing intake of nutrients & foods stimulating iron absorption (e.g., Vi-Ta-Min C, meat, and fish) or reducing intake of foods inhibiting iron absorption (e.g., phytates).

Older, but still useful, methods for evaluating body toàn thân iron stores include determination of the plasma iron màn chơi & iron-binding capacity. Measurement of serum ferritin and miễn phí 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 & interstitial fibrosis (Rossi and Carillo, 1983). In other studies, Rosđắm say & colleagues treated iron-deficient anemic rats with reserpine (Rosđê mê và Carillo, 1982; Rossay mê et al., 1981). The hearts of anemic rats not given reserpine were marked by cardiac hypertrophy, as indicated by increases in both heart weight & size of muscle cells. The hearts of reserpine-treated animals were not enlarged. The researchers speculated that noradrenaline may play a key role in the cardiac hypertrophy of iron-deficiency anemia.


Zinc

Zinc, a constituent of more than 200 enzymes, plays an important role in nucleic acid metabolism, cell replication, tissue repair, và 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 và biologically important interactions with hormones & plays a role in production, storage, and secretion of individual hormones. Severe, moderate, and marginal zinch deficiencies have sầu been reported in the United States (Hambidge et al., 1986).

The richest sources of zinc are shellfish (especially oysters), beef, & other red meats. Poultry, eggs, hard cheeses, milk, yogurt, legumes, nuts, & whole-grain cereals are also good sources. Many dietary factors, including other minerals, phytates, và dietary fiber, may adversely affect zinch absorption (Hambidge et al., 1986). Food sources of zinc have sầu changed since the turn of the century. Until the middle 1930s, people obtained about equal amounts of zinh from foods of animal và plant origin, but since 1960, people have obtained approximately 70% of food-supply zinc from animal foods. Zinch from animal sources appears to lớn be better absorbed than that from plant sources.

The 1980 RDA for zinh is 15 mg/day for people 11 years of age và older (NRC, 1980), but zinh available in the food supply amounts khổng lồ only 12.3 mg per capita (see Table 3-5). Zinh intakes have been estimated in national surveys only since 1984. According lớn the 1985 NFCS, men and women 19 lớn 50 years of age consumed an average of 94 & 56% of their RDA, respectively, và children 1 khổng lồ 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 zinh levels are inadequate for assessing the nutritional status of zinch in individuals, but that low values may aid in identifying groups whose zinh status should be further investigated.


Epidemiolô ghích and Clinical Studies

On the basis of knowledge concerning the relationships of zinh and copper lớn several risk factors for CHD, including elevated serum cholesterol & hypertension, Klevay mượn (1975) hypothesized that an excess of zinh 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 lớn 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 khổng lồ it are discussed in the section on copper.


Animal Studies

The committee found no animal studies on the relationship between zinc and cardiovascular diseases.


Epidemiolô ghích & Clinical Studies

Few epidemioxúc tích studies have sầu been conducted lớn examine the relationship between exposure to lớn zinc, especially dietary zinch, & 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 & Davies, 1964).

In an effort khổng lồ identify etiosúc tích factors for esophageal cancer in the very-high-risk area of Linxian in Hunan Province, Đài Loan Trung Quốc, blood và hair samples from a random sample of 58 men & 53 women who had undergone esophagoscopy with biopsy were analyzed for zinc, riboflavin, & vitamin A components (Thurnđắm đuối et al., 1982). Zinch levels in plasma and hair were not significantly different between subjects with normal histology và those with lesions presumed to lớn be precusors of cancer (e.g., esophagitis, dysplasia, acanthosis). No differences in zinh levels in blood và hair were found in another study of a similar random sample from a low-risk area in Shandong Province (Thurnmê man 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 & older ingested more zinc (from supplements but not from food) prior khổng lồ the onmix of cancer than did matched population controls. Occupational studies of workers exposed lớn zinh by inhalation (usually in the presence of other trace elements such as copper, lead, arsenic, và chromium) have sầu 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 khổng lồ the cases, even on age; & potential confounding factors were not considered in the analyses. The results have sầu been mixed. In studies of patients with cancers at several different sites, investigators have sầu found both decreased serum zinh 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 lớn controls. In other studies, no differences were found between patients và controls (Feustel và Wennrich, 1986; Manousos et al., 1981; Smith et al., 1971; Strain et al., 1972; Thurnham mê 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 khổng lồ lowered zinc-to-copper ratquả táo. 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 khổng lồ normal following chemotherapy.

The prostate normally contains the highest concentrations of zinc in the body and is therefore of great interest in studies of zinch và cancer (Hambidge et al., 1986). In several studies, investigators have compared zinch levels in prostate tissue from healthy subjects and from patients with benign prostatic hypertrophy (BPH) and cancer. Zinch concentrations were lowest in carcinomatous tissue, highest in BPH tissue, and intermediate in normal tissue (Feustel và Wennrich, 1984; Feustel et al., 1982; Györkey et al., 1967).

Zinch interacts with other trace elements & is an antagonist khổng lồ copper (Mertz, 1982) (see discussion below under Zinc-Copper Interactions). Zinh also interacts with Vi-Ta-Min A (Solomons và Russell, 1980). Thus, the findings on zinc in human studies could reflect fundamental relationships between other nutrients và the diseases of interest. In general, however, human studies provide no evidence that zinch intake plays an important role in the etiology of cancer.


Animal Studies

Investigators have reported both enhancing & retarding effects of zinc on tumor growth in animals. Several have sầu suggested that a zinc-deficient diet strongly inhibits the growth of transplanted tumors và prolongs survival (Barr & 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 zinch for growth. Zinh deficiency is not recommended as a therapeutic modality, however, because serious zinh deficiency, with or without concomitant malignancies, is itself lethal.

In contrast lớn transplanted tumors, chemically induced carcinogenesis appears lớn be enhanced by zinch 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 zinh intake well above sầu nutritional requirements suppresses the carcinogenesis of dimethylbenzylamine in Syrian hamsters (Poswillo & Cohen, 1971) & of azo dyes in rats (Duncan and Dreosti, 1975). On the other h&, Schrauzer (1979) demonstrated that high concentrations of zinc (200 mg/ liter) in the drinking water of C3H mice countered the protective sầu effect of selenium against spontaneous mammary carcinoma và 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 zinch beginning at 6, 3, 1, & 0 weeks before injection of Moloney sarcoma virus (MSV). Mice fed marginal và 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 lớn be initiated and slower progression of the tumors. After sufficient severity and duration of zinc deprivation, mice also had a longer tumor latency & shorter tumor regression time.

These apparently contradictory effects of zinch 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). Zinh 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 immunolô ghích function through zinc deprivation may contribute lớn changes in host-tumor interactions. However, zinh is also known khổng lồ influence many aspects of host & tumor metabolism, including nucleic acid and protein synthesis, & tissues in the phase of rapid growth are most severely affected by zinch deprivation (Hurley, 1981). Thus, zinc is also necessary for tumor growth. Altered DNA synthesis by neoplastic tissue contributes lớn the inhibition of tumor growth in zinc-deficient animals. Zinh deficiency also causes chromosome aberrations in pregnant and fetal rats (Bell et al., 1975).

It is difficult khổng lồ assess the relative sầu roles of host immune responsiveness & the interaction of host và tumor metabolism. Nevertheless, it appears that the influence of zinc nutrition on carcinogenesis reflects, at least in part, the interaction of the host & 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

Zinh can affect both the tumor cell & the host, interfering with mechanisms that may be important for metastasis. It also promotes the adhesion of leukocytes khổng lồ 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 zinch caused a dramatic decrease in their intravenous transplantability. They postulated that this may be due khổng lồ an impairment of cell adhesion.

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Epidemiolô ghích & Clinical Studies

The relationship between diabetes & zinc metabolism has been the subject of recent retìm kiếm. In humans, hyperzincuria is frequently found in diabetics. This condition is not entirely reversed following insulin treatment & does not seem lớn be compensated for by increased intestinal absorption (Kinlaw et al., 1983; Hallmans và Lithner, 1980; Levine et al., 1983). The increased loss of urinary zinh in diabetics is positively related khổng lồ glycosuria (McNair et al., 1981; Pidduck et al., 1970).

Stunted growth observed in many diabetic children suggests that the diabetes-induced change in zinh metabolism could be functionally important (Canfield et al., 1984). It is possible that the teratogenicity of diabetes may be due in part to lớn the induction of zinc deficiency in the embryo or fetus. The observation that the offspring of diabetic rats have low zinh concentrations in their livers, compared to lớn controls, supports this suggestion (Uriu-Hare et al., 1985).

Although there is considerable evidence that abnormal zinch metabolism occurs in diabetics, the role of zinh, 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 khổng lồ be normal, whereas serum levels were lower và 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 zinh 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 zinch concentrations were best predicted by the copper and fluoride nội dung of the bone (Lappalainen et al., 1982). An opposite finding was reported in a small study of 10 male patients with senile osteoporosis & 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 sầu intakes of zinch interfere with the absorption và utilization of iron and copper in animals. Campbell and Mills (1974) fed diets with a low or marginal copper content lớn weanling rats và found that 300 µg of additional zinc per gram of diet reduced plasma ceruloplasmin activity; more zinc, up to lớn 1,000 µg, caused growth depression, hair depigmentation, & 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, và amine oxidase (Campbell & Mills, 1979).

An antagonistic effect of dietary zinh on copper concentrations in maternal and fetal tissues was observed in pregnant rats fed diets with various levels of copper & zinc (Reinstein et al., 1984). The authors concluded that in zinc-deficient diets, the high copper-to-zinc ratio potentiates the teratogenic effects of zinch deficiency.

In humans, prolonged use of oral zinch supplements, even at relatively modest levels, may have sầu adverse clinical consequences. For example, copper deficiency, evidenced by microcytic anemia, neutropenia, and decreased levels of plasma copper & ceruloplasmin, was found in a man who had been taking 150 mg of zinc daily for 2 years (Prasad et al., 1978).


Fluoride

Fluoride is an integral part of the food chain. Kumpulainen và Koivistoinen (1977) reported that the measured fluoride nội dung of the diet is three times higher in communities with fluoridated water than in those where the water is not fluoridated. Singer & Ophaug (1979) found that the fluoride nội dung 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 và Ophaug, 1979). Fluoride is also consumed unintentionally from two major sources: products containing mechanically boned meat và fluoridated dentifrices. The highest daily average consumption (equivalent khổng lồ 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 & Kramer, 1985; Spencer et al., 1981). For infants not drinking fluoridated water, & 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 và Chapter 23, Osteoporosis). Modest accumulations of fluoride in the bone mineral complex result in increased bone crystallinity & decreased solubility. The net result is the formation of a more stable mineral system that is less susceptible to lớn bone resorption (Spencer & Kramer, 1985).


Epidemiongắn gọn xúc tích Studies

Fluoride therapy has been used since 1949 lớn prsự kiện dental caries (Dunning, 1979). In the late 1930s, large-scale epidemiongắn gọn xúc tích studies first elucidated the relationship between fluoride in water supplies and reduced prevalence of dental caries (Brown và König, 1977; Dean, 1936; Dean and Elvove sầu, 1935; Levine, 1976). More recently, Burt et al. (1986) determined that children who have sầu lived for a few years in a community with optimal water fluoride have a 30 to 40% lower caries incidence than children who have sầu 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 & adequate intake và therefore much concern among mỏi health activists about its potential toxiđô thị. 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 & 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 lớn increases in dental caries prevalence internationally (Taylor, 1980; Yassin and Low, 1975), World Health Organization data indicate that caries is decreasing in Western countries & increasing in developing countries (WHO, 1988). Reports from the National Institute of Dental Retìm kiếm (NIDR) substantiate this observation (NIDR, 1981). The decline in caries incidence in the United States has been attributed primarily lớn the widespread use of fluoride in many forms (Dunning, 1979; Newbrun, 1975; Shaw, 1954), to improved oral hygiene, & to lớn 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 sầu to lớn fluoride. Abnormalities in permanent dentition are the most obvious signs of excessive fluoride ingestion. The tooth becomes mottled, perhaps with hypoplasia (thin enamel), và is subject lớn more rapid wear & possible erosion of the enamel (NRC, 1971). Brown et al. (1960) established that developing incisors in cattle are vulnerable up lớn 30 months of age. Shupe et al. (1962) fed young dairy heifers various levels of fluoride for 7.5 years. They reported that dental & 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 màn chơi of fluoride was reduced.

Fluoride concentrations appear khổng lồ 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 sầu binding of fluoride by newly synthesized matrix proteins may in large measure trương mục 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 lớn the fluoride-induced changes in enamel crystallinity.


Epidemiosúc tích Studies

Epidemioxúc tích và ngắn gọn studies have sầu 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 & mortality in communities with & without naturally high fluoride levels in their water supplies (Hagan et al., 1954; Nixon and Carpenter, 1974), which led the way lớn the introduction of water fluoridation in many communities.

In the 1970s, attention was abruptly redirected to lớn 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 & routine adjustments for such demographic differences ahy vọng populations as age, sex, và racial composition. Subsequently, different investigators reanalyzed in a more appropriate fashion the same data, as well as more comprehensive sầu 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 và Doll, 1981; Oldđê mê and Newell, 1977; Rogot et al., 1978; Taves, 1979). Similar ecological studies have sầu been conducted in Great Britain, Canada, nước Australia, New Zeal&, Austria, và 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 và fluoride-treated sperm cells had more chromosome aberrations than did controls.

Jagiello và Lin (1974) found that in vitro exposure to lớn sodium fluoride sharply reduced the percentage of cow và ewe oocytes undergoing meiotic division. In cells of bone và testes of mice, the number of chromosome breaks và abnormalities increased with increasing fluoride levels in drinking water (Mohamed & Weitzenkamp-Chandler, 1976). Similar mutagenic effects và dose responses were observed when bone cells of Trắng rats were exposed to inorganic fluoride (Gileva et al., 1972; Voroshilin et al., 1975). In general, fluoride interacts with DNA & RNA và alters biolô ghích activity in mammalian cells (Clark và 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 lớn newborn Syrian hamsters. The dose levels used in these experiments were much higher than those to lớn which humans are normally exposed; it is not known what results would be observed at lower doses.


Epidemiolô ghích 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 và induced cardiac changes in several studies in animals. For example, Leone et al. (1956) subjected dogs lớn intravenous infusion of fluoride at doses of trăng tròn and 30.6 mg/kilogam toàn thân weight. There was a dose-related depression of the respiratory rate and a conversion lớn atrioventricular nodal or ventricular rhythm with terminal ventricular fibrillation. Lu et al. (1965) observed the same response in monkeys.


Epidemiologic và Clinical Studies

The use of fluoride khổng lồ reverse or delay the progression of osteoporosis & hence lớn 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 nguồn và 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 lớn whether vertebral fractures are reduced among muốn 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 và Roos, 1978; Ivey & 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 lớn 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 khổng lồ reduce osteoporosis & fractures remain unanswered.


Animal Studies

Miller et al. (1977) reported that the bones of cows with osteoporosis resulting from environmental exposure lớn fluoride had higher calcium levels và a somewhat lower phosphorus nội dung than the bones of cows not exposed to fluoride. Henrikson et al. (1970) studied the ash of osteoporotic bones from dogs và 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 Mã Sản Phẩm for osteoporosis.


Selenium

In the 1950s, recognition of the economic importance of selenium deficiency in food animals led to lớn the mapping of selenium distributions in the soils, forages, và blood of humans in several continents. Extreme differences in exposure were found, even within countries. This knowledge enabled investigators to make epidemioxúc tích correlations of diseases in humans & animals & to lớn conduct laboratory experiments to lớn kiểm tra hypotheses. In 1980, a committee of the National Research Council set the estimated safe và adequate daily intake of selenium at 10 to 40 µg/day for infants, đôi mươi to 200 µg/day for children, & 50 khổng lồ 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 toàn thân weight and incorporating a safety factor, a dietary recommendation of 70 và 55 µg/ day can be calculated for North American men và women, respectively (Levander, 1987). The average dietary selenium intake for U.S. men was 108 µg/day between 1974 & 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 lớn participate in several important metabolic interactions with a variety of hazardous elements such as mercury, cadmium, & arsenic, which may be important khổng lồ public health (Levander và Cheng, 1980).


Epidemioxúc tích và ngắn gọn and Clinical Studies

Several reports on the relationship of serum selenium khổng lồ the risk of cardiovascular diseases have been published by investigators in Finland—a country with reportedly low selenium intakes. In two prospective sầu 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 tobacteo consumption và 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 Finl&, Kok et al. (1987b) found no significant association between serum selenium cấp độ 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 Finlvà bởi not correlate inversely with CHD mortality suggests that selenium is unlikely khổng lồ be a major determinant of risk for this disease (Virtamo et al., 1985).

Ellis et al. (1984) studied the relationship of blood selenium levels lớn smoking và alcohol consumption in healthy male volunteers. They found much lower selenium levels in the whole blood và 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, và 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 & selenium levels (Aro et al., 1986; Masironi & Parr, 1976; Shamberger et al., 1978; Westermarông xã, 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 sầu 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, và hair are substantially lower in the affected areas than in other parts of Đài Loan Trung Quốc.

Trials in children given diets supplemented with sodium selenite provided convincing evidence that selenium deficiency is a major etiosúc tích 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 và results from disease of the coronary arteries, not the myocardium, the observations on Keshan disease vì not implicate selenium deficiency as a likely risk factor for cardiovascular diseases in the United States, & 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 Vi-Ta-Min E và 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 sầu 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 lớn human health has not yet been established.


Epidemiongắn gọn xúc tích 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) & found an inverse relationship with cancers of several different sites (including the lung, colon, rectum, bladder, esophagus, pancreas, female breast, ovary, và cervix). In the report by Clark (1985), liver và stomach cancers, Hodgkin"s disease, và leukemia were positively associated. Schrauzer and colleagues (1977a) estimated per-capita selenium intakes for more than đôi mươi countries on the basis of food disappearance data và found an inverse association between consumption levels and mortality from leukemia and certain other cancers. In other geographic correlation studies, investigators have sầu found inverse associations between pooled blood selenium levels và total cancer mortality as well as mortality from cancer at various sites (Schrauzer et al., 1977a,b; Yu et al., 1985).

Many investigators have sầu 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 aao ước the different reports. These studies are limited by the generally small sample sizes, the failure khổng lồ 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 & 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, & the United States, investigators analyzed stored prediagnostic serum from cancer cases & 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 Finlvà, 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 lớn men, particularly smokers. In the Netherlands, Kok et al. (1987a) also found lower selenium intake khổng lồ be significantly associated with increased mortality from cancer aao ước men only. In the United States, Willett et al. (1983) reported the same inverse association khổng lồ be limited lớn 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 & matched controls, these investigators found a positive sầu association between selenium cấp độ 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 & oropharynx than in controls.

Although the analysis of selenium in the prediagnostic serum of subjects in prospective cohorts has the advantage of precise measurement & 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; và 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 & possibly other trace metals. Willett et al. (1983) found that selenium-associated risk was enhanced by low serum retinol và 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 khổng lồ assess selenium intake from dietary histories, because plants are highly sensitive to lớn soil concentrations of selenium, leading lớn great variation in the selenium nội dung of foods. Thus, estimates of consumption may not reliably reflect actual intake. This may tài khoản for the low correlations reported between individual estimates of dietary selenium and serum or hair levels (Goodwin et al., 1983; Thimaya và Ganapathy, 1982).

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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 & 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) & the skin (Clark et al., 1984; Salonen et al., 1984), và the laông xã of studies based on direct dietary assessment, a firm conclusion on the role of selenium in human cancer risk is not justified at present.


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