7

Selenium

SUMMARY

Selenium functions through selenoproteins, several of which are oxidant defense enzymes. The Recommended Dietary Allowance (RDA) for selenium is based on the amount needed to maximize synthesis of the selenoprotein glutathione peroxidase, as assessed by the plateau in the activity of the plasma isoform of this enzyme. The RDA for both men and women is 55 µg (0.7 µmol)/day. The major forms of selenium in the diet are highly bioavailable. Selenium intake varies according to geographic location, but there is no indication of average intakes below the RDA in the United States or Canada. A study done in Maryland reported that adults consumed an average of 81 µg (1.0 µmol)/day of selenium (Welsh et al., 1981). A Canadian survey reported selenium intakes of 113 to 220 µg (1.4 to 2.8 µmol)/day (Thompson et al., 1975). The Tolerable Upper Intake Level (UL) for adults is set at 400 µg (5.1 µmol)/day based on selenosis as the adverse effect.

BACKGROUND INFORMATION

Most selenium in animal tissues is present as selenomethionine or selenocysteine. Selenomethionine, which cannot be synthesized by humans and is initially synthesized in plants, is incorporated randomly in place of methionine in a variety of proteins obtained from plant and animal sources. Selenium is present in varying amounts in these proteins, which are called selenium-containing proteins.



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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids 7 Selenium SUMMARY Selenium functions through selenoproteins, several of which are oxidant defense enzymes. The Recommended Dietary Allowance (RDA) for selenium is based on the amount needed to maximize synthesis of the selenoprotein glutathione peroxidase, as assessed by the plateau in the activity of the plasma isoform of this enzyme. The RDA for both men and women is 55 µg (0.7 µmol)/day. The major forms of selenium in the diet are highly bioavailable. Selenium intake varies according to geographic location, but there is no indication of average intakes below the RDA in the United States or Canada. A study done in Maryland reported that adults consumed an average of 81 µg (1.0 µmol)/day of selenium (Welsh et al., 1981). A Canadian survey reported selenium intakes of 113 to 220 µg (1.4 to 2.8 µmol)/day (Thompson et al., 1975). The Tolerable Upper Intake Level (UL) for adults is set at 400 µg (5.1 µmol)/day based on selenosis as the adverse effect. BACKGROUND INFORMATION Most selenium in animal tissues is present as selenomethionine or selenocysteine. Selenomethionine, which cannot be synthesized by humans and is initially synthesized in plants, is incorporated randomly in place of methionine in a variety of proteins obtained from plant and animal sources. Selenium is present in varying amounts in these proteins, which are called selenium-containing proteins.

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids Selenomethionine is not known to have a physiological function separate from that of methionine. Selenocysteine is present in animal selenoproteins that have been characterized (see below) and is the form of selenium that accounts for the biological activity of the element. In contrast to selenomethionine, there is no evidence that selenocysteine substitutes for cysteine in humans. Function Selenium functions largely through an association with proteins, known as selenoproteins (Stadtman, 1991), and disruption of their synthesis is lethal for embryos (Bösl et al., 1997). A selenoprotein is a protein that contains selenium in stoichiometric amounts. Fourteen selenoproteins have been characterized to date in animals. The four known selenium-dependent glutathione peroxidases designated as GSHPx 1 through 4 defend against oxidative stress (Flohe, 1988). Selenoproteins P and W are postulated to do so as well (Arteel et al., 1998; Burk et al., 1995; Saito et al., 1999; Sun et al., 1999). Three selenium-dependent iodothyronine deiodinases regulate thyroid hormone metabolism (Berry and Larsen, 1992). Three thioredoxin reductases have been identified (Sun et al., 1999). Their functions include reduction of intramolecular disulfide bonds and regeneration of ascorbic acid from its oxidized metabolites (May et al., 1998). The selenium-dependent isoform of selenophosphate synthetase participates in selenium metabolism (Guimaraes et al., 1996). Other selenoproteins have not yet been characterized to the same extent with respect to function (Behne et al., 1997). Thus, the known biological functions of selenium include defense against oxidative stress, regulation of thyroid hormone action, and regulation of the redox status of vitamin C and other molecules. Physiology of Absorption, Metabolism, and Excretion Absorption Absorption of selenium is efficient and is not regulated. More than 90 percent of selenomethionine, the major dietary form of the element, is absorbed by the same mechanism as methionine itself (Swanson et al., 1991). Although little is known about selenocysteine absorption, it appears to be absorbed very well also. An inorganic form of selenium, selenate (SeO42−), is absorbed almost completely, but a significant fraction of it is lost in the urine before it can be incorporated into tissues. Another inorganic form

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids of selenium, selenite (SeO32−), has a more variable absorption, probably related to interactions with substances in the gut lumen, but it is better retained, once absorbed, than is selenate (Thomson and Robinson, 1986). Absorption of selenite is generally greater than 50 percent (Thomson and Robinson, 1986). Although selenate and selenite are not major dietary constituents, they are commonly used to fortify foods and as selenium supplements. Body Stores Two pools of reserve selenium are present in humans and animals. One of them, the selenium present as selenomethionine, depends on dietary intake of selenium as selenomethionine (Waschulewski and Sunde, 1988). The amount of selenium made available to the organism from this pool is a function of turnover of the methionine pool and not the organism's need for selenium. The second reserve pool of selenium is the selenium present in liver glutathione peroxidase (GSHPx-1). In rats, 25 percent of total body selenium is present in this pool (Behne and Wolters, 1983). As dietary selenium becomes limiting for selenoprotein synthesis, this pool is downregulated by a reduction of GSHPx-1 messenger ribonucleic acid (RNA) concentration (Sunde, 1994). This makes selenium available for synthesis of other selenoproteins. Metabolism Selenomethionine, derived mainly from plants, enters the methionine pool in the body and shares the fate of methionine until catabolized by the transsulfuration pathway. The resulting free selenocysteine is further broken down with liberation of a reduced form of the element, which is designated selenide (Esaki et al., 1982). Ingested selenite, selenate, and selenocysteine are all apparently metabolized directly to selenide. This selenide may be associated with a protein that serves as a chaperone (Lacourciere and Stadtman, 1998). The selenide can be metabolized to selenophosphate, the precursor of selenocysteine in selenoproteins (Ehrenreich et al., 1992) and of selenium in transfer RNA (Veres et al., 1992), or it can be converted to excretory metabolites (Mozier et al., 1988), some of which have been characterized as methylated forms. Excretion The mechanism that regulates production of excretory metabolites has not been elucidated, but excretion has been shown to be responsible for maintaining selenium homeostasis in the animal

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids (Burk et al., 1972). The excretory metabolites appear in the urine primarily, but when large amounts of selenium are being excreted, the breath also contains volatile metabolites (e.g., dimethylselenide) (McConnell and Portman, 1952). Clinical Effects of Inadequate Intake In experimental animals, selenium deficiency decreases selenoenzyme activities, but if the animals are otherwise adequately nourished, it causes relatively mild clinical symptoms. However, certain types of nutritional, chemical, and infectious stresses lead to serious diseases in selenium-deficient animals. For example, induction of vitamin E deficiency in selenium-deficient animals causes lipid peroxidation and liver necrosis in rats and pigs and cardiac injury in pigs, sheep, and cattle (Van Vleet, 1980). Another example of this phenomenon is the conversion of a nonpathogenic strain of coxsackie B3 virus to a pathogenic one that causes myocarditis when it infects selenium-deficient mice (Beck and Levander, 1998). Keshan disease, a cardiomyopathy that occurs only in selenium-deficient children, appears to be triggered by an additional stress, possibly an infection or a chemical exposure (Ge et al., 1983). Clinical thyroid disorders have not been reported in selenium-deficient individuals with adequate iodine intake, but based on observations in Africa, it has been postulated that infants born to mothers deficient in both selenium and iodine are at increased risk of cretinism (Vanderpas et al., 1992). Kashin-Beck disease, an endemic disease of cartilage that occurs in preadolescence or adolescence, has been reported in some of the low-selenium areas of Asia (Yang et al., 1988). It is possible that this disease, like Keshan disease, occurs only in selenium-deficient people. However, there has been no demonstration that improvement of selenium nutritional status can prevent Kashin-Beck disease, so involvement of selenium deficiency in its pathogenesis remains uncertain. These considerations indicate that selenium deficiency seldom causes overt illness when it occurs in isolation. However, it leads to biochemical changes that predispose to illness associated with other stresses. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR SELENIUM A search of the literature revealed several indicators that could be considered as the basis for deriving an Estimated Average Require-

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids ment (EAR) for selenium in adults. These included prevention of Keshan disease or various chronic diseases; concentration of selenium in blood, hair, and nails; concentration of selenoproteins in blood; and urinary excretion of the element. Keshan Disease Keshan disease, a cardiomyopathy that occurs almost exclusively in children, is the only human disease that is firmly linked to selenium deficiency (Keshan Disease Research Group, 1979). In addition to a low selenium intake, low blood and hair selenium concentrations are associated with Keshan disease. The disease occurs with varying frequency in areas of China where the population is severely selenium deficient (Ge et al., 1983). Based on these observations, the occurrence of Keshan disease in a population would indicate that the population is selenium deficient. Selenium in Hair and Nails Although the forms of selenium in hair and nails have not been characterized, some correlations between dietary intake of the element and hair and nail concentrations of selenium have been demonstrated. However, the use of hair and nail selenium as markers of selenium status has been limited because factors such as the form of selenium fed, the methionine content of the diet, and the color of the hair affect the deposition of selenium in these tissues (Salbe and Levander, 1990). In addition, some shampoos in the United States and Canada contain selenium. Therefore, only well-controlled studies can make use of hair and nail selenium concentrations, and these markers are of little value in determining selenium requirements across population groups. Selenium in Blood Several forms of selenium are present in blood and in metabolizing tissues; thus, they can be discussed together. Physiologically active forms include the selenoproteins and some as yet uncharacterized forms that are present in low abundance. These forms of selenium are under physiological regulation. Within a specific range of dietary selenium intakes, selenoprotein concentrations are a function of selenium intake. Above this range of intakes, selenoprotein concentrations become regulated only by genetic and environmental factors. This lack of selenium effect implies that the selenium

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids requirement for selenoprotein synthesis has been met (Yang et al., 1987). At this plateau point, human plasma selenoproteins contain 0.8 to 1.1 µmol/L (7 to 9 µg/dL) of selenium (Hill et al., 1996). Thus, when tissue concentrations of selenium are below the level at which selenoproteins have plateaued, it can be stated with confidence that selenium supplies are limiting. Under these conditions, tissue (plasma) concentrations of the element are useful as indices of nutritional selenium status. Above plateau concentration, however, the chemical form of selenium ingested and other factors become important in determining the tissue selenium concentration. Tissue (plasma) concentrations of selenium do not always correlate with selenium intake under these conditions (concentration greater than the plateau). As stated earlier, much of the dietary selenium supply is selenomethionine, which is synthesized by plants and appears to enter the methionine pool in animals where it is incorporated into protein randomly at methionine sites. Since selenomethionine is not subject to homeostatic regulation, blood levels of selenium will generally be higher when this form is consumed (Burk and Levander, 1999). The selenium released by the catabolism of selenomethionine will be present as selenocysteine in selenoproteins. Based on these considerations, plasma selenium concentration has utility in assessing selenium intake of all forms of the element only when it is less than 0.8 µmol/L (7 µg/dL). Such values indicate that the synthesis of selenoproteins has not yet plateaued. Above these values, the plasma selenium concentration is highly dependent on the chemical form of the element ingested. Glutathione Peroxidases and Selenoprotein P in Blood Several selenoproteins are present in blood. Plasma contains the extracellular glutathione peroxidase (GSHPx-3) and selenoprotein P. Erythrocytes and platelets contain the most abundant form of selenium-containing glutathione peroxidase, intracellular glutathione peroxidase (GSHPx-1). Other selenoproteins have not been identified in blood. All three of these blood selenoproteins (GSH-Px-3, selenoprotein P, and GSHPx-1) have been used to assess selenium status, but plasma GSHPx-3 has been preferred in recent years because its determination is more accurate than the determination of the erythrocyte enzyme GSHPx-1. Since hemoglobin interferes with the measurement of GSHPx-1 in the erythrocyte, use of this marker is problematic and consequently few data are available that can be used to set a selenium requirement. Also studies indicate

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids that plasma GSHPx-3 activity reflects the activity of tissue selenoenzymes better than does GSHPx-1 activity in erythrocytes (Cohen et al., 1985). The limited information available on selenoprotein P indicates that it is the major form of selenium in plasma and suggests that it will be as good an indicator of selenium status as plasma GSHPx-3 (Hill et al., 1996). However, since an assay for it is not widely available at present, the data for selenoprotein P are insufficient to use it to estimate a dietary requirement. Cancer In some animal models, high selenium intakes reduce the incidence of cancer (Ip, 1998). In these studies, selenium was fed in amounts greater than that needed to support maximum concentrations of selenoproteins. In humans, some but not all observational studies have shown that individuals who self-select diets that produce high plasma and nail selenium tend to have a lower incidence of cancer (Clark et al., 1991). Randomized trial data are limited to three studies, one conducted with poorly nourished rural Chinese (Blot et al., 1995), another with U.S. patients with a history of treated nonmelanoma skin cancer (Clark et al., 1996), and a third with participants in the Health Professional Follow-up Study (Yoshizawa et al., 1999). In the China trial, among eight combinations tested, subjects assigned a daily combination of selenium (50 µg [0.6 µmol]), β-carotene (15 mg), and α-tocopherol (30 mg) achieved a significant (21 percent) decrease in gastric cancer mortality, resulting in a significant 9 percent decline in total all-cause mortality. However, these results cannot be attributed to selenium alone, because the individuals consumed selenium in combination with β-carotene and vitamin E. In the second trial, 200 µg (2.5 µmol)/day of selenium administered in the form of yeast showed no effect on recurrence of non-melanoma skin cancer compared to a similar placebo group (Clark et al., 1996). Although the numbers of subjects were small (1,312 patients randomly assigned to the supplement or a placebo, ≈ 75% male) and the outcomes not prespecified, significantly lower rates of prostate, colon, and total cancer were observed among those assigned to the selenium group. Similar prostate cancer results were reported from a nested case-control design within the Health Professionals Follow-up Study; the risk of prostate cancer for men receiving 200 µg (2.5 µmol)/day of selenium was one-third that of men receiving the placebo (Yoshiza-

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids wa et al., 1999). The inverse association seen between the selenium level in toenail clippings and the risk of advanced prostate cancer was not confounded by age, other dietary factors, smoking, body mass index, geographic region, family history of prostate cancer, or vasectomy. Results of these three studies are compatible with the possibility that intakes of selenium above those needed to maximize selenoproteins have an anticancer effect in humans. These findings support the need for large-scale trials. They can not, however, serve as the basis for determining dietary selenium requirements at this time. Other Measurements Urine Attempts have been made to use urinary selenium excretion as an index of selenium status. While excretion of the element is proportional to selenium status, excretion is also sensitive to short-term changes in selenium intake (Burk et al., 1972). Thus, urinary excretion in selenium deficiency may reflect immediate selenium intake more than nutritional selenium status. This limits the utility of urinary selenium measurements. Labeled Selenium Uptake of selenium-75 (75Se) by erythrocytes in vitro has been studied (Wright and Bell, 1963) as an indicator of selenium status. Although this method showed validity in sheep (Wright and Bell, 1963), its value in other species, including humans, has not been demonstrated (Burk et al., 1967). FACTORS AFFECTING THE SELENIUM REQUIREMENT Bioavailability Most dietary selenium is highly bioavailable. Selenomethionine, which is estimated to account for at least half of the dietary selenium, is absorbed by the same mechanism as methionine, and its selenium is made available for selenoprotein synthesis when it is catabolized via the transsulfuration pathway (Esaki et al., 1982). The bioavailability of selenium in the form of selenomethionine is greater than 90 percent (Thomson and Robinson, 1986). The selenium

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids in selenocysteine, another significant dietary form, is also highly bioavailable (Swanson et al., 1991). There appear to be some minor dietary forms of selenium (especially present in fish) that have relatively low bioavailability, but these forms have not been identified (Cantor and Tarino, 1982). Selenate and selenite, two inorganic forms of selenium, have roughly equivalent bioavailability which generally exceeds 50 percent (Thomson and Robinson, 1986). Although they are not major dietary constituents, these inorganic forms are commonly used as selenium supplements. Gender Earlier reports from China (Ge et al., 1983), from a time when selenium deficiency was more severe than in recent years, indicated that women of childbearing age were susceptible to developing Keshan disease, whereas men were resistant. However, cases of the disease reported in the past 20 years appear to be limited to children, with equal prevalence in boys and girls (Cheng and Qian, 1990). Thus, a gender effect in susceptibility to this disease may be present at extremely low selenium intakes, but no such effect has been demonstrated at current intakes. Given women's apparently increased susceptibility to Keshan disease, selenium requirements for the various age groups are based on male reference weights. FINDINGS BY LIFE STAGE AND GENDER GROUP Infants Ages 0 through 12 Months Method Used to Set the Adequate Intake No functional criteria of selenium status have been demonstrated that reflect response to dietary intake in infants. Thus, recommended intakes of selenium are based on an Adequate Intake (AI) that reflects the observed mean selenium intake of infants fed principally with human milk. Human milk is recognized as the optimal milk source for infants throughout at least the first year of life and is recommended as the sole nutritional milk source for infants during the first 4 to 6 months of life (IOM, 1991). Therefore, determination of the AI for selenium for infants is based on data from infants fed human milk as the principal fluid during periods 0 through 6 and 7 through 12 months of age. The AI is the mean value of observed intakes as calculated

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids from data on the selenium content of human milk and other studies which estimated the volume typically consumed as determined by test weighing of infants in the age category. In the age group 7 through 12 months, an amount is added for the contribution to intake of selenium obtained from weaning foods. Average selenium concentrations of human milk consumed by infants at different ages are shown in Table 7-1. In general, the selenium content of human milk is highest in colostrum (33 to 80 µg [0.4 to 1.0 µmol]/L) (Ellis et al., 1990; Higashi et al., 1983; Hojo, 1986; Smith et al., 1982), whereas concentrations in transitional milk at 1 week (18 to 29 µg [0.2 to 0.4 µmol]/L) are less than half those of colostrum (Ellis et al., 1990; Higashi et al., 1983; Hojo, 1986). There is wide interindividual variation in the selenium content of human milk (Higashi et al., 1983), and the selenium content of hind milk (milk at the end of an infant feeding) is greater than that of the fore milk (milk at the beginning of the feeding) (Smith et al., 1982). Selenium is also present in human milk in extracellular glutathione peroxidase (GSHPx-3) (Avissar et al., 1991), but the distribution of selenium among milk proteins needs further characterization. It is also likely that a large and variable fraction of milk selenium is present as selenomethionine substituting for methionine as has been described for plasma. The average selenium content of mature human milk sampled between 2 and 6 months lactation appears to be relatively constant within a population group (Debski et al., 1989; Funk et al., 1990). However, human milk selenium varies with maternal selenium in-take. Selenium concentrations in mature human milk in Finnish women consuming 30, 50, or 100 µg (0.4, 0.6, or 1.3 µmol)/day of selenium were 6, 11, or 14 µg (0.08, 0.14, or 0.18 µmol)/L of selenium, respectively (Kumpulainen et al., 1983, 1984, 1985). Other studies reported average selenium concentrations of mature human milk of 10 to 23 µg/L (with a range of 6 to 39 µg/L) (Cumming et al., 1992; Debski et al., 1989; Ellis et al., 1990; Funk et al., 1990; Higashi et al., 1983; Hojo, 1986; Levander et al., 1987; Mannan and Picciano, 1987; Smith et al., 1982). The average selenium content of human milk from mothers in Canada and the United States was 15 to 20 µg (0.19 to 0.25 µmol)/L (Levander et al., 1987; Mannan and Picciano, 1987; Smith et al., 1982). An older study analyzed human milk samples from women living in 17 states in the United States. The authors reported mean milk selenium values to be 28 µg (0.35 µmol)/L in areas with high soil selenium content and 13 µg (0.16 µmol)/L in areas with low

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids TABLE 7-1 Selenium Content of Human Milk Reference Selenium Content of Milk (µg/L) Stage of Lactation Shearer and Hadjimarkos, 1975 18 (7–60) 17–869 d Smith et al., 1982a 41.2 ± 17.3 18 ± 3.8 15.7 ± 4.6 15.1 ± 5.8 1–4 d (colostrum), from a different sample of women 1 mo 2 mo 3 mo Higashi et al., 1983b 80 (35–152) 29 (15–79) 18 (9–39) 17 (6–28) 18 (9–33) Day 1 (colostrum) 1 wk (transitional milk) 1 mo 3 mo 5 mo Kumpulainen et al., 1983 10.7 ± 1.6 (SDc) 5.8 ± 1.2 5.6 ± 0.4 1 mo 3 mo 6 mo Kumpulainen et al., 1984 11.8 ± 1.7 10.9 ± 1.9 10.0 ± 1.9 1 mo 2 mo 3 mo Kumpulainen et al., 1985 13–14 2 mo Hojo, 1986e 34.2 ± 12.8 24.0 ± 4.2 22.5 ± 4.2 4 d (colostrum) 7–8 d (transitional milk) 36–86 d Levander et al., 1987 20 ± 1 (SEMg) 15 ± 1 15 ± 1 1 mo 3 mo 6 mo

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids Identification of a No-Observed-Adverse-Effect Level (NOAEL) and a Lowest-Observed-Adverse-Effects Level (LOAEL). The lowest blood level of selenium measured in the five subjects at initial examination was 13.3 µmol/L (105 µg/dL), corresponding to a selenium intake of 913 µg (12 µmol)/day (range: 913 to 1,907 µg [12 to 24 µmol]/day). The average blood selenium level was 16.9 µmol/L (135 µg/dL). At the time of reexamination in 1992, all five patients were described as recovered from selenium poisoning, although their fingernails reportedly appeared brittle. The mean blood selenium level had decreased to 12.3 µmol/L (97 µg/dL), corresponding to a selenium intake of about 800 µg (10 µmol)/day (range 654 to 952 µg [8.3 to 12 µmol]/day). The lower limit of the 95 percent confidence interval was 600 µg (7.6 µmol)/day. Yang and Zhou (1994) therefore suggested that 913 µg (12 µmol)/day of selenium intake represents an individual marginal toxic daily selenium intake or LOAEL. They further suggested that the mean selenium intake upon reexamination (800 µg [10 µmol]/day), represented a NOAEL, while 600 µg (7.6 µmol)/day of selenium intake was the lower 95 percent confidence limit for the NOAEL. These values appear reasonable, although the number of subjects was small. Nevertheless, the LOAEL for selenosis in this small data set appears to be representative of the larger data set, and the reexamination of the subjects provides valuable dose-response data. Uncertainty occurs because of the smallness of the data set and because the Chinese subjects may not be typical (e.g., they may be more or less sensitive to selenium than other populations). Longnecker et al. (1991) studied 142 ranchers, both men and women, from eastern Wyoming and western South Dakota who were recruited to participate and were suspected of having high selenium intakes based on the occurrence of selenosis in livestock raised in that region. Average selenium intake was 239 µg (3 µmol)/day. Dietary intake and selenium in body tissues (whole blood, serum, urine, toenails) were highly correlated. Blood selenium concentrations in this western U.S. population were related to selenium intake in a similar manner to that found in the Chinese studies, presumably because the form of selenium ingested was selenomethionine. No evidence of selenosis was reported, nor were there any alterations in enzyme activities, prothrombin times, or hematology that could be attributed to selenium intake. The highest selenium intake in the study was 724 µg (9 µmol)/day. It thus appears that a UL based on the Chinese studies is protective for the population in the United States and Canada. Therefore a NOAEL of 800 µg (10 µmol)/day is selected.

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids Uncertainty Assessment. An uncertainty factor (UF) of 2 was selected to protect sensitive individuals. The toxic effect is not severe, but may not be readily reversible, so a UF greater than 1 is needed. Derivation of a UL. The NOAEL of 800 µg/day was divided by a UF of 2 to obtain a UL for adults as follows: Selenium UL Summary, Ages 19 Years and Older UL for Adults   19 years and older 400 µg (5.1 µmol)/day of selenium Pregnancy and Lactation Brätter et al. (1996) studied the effects of selenium intake on metabolism of thyroid hormones in lactating mothers in seleniferous regions in the foothills of the Venezuelan Andes. Selenium intakes ranged from 170 to 980 µg (2.2 to 12.4 µmol)/day. An inverse correlation between selenium intake and free triiodothyronine (FT3) was observed, but all values were found to be within the normal range. There are no reports of teratogenicity or selenosis in infants born to mothers with high but not toxic intakes of selenium. Therefore, ULs for pregnant and lactating women are the same as for nonpregnant and nonlactating women (400 µg [5.1 µmol]/day). Selenium UL Summary, Pregnancy and Lactation UL for Pregnancy   14–18 years 400 µg (5.1 µmol)/day of selenium 19 years and older 400 µg (5.1 µmol)/day of selenium UL for Lactation   14–18 years 400 µg (5.1 µmol)/day of selenium 19 years and older 400 µg (5.1 µmol)/day of selenium Infants and Children Data Selection. There are several approaches for estimating a UL in human milk-fed infants (Levander, 1989). However, the most conservative approach is to use the data of Shearer and Hadjimarkos (1975).

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids Identification of a NOAEL. The data of Shearer and Hadjimarkos (1975) showed that a human milk selenium concentration of 60 µg (0.8 µmol)/L was not associated with known adverse effects. Thus, 60 µg (0.8 µmol)/L is the NOAEL selected. Multiplying the NOAEL for infants 0 through 6 months of age by the estimated average intake of human milk of 0.78 L/day results in a NOAEL of 47 µg (0.6 µmol) or approximately 7 µg (90 nmol)/kg/day. This is in agreement with another study by Brätter et al. (1991). Brätter et al. (1991) studied effects of selenium intake on children in two seleniferous areas of the foothills of the Venezuelan Andes, using Caracas as a control. Mean human milk selenium content was 46 µg (0.6 µmol)/L in Caracas compared to 60 and 90 µg (0.8 and 1.1 µmol)/L in the two seleniferous areas. Mean selenium concentrations in infant blood in the area with the highest adult selenium intake were reported to be intermediate between those seen in the seleniferous and the nonseleniferous regions. Uncertainty Assessment. There is no evidence that maternal intake associated with a human milk level of 60 µg (0.8 µmol)/L results in infant or maternal toxicity (Shearer and Hadjimarkos, 1975). Therefore, a UF of 1 is specified. Derivation of a UL. The NOAEL of 47 µg (0.6 µmol)/day was divided by a UF of 1, resulting in a UL of 47 µg (0.6 µmol) or approximately 7 µg (90 nmol)/kg/day for 2 through 6-month-old infants. Thus, the infant UL and the adult UL are similar on a body weight basis. Also, there is no evidence indicating increased sensitivity to selenium toxicity for any age group. Thus, the UL of 7 µg/kg body weight/day was adjusted for older infants, children, and adolescents on the basis of relative body weight as described in Chapter 4 using reference weights from Chapter 1 (Table 1-1). Values have been rounded down to the nearest 5 µg. Selenium UL Summary, Ages 0 Months through 18 Years UL for Infants   0–6 months 45 µg (0.57 µmol)/day of selenium 7–12 months 60 µg (0.76 µmol)/day of selenium UL for Children   1–3 years 90 µg (1.1 µmol)/day of selenium 4–8 years 150 µg (1.9 µmol)/day of selenium 9–13 years 280 µg (3.6 µmol)/day of selenium UL for Adolescents   14–18 years 400 µg (5.1 µmol)/day of selenium

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids Intake Assessment Selenium intake is primarily in the form of food. Reliance on foods grown in high-selenium areas causes selenosis in China (Yang et al., 1983). There are high-selenium areas in the United States, but the U.S. Department of Agriculture has identified them and proscribed their use for raising animals for food. The extensive food distribution system in Canada and the United States ensures that individuals do not eat diets that originate solely from one locality. This moderates the selenium content of diets, even in high-selenium areas. The study of dietary selenium intake in a high-selenium area (western South Dakota and eastern Wyoming) indicated daily intakes of 68 to 724 µg (0.9 to 9.2 µmol) in 142 subjects (Longnecker et al., 1991). About half the subjects were consuming more than 200 µg (2.5 µmol)/day. No evidence of selenosis was found, even in the subjects consuming the most selenium. Water selenium content is usually trivial compared to food selenium content. However, irrigation runoff water has been shown to contain significant amounts of selenium when the soil irrigated contains large amounts of the element (Valentine et al., 1978). Selenium is available over the counter in many doses but usually under 100 µg (1.3 µmol)/dose. Some individuals may consume larger quantities than are recommended by the manufacturer. At least one manufacturing error has been reported to have led to selenium intoxication in 13 people who took a selenium supplement containing 27.3 mg, several hundred times the amount of selenium stated to be in the product (Helzlsouer et al., 1985). Risk Characterization The risk of selenium intake above the UL for the U.S. and Canadian populations appears to be small. There is no known seleniferous area in the United States and Canada where there have been recognized cases of selenosis. Specifically as noted above, there have been no cases of selenosis in the high-selenium areas of Wyoming and South Dakota (Long-necker et al., 1991). There is some potential for selenium intake to exceed the UL in this area. These authors note that selenium intake exceeded 400 µg (5.1 µmol)/day in 12 subjects, with the highest intake being 724 µg (9.2 µmol)/day. Since 724 µg (9.2 µmol)/day is 3.4 standard deviations above the mean intake, intakes this high would be very rare. Even at this level, toxic effects would be unlike-

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids ly, since the LOAEL is about 900 µg (11.4 µmol)/day, and many people would not be affected even at this level of intake. Although intakes above the UL indicate an increased level of risk, these intakes—if below the LOAEL—would nevertheless be unlikely to result in observable clinical disease. This is especially true in a population that could self-select for high intake, so that people who might experience symptoms could alter their diets or move. In light of evaluating possible benefits to health, clinical trials at doses of selenium above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. Also, the UL is not meant to apply to individuals who are receiving selenium under medical supervision. RESEARCH RECOMMENDATIONS FOR SELENIUM Biomarkers for use in assessment of selenium status are needed to prevent selenium deficiency and selenium toxicity. The relationship of plasma selenoprotein concentrations to graded selenium intakes must be studied in a severely selenium-deficient population in order to establish a more precise dietary selenium requirement. Plasma selenium levels (and other measurements of the element) have to be carried out in subjects fed levels of selenium (both organic and inorganic forms) up to the Tolerable Upper Intake Level (UL). This could validate use of plasma selenium concentrations to assess high levels of selenium intake. Since the Recommended Dietary Allowances (RDAs) for children ages 1 through 18 years are extrapolated from the adult RDAs, it is critically important to conduct large-scale studies with children using state-of-the-art biomarkers to assess their selenium requirements. Selenium functions largely through selenoproteins. Although the functions of some selenoproteins are known, those of others are not. Moreover, there appear to be a number of selenoproteins that have not yet been characterized. Therefore, the functions of known and new selenoproteins need to be determined. At present the recommendation for selenium intake has been set at the amount needed to achieve a plateau of the plasma selenoprotein glutathione peroxidase. Most residents in Canada and the United States can reach this level of selenium intake with their usual diet, but residents of many regions of the world have lower selenium intakes. Research is needed to determine the health conse

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids quences of selenium intakes inadequate to allow full selenoprotein expression. Limited evidence has been presented that intakes of selenium greater than the amount needed to allow full expression of selenoproteins may have chemopreventive effects against cancer. Controlled intervention studies are needed to fully evaluate selenium as a cancer chemopreventive agent. REFERENCES Allen JC, Keller RP, Archer P, Neville MC. 1991. Studies in human lactation: Milk composition and daily secretion rates of macronutrients in the first year of lactation. Am J Clin Nutr 54:69–80. Arteel GE, Mostert V, Oubrahim H, Briviba K, Abel J, Sies H. 1998. Protection by selenoprotein P in human plasma against peroxynitrite-mediated oxidation and nitration. Biol Chem 379:1201–1205. Avissar N, Slemmon JR, Palmer IS, Cohen HJ. 1991. Partial sequence of human plasma glutathione peroxidase and immunologic identification of milk glutathione peroxidase as the plasma enzyme . J Nutr 121:1243–1249. Beck MA, Levander OA. 1998. Dietary oxidative stress and the potentiation of viral infection. Annu Rev Nutr 18:93–116. Behne D, Wolters W. 1983. Distribution of selenium and glutathione peroxidase in the rat. J Nutr 113:456–461. Behne D, Kyriakopoulos A, Kalcklosch M, Weiss-Nowak C, Pfeifer H, Gessner H, Hammel C. 1997. Two new selenoproteins found in the prostatic glandular epithelium and in the spermatid nuclei. Biomed Environ Sci 10:340–345. Berry MJ, Larsen PR. 1992. The role of selenium in thyroid hormone action. Endocr Rev 13:207–219. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey SM, Li B. 1995. The Linxian trials: Mortality rates by vitamin-mineral intervention group. Am J Clin Nutr 62:1424S–1426S. Bösl MR, Takaku K, Oshima M, Nishimura S, Taketo MM. 1997. Early embryonic lethality caused by targeted disruption of the mouse selenocysteine tRNA gene (Trsp). Proc Natl Acad Sci USA 94:5531–5534. Bratakos MS, Zafiropoulos TF, Siskos PA, Ioannou PV. 1988. Total selenium co centration in tap and bottled drinking water and coastal waters of Greece. Sci Total Environ 76:49–54. Brätter P, Negretti de Brätter VE. 1996. Influence of high dietary selenium intake on the thyroid hormone level in human serum. J Trace Elem Med Biol 10:163–166. Brätter P, Negretti de Brätter VE, Jaffe WG, Mendez Castellano H. 1991. Selenium status of children living in seleniferous areas of Venezuela . J Trace Elem Electr lytes Hlth Dis 5:269–270. Burk RF, Brown DG, Seely RJ, Scaief CC III. 1972. Influence of dietary and injected selenium on whole-body retention, route of excretion, and tissue retention of 75SeO32− in the rat. J Nutr 102:1049–1055. Burk RF, Hill KE, Awad JA, Morrow JD, Kato T, Cockell KA, Lyons PR. 1995. Pathogenesis of diquat-induced liver necrosis in selenium-deficient rats. As

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids sessment of the roles of lipid peroxidation and selenoprotein P. Hepatology 21:561–569. Burk RF, Levander OA. 1999. Selenium. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease, 9th edition. Baltimore, MD: Williams & Wilkins. Pp. 265–276. Burk RF, Pearson WN, Wood RP II, Viteri F. 1967. Blood selenium levels and in vitro red blood cell uptake of 75Se in kwashiorkor. Am J Clin Nutr 20:723–733. Butte NF, Garza C, Smith EO, Nichols BL. 1984. Human milk intake and growth in exclusively breast-fed infants. J Pediatr 104:187–195. Cantor AH, Tarino JZ. 1982. Comparative effects of inorganic and organic dietary sources of selenium on selenium levels and selenium-dependent glutathione peroxidase activity in blood of young turkeys. J Nutr 112:2187–2196. Carter RF. 1966. Acute selenium poisoning. Med J Aust 1:525–528. CDC (Centers for Disease Control and Prevention). 1984. Selenium intoxication—New York. Morbid Mortal Wkly Rep 33:157–158. Cheng Y-Y, Qian P-C. 1990. The effect of selenium-fortified table salt in the prevention of Keshan disease on a population of 1.05 million. Biomed Environ Sci 3:422–428. Clark LC, Cantor KP, Allaway WH. 1991. Selenium in forage crops and cancer mortality in U.S. counties. Arch Environ Health 46:37–42. Clark LC, Combs GF, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A, Lesher JL, Park HK, Sanders BB, Smith CL, Taylor JR. 1996. Effects of selenium supplementation for ca cer prevention in patients with carcinoma of the skin. A randomized controlled trial. J Am Med Assoc 276:1957–1963. Cohen HJ, Chovaniec ME, Mistretta D, Baker SS. 1985. Selenium repletion and glutathione peroxidase—Differential effects on plasma and red blood cell enzyme activity . Am J Clin Nutr 41:735–747. Cumming FJ, Fardy JJ, Woodward DR. 1992. Selenium and human lactation in Australia: Milk and blood selenium levels in lactating women, and selenium intakes of their breast-fed infants. Acta Paediatr 81:292–295. Debski B, Finley DA, Picciano MF, Lonnerdal B, Milner J. 1989. Selenium content and glutathione peroxidase activity of milk from vegetarian and nonvegetarian women. J Nutr 119:215–220. Dewey KG, Finley DA, Lonnerdal B. 1984. Breast milk volume and composition during late lactation (7–20 months). J Pediatr Gastroenterol Nutr 3:713–720. Duffield AJ, Thomson CD, Hill KE, Williams S. 1999. An estimation of selenium requirements for New Zealanders. Am J Clin Nutr 70:896–903. Ehrenreich A, Forchhammer K, Tormay P, Veprek B, Böck A. 1992. Selenoprotein synthesis in E. coli. Purification and characterization of the enzyme catalysing selenium activation. Eur J Biochem 206:767–773. Ellis L, Picciano MF, Smith AM, Hamosh M, Mehta NR. 1990. The impact of gest tional length on human milk selenium concentration and glutathione peroxidase activity. Pediatr Res 27:32–35. Esaki N, Nakamura T, Tanaka H, Soda K. 1982. Selenocysteine lyase, a novel e zyme that specifically acts on selenocysteine. Mammalian distribution and purification and properties of pig liver enzyme. J Biol Chem 257:4386–4391. Flohe L. 1988. Glutathione peroxidase. Basic Life Sci 49:663–668. Fomon SJ, Anderson TA. 1974. Infant Nutrition, 2nd edition. Philadelphia: WB Saunders. Pp. 104–111.

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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids Funk MA, Hamlin L, Picciano MF, Prentice A, Milner JA. 1990. Milk selenium of rural African women: Influence of maternal nutrition, parity, and length of lactation. Am J Clin Nutr 51:220–224. Ge K, Xue A, Bai J, Wang S. 1983. Keshan disease—An endemic cardiomyopathy in China. Virchows Arch A Pathol Anat Histopathol 401:1–15. Griffiths NM. 1973. Dietary intake and urinary excretion of selenium in some New Zealand women. Proc Univ Otago Med Sch 51:8–9. Guimaraes MJ, Peterson D, Vicari A, Cocks BG, Copeland NG, Gilbert DJ, Jenkins NA, Ferrick DA, Kastelein RA, Bazan JF, Zlotnik A. 1996. Identification of a novel selD homolog from eukaryotes, bacteria, and archaea: Is there an autoregulatory mechanism in selenocysteine metabolism? Proc Natl Acad Sci USA 93:15086–15091. Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B, Dewey KG. 1993. Energy and protein intakes of breast-fed and formula-fed infants during the first year of life and their association with growth velocity: The DARLING Study. Am J Clin Nutr 58:152–161. Helzlsouer K, Jacobs R, Morris S. 1985. Acute selenium intoxication in the United States. Fed Proc 44:1670. Higashi A, Tamari H, Kuroki Y, Matsuda I. 1983. Longitudinal changes in selenium content of breast milk. Acta Paediatr Scand 72:433–436. Hill KE, Xia Y, Åkesson B, Boeglin ME, Burk RF. 1996. Selenoprotein P concentr tion in plasma is an index of selenium status in selenium-deficient and selenium-supplemented Chinese subjects . J Nutr 126:138–145. Hojo Y. 1986. Sequential study on glutathione peroxidase and selenium contents of human milk. Sci Total Environ 52:83–91. IOM (Institute of Medicine). 1991. Nutrition During Lactation. Washington, DC: National Academy Press. Ip C. 1998. Lessons from basic research in selenium and cancer prevention. J Nutr 128:1845–1854. Jensen R, Closson W, Rothenberg R. 1984. Selenium intoxication—New York. Morbid Mortal Wkly Rep 33:157–158. Jochum F, Fuchs A, Cser A, Menzel H, Lombeck I. 1995. Trace mineral status of full-term infants fed human milk, milk-based formula or partially hydrolysed whey protein formula. Analyst 120:905–909. Keshan Disease Research Group. 1979. Observations on effect of sodium selenite in prevention of Keshan disease. Chin Med J 92:471–476. Kumpulainen J, Vuori E, Kuitunen P, Makinen S, Kara R. 1983. Longitudinal study on the dietary selenium intake of exclusively breast-fed infants and their mothers in Finland. Int J Vitam Nutr Res 53:420–426. Kumpulainen J, Vuori E, Siimes MA. 1984. Effect of maternal dietary selenium intake on selenium levels in breast milk. Int J Vitam Nutr Res 54:251–255. Kumpulainen J, Salmenpera L, Siimes MA, Koivistoinen P, Perheentupa J. 1985. Selenium status of exclusively breast-fed infants as influenced by maternal organic or inorganic selenium supplementation. Am J Clin Nutr 42:829–835. Lacourciere GM, Stadtman TC. 1998. The NIFS protein can function as a selenide delivery protein in the biosynthesis of selenophosphate. J Biol Chem 273:30921–30926. Levander OA. 1976. Selenium in foods. In: Proceedings of the Symposium on Selenium-Tellurium in the Environment . South Bend, IN: University of Notre Dame. Levander OA. 1989. Upper limit of selenium in infant formulas. J Nutr 119:1869–1873.

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