Iron is a constituent of hemoglobin, myoglobiin, and a number of enzymes and, therefore, is an essential nutrient for humans (Bothwell et al., 1979). In addition to these functional forms, as much as 30% of the body iron is found in storage forms such as ferritin and hemosiderin (mainly in the spleen, liver, and bone marrow), and a small amount is associated with the blood transport protein transferrin.
Body iron content is regulated mainly through changes in the amount of iron absorbed by the intestinal mucosa (Finch and (Cook, 1984). The absorption of iron is influenced by body stores (Bothwell et al., 1979; Cook et al., 1974), by the amount and chemical nature of iron in the ingested food (Layrisse et al., 1968), and by a variety of dietary factors that increase or decrease the availability of iron for absorption (Gillooly et al., 1983; Hallberg, 1981). When the dietary supply of absorbable iron is sufficient, the intestinal mucosa regulates iron absorption in a manner that tends to keep body iron content constant. In iron deficiency, the efficiency of iron absorption increases (Finch and Cook, 1984). However, this response may not be sufficient to prevent anemia in subjects whose intake of available iron is marginal. Similarly, intestinal regulation is not sufficient to prevent excessive body accumulation of iron in the presence of continued high levels of iron in the diet.
General Signs of Deficiency
Three stages of impaired iron status have been identified. In the first stage, iron depletion, iron stores are diminished, as reflected in
a fall in plasma ferritin to levels below 12 µg/liter, but no functional impairment is evident. The second stage is recognized by iron-deficient erythropoiesis, in which the hemoglobin level is within the 95%, reference range for age and sex but red cell protoporphyrin levels are elevated, transferrin saturation is reduced to less than 16% in adults, and work capacity performance may be impaired. In the third stage, iron deficiency anemia, total blood hemoglobin levels are reduced below normal values for age and sex of the subject. Severe iron deficiency anemia is characterized by small red blood cells (microcytosis) with low hemoglobin concentrations (hypochromia).
Currently there is no single biochemical indicator available to reliably assess iron inadequacy in the general population. Three approaches for estimating the prevalence of impaired iron status were used by the Life Sciences Research Office (LSRO, 1985). One (the ferritin model) involved the use of three indicatorsserum ferritin, transferrin saturation, and erythrocyte protoporphyrinand required that at least two of these be abnormal. In another, mean cell volume (MCV) was substituted for ferritin, but there was also a requirement that at least two of the three indicators be abnormal. The third approach (hemoglobin percentile shift) was defined as the change in median hemoglobin concentration after exclusion of individuals with one or more abnormal iron status values.
Operational definitions of anemia have been established by a World Health Organization (WHO) Expert Committee (WHO, 1968) in terms of hemoglobin level. For males and females age 14 years and over, anemia is defined as a hemoglobin level below 13 g/dl and 12 g/dl, respectively. For pregnant women, values below 11 g/dl for the first trimester, 10.5 for the second, and 11.0 for the third have recently been proposed by the Centers for Disease Control as levels defining anemia (CDC, 1989). Since the range of normal hemoglobin values is rather broad (13 to 16 g/dl in men and 12 to 16 g/dl in women), the actual deficit in hemoglobin may vary considerably in individuals with a given level of hemoglobin below the cut-off point.
The consequences of iron deficiency are usually ascribed to the resulting anemia, although some effects of deficiency have been found before reduced hemoglobin levels were observed (NRC, 1979). An association between hemoglobin concentration and work capacity is the most clearly identified functional consequence of iron deficiency (Viteri and Torun, 1974). However, there are reports of reduced physical performance in iron deficiency even before anemia is present (Dallman et al., 1978). Iron deficiency also has been associated with decreased immune function as measured by changes in several components of the immune system during iron deficiency. The functional
consequences of these immune system changes to actual resistance to infection still remains to be determined. In children, iron deficiency has been associated with apathy, short attention span, irritability, and reduced ability to learn (Lozoff and Brittenham, 1986). The degree to which milder forms of iron deficiency, as opposed to severe anemia, result in impaired school performance by children is uncertain (Pollitt, 1987).
In the United States, iron deficiency may be observed primarily during four periods of life: (1) from about 6 months to 4 years of age, because the iron content of milk is low, the body is growing rapidly, and body reserves of iron are often insufficient to meet needs beyond 6 months; (2) during the rapid growth of early adolescence, because of the needs of an expanding red cell mass and the need to deposit iron in myoglobin; (3) during the female reproductive period, because of menstrual iron losses; and (4) during pregnancy, because of the expanding blood volume of the mother, the demands of the fetus and placenta, and blood losses during childbirth. Analyses of data from the Second National Health and Nutrition Examination Survey (NHANES II) of the U.S. population, 1976-1980, depending on the assessment model used, indicated a prevalence of impaired iron status ranging from 1 to 6% of the total population, including 9% of children aged 1 to 2 years of age, 4 to 12% of males ages 11 to 14 years, and 5 to 14% of females ages 15 to 44 (LSRO, 1985). The frequency of iron depletion as determined by measurement of serum ferritin, and of iron-deficient erythropoiesis as determined by transferrin saturation and protoporphyrin, is substantially greater than the frequency of iron deficiency anemia in the population surveyed in NHANES II (Bothwell et al., 1979; Dallman et al., 1984; Meyers et al., 1983).
Iron is widely distributed in the U.S. food supply; meat, eggs, vegetables, and cereals (especially fortified cereal products) are the principal dietary sources. In examining food consumption data for women 18 to 24 years of age from NHANES II, Murphy and Calloway (1986) found that of a daily iron intake of 10.7 mg, 31% came from meat, poultry, and fish and that 25% was provided by iron added to foods, mainly cereals, as fortification or enrichment. Fruits, vegetables, and juices contain varying amounts of iron, but as a group represent another major source of dietary iron. Heme iron, a highly available source, represents from 7 to 10% of the dietary iron of girls and women and from 8 to 12% of dietary iron of boys and men,
according to data from the 1977-1978 Nationwide Food Consumption Survey (Raper et al., 1984).
Iron availability may be enhanced by consumption of foods containing ascorbic acid. Ascorbic acid intake is relatively high in U.S. diets, ranging from 86 to 112 mg/day in various groups of men aged 15 years of age and older and from 76 to 92 mg/day for women 15 or more years old and over (Raper et al., 1984).
Absorption of Dietary Iron
Heme and nonheme forms of iron are absorbed by different mechanisms (Bjorn-Rasmussen et al., 1974). Heme iron is highly absorbable. The proportion of heme iron in animal tissues varies, but it averages about 40% of the total iron in all animal tissues, including meat, liver, poultry, and fish. The remaining 60% of the iron in animal tissues and all the iron in vegetable products is present as nonheme compounds.
The absorption of nonheme iron can be enhanced or inhibited by several factors. The two most well-defined enhancers of nonheme iron are some organic acids (especially ascorbic acid) (Gillooly et al., 1983) and the animal tissues present in each meal (Cook and Monsen, 1976). On the other hand, some dietary and medicinal substances such as calcium phosphate, phytates, bran, polyphenols in tea, and antacids may decrease nonheme iron absorption substantially (Gillooly et al., 1983; Monsen et al., 1978). Overall, nonheme iron absorption may vary up to tenfold, depending on the dietary content of such inhibiting and enhancing factors (Hallberg and Rossander, 1984).
The percentage of iron absorbed from a meal decreases as the amount of iron present increases. Bezwoda et al. (1983) reported that mean absorption of nonheme iron decreased from 18 to 6.4% as the nonheme iron content of four meals increased from 1.52 to 5.72 mg, resulting in little variation in the actual amount absorbed from the different meals. This presumably reflects tight control of nonheme iron absorption by the intestinal mucosa. On the other hand, 20% of the heme iron in all four meals was absorbed, despite a heme iron content ranging from 0.28 to 4.48 mg, suggesting that heme iron is less affected by other dietary components and at least partly bypasses intestinal mucosal control. On the basis of results of numerous studies of iron absorption in human subjects, Monsen et al. (1978) have suggested a method for planning and evaluating iron intakes that takes account of the enhancement of nonheme iron absorption by ascorbic acid and the presence of meat in the diet.
Absorption of iron also depends on the iron status of the individual. Mean absorption of dietary iron is relatively low when body stores are high but may be increased when stores are low (Bothwell et al., 1979). Therefore, iron deficiency may not occur to the extent that might be predicted from a given iron intake below recommended allowance levels.
In calculating the RDA, the subcommittee assumed that there are some iron stores, but it concluded that the size of the iron store needed as a reserve against periods of negative iron balance is a value judgment rather than a scientific determination. In U.S. women, average iron stores are approximately 300 mg; in men, they are approximately 1,000 mg (Bothwell et al., 1979). The subcommittee concluded that a dietary intake that achieves a target level of 300 mg of iron stores meets the nutritional needs of all healthy people. This level would be sufficient to provide the iron needs of an individual for several months, even when on a diet nearly devoid of iron.
The average loss of iron in the healthy adult man is estimated to be approximately 1 mg/day (Green et al., 1968). In adult women, there is an additional loss of about 0.5 mg/day, the amount of iron in the average menstrual blood flow averaged over 1 month (Hallberg et al., 1966). In approximately 5% of normal women, however, menstrual losses of more than 1.4 mg/day have been observed. As menstrual losses deplete iron stores, absorption of dietary iron increases. Concordant figures are found using radio-labeled iron loss from circulating erythrocytes. This method gives reliable turnover information for adults and indicates that average requirements to replace daily losses for adults ages 20 to 50 are approximately 14 µg of iron per kilogram of body weight for males (1.10) mg/79 kg) and 22 µg for premenopausal females (1.38 mg/63 kg) (Bothwell and Finch, 1968).
There is little or no population-based information from which to assess variability of iron losses among individuals. A reasonable estimate of the coefficient of variation may be approximately 15% (NRC, 1986), but iron losses are not normally distributed among women. For men, absorbed iron would need to be sufficient to replace a potential loss of 1.3 mg/day (1.03 + 30%) to cover the needs of essentially the entire population. The variability estimate indicates that a replacement of 1.8 mg of iron per day would cover the needs
of most women, except for the 5% with the most extreme menstrual losses.
Some impairment of iron status in 9.6 to 14.2% of nonpregnant females 15 to 44 years of age was suggested by population-based data showing two abnormal values among measurements of serum ferritin, erythrocyte protoporphyrin, and transferrin saturation (LSRO, 1985). When hemoglobin was used as an indicator, however, only 2.5 to 4% of the women showed evidence of iron deficiency. The average iron intake of this population group was found to be 10 to 11.0 mg/day in surveys conducted by the U.S. Department of Agriculture (USDA), the National Center for Health Statistics (NCHS), and the Food and Drug Administration (FDA) (Murphy and Calloway, 1986; Pennington et al., 1986; Raper et al., 1984). This suggests that a mean population consumption of about 10 mg/day is associated with adequate iron status in at least 86% of the population of women 15 to 44 years of age. Distribution analysis, considering both the variation in iron losses by menstruating women and in population iron intake, indicate that an iron intake of 14 mg/day is sufficient to meet the needs of all but about 5% of menstruating women (NRC, 1986).
From the available data, it seems reasonable to conclude that a daily intake of 10 to 1 1 mg of iron from typical U.S. diets is sufficient for most women. Those with high menstrual losses appear to compensate for those losses by improved absorption of dietary iron, since the prevalence of iron deficiency anemia in that group is quite low (Meyers et al., 1983). The most recent WHO recommendations (FAO, 1988) suggest that iron in the diets typical of most populations of industrialized countries is relatively highly available, iron absorption ranging from 10 to 15%. Thus, at an intake of 15 mg/day, approximately 1.5 to 2.2 mg of absorbed iron could be available to replace iron losses in adult women. This level would be expected to replace iron losses of most women.
The subcommittee concluded that an RDA of 15 mg/day would provide a sufficient margin of safety and should cover the needs of essentially all the adult women in the United States except for those with the most extreme menstrual losses, given usual dietary patterns. This is a reduction from the 1980 recommendation of 18 mg/day.
In the United States, very little iron deficiency has been reported for 15- to 60-year-old males (LSRO, 1985), whose average intake is about 15 mg/day. Given usual diets in the United States, an allowance of 10 mg/day for adult males should be sufficient to replace losses of up to 1.5 mg/dayan amount exceeding estimates of usual daily iron loss by men.
There is no evidence of a high prevalence of iron deficiency in the elderly (Lynch et al., 1982). Survey data suggest that inflammatory disease, rather than iron deficiency, is the main cause of anemia in this group (Dallman et al., 1984). In addition, after the menstrual years, the daily iron needs of women approximate those of men. Therefore, the subcommittee recommends the same iron RDA for elderly women and men10 mg/day.
Pregnancy and Lactation
Pregnant women need iron to replace the usual basal losses, to allow expansion of the red cell mass, to provide iron to the fetus and placenta, and to replace blood loss during delivery. Hallberg (1988) estimates that the total iron needed for a pregnancy is approximately 1,040 mg, of which 840 mg are lost from the body permanently and 200 mg are retained and serve as a reservoir of iron when blood volume decreases after delivery. Over the entire period of gestation, the amount of iron absorbed daily averages about 3 mg/day. There is little need for increased iron intake in the first trimester of pregnancy, since the cessation of iron loss from menstruation compensates for any increased needs during this period. In later stages of pregnancy, however, the requirement increases substantially (INACG, 1981). During the later stages of pregnancy, the absorbability of dietary iron also increases (Apte and Iyengar, 1970). To ensure sufficient absorbed iron to satisfy the demands of a normal pregnancy, a daily increment of 15 mg of iron, averaged over the entire pregnancy, should satisfy the needs of most women. However, since the increased pregnancy requirement cannot be met by the iron content of habitual U.S. diets or by the iron stores of at least some women, daily iron supplements are usually recommended.
Loss of iron through lactation is approximately 0.15 to 0.3 mg/day (Lonnerdal et al., 1981). This is less than menstrual loss, which often is absent during lactation (Habicht et al., 1985). Thus, since iron needs for lactating women are not substantially different from those of nonpregnant women, no additional iron allowance for this group is recommended.
Because of stored iron (Dahro et al., 1983), the normal term infant can maintain satisfactory hemoglobin levels from human milk without other iron sources during the first 3 months of life. From birth to age 3 years, infants not breastfed should have an iron intake of approximately 1 mg/kg per day. The RDA for 6 months to 3 years of age is set at 10 mg/daya level considered adequate for most healthy children during this time. Low birth weight infants (1,000 to 2,500 g) and those with a substantial reduction in total
hemoglobin mass require 2 mg/kg per day, starting no later than 2 months of age (AAP, 1976; Dallman et al., 1980). For infants of normal or low birth weight, iron intake should not exceed a maximum of 15 mg/day.
Children and Adolescents
Children and adolescents need iron not only to maintain hemoglobin concentrations but also to increase their total iron mass during the period of growth. Because of the allowance for increases in iron mass related to growth in body size, the iron requirements of children and adolescents are considered to be slightly higher than those of adult men.
To attain a target iron storage level of 300 mg for both sexes by age 20 to 25, an allowance of 10 mg/day is recommended for children. An additional 2 mg/day is recommended for males during the pubertal growth spurtwhich occurs between the ages of 10 and 17 and all additional 5 mg for females starting with the pubertal growth spurt and menstruationwhich begins at approximately age 10 or shortly thereafter and continues through the menstrual years.
The RDAs have been established to be adequate for essentially all healthy people who daily consume diets containing 30 to 90 g of meat, poultry, or fish, or foods containing 25 to 75 mg of ascorbate after preparation. People who eat little or no animal protein, such as those whose diets consist largely of beans and rice, and those whose diets are low in ascorbate due to prolonged heating or storage of food (Kies, 1982) may require higher amounts of food iron or a reliable source of ascorbic acid.
Excessive Intakes and Toxicity
In people without genetic defects that increase iron absorption, there are no reports of iron toxicity from foods other than long-term ingestion of home brews made in iron vessels (Walker and Arvidsson, 1953). Deleterious effects of daily intakes between 25 and 75 mg are unlikely in healthy persons (Finch and Monsen, 1972). On the other hand, there are approximately 2,000 cases of iron poisoning each year in the United States, mainly among young children who ingest the medicinal iron supplements formulated for adults. The lethal dose of ferrous sulfate for a 2-year-old child is approximately 3 g; for adults, it ranges from 200 to 250 mg/kg body weight (NRC, 1979).
Some people are genetically at risk from iron overload or hemochromatosis. Idiopathic hemochromatosis, which can result in the failure of multiple organ systems, is the result of an inborn error of metabolism (not yet elucidated), which leads to enhanced iron absorption. The disease is caused by an autosomal recessive gene. Reports suggest that the prevalence of this disease is higher than previously believed (Beaumont et al., 1979; Cartwright et al., 1979; Olsson et al., 1983). The studies by Cartwright et al. (1979) in Utah and Beaumont et al. (1979) in Brittany establish gene frequencies in the relatives of cases identified with the disease and so do not estimate general population prevalence. Olsson et al. (1983) studied a population of males ages 30 to 39 in central Sweden and reported an estimated gene frequency of 6.9%. This would result in a prevalence of heterozygotes in this population of 13.8%. The prevalence of the gene has not been reliably established in the United States. In NHANES II, five of the 3,540 people whose serum ferritin was assessed were diagnosed as having idiopathic hemochromlatosis, i.e., they were assumed to be homozygous for the gene. This implies a gene frequency of 3.8%, and prevalence of heterozygotes of 7.5% (LSRO, 1985). Further work is needed to determine the prevalence of this gene in the population and to establlish the risks of iron fortification of foods to both homozygotes and heterozygotes.
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Zinc, a constituent of enzymes involved in most major metabolic pathways, is an essential element for plants, animals, and humans
(Hambidge et al., 1986). Relatively large amounts of zinc are deposited in bone and muscle, but these stores are not in rapid equilibrium with the rest of the organism. The body pool of readily available zinc appears to be small and to have a rapid turnover rate, as shown by the prompt appearance of deficiency signs in laboratory animals. No single enzyme function has yet been identified that could explain the rapid onset of physiological and biochemical changes that follow the induction of zinc deficiency, but the requirement for zinc by many enzymes involved in gene expression (Chesters, 1982) could explain the immediate effect of deficiency on cell growth and repair.
Zinc status is subject to strong homeostatic regulation. Small amounts of zinc are more efficiently absorbed than large amounts, and persons in poor zinc status absorb more efficiently than those in good status. The amount of zinc excreted, predominantly through the intestine, is roughly proportional to dietary intake and to the zinc status of the person. Zinc balance was observed in subjects fed moderately low zinc levels (5.5 mg/day) (King and Turnilund, 1989). Obligatory losses in young men fed a low-zinc diet of 0.3 mg/day were reduced to 0.67 mg/day and resulted in only a small negative balance.
Because of such efficient regulation, a person's zinc requirement, whether determined by balance studies or by factorial calculations of endogenous losses, depends predominantly on that person's zinc status or body pool of mobilizable zinc. The requirement to maintain balance will be high if a high zinc status is to be maintained and low to maintain a low zinc status.
The composition of the diet has important effects on the bioavailability of dietary zinc. Interactions with other dietary components, such as protein, fiber, phytates, and some minerals, have been described. For example, absorption of zinc isotopes added to meals of different composition ranged from 2.4 to 38.2% of the dose supplied (Sandström and Cederblad, 1980; Sandström et al., 1980). The low values were associated with meals containing bran or whole-meal bread, and the higher values, with white bread, meats, milk, and soy products (see below).
General Signs of Deficiency
The signs and symptoms of dietary zinc deficiency in humans include loss of appetite, growth retardation, skin changes, and immunological abnormalities. Studies in laboratory and domestic animials have shown that zinc deficiency during pregnancy may lead to developmental disorders in the offspring (Hurley and Baly, 1982).
Pronounced zinc deficiency in men resulting in hypogonadism and dwarfism has been found in the Middle East (Prasad, 1982). Marginal states of zinc nutrition may exist in segments of the U.S. population, but data are fragmentary. In human patients with low plasma zinc levels, accelerated rates of wound healing have been observed as a result of increased zinc intake, suggesting that the zinc requirement of these subjects was not fully met by their diets (Pories et al., 1976). Marginal zinc deficiency was also described in a survey of apparently healthy children who exhibited low hair zinc levels, suboptimal growth, poor appetite, and impaired taste acuity (Hambidge et al., 1972). Increasing the daily zinc intake by 0.4 to 0.8 mg/kg brought about marked improvement. Supplementation of infant formulas to increase zinc levels from 1.8 to 5.8 mg/liter resulted in increased growth rates in male, but not in female, infants (Walravens and Hambidge, 1976).
Dietary Sources, Bioavailability, and Usual Intakes
Approximately 70% of the zinc consumed by most people in the United States is provided by animal products, especially meat (Welsh and Marston, 1982). Most of the zinc consumed in plant products comes from cereals. Drinking water in the United States generally contains less than 0.1 mg zinc/liter; its contribution to total intake is negligible.
The bioavailability of zinc in different foods varies widely (Inglett, 1983). Meat, liver, eggs, and seafoods (especially oysters) are good sources of available zinc, whereas whole grain products contain the element in a less available form. Of the various factors believed to affect zinc availability adversely, high concentrations of phytate and dietary fiber have great practical importance worldwide, but probably not in the United States, where the phytate content of the average diet is not high enough to impair the utilization of zinc (Erdman et al., 1987; Morris and Ellis, 1983).
For the U.S. population, the interaction of zinc with dietary protein, phosphorus, and iron may have greater practical importance. However, the data are not consistent. Sandstead (1985) observed that increasing dietary intake of phosphorus greatly increased zinc requirements of humans in balance studies. Others have observed that the ingestion of additional phosphorus, as polyphosphates but not generally as orthophosphates, tended to depress zinc absorption slightly (Greger, 1988).
Several investigators have observed that alterations in dietary protein levels and composition affected zinc utilization. Although Sand-
stead (1985) noted that zinc requirements were increased somewhat when protein intake was increased, others observed improved zinc utilization when protein levels were increased (Greger, 1988; Lönnerdal, 1987).
The simultaneous ingestion of equal amounts of ferrous iron and zinc (as sulfates) depressed zinc absorption in volunteers, but no such effects occurred with heme iron or when a food source of zinc was used (Solomons and Jacob, 1981). Thus, it is unlikely that the iron-zinc interaction has a major influence on zinc requirements under most dietary conditions (Solomons and Cousins, 1984).
The zinc content of typical mixed diets of North American adults has been reported to furnish between 10 and 15 mg/day. Pennington et al. (1984), in a survey of U.S. foods, found 13.2 mg of zinc in a 2,850 kcal diet. Infant and toddler diets containing 880 and 1,300 kcal contained 5.5 and 8.5 mg zinc, respectively. Elderly people generally have been found to consume 7 to 10 mg zinc daily (Greger, 1989).
Because of the lack of sensitive indicators of zinc status, the estimation of a zinc requirement for adults and the setting of a recommended allowance is beset with several uncertainties. As discussed above, strong homeostatic control of absorption and excretion can maintain persons in zinc balance with intakes lower than those furnished by typical U.S. diets. The long-term health effects of such intakes for adults are not known, but it has been postulated that marginal zinc status is responsible for delayed wound healing, disturbances of taste and smell acuity, and declining immune functions sometimes observed in older populations (Greger, 1989). Such conditions are usually treated with massive zinc supplements; therefore, these therapeutic trials provide no quantitative information on which to base the zinc requirement to maintain optimal health.
To estimate zinc requirements, the subcommittee assumed that the zinc status of healthy young adult men and women consuming mixed U.S. diets was adequate for all zinc-dependent functions. The zinc requirements to maintain that status can be determined either by balance studies or by determining endogenous zinc losses and translating the requirement for absorbed zinc into a dietary requirement, taking into account that zinc is incompletely absorbed to an extent that varies with the nature of the diet.
An evaluation of the most reliable balance studies indicates that at least 12 mg of zinc in a mixed U.S. diet is required to maintain the
existing zinc status of healthy young men (Sandstead, 1985). This is a conservative estimate, valid for diets of moderate phytate and fiber content, and it does not include dermal and seminal losses. Another long-term study in 28 men and women eating self-selected diets with approximately 10 mg of zinc per day resulted in an average negative balance of 1 to 2 mg/day (Patterson et al., 1984). Endogenous losses estimated by regression analysis in adequately nourished, healthy young men were 2.2 mg/day (Baer and King, 1984), including 0.8 mg through dermal losses. Seminal emissions contained an average of 0.6 mg of zinc per ejaculum. Thus, the daily loss can be estimated to be between 2.2 and 2.8 mg, similar to the average of 2.7 mg determined by turnover measurements of metastable zinc in men and women (Foster et al., 1979).
Taking into account the uncertainties in determining dermal and seminal zinc excretion, the subcommittee assumed an average requirement for absorbed zinc of 2.5 mg/day and an absorption efficiency of 20%. This assumption is arbitrary and includes a generous safety factor. Although zinc is absorbed with a higher efficiency from meat-containing meals, the factor of 20% was used to take into account the lower absorption of zinc from fiber-rich diets.
The resulting dietary requirement of 12.5 mg/day agrees with the 12.7 mg/day estimated from balance studies in men (Sandstead, 1985). To meet the needs of practically all healthy persons, including those who habitually consume diets with low zinc bioavailability, the recommended allowance for adult men is set at 15 mg/day. The allowance for adult women, because of their lower body weight, is set at 12 mg/day.
Pregnancy and Lactation
Sandstead (1973) estimated the additional average need for absorbed zinc due to the products of conception as less than 0.1, approximately 0.4, and 0.75 mg/day during the first 10, the second 10, and the last 20 weeks of gestation, respectively, as compared to more recent estimates of 0.1, 0.2, and 0.6 mg/day (Swanson and King, 1987). Hambidge et al. (1986) pointed out that the actual zinc concentrations in the fetus may be higher than those on which the above calculations were based. Thus, in the absence of evidence for increased absorption efficiency in pregnant women (Swanson et al., 1983), a dietary zinc intake of 15 mg/day is recommended during pregnancy.
The increased zinc requirement of lactating women can be calculated from the amount of zinc lost each day in the different phases of lactation. The mean zinc content of human milk in the United States is approximately 1.5 and 1.0 mg/liter during the first and
second half year, respectively (Krebs et al., 1985; Moser and Reynolds, 1983), the highest concentrations occurring during the first month of lactation. Average milk productions of 750 ml/day and 600 ml/day during the first and second 6 month periods, respectively, uses an extra 1.2 and 0.6 mg of absorbed zinc. Assuming an absorption efficiency of 20% and a coefficient of variation of 12.5% in milk production, the subcommittee recommends extra dietary intakes of 7 and 4 mg/day for the first and second 6 months of lactation.
Infants and Children
Full-term infants consuming only human milk do not show any signs of zinc depletion (Hambidge et al., 1979). Therefore, their zinc requirement must be satisfied by the zinc in their mother's milk plus liver stores. During the first month of life, breastfed infants consume an average of 2 mg of zinc per day (Casey et al., 1985). Beyond the age of 6 months, infants would receive from 600 ml of breast milk only 0.6 mg of zinc per dayan amount that is usually augmented by the zinc in solid foods. The dietary zinc requirement of infants consuming formula is higher than that of breastfed infants because of lower zinc availability of the formulae (Casey et al., 1981; Lönnerdal et al., 1984). Walravens and Hambidge (1976) demonstrated that male infants consuming formula supplemented with zinc to a total of 5.8 mg/liter grew better than those on an unsupplemented formula containing 1.8 mg/liter. Assuming a consumption of 750 ml/day, plus two standard deviations, the subcommittee recommends 5 mg/day of zinc as the intake for formulafed infants.
Although earlier balance studies suggested a zinc requirement of 6 to 7 mg/day for preadolescent children (Engel et al., 1966), Walravens et al. (1983) found low hair and plasma zinc levels suggestive of marginal deficiency in Spanish-American children 2 to 6 years old whose intake was 5 to 6 mg/day. Their height-for-age was below the tenth percentile, and their rate of linear growth improved as a result of supplementation to a total zinc intake of approximately 10 mg/ day. That intake is recommended for preadolescent children.
Excessive Intakes and Toxicity
Acute toxicity, resulting in gastrointestinal irritation and vomiting, has been observed following the ingestion of 2 g or more of zinc in the form of sulfate (Prasad, 1976). The more subtle effects of moderately elevated intakes, not uncommon in the U.S. population, are of greater concern, because they are not easily detected. Impairment of the copper status of volunteers by dietary zinc intakes of 18.5 mg
(Festa et al., 1985) or 25 mg/day (Fischer et al., 1984) has been reported. Patients given zinc in quantities 10 to 30 times the RDA for several months developed hypocupremia, microcytosis, and neutropenia (Prasad et al., 1978). Zinc supplementation of healthy adults with amounts 20 times the RDA for 6 weeks resulted in the impairment of various immune responses (Chandra, 1984). Daily supplements of 80 to 150 mg caused a decline of high-density lipoproteins in serum after several weeks (Hooper et al., 1980). For these reasons, chronic ingestion of zinc supplements exceeding 15 mg/day is not recommended without adequate medical supervision.
Baer, M.T., and J.C. King. 1984. Tissue zinc levels and zinc excretion during experimental zinc depletion in young men. Am. J. Clin. Nutr. 39:556-570.
Casey, C.E., P.A. Walravens, and K.M. Hambridge. 1981. Availalility of zinc: loading tests with human milk, cow's milk, and infant formulas. Pediatrics 68:394-396.
Casey, C.E., K.M. Hambidge, and M.C. Neville. 1985. Studies in human lactation: zinc, copper, manganese, and chromium in human milk in the first month of lactation. Am. J. Clin. Nutr. 41:1193-1200.
Chandia. R. K. 1984. Excessive intake of zinc impairs immune responses. J. Am. Med. Assoc. 252:1443-1446.
Chesters, J.K. 1982. Metabolism and biochemistry- of zinc. Pp. 221-238 in A.S. Prasad, ed. Clinical, Biochemical, and Nutritional Aspects of Trace Elements. Current Topics in Nutrition and Disease, Vol. 6. Alan R. Liss, New York.
Engel, R.W., R.F. Miller, and N.O. Price. 1966. Metabolic patterns in preadolescent children. XIII. Zinc balance. Pp. 326-338 in A.S. Prasad, ed. Zinc Metabolism. Charles C. Thomas, Springfield, Ill.
Erdman, J.W., Jr., S. Garcia-Lopez, and A.R. Sherman. 1987. Processing and fortification: How do they affect mineral interactions? Pp. 23-26 in O.A. Levander, ed. Nutrition 1987. American Institute of Nutrition, Bethesda, Md.
Festa, M.D., H.L,. Anderson, R.P. Dowdy, and M.R. Ellersieck. 1985. Effect of zinc intake on copper excretion and retention in men. Am. J. Clin. Nutr. 41:285292.
Fischer, P.W.F., A. Giroux, and M.R. L'Abbé. 1984. Effect of zinc supplementation on copper status in adult man. Am. J. Clin. Nutr. 40:743-746.
Foster, D.M., R.L. Aamodt, R.I. Henkin, and M. Berman. 1979. Zinc metabolism in humans: a kinetic model Am. J. Physiol. 237:R340-R349.
Greger, J.L. 1988. Effect of variations in dietary protein, phosphorus, electrolytes and vitamin D on calcium and zinc utilization. Pp. 205-227 in C.E. Bodwell and J.W. Erdman, Jr., eds. Nutrient Interactions. Marcel Dekker, New York.
Greger,J.L,. 1989. Potential for trace mineral deficiencies and toxicities in the elderly. Pp. 171-200 in C.W. Bales, ed. Mineral Homeostasis in the Elderly. Current Topics in Nutrition and Disease, Vol. 21. Alan R. Liss, New York.
Hambidge, K.M., C. Hambidge, M. Jacobs, and J.D. Baum. 1972. Low levels of zinc in hair, anorexia, poor growth, and hypogensia in children. Pediatr. Res. 6:868874.
Hambidge, K.M., P.A. Walravens, C.E. Casey, R.M. Brown, and C. Bender. 1979. Plasma zinc concentrations of breast-fed infants. J. Pediatr. 94:607-608.
Hambidge, K.M., C.E. Casey. and N.F. Krebs. 1986. Zinc. Pp. 1-137 in W. Mertz, ed. Trace Elements in Human and Animal Nutrition, Vol. 2. 5th ed. Academic Press, Orlando, Fla.
Hooper, P.L., L. Visconti, P.J. Garry, and G.E. Johnson. 1980. Zinc lowers highdensity lipoprotein-chlolesterol levels. J. Am. Med. Assoc. 244:1960-1961.
Hurley, L.S., and D.L. Baly. 1982. The effects of zinc deficiency during pregnancy. Pp. 145-159 in A.S. Prasad, ed. Clinical, Biochemical, and Nutritional Aspects of Trace Elements. Current Topics in Nutrition and Disease, Vol. 6. Alan R. Liss, New York.
Inglett, G.E., ed. 1983. Nutritional Bioavailability of Zinc. ACS Symposium Series No. 210. American Chemical Society, Washington, D.C.
King, J.C., and J.R. Turnlund. In press. Human zinc requirements. C.F. Mills, ed. Zinc in Human Biology. International Life Sciences Institute. London.
Krebs, N.F., K.M. Hambidge, M.A. Jacobs, and J.O. Rasbach. 1985. The effects of a dietary zinc supplement during lactation on longitudinal changes in maternal zinc status and milk zinc concentrations. Am. J. Clin. Nutr. 41:560-570.
Lönnerdal, B. 1987. Protein-mineral interactions. Pp. 32-36 in O.A. Levander, ed. Nutrition 1987. American Institute of Nutrition, Bethesda, Md.
Lönnerdal, B., A. Cederblad, L. Davidsson, and B. Sandström. 1984. The effect of individual components of soy formula and cows' milk formula on zinc bioavailability. Am. J. Clin. Nutr. 40:1064-1070.
Morris, E.R., and R. Ellis. 1983. Dietary phytate/zinc molar ratio and zinc balance in humans. Pp. 159-172 in G.E. Inglett, ed. Nutritional Bioavailability of Zinc. ACS Symposium Series No. 210. American Chemical Society, Washington, D.C.
Moser, P.B., and R.D. Reynolds. 1983. Dietary zinc intake and zinc concentrations of plasma erythrocytes, and breast milk in antepartum and postpartum lactating and nonlactating women: a longitudinal study. Am. J. Clin. Nutr. 38:101-108.
Patterson, K.Y., J.T. lolbrook, J.E. Bodner, J.L. Kelsay, J.C. Smith, Jr., and C. Veillon. 1984. Zinc, copper, and manganese intake and balance for adults consuming self-selected diets. Am. J. Clin. Nutr. 40:1397-1403.
Pennington, J.A., D.B. Wilson, R.F. Newell, B. F. Harland, R.D. Johnson, and J.E. Vanderveen. 1984. Selected minerals in foods surveys, 1974 to 1981/82. J. Am. Diet. Assoc. 84:771-780.
Pories, W.J., E.G. Mansour, F.R. Plecha, A. Flynn, and W.H. Strain. 1976. Metabolic factors affecting zinc metabolism in the surgical patient. Pp. 115-141 in A.S. Prasad, ed. Trace Elements in Health and Disease. Vol. 1, Zinc and Copper. Academic Press, New York.
Prasad, A.S. 1976. Deficiency of zinc in man and its toxicity. Pp. 1-20 in A.S. Prasad, ed. Trace Elements in Health and Disease. Vol. I, Zinc and Copper. Academic Press, New York.
Prasad, A.S. 1982. Clinical and biochemical spectrum of zinc deficiency in human subjects. Pp. 3-62 in A.S. Prasad, ed. Clinical, Biochemical, and Nutritional Aspects of Trace Elements. Current Topics in Nutrition and Disease, Vol. 6. Alan R. Liss, New York.
Prasad, A.S., G.J. Brewer, F.B. Schoolmaker, and P. Rabbani. 1978. Hypocupremia induced by zinc therapy in adults. J. Am. Med. Assoc. 240:2166-2168.
Sandstaed, H.H. 1973. Zinc nutrition in the United States. Am. J. Clin. Nutr. 26:12511260.
Sandstead, H.H. 1985. Are estimates of trace element requirements meeting the needs of the user? Pp. 875-878 in C.F. Mills, I. Bremner, and J.K. Chesters, eds. Trace Elements in Man and Animals, TEMA-5. Commonwealth Agricultural Bureaux, Farnham Royal, United Kingdom.
Sandström, B., and Å. Cederblad. 1980. Zinc absorption from composite meals. II. Influence of the main protein source. Am. J. Clin. Nutr. 33:1778-1783.
Sandström, B., B. Arvidsson, Å. Cederblad, and E. Björn-Rasmussen. 1980. Zinc absorption from composite meals. 1. The significance of wheat extraction rate, zinc, calcium, and protein content in meals based on bread. Am. J. Clin. Nutr. 33:739-745.
Solomons, N.W., and R. J. Cousins. 1984. Zinc. Pp. 125-197 in N.W. Solomons and I.H. Rosenberg, eds. Absorption and Malabsorption of Mineral Nutrients. Alan R. Liss, New York.
Solomons, N.W., and R.A. Jacob. 1981. Studies on the bioavailability of zinc in humans: effects of heme and non-heme iron on the absorption of zinc. Am. J. Clin. Nutr. 34:475-482.
Swanson, C.A., and J.C. King. 1987. Zinc and pregnancy outcome. Am.J. Clin. Nutr. 46:763-771.
Swanson, C.A., J.R. Turnlund, and J.C. King. 1983. Effect of dietary zinc sources and pregnancy on zinc utilization in adult women fed controlled diets. J. Nutr. 113:2557-2567.
Walravens, P.A., and K.M. Hambidge. 1976. Growth of infants fed a zinc supplemented formula. Am. J. Clin. Nutr. 29:1114-1121.
Walravens, P.A., N.F. Krebs, and K.M. Hambidge. 1983. Linear growth of low income preschool children receiving a zinc supplement. Am. J. Clin. Nutr. 38:195-201.
Welsh, S.O., and R.M. Marston. 1982. Zinc levels of the U.S. food supply: 19091980. Food Technol. 36:70-76.
Iodine, an integral part of the thyroid hormones thyroxine and triiodothyronine, is an essential micronutrient for all animal species, including humans (Hetzel and Maberly, 1986). It is present in food and water predominantly as iodide and, to a lesser degree, organically bound to amino acids. Iodide is rapidly and almost completely absorbed and transported to the thyroid gland for synthesis into the thyroid hormones, to salivary and gastric glands, and to the kidneys for excretion into the gastrointestinal tract and urine. Organically bound iodine is less well absorbed, and part of it is excreted in the feces. Since all the iodide secreted into the gastrointestinal tract is reabsorbed, the main excretory route for the inorganic form of iodine is the urine. Although losses in the milk of lactating women and losses in sweat in hot climates can be considerable, urinary excretion is a reliable indicator of iodine status under most circumstances.
Iodine is unevenly distributed in the environment. In large areas, often mountainous, environmental levels are inadequate for humans and animals. Deficiency can lead to a wide spectrum of diseases, ranging from severe cretinism with mental retardation to barely visible enlargement of the thyroid. Endemic goiter and the more severe forms of iodine deficiency disorders continue to be a worldwide problem. In 1983 there were an estimated 400 million iodine-deficient
persons in the less developed regions of the world (Hetzel and Maberly, 1986), an estimated 1 12 million in the more developed areas (Matovinovic, 1983).
Iodine deficiency disorders, including goiter, can be prevented but not cured by providing an adequate iodine intake. The incidence of endemic goiter in the United States fell sharply after the introduction of iodized salt in 1924 (Brush and Atland, 1952). There are, however, residual cases of goiter remaining, mainly in women and children living in certain areas of the United States (California, Texas, Kentucky, Louisiana, and South Carolina) (Matovinovic, 1970; McGanity, 1970) and in the prairie regions of Canada (Nutrition Canada National Survey, 1973). These are most probably not caused by iodine deficiency, since they bear no relation to urinary iodine excretion, which is accepted as a reliable indicator of iodine status. Natural goitrogens, such as those found in cabbage or cassava, have been implicated in the pathogenesis of goiter in some parts of the world. It is not known if they pose a problem in the United States (Matovinovic, 1983).
Dietary Sources and Usual Intakes
The environmental levels of iodine and their contribution to the daily intake of animals and humans vary widely in the United States. In the coastal areas, seafoods, water, and iodine-containing mist from the ocean are important sources, whereas further inland, the iodine content of plant and animal products is variable, depending on the geochemical environment and on fertilizing, feeding practices, and food processing. In these areas, iodized table salt is a reliable source, providing 76 µg of iodine per gram of salt.
In addition, several adventitious sources of iodine find their way into the U.S. diet. Iodates are still used as dough oxidizers in the continuous bread making process, adding about 500 µg/100 g of bread. Dairy products accumulate iodine because of the use of iodinecontaining disinfectants on cows, milking machines, and storage tanks, and by iodine-containing additives to the animals' feeds. All this can raise iodine concentrations severalfold over natural levels (Hemken, 1979).
The U.S. Food and Drug Administration in its Total Diet Study has found a tendency toward steadily declining iodine levels since 1982. In 1985-1986, the typical intake for men and women was 250 µg and 170 µg/day, respectively, excluding intakes from iodized salt (Pennington et al., 1989).
Because of the high contribution by adventitious sources to the daily iodine intake in the United States, maintenance of the existing nutritional status is not a valid criterion for determining iodine requirements. It is customary to relate urinary iodine excretion, a reliable indicator of iodine intake and status, to the risk for goiter and other iodine deficiency disorders. An expert group of the Pan American Health Organization considered an excretion of more than 50 µg of iodine per gram of creatinine as adequate for normal function, excretion of 25 to 50 µg/g as associated with increased risk for hypothyroidism, and excretion of less than 25 µg/g as indicative of serious risk for endemic cretinism (Querido et al., 1974). Since dietary iodine is well absorbed, albeit not completely, a minimum intake of 50 to 75 µg/day is needed to maintain the higher level of iodine excretion in a population (NRC, 1970).
Although the levels of goitrogens in the U.S. diet and their effects on the iodine requirement have not been quantified, the recommended allowance for adults of both sexes is set at 150 µg/day to provide an extra margin of safety. This amount is close to the 160 µg calculated to maintain plasma inorganic iodide levels within the normal range in most of the U.S. population (Wayne et al., 1964).
Pregnancy and Lactation
An increment of 25 µg/day in the dietary allowance is recommended during pregnancy to cover the extra demands of the fetus. The additional allowance for lactating women, 50 µg/day, is based on the estimated need of the infant, not on the iodine loss via breast milk (Fomon, 1984; Man and Benotti, 1964).
Infants and Children
The amounts of iodine in the milk of North American women are much greater than the needs of their infants. They reflect the elevated dietary iodine intakes of the mothers (Gushurst et al., 1984). In the absence of a better basis, the relative energy requirements of adults has been used to set the iodine allowance for infants and children.
Excessive Intakes and Toxicity
The acute toxicity of iodides and iodates has been thoroughly studied (LSRO, 1975). Amounts between 200 and 500 mg/kg per day produced death in different species of laboratory animals.
The potential chronic toxic effects of dietary iodine are less clear. In an attempt to reduce the high incidence of goiter in Tasmania,
bread was fortified with iodine to yield a concentration of 2 to 4 µg/ g (dry) bread. Once the iodinated bread was available to the islanders, the incidence of thyrotoxicosis more than doubled. Most patients were in the older age groups and had been exposed to decades of iodine deficiency (Connolly, 1973). Goiter induced by high iodine intake has also been documented in Japan, where seaweeds rich in iodine (up to 4.5 mg/g dry weight) are consumed (Nagataki, 1974).
Generally, iodine intakes of up to 2 mg/day have caused no adverse physiological reactions in healthy adults, and 1 mg/day produced no indications of physiological abnormalities in children (Crocco and White, 1981). There is no evidence of adverse reactions, such as chronic toxicity or hypersensitivity, to the much lower iodine intakes in the United States, and the present iodine intake by the majority of the U.S. population is considered to be adequate and safe (LSRO, 1975).
The public health value of iodized salt in the prevention of iodine deficiency disorders is well established. The use of iodized salt in all noncoastal regions where environmental and dietary levels are low is recommended.
The present iodine intake in the United States is safe and decreasing toward recommended levels. The subcommittee notes that the use of iodine-containing compounds has declined and recommends that no additional sources of iodine be introduced into the U.S. diet.
Brush, B.E., and J.K. Altland. 1952. Goiter prevention with iodized salt: results of a thirty-year study. J. Clin. Endocrin. Metab. 12:1380-1388.
Connally, R.J. 1973. The changing age incidence of iodbasedow in Tasmania. Med. J. Austr. 2:171-174.
Crocco, S.C., and P.L.. White. 1981. Iodine: Fifty Years After Goiter. Proceedings of the Stokely-Van Camp Annual Symposium, Food in Contemporary Society: Emerging Patterns, May 27-29, 1981. University of Tennessee, Knoxville. 16 pp.
Fomon, S.J. 1974. Infant Nutrition, 2nd ed. Saunders, Philadelphia. 575 pp.
Gushurst, C.A., J.A. Mueller, J.A. Green, and F. Sedor. 1984. Breast milk iodide: reassessment in the 1980s. Pediatrics 73:354-357.
Hemken, R.W. 1979. Factors that influence the iodine content of milk and meat: a review. J. Anim. Sci. 48:981-985.
Hetzel, B.S., and G.F. Maberly. 1986. Iodine. Pp. 139-208 in W. Mertz, ed. Trace Elements in Human and Animal Nutrition, 5th ed. Academic Press, New York.
LSRO (Life Sciences Research Office). 1975. Evaluation of the Health Aspects of Potassium Iodide, Potassium Iodate, and Calcium Iodate as Food Ingredients. Federation of American Societies for Experimental Biology, Bethesda, Md.
Man, E.B., and J. Benotti. 1969. Butanol-extractable iodine in human and bovine colostrum and milk. Clin. Chem. 15:1141-1146.
Matovinovic, J. 1970. Extent of iodine insufficiency in the United States. Pp. 1-5 in Iodine Nutriture in the United States. Report of the Committee on Food Protection, Food and Nutrition Board, National Academy of Sciences, Washington, D.C.
Matovinovic, J. 1983. Endemic goiter and cretinism at the dawn of the third millennium. Annu. Rev. Nutr. 3:341-412.
McGanity, W. 1970. Extent of iodine insufficiency in the United States. Pp. 5-8 in Iodine Nutriture in the United States. Food and Nutrition Board, National Research Council. National Academy of Sciences, Washington, D.C.
Nagataki, S. 1974. Effect of excess quantities of iodide. Pp. 329-344 in Handbook of Physiology, III, Endocrinology. American Physiological Society, Washington, D.C.
NRC (National Research Council). 1970. Iodine Nutriture in the United States. Summary of a Conference, October 31, 1970. Report of the Committee on Food Protection, Food and Nutrition Board, National Academy of Sciences. Washington, D.C. 53 pp.
Nutrition Canada National Survey. 1973. Nutrition Problems in Perspective. Information Canada, Ottawa. 115 pp.
Pennington, J.A.T., B.E. Young, and D.B. Wilson. 1989. Nutritional elements in U.S. diets: results from the Total Diet Study, 1982 to 1986.J. Am. Diet. Assoc. 89:659664.
Querido, A., F. Delange,J.T. Dunn, R. Fierro-Benitez, H.K. Ibbertson, D.A. Koutras, and H. Perinetti. 1974. Definitions of endemic goiter and cretinism, classification of goiter size and severity of endemias, and survey techniques. Pp. 267-272 in J.T. Dunn and G.A. Medeiros-Neto, eds. Endemic Goiter and Cretinism: Continuing Threats to World Health. Scientific Publ. No. 292. Pan American Health Organization, Washington, D.C.
Wayne, E.J., D.A. Koutras, and W.D. Alexander. 1964. Clinical Aspects of Iodine Metabolism. Blackwell, Oxford. 303 pp.
The biochemical basis for the essentiality of selenium is its presence at the active site of glutathione peroxidase, an enzyme that catalyzes the breakdown of hydroperoxides (Hoekstra, 1975). Although the role of selenium in hydroperoxide destruction helps explain its close metabolic interrelationship with the antioxidant vitamin E, evidence for other possible functions is accumulating (Burk, 1983).
Direct evidence of a requirement for selenium in human nutrition was lacking until 1979, when Chinese scientists reported an association between low selenium status and Keshan disease, a cardiomyopathy that affects primarily young children and women of childbearing age (Keshan Disease Research Group, 1979a). A large-scale intervention trial involving several thousand Chinese children demonstrated the value of selenium in preventing the disease (Keshan Disease Research Group, 1979b). Selenium deficiency cannot account
for all aspects of Keshan disease, and the possible involvement of a cardiotoxic virus has been suggested (Yang et al., 1988), but it seems clear that selenium deficiency is the underlying condition predisposing people to the development of the disease.
General Signs of Deficiency
In animals, many diseases are caused by simultaneous deficiencies of selenium and vitamin E, and they can be prevented or cured by supplementation with either nutrient alone (NRC, 1983). Pure selenium deficiency in the presence of adequate levels of vitamin E has been demonstrated conclusively only in rats fed a selenium-deficient diet for two generations (McCoy and Weswig, 1969). Signs of selenium deficiency observed in squirrel monkeys (Muth et al., 1971) have not been seen in more recent studies of rhesus monkeys (Butler et al., 1988). Nutritional pancreatic atrophy in chicks, long believed to be a selenium-specific deficiency syndrome, has now been shown to respond to high dietary levels of vitamin E and certain other antioxidants (Whitacre et al., 1987).
Intravenous feeding solutions used in total parenteral nutrition (TPN) are practically devoid of selenium, and patients undergoing TPN have low erythrocyte glutathione peroxidase activities and low levels of selenium in plasma and red cells (Levander and Burk, 1986). In three such patients, muscular discomfort or weakness responded to selenium therapy (Brown et al., 1986; Kien and Ganther, 1983; van Rij et al., 1979), thereby providing additional evidence of a selenium requirement for humans. Some cases of cardiomyopathy have also occurred in TPN patients with low selenium status (Fleming et al., 1982; Johnson et al., 1981).
Dietary Sources and Usual Intakes
Seafoods, kidney, and liver, and to a lesser extent other meats, are consistently good sources of selenium, whereas grains and other seeds are more variable, depending on the selenium content of the soils in which they are grown (WHO, 1987). Fruits and vegetables generally contain little selenium. Drinking water usually makes only a small contribution to selenium intake (WHO, 1987).
Studies in animals have shown that the bioavailability of selenium in certain fish is less than that in other foods (Mutanen, 1986). Few data exist on the bioavailability of selenium in foods consumed by humans. However, bioavailability trials conducted in subjects with poor selenium status indicated that organically bound forms of se-
lenium are retained better than inorganic selenium, but all forms tested caused similar increases in glutathione peroxidase activity (Levander et al., 1983; Thomson et al., 1982).
Analyses of national food composites in the United States indicate that the overall adult mean dietary selenium intake was 108 µg/day between 1974 and 1982. The daily means for each year ranged from 83 to 129 µg (Pennington et al., 1984).
Assessment of Selenium Status
Selenium status in humans is commonly assessed by estimating dietary selenium intakes, measuring selenium levels in various tissues and excreta, or determining glutathione peroxidase activity in certain blood components (for a review, see Levander, 1985). Dietary selenium intakes are difficult to estimate because of the variation in the selenium content of locally produced and consumed foods, which is determined by the selenium content of the soil in which the food is grown. Selenium levels in erythrocytes are an index of longer term selenium status than levels in plasma, and animal studies indicate that the latter may not always reflect other body selenium pools, especially when sudden shifts in selenium intake occur. It is easier to measure glutathione peroxidase activity than to perform the chemical analysis for selenium. Moreover, the enzymatic method has the advantage of measuring only biologically active selenium. However, glutathione peroxidase activity is a valid index of human selenium status only in populations with low selenium intakes, since the activity of the enzyme plateaus at higher intakes (Whanger et al., 1988).
Several balance studies have been conducted to investigate selenium requirements of humans. However, humans apparently can adjust their selenium homeostatic mechanisms to remain in balance over rather wide ranges of dietary intakes. Therefore, the balance technique is of little help in delineating the selenium requirements of humans (Levander, 1987).
Another approach to estimating human selenium requirements is to examine dietary intakes in areas with and without selenium deficiency. In China, for example, dietary surveys of selenium intake in endemic and nearby nonendemic Keshan disease areas indicated that the minimum daily selenium requirements for adult Chinese men and women are 19 and 13 µg, respectively (Yang et al., 1988). In New Zealand, however, daily selenium intakes of 33 g by men and
23 µg by women were not associated with any selenium deficiency symptoms (Thomson and Robinson, 1980).
A so-called physiological human selenium requirement was estimated by following increases in plasma glutathione peroxidase activity in adult Chinese men with low selenium status (i.e., a daily dietary intake of approximately 10 µg), who were supplemented with graded doses of selenomethionine (Yang et al., 1987). After 5 months, the plasma glutathione peroxidase activity plateaued at similar levels for groups receiving 30 µg or more of supplemental selenium per day. On this basis, the authors suggested a physiological selenium requirement of' approximately 40 µg/day (diet plus supplement) for their adult Chinese male subjects. Since the Chinese men in this study weighed approximately 60 kg and the selenium requirement of adults appears to be related to body weight, the estimated requirements for the reference North American adult male and female must be adjusted for differences in body weight, i.e., 79 kg for males and 63 kg for females. Individual variation in selenium requirements was accounted for by using a safety factor of 1.3, which was based on an arbitrarily assumed coefficient of variation of 15%. Multiplying the Chinese estimate of the physiological human selenium requirement by these two factors (adjustments for body weight and individual variation) results in a recommended dietary selenium allowance of 0.87 µg/kg or, with rounding, 70 and 55 µg/day for the reference adult North American male and female, respectively. In the absence of specific data on requirements of the elderly, the figures for younger adults are used.
Pregnancy and Lactation
A metabolic balance study demonstrated that the amounts of selenium retained during the second and fourth quarters of pregnancy were 10 and 23 µg/day, respectively (Swanson et al., 1983). However, these retention values were believed to be high because the levels of dietary selenium fed during that study (150 µg/day) were elevated, compared to the usual intake of the subjects, and resulted in positive selenium balances, even in the nonpregnant subjects. If a factorial technique is used to estimate the human selenium requirement for pregnancy, and it is assumed that 5 kg of lean tissue containing an average selenium concentration of 0.25 mg/kg (Schroeder et al., 1970) is deposited during pregnancy, a total of 1.25 mg of selenium would have to be retained. Thus, an average selenium accretion of 5 µg/day, or 6.5 µg/day allowing for variability, would be needed. If an absorption rate of 80% is assumed (Levander, 1983), the average increase in dietary selenium during pregnancy would be 10 µg/day.
Milk from North American women contains an average selenium concentration of 15 to 20 µg/liter (Mannon and Picciano, 1987). During lactation, a daily selenium loss of 13 µg may occur in a secretion of 750 ml of milk. If a population variance is allowed and a dietary absorption of 80% is assumed, an additional selenium allowance of 20 µg/day is recommended for lactation to maintain a satisfactory level of the mineral in milk and to prevent depletion in the mother.
Infants and Children
The maintenance selenium requirements for infants, extrapolated from adult values, would be 5 µg/day from birth to 6 months of age. To allow for growth, this figure was increased to 10 µg/day. The North American breastfed infant would receive ample selenium, since consumption of 750 ml of breast milk per day would result in an intake of about 13 µg of selenium per day. The allowance during the second 6 months, calculated similarly, is 15 µg/day. Moreover, these recommendations provide a substantial margin of safety, since infants in Finland and New Zealand suffer no observable ill effects of low selenium intake even though the average selenium content of human milk in those countries ranges from only 6 to 8 µg/liter (Kumpulainen et al., 1983; Williams, 1983), in contrast to 15 to 20 µg/liter in the United States.
Because little is known about the selenium requirements of children, recommendations for them have been extrapolated from adult values on the basis of body weight, and a factor arbitrarily allowed for growth.
Excessive Intakes and Toxicity
The level of dietary selenium exposure needed to cause chronic poisoning in humans is not known with certainty, but approximately 5 mg/day from foods resulted in fingernail changes and hair loss in a seleniferous zone of China (Yang et al., 1983). The Chinese investigators also reported that a person who had consumed 1 mg of selenium daily as sodium selenite for more than 2 years had thickened but fragile nails and a garlic odor in dermal excretions. In the United States, 13 people developed selenium intoxication after taking an improperly manufactured dietary supplement that contained 27.3 mg of selenium per tablet. Symptoms included nausea, abdominal pain, diarrhea, nail and hair changes, peripheral neuropathy, fatigue, and irritability (Helzlsouer et al., 1985). The woman who consumed the most selenium (2,387 mg over a 2.5-month period) experienced hair loss, fingernail tenderness and loss, nausea and vomiting, a sourmilk breath odor, and increasing fatigue (Jensen et al., 1984). The
molecular mechanism of selenium toxicity has not been clearly established (Levander, 1982), and sensitive biochemical indicators of selenium poisoning are not known.
Brown, M.R., H.J. Cohen, J..M. Lyons, T.W. Curtis, B. Thunberg, W.J. Cochran, and W.J. Klish. 1986. Proximal muscle weakness and selenium deficiency associated with long term parenteral nutrition. Am. J. Clin. Nutr. 43:549-554.
Burk, R.F. 1983. Biological activity of selenium. Annu. Rev. Nutr. 3:53-70.
Butler, J.A., P.D. Whanger, and N. M. Patton. 1988. Effect of feeding seleniumdeficient diets to rhesus monkeys (Macaca mulatta). J. Am. Coll. Nutr. 7:43-56.
Fleming, C.R.,.J.T. Lie, J.T. McCall, J.F. O'Brien, E.E. Baillie, and J.L. Thistle. 1982. Selenium deficieny and fatal cardiomyopalthy in a patient on home parenteral nutrition. Gastroenterology 83:689-693.
Helzlsouer. K. R. Jacobs, and S. Morris. 1985. Acute selenium intoxication in the United States. Fed. Proc. 44: 1670.
Hoekstra. W.G. 1975. Biochemical function of selenium and its relation to vitamin E. Fed. Proc. 34:2083-2089.
Jensen, R., W. Closson, and R. Rothenberg. 1984. Selenium intoxicationNew York. Morb. Mortal. Week. Rep. 33:157-158.
Johnson, R.A., S.S. Baker. J.T. Fallon, E.P. Maynard, J.N. Ruskin, Z. Wen, K. Ge, and H.J. Cohen. 1981. An accidental case of cardiomyopathy and selenium deficiency. N. Engl. J. Med. 304:1210-1212.
Keshan Disease Research Group. 1979a. Epidemiologic studies on the etiologic relationship of selenium and Keshan disease. Chin. Med. J. 92:477-482.
Keshan Disease Research Group. 19791b. Observations on effect of sodium selenite in prevention of Keshan disease. Chin. Med. J. 92:471-476.
Kien, C.L., and H.F. Ganther. 1983. Manifestations of chronic selenium deficiency in a child receiving total parenteral nutrition. Am. J. Clin. Nutr. 37:319-328.
Kumpulainen, J. F. Vuori, P. Kuilunen, S. Mäkinen, and R. Kara. 1983. Longitudinal study on the dietary selenium intake of exclusively breast-fed infants and their mothers in Finland. Int. J. Vit. Nutr. Res. 53:420-426.
Levander, O. A. 1982. Selenium: biochemical actions, interactions and some human health implications. Pp. 345-368 in A.S. Prasad, ed. Clinical, Biochemical, and Nutrititional Aspects of Trace Elements. Current Topics in Nutrition and Disease, Vol. 6. Alan R. Liss, New York.
Levander, O.A. 1983. Considerations in the design of selenium bioavailability studies. Fed. Proc. 42:1721-1725.
Levander, O.A. 1985. Considerations on the assessment of selenium status. Fed. Proc. 44:2579-2583.
Levander, O.A. 1987. A global view of selenium nutrition. Annu. Rev. Nutr. 7:227250.
Levander, O.A., and R. F. Burk. 1986. Report on the 1986 A.S.P.E.N. Research Workshop on Selenium in clinical Nutrition. Parenter. Enteral. Nutr. 10:545549.
Levander, O.A., G. Alfthan, H. Arvilommi, C. G. Gref, J.K. Huttunen, M. Kataja, P. Koivistoinen, and J. Pikkarainen. 1983. Bioavailability of selenium to Finnish
men as assessed by platelet glutathione peroxidase activity and other blood parameters. Am. J. Clin. Nutr. 37:887-897.
Mannan, S., and M.F. Picciano. 1987. Influence of maternal selenium status on human milk selenium concentration and glutathione peroxidase activity. Am. J. Clin. Nutr. 46:95-100.
McCoy, K.E.M., and P.H. Weswig. 1969. Some selenium responses in the rat not related to vitamin E. J. Nutr. 98:383-389.
Mutanen, M. 1986. Bioavailability of selenium. Ann. Clin. Res. 18:48-54.
Muth, O.H., P.H. Weswig, P.D. Whanger, and J.E. Oldfield. 1971. Effect of feeding selenium-deficient ration to the subhuman primate (Saimiri sciureus). Am. J. Vet. Res. 32:1603-1605.
Vanderveen. 1984. Selected m NRC (National Research Council). 1983. Selenium in Nutrition, rev. ed. Report of the Subcommittee on Selenium, Committee on Animal Nutrition, Board on Agriculture. National Academy Press, Washington, D.C. 174 pp.
Pennington, J.A.T., D.B. Wilson, R.F. Newell, B.F. Harland, R.D. Johnson, and J.E. inerals in foods surveys, 1974 to 1981/82. J. Am. Diet. Assoc. 84:771-780.
Schroeder, H.A., D.V. Frost, and J.J. Balassa. 1970. Essential trace metals in man: selenium. J. Chronic Dis. 23:227-243.
Swanson, C.A., D.C. Reamer, C. Veillon, J.C. King, and O.A. Levander. 1983. Quantitative and qualitative aspects of selenium utilization in pregnant and nonpregnant women: an application of stable isotope methodology. Am. J. Clin. Nutr. 38:169- 180.
Thomson, C.D., and M.F. Robinson. 1980. Selenium in human health and disease with emphasis on those aspects peculiar to New Zealand. Am. J. Clin. Nutr. 33:303-323.
Thomson, C.D., M.F. Robinson, D.R. Campbell, and H.M. Rea. 1982. Effect of prolonged supplementation with daily supplements of selenomethionine and sodium selenite on glutathione peroxidase activity in blood of New Zealand residents. Am. J. Clin. Nutr. 36:24-31.
van Rij, A.M., C.D. Thomson, J.M. McKenzie, and M.F. Robinson. 1979. Selenium deficiency in total parenteral nutrition. Am. J. Clin. Nutr. 32:2076-2085.
Whanger, P.D., M.A. Beilstein, C.D. Thomson, M.F. Robinson, and M. Howe. 1988. Blood selenium and glutathione peroxidase activity of populations in New Zealand, Oregon, and South Dakota. FASEB J. 2:2996-3002.
Whitacre, M.E., G.F. Combs, Jr., S.B. Combs, and R.S. Parker. 1987. Influence of dietary vitamin E on nutritional pancreatic atrophy in selenium-deficient chicks. J. Nutr. 117:460-457.
WHO (World Health Organization). 1987. Selenium, Envionmental Health Criteria 58: A Report of the International Programme on Chemical Safety. World Health Organization, Geneva.
Williams, M. 1983. Selenium and glutathione peroxidase in mature human milk. Proc. Univ. Otago Med. Sch. 61:20-21.
Yang, G. S. Wang, R. Zhou, and S. Sun. 1983. Endemic selenium intoxication of humans in China. Am. J. Clin. Nutr. 37:872-881.
Yang, G., L.Z. Zhu, S.J. Liu, L.Z. Gu, P.C. Qian, J.H. Huang, and M.O. Luu. 1987. Human selenium requirements in China. Pp. 589-607 in G.F. Combs, Jr., J.F. Spallholz. O.A. Levander, and J.E. Oldfield, eds. Proceedings of the Third International Symposium on Selenium in Biology and Medicine. AVI Publishing, Westport, Conn.
Yang, G., K. Ge, J. Chen, and X. (Chen. 1988. Selenium-related endemic diseases and the daily selenium requirement of humans. World Rev. Nutr. Diet. 55:98-152.
Copper is an essential nutrient for all vertebrates and some lower animal species (Davis and Mertz, 1987). Several abnormalities have been observed in copper-deficient animals, including anemia, skeletal defects, demyelination and degeneration of the nervous system, defects in pigmentation and structure of hair or wool, reproductive failure, myocardial degeneration, and decreased arterial elasticity. There are a number of important copper-containing proteins and enzymes, some of which are essential for the proper utilization of iron (Davis and Mertz, 1987).
Assessment of Copper Status
Although hypocupremia is readily produced in animals during experimental copper deficiency, circulating copper concentration is not necessarily a valid index of copper nutriture in humans (Solomons, 1979). Ceruloplasmin, a protein-copper complex, is strongly influenced by hormonal changes or inflammation, thus limiting its usefulness as an indicator (Mason, 1979). Determination of erythrocyte superoxide dismutase (SOD) activity appears to be a promising technique for assessing copper status in humans (Uauy et al., 1985).
Evidence for Human Requirement
Severe copper deficiency is rare in human beings (Cartwright and Wintrobe, 1964; Danks, 1988). Copper depletion sufficient to cause hypocupremia has been observed during total parenteral nutrition (Shike, 1984) and in cases of Menkes' steely hair diseasea rare, inherited disease resulting in impaired copper utilization (Menkes et al., 1962). The hypocupremia reported in protein-calorie malnutrition, sprue, nephrotic syndrome, and certain other diseases is probably unrelated to dietary copper intake and is believed to be secondary to a state of hypoproteinemia and inability to provide adequate amounts of the aproprotein for ceruloplasmin synthesis (Mason, 1979). Under normal circumstances, dietary copper deficiency is not known to occur in adults, but it has been observed in malnourished children in Peru; its manifestations are anemia, neutropenia, and severe bone demineralization (Cordano et al., 1964). In the early 1970s in the United States, similar findings were recognized in a few
very small premature infants who were hospitalized for long periods and exclusively fed modified cow's milk formula or received prolonged parenteral alimentation. Presumably, these aberrations reflected a deficient dietary intake of copper (Cordano, 1974). More recently, copper deficiency has been shown to impair the growth of Chilean infants recovering from malnutrition (Castillo-Duran and Uauy, 1988).
The concentration of copper in the human fetus increases substantially during gestation, about half of the total fetal copper accumulating in the liver (Widdowson et al., 1974). These hepatic reserves are believed to protect the full-term infant against copper deficiency during the first few months of life. In the United States, tissue copper concentrations remain remarkably steady throughout adult life (Schroeder et al., 1966). The relatively constant copper concentrations in most tissues indicate sufficient dietary intake and effective homeostatic control of copper.
Epidemiological and experimental animal studies suggest a positive correlation between the zinc-to-copper ratio in the diet and the incidence of cardiovascular disease (Klevay, 1984). Elevated plasma cholesterol levels, impaired glucose tolerance, and heart-related abnormalities have been observed in some human subjects consuming only 0.8 to 1.0 mg copper per day (Klevay et al., 1984; Reiser et al., 1985), but not in others (Turnlund et al., 1989).
Dietary Sources and Usual Intakes
Organ meats, especially liver, are the richest sources of copper in the diet, followed by seafoods, nuts, and seeds. The concentration of copper in drinking water is highly variable; it is much influenced by the interaction of the water's acidity with the piping system. Additional contributions to intake may come from adventitious sources, such as copper-containing fungicides sprayed on agricultural products. Human milk contains approximately 0.3 mg/liter; cow's milk only about 0.09 mg/liter (Varo et al., 1980)
Older analytical data indicating that most U.S. diets provide a daily copper intake between 2 and 5 mg are now being reexamined and questioned (Klevay, 1984). The Total Diet Study, based on the extensive dietary analyses performed by the U.S. Food and Drug Administration, showed that the daily intake of copper for adult males and females averaged about 1.2 and 0.9 mg, respectively, from 1982 to 1986 (Pennington et al., 1989). The intakes for infants 6 to 11 months old and toddlers 2 years old were 0.45 and 0.57 mg daily.
Several different factors may affect the bioavailability of dietary copper. Jacob et al. (1987) observed that high intakes of vitamin C (605 mg/day) decreased serum ceruloplasmin but had no effect on overall body copper status. Zinc intakes slightly above RDA levels reduced apparent copper retention in young men and adolescent females (Festa et al., 1985; Greger et al., 1978). The degree of copper deficiency may be influenced by the type of carbohydrate consumed, since rats fed a diet containing fructose developed more severe signs of copper deficiency than did rats fed a diet containing either glucose or starch (Fields et al., 1984). Although it may be assumed that the interaction between copper and ascorbic acid involves reduction and chelation of the metal in the intestine, the nature of the interaction of copper with zinc or carbohydrates is not yet known.
Estimated Safe and Adequate Daily Dietary Intakes
In the past, estimates of the copper requirement for humans were derived from metabolic balance studies. However, the balance technique can lead to false estimates of nutritional requirements because the efficiency of copper absorption is increased or decreased in response to low or high copper intakes, respectively (Turnlund et al., 1989). Older balance studies suggested that the adult requirement for copper ranged from 2.0 to 2.6 mg/day, whereas later studies indicated that intakes less than 2.0 mg/day, and often not much more than 1.0 mg/day, could maintain positive copper balance (Mason, 1979). In a recent metabolic ward study, 13 men consuming a variety of typical U.S. diets were found to need 1.30 mg/day to replace fecal and urinary losses (Klevay et al., 1980).
Whole-body surface losses of copper are highly variable. Such variability makes it difficult to select an appropriate value for the losses incurred through this pathway, but recent estimates indicate that copper losses from the body's surface are less than 0.1 mg/day (Turnlund et al., 1989). If the true gastrointestinal absorption of copper at intakes of 1.7 to 2.0 mg is 36% (± 1.3 SEM) (Turnlund et al., 1989), then a dietary intake of 0.3 mg/day is required to replace body surface losses. Adding this figure to the average dietary intake of 1.3 mg/day needed to replace urinary and fecal losses indicates that a total dietary copper intake of approximately 1.6 mg/day is required to maintain balance in adult men.
Many U.S. diets provide less than 1.6 mg of copper daily (Klevay, 1984). Since anemia or neutropenia ascribable to copper deficiency
has not been observed in adults consuming typical U.S. diets, there is an obvious discrepancy between the experimentally derived copper requirement as defined by balance studies and currently estimated dietary copper intakes. This suggests either a long-term homeostatic adaptation to low copper intakes, or an incorrect estimate of dietary copper intake due to the underreporting of certain foods and water that are sources of the element. Because of the uncertainty about the quantitative human requirement for copper, it is not possible to establish an RDA for this trace element. Rather, the subcommittee recommends 1.5 to 3 mg/day as a safe and adequate range of dietary copper intake for adults.
Infants and Children
The average daily intake of copper by exclusively breastfed North American infants was 0.23 ± .07 mg over the first 4 months of lactation (Butte et al., 1987), or approximately 40 ± 16 µg/kg per day. This intake is substantially less than the 80 µg/kg per day recommended by a World Health Organization Expert Committee (WHO, 1973), but approaches the lower limit of the estimated requirement range of 45 to 135 µg/kg per day suggested by Co(rdano (1974) for rapidly growing infants with poor stores. Positive copper balance has been observed in normal children ages 3 months to 8 years with intakes as low as 35 ± 22 µg/kg per day (Alexander et al., 1974).
Studies in animals have shown high bioavailability of copper from human milk (Lönnerdal et al., 1985). Furthermore, the sizeable hepatic copper reserve built up during fetal development appears to contribute to the early needs of the growing full-term infant (Widdowson et al., 1974). After 3 months of age, the recommended copper intake of 75 µg/kg/day translates into dietary ranges of 0.4 to 0.6 and 0.6 to 0.7 mg/day for reference infants from birth to 6 months and from 6 to 12 months old, respectively. The introduction of solid foods at 4 to 6 months of age should enable the older infant fed a mixed diet to meet the copper recommendations (Gibson and De Wolfe, 1980), but the exclusively breastfed infant will have difficulty in achieving those levels because copper levels in human milk decline from 0.6 to 0.2 mg/liter during the first 6 months of lactation (Vuori and Kuitunen, 1979). These recommended intakes may be inadequate for the premature infant, who is always born with low copper stores (Shaw, 1973).
The American Academy of Pediatrics has recently recommended that infant formulas provide 60 µg of copper per 100 kcal (AAP, 1985). By following this recommendation, a typical formula-fed in-
fant from birth to 6 months of age receiving 700 kcal per day would consume approximately 0.4 mg of copper per day.
In preadolescent and adolescent girls, fecal and urinary losses were at or near equilibrium with a dietary copper intake of 1 to 1.3 mg/ day (35 to 45 µg/kg body weight per day) (Engel et al., 1967; Greger et al., 1978; Price and Bunce, 1972). The recommended copper range of 1.0 to 2.0 mg/day for 7- to 10-year-old children provides at least 40 µg/kg body weight/day.
Excessive Intakes and Toxicity
An FAO/WHO Expert Committee concluded that no deleterious effects can be expected in humans whose copper intake is 0.5 mg/kg body weight per day (FAO/WHO, 1971). Usual diets in the United States rarely supply more than 5 mg/day, and an occasional intake of up to 10 mg/day is probably safe for human adults. Although storing or processing acidic foods or fluids in copper vessels can add to the daily intake, overt toxicity from dietary sources is extremely rare in the U.S. population (NRC, 1977)
AAP (American Academy of Pediatrics). 1985. Recommended ranges of nutrients in formulas. Appendix 1. Pp. 356-357 in Pediatric Nutrition Handbook, 2nd ed. American Academy of Pediatrics, Elk Grove Village, Ill.
Alexander, F.W., B.E. Clayton, and H.T. Delves. 1974. Mineral and trace-metal balances in children receiving normal and synthetic diets. Q.J. Med. 43:89-111.
Butte, N.F., C. Garza, E.O. Smith, C. Wills, and B.L. Nichols. 1987. Macro- and tracemineral intakes of exclusively breast-fed infants. Am. J. Clin. Nutr. 45:42-48.
Cartwright, G.E., and M.M. Wintrobe. 1964. The question of copper deficiency in man. Am. J. Clin. Nutr. 15:94-110.
Castillo-Duran, C., and R. Uauy. 1988. Copper deficiency impairs growth of infants recovering from malnutrition. Am. J. Clin. Nutr. 47:710-714.
Cordano, A. 1974. The role played by copper in the physiopathology and nutrition of the infant and the child. Ann. Nestle 33:1-16.
Cordano, A., J.M. Baertl, and G.G. Graham. 1964. Copper deficiency in infancy. Pediatrics 34:324-336.
Danks, D.M. 1988. Copper deficiency in humans. Annu. Rev. Nutr. 8:235-257.
Davis, G.K., and W. Mertz. 1987. Copper. Pp. 301-364 in W. Mertz, ed. Trace Elements in Human and Animal Nutrition, 5th ed., Vol. 2. Academic Press, Orlando, Fla.
Engel, R.W., N.O. Price, and R.F. Miller. 1967. Copper, manganese, cobalt, and molybdenum balance in pre-adolescent girls. J. Nutr. 92:197-204.
FAO/WHO (Food and Agriculture Organization/World Health Organization). 1971. Evaluation of Food Additives. WHO Technical Report Series No. 462. World Health Organization, Geneva.
Festa, M.D., H.L. Anderson, R.P. Dowdy, and M.R. Ellersieck. 1985. Effect of zinc intake on copper excretion and retention in men. Am. J. Clin. Nutr. 41:285292.
Fields, M., R. . Ferretti, J.C. Smith, and R. Reiser. 1984. The interaction of type of dietary carbohydrates with copper deficiency. Am. J. Clin. Nutr. 39:289-295.
Gibson, R.S., and M.S. DeWolfe. 1980. The dietary trace metal intake of some Canadian full-term and low birthweight infants during the first twelve months of infancy. J. Can. Diet. Assoc. 41:206-215.
Greger, J.L., S.C. Zaikis, R.P. Abernathy, O.A. Bennett, and J. Huffman. 1978. Zinc, nitrogen, copper, iron and manganese balance in adolescent females fed two levels of zinc. J. Nutr. 108:1449-1456.
Jacob, R.A., J.H. Skala, S.T. Omaye, and J.R. Turnlund. 1987. Effect of varying ascorbic acid intakes on copper absorption and ceruloplasmin levels of young men. J. Nutr. 117:2109-2115.
Klevay, L.M. 1984. The role of copper, zinc, and other chemical elements in ischemic heart disease. Pp. 129-157 in O.M. Rennert and W.-Y. Chan, eds. Metabolism of Trace Metals in Man, Vol. 1. Developmental Aspects. CRC Press, Boca Raton, Fla.
Klevay, L.M., S.J. Reck, R.A. Jacob, G.M. Logan, Jr., J.M. Munoz, and H.H. Sandstead. 1980. The human requirement for copper. 1. Healthy men fed conventional American diets. Am. J. Clin. Nutr. 33:45-50.
Klevay, L.M., L. Inman, K. Johnson, M. Lawler, J.R. Mahalko, D.B. Milne, H.C. Lukaski, W. Bolonchuk, and H.H. Sandstead. 1984. Increased cholesterol in plasma in a young man during experimental copper depletion. Metabolism 33:1112-1118.
Lönnerdal, B., J.G. Bell, and C.L. Keen. 1985. Copper absorption from human milk, cow's milk, and infant formulas using a suckling rat model. Am. J. Clin. Nutr. 42:836-844.
Mason, K.E. 1979. A conspectus of research on copper metabolism and requirements of man. J. Nutr. 109:1979-2066.
Menkes, J.H., M. Alter, G.K. Steigledger, D.R. Weakley, and J.H. Sung. 1962. A sexlinked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 29:764-779.
NRC (National Research Council). 1977. Medical and Biological Effects of Environmental Pollutants: Copper. Report of the Committee on Medical and Biologic Effects of Environmental Pollutants, Division of Medical Sciences, Assembly of Life Sciences, National Academy of Sciences, Washington, D.C. 115 pp.
Pennington,J.A.T., B.E. Young, and D.B. Wilson. 1989. Nutritional elements in U.S. diets: results from the Total Diet Study, 1982-86. J. Am. Diet. Assoc. 89:659664.
Price, N.O., and G.E. Bunce, 1972. Effect of nitrogen and calcium on balance of copper, manganese, and zinc in preadolescent girls. Nutr. Rep. Int. 5:275-280.
Reiser, S., J.C. Smith, Jr., W. Mertz., J.T. Holbrook, D.J. Scholfield, A.S. Powell, W.K. Canfield, and JJ. Canary. 1985. Indices of copper status in humans consuming a typical American diet containing either fructose or starch. Am. J. Clin. Nutr. 42:242-251.
Schroeder, H.A., A.P. Nason, I.H. Tipton, and J.J. Balassa. 1966. Essential trace elements in man: copper. J. Chronic Dis. 19:1007-1034.
Shaw, J.C.L. 1973. Parenteral nutrition in the management of sick low birthweight infants. Pediatr. Clin. North Am. 20:333-358.
Shike, M. 1984. Copper in parenteral nutrition. Bull. N.Y. Acad. Med. 60:132-143.
Solomons, N.W. 1979. On the assessment of zinc and copper nutriture in man. Am. J. Clin. Nutr. 32:856-871.
Turnlund, J.R., W.R. Keyes, H.L. Anderson, and L.L. Acord. Copper absorp- tion and retention in young men at three levels of dietary copper using the stable isotope. 65Cu. Am. J. Clin. Nutr. 49:870-878.
Uauy, R., C. Castillo-Duran, M. Fisberg, N. Fernandez, and A. valenzuela. 1985. Red cell superoxide dismutase activity as an index of human copper nutrition. J. Nutr. 115:1650-1655.
Varo, P., M. Nuurtamo, E. Saari, and P. Koivistoinen. 1980. Mineral element composition of Finnish foods. VIII. Dairy products, eggs and margarine. Acta Agric. Scand. Suppl. 22:115- 126.
Vuori, F.. and P. Kuitenen. 1979. The concentrations of copper and zinc in human milk. A longitudinal study. Acta Paediatr. Scand. 68:33-37.
WHO (World Health Organization). 1973. Trace Elements in Human Nutrition. Report of a WHO Expert Committee. WHO Technical Report Series No. 532. World Health. Organization, Geneva.
Widdowson, F.M., J. Dauncey, and J.C.I. Shaw. 1974. Trace elements in foetal and early postnatal development. Proc. Nutr. Soc. 33:275-284.
Manganese has been shown to be an essential element in every animal species studied. Signs of deficiency include poor reproductive performance, growth retardation, congenital malformations in the offspring, abnormal formation of bone and cartilage, and impaired glucose tolerance (Hurley and Keen, 1987). Several enzymes, such as decarboxylases, hydrolases, kinases, and transferases, are nonspecifically activated by manganese in vitro. There are two known manganese metalloenzymes: pyruvate carboxylase and superoxide dis mutase, both localized in mitochondria.
Manganese deficiency has never been observed in noninstitutionalized human populations because of the abundant supply of manganese in edible plant materials compared to the relatively low requirements of mammals (Underwood, 1981). Analyses of a variety of tissues taken from humans of various ages have indicated that there is no tendency for either a decrease or an increase in manganese accumulation throughout most of the life cycle (Schroeder et al., 1966). This constancy of manganese concentration in the tissues suggests adequate dietary intake coupled with strong homeostatic control. There has been only one recorded case of a possible manganese deficiency in a humana male subject in a vitamin K deficiency study who was fed a purified diet from which manganese was inadvertently omitted (Doisy, 1973). His total diet (food and water) furnished only about 0.35 mg of manganese per day. Retrospective analyses revealed that there were 55 and 85% declines in his serum and stool manganese levels, respectively, over a 17-week period (Doisy, 1974).
Progress in the field of manganese nutrition has been hampered because of the lack of a practical method for assessing manganese status. Blood manganese levels appear to reflect body manganese status of rats fed deficient or adequate amounts of manganese (Keen et al., 1983), but consistent changes in blood or plasma manganese levels have not been observed in depleted or repleted human subjects (Freeland-Graves et al., 1988; Friedman et al., 1987). Animal studies have shown that the activity of mitochondrial superoxide dismutase is a function of dietary manganese intake, but practical usefulness of this enzyme as an indicator is uncertain since tissues containing mitochondria are generally not readily available for nutritional status assessment purposes.
Dietary Sources and Usual Intakes
Whole grains and cereal products are the richest dietary sources of manganese, and fruits and vegetables are somewhat less so. Dairy products, meat, fish, and poultry are poor sources. Tea is a rich source of manganese, but typical drinking water consumed at the rate of 2 liters daily contributes only about 40 to 64 µg, or about 2 to 3% of the amount furnished by diet (NRC, 1980).
Although there is now a body of data concerning the levels of manganese in the diet, little is known about the chemical form or nutritional bioavailability of the manganese in foods (Kies, 1987). Extreme dietary habits can result in manganese intake outside the provisionally recommendled limits; consumption of a varied and balanced diet will reliably furnish safe and adequate amounts.
The Total Diet Study conducted in the United States between 1982 and 1986 indicated that the mean daily dietary manganese intake was 2.7 and 2.2 mg for adult men and women, respectively (Pennington et al., 1989). Teenage boys consumed an average of 2.8 mg/ day, whereas girls consumed only 1.8 mg/day. Mean manganese intakes were 1. 1 and 1.5 mg/day for 6- to 11-month-old babies and 2-year-old toddlers, respectively.
Estimated Safe and Adequate Daily Dietary Intakes
Several short-term balance studies in adult humans fed different amounts of manganese have been conducted in an attempt to define the requirement for this trace element (reviewed by Freeland-Graves et al., 1987). However, there are many problems with using the balance method to estimate trace element requirements (Freeland-Graves et al., 1988). At best, such studies determine the
intake needed to maintain a given pool size of a nutrient in test subjects (Mertz, 1987). Factorial methods have also been used to estimate manganese requirements (Freeland-Graves et al., 1988; Friedman et al., 1987), but as with zinc, endogenous manganese loss is likely to be a function of manganese status. Therefore, the validity of this approach is also doubtful. Given the apparent lack of manganese deficiency as a practical nutritional problem in adults, it would seem that current dietary intakes satisfy needs for the element. Therefore, a provisional daily dietary manganese intake for adults of 2.0 to 5.0 mg is recommended.
Infants and Children
Little is known about the manganese requirement of human infants. McLeod and Robinson (1972) reported the manganese content of human milk to average 15 ng/ml (range, 12 to 20.2 ng/ml). Casey et al. (1985) calculated that the average daily intake of manganese from human milk from North American mothers during the first month after birth was only 2 µg. Such low intakes are associated with negative manganese balances (Widdowson, 1969), which are reflected in the decreases in tissue manganese levels that occur during the first weeks of life (Schroeder et al., 1966). Nonetheless, no cases of manganese deficiency in human infants have been documented (Lönnerdal et al., 1983). This suggests utilization of tissue reserves built up in the infant during gestation, but the site of such reserves, if any, is not clear, since manganese, unlike copper, is not stored in the fetal liver (Widdowson et al., 1972). In the absence of reports on manganese deficiency in human infants, no supplementation of the breastfed infant is recommended.
With the introduction of other foods at an assumed age of 4 months, manganese consumption increases accordingly and intakes of 71 and 80 µg/kg have been reported for infants 6 and 12 months old, respectively (Gibson and De Wolfe, 1980). For reference infants at birth to 0.5 year old and at 0.5 to 1 year of age, this would be equivalent to intakes of 0.4 and 0.7 mg/day, respectively. Therefore, the provisional recommended ranges for daily dietary intakes of manganese for these age groups are 0.3 to 0.6 and 0.6 to 1.0 mg/day, respectively. The ranges for children and adolescents are derived through extrapolation on the basis of body weight and expected food intake.
Pregnancy and Lactation
The requirement for manganese during pregnancy is not known, since the manganese content of the fetus has not been determined (Shaw, 1980). If an increased need exists, however, it may be met largely by enhanced absorption. Studies in
isolated rat intestinal sacs have shown that manganese absorption during the third trimester is triple that of nonpregnant, nonlactating controls (Kirchgessner et al., 1982). Because the manganese content of human milk is so low (Casey et al., 1985), lactation is not likely to result in any appreciable additional demand for dietary manganese.
Excessive Intakes and Toxicity
In animals, the toxicity of ingested manganese is low and signs of a toxic response generally appear only after concentrations higher than 1,000 µg/g diet are fed (Hurley and Keen, 1987). In contrast, when the element was injected or inhaled as dust, adverse effects on the central nervous system became apparent at much smaller doses. The biochemical mechanism of manganese neurotoxicity has not been established, but studies in rats suggest that higher valency forms of the element might potentiate the autooxidation of catecholamines (Donaldson et al., 1982).
In humans, toxicity has been observed only in workers exposed to high concentrations of manganese dust or fumes in air, but not as a consequence of dietary intake by people consuming 8 to 9 mg of manganese per day in their food (WHO, 1973). In view of the remarkably steady tissue concentrations of manganese in the U.S. population (Schroeder et al., 1966) and the low toxicity of dietary manganese, an occasional intake of 10 mg/day by adults can be considered safe. To include an extra margin of safety, however, the subcommittee recommends a range of manganese intake from 2 to 5 mg/ day for adults.
In the young of certain animal species, the homeostatic mechanism for manganese is relatively undeveloped (Cotzias et al., 1976). There have also been reports that learning disabilities in children might be associated with increased manganese levels in hair (Collipp et al., 1983); however, more evidence is required before this association can be substantiated.
Casey, C.E., K.M. Hambidge, and M.C. Neville. 1985. Studies in human lactation: zinc, copper, manganese, and chromium in human milk in the first month of lactation. Am. J. Clin. Nutr. 41:1193-1200.
Collipp, P.J., S.Y. Chen, and S. Maitinsky. 1983. Manganese in infant formulas and learning disability. Ann. Nutr. Metab. 27:488-494.
Cotzias, G.C., S.T. Miller, P.S. Papavasiliou, and L.C. Tang. 1976. Interactions between manganese and brain dopamine. Med. Clin. N. Am. 60:729-738.
Doisy, E.A., Jr. 1973. Micronutrient controls on biosynthesis of clotting proteins and cholesterol. Pp. 193-199 in D.D. Hemphill, ed. Trace Substances in Environmental HealthVI. University of Missouri, Columbia, Mo.
Doisy, E.A.,Jr. 1974. Effects of deficiency in manganese upon plasma levels of clotting proteins and cholesterol in man. Pp. 668-670 in W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz, eds. Trace Element Metabolism in Animals2. University Park Press, Baltimore.
Donaldson, J., D. McGregor, and F. La Bella. 1982. Manganese neurotoxicity: a model for free radical mediated neurodegeneration. Can. J. Physiol. Pharmacol. 60:1398-1405.
Freeland-Graves, J. H.,C.W. Bales, and F. Behmardi. 1987. Manganese requirements of humans. Pp. 90-104 in C. Kies. ed. Nutritional Bioavailability of Manganese. American Chemical Society., Washington, D.C.
Freeland-Graves, J.H., F. Behmardi, C.W. Bales, V. Dougherty, P.-H. Lin, J.B. Crosby, and P.C. Trickett. 1988. Metabolic balance of manganese in young men consuming diets containing five levels of dietary manganese. J. Nutr. 1 18:764773.
Friedman, B.J., J.H. Freeland-Graves, C.W. Bales, F. Behmardi, R.I,. ShoreyKutschke, R.A. Willis, J.B. Crosby, P.C. Trickett, and S.D. Houston. 1987. Manganese balance and clinical observations in young men fed a manganese-deficient diet. J. Nutr. 117:133-143.
Gibson, R.S., and M.S. De Wolfe. 1980. The dietary trace metal intake of some Canadian full-term and low birthweight infants during the first twelve months of infancy. J. Can. Diet. Assoc. 41:206-215.
Hurley, L.S., and C.L., Keen. 1987. Manganese. Pp. 185-223 in W. Mertz, ed. Trace Elements in Human and Animal Nutrition, Vol. 1. Academic Press, Orlando, Fla.
Keen, C.L., M.S. Clegg, B. Lönnerdal, and L.S. Hurley. 1983. Whole-blood manganese as an indicator of body manganese. N. Engl. J. Med 308:1230.
Kies, C., ed. 1987. Nutritional Bioavailability of Manganese. American Chemical Society, Washington, D.C.
Kirchgessner, M., Y.S. Sherif, and F.J. Schwarz. 1982. Changes in absorption of manganese during pregnancy and lactation. Ann. Nutr. Metab 26:83-89.
Lönnerdal, B., C. L. Keen, M. Ohtake, and T. Tamura. 1983. Iron, zinc, copper, and manganese in infant formulas. Am. J. Dis. Child. 137:433-437.
McLeod, B.F., and Robinson, M.F. 1972. Dietary intake of manganese by New Zealand infants during the first six months of life. Br. J. Nutr. 27:229-232.
Mertz, W. 1987. Use and misuse of balance studies. J. Nutr. 117:1811-1813.
NRC (National Research Council). 1980. The contribution of drinking water to mineral nutrition in humans. Pp. 265-403 in Drinking Water and Health, Vol. 3. Report of the Safe Drinking Water Committee, Board on Toxicology and Environmental Health Hazards, Assembly of Life Sciences. National Academy Press, Washington, D.C. 415 pp.
Pennington, J.A.T., B.E. Young, and D.B. Wilson. 1989. Nutritional elements in U.S. diets: results from the Total Diet Study, 1982-86. J. Am. Diet. Assoc. 89:659664.
Schroeder, H.A., J.J. Balassa, and I.H. Tipton. 1966. Essential trace elements in man manganese. J. Chronic Dis. 19:545-571.
Shaw, J.C. L. 1980. Trace elements in the fetus and young infant. II. Copper, manganese, selenium, and chromium. Am. J. Dis. Child. 134:74-81.
Underwood, E.J. 1981. The incidence of trace element deficiency diseases. Phil. Trans. R. Soc. Lond. B 294:3-8.
WHO (World Health Organization). 1973. Trace elements in human nutrition. Report of a WHO Expert Committee. WHO Technical Report Series No. 532. World Health Organization, Geneva.
Widdowson, F.M., 1969. Trace elements in human development. Pp. 85-98 in D. Barltrop, ed. Mineral Metabolism in Paediatrics. Blackwell, Oxford.
Widdowson, F.M., H. Chan, G.E. Harrison, and R.D.G. Milner. 1972. Accumulation of Cu, Zn, Mn, Cr and Co in the human liver before birth. Biol. Neonate 20:360367.
Fluorinea is present in small but widely varying concentrations in practically all soils, water supplies, plants, and animals, and is a constituent of all diets. The major tissues known to incorporate fluoride are bones and tooth enamel, the incorporation being proportional to the total intake (Hodge and Smith, 1970). The primary route of fluoride excretion is the kidney, and urine generally accounts for approximately 90% of the total fluoride excreted (Maheshwari et al., 1981; Spencer et al., 1981). There is a direct linear relationship between plasma fluoride level and the concentration of fluoride in the community water supply up to 6 mg/liter (Taves and Guy, 1979), but there can be substantial diurnal variations of these levels (Ekstrand, 1978).
The status of fluorine as an essential nutrient has been debated. Several studies in rodents have provided conflicting results. Addition of 2.5 mg of fluoride per kilogram of basal diet, the content of which varied but occasionally dropped below 0.04 mg/kg, stimulated the growth of rats housed in a trace element-controlled environment (Milne and Schwarz, 1974; Schwarz and Milne, 1972). In contrast, no effect of fluoride was seen in mice fed another low-fluorine diet (0.2 mg/kg) containing ingredients grown hydroponically, even when the diet was fed over six generations (Weber and Reid, 1974). An earlier report that fluoride added to the drinking water at 50 mg/ liter protected pregnant mice against impaired reproduction and severe anemia (Messer et al., 1973) was not confirmed (Tao and Suttie, 1976). These contradictory results do not justify a classification of fluorine as an essential element, according to accepted standards. Nonetheless, because of its valuable effects on dental health, fluorine is a beneficial element for humans.
a Fluoride is the term for the ionized form of the element flourine, as it occurs in drinking water. The two terms are used interchangeably.
Effects on Dental Caries
The negative correlation between tooth decay in children and fluoride concentrations in their drinking water was first demonstrated in a large study in the United States almost 50 years ago (Dean et al., 1942). Subsequently, many studies (see review by Burt, 1982) proved that fluoridation of public water supplies, wherever natural fluoride concentrations are low, is an effective and practical means of reducing dental caries (Council on Dental Therapeutics, 1982). Recommendations approved by virtually all national and international health organizations call for fluoride concentrations between 0.7 and 1.2 mg/liter, depending on average local temperature (as a predictor of water intake).
There is evidence that dental health has been improving, even in communities with low water fluoride concentrations, presumably because of increased fluoride intake from other sources (e.g., from foods processed with fluoridated water, topical fluoride applications by dentists, fluoride supplementation, and unintentional ingestion of fluoride dentifrices).
Although no one theory explains completely the exact role of fluoride in reducing caries (Council on Dental Therapeutics, 1982), it is known that fluoride replaces hydroxyl ions in developing enamel prior to tooth eruption, thereby forming an apatite crystal that is less susceptible to solubilization by acid and, hence, more resistant to caries formation. Some topically applied fluoride is also taken up by the enamel. The protective effect against caries is greatest during maximal tooth formation, i.e., during the first 8 years of childhood, but there is evidence to suggest that adults as well as children continue to benefit from the consumption of fluoridated water (Council on Dental Therapeutics, 1982).
Effects on Bone Disease
Although it has been suggested that fluoride intakes greater than those recommended for caries control may have some benefit in protecting adult bone, definitive evidence for such an effect is lacking. Bernstein et al. (1966) found a higher prevalence of reduced bone density and of collapsed vertebrae in an area with low-fluoride water (0.15 to 0.30 mg/liter) compared to that in an area with naturally high-fluoride water (4 to 5.8 mg/liter); these findings have not yet been confirmed.
Dietary Sources and Usual Intakes
A recent estimate of fluoride intake in the United States from food, beverages, and water ranged from approximately 0.9 mg/day in an area with unfluoridated water to 1.7 mg/day in an area with fluoridation (Singer et al., 1980). Daily fluoride intake was reported to be approximately 1.8 mg from a hospital diet in a fluoridated area of the United States (Taves, 1983), but drinking water was not taken into account. Most of the difference in fluoride intake between the fluoridated and unfluoridated areas was due to beverages, since foods marketed in different parts of the country contributed only 0.3 to 0.6 mg/day. This suggests that any effect of locally grown foods is largely negated by the supraregional distribution of the majority of foods in the United States.
Food processing has a strong influence on the fluoride content of foods. The fluoride content of various foods can be increased severalfold by cooking them in fluoridated water (Marier and Rose, 1966; Martin, 1951). Even the type of cooking vessel can be important. Cooking in utensils treated with Teflon, a fluoride-containing polymer, can increase the fluoride content, whereas an aluminum surface can reduce it (Full and Parkins, 1975).
The richest dietary sources of fluoride are tea and marine fish that are consumed with their bones (Kumpulainen and Koivistoinen, 1977). The bones of some land-based animals also contain high levels of fluoride. In countries where tea drinking is common, this beverage can make a substantial contribution to the total fluoride intake. In the United Kingdom Total Diet Study, tea was the main source of dietary fluoride for adults, accounting for 1.3 mg of the total daily intake of 1.8 mg (Walters et al., 1983).
Current intake estimates for 6-month-old infants range from 0.23 to 0.42 mg/day in different regions of the United States (Ophaug et al., 1985). This small range is due to the agreement among the producers of infant formulas to use only water low in fluoride for all their products (Barness, 1981; Horowitz and Horowitz, 1983).
The fluoride content of cow's milk is approximately 20 µg/liter (Taves, 1983). Mean reported values of human milk range from 5 to 25 µg/liter (Esala et al., 1982; Krishnamachari, 1987; Spak et al., 1983), reflecting maternal intake. The low and high concentrations in human milk were found in samples from mothers drinking water with fluoride concentrations of 0.2 and 1.7 mg/liter, respectively.
The quantitative estimates of fluoride intake discussed above give no indication about the relative absorption of dietary fluoride (see review by Subba Rao, 1984). In general, free fluoride as it exists in
water is more available than the protein-bound fluorine in foods, and the absorption of fluoride from sodium fluoride in aqueous solution is estimated to be 100%. In young adults, the absorption of fluoride from sodium fluoride added to milk or baby formula was only 72 and 65%, respectively, of that added to water in a study by Spak et al. (1982). An even poorer absorption, from 37 to 54% , has been reported for the fluorine in bone meal (Krishnamachari, 1987). These differences in fluoride absorption indicate the difficulties in establishing dietary recommendations for fluoride based solely on quantitative data about the fluoride content of foods and drinking water.
Excessive Intakes and Toxicity
Fluorine, like other trace elements, is toxic when consumed in excessive amounts. Chronic toxicityfluorosisaffects bone health, kidney function, and possibly muscle and nerve function (Krishnamachari, 1987). The condition occurs after years of daily exposures of 20 to 80 mg of fluorine, far in excess of the average intake in the United States. Mottling of the teeth in children has been observed at 2 to 8 mg/kg concentrations of fluoride in diet and drinking water (NRC, 1971). Many detailed epidemiological studies in the United States and abroad have failed to find any indication for an increased cancer risk associated with fluoride in the water supply (LARC, 1982).
The acute toxicity of fluoride resulting in death has been described in a 70-kg adult who ingested one dose of 5 to 10 g of sodium fluoride (Heifetz and Horowitz, 1984). Recently, investigators have suggested that the use of pharmacological doses of fluoride (50 mg/day) for 3 months was helpful in the treatment of women with osteoporosis (Pak et al., 1989). At these doses there is a potential for toxicity, and these patients should be monitored carefully.
Estimated Safe and Adequate Daily Dietary Intakes
The estimated range of safe and adequate intakes of fluoride for adults is 1.5 to 4.0 mg/day. This takes into account the widely varying fluoride concentrations of diets consumed in the United States and includes both food sources and drinking water. For younger age groups, the range is reduced to a maximal level of 2.5 mg in order to avoid mottling of the teeth. Ranges of 0.1 to 1 mg during the first year of life and 0.5 to 1.5 mg during the subsequent 2 years are suggested as adequate and safe.
Infants receiving human milk, ready-to-use formula, or concentrated formulas prepared with nonfluoridated water are all ingesting low levels of fluoride. In such cases, the American Academy of Pediatrics Committee on Nutrition advises the use of a fluoride supplement of 0.25 mg/day for children from 2 weeks to 2 years of age (Barness, 1981).
In view of fluoride's beneficial effects on dental health and its safety at the prescribed intakes, the Food and Nutrition Board recommends fluoridation of public water supplies if natural fluoride levels are substantially below 0.7 mg/liter.
Barness, L.A. 1981. Fluoride in infant formulas and fluoride supplementation. Pediatrics 67:582-583.
Bernstein, D.S., N. Sadowsky, I).M. Hegsted, C.D. Guri, and F.J. Stare. 1966. Prevalence of osteoporosis in high- and low-fluoride areas in North Dakota. J. Am. Med. Assoc. 198:499-504.
Burt, B.A. 1982. The epidemiological basis for water fluoridation in the prevention of dental caries. J. Public Health Policy 3:391-407.
Council on Dental Therapeutics. 1982. Fluoride compounds. Pp. 344-368 in Accepted Dental Therapeutics, 39th ed. American Dental Association, Chicago, Ill.
Dean, H.T., F.A. Arnold, Jr., and E. Elvove. 1942. Domestic water and dental caries: additional studies of relation of fluoride domestic waters to dental caries experience in 4,425 white children aged 12 to 14 years, of 13 cities in 4 states. Public Health Rep. 57:1155-1179.
Ekstrand,J. 1978. Relationship between fluoride in the drinking water and the plasma fluoride concentration in man. Caries Res. 12:123-127.
Esala, S., E. Vuori, and A. Helle. 1982. Effect of maternal fluorine intake on breast milk fluorine content. Br. J. Nutr. 48:201-204.
Full, C.A., and F.M. Parkins. 1975. Effect of cooking vessel composition on fluoride. J. Dent. Res. 54:192.
Heifetz, S.B., and H.S. Horowitz. 1984. The amounts of fluoride in current fluoride therapies: safety considerations for children. J. Dent. Child. 51:257-269.
Hodge, H.C., and F.A. Smith. 1970. Minerals: fluorine and dental caries. Pp. 93115 in R.F. Gould, ed. Dietary Chemicals vs. Dental Caries. Advances in Chemistry Series No. 94. American Chemical Society, Washington, D.C.
Horowitz, A.M., and H.S. Horowitz. 1983. Fluorides and dental caries. Science 220:142-144.
IARC (International Agency for Research on Cancer). 1982. Inorganic fluorides used in drinking-water and dental preparations. Pp. 237-303 in IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 27. Some Aromatic Amines, Anthraquinones and Nitroso Compounds, and Inorganic Fluorides Used in Drinking-Water and Dental Preparations. IARC, Lyon, France.
Krishnamachari, K.A.V.R. 1987. Fluorine. Pp. 365-415 in W. Mertz, ed. Trace Elements in Human and Animal Nutrition, Vol. 1. Academic Press, San Diego, Calif.
Kumpulainen, J., and P. Koivistoinen. 1977. Fluorine in foods. Residue Rev. 68:3757.
Maheshwari, U.R., J.T. McDonald, V.S. Schneider, A.J. Brunetti, L. Leybin, E. Newbrun, and H.C. Hodge. 1981. Fluoride balance studies in ambulatory healthy men with and without fluoride supplements. Am. J. Clin. Nutr. 34:2679-2684.
Marier, J.R., and D. Rose. 1966. The fluoride content of some food and beveragesA brief survey using a modified Zr-SPADNS method. J. Food Sci. 31:941-946.
Martin, D.J. 1951. The Evanston Dental Caries Study. VIII. Fluorine content of vegetables cooked in fluorine containing waters. J. Dent. Res. 30:676-681.
Messer, H.H., W.D. Armstrong, and L. Singer. 1973. Influence of fluoride intake on reproduction in mice. J. Nutr. 103:1319-1326.
Milne, D.B., and K. Schwarz. 1974. Effect of different fluorine compounds on growth and bone fluoride levels in rats. Pp. 710-714 in W. G. Hoekstra, J. W. Suttie, H. E. Ganther, and W. Mertz, eds. Trace Element Metabolism in Animals, 2. University Park Press, Baltimore.
NRC (National Research Council). 1971. Fluorides. Report of the Committee on Biologic Effects of Atmospheric Pollutants. National Academy of Sciences, Washington, D.C. 295 pp.
Ophaug, R.H., L. Singer, and B.F. Harland. 1985. Dietary fluoride intake of 6-month and 2-year-old children in four dietary regions of the United States. Am. J. Clin. Nutr. 42:701-707.
Pak, C.Y.C., K. Sakhafe, J.E. Zerwekh, C. Parcel, R. Peterson, and K. Johnson. 1989. Safe and effective treatment of osteoporosis with intermittent slow release sodium fluoride: augmentation of vertebral bone. J. Clin. Endocrinol. Metab. 68:150159.
Schwarz, K., and D.B. Milne. 1972. Fluorine requirement for growth in the rat. Bioinorg. Chem. 1:331-338.
Singer, L., R.H. Ophaug, and B.F. Harland. 1980. Fluoride intake of young male adults in the United States. Am. J. Clin. Nutr. 33:328-332.
Spak, C.J., J. Ekstrand, and D. Zylberstein. 1982. Bioavailability of fluoride added to baby formula and milk. Caries Res. 16:249-256.
Spak, C.J., L.I. Hardell, and P. deChateau. 1983. Fluoride in human milk. Acta Paediatr. Scand. 72:699-701.
Spencer, H., D. Osis, and M. Lender. 1981. Studies of fluoride metabolism in man: a review and report of original data. Sci. Total Environ. 17:1-12.
Subba Rao, G. 1984. Dietary intake and bioavailability of fluoride. Annu. Rev. Nutr. 4:115-136.
Tao, S., and J.W. Suttie. 1976. Evidence for a lack of an effect of dietary fluoride level on reproduction in mice. J. Nutr. 106:1115-1122.
Taves, D.R. 1983. Dietary intake of fluoride ashed (total fluoride) v. unashed (inorganic fluoride) analysis of individual foods. Br. J. Nutr. 49:295-301.
Taves, D.R., and W.S. Guy. 1979. Distribution of fluoride among body compartments. Pp. 159-185 in E. Johansen, D.R. Taves, and T.O. Olsen, eds. Continuing Evaluation of the Use of Fluorides. Westview Press, Boulder, Colo.
Walters, C.B., J.C. Sherlock, W.H. Evans, and J.I. Read. 1983. Dietary intake of fluoride in the United Kingdom and fluoride content of some foodstuffs. J. Sci. Food Agric. 34:523-528.
Weber, C.W., and B.L. Reid. 1974. Effect of low-fluoride diets fed to mice for six generations. Pp. 707-709 in W.G. Hoekstra, J.W. Suttie, H.E. Ganther, and W. Mertz, eds. Trace Element Metabolism in Animals, 2. University Park Press, Baltimore.
Trivalent chromium is required for maintaining normal glucose metabolism in laboratory animals; it acts as a cofactor for insulin (Mertz, 1969). Experimental chromium deficiency has been induced in several animal species, resulting in impaired glucose tolerance in the presence of normal concentrations of circulating insulin and, in severe cases, in a diabetes-like syndrome (Schroeder, 1966). Three cases of pronounced chromium deficiency have been reported in patients on long-term total parenteral alimentation (Brown et al., 1986; Freund et al., 1979; Jeejeebhoy et al., 1977); all three had in common a relative insulin resistance and peripheral or central neuropathy. Chromium-responsive impairment of glucose tolerance has been reported in malnourished children, in some but not all studies of mild diabetics, and in middle-aged subjects with impaired glucose tolerance. (For a review, see IPCS, 1988.)
Chromium concentrations in human tissues decline with age, except for the lungs in which chromium accumulates. Parity, juvenile diabetes, and coronary artery disease are associated with low-chromium concentrations in hair or serum (IPCS, 1988).
The intestinal absorption of dietary chromium at daily intakes of 40 µg and more is approximately 0.5% of the total amount present; intakes of less than 40 µg/day are absorbed with an increasing efficiency, up to about 2% of the total (Anderson and Kozlovsky, 1985). Absorbed chromium is excreted almost completely through the urine.
Chromium intake from typical Western diets varies widely between a low of 25 µg/day in elderly persons in England to approximately 200 µg in Belgian and Swedish diets, but in the most recent international studies (IPCS, 1988), intakes below 100 µg/day were reported. Two experimental diets prepared to meet the RDAs for all nutrients and furnishing 2,800 calories contained 62 and 89 µg of chromium at a fat content of 43 and 25% of the energy, respectively (Kumpulainen et al., 1979). This is in contrast to the average chromium intake of 33 and 25 µg/day from self-selected diets of adults in Beltsville, Maryland, in diets containing 2,300 and 1,600 kcal, respectively (Anderson and Kozlovsky, 1985).
Estimated Safe and Adequate Daily Dietary Intakes
Because of the lack of methods to diagnose chromium status, it is difficult to estimate a chromium requirement. In the majority of all
chromium supplementation studies in the United States, at least half' the subjects with impaired glucose tolerance improved upon chromium supplementation, suggesting that the lower ranges of chromium intakes from typical U.S. diets are not optimal with regard to chromium nutriture (Anderson et al., 1983).
Experiments in vitro and in animals have demonstrated substantial differences in the biological activity of different chromium compounds. Although the chemical forms of chromium in foods are not known with certainty, a chromium-dinicotinic acid-glutathione complex with high bioavailability has been identified in brewer's yeast. The bioavailability of chromium in calf's liver, American cheese, and wheat germ is also relatively high. More precise data on the nutritional value of chromium in various foods are not yet available. Thus, the best assurance of an adequate and safe chromium intake is the consumption of a varied diet balanced with regard to other essential nutrients. A range of chromium intakes between 50 and 200 µg/day is tentatively recommended for adults. This range is based on the absence of signs of chromium deficiency in the major part of the U.S. population consuming an average of 50 µg/day. The safety of an intake of 200 µg has been established in long-term supplementation trials in human subjects receiving 150 µg/day in addition to the dietary intake (Glinsmann and Mertz, 1966). Habitual dietary intakes of around 200 µg/day have been reported in several studies; no adverse effects of such intakes are known. The suggested range of chromium intake is predicated on the assumption that a varied diet providing an adequate intake of other essential micronutrients will furnish chromium with an average absorbability of 0.5%.
The tentative recommendations for younger age groups are derived by extrapolation on the basis of expected food intake. Until more precise recommendations can be made, the consumption of a varied diet, balanced with regard to other essential nutrients, remains the best assurance of an adequate and safe chromium intake.
Excessive Intakes and Toxicity
The toxicity of trivalent chromium, the chemical form that occurs in diets, is so low that there is a substantial margin of safety between the amounts normally consumed and those considered to have harmful effects. No adverse effects were seen in rats and mice consuming 5 mg/liter in drinking water throughout their lifetimes, and no toxicity was observed in rats exposed to 100 mg/kg in the diet (IPCS, 1988).
An increased incidence of bronchial cancer has been correlated with chronic occupational exposure of workers to dusts containing chromate, the hexavalent form of chromium (IPCS, 1988). Humans cannot oxidize the nontoxic trivalent food chromium to the potentially carcinogenic hexavalent chromate compounds. Therefore, the carcinogenicity of certain chromates bears no relevance to the nutritional role of trivalent chromium.
Anderson, R.A., and A.S. Kozlovsky. 1985. Chromium intake, absorption, and excretion of subjects consuming self-selected diets. Am. J. Clin. Nutr. 41:11771183.
Anderson, R.A., M.M. Polansky, N.A. Bryden, E.E. Roginski, W. Mertz, and W.H. Glinsmann. 1983. Chromium supplementation of human subjects: effects on glucose, insulin, and lipid variables. Metabolism 32:894-899.
Brown, R.O., S. Forloines-Lynn, R.E. Cross, and W.D. Heizer. 1986. Chromium deficiency after long-term total parenteral nutrition. Dig. Dis. Sci. 31:661-664.
Freund, H., S. Atamian, and J.E. Fischer. 1979. Chromium deficiency during total parenteral nutrition. J. Am. Med. Assoc. 241:496-498.
Glinsmann, W.H., and W. Mertz. 1966. Effect of trivalent chromium on glucose tolerance. Metabolism 15:510-520.
IPCS (International Programme on Chemical Safety). 1988. Chromium. Environmental Health Criteria 61. World Health Organization, Geneva.
Jeejeebhoy, K.N., R.C. Chu, E.B. Marliss, G.R. Greenberg, and A. Bruce-Robertson. 1977. Chromium deficiency, glucose intolerance and neuropathy reversed by chromium supplementation in a patient receiving long-term total parenteral nutrition. Am. J. Clin. Nutr. 30:531-538.
Kumpulainen, J.T., W.R. Wolf, C. Veillon, and W. Mertz. 1979. Determination of chromium in selected United States diets. J. Agric. Food Chem. 27:490-494.
Mertz, W. 1969. Chromium occurrence and function in biological systems. Physiol. Rev. 49:163-239.
Schroeder, H.A. 1966. Chromium deficiency in rats: a syndrome simulating diabetes mellitus with retarded growth. J. Nutr. 88:439-445.
Molybdenum plays a biochemical role as a constituent of several mammalian enzymes, such as aldehyde oxidase, xanthine oxidase, and sulfite oxidase (Rajagopalan, 1988); however, production of characteristic pathological lesions in animals due to nutritional molybdenum deficiency has been difficult (Mills and Bremner, 1980). Although naturally occurring deficiency, uncomplicated by antagonists, is not known with certainty, molybdenum deficiency has been produced experimentally in goats by feeding them purified rations containing less than 0.07 µg of molybdenum per gram of diet. The consequences are retarded weight gain, decreased food consumption,
impaired reproduction, and shortened life expectancy (Anke et al., 1985). On the basis of these studies, Anke et al. (1985) suggested that the minimum molybdenum requirement of goats was approximately 100 µg/kg of ration dry matter. However, the molybdenum requirement of monogastric species may be less than that of ruminants because of the molybdenum needs of rumen microflora (Anke et al., 1985).
Two recent lines of investigation have suggested a role for molybdenum in human nutrition. The first involved a patient on long-term total parenteral nutrition who developed a variety of symptoms, including amino acid intolerance, irritability, and, ultimately, coma (Abumrad et al., 1981). This person also displayed hypermethioninemia, increased urinary excretion of xanthine and sulfite, and decreased urinary excretion of uric acid and sulfate. Treatment with 300 µg of ammonium molybdate (equivalent to about 163 µg of molybdenum) per day resulted in clinical improvement and normalization of sulfur metabolism and uric acid production. The authors concluded that this may be the first report of a feeding-induced molybdenum deficiency in humans.
The second line of evidence concerns a rare inborn error of metabolism that leads to a combined deficiency of sulfite oxidase and xanthine dehydrogenase (Rajagopalan, 1988). This metabolic disease is due to a lack of the molybdenum cofactor (molybdopterin), which is an essential constituent of these enzymes. Patients with this defect display severe neurological dysfunction, dislocated ocular lenses, and mental retardation. Biochemical abnormalities are similar to those observed in the intravenously fed patient cited above. Structural characterization of molybdopterin indicates the presence of a reduced pterin ring, a 4-carbon side chain containing an enedithiol, and a terminal phosphate ester (Rajagopalan, 1988).
Dietary Sources and Usual Intakes
The concentration of molybdenum in food varies considerably, depending on the environment in which the food was grown (Mills and Davis, 1987). Therefore, tabulations of expected molybdenum concentrations in various foods are of limited value (Chappell, 1977). Tsongas et al. (1980) calculated that the dietary intake of molybdenum in the United States ranged from 120 to 240 µg/day, depending on age and sex, and averaged about 180 µg/day. The foods that contributed the most to the molybdenum intake were milk, beans, breads, and cereals. Pennington and Jones (1987) found a lower molybdenum content in the 1984 collection of the Food and Drug
Administration's Total Diet Study ranging from 76 to 109 µg/day for adult females and males, respectively. Human milk contains very low levels of molybdenum, and after the first month of lactation, furnishes only approximately 1.5 µg/day (Casey and Neville, 1987). little is known about the chemical form or nutritional bioavailability of molybdenum in foods. Most public water supplies would be expected to contribute between 2 to 8 µg of molybdenum per day (NRC, 1980), which would constitute 10% or less of the lower limit of the provisional recommended intake. Since most diets should meet the molybdenum requirements of humans, supplements of additional molybdenum are not recommended.
Estimated Safe and Adequate Daily Dietary Intakes
Aside from the exceptions discussed above, no disturbances in uric acid or sulfate production have ever been related to molybdenum deficiency in humans. The human requirement apparently is so low that it is easily furnished by common U.S. diets. Therefore, the provisional recommended range for the dietary intake of molybdenum, based on average reported intakes, is set at 75 to 250 µg/day for adults and older children. The range for other age groups is derived through extrapolation on the basis of body weight.
Excessive Intakes and Toxicity
The toxicity of molybdenum presents a substantial problem for animal nutrition because molybdenum is antagonistic to the essential element copper (Mills and Davis, 1987). Adverse effects of high environmental concentrations of molybdenum were observed in humans living in a province of the USSR (Koval'skiy and Yarovaya, 1966). The authors suggested that the excessive dietary intake of 10 to 15 mg/day may be the cause of a high incidence of a goutlike syndrome associated with elevated blood levels of molybdenum, uric acid, and xanthine oxidase. Even a moderate dietary exposure of 0.54 mg/day has been associated with loss of copper in the urine (Deosthale and Gopalan, 1974).
Abumrad, N.N., A.J. Schieider, D. Steel, and L.S. Rogers. 1981. Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate theraps. Am. J. Clin. Nutr. 34:2551-2559.
Anke, M., B. Groppel, and M. Grun. 1985. Essentiality, toxicity, requirement and supply of molybdenum in humans and animals. Pp. 154-157 in C.F. Mills, I. Bremner, and J.K. Chesters, eds. Trace Elements in Man and AnimalsTEMA 5. Commonwealth Agricultural Bureaux, Slough, United Kingdom.
Casey, C.E., and M.C. Neville. 1987. Studies in human lactation 3: molybdenum and nickel in human milk during the first month of lactation. Am. J. Clin. Nutr. 45:921-926.
Chappell, W.R., ed. 1977. Proceedings: Symposium on Molybdenun in the Environment, Vol. 2. Marcel Dekker, New York. 812 pp.
Deosthale, Y.G., and C. Gopalan. 1974. The effect of molybdenum levels in sorghum (Sorghum vulgare Pers.) on uric acid and copper excretion in man. Br. J. Nutr. 31:351 -355.
Koval'skiy, V.V., and G.A. Yarovaya. 1966. Molybdenum-infiltrated biogeochemical provinces. Agrokhlimiiya 8:68-91.
Mills, C.F., and I. Bremner. 1980. Nutritional aspects of molybdenum in animals. Pp. 517-542 in M.P. Coughlan, ed. Molybdenum and Molybdenum-Containing Enzymes. Pergamon Press, Oxford.
Mills, C.F., and G. K. Davis. 1987. Molybdenum. Pp. 429-463 in W. Mertz, ed. Trace Elements in Human and Animal Nutrition, 5th ed, Vol. 1. Academic Press, Orlando, Fla.
NRC (National Research Council). 1980. The contribution of drinking water to mineral nutrition in humans. Pp. 265-404 in Drinking Water and Health, Vol. 3. Safe Drinking Water Committee, Board on Toxicology and Environmental Health Hazards, Assembly of Life Sciences. National Academy Press, Washington, D.D.
Pennington, J.A.T., and J.W. Jones. 1987. Molybdenum, nickel, cobalt, vanadium, and strontium in total diets. J. Am. Diet. Assoc. 87:1644-1650.
Rajagopalan, K.V. 1988. Molybdenum an essential trace element in human nutrition. Annu. Rev. Nutr. 8:401-427.
Tsongas T.A., R.R. Meglen, P.A. Walravens, and W.R. Chappell. 1980. Molybdenum in the diet: an estimate of average daily intake in the United States. Am. J. Clin. Nutr. 33:1103-1107.