Trace minerals in the nutrition of children J. A. M i l n e r , PhD From the Nutrition Department and Graduate Program in Nutrition, Pennsylvania State University, University Park

Trace elements perform important functions in growth and development. However, little information exists about their dietary requirements during the demanding period of infancy. Opportunities to a d d to knowledge of the physiologic significance and dietary a d e q u a c y of trace elements in human nutrition are provided by recent analytic advances. Specific, sensitive, and reliable methods for the detection of trace element imbalances are sorely needed. Although several factors influence the dietary needs of these essential elements, the basis for establishing dietary needs in infants is hindered by the dearth of studies that have assessed their bioavailability in this a g e group. Thus until it has been conclusively shown otherwise, the physiologic response to human milk is used as the standard for infant feeding practices. This review is limited primarily to the physiologic significance and bioavailability of zinc, copper, manganese, molybdenum, chromium, fluoride, and selenium. The space devoted to each trace element is not meant to represent the element's importance but, rather, to reflect some of the present understanding of its metabolism and utilization. (J PEDIATR1990;117:S147-55)

Trace elements, despite their relative scarcity in tissues, perform important functions in health and resistance to disease. Animal studies document that the inadequate intake of several trace elements leads to abnormal development, poor growth, or a higher frequency of neonatal deaths. The recognition that trace elements regulate key metabolic pathways, modulate the immune response, and suppress the incidence of various disease states serves to emphasize their direct importance in health maintenance. Infancy is probably the most demanding period of life for meeting the body's nutritional demands. Weight typically doubles during the first 4 to 6 months of life and triples by the end of the first year. This rate of growth necessitates a diet that contains highly nutritious foods to minimize concerns associated with osmotic load and toxicity. Infants ' generally receive a single source of nourishment, either human milk or a product formulated to resemble human milk, Supported in part by National Institute of Child Health and Human Developmentgrant No. 18689. Reprint requests: John A. Milner, PhD, Nutrition Department, 126 Henderson Bldg. South, PennsylvaniaState University, University Park, PA 16802. 9/0/21642

Table I. Representative values of some trace elements in human milk and in formulas

Trace elements

Mature human milk (units/L)

Infant formulas (units/L)

Zinc (rag) Copper (gg) Manganese (/zg) Molybdenum (/xg) Chromium (#g) Fluoride (/~g) Selenium 0zg)

0.14-4.0 90-630 1.9-27.5 0.1-1.7 40-80 5-50 8-50

3.7-12 500-2000 70-530 30-70 10-20 30-100 5-10

during this period, so it is of paramount importance to ensure that adequate quantities of utilizable essential trace elements are provided. Table I contains representative values of some of the trace elements found in human milk and infant formulas. Although considerable knowledge exists about the physiologic significance of trace elements in human nutrition, the incidence of deficiency of trace elements remains largely undetermined. Diagnosis of specific trace element inade-

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The Journal of Pediatrics August 1990

T a b l e II. Recommended dietary intakes of trace

elements during the first half of infancy Trace elements

Recommended Intake (mg/day)

Iron Zinc Iodine Copper Manganese Molybdenum Chromium Selenium Fluoride Data from Foodand Nutrition Board.7~

6 5 0.4 0.4-0.6 0.3-0.6 0.015-0.03 0.01-0.04 0.01 0.1-0.5

quacy should recognize degrees of imbalance within specific subdivisions according to the severity of the defects. Unfortunately, these subdivisions are not always easily definable because of the limited ability to detect subtle yet specific metabolic defects. Abnormal growth must be considered an insensitive indicator and is unsatisfactory for the detection of trace element imbalances. Specific reliable and Sensitive methods for the detection of imbalances are needed for the diagnosis of specific trace element inadequacy. Recent analytic developments offer exciting opportunities for the continued examination of the physiologic significance of these essential nutrients and for determining their adequacy in the diet. Experience indicates that complacency about the adequacy of consumption of the trace elements is not justifiable, even for those elements for which there is no known physiologic role. The dearth of information about the specific need for the various trace and ultratrace elements should be a historical issue and not a concern about infant and weaning feeding practices before the end of this century. TRACE ELEMENT NEEDS AND BIOAVAILABILITY Of the 90 naturally occurring chemical elements, 27 are known or claimed to be essential for life. Of these, 15 elements (arsefiic, chromium, cobalt, copper, fluorine, iron, iodine, manganese, molybdenum, nickel, selenium, silicon, tin, vanadium, zinc) are generally recognized as trace elements. Several factors influence trace element nutrition of infants: 1. 2. 3. 4. 5.

Tissue reserves Growth demands Genetic variables Physical characteristics of the diet Chemical composition of the diet a. Form and content

b. Presence of ligands c. Presence of organic or inorganic agonists and antagonists 6. Interactions within the intestinal lumen 7. Interactions at the intestinal membrane 8. Intercellular binding proteins and endogenous mediators 9. Drugs and other chemicals 10. Infections and diseases In addition to the rate of growth, tissue reserves and the content and bioavailability of the element are major issues to be considered in evaluating the adequacy of a diet. Assessing daily needs is particularly complicated by fluctuations in quantity and form of trace elements within and among the tissues. When intakes are inadequate, obligatory losses eventually deplete any tissue reserves. Bioavailability refers to that fraction of the element in food which is absorbed and utilizedJ Although bioavailability applies to all nutrients, it is particularly pertinent to trace elements because many factors affect their absorption and assimilation. 13 The introduction of solid foods poses additional bioavailability issues, not only in regard to the nutrients in the introduced food, but also concerning the potential changes in the bioavailability of nutrients that had been obtained from human milk or proprietary formula. Unfortunately, few studies have monitored nutrient bioavailability in the infant who is consuming a single source of nourishment, and even fewer in the infant consuming a complex diet. Thus the estimates of dietary needs during infancy (Table II) are frequently based on extrapolation of data from animal studies or studies of adult human beings, or on typical nutrient intakes of apparently healthy infants. The dietary needs for the trace elements are known with varying degrees of certainty, especially during infancy (Figure). Although significant contributions to the understanding of nutrient requirements throughout the phases of life, especially for the premature infant, have been made during recent years, additional information about the requirements of infants is needed. For example, knowledge of nutrient requirements of the weaning infant is practically nonexistent. The physiologic role of these trace elements is known with varying degrees of certainty, and only limited information exists on the bioavailability of these elements in weaning foods; this review will therefore be limited primarily to zinc, copper, manganese, molybdenum, chromium, fluoride, and selenium. The discussion of these trace elements reflects the present understanding of their metabolism and utilization. Issues about iron nutrition of infants are discussed by Filer4 elsewhere in these proceedings.

Volume 117 Number 2, Part 2

Trace minerals in the nutrition o f children

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Figure. Kn•w•edge •f nutriti•na• requirements •f infants• chi•dr•n• and y•ung adu•ts. EFA• Ess•ntia• fatty acids. (Modified from W. Mertz, personal communication, 1976.)

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ZINC Zinc is an essential nutrient that functions in growth, reproduction, tissue repair, and cellular immunity. It has four distinct roles in metabolism: as a component of zinccontaining metalloenzymes, in polyribosome conformation, in membrane stabilization, and in assorted cellular ionic functions. Its functions as a constituent of metalloenzymes include catalytic, structural, and regulatory roles. 5 Although the essentiality of zinc has long been recognized, its ubiquity was for many years incorrectly construed to mean that a dietary deficiency was not a plausible problem in human nutrition. Nevertheless, by 1961, evidence mounted that a clinical zinc deficiency syndrome consisting of growth retardation, male hypogonadism, skin changes, mental lethargy, hepatosplenomegaly, iron deficiency anemia, and geophagia occurred in specific populations. 6 Nutritional deficiencies of zinc in human beings are now recognized as being fairly prevalent throughout the world. 79 Most recently, a nutritional deficiency of zinc in children and infants was reported in the United States] ~ These growth-retarded children, from middle and upper income families living in Denver, responded to zinc supplementation by increased linear growth. Mean plasma zinc concentrations of exclusively human milk-fed infants have been reported to be similar to those found in adults11; reduced zinc bioavailability in at least some formulas probably accounts for the observed incidence of zinc inadequacy in these infants. Although the occurrence of zinc inadequacy in infants and children in the United States remains a topic of considerable debate, the prevalence does not appear to be universal. Nevertheless, determining adequate and reasonable quantities of zinc for infants is particularly difficult because information about losses (endogenous fecal and dermal) is inadequate and because sensitive methods of detecting imbalances to estimate zinc requirements properly are lacking. Plasma or serum concentrations of zinc do not appear to respond quickly to dietary changes in zinc intake. 12 Fluctuations in the quantity of zinc absorbed probably limit the utility of plasma or serum measurements as a sensitive indicator of zinc intakes. Nevertheless, plasma and serum concentrations are useful in detecting frank zinc deficiency. The levels and activities of zinc metalloenzymes and zinc-dependent enzymes in tissues of zinc-deficient animals have been studied extensively.5 Sensitivity to deficiency varies with zinc affinity and the rate of turnover of the enzyme. The appropriate enzyme for assessing status is difficult to establish because of known differences in the sensitivity of zinc-containing enzymes to dietary imbalances across tissues. Alkaline phosphatase is notable for its rapid loss of activity after the induction of zinc deficiency. 13 Pancreatic carboxypeptidases A and B are also sensitive to

The Journal of Pediatrics August 1990

zinc depletion, but erythrocyte carbonic anhydrase activity is less sensitive. 13 Nevertheless, at present, no universally accepted enzymatic change is used to indicate marginal zinc inadequacy. Although the mechanisms and control of zinc absorption are not completely understood, Cousins 14 proposed that intestinal absorption involves uptake by the intestinal cell, movement through the mucosal cell, transfer to the portal circulation, and secretion of endogenous zinc back into the intestinal cell. Zinc supply and tissue reserves are major factors in the homeostatic control of zinc absorption by the regulation of mucosal cell absorption. The induction of metallothioneine by high circulating zinc concentrations allows intestinal mucosa cells to trap zinc and thereby exert control over zinc homeostasis. Although zinc balance data in infants are limited, it appears that the most important factor in determining requirements relates to new tissue deposition. 15Thus the more rapid the growth rate, the higher are the requirements for zinc. The most dominant factor affecting dietary needs relates to the variation in the percentage of absorption of zinc from individual foods. The percentage and absolute quantity of zinc absorbed vary with the quantity of zinc in the diet. The percentage of absorbed zinc is considerably lower when the mineral is ingested as part of, or in conjunction with, a meal, with the possible exception of human milk. Using the rat as a model, Johnson and Evans 16observed zinc absorption values of 59%, 42% to 50%, and 27% to 39% for human milk, cow milk, and infant formulas, respectively. The association of zinc with low-molecular-weight constituents or readily digestible proteins is proposed to account for the higher bioavailability of zinc in human milk than in bovine milk. 17, 18 Phytate has attracted considerable interest as a major factor interfering with the intestinal absorption of zinc. Zinc deficiency occurring in Iranian children, adolescents, and young adults has been attributed to the consumption of a phytate-rich flat bread, tanok, a major staple of the rural parts of central and southern Iran. 19 Despite the publicity regarding phytate as a major regulator of bioavailability, the importance of phytate-zinc ratios in determining zinc status is confusing, if not contradictory. The phytate content of Iranian flatbread does not appear to account totally for the observed depression in zinc bioavailability, and it has been suggested that the quantity or type of fiber associated with the food may be critical. 2~ Although several studies have examined the significance of dietary fiber on the zinc status of human beings, these data are as confusing, if not more so, than the data obtained in studies examining phytate. Part of the difficulty in interpretation of zinc bioavailability may reside in differences in the effects of phytate when it is added in a purified form, rather than in-

Volume 117 Number 2, Part 2

gested as a component of a food within a composite meal. Part of the variation in zinc bioavailability may also relate to factors influencing the rate of phytate hydrolysis. Dietary calcium is a significant modifier of zinc-phytate hydrolysis.2 The overall significance of interactions of zinc with calcium in human beings is equivocal. Spencer et al. a~ were unable to detect differences in the intestinal absorption of zinc in persons consuming from 200 to 2000 mg calcium. Likewise, Price et al. 22 reported that dietary calcium had no effect on zinc balance in children. Dietary protein is another suggested modifier of zinc bioavailability. Again, conflicting reports on the relationship between protein intake and zinc bioavailability are evident.23, 24 Solomons and Jacob 25 observed a significant reduction in apparent zinc absorption, as shown by alterations in plasma zinc concentration, when iron was supplied in the ferrous form in a molar ratio to zinc at 2:1 or greater. Ferric iron supplementation produced a less pronounced effect, and heine iron had no detectable influence on zinc bioavailability.26 Variation in zinc absorption from different milks and formulas is of particular practical concern in infant feeding practices. Zinc bioavailability from, or with, human milk is considerably greater than that from bovine milk.27, 28 Hence, zinc requirements of infants fed cow milk-based formula appear to be higher than in those fed human milk. Markedly depressed plasma zinc concentrations in infants fed soy-based infant formulas likely relate to the relatively poor bioavailability of zinc from this food source. 27' 28 COPPER The physiologic significance of copper was not appreciated until 1928, when Hart et al. 29 demonstrated its essentiality in the rat. Copper is now known to be an essential component of a number of copper metalloenzymes. The essentiality of copper within these enzymes relates primarily to its ability to engage in oxidation-reduction reactions. 3~ The principal symptoms of subjects with copper deficiency are associated with severe malnutrition, significant malabsorption, and low birth weight. 31 Anemia and neutropenia are regular features of copper deficiency. Copper, apart from its association with iron in cytochrome oxidase, is also necessary for the release of iron from stores and the !ncorporation of iron into plasma transferrin. As a component of lysyl oxidase, it is essential for proper cross-linking of both collagen and elastin polypeptide chains. Changes in cytochrome c oxidase activity have been used to examine copper bioavailability. A 50% reduction in the activity of cytochrome oxidase is associated with serious neurologic, cardiac, and muscle disease. 32 Other enzymes, including superoxide dismutase, have been used to demonstrate the antagonistic effect of zinc on copper status, 33' 34

Trace minerals in the nutrition o f children

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Acute copper deficiency has been described in several cases of long-term parenteral nutrition. Prematurity is a predisposing factor to the onset of a deficiency, unless adequate provisions are taken to ensure adequate intakes of copper. Deficiency symptoms can become evident within 7 weeks in preterm infants receiving total parenteral nutrition with no oral supplements.35 Absorption of copper in the small intestine has both active and passive components that do not appear to be dramatically influenced by the form in which the copper is presented. Within the mucosal ceils, copper can associate with metallothioneine. It is unclear whether metallothioneine has any role in the normal absorption process or whether it primarily prevents excessive absorption when copper intakes are high. The primary route of excretion is in the bile, where it is complexed to proteins and low-molecular-weight ligands. This protein-bound copper is poorly reabsorbed, although some does enter an enterohepatic circulation. Information regarding the bioavailability of copper is limited, most likely because of the lack of a convenient radioisotope. Lo et al., 36 using a slope ratio method to assess the absorption of copper from isolated soybean protein in the rat, found that the copper in soy protein replenished serum and liver copper levels of immature rats at the same rate as did copper from cupric carbonate. Lonnerdal et al. 37 using an extrinsic tag, found no significant differences between human milk (25%) and cow milk formula (23%); however, when suckling rats were examined, copper in cow milk (18%), cereal milk formula (17%), and soy formula (10%) was absorbed to a significantlylower extent than that from human milk. Differences between these studies may be explained by physiologic age and by maturation of intestinal enzymes. The absence of appreciable low-molecularweight copper complexes in human milk, as occurs with zinc, may explain the relatively consistent rates of utilization and the inability of human milk to improve copper absorption in Menkes kinky-hair syndrome.38' 39 The dietary source of carbohydrates is a factor capable of modifying copper bioavailability. Fructose and sucrose accentuate the deficiency signs induced by a diet low in copper, compared with the effect of starch and glucose. 4~ MANGANESE In 1931, Orent and McCollum41 demonstrated the essentiality of manganese for the rat. These investigators noted a high neonatal mortality rate in offspring of manganese-deficient animals. Subsequently, manganese metabolism has been studied in numerous other species. 42 Deficiency symptoms in animals include, in addition to impaired reproductive performance, poor growth, congenital ataxia, and skeletal dyschondroplasia. Manganese is required for the synthesis of the mucopolysaeeharides (structural corn-

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ponents of cartilage) and of prothrombin. Only one case of manganese deficiency has been reported in a human being; the symptoms included hypocholesterolemia, slowed growth of hair and nails, hair depigmentation, and reduced levels of blood clotting proteins. 43 Manganese metabolism is poorly understood. The human fetal liver does not accumulate manganese, as it does copper and, to a lesser extent, iron and zinc. Furthermore, there are only limited data on the content of manganese in other tissues. It is possible that bone may represent a significant storage site for this element. A positive correlation between iron and manganese in stool has been noted. 44 Animal studies indicate that high iron intakes interfere with manganese absorption, whereas manganese absorption is increased when the iron level is low. Likewise, high dietary levels of manganese tend to block iron absorption. The manganese content of human milk was reported during the early 1970s to be 15 #g/L. Recent data indicate lower amounts, with the concentration declining from approximately 7 ~ g / L in the first month to 4 # g / L in later months. 45 The quantity of manganese in cow milk is about 35/~g/L, whereas U.S. formulas provide between 70 and 3 50 #g/L. Differences among human milk, bovine milk, and infant formula in the number and type of manganese ligands that may affect bioavailability have been reported. 46 High levels of manganese are no longer added to some infant formulas because such supplementation is deemed unnecessary. Gibson 47 reported that the major food sources of manganese were fruits and juices. In older infants, cereals provided a greater proportion of the intake of manganese; however, fruit and juices remained significant sources. MOLYBDENUM Although the essentiality of molybdenum for plant growth and the functional role of the metal in several bacterial, plant, and animal enzymes has long been recognized, it has been difficult to establish the importance of this element to human health. Difficulty in inducing a deficiency has hampered the understanding of the significance of this trace element. The severity of the pathologic changes associated with deficiency of hereditary sulfite oxidase, a molybdenum-containing enzyme, established the essentiality of this trace element for normal human development. 48 Over 20 cases of inborn errors leading to sulfite oxidase deficiency have been recognized. 49 The biologic functions of molybdenum can be traced to its role as a prosthetic group in three enzymes: xanthine oxidase-dehydrogenase, aldehyde oxidase, and sulfite oxidase. The inability to regulate sulfur metabolism appears to be one of the primary defects associated with molybdenum deficiency.

The Journal of Pediatrics August 1990

Interesting metabolic interrelationships exist between molybdenum and other trace elements. Tungstate, a competitive inhibitor of molybdenum uptake, when added to the diet of adult rats, did not lead to gross anatomic problems but increased the sensitivity of these animals to sulfite toxicity.5~Excess molybdenum also results in the precipitation of copper deficiency. Likewise, excess copper alleviates the toxic effects of molybdenum in several species. The content of molybdenum in food is somewhat dependent on the soil content. Milk, cereals, and meats generally are recognized as major dietary sources of this trace element. However, bioavailability from these foods fed to infants has not been assessed. I know of no report of dietary molybdenum deficiency in human beings. Likewise, studies of molybdenum metabolism during infancy are virtually nonexistent. Balance studies in adults have detected retention after intakes of 2 #g/kg/day. 51 The safe and adequate range of intakes for infants (Table II) was derived by extrapolation from these balance studies. CHROMIUM

Despite the acceptance of chromium as a nutritionally essential trace element for animals and humans, information about its biologic functions is sketchy and inconclusive. Although typically found in nanogram quantities in nature, chromium is ubiquitous, and this has limited the concerns about inadequacy in the human diet. The methodologic problems associated with chromium analysis have also limited the understanding of the physiologic significance and dietary adequacy of this trace element. Adequate measures of chromium status, its chemistry, or its bioavailability are not well understood. Amino acids and oxalates may increase absorption; phytate may decrease bioavailability. Cow milk is reported to contain less chromium than human milk, and the element is present in cow milk in a form that is not biologically available. 52 The concentration of chromium in hair has been used as an index of status. Its concentration is normally high in term infants and may be substantially lower in preterm infants. Children recovering from protein-energy malnutrition often have improved growth as well as improved glucose tolerance after administration of chromium, s3 Three cases of deficiency after total parenteral nutrition have been reported. 54 Symptoms included abnormal glucose tolerance, ataxia, and peripheral neuropathy. These reports suggest that urine, hair, serum, or plasma chromium concentrations are not good markers of body status. 54 The use of erythrocytes, leukocytes, and adipose cells poses special analytic problems that limit their usefulness in assessing chromium status. As a result, there is no effective method to assess the incidence of chromium inadequacy, and it is impossible to determine accurately the role of chromium in human nutrition.

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On the basis of the chromium content (25 #g/1000 kcal) of the American food supply, and an average availability of less than 1% to 2%, the Food and Nutrition Board of the National Research Council has proposed a range of safe and adequate intake of 50 to 200 #g/day for adults. Recommendations for infants (Table II) are extrapolated from expected food intake. FLUORIDE The essentiality of fluoride for higher animals, including human beings, is disputable. Fluoride confers maximal resistance to dental caries and may assist in skeletal structure maintenance. Fluoride can be recognized as an essential trace element because of its role in health maintenance. The concentration of fluoride in human milk ranges from approximately 5 to 50/zg/L, and the milk content is similar for women drinking fluoridated water and those drinking water naturally low or high in this element.55 Cow milk normally contains greater amounts of fluoride. The Committee on Nutrition of the American Academy of Pediatrics 56 recently revised its recommendation for fluoride supplementation during infancy. This group recommends 0.25 mg/day, the midpoint of the safe and adequate range proposed by the Food and Nutrition Board of the National Research Council (Table II). Fluoride supplementation of infants is advised only when the water supply contains fluoride at concentrations less than 0.3 ppm, and human milk provides total nourishment for more than 6 months. The Committee on Nutrition also recommended that formulas be prepared with water low in fluoride to prevent possible fluorosis, because such products may be diluted with water containing high levels of this element. SELENIUM Selenium is recognized as a nutritionally essential element for numerous species. 57 Deficiencies are associated with various disorders, including muscle disease in lambs and calves, exudative diathesis and pancreatic fibrosis in chicks, hepatosis dietetica in pigs, and liver necrosis in rats. The role of selenium in metabolic regulation of a wide variety of tissues and in the reduction of the incidence of various types of cancer in experimental animals5s supports the basic biologic function of this trace element, probably in addition to its role as part of the enzyme glutathione peroxidase.59, 60 Dietary supplementation of selenium has been reported to increase the growth of children with kwashiorkor, to prevent muscle pains in adults receiving long-term parenteral feeding, and to prevent Keshan disease, a cardiomyopathy. 57-59 In 1989, Lockitch et al. 61 reported that selenium deficiency may be an unrecognized problem in low birth weight neonates. This report and other evidence support the essentiality of this trace element in the human diet.

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In all species studied, the young and the reproductive female are at greatest risk of the development of selenium deficiency.62 Infants are at particularly high risk because of their rapid rate of growth and their reliance on a single source of nourishment. The quantity of selenium in milk varies geographically, possibly reflecting differences in maternal intake.63, 64 The content of selenium in U.S. infant formulas has been reported to be approximately half that of human milk from U.S. women.64 Selenium resembles sulfur in manY chemical respects, 57 but these elements are not interchangeable in biologic systems. Selenium exists in a number of biologic states in nature. Most forms appear to be metabolized to selenite, further reduced to selenides, or both. Thus most naturally occurring forms of selenium appear to enter a common metabolic pool. These forms are not equal in their bioavailability. Early studies showed that both inorganic and organic forms of selenium were rather rapidly absorbed, with little evidence of an influence of a valence state. However, the retention of selenium was superior when it was offered as selenomethioninerather than selenite. Recent data show that these differences in retention relate to the incorporation of selenomethionine into nonspecific cellular proteins. The transfer RNA for methionine is unable to detect the presence of selenium, and therefore selenomethionineis incorporated into sites where methionine would normally be present. 65 Thus the simple measurement of tissue retention can give a false impression of the bioavailability of selenium. Incorporation of selenium into glutathione peroxidase appears to be a better measure of bioavailability until proven otherwise. Relatively few studies have focused on selenium nutrition of infants. Early data indicated that serum, whole blood, and hair concentrations, although high at birth, declined to 30% to 50% of neonatal values by 5 to 6 months of age. 66 This reported decline probably reflects the lower content of selenium, its lesser degree of bioavailability, or both, in formulas, in comparison with human milk. Nevertheless, the clinical significance of these observations is unclear. As evidenced for other trace elements, the selenium level is high in colostrum but falls to a level typical of mature mammary secretions within 2 weeks and remains relatively unchanged.64 Bioavailability of selenium from human milk appears to be somewhat greater than that from bovine milk.6769 Corresponding differences in selenium intakes by formula and human milk are reflected in serum and plasma concentrations and in plasma glutathione peroxidase activities of 3-month-old infants.64' 66 Selenium exists in various selenoproteins in human milk. 69 Whether this accounts for the greater bioavailability of selenium in human than in bovine milk is unknown. The infant's requirement for selenium has not been defined. A range of safe and adequate dietary intakes of se-

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lenium has been estimated, primarily by extrapolation from the selenium r e q u i r e m e n t of m a m m a l i a n a n i m a l species. This extrapolation makes the b r o a d assumption t h a t this dietary concentration of selenium will also meet the h u m a n requirement. These estimates do not seem to reflect the selenium intake of infants in the U n i t e d States; recent data have shown t h a t in approximately 60% of the h u m a n m i l k fed and in 95% of the formula-fed infants, selenium intakes were less t h a n the 10 to 40 t~g/day proposed by the N a t i o n a l R e s e a r c h Council. 64 SUMMARY M o d e r n trace element research is primarily concerned with approximately 17 elements, the essentiality of which either has been established or is strongly suspected. Even when one concentrates on the seven or eight trace elements for which problems of deficiency or excess occur in h u m a n beings, the m a g n i t u d e of the effects on metabolic pathways and possible physiologic interactions is enormous. Nevertheless, it is essential t h a t a more comprehensive understanding of the physiologic action a n d the needs for trace elements of the infant be established. REFERENCES

1. O'Dell BL. Bioavailability of and interactions among trace elements. In: Chandra RK, ed. Trace elements in nutrition of children. New York: Raven Press, 1985:41-62. 2. Mills CF. Dietary interactions involving the trace elements. Ann Rev Nutr 1985;5:173-93. 3. Forbes RM, Erdman JW Jr. Bioavailability of trace mineral elements. Ann Rev Nutr 1983;3:213-31. 4. Filer LJ Jr. Iron needs during rapid growth and mental development. J PEDIATR 1990;117:S143-6. 5. Valee BL. A role of zinc in gene expression. J Inher Metab Dis 1983;6:31-3. 6. Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 1961;31:532-46. 7. Sandstead HH, Prasad AS, Schulert AR, et al. Human zinc dei]ciency, endocrine manifestations and response to treatment. Am J Clin Nutr 1967;20:422-42. 8. Ronaghy HS, Reinhold JG, Mahloudji M, Ghakami P, Fox MRS, I-lalstead JA. Zinc supplementation of malnourished schoolboys in Iran: increased growth and other effects. Am J Clin Nutr 1974;27:112-21. 9. Halsted JA, Ronaghy HA, Abadi P, et al. Zinc deficiency in man: the Shiraz experiment. Am J Med 1972;53:277-84. 10. Walravens PA, Hambidge KM. Growth of infants fed a zinc supplemented formula. Am J Clin Nutr 1976;29:1114-21. 1 i. Hambidge KM, Walravens PA, Casey CE, Brown BM, Bender C. Plasma zinc concentrations of breast-fed infants. J PEDIATR 1979;94:607-8. 12. Prasad AS. Clinical manifestations of zinc deficiency. Ann Rev Nutr 1985;5:341-63. 13. Kirchgessner M, Roth HP. In: Nriagu JO, ed. Zinc in the environment; pt 2. New York: Wiley & Sons, 1980:71-104. 14. Cousins RJ. Regulatory aspects of zinc metabolism in liver and intestine. Nutr Rev 1979;37:97-103.

The Journal of Pediatrics August 1990

15. Golden MHN, Golden BE. Effect of zinc supplementation on the dietary intake, rate of weight gain, and energy cost of tissue deposition in children recovering from severe malnutrition. Am J Clin Nutr 1981;34:900-8. 16. Johnson PE, Evans GW. Relative zinc availability in human breast milk, infant formulas, and cow milk. Am J Clin Nutr 1978;31:416-21. 17. Lonnerdal B, Hoffman BS, Hurley LS. Zinc and copper binding proteins in human milk. Am J Clin Nutr 1982;36:1170-6. 18. Cousins RJ, Smith KT. Zinc-binding properties of bovine and human milk in vitro: influence of changes in zinc content. Am J Clin Nutr 1980;33:1083-7. 19. Reinhold JG, Nasr K, Lahimgarzadeh A, Hedayati H. Effect of purified phytate and phytate-rich bread upon metabolism of zinc, calcium, phosphorus, and nitrogen in man. Lancet 1973; 1:283-8. 20. Ismail-Beigi F, Reinhold JG, Faraji B, Abadi P. Effect of cellulose added to diets of low and high fiber content upon the metabolism of calcium, magnesium, zinc and phosphorus by man. J Nutr 1977;107:510-8. 21. Spencer H, Vankinscott V, Lewin I, Samachsan JJ. Zinc-65 metabolism during low and high calcium intake in man. J Nutr 1965;86:169-97. 22. Price NO, Bunce GE, Engel RW. Copper, manganese, and zinc balance in preadolescent girls. Am J Clin Nutr 1970; 23:258-60. 23. Greger JL, Snedeker SM. Effects of dietary protein and phosphorous levels on the utilization of zinc, copper and manganese by adult males. J Nutr 1980;110:2243-53. 24. Colin MA, Taper J, Ritchey SJ. Effects of dietary zinc and protein levels on the utilization of zinc and copper by adult females. J Nutr 1983;113:1480-8. 25, Solomons NW, Jacob RA. Studies on the bioavailability of zinc in humans: effects of heine and non-heme iron on the absorption of zinc. Am J Clin Nutr 1981;34:475-82. 26. Solomons NW, Pineda O, Viteri F, Sandstead HH. Studies on the bioavailability of zinc in humans: mechanism of the intestinal interaction of non/heine iron and zinc. J Nutr 1983; 113:337-49. 27. Lonnerdal B, Keen CL, Hurley LS. Iron, copper, zinc, and manganese in milk. Ann Rev Nutr 1981;1:149-74. 28. Lonnerdal B, Keen CL, Hurley LS. In: McHowell J, Gawthorne JM, White CL, eds. Trace element metabolism in man and animals; vol 4. Canberra: Australian Academy of Science, 1981:249-51. 29. Hart EB, Steenbock H, Waddell J, et al. Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin binding in the rat. J Biol Chem 1928;77:797-812. 30. Evans GW. Copper homeostasis in the mammalian system. Physiol Rev 1973;53:535-70. 31. Williams DM. Copper deficiency in humans. Semin Hematol 1983;20:118-28. 32. DiMauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol 1985;17:521-38. 33. L'Abbe M, Fischer PWF. The effects of high dietary zinc and copper deficiency on the activity of copper-requiring metalloenzymes in the growing rat. J Nutr 1984;114:813-22. 34. Fisher PWF, Giroux A, L'Abbe MR. Effect of zinc and copper status in adult man. Am J Clin Nutr 1984;40:743-6. 35. Arlette JP, Johnston MM. Zinc deficiency dermatosis in premature infants receiving prolonged parenteral alimentation. J Am Acad Dermatol 1981;5:37-42.

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Trace minerals in the nutrition o f children

36. Lo GS, Settle SL, Steinke FH. Bioavailability of copper in isolated soybean protein using the rat as an experimental model. J Nutr 1984;114:332-40. 37. Lonnerdal B, Bell JG, Keen CL. Copper absorption from human milk, cow's milk, and infant formulas using a suckling rat model. Am J Clin Nutr 1985;42:836-44. 38. Williams DM, Alkin CL, Frens DB, et al. Menkes' kinky-hair syndrome: studies of copper metabolism and long-term copper therapy. Pediatr Res 1977;11:823-6. 39. Fransson GB, Lonnerdal B. Distribution of trace elements and minerals in human and cow's milk. Pediatr Res 1983;17: 921-5. 40. Reiser S, Smith JC, Mertz W, et al. Indices of copper status in humans consuming a typical American diet containing either fructose or starch. Am J Clin Nutr 1985;42:242-51. 41. Orent ER, McCollum EV. Effects of deprivation of manganese in the rat. J Biol Chem 1931;92:651-78. 42. Leach RM, Lillburn RM. Manganese metabolism and its function. World Rev Nutr Diet 1978;32:123-34. 43. Doisy EA. Effects of deficiency in manganese upon plasma levels of clotting proteins and cholesterol in man. In: Hoekstra WG, Suttie JW, Ganther HE, Mertz W, eds. Trace element metabolism in animals; vol 2. Baltimore: University Park Press, 1974:668-9. 44. Thomson ABR, Olatunbosun D, Valberg LS. Interrelation of intestinal transport system for~manganese and iron. J Lab Clin Med 1971;78:642-55. 45. Vuori E, Makinen SM, Kara R, Kuitunen P. The effect of dietary intakes of copper, iron, manganese and zinc on the trace element content of human milk. Am J Clin Nutr 1980;33: 227-31. 46. Chan W-Y, Bates JM, Rennert OM. Comparative studies of manganese binding in human breast milk, bovine milk and infant formula. J Nutr 1982;112:642-51. 47. Gibson RS. Dietary intakes of trace elements in infants during their first year. Food Nutr News 1984;57:1-3. 48. Mudd SH, Irreverre F, Laster L. Sulfite oxidase deficiency in man: demonstration of the enzymatic defect. Science 1967; 156:1599-602. 49. Rajagopalan KV. Molybdenum: an essential trace element in human nutrition. Ann Rev Nutr 1988;8:401-27. 50. Gunnison AF, Farruggella T J, Chiang G, Dulak L, Zaccardi J, Birker J. A sulphite-oxidase-deficientrat model: metabolic characterization. Food Cosmet Toxicol 1981 ;19:209-20. 51. Report of a WHO Expert Committee. Trace elements in human nutrition. WHO Technical Report Series No. 532. Geneva: World Health Organization, 1973. 52. Hambidge KM. Chromium nutrition in man. Am J Clin Nutr 1974;27:505-14. 53. Gurson C J, Saner G. Effect of chromium on glucose utilization

in marasmic protein-calorie malnutrition. Am J Clin Nutr 1971;24:1313-9. Offenbacher EG, Pi-Sunyer FX. Chromium in human nutrition. Ann Rev Nutr 1988;8:543-63. Dirks OB, Jongeling-Eijindhoven PA, Flisseballje TD, Gedalia I. Total and free ionic fluoride in human and cow milk as determined by gas-liquid chromatography and the fluoride electrode. Caries Res 1974;8:181-6. American Academy of Pediatrics Committee on Nutrition. Fluoride supplementation: revised dosage schedule. Pediatrics t979;63:150-2. Combs GF Jr, Combs SB. The nutritional biochemistry of selenium. Ann Rev Nutr 1984;4:257-80. Milner J, Hsu CY. Inhibitory effects of selenium on the growth of L1210 leukemic cells. Cancer Res 1981;41:1652-6. Burk RF. Biological activity of selenium. Ann Rev Nutr i983;3:53-70. Levander OA. A global view of human selenium nutrition. Ann Rev Nutr 1987;7:227-50. Lockitch G, Jacobson B, Quigley G, Dison P, Pendray M. Selenium deficiency in low birth weight neonates: an unrecognized problem. J PEDIATR 1989;114:865-70. Smith AM, Picciano MF. Evidence for increased selenium requirement for the rat during pregnancy and lactation. J Nutr 1986;116:1068-79. Shearer TR, Hadjimarkos DM. Geographic distribution of selenium in human milk. Arch Environ Health 1973;30:230-3. Smith A, Piceiano MF, Milner JA. Selenium intake and status of human milk and formula fed infants. Am J Clin Nutr 1982;35:521-6. McConnell KP, Hoffman JL. Methionine-selenomethionine parallels in rat liver polypeptide chain synthesis. FEBS Lett 1972;24:60-2. Lombeck I, Kasperck K, Harbisch HD, Feinendegen LE, Bremer HJ. The selenium status of healthy children. I. Serum selenium concentration at different ages: activity of glutathione peroxidase of erythrocytes at different ages selenium content of food of infants. Eur Pediatr 1977;125:81-8. Hatano S, Aihara K, Nishi Y, Usui T. Trace elements (copper, zinc, manganese and selenium) in plasma and erythrocytes in relation to dietary intake during infancy. J Pediatr Gastroenterol Nutr 1985;4:87-92. Adams AK, Milner JA, Picciano MF. Relative bioavailability of selenium from human milk and supplemented infant formulas [Abstract]. Fed Proc 1987;46:908. Milner JA, Sherman L, Picciano MF. Distribution of selenium in human milk. Am J Clin Nutr 1987;45:617-24. Foods and Nutrition Board, National Research Council. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press, 1989.

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Trace minerals in the nutrition of children.

Trace elements perform important functions in growth and development. However, little information exists about their dietary requirements during the d...
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