ments, and it is not recommended that formulas should ... â€¢zinc â€¢copper â€¢manganese â€¢infant formulas â€¢concentrations â€¢upper limits.
Upper Limits of Zinc, Copper and Manganese in Infant Formulas1'2 K. MICHAEL HAMB1DGEAND NANCY F. KREBS Department of Pediatrics, university of Colorado Health Science Center, Denver, CO 80262
ABSTRACT Upper limits are proposed for zinc, copper and manganese in infant formulas. At these limits intakes would be lower than would intakes shown to be associated with toxicity, but the upper limits of an entirely safe range of intake remain uncertain. The proposed limits provide a considerable margin beyond normal nutritional require ments, and it is not recommended that formulas should typically contain these quantities. The proposed upper lim its (per 100 kcal) are 1.5 mg of zinc, 200 jxg of copper and 50 |ig of manganese. J. Nutr. 119: 1861-1864, 1989.
INDEXING KEY WORDS: ZINC
â€¢zinc â€¢copper â€¢manganese â€¢infant formulas â€¢concentrations â€¢upper limits
Both acute and chronic toxicity syndromes occur with large overdoses of zinc (Zn). The principle features are epigastric pain, diarrhea, nausea and vomiting. In ad dition to the gastrointestinal effects, the central nerv ous system may be involved, as suggested by symptoms such as irritability, headache and lethargy (1). These features have been observed with an intake 40 times the current Recommended Dietary Allowance (RDA) (2). Prolonged intake of a relatively modest excess of zinc may depress serum high density lipoprotein cholesterol levels. This has been observed with the administration of 160 mg of zinc daily for 6 wk in normal men (3),but not with 100 mg of zinc daily for 8 wk in normal women (4). Early chronic toxicity studies in the rat revealed no adverse effects of intakes 100 times the dietary require ments, but further increases in intake led to severe copper deficiency (1).More recently, human copper de ficiency has been induced by the intake of 150 mg of Zn (10 times the RDA) for 2 yr by an adult (5). Some depression of serum copper has been observed with a
Severe zinc, copper and manganese toxicities in hu mans and other species are well recognized. However, intakes necessary to produce these more classical tox icity syndromes are more than two orders of magnitude greater than nutritional requirements. Hence, these particular micronutrients have been regarded as rela tively "safe," and there has not appeared to be the same need to establish upper limits of intake as has been the case for some of the other micronutrients. More recently, however, there has been a growing appreciation of the potential adverse effects from quite small excesses on a chronic basis. This has stemmed from a number of factors, including the following: a) detection of more subtle early adverse effects of exces sive intake, especially for zinc; b) recognition of pu tative gene-nutrient interactions, as in the role of cop per in the etiology of Indian childhood cirrhosis; c) growing awareness of the potential for nutrient-nu trient interactions, especially those between different trace elements. These interactions are discussed else where in this symposium, but re-emphasis of their po tential importance is necessary in the context of this discussion; and d] better understanding of how com promised homeostatic control mechanisms, due to im maturity, disease or possibly to genetic variations, may diminish the safety margin in a significant number of individuals.
'This paper was presented at a symposium, "Upper Limits of Nu trients in Infant Formulas," November 7-8, 1988, in Iowa City, IA. Supported in part by a grant from the National Institutes of Health, NIADDKD, 5R22 AM12432, and grant RR-69 from National Insti tutes of Health, General Clinical Research Center.
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Published data are not available that will permit pre cise definition of upper limits at which it is desirable to provide zinc, copper or manganese in infant for mulas. In reaching the recommendations discussed herein, some or all of the following sources of infor mation have been considered: intake levels that are known to be associated with toxicity or increased tis sue levels of that nutrient; concentrations that had been used in formulas without any recognized adverse ef fects; and calculated extreme upper limits of possible nutritional requirements.
HAMBIDGE AND KREBS
Acute ingestion of quantities of copper (Cu) 1000 times the daily requirement can have a fatal outcome (14). Copper intoxication has occurred from consump tion of copper-contaminated drinking water with a cop per concentration of 2-7.8 mg/1 (15). Contamination of cow's milk with copper from brass containers has been cited as the major environmental factor in the etiology of Indian childhood cirrhosis (16,17). This may be an example of gene-nutrient interaction (18),or there may be more than one environmental factor involved. It has been calculated that cow's milk stored in brass utensils would supply 400 Â±90 fig Cu/(kg â€¢ d) to an infant. More data are needed on the role of excess cop per intake in the etiology of this disease and of the actual levels of intake associated with hepatic toxicity in Indian childhood cirrhosis. Excess hepatic copper accumulates in other cholestatic liver diseases (18).
Though the clinical significance of these high, acquired hepatic copper concentrations is not known, it is ju dicious to limit copper intake when biliary excretion, the primary homeostatic control mechanism, is com promised. Formulas providing 300 \ig Cu/100 kcal have been fed to premature infants for periods of approximately 1 mo without evidence of adverse effects. Zinc balance was not affected by increasing the copper from about 140 to 300 M.gCu/100 kcal (19). The Food and Drug Administration's (FDA) mini mum specification for infant formulas of 60 (xgCu/100 kcal (20) is more than adequate for term infants fed cow's milk formulas. Current recommendations for premature infants are higher, 100 |xg Cu/100 kcal (21), which allows for poor absorption from cow's milk for mulas. Though negative copper balance has been ob served with higher copper intakes in premature infants, this could be related to release of copper from hepatic stores. These stores are thought to be significant even in very low-birth-weight premature infants (21). Recommendations. The recommended maximum nutrient specification for infant formulas is 200 ^g Cu/ 100 kcal. Only low copper formulas should be admin istered to any infant with cholestatic liver disease. MANGANESE
Chronic severe manganese (Mn) toxicity has been documented, primarily in manganese miners, and re sults from both inhalation and ingestion of manganese dust. Severe extrapyramidal neurological disease is the major clinical feature. No adverse effects from excess oral manganese intake have been reported in infants. In normal circumstances, manganese appears to have a very wide margin between requirements and toxic levels when taken enterally. This is attributable primarily to the highly effective homeostatic control maintained by the intestinal mu cosa and the liver. When these control mechanisms are bypassed and/or impaired, as in intravenously fed pa tients with cholestatic liver disease, markedly elevated plasma manganese levels occur at very low levels of intravenous intake, i.e., about 3 jig Mn/100 kcal (22). Concentrations documented recently in infant for mulas have ranged up to 3.5 mg Mn/1 or more (10).This intake would provide in excess of 0.5 mg Mn/100 kcal, which is 1000 times the quantity provided to the fully breast-fed infant (23). No toxic effects have been re ported from these high intakes, but there is no good evidence that careful studies have been undertaken. In the mouse, manganese absorption is especially high in very early postnatal life, and little manganese is ex creted (24). The premature infant has been reported to absorb and retain more manganese than does the adult (25).Thus, caution is required in extrapolating to young infants from data on dietary manganese intakes and
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much shorter period of excess zinc intake and with levels of intake of only 50 mg Zn/d (6). Hematological and radiological evidence of copper deficiency has been noted in a 3-mo-old infant with severe zinc deficiency who was treated with 30 mg of zinc daily for 3 wk (7). Reduced apparent absorption of copper has been re ported in adult men when zinc intake was increased to a level of only 18.5 mg/d (8) but was not observed in another study with an intake of 16.5 mg Zn/d (9). Infant formulas marketed in this country in recent years have had zinc concentrations ranging up to 13.5 mg Zn/1 or approximately 2 mg/100 kcal (10).This level of intake has not been reported to have any adverse effects, but detailed studies at this level of intake have not been reported. Traditional balance studies have indicated that a zinc intake of 0.82 mg/(kg â€¢ d) is adequate to achieve positive balance in all term infants, including those fed a soy protein formula (11).On a factorial basis, requirements for growth and to replace endogenous losses in urine and sweat (i.e., apparent absorption) have been calcu lated to be 0.8 mg Zn/d in early infancy, declining to less than 0.5 mg Zn/d by 4 mo (12). In a pilot study, endogenous fecal losses have been calculated to be at least 0.075 mg Zn/(kg â€¢ d) (13). Thus, the very young infant appears to require absorption of about 0.3 mg Zn/100 kcal, but this declines to 0.15 mg Zn/100 kcal by 4 mo. If absorption is as low as 20%, the dietary requirement calculated on this factorial basis could range up to 1.25 mg Zn/100 kcal. Recommendations. Until more data are available on the potential effects of relatively high zinc intakes on copper retention, a maximum specification for zinc in infant formulas is proposed at 1.5 mg Zn/100 kcal. This upper limit is specified with the knowledge that the formula will provide no less than 60 (ig copper/100 kcal.
1863 TABLE 1 Recommended
nutrient specifications for infant formulas Minimum'
Maximum per 100 kcal
Zinc, mg Copper, tig Manganese,
0.5 60 5
1.5 200 50
SUMMARY The recommendations given in Table 1 appear to provide a comfortable margin beyond nutritional re quirements even for special formulas and premature infants. They are, in each case, more than twice the concentrations required by term infants fed cow's milk formulas. While concentrations considerably higher than these recommendations may have no adverse effects, there is currently a degree of uncertainty for zinc and, especially, for copper.
LITERATURE CITED 1. HAMBIDGE, K. M., CASEY,C. E. & KREBS,N. F. (1986| Zinc. In: Trace Elements in Human and Animal Nutrition, 5th ed., Vol. 2, (Mertz, W., ed.), pp. 1-137, Academic Press, Orlando, FL.
2. FOODANDNUTRITIONBOARD. (1980) Recommended Dietary Allowances, 9th ed., National Research Council, National Acad emy of Sciences, Wasington, D.C. 3. HOOPER,P. H., VISCONTI,L., GARRY,P. H. & JOHNSON,G. E. (1980) Zinc lowers density lipoprotein-cholesterol levels. Â¡AMA 244(17): 1960-1961. 4. FREELAND-GRAVES, f. E., HAN, W. H., FRIEDMAN,B. J. & SHOREY, R. L. (1980) Effect of dietary Zn/Cu ratios on cholesterol and HDL-cholesterol levels in women. Nutr. Rep. Int. 22: 285-293. 5. PRASAD,A. S., BREWER,G. J., SCHOOMAKER, E. B. & RABBANI,P. (1978) Hypocupremia induced by large doses of zinc therapy in adults. Â¡AMA240: 2166-2168. 6. ADBULLA,M. & SVENSSON,S. (1982) Influence of oral zinc in take on whole blood and plasma levels of copper. In: Inflam matory Diseases and Copper (Sorenson, J. R. J., Ã©d.),pp. 601, Humana Press, New Jersey. 7. HAMBIDGE,K. M., WALRAVENS, P. A. & NELDNER,K. H. (1978) Zinc, copper and fatty acids in acrodermatitis enteropathica. In: Trace Element Metabolism in Man and Animals-3 (Kirchgessner, M., Ã©d.), pp. 413-417, Arbeitskreis fÃ¼rTierernÃ¤hrungsfor schung, Freising-Weihenstephan. 8. FESTA,M. D., ANDERSON,H. L., DOWDY,R. P. & ELLERSIECK, M. R. (1985) Effect of zinc intake on copper excretion and reten tion in men. Am. f. Clin. Nutr. 41: 285-292. 9. TURNLAND,J. R., WADA,L., KING, J. C., KEYES,W. R. & ACORO, L. A. (1986) Copper absorption in young men fed adequate and low zinc intakes. Fed. Proc. 45 (3): 234 (abs.). 10. LÃ–NNERDAL, B., KEEN,C. L., OHTAKE,M. & TAMURA,T. (1983) Iron, zinc, copper, and manganese in infant formulas. Am. ]. Dis. Child. 137: 433-437. 11. ZIEGLER,E. E., EDWARDS, B. B., JENSEN,R. J., FILER,L. J. & FOMON, S. J. (1978) Zinc balance studies in normal infants. In: Trace Element Metabolism in Man and Animals-3, (Kirchgessner, M., ed.), pp. 292-295, Arbeitskreis fÃ¼rTierernÃ¤hrungsforschung, Freising-Weihenstephan. 12. KREBS,N. F. & HAMBIDGE, K. M. (1986) Zinc requirements and zinc intakes of breast fed infants. Am. /. Clin. Nutr. 43: 288292. 13. ZIEGLER,E. E., FIGUEROA-COLON, R., SERFASS,R. E. & NELSON, S. E. (1987) Effect of low dietary zinc on zinc metabolism in infancy: stable isotope studies. Am. J. Clin. Nutr. 45: 849 (abs.). 14. DAVIS,G. K. & MERTZ,W. (1987) Copper. In: Trace Elements in Human and Animal Nutrition (Mertz, W., ed.), 5th ed., Vol. 1, pp. 301-364, Academic Press, San Diego, CA. 15. SPITALNY,K. C., BRONDUM,J., VOGT, R. L., SARGENT,H. E. & KAPPEL,S. (1984) Drinking-water-induced copper intoxication in a Vermont family. Pediatrics 74: 1103-1106. 16. TANNER, M. S., BHAVE,S. A., KANTARIIAN,A. H. &. PANDIT, A. N. (1983) Early introduction of copper-contaminated ani mal milk feeds as a possible cause of Indian childhood cirrhosis. Lancet 11:992-995. 17. BHAVE,S. A., PANDIT,A. N. & TANNER,M. S. (1987) Comparison of feeding history of children with Indian childhood cirrhosis and paired controls. /. Pediatr. Gastroenterol. Nutr. 6: 562-567. 18. WALSHE,J. M. (1984) Copper: its role in the pathogenesis of liver disease. Semin. Liver Dis. 4: 252-263. 19. TYRALA,E. E. (1986) Zinc and copper balances in preterm in fants. Pediatrics 77: 513-517. 20. FOODAND DRUG ADMINISTRATION(1985) Rules and regula tions. Nutrient requirements for infant formulas. Fed. Regist. 50: 45106-45108. 21. CASEY,C. E. & HAMBIDGE,K. M. (1985) Trace element re quirements. In: Vitamin and Mineral Requirements of Preterm Infants (Tsang, R., Ã©d.), pp. 153-184, Marcel Dekker, New York, NY. 22. HAMBIDGE,K. M., SOKOL,R. J., FIDANZA,S. J. & JACOBS,M. A. (1989) Plasma manganese concentrations in infants and chil dren receiving parenteral nutrition. /. Patenter. Enter. Nutr. 14: 168-171.
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manganese absorption from other stages of the life cycle. Requirements for manganese have not been well de fined. The manganese intake of the fully breast-fed in fant is only about 0.5 (jig/100 kcal. Though balance has been reported to be negative in the breast-fed neonate (21), there is no evidence to suggest that any breast-fed infant suffers from a suboptimal manganese intake. Thus, even allowing for poorer absorption from cow's milk and especially from soy protein and iron-fortified for mulas (26), the FDA minimal specification (20) of 5 p,g Mn/100 kcal appears reasonable. However, since other balance studies have suggested that more than 8.5 jig Mn/(kg â€¢ d) is needed to achieve positive balance, it appears that an intake of 10-20 |j,g Mn/100 kcal in the formula-fed infant may be desirable pending additional information. Soy formulas are naturally high in man ganese; there is no evidence at this time to support the need for reducing manganese concentrations in these formulas. Hence, a relatively generous upper limit is recommended. Substantial quantities of Mn are derived from cereals and other nonformula foods. Thus, infants are not dependent on formulas as a source of manganese once beikost is introduced. Recommendations. The recommended maximum specification for manganese in infant formulas is 50 (jig/100 kcal. This provides a considerable excess above calculated nutrient requirements, but also appears to be within a safe range of intake.
IN INFANT FORMULAS
nate, so far as possible, the likelihood of adverse inter action with copper and should not impose an undue burden on the manufacturer. With the current lower limit of 0.06 mg/100 kcal for copper, an upper limit of 1.5 mg per 100 kcal for zinc would permit a zinc to copper ratio in infant formulas of 25:1, certainly greater than the 10:1 ratio recom mended by Senterre. The safety of 25:1 ratio is un known. Fischer et al. (Am. f. Clin. Nutr. 40: 743, 1984) reported that administration of a 50-mg zinc supple ment to adult men was associated with decreased ac tivity of Cu, Zn-superoxide dismutase. Neither the cop per nor the zinc content of the diet was given; however, if the diet provided 10 mg of zinc and 3 mg of copper per day, the zinc to copper ratio would have been about Comment by Senterre 20:1. We believe that studies designed to determine the As indicated in Table A there are relatively few rec effects of various zinc to copper ratios in the infant's ommendations for maximal levels of trace elements. diet should be given high priority. Such studies should There are possible interactions between iron and zinc take into consideration the bioavailability of zinc from as well as between zinc and copper. Taking into ac various formula ingredients. The desirability of increas count that the Fe:Zn ratio must be at the maximum ing the lower limit of copper in infant formulas should 2:1 and Zn:Cu ratio must be at the maximum 10:1, it be considered. seems consistent to propose as upper limit for iron, zinc Copper. Hambidge and Krebs recommended an up and copper: 2 mg, l mg and 0.1 mg/100 kcal, respec per limit for copper of 0.20 mg/100 kcal, LÃ¶nnerdal tively. However, with the exception of Denmark, no recommends an upper limit of 0.18 mg/100 kcal, and committee on nutrition has specified upper limits for Senterre recommends an upper limit of 0.1 mg/100 kcal. the ratios between trace elements. We prefer an upper limit of 0.12 mg/100 kcal for added copper. This quantity of added copper (providing twice Editorial Comment the required minimum concentration) will rarely result in concentrations as great as 0.25 mg/100 kcal and avoids Zinc. LÃ¶nnerdalrecommends an upper limit for zinc the need to analyze each batch of formula for copper. in infant formulas of 1.5 mg/100 kcal; Hambidge and In view of the minimum nutrient levels established for Krebs recommended an upper limit of 1.8 mg/100 kcal, other nutrients, there is at present no basis for antici and Senterre recommends an upper limit of 1 mg/100 pating adverse nutrient interactions from copper in kcal. We agree that an upper limit for zinc is desirable, takes in the range of 0.25 mg/100 kcal. and in this case, we believe that the upper limit should Manganese. Hambidge and Krebs recommend 0.50 be based on the final concentration in the formula, not mg/100 kcal, and LÃ¶nnerdalrecommends 0.90 mg/100 the quantity added by the manufacturer. The upper kcal as the upper limit for manganese in infant for limit for concentration of zinc should be set to elimimulas. We believe that an upper limit for added rather than total manganese is appropriate, and suggest 0.10 TABLE A mg of added manganese per 100 kcal (i.e., twice the minimum level). Although isolated soy protein-based Upper limits of zinc, copper, iodine and manganese in infant formulas may provide relatively large amounts of man formulas ganese, these formulas also provide generous amounts limitSourceZnCuIMnjig/JOO Upper of iron, and one would therefore not anticipate an ad verse effect of manganese on iron absorption (see OTJell, p. 1832 of this issue). kcalFranceNetherlands Perhaps the recommendation for an upper limit for added manganese should apply to currently marketed (proposed)European formulas and to future iron-fortified formulas. Recon communitySwedenUnited sideration of the upper limit for manganese may be StatesESPGAN1 necessary if noniron-fortified formulas are prepared from (preterm formulas)8001000â€”â€”â€”1100808080â€”â€”1202020â€”1575451250â€”â€”â€”â€” ingredients that provide generous quantities of man 'European Society for Pediatrie Gastroenterology and Nutrition. ganese.
23. CASEY,C. E., HAMBIDCE, K. M. & MEBILLE, M. C. (1985) Studies in human lactation: Zinc, copper, manganese and chromium in human milk in the first month of lactation. Am. ]. Clin. Nutr. 41: 1193-1200. 24. MILLER,S. T., COTZIAS,G. C. & EVERT,H. A. (1975) Control of tissue manganese: initial absence and sudden emergence of excretion in the neonatal mouse. Am. f. Physiol. 229 (4): 10801084. 25. MENA,I. (1981) Manganese. In: Disorders of Mineral Metab olism, Vol. l, (Bronner, F. & Coburn, I. W., eds.), pp. 233-270, Academic Press, New York, NY. 26. DAVIDSSON,L., CEDERBLAD, A., LÃ–NNERDAL, B. & SANDSTROM, B. (1989| Manganese absorption from human milk, cow's milk and infant formulas. In: Trace Elements in Man and Animals6, (Keen, C. L., LÃ¶nnerdal,B. & Rucker, R. B., eds.), pp. 511-512, Plenum Press, New York, NY.
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