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7 Copper SUMMARY Copper functions as a component of a number of metalloenzymes acting as oxidases to achieve the reduction of molecular oxygen. The primary criterion used to estimate the Estimated Average Re- quirement (EAR) for copper is a combination of indicators, includ- ing plasma copper and ceruloplasmin concentrations, erythrocyte superoxide dismutase activity, and platelet copper concentration in controlled human depletion/repletion studies. The Recommended Dietary Allowance (RDA) for adult men and women is 900 Âµg/day. The median intake of copper from food in the United States is approximately 1.0 to 1.6 mg/day for adult men and women. The Tolerable Upper Intake Level (UL) for adults is 10,000 Âµg/day (10 mg/day), a value based on protection from liver damage as the critical adverse effect. BACKGROUND INFORMATION Function The biochemical role for copper is primarily catalytic, with many copper metalloenzymes acting as oxidases to achieve the reduction of molecular oxygen. Many copper metalloenzymes have been iden- tified in humans (da Silva and Williams, 1991; Harris, 1997). Amine oxidases participate in important reactions that have markedly different effects. Diamine oxidase inactivates histamine 224
COPPER 225 released during allergic reactions. Monoamine oxidase (MAO) is important in serotonin degradation to excretable metabolites and in the metabolism of catecholamines (epinephrine, norepinephrine, and dopamine). MAO inhibitors are used as antidepressant drugs. Lysyl oxidase uses lysine and hydroxylysine found in collagen and elastin as substrates for posttranslational processing to produce cross-linkages needed for the development of connective tissues, including those of bone, lung, and the circulatory system. Ferroxidases are copper enzymes found in plasma, with a func- tion in ferrous iron oxidation (Fe2+âFe3+) that is needed to achieve ironâs binding to transferrin (Linder and Hazegh-Azam, 1996). Ferroxidase I, also called ceruloplasmin, is the predominant copper protein in plasma and may also have antioxidant functions. Defects in ceruloplasmin function produce cellular iron accumulation, a result that supports its ferroxidase role (Harris and Gitlin, 1996). Ferroxidase II is found in human plasma, but it may have a role in iron metabolism in specific cellular sites. A transmembrane copper- containing protein (hephaestatin) with ferroxidase activity has been described (Pena et al., 1999; Vulpe et al., 1999). Cytochrome c oxi- dase is a multisubunit enzyme in mitochondria that catalyzes reduc- tion of O2 to H2O. This establishes a high energy proton gradient required for adenosine triphosphate (ATP) synthesis. This copper enzyme is particularly abundant in tissues of greatest metabolic ac- tivity including heart, brain, and liver. Dopamine Î² monooxygenase uses ascorbate, copper, and O2 to convert dopamine to norepineph- rine, a neurotransmitter, produced in neuronal and adrenal gland cells. Dopa, a precursor of dopamine, and metabolites used in melanin formation are oxidatively produced from tyrosine by the copper enzyme tyrosinase. Î±-Amidating monooxygenase (Î±-AE), also called peptidylglycine Î±-AE, uses copper and ascorbate to remove two car- bons from a C-terminal glycine of peptides, thus generating an amide. A number of peptide hormones are posttranslationally mod- ified by Î±-AE (Harris, 1997). Two forms of superoxide dismutase are expressed in mammalian cells, a mangano and cupro/zinc form (Harris, 1997). Copper/zinc superoxide dismutase (Cu/Zn SOD) uses two copper atoms for con- version of the superoxide anion (O2-+) to H2O2 and O2. Zinc atoms have a structural role in the enzyme. The enzyme is localized in the cytosol and, along with the mitochondrial manganese-containing form, provides a defense against oxidative damage from superoxide radicals that, if uncontrolled, can lead to other damaging reactive oxygen species. Mutations in the Cu/Zn SOD gene, which alter the
226 DIETARY REFERENCE INTAKES proteinâs redox behavior, produce amyotrophic lateral sclerosis (Lou Gehrigâs disease). These are the principal copper metalloenzymes found in humans. There is substantial documentation from animal studies that diets low in copper reduce the activities of many of these copper metallo- enzymes. Activities of some copper metalloenzymes have been shown to decrease in human copper depletion (Milne, 1994; Turnlund, 1999). Physiologic consequences resulting from copper deficiency include defects in connective tissue that lead to vascular and skeletal problems, anemia associated with defective iron utilization, and pos- sibly specific aspects of central nervous system dysfunction (Harris, 1997; Turnlund, 1999). Some evidence suggests that immune and cardiac dysfunction occurs in experimental copper deficiency and the development of such signs of deficiency has been demonstrated in infants (Graham and Cordano, 1969; Olivares and Uauy, 1996; Turnlund, 1999). Physiology of Absorption, Metabolism, and Excretion Metabolism of copper in humans relies on the intestine for con- trol of homeostasis as the capacity for renal copper excretion is limited. Nearly two-thirds of the body copper content is located in skeleton and muscle, but studies with stable isotopes have shown that the liver is a key site in maintaining plasma copper concentra- tions (Olivares and Uauy, 1996; Turnlund et al., 1998). Copper has a higher binding affinity for proteins than all other divalent trace elements (da Silva and Williams, 1991). Consequently, precise con- trol of intracellular copper trafficking is needed to regulate how it is donated to appropriate sites. Copper absorption occurs primarily in the small intestine. Some absorption may occur in the stomach where the acidic environment promotes copper solubility by dissociation from copper-containing macromolecules derived from dietary sources (Harris, 1997; Turnlund, 1999). Both saturable-mediated and nonsaturable-nonmediated (possibly paracellular) transepithelial copper movements have been reported. The Menkes P-type ATPase (MNK; ATP7A) is believed to be responsible for copper trafficking to the secretory pathway for efflux from cells, including enterocytes (Harris and Gitlin, 1996). A defective MNK gene causes Menkesâ disease, which is characterized by reduced copper absorption and placental copper transport. The extent of copper absorption varies with dietary copper intake (Turnlund, 1998). It ranges from over 50 percent at an intake of less than 1 mg/day to less than 20 percent above 5 mg/day. About
COPPER 227 35 percent of a 2 mg/day intake is absorbed and is transported via the portal vein to the liver, bound to albumin, for uptake by liver parenchymal cells. Biliary copper excretion is adjusted to maintain balance. Copper is released via plasma to extrahepatic sites where up to 95 percent of the copper is bound to ceruloplasmin (Turnlund, 1999). The biological role of ceruloplasmin in copper metabolism has been widely investigated. The autosomal recessive disorder in humans, aceruloplasminemia, does not produce abnormal copper metabo- lism, thus contradicting a role for the protein in copper delivery to cells. However, this genetic defect results in tissue iron accumula- tion, supporting the proteinâs role in cellular iron release. Other P-type ATPases (e.g., Wilson, NND, ATP7B) are responsible for copper trafficking to the secretory pathway for ceruloplasmin syn- thesis or for endosome formation before transport into the bile (Harris and Gitlin, 1996; Pena et al., 1999). Mutations of this copper-transporting ATPase result in cellular copper accumulation called Wilsonâs disease. Urinary copper excretion is normally very low (< 0.1 mg/day) over a wide range of dietary intakes (Turnlund, 1999). As with other trace elements, renal dysfunction can lead to increased urinary losses. Clinical Effects of Inadequate Intake Frank copper deficiency in humans is rare, but has been found in a number of special conditions. It has been observed in premature infants fed milk formulas, in infants recovering from malnutrition associated with chronic diarrhea and fed cowâs milk (Shaw, 1992), and in patients with prolonged total parenteral nutrition (Fujita et al., 1989). In these cases, serum copper and ceruloplasmin concen- trations were as low as 0.5 Âµmol and 35 mg/L, respectively, com- pared to reported normal ranges of 10 to 25 Âµmol/L for serum copper concentration and 180 to 400 mg/L for ceruloplasmin con- centration (Lentner, 1984). Supplementation with copper resulted in rapid increases in serum copper and ceruloplasmin concentra- tions. Symptoms accompanying the copper deficiency included normocytic, hypochromic anemia, leukopenia, and neutropenia (Fujita et al., 1989). Osteoporosis was observed in copper-deficient infants and growing children. Copper deficiency developed in six severely handicapped patients between the ages of 4 and 24 years who were fed an enteral diet containing 15 Âµg of copper/100 kcal for 12 to 66 months (Higuchi
228 DIETARY REFERENCE INTAKES et al., 1988). Their serum copper concentrations ranged from 0.9 to 7.2 Âµmol/L and ceruloplasmin concentrations ranged from 30 to 125 mg/L. Two patients had neutropenia, one had macrocytic, normochromic anemia, and some had bone abnormalities includ- ing reduced bone density. Neutrophil counts normalized and bone abnormalities improved after copper supplementation. If the copper intake of these patients is extrapolated to adults on the basis of caloric intake, copper deficiency might be expected to develop in adults at an intake of 440 Âµg/2,900 kcal for men and 290 Âµg/1,900 kcal for women. This deduction is consistent with a study in which healthy young men who were fed a diet containing 380 Âµg/day of copper for 42 days had a decline in serum copper and cerulo- plasmin concentrations and then an increase with copper repletion (Turnlund et al., 1997). Although serum copper and ceruloplasmin concentrations of these men did not fall to the deficient range in 42 days and clinical symptoms did not appear, these effects might be expected had the low copper diet been continued. In a number of other studies at higher levels of copper intake (i.e., at 600 Âµg/day and above), serum copper and ceruloplasmin concentrations did not decline significantly (Milne, 1998; Turnlund et al., 1990). Results of depletion studies in laboratory animals have led to in- terest in a number of conditions in humans that may be associated with marginal copper intake over a long period. Insufficient data are available at this time to establish whether these conditions are related to dietary copper. A report of increased blood cholesterol concentrations in one young man consuming 830 Âµg/day of copper (Klevay et al., 1984) suggested that elevated blood cholesterol concentration may be associated with marginal amounts of dietary copper. This effect was not observed in other subjects or in a number of other studies with this or lower levels of dietary copper. In one study, blood cholesterol concentration decreased with lower dietary copper (Milne and Nielsen, 1996), and in a copper supplementation study investiga- tors found increased blood cholesterol concentrations with supple- mentation (Medeiros et al., 1991). Heart beat irregularities were reported in some studies, and inves- tigators linked them to dietary copper intake (Milne, 1998). How- ever, heart beat irregularities are common in normal, healthy people, and other studies with lower copper intake demonstrated that such irregularities, monitored during copper depletion and repletion, were common at all intake levels of dietary copper (Turnlund et al., 1997). Myocardial disease occurs in severely deficient weanling rats, and one investigator has hypothesized that ischemic heart disease is
COPPER 229 related to marginal copper status (Klevay, 1989). However, the myo- cardial changes observed in copper-deficient animals are very dif- ferent from those of ischemic heart disease in humans (Danks, 1988). In severely deficient animals, the myocardium is hyper- trophied and may rupture. Coronary artery resistance is decreased in copper-deficient animals, but it is increased in ischemic heart disease. Several other clinical observations deserve further investigation, but there is insufficient evidence to link them to marginal copper status. Glucose tolerance was lower in two of a group of eight men consuming 80 Âµg/day of copper than in men consuming higher levels of copper (Klevay et al., 1986), but similar observations have not been reported at lower intakes of copper in other studies. One study reported a negative correlation between ceruloplasmin con- centration and blood pressure during a hand grip exercise (Lukaski et al., 1988), but the link between blood pressure and dietary copper has not been investigated further in humans. An index of immune function declined in a depletion study with copper intakes of 380 Âµg/day that resulted in decreases in indexes of copper status, but other indexes of immune function did not decline and repletion did not result in reversal of the change (Kelley et al., 1995). Changes in blood clotting factors V and VIII were observed in one study with copper intakes of 570 Âµg/day (Milne and Nielsen, 1996). The role of copper as an antioxidant has led to interest in the possibility that copper deficiency impairs antioxidant status (Johnson et al., 1992). A report of changes in some, but not other, markers of bone metab- olism with a dietary copper intake of 700 Âµg/day deserves further investigation (Baker et al., 1999). Changes in catecholamine metab- olism have been investigated, but results are inconsistent (Bhathena et al., 1998). SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR COPPER Several indicators are used to diagnose copper deficiency. These indicatorsâserum or plasma copper concentration, ceruloplasmin concentration, and erythrocyte superoxide dismutase activityâare low with copper deficiency and respond to copper supplementa- tion. However, except when diets are deficient in copper, they do not reflect dietary intake and may not be sensitive to marginal copper status. In addition, serum copper and ceruloplasmin con- centrations increase during pregnancy and with a number of dis- eases, and therefore copper deficiency could be masked under these
230 DIETARY REFERENCE INTAKES conditions. Platelet copper concentration and cytochrome c oxi- dase activity may be more sensitive to marginal intakes of dietary copper than plasma copper or ceruloplasmin concentration, but they have been measured in very few studies to date. No single indicator provides an adequate basis on which to estimate the copper requirement. Serum Copper Concentrations Serum copper concentration is a reliable indicator of copper deficiency, falling to very low concentrations in copper-deficient individuals. The lower end of the normal range for serum copper concentration is reported to be 10 Âµmol/L, but serum copper con- centrations were considerably lower than this when cases of copper deficiency were discovered. Serum copper concentration returns to normal within a few days of copper supplementation (Danks, 1988). While serum copper concentration is an index of copper deficiency, it does not reflect dietary intake except when intake is below a cer- tain level. Above this level, supplementation with copper does not increase serum copper concentration. Serum copper concentration increases under a number of conditions due to increased concen- trations of ceruloplasmin. Ceruloplasmin Concentration Ceruloplasmin concentration is also a reliable indicator of copper deficiency. Ceruloplasmin carries between 60 and 95 percent of serum copper, and changes in serum copper concentration usually parallel the ceruloplasmin concentration in the blood. Cerulo- plasmin, too, falls to low concentrations with copper deficiency, far below the lower end of the normal range of 180 mg/L, and it responds quickly to repletion (Danks, 1988). Ceruloplasmin does not respond to dietary intake, unless intake is very low. The dietary copper intake at which ceruloplasmin concentration no longer in- creases in response to increased dietary copper might be consid- ered the copper requirement for ceruloplasmin synthesis. Cerulo- plasmin is an acute phase protein and increases markedly with a number of diseases, including liver disease, malignancy, inflamma- tory diseases, myocardial infarction, and a variety of infectious diseases (Mason, 1979). It also increases with pregnancy and oral contraceptive use. With any of these conditions, copper deficiency might not be diagnosed on the basis of serum copper or cerulo- plasmin concentrations.
COPPER 231 Erythrocyte Superoxide Dismutase Activity Erythrocyte superoxide dismutase (SOD) activity, though not as specific as serum copper or ceruloplasmin concentration, may be a reliable indicator of copper status, and some suggest it is more sen- sitive (Milne, 1998; Uauy et al., 1985). It does not increase with the conditions that increase serum copper and ceruloplasmin concen- trations. However, it can increase in situations that produce oxida- tive stress, and SOD activity is high in some conditions, including alcoholism and Downâs syndrome. Methods of analysis are not stan- dardized, and normal ranges for SOD activity are not available. Although SOD activity was measured in fewer studies than were the two indicators above, sufficient data are available to include it as an indicator of change in copper status when it is measured in con- trolled studies at different levels of dietary copper intake. Platelet Copper Concentration and Cytochrome c Oxidase Activity Two studies in women suggest that both platelet copper concen- tration and platelet cytochrome c oxidase activity may respond more rapidly to low dietary copper than the indicators discussed above. In one study both of these indicators declined when copper intake was 570 Âµg/day (Milne and Nielsen, 1996). Platelet copper concen- tration increased after repletion, but platelet cytochrome c oxidase activity did not. In another study, both platelet copper concentra- tion and platelet cytochrome c oxidase activity increased after sup- plementation of a diet containing 670 Âµg/day of copper, but base- line measurements were not made, so it is not known whether these parameters declined (Milne et al., 1988). Moreover, an intervening vitamin C supplementation period added another variable to the data interpretation. The fact that serum copper and ceruloplasmin concentrations and SOD activity were not affected at this level of dietary copper suggests the requirement for maintaining serum copper and ceruloplasmin concentration had been met. Therefore, the above research suggests that platelet copper concentration and platelet cytochrome c oxidase activity, when measured in controlled studies, may be more sensitive to changes in copper dietary intake. Urinary Copper Urinary copper excretion is extremely low and does not con- tribute significantly to copper retention, but it has been found to decline when diets are low enough in copper that other indexes of
232 DIETARY REFERENCE INTAKES copper status change (Turnlund et al., 1997). Above those levels of dietary intake, urinary copper does not respond to increases in dietary copper. In controlled studies, a decline in urinary copper excretion can be used as supporting evidence for inadequate intake. Leukocyte Copper Concentration Leukocyte copper concentration was found to decline along with other indexes of copper status in one study (Turnlund et al., 1997), but it has not been reported in others. Too few data are currently available to use it for establishing dietary recommendations for copper. Lysyl Oxidase Activity Lysyl oxidase activity in the skin, which declined with low dietary copper and increased with repletion, is potentially a useful indica- tor of copper status (Werman et al., 1997). It is not known if lysyl oxidase activity reflects dietary intake at higher levels of dietary copper in humans. Because data are available from only one study, it cannot yet be used as an indicator for estimating copper require- ments. Peptidyl Glycine Î±-Amidating Monooxygenase Activity Peptidyl glycine Î±-amidating monooxygenase (PAM) activity in serum of rats and stimulation of activity are sensitive indicators of copper intake in the rat (Prohaska et al., 1997). Patients with Menkesâ disease, who have severe copper deficiency due to a metabolic defect in copper transport, had an increased copper stimulation index of plasma PAM as compared with healthy control subjects. This find- ing suggests that PAM activity may be a useful indicator of copper status in humans when human dose-response data become avail- able. Diamine Oxidase Activity Two copper supplementation studies demonstrated that the activity of serum diamine oxidase (DAO), another cuproenzyme, increases when supplements containing 2 mg (Jones et al., 1997) and 6 mg (Kehoe et al., 2000) of copper were administered daily, a result that suggests the enzyme may be sensitive to increased dietary copper. It has not yet been studied under conditions of copper
COPPER 233 depletion. Because intestinal damage and a number of conditions also elevate DAO activity, its use as an indicator of copper status is possibly limited. Copper Balance Balance studies have been used in the past to estimate dietary recommendations. Numerous copper balance studies in humans have been conducted over a wide range of intakes (Mason, 1979). Unfortunately, there are a number of problems with this approach, as reviewed by Mertz (1987). Copper balance, which can be achieved over a broad range of dietary copper intakes, reflects prior dietary intake; thus long adaptation is required for results to be meaningful. Seldom are studies long enough. Such studies are prone to numerous errors, and data from some studies would sug- gest that an unacceptable amount of copper would accumulate over time if these levels of retention were continued. In addition, miscel- laneous losses, while small, are very difficult to quantify. Therefore, balance studies were not used as an indicator of copper status. Factorial Analysis One approach to estimating minimum dietary mineral require- ments is by the factorial method. Obligatory losses, the amounts of an element excreted with no dietary intake, are determined, and then the amount needed in the diet to replace these obligatory losses is calculated. Obligatory losses include urinary losses, gastro- intestinal losses, sweat, integument, hair, nails, and other miscella- neous losses such as menstrual and semen losses. For copper, as for other elements, reliable values for many of these losses are not avail- able. However, sufficient data are available to make reasonable esti- mates; therefore, this method can be used in support of estimates of dietary copper requirements made by other methods. FACTORS AFFECTING THE COPPER REQUIREMENT The composition of the diet has little effect on the bioavailability of copper, except in unusual circumstances. The bioavailability of copper is influenced markedly by the amount of copper in the diet. Bioavailability ranges from 75 percent of dietary copper absorbed when the diet contains only 400 Âµg/day to 12 percent absorbed when the diet contains 7.5 mg/day (Turnlund et al., 1989, 1998). The absolute amount of copper absorbed is higher with increasing
234 DIETARY REFERENCE INTAKES intake. In addition, excretion of copper into the gastrointestinal tract regulates copper retention. As more copper is absorbed, turn- over is faster and more copper is excreted into the gastrointestinal tract (Turnlund et al., 1998). This excretion is probably the primary point of regulation of total body copper. This efficient homeostatic regulation of absorption and retention helps protect against copper deficiency and toxicity. Zinc Zinc intakes, well in excess of the amount normally found in the diet, can decrease copper absorption in adults (Turnlund, 1999) (see Table 12-7). In one case report, an infant who was given 16 to 24 mg/day of zinc developed copper deficiency (Botash et al., 1992). Very high doses of zinc have been used to treat patients with Wilsonâs disease, an inborn error of copper metabolism resulting in copper toxicity (Brewer et al., 1983). This zinc-induced inhibition of copper absorption could be the result of competition for a com- mon, apically oriented transporter or the induction of metallo- thionein in intestinal cells by zinc. Because this protein has a higher binding affinity for copper than for zinc, copper is retained within enterocytes and its absorption is reduced. This response has been used as a therapy to diminish copper absorption in patients with Wilsonâs disease (Yuzbasiyan-Gurkan et al., 1992). The interaction could also be responsible for reducing copper absorption during consumption of zinc supplements. When zinc-to-copper ratios of 2:1, 5:1, and 15:1 were fed to humans, there were limited effects on copper absorption (August et al., 1989). Iron High iron intakes may interfere with copper absorption in infants. Infants fed a formula containing low concentrations of iron absorbed more copper than infants consuming the same formula with a higher iron concentration (Haschke et al., 1986). Such an interaction has been reported to produce reduced copper status in infants (Lonnerdal and Hernell, 1994; Morais et al., 1994). Fructose Studies in rats demonstrated that diets very high in fructose were associated with increased severity of copper deficiency in rats (Fields et al., 1984), but a similar effect was not observed in pigs
COPPER 235 (Schoenemann et al., 1990), which have cardiovascular systems and gastrointestinal tracts more similar to those of humans. The effects were inconsistent in humans (Reiser et al., 1985) but did not result in copper depletion, and the extremely high levels of fructose fed (20 percent of energy intake) suggest the effect would not be rele- vant to normal diets. FINDINGS BY LIFE STAGE AND GENDER GROUP Infants Ages 0 through 12 Months Method Used to Set the Adequate Intake No functional criteria of copper status have been demonstrated that reflect response to dietary intake in infants. Thus, recommend- ed intakes of copper are based on an Adequate Intake (AI) that reflects the observed mean copper intake of infants principally fed human milk. Ages 0 through 6 Months. The AI for infants ages 0 through 6 months was based on the usual intake from human milk. The cop- per content of human milk is highest during early lactation and then declines during the course of lactation. According to a num- ber of reports (Biego et al., 1998; Raiten et al., 1998; Rossipal and Krachler, 1998), the mean copper content of human milk during the first 6 months of lactation is approximately 250 Âµg/L (Table 7-1). There are no indications that the copper content of human milk is inadequate to maintain copper status. Liver copper stores are high (Widdowson and Dickerson, 1964) and serum copper and ceruloplasmin concentrations are low (Salmenpera et al., 1986) in newborn infants. During the first 6 months of life, liver stores de- cline and serum copper concentration increases to adult levels, in- dependent of copper intake. Based on the copper content of human milk and milk consump- tion (Chapter 2), the AI for infants ages 0 through 6 months is 200 Âµg/day (250 Âµg/L Ã 0.78 L/day) after rounding. For a 7 kg infant (reference weight for 0 through 6 months, Chapter 2), this would be 28 Âµg/kg/day (200 Âµg/day/7 kg), rounded up to 30 Âµg/kg/day. Ages 7 through 12 Months. One method for estimating the AI for infants receiving human milk, ages 7 through 12 months, is based on the average intake from human milk plus an added increment for complementary foods (Chapter 2). According to the Third
236 DIETARY REFERENCE INTAKES TABLE 7-1 Copper Concentration in Human Milk Milk Estimated Study Stage of Concentration Copper Intake Reference Group Lactation (Âµg/L) of Infants (Âµg/d)a Picciano and 50 women 6â12 wk 245 190 Guthrie, 1976 Vaughan et 38 women, 1â3 mo 430 330 al., 1979 19â42 y 4â6 mo 330 260 7â9 mo 300 180 10â12 mo 240 140 13â18 mo 290 170 19â31 mo 280 170 Vuori and 27 women 2 wk 600 470 Kuitunen, 20 wk 250 150 1979 Vuori et al., 15 women, 6â8 wk 360 280 1980 24â35 y 17â22 wk 210 160 Higashi et al., 21 women, 1 mo 450 350 1982 21â35 y 3 mo 290 230 5 mo 200 160 Dewey and 20 women 1 mo 250 Lonnerdal, 2 mo 230 1983 3 mo 220 4 mo 200 5 mo 150 6 mo 200 Fransson and 15 milk 2â4 mo 320 250 Lonnerdal, samples 1984 Casey et al., 11 women, 8 d 590 460 1985 26â39 y 14 d 490 380 21 d 420 320 28 d 410 320 Lipsman et al., 7â13 teens 1 mo 350 270 1985 2 mo 290 230 3 mo 380 290 4 mo 280 220 5 mo 210 160 6 mo 200 120 7 mo 190 110
COPPER 237 TABLE 7-1 Continued Milk Estimated Study Stage of Concentration Copper Intake Reference Group Lactation (Âµg/L) of Infants (Âµg/d)a Butte et al., 45 women 1 mo 270 1987 2 mo 230 3 mo 210 4 mo 200 Casey et al., 22 women 7d 620 480 1989 5 mo 220 170 Anderson, 1992 7 women Up to 5 mo 310 240 Anderson, 1993 6 women, 110â380 20â30 y Biego et al., 17 milk Mature 250 190 1998 samples milk Rossipal and 46 women 1â3 d 570 440 Krachler, 42â60 d 230 180 1998 97â293 d 150 90 NOTE: Maternal intakes were reported in only two studies: in Vaughan et al. (1979), mean intakes (mg/day) were 3.64, 1.90, 2.37, 6.80, and 2.50 at 4â6, 7â9, 10â12, 13â18, and 19â31 months; in Vuori et al. (1980), mean intakes (mg/day) were 1.88 at 6â8 weeks and 1.73 at 17â22 weeks. a Copper intake based on reported data or concentration (Âµg/L) Ã 0.78 L/day for 0â6 months postpartum and concentration (Âµg/L) Ã 0.6 L/day for 7â12 months postpartum. National Health and Nutrition Examination Survey, the median copper intake from weaning food for children aged 7 through 12 months is 100 Âµg/day (n = 45). The average copper concentration in human milk declines over time, and between 7 and 12 months postpartum the concentration is 200 Âµg/L or less (Table 7-1). Based on an average volume of 0.6 L/day of human milk that is secreted, the copper intake from human milk is 120 Âµg/day (0.6 Ã 200). Therefore the total intake of copper from human milk and comple- mentary foods is 220 Âµg/day (120 + 100). For a 9 kg infant (refer- ence weight 7 through 12 months, Chapter 2), this would be 24 Âµg/ kg/day (220 Âµg/kg Ã· 9 kg). If the AI were extrapolated from the AI for younger infants by using the calculation in chapter 2, the average intake would be 241 Âµg/day.
238 DIETARY REFERENCE INTAKES Copper AI Summary, Ages 0 through 12 Months AI for Infants 0â6 months 200 Âµg/day of copper 30 Âµg/kg/day 7â12 months 220 Âµg/day of copper 24 Âµg/kg/day Special Considerations The concentration of copper in cow milk has been reported to range from 60 to 90 Âµg/L (Fransson and Lonnerdal, 1983) which is lower than that reported for human milk (Table 7-1). Copper is bound to the fat fraction (15 percent) in cow milk with the remain- ing bound to casein (King et al., 1959). It has been reported that copper absorption in infants fed human milk is greater than in infants fed a cow milk-based formula (Dorner et al., 1989; Johnson and Canfield, 1989). Copper deficiency has been observed in in- fants fed cow milk (Cordano et al., 1964; Levy et al., 1985). Dorner and coworkers (1989) showed that 20 percent of children were in negative balance when fed unsupplemented formula, whereas all children were in positive balance when fed either human milk or supplemented formula. Children and Adolescents Ages 1 through 18 Years Method Used to Estimate the Average Requirement No data are available on which to base the Estimated Average Requirement (EAR) for copper for children or adolescents. In the absence of additional information, EARs and Recommended Dietary Allowances (RDAs) for children and adolescents have been estimated by using the method described in Chapter 2, which extrapolates from the adult EAR. Although there are no studies available to indi- cate that the copper requirement is associated with energy expendi- ture, metabolic weight (kg0.75) was used for extrapolating because of the structural and functional role of copper in a number of enzymes and because using metabolic weight yields an EAR that is higher than when total body weight is used. Copper EAR and RDA Summary, Ages 1 through 18 Years EAR for Children 1â3 years 260 Âµg/day of copper 4â8 years 340 Âµg/day of copper
COPPER 239 EAR for Boys 9â13 years 540 Âµg/day of copper 14â18 years 685 Âµg/day of copper EAR for Girls 9â13 years 540 Âµg/day of copper 14â18 years 685 Âµg/day of copper The RDA for copper is set by using a coefficient of variation (CV) of 15 percent (see Chapter 1 and the discussion of adult require- ments that follows) because information is not available on the stan- dard deviation of the requirement for these age groups. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for copper the RDA is 130 percent of the EAR). The calculated RDA is rounded to the nearest 10 Âµg. RDA for Children 1â3 years 340 Âµg/day of copper 4â8 years 440 Âµg/day of copper RDA for Boys 9â13 years 700 Âµg/day of copper 14â18 years 890 Âµg/day of copper RDA for Girls 9â13 years 700 Âµg/day of copper 14â18 years 890 Âµg/day of copper Adults Ages 19 Years and Older Evidence Considered in Estimating the Average Requirement Biochemical Indicators. No single indicator was judged as sufficient for deriving an EAR for adults. Results for specific indicators vary between studies. To determine the EAR, a combination of indicators was used, including plasma copper concentration, serum cerulo- plasmin concentration, erythrocyte superoxide dismutase activity (SOD), and platelet copper concentration in controlled human depletion/repletion studies using specific amounts of copper. If there were significant decreases in serum copper and ceruloplasmin concentrations and SOD activity when the experimental copper diet was fed, and if this decrease was reversed with added copper, then
240 DIETARY REFERENCE INTAKES the experimental diet was considered insufficient to maintain status and therefore deficient in copper. If plasma copper and serum ceruloplasmin concentrations did not change significantly when the experimental diet was fed, but platelet copper concentration de- creased, then the experimental diet was judged to be marginally adequate in copper. A lack of change in the copper status indica- tors indicated that the level of copper in the experimental diet was adequate to maintain status. Because of limited data, data from men and women were combined. Three studies were used to estimate the average requirement on the basis of copper status. These studies are summarized in Table 7-2. Serum copper and ceruloplasmin concentrations and SOD ac- tivity declined significantly in eight of 11 young men fed an experi- mental, depletion diet containing 388 Âµg/day and increased with repletion (Turnlund et al., 1997). Although these indicators de- creased significantly, they did not fall to the deficient range while the deficient diet was fed for 42 days. However, it is expected that they would have fallen to the deficient range over a longer time. Other changes suggesting copper depletion were observed. When young men were fed 790 Âµg/day of copper, the above men- tioned indicators did not decline significantly (Turnlund et al., 1990). After a decline in copper status, two of the 11 men responded to copper repletion. Therefore, the copper requirement to main- tain copper status in half of a group is more than 380 Âµg/day but less than 790 Âµg/day. On the basis of these data, a linear model was used to estimate a response curve. The model estimated that half of these men would not maintain copper status at 550 Âµg/day. Serum copper and ceruloplasmin concentrations did not decline significantly when ten women were fed 570 Âµg/day of copper (Milne and Nielsen, 1996). Platelet copper concentration, however, de- clined significantly for eight of ten women fed 570 Âµg/day and increased with supplementation. Other indicators did not respond to depletion. Platelet cytochrome c oxidase and erythrocyte SOD activity declined but did not respond significantly to repletion. While an EAR based on the first two studies was estimated at 550 Âµg/day, the latter study suggests that 600 Âµg/day may be a marginal intake in over half of the population. Therefore, another incre- ment was added to cover half of the population, and the EAR was set at 700 Âµg/day. Factorial Analysis. Another approach for estimating the minimum copper requirement is to estimate obligatory losses of copper and calculate the amount of copper required in the diet to replace these
COPPER 241 TABLE 7-2 Effects of Copper (Cu) Intake on Copper Status Duration Dietary Cu of Intake Reference Subjects Study (mg/d) Results Turnlund 11 healthy 90 d 1.68 Ã 24 d Plasma Cu, ceruloplasmin, et al., men 0.79 Ã 42 d superoxide dismutase 1990 7.53 Ã 24 d (SOD), urinary and salivary Cu: no change due to Cu intake Cu sweat losses very low Milne and 10 post- â 6 mo 0.57 Ã 105 d Urinary Cu: no change Nielsen, menopausal 2.57 Ã 35 d throughout study 1996 women, (2 mg as Plasma Cu and aged 49â75 y supple- ceruloplasmin: no (mean 63 y) ment) significant change SOD and platelet cytochrome c oxidase: significantly lower after depletion, but no increase during repletion Platelet Cu declined during depletion and increased with repletion Turnlund 11 healthy 90 d 0.66 Ã 24 d Plasma Cu, SOD, et al., men, mean 0.38 Ã 42 d ceruloplasmin, and 1997 age 26 y 2.49 Ã 24 d urinary Cu declined with depletion and increased with repletion obligatory losses. This approach provides supporting evidence for the EAR based on copper status estimated above. Endogenous losses, estimated from total parenteral nutrition (TPN) data, were estimated to be 300 Âµg/day by Shike and coworkers (1981). This estimate was based on gastrointestinal losses from patients without excessive gastrointestinal secretions (less than 0.3 L/day) of 191 Âµg/day and urinary losses of 90 Âµg/day, which are higher than urinary losses in normal, healthy adults, and would provide an increment for miscel- laneous losses. The TPN patients received no copper orally, but copper from TPN ranged from 250 to 1,850 Âµg/day. There are no data on obligatory copper losses in healthy people; therefore the study with the lowest copper intake and data on
242 DIETARY REFERENCE INTAKES endogenous losses was used to estimate obligatory losses in healthy people (Turnlund et al., 1997, 1998). When copper intake was 380 Âµg/day, copper status declined significantly. Endogenous fecal losses were calculated to be 240 Âµg/day, slightly higher than the estimate from TPN data (Shike et al., 1981), and urinary losses were less than 20 Âµg/day. A careful study of surface copper losses in men reported that these averaged 42 Âµg/day (Milne et al., 1991). Other losses, such as hair, nails, semen, or menstrual, have not been mea- sured, and it is assumed they are similar to surface losses. Therefore the amount of absorbed copper needed to replace obligatory losses is 344 Âµg/day (240 + 20 + 42 + 42). Copper absorption at this level of intake is approximately 75 percent. Therefore, 460 Âµg/day of dietary copper would be the minimum amount required to replace obligatory losses. Endogenous fecal copper was 50 Âµg/day higher at 380 Âµg/day than at 460 Âµg/day, and so 50 Âµg/day was added to endogenous fecal losses to account for the increase that occurs be- tween 380 and 460 Âµg/day. Thus 510 Âµg/day (460 + 50) of dietary copper is required to replace copper losses from all sources and to achieve zero balance. Estimation of the average requirement based on indicators of copper status is similar to, but slightly higher than, the average requirement determined by the factorial approach. The EAR is based on biochemical indicators of copper status of men and women, and there was no basis for a difference in requirement based on gender. There are no data on which to base an EAR for older adults, and no evidence to suggest that the requirements would be different. Copper EAR and RDA Summary, Ages 19 Years and Older EAR for Men 19â50 years 700 Âµg/day of copper 51â70 years 700 Âµg/day of copper > 70 years 700 Âµg/day of copper EAR for Women 19â50 years 700 Âµg/day of copper 51â70 years 700 Âµg/day of copper > 70 years 700 Âµg/day of copper The data available to set an EAR are limited for men and women, as well as the number of levels of dietary copper in depletion/reple- tion studies. Thus, a CV of 15 percent is used. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98
COPPER 243 percent of individuals in the group (therefore, for copper the RDA is 130 percent of the EAR). The calculated RDA is rounded to the nearest 100 Âµg. RDA for Men 19â50 years 900 Âµg/day of copper 51â70 years 900 Âµg/day of copper > 70 years 900 Âµg/day of copper RDA for Women 19â50 years 900 Âµg/day of copper 51â70 years 900 Âµg/day of copper > 70 years 900 Âµg/day of copper Pregnancy Evidence Considered in Estimating the Average Requirement There are no data for establishing an EAR for pregnancy. There- fore, the EAR was based on estimates of the amount of copper that must be accumulated during pregnancy to account for the fetus and products of pregnancy. The full-term fetus contains about 13.7 mg copper (Widdowson and Dickerson, 1964). The copper content of the fetus is high compared to that of adults due to the high concentration of copper in the liver. In addition to the amount of copper accumulated by the fetus, other products that accumulate copper during pregnancy, including placenta amniotic fluid and maternal tissue, should be considered. The concentration of these tissues is lower, about one-third of the concentration of the fetus; therefore another 4.6 mg is added to 13.7 mg for a total of 18 mg copper. Over the course of pregnancy, this additional requirement is approximately 67 Âµg/day of absorbed copper or 100 Âµg/day of dietary copper, a value based on 65 to 70 percent bioavailability and rounding. Evidence suggests that copper absorption may be more efficient during pregnancy, and such efficiency could result in ab- sorption of this amount of copper (Turnlund et al., 1983); there- fore no additional increment would be required. However, too few data are available to draw this conclusion. Consequently, an addi- tional 100 Âµg/day was added to the EARs for adolescent girls and women during pregnancy for EARs of 785 and 800 Âµg/day, respec- tively.
244 DIETARY REFERENCE INTAKES Copper EAR and RDA Summary, Pregnancy EAR for Pregnancy 14â18 years 785 Âµg/day of copper 19â30 years 800 Âµg/day of copper 31â50 years 800 Âµg/day of copper The data available to set an EAR are limited for men and women, as well as the number of levels of dietary copper in the depletion/ repletion studies. Thus, a CV of 15 percent is used because informa- tion is not available on the standard deviation of the requirement for pregnant women. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of individuals in the group (therefore, for copper the RDA is 130 percent of the EAR). The calculated RDA is rounded to the nearest 100 Âµg. RDA for Pregnancy 14â18 years 1,000 Âµg/day of copper 19â30 years 1,000 Âµg/day of copper 31â50 years 1,000 Âµg/day of copper Lactation Evidence Considered in Estimating the Average Requirement The EAR for lactation is determined on the basis of the copper intake necessary to replace copper secreted daily in human milk plus the EAR for adolescent girls and adult women. The average amount of copper that is secreted in human milk and must be ab- sorbed is approximately 200 Âµg/day. Copper bioavailability for the adult consuming the EAR for copper is about 65 to 70 percent; therefore an additional 300 Âµg/day of copper must be consumed to replace the copper secreted in human milk, assuming that there is no increase in the efficiency of copper absorption during lactation. Animal data suggest that maternal absorption of copper increases during lactation and could provide for about half of the added increment, but data are not available for humans on copper absorp- tion during lactation.
COPPER 245 Copper EAR and RDA Summary, Lactation EAR for Lactation 14â18 years 985 Âµg/day of copper 19â30 years 1,000 Âµg/day of copper 31â50 years 1,000 Âµg/day of copper The data available to set an EAR are limited for men and women, as is the number of levels of dietary copper in the depletion/reple- tion studies. Thus, a CV of 15 percent is used because information is not available on the standard deviation of the requirement for lactating women. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of individuals in the group (therefore, for copper the RDA is 130 percent of the EAR). The calculated RDA is rounded to the nearest 100 Âµg. RDA for Lactation 14â18 years 1,300 Âµg/day of copper 19â30 years 1,300 Âµg/day of copper 31â50 years 1,300 Âµg/day of copper INTAKE OF COPPER Food Sources Copper is widely distributed in foods. The accumulation of copper in plants is not affected by the copper content of the soil in which they grow. Organ meats, seafood, nuts, and seeds are major contrib- utors of dietary copper (Pennington et al., 1995). Wheat bran cereals and whole grain products are also sources of copper. Foods that contribute substantial amounts of copper to the U.S. diet include those high in copper, such as organ meats, grains, and cocoa prod- ucts, and those relatively low in copper that are consumed in sub- stantial amounts, such as tea, potatoes, milk, and chicken. Dietary Intake Data from nationally representative U.S. surveys are available to estimate copper intakes (Appendix Tables C-15, C-16, D-2, E-3). The median intake of copper for women is approximately 1.0 to 1.1 mg/day, whereas the median intake for men ranges from 1.2 to 1.6 mg/day (Appendix Tables C-15 and D-2).
246 DIETARY REFERENCE INTAKES Intake from Supplements In 1986, approximately 15 percent of adults in the United States consumed supplements that contained copper (Moss et al., 1989; see Table 2-2). Based on data from the Third National Health and Nutrition Examination Survey provided in Appendix Table C-16, the median dietary plus supplemental copper intake was similar to the intake from food alone. The mean intake of dietary and supple- mental copper (1.3 to 2.2 mg/day) was approximately 0.3 to 0.5 mg/day greater for men and women than the mean intake from food (1.0 to 1.7 mg/day). TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, in- take above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxic- ity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to indi- viduals who are receiving copper under medical supervision. Hazard Identification Reviews of the toxicity studies in experimental animals (ATSDR, 1990; EPA, 1987; IPCS, 1998; NRC, 1977) indicate that these studies are not useful for setting a UL for humans. Very few of these studies used chronic exposures, only one or two doses were used, and the reporting of experimental details and results was incomplete. In addition, some studies used routes of exposure that are not relevant to human intake (Toyokuni and Sagripanti, 1994). Finally, animal species vary markedly in their sensitivity to copper (Davis and Mertz, 1987); thus it is difficult to determine the most appropriate model in which to assess human toxicity to copper. The long-term toxicity of copper is not well studied in humans, but it is rare in normal populations not having some hereditary defect in copper homeostasis (Olivares and Uauy, 1996). Copper homeostasis is affected by the interaction among zinc, copper, iron, and molybdenum. In addition, the level of dietary protein, interact-
COPPER 247 ing cations, and sulfate all can influence the absorption and utiliza- tion of copper (Davis and Mertz, 1987). Therefore, the derivation of a UL for copper must be made in the context of these inter- actions. The adverse effects associated with intake of soluble copper salts in supplements and drinking water are reviewed below. Adverse Effects Gastrointestinal Effects. There are data from studies of humans indi- cating gastrointestinal illness including abdominal pain, cramps, nausea, diarrhea, and vomiting from the consumption of beverages or drinking water containing high levels of copper (Berg and Lundh, 1981; Knobeloch et al., 1994; Olivares et al., 1998; Pizarro et al., 1999; Spitalny et al., 1984; Wylie, 1957). Many of these studies had serious experimental design weaknesses and involved very few subjects, or the copper exposures were extremely poorly character- ized. Thus they are not suitable for the development of a UL. In a survey of gastrointestinal effects resulting from high levels of copper in carbonated soft drinks, Donohue (1997) reported ad- verse effects at copper intakes of 4 mg/L. This concentration is equivalent to approximately 4.8 mg/day based on a mean intake of 1.2 L/day of water (Appendix Table C-27). In a double-blind study, 60 healthy Chilean women were given normal drinking water to which graded concentrations of copper sulfate had been added for 11 weeks (Pizarro et al., 1999). Although the exact threshold could not be determined, the authors reported an increased incidence of nausea and other gastrointestinal effects at copper levels greater than 3 mg/L. The mean consumption of water was 1.6 L/day, and therefore the average copper intake from water was 4.8 mg/day. From these two studies it would appear that the threshold for acute gastrointestinal effects from copper in water is about 4.8 mg/day. However, individuals may be able to adapt to even higher concen- trations of copper in drinking water. No adverse gastrointestinal effects were reported in U.S. adults who consumed water contain- ing approximately 8.5 to 8.8 mg/L of copper for over 20 years be- ginning in childhood (aged 0 through 5 years) (Scheinberg and Sternlieb, 1996). Based on water consumption data from the 1988â 1994 Third National Health and Nutrition Examination Survey (NHANES III) (Appendix Table C-27), the mean water consump- tion for young children is approximately 400 mL, which would be equivalent to 3.5 mg/day of copper.
248 DIETARY REFERENCE INTAKES Liver Damage. Liver damage in humans is observed almost exclu- sively in patients with Wilsonâs disease and children with Indian childhood cirrhosis (ICC) and idiopathic copper toxicosis (ICT). ICC and ICT have been associated with high copper intakes. How- ever, familial relationships and genetic factors are required for the expression of liver toxicity from high levels of copper intake (Joshi et al., 1987; Kishore and Prasad, 1993; Pandit and Bhave, 1996; Tanner, 1998). The rarity of ICT and ICC outside of Germany and India and the lack of liver damage noted in children in the United States exposed to levels of copper between 8.5 and 8.8 mg/L in drinking water support the hypothesis that copper is only one fac- tor required for the expression of these diseases (Scheinberg and Sternlieb, 1994). Further evidence of an underlying hereditary defect in copper homeostasis in ICC comes from Kishore and Prasad (1993). These authors found that one-third of the ICC cases examined have Î±-1- antitrypsin deficiency. In view of the weight of evidence supporting a genetic basis for the liver damage in Wilsonâs disease, ICC, and ICT, it is not appropriate to use data from such populations to develop a UL for copper in populations with normal copper homeo- static mechanisms. Pratt and coworkers (1985) reported no evidence of liver damage or gastrointestinal effects in a double-blind study of seven subjects given 10 mg/day of copper gluconate for a period of 12 weeks. Although from a small study, these results are consistent with the safe upper level of intake of 10 to 12 mg/day of copper proposed by the World Health Organization (WHO, 1996) and the International Programme on Chemical Safety (IPCS, 1998). At higher doses, acute liver failure was reported in one subject, who had no known genetic defect in copper homeostasis, after consuming 30 mg/day of copper from supplements for 2 years, followed by 60 mg/day for an addi- tional but unspecified period of time (OâDonohue et al., 1993). Other Systemic Effects. Little evidence indicates that chronic expo- sure to copper results in systemic effects other than liver damage. No association between the level of copper intake and spontaneous abortions has been found, and data are inadequate to assess the reproductive or developmental effects of copper in humans (IPCS, 1998). Also, there is little convincing evidence that copper is causally associated with the development of cancer in humans.
COPPER 249 Summary On the basis of considerations of causality, relevance, and the quality and completeness of the database, liver damage was selected as the critical endpoint on which to base a UL. The selection of gastrointestinal effects as a critical endpoint was considered because of the data involving acute ingestion of soluble (highly ionized) copper salts in drinking water. However, in the United States and Canada, liver damage is a much more relevant endpoint because of the potential for excess intake from food and supplements. Fur- thermore, extensive evidence from studies in humans and experi- mental animals indicates that liver damage is the critical endpoint resulting from daily intake of high levels of copper salts (IPCS, 1998). Dose-Response Assessment Adults Data Selection. The human data evaluating liver effects after chronic consumption of copper gluconate appear most relevant to setting a UL. The UL derived below does not apply to individuals at increased risk of adverse effects from excess intake of copper. These sub- groups are identified under âSpecial Considerations.â Identification of a No-Observed-Adverse-Effect Level (NOAEL) and a Lowest-Observed-Adverse-Effect Level (LOAEL). A NOAEL of 10 mg/day of copper was identified on the basis of the results of Pratt and coworkers (1985). In a 12-week, double-blind study, 10 mg of copper as copper gluconate capsules was consumed daily by seven adults. Liver function tests were normal. From a case report, consumption of 30 mg/day as copper tablets for 2 years, followed by 60 mg/day for an additional period of time, resulted in acute liver failure (OâDonohue et al., 1993). Uncertainty Assessment. The NOAEL of 10 mg/day was considered to be protective of the general population. Therefore, an uncer- tainty factor (UF) of 1.0 was selected. A larger UF was considered unnecessary in view of the large international database in humans indicating no adverse effects from daily consumption of 10 to 12 mg/day of copper in foods and the rarity of observed liver damage from copper exposures in human populations with normal copper homeostasis.
250 DIETARY REFERENCE INTAKES Derivation of a UL. The NOAEL of 10 mg/day was divided by the UF of 1.0 to obtain a UL of 10 mg/day (10,000 Âµg/day) of copper intake from food and supplements. UL = NOAEL = 10 mg/day = 10 mg/day UF 1.0 Copper UL Summary, Ages 19 Years and Older UL for Adults â¥ 19 years 10 mg/day (10,000 Âµg/day) of copper Other Life Stage Groups Infants. For infants, the UL was judged not determinable because of insufficient data on adverse effects in this age group and concern about the infantâs ability to handle excess amounts of copper. To prevent high levels of copper intake, the only source of intake for infants should be food and formula. Children and Adolescents. In the general, healthy population there are no reports of liver damage from copper ingestion; however, there are many reports of liver damage in children having defects in copper homeostasis. Given the dearth of information, the UL values for children and adolescents are extrapolated from those established for adults. Thus, the adult UL of 10,000 Âµg/day of copper was adjusted for children and adolescents on the basis of relative body weight as described in Chapter 2 using reference weights from Chapter 1 (Table 1-1). Values have been rounded down. Pregnancy and Lactation. No studies involving supplemental copper intake by pregnant or lactating women were found. Given the dearth of information, it is recommended that the UL for pregnant and lactating females be the same as that for the nonpregnant and nonlactating females. Copper UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation UL for Infants 0â12 months Not possible to establish; source of intake should be from food and formula only
COPPER 251 UL for Children 1â3 years 1 mg/day (1,000 Âµg/day) of copper 4â8 years 3 mg/day (3,000 Âµg/day) of copper 9â13 years 5 mg/day (5,000 Âµg/day) of copper UL for Adolescents 14â18 years 8 mg/day (8,000 Âµg/day) of copper UL for Pregnancy 14â18 years 8 mg/day (8,000 Âµg/day) of copper 19â50 years 10 mg/day (10,000 Âµg/day) of copper UL for Lactation 14â18 years 8 mg/day (8,000 Âµg/day) of copper 19â50 years 10 mg/day (10,000 Âµg/day) of copper Special Considerations Certain subgroups may be at increased risk of adverse effects from excess intake of copper (Joshi et al., 1987; Kishore and Prasad, 1993; Pandit and Bhave, 1996; Scheinberg and Sternlieb, 1996; Tanner, 1998). These include individuals with Wilsonâs disease (homozygous), ICT, and ICC. In addition, heterozygotes for Wilsonâs disease may be at increased risk of adverse effects from excess copper intake. Intake Assessment Based on data from NHANES III (Appendix Table C-16), the highest median intake of copper from the diet and supplements for any gender and life stage group was about 1,700 Âµg/day for men aged 19 through 50 years and about 1,900 Âµg/day for lactating women. The highest reported intake from food and supplements at the ninety-ninth percentile was 4,700 Âµg/day in lactating women. The next highest reported intake at the ninety-ninth percentile was 4,600 Âµg/day in pregnant women and men aged 51 through 70 years. In situations where drinking water that contains copper at the present U.S. Environmental Protection Agency (EPA) Maximum Contaminant Level Goal is consumed daily, an additional intake of 2,600 Âµg of copper in adults and 1,000 Âµg in 1- through 4-year-old children is possible. However, as reported by IPCS (1998), data from the EPA indicate 98 percent of flushed drinking water samples had copper levels of less than 460 Âµg/L. According to these values, most
252 DIETARY REFERENCE INTAKES of the U.S. population receives less than 100 to 900 Âµg/day of copper from drinking water. Whether total daily intakes of copper will lead to adverse health effects will depend upon the species of copper in the media of concern, its degree of ionization, and its bioavailability. Risk Characterization The risk of adverse effects resulting from excess intake of copper from food, water, and supplements appears to be very low in adults at the highest intakes noted above. However, copper intake data indicate that a small percentage of children aged 1 through 8 years are likely to exceed the UL for their age group. Although members of the general population should be advised not to exceed the UL routinely, intake above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to individuals who are receiving copper under medical super- vision. RESEARCH RECOMMENDATIONS FOR COPPER â¢ Determine the specific health risks associated with marginal copper deficiency. â¢ Define the adverse effects of chronic high copper consumption for establishing upper intake levels and to evaluate the health effects of copper supplements. â¢ Determine the involvement of low and high copper intakes on neurological and cognitive function. REFERENCES Anderson RR. 1992. Comparison of trace elements in milk of four species. J Dairy Sci 75:3050â3055. Anderson RR. 1993. Longitudinal changes of trace elements in human milk dur- ing the first 5 months of lactation. Nutr Res 13:499â510. ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for Copper. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
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