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TABLE 1 Dietary Reference Intakes for Copper by Life Stage Group DRI values (mg/day) EARa RDAb AIc ULd males females males females Life stage group NDe 0 through 6 mo 200 7 through 12 mo 220 ND 1 through 3 y 260 260 340 340 1,000 4 through 8 y 340 340 440 440 3,000 9 through 13 y 540 540 700 700 5,000 14 through 18 y 685 685 890 890 8,000 19 through 30 y 700 700 900 900 10,000 31 through 50 y 700 700 900 900 10,000 51 through 70 y 700 700 900 900 10,000 > 70 y 700 700 900 900 10,000 Pregnancy £ 18 y 785 1,000 8,000 19 through 50 y 800 1,000 10,000 Lactation £ 18 y 985 1,300 8,000 19 through 50 y 1,000 1,300 10,000 a EAR = Estimated Average Requirement. b RDA = Recommended Dietary Allowance. c AI = Adequate Intake. d UL = Tolerable Upper Intake Level. Unless otherwise specified, the UL represents total intake from food, water, and supplements. e ND = Not determinable. This value is not determinable due to the lack of data of adverse effects in this age group and concern regarding the lack of ability to handle excess amounts. Source of intake should only be from food to prevent high levels of intake.

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PART III: COPPER 305 COPPER C opper functions as a component of several metalloenzymes, which act as oxidases in the reduction of molecular oxygen. The activities of some copper metalloenzymes have been shown to decrease in human cop- per depletion. The requirements for copper are based on a combination of indicators, including plasma copper and ceruloplasmin concentrations, erythrocyte super- oxide dismutase activity, and platelet copper concentration in controlled hu- man depletion/repletion studies. The Tolerable Upper Intake Level (UL) is based on protection from liver damage as the critical adverse event. DRI values are listed by life stage group in Table 1. Sources of copper include organ meats, seafood, nuts, seeds, wheat-bran cereals, and whole-grain products. Frank copper deficiency in humans is rare. Symptoms associated with deficiency include normocytic, hypochromic ane- mia; leucopenia; and neutropenia; and, in copper-deficient infants and growing children, osteoporosis. Copper toxicity is generally rare except in individuals genetically susceptible to the increased risk of adverse effects from excess cop- per intake. COPPER AND THE BODY Function Copper functions as a component of several metalloenzymes, which act as oxi- dases in the reduction of molecular oxygen. Some of the principal copper metalloenzymes found in humans include the following: • Diamine oxidase, which inactivates the histamine released during aller- gic reactions • Monoamine oxidase (MAO), which is important in serotonin degrada- tion and in the metabolism of epinephrine, norepinephrine, and dopa- mine; MAO inhibitors are used as antidepressant drugs • Ferroxidases, which are copper enzymes found in the plasma and func- tion in ferrous iron oxidation that is needed to bind iron to transferrin • Dopamine b-monooxygenase, which uses ascorbate, copper, and O2 to convert dopamine to norepinephrine

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 306 • Copper/zinc superoxide dismutase (Cu/Zn SOD), which defends against oxidative damage; mutations in the Cu/Zn SOD gene, which alter the protein’s redox behavior, produce amyotrophic lateral sclerosis (Lou Gehrig’s disease) Absorption, Metabolism, Storage, and Excretion Copper absorption primarily occurs in the small intestine via both saturable- mediated and nonsaturable-nonmediated mechanisms. 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. A defective MNK gene causes Menkes’ disease, which is characterized by reduced copper absorption and placental copper transport. The extent of copper absorption varies with dietary copper intake; it ranges from more than 50 percent at an intake of less than 1 mg/day to less than 20 percent at intakes above 5 mg/day. About 35 percent of a 2 mg/day intake is absorbed and transported via the portal vein to the liver, bound to albumin, for uptake by liver parenchymal cells. Nearly two-thirds of body copper content is found in the skeleton and muscle, but the liver appears to be the key site in maintaining plasma copper concentration. Biliary copper excretion is adjusted to maintain balance. Copper is released via the plasma to extrahepatic sites, where up to 95 percent of the copper is bound to cerulosplasmin. Urinary copper excretion is normally very low (< 0.1 mg/day) over a wide range of dietary intakes. As with other trace elements, renal dysfunction can lead to increased urinary losses. DETERMINING DRIS Determining Requirements The primary criterion used to estimate the requirements for copper is based on a combination of indicators, including plasma copper and ceruloplasmin con- centrations, erythrocyte superoxide dismutase activity, and platelet copper concentration in controlled human depletion/repletion studies. Criteria for Determining Copper Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Average copper intake from human milk 7 through 12 mo Average copper intake from human milk and complementary foods

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PART III: COPPER 307 1 through 18 y Extrapolation from adult EAR 19 through 50 y Plasma copper, serum ceruloplasmin, and platelet copper con- centrations and erythrocyte superoxide dismutase activity 51 through > 70 y Extrapolation from 19 through 50 y Pregnancy £ 18 y Adolescent female EAR plus fetal accumulation of copper 19 through 50 y Adult female EAR plus fetal accumulation of copper Lactation £ 18 y Adolescent female EAR plus average amount of copper secreted in human milk 19 through 50 y Adult female EAR plus average amount of copper secreted in human milk The UL The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse effects for almost all people. Members of the general population should not routinely exceed the UL. The UL for copper is based on liver damage as the critical endpoint and represents intake from food, water, and supplements. Based on data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994), the highest median intakes of copper from the diet and supplements for any gender and life stage group were approxi- mately 1,700 mg/day for men aged 19 through 50 years and approximately 1,900 mg/day for lactating women. The highest reported intake from food and supplements at the 99th percentile was 4,700 mg/day, also in lactating women. The next highest reported intake at the 99th percentile was 4,600 mg/day in pregnant women and men aged 50 through 70 years. The risk of adverse effects resulting from excess intake of copper from food, water, and supplements ap- pears to be low in the highest intakes noted above. DIETARY SOURCES Foods 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 are grown. Major contributors of copper include organ meats, seafood, nuts, and seeds. 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

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 308 copper, such as organ meats, grains, and cocoa products, as well as foods rela- tively low in copper, but which are consumed in substantial amounts, such as tea, potatoes, milk, and chicken. Dietary Supplements According to U.S. data from the 1986 National Health Interview Survey (NHIS) approximately 15 percent of adults in the United States consumed supplements that contained copper. Based on data from the NHANES III, the median dietary plus supplemental copper intake was similar to the intake from food alone. The mean intake of dietary and supplemental copper (1.3–2.2 mg/day) was ap- proximately 0.3–0.5 mg/day greater for men and women than the mean intake from food (1.0–1.7 mg/day). Bioavailability The bioavailability of copper is markedly influenced by the amount of copper in the diet, rather than by the diet’s composition. Bioavailability ranges from 75 percent of dietary copper absorbed by the body when the diet contains only 400 mg/day to 12 percent absorbed when the diet contains 7.5 mg/day. The absolute amount of copper absorbed is higher with increased intake. In addi- tion, the excretion of copper into the gastrointestinal tract regulates copper retention. As more copper is absorbed, turnover is faster and more copper is excreted into the gastrointestinal tract. 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. Dietary Interactions Copper homeostasis is affected by interactions among zinc, copper, iron, and molybdenum. In addition, the level of dietary protein, interacting cations, and sulfate all can influence the absorption and utilization of copper. Some evi- dence that copper may interact with certain nutrients and dietary substances appears in Table 2. INADEQUATE INTAKE AND DEFICIENCY Frank copper deficiency in humans is rare, but it has been found in a number of special conditions. It has also been observed in premature infants fed milk formulas deficient in copper, infants recovering from malnutrition associated with chronic diarrhea and fed cow milk, and patients with prolonged total

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PART III: COPPER 309 TABLE 2 Potential Interactions with Other Dietary Substances Substance Potential Interaction Notes SUBSTANCES THAT AFFECT COPPER Zinc Zinc (at very high intakes) This usually only occurs at intakes well in excess of may decrease copper the amount of zinc normally found in the diet. absorption. Iron High iron may interfere with Infants fed a formula that contained low copper absorption in infants. concentrations of iron absorbed more copper than infants who consumed the same formula with a higher iron concentration. Such an interaction has been reported to produce reduced copper status in infants. parenteral nutrition (TPN). In these cases, serum copper and ceruloplasmin concentrations were as low as 0.5 mmol/L and 35 mg/L, respectively, compared with reported normal ranges of 10–25 mmol/L for serum copper concentration and 180–400 mg/L for ceruloplasmin concentration. Supplementation with copper resulted in rapid increases in serum copper and ceruloplasmin concentrations. The symptoms associated with copper deficiency include the following: • Normocytic, hypochromic anemia • Leukopenia • Neutropenia • Osteoporosis (in copper-deficient infants and growing children) EXCESS INTAKE The long-term toxicity of copper has not been well studied in humans, but it is rare in normal populations without some hereditary defect in copper homeo- stasis. Potential adverse effects have been associated with excess intake of soluble copper salts in both supplements and drinking water, although most have only been reported based on acute and not chronic intakes. The consumption of drinking water or other beverages containing high levels of copper has resulted mostly in gastrointestinal illness, including abdominal pain, cramps, nausea, diarrhea, and vomiting.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 310 Special Considerations Individuals susceptible to adverse effects: Liver damage in humans due to ex- cess intake of copper is observed almost exclusively in individuals with Wilson’s disease, idiopathic copper toxicosis (ICT), and children with Indian childhood cirrhosis (ICC). Thus, these individuals will be at an increased risk of adverse effects from excess copper intake.

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PART III: COPPER 311 KEY POINTS FOR COPPER Copper functions as a component of several metalloenzymes, 3 which act as oxidases in the reduction of molecular oxygen. The requirements for copper are based on a combination of 3 indicators, including plasma copper and ceruloplasmin concentrations, erythrocyte superoxide dismutase activity, and platelet copper concentration in controlled human depletion/ repletion studies. The UL is based on protection from liver damage as the critical adverse event. The risk of adverse effects resulting from excess intake of 3 copper from food, water, and supplements appears to be low. Good sources of copper include organ meats, seafood, nuts, 3 seeds, wheat-bran cereals, and whole-grain products. Frank copper deficiency in humans is rare. The signs and 3 symptoms of deficiency include normocytic, hypochromic anemia; leucopenia; and neutropenia; and, in copper-deficient children, osteoporosis. The long-term toxicity of copper has not been well studied in 3 humans, but it is rare in normal populations without some hereditary defect in copper homeostasis. Potential adverse effects have been associated with excess intake of soluble copper salts in both supplements and drinking water, although most have only been reported based on acute and not chronic intakes. People at an increased risk of adverse effects from excess 3 copper intake include individuals with Wilson’s disease (homozygous and heterozygous), idiopathic copper toxicosis (ICT), and Indian childhood cirrhosis (ICC).