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OCR for page 304
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).
