Copper - Toxicology of Metals - page 525

activity. This fi nding suggests that the concentration
of noncopper-containing apo-ceruloplasmin increases
during infl ammatory acute-phase reactions (Gitlin et al .,
1992). The half-time of apo-ceruloplasmin (5 hours) is
much shorter than the half-time of holoceruloplasmin
(5.5 days) (Gitlin, 1998). Diurnal fl uctuations of plasma
copper have been reported (Lifshitz and Henkin, 1971).
Women have generally higher plasma copper levels
than men (Milne, 1998). Higher levels have also been
measured in women taking oral contraceptives and
postmenopausal women receiving estrogen (Johnson
et al ., 1992; Milne and Johnson, 1993). Serum copper
levels increase during pregnancy (Aaseth et al ., 2001).
The serum ceruloplasmin concentration also increases
during pregnancy, reaching values at parturition that
are approximately twice those found in nonpregnant
women (Flynn, 1982).
In healthy adults, the urinary excretion of copper
is generally between 30 and 60

tablets for 6 weeks (Turnlund et al ., 1990; Medeiros
et al ., 1991; Pizarro et al ., 1999; Araya et al ., 2003). The
activities of ceruloplasmin in serum and CuZn-SOD
in erythrocytes, but not the concentration of copper
in serum, increased when the study was extended
to 5 months and the supplementation increased to
7 mg Cu/day (Turnlund et al ., 2004). These results sug-
gest that gastrointestinal copper intakes several fold
higher than the dietary reference intake is necessary to
change the levels of these biomarkers, thus not mak-
ing them very useful for the purpose of exposure sur-
veillance. Whether these biomarkers may be related to
exposure at even higher oral intakes remains to be elu-
cidated. Because the described biomarkers of copper
status are not sensitive enough to detect moderately
increased dietary intakes of copper, other biomarkers
like benzylamine oxidase are currently investigated
(Turnlund et al ., 2004). An increase in platelet cyto-
chrome c oxidase and serum diamine oxidase activity
suggested that these markers may be more sensitive
to copper supplementation than the more traditional
biomarkers of exposure (Kehoe et al ., 2000). No data
are available on these biomarkers in the assessment
of pulmonary uptake of copper, as for instance in the
occupational setting.
In defi ciency states it has been shown that infants
suffering from malnutrition normalized their levels of
SOD in erythrocytes and copper in serum after supple-
mentation with 80

g Cu/day (Harris,
1991). Dietary intakes of 0.785 mg Cu/day for 42 days,
1.68 mg Cu/day for 24 days, or 7.53 mg Cu/day for 24
days did not result in altered urinary copper excretion
(Turnlund et al ., 1990). This suggests that even an oral
intake several-fold higher than the daily recommended
intake does not increase the urinary copper excretion.
Thus, urinary copper is unsuitable for biological moni-
toring at moderately elevated oral intakes. However,
if this is true when exposure occurs by inhalation,
has hardly been studied. An increased urinary excre-
tion >100

µ

g Cu/kg/day for 120 days (Uauy
et al ., 1985). The increase of erythrocyte SOD and serum
copper in women supplemented with 3 and 6 mg cop-
per daily during 4 weeks was attributed to marginal
copper status prior to the study (Cashman et al ., 2001).
It has been suggested that in copper depletion only
lower liver copper levels may be found (Olivares et al.,
2000). At mild copper defi ciency erythrocyte SOD or
cytochrome-c-oxidase in leukocytes or platelets may be
useful biomarkers (Milne, 1998). At moderate defi ciency
the serum copper concentration and the serum cerulo-
plasmin level may be reduced, and eventually also the
hemoglobin content of the blood (Olivares et al ., 2000).

µ

g Cu/24 hours is often observed in patients
with Wilson's disease (Langner and Denk, 2004). Uri-
nary copper concentrations as high as 1787

µ

g Cu/24
hours have been reported in these patients (Wang et al .,
2004).
The daily excretion of copper into the bile in humans
is approximately 2500

µ

g (Linder and Hazegh-Azam,
1996). The copper content of human milk decreases
during lactation, and mean levels of 750

µ

µ g/L or

570 g/L have been measured soon after birth (Davis

and Mertz, 1987). Also, the milk content of ceruloplas-
min decreases during lactation (Linder et al ., 1998).
Copper in human milk is more easily absorbed by the
infant than copper in cow's milk (Olivares et al ., 2000).

µ

7 EFFECTS AND DOSE-RESPONSE
RELATIONSHIPS

6.2 Biomarkers of Exposure
Several potential biomarkers of exposure other than
copper in serum or in urine have been assessed. Healthy
adults with presumably normal copper status had no
increase in the levels of CuZn-SOD in erythrocytes,
serum ceruloplasmin or copper in serum after supple-
mentation of up to 150

Copper is an essential trace element. The redox
chemistry makes copper highly suitable as a catalytic
cofactor in oxidative enzymes. Copper is involved in
numerous biological processes primarily as an integral
part of enzymes, and thus in body functions like cellular
respiration (cytochrom c oxidase), antioxidant defense
(superoxide dismutase), connective tissue formation
(lysyl oxidase and related proteins), neurotransmitter

g Cu/kg/day for two months
or 7.53 mg Cu/day for 24 days or 5 mg Cu/l added to
drinking water, or 3 mg Cu/day as copper gluconate

µ