conspectus of researchon copper metabolism and requirements

2020 KARL E. MASON
The states of hypercupremia to which
reference has been made clearly indicate
the remarkable homeostatic mechanism in
copper metabolism. These involve to a
large degree the increased synthesis of
ceruloplasmin in response to a variety of
body stresses, including hormonal influ
ences (44). Also, in body states involving
inflammatory reactions, ceruloplasmin may
function in the role of an "acute phase
reactant" (48, 636, 637).
COPPER TOXICITY
Hemochromatosis. There is a long history
of acute and chronic toxicity of copper in
man. Some of this was recorded in 1891 by
Lehmann (448) who was one of the earli
est investigators to test the effects of vari
ous copper salts on experimental animals.
He also states that two of his students
showed no ill effects of additions of up to
10 to 20 mg of copper sulfate and up to
5 to 30 mg of copper acetate to their daily
beer. This is somewhat greater than a
current estimated toxic level of 10 to 15
mg of inorganic copper for adult man
(75, 865). In 1898, Baum and Seeliger
(35) described extensive deposition of
blood pigments, then designated hematoidin
and hemosiderin, in the liver cells
of the goat, sheep, dog and cat fed copper
salts. These observations were more ex
tensively explored by Mallory et al. (480-
484) who reported that chronic oral intake
of copper acetate in the rabbit, sheep and
monkey produces a condition comparable
to hepatic hemosiderosis in man.
Mallory (481) described in detail the
hepatic changes characteristic of human
hemochromatosis (pigment cirrhosis) based
upon 19 necropsies, presenting circum
stantial evidence of copper toxicity as
basically involved. These interpretations
were supported by other pathologists re
porting liver copper levels up to 10-fold
normal in a large series of cases of hemo
chromatosis (295, 327, 586). Yet Mills
(522) found no evidence of hemochroma
tosis in 100 necropsies of Korean people
using copper and brass utensils routinely
in daily life. Although the animal studies
of Mallory and coworkers (480, 482, 484)
on which their hypothesis of the cause of
hemochromatosis was based were also con
firmed by certain investigators (295, 519),
others attempted in vain to duplicate their
results (218, 587, 607). Differences in sus
ceptibility and in levels and duration of
exposure to copper salts were proposed
(482) to explain the discrepancies in the
experimental findings.
Copper poisoning in man The oral in
gestion of excess copper produces a metal
lic taste in the mouth, nausea, vomiting,
epigastric pain, diarrhea and, to variable
degrees, jaundice, hemolysis, hemaglobinuria,
hematuria and oliguria. The vomitus,
stool and saliva may appear blue or green.
In severe cases, anuria, hypotension and
coma occur. The ingested copper is
promptly absorbed from the upper gut and
rapidly and dramatically increases the level
of direct reacting copper in the blood, due
in large part to its accumulation in the red
blood cells. When this accumulation
reaches a certain level, hemolysis occurs,
whether it be the result of oral ingestion
(120, 203, 641), absorption through de
nuded skin (353), dialysis procedures (51,
52, 376, 487) or exchange transfusions
(50). This hemolysis is comparable to that
commonly seen in Wilson's disease, which
is attributed to a sudden release of copper
into the blood stream from a liver dam
aged by an increasing load of copper un
able to be utilized in ceruloplasmin syn
thesis or excreted via the biliary system
(97, 155, 508, 516). This hemolysis may
reflect, to variable degrees, inhibition of
erythrocyte glycolysis and of glucose-6phosphate
dehydrogenase, oxidation of glutathione
and denaturation of hemoglobin
with Heinz body formation (203). A
variety of other factors may be involved
(588). Manifestations of slow copper
poisoning of a non-fatal type as seen in
copper and brass workers are well de
scribed by Chatterji and Ganguly (111).
There are symptoms of laryngitis, bron
chitis, intestinal colic with catarrh and
diarrhea, general emaciation and anemia.
Since much of the information on cop
per toxicity comes from instances of acci
dental or intentional intake (mostly sui
cide), data concerning oral intake neces
sary to produce symptoms of toxicity are
decidedly meager. Ingestion of 10 to 15
mg of inorganic copper will cause nausea,
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