Copper - Toxicology of Metals - page 527

et al ., 2003). Experiments in adults have shown mild
nausea to be the most frequently reported gastrointes-
tinal symptom, increased reporting starting at around
4 mg Cu/L (as CuSO 4 ) in drinking water (Pizarro et al .,
1999; Araya et al ., 2001; Olivares et al ., 2001). The inci-
dence of vomiting may increase at 6 mg Cu/L drinking
water (Olivares et al ., 2001). Adding the same amount
of copper to an orange-fl avored powder drink resulted
in less often reporting of nausea and no vomiting
(Olivares et al ., 2001). Women reported gastrointestinal
symptoms more frequently than men when exposed to
copper in drinking water (Araya et al ., 2004).
Drinking 200 ml of water containing 10 mg Cu/L (as
CuSO 4 ) as a single bolus resulted in increased urinary
sucrose excretion suggestive of increased permeabil-
ity of the gastric mucosa (Gotteland et al ., 2001). The
biological mechanisms for the gastric symptoms have
not been completely elucidated, but altered permeabil-
ity of the tight junctions of human intestinal Caco-2
cells after in vitro exposure to CuCl 2 has been shown
(Ferruzza et al ., 1999).
Although industrial exposure to copper is wide-
spread, well-designed epidemiological studies are
lacking from copper exposed populations. Also many
occupational exposures consist of a mixture of copper
and other compounds, making it diffi cult to attribute a
particular effect to copper alone (WHO, 1998). Some
small studies suggest that copper exposure may cause
respiratory irritation, which also is compatible with
results from animal studies. Long-term occupational
exposure to a mixture of copper salts resulted in mucosal
and suspected atrophic changes in the mucous mem-
branes of the nose (Askergren and Mellgren, 1979). The
study of Suciu et al . (1981) reported dyspnoea, thoracic
pain, emphysema, and pulmonary fi brosis in copper
exposed workers, but methodological weaknesses
severly limit the usefulness of this information.
Reports on chronic lung damage after exposure
to copper dust or fumes in industry are negative
(Gleason, 1968; Cohen, 1974). Pimentel and Marques
(1969), and Villar (1974) reported 2 and 15 cases,
respectively, of the so-called 'vineyard sprayers lung'
that was attributed to the inhalation of copper sulfate
during spraying of vineyards with Bordeaux mixture.
Macroscopical, greenish blue patches were seen on the
lung surfaces. The histological nodular changes resem-
bled those seen in silicosis, but only copper could be
demonstrated.
Among the 15 patients described by Villar (1974),
3 cases of lung cancer and 5 cases of tuberculosis were
diagnosed.
A form of contact dermatitis associated with cop-
per has been reported (Saltzer and Wilson, 1968), but
generally few published cases of dermatitis caused

by copper metal or compounds are available from
industrial settings.
Copper allergies have been reported, either related
to skin contact with copper dust or salts, to copper-
containing intrauterine devices, or dental restora-
tions (Barkoff, 1976; Barranco, 1972; Hackel et al ., 1991;
Nordlind and Lidén, 1992). Only 13 of 1190 eczema
patients showed a positive patch test on copper sul-
fate, although copper has a widespread use in the gen-
eral population as, for instance, in coinage materials.
This suggests that copper may be a quite rare sensitizer
(Karlberg et al ., 1983). Green skin coloration and itch-
ing were reported in workers producing components
for turbine generators (NIOSH, 1981b).

7.2 Systemic Effects and Dose-Response
Relationships
7.2.1 Laboratory and Domestic Animals

LD 50 values of copper after a single exposure depend
on animal species, copper species, and the route of
administration. Soluble copper compounds are gener-
ally more acutely toxic than less soluble compounds
(WHO, 1998). LD 50 values between 32 and 1600 mg/kg
body weight have been reported after a single oral
exposure (WHO, 1998).
Rats were orally administered between 8 and 138 mg
Cu/kg body weight as copper sulfate pentahydrate
(Hébert et al ., 1993). Hyperplasia and hyperkerato-
sis of the forestomach was observed at 34 mg Cu/kg
body weight, and infl ammation of the liver in most
rats at 67 mg Cu/kg body weight. The kidney lesions
were described as minimal nuclear enlargement and
degeneration of the tubule epithelium. Also, urinalysis
indicated damage to the tubular cells. Pigs acciden-
tally receiving feed containing 700 mg/kg of copper
for several months developed an iron-defi ciency type
of anemia and gastric ulcers (Hatch et al ., 1979). The
copper concentration in the liver was 100-170 mg/kg
wet weight, and hepatic centric lobular necrosis was
found.
Hébert et al . (1993) also studied the hepatotoxic
effects of copper. A chronic-active infl ammation of the
liver and degenerative changes consisting of increases
in the number of secondary lysosomes in the peripor-
tal hepatocytes were observed. A concomitant increase
in serum enzymes related to the liver function was also
found.
Sheep are more vulnerable to copper toxicity than
many other species. During copper loading, the number
of copper-containing lysosomes increase. Necrosis
of hepatocytes may occur by further increase in the
intracellular copper levels. This may result in a sharp