UKPID MONOGRAPH
COPPER (II) CHLORIDE
ST Beer BSc
SM Bradberry BSc MB MRCP
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
COPPER CHLORIDE
Toxbase summary
Type of product
Soluble copper salt used in electroplating, dyes, inks, disinfectants,
wood preservatives, as an industrial oxidizing agent and catalyst and
as a reagent in photography.
Toxicity
Copper chloride is an oxidizing agent and irritant to mucous
membranes. There are no case reports specific to copper chloride
poisoning.
Copper contact sensitivity is recognized.
Features
Dermal
- Mild irritant to intact skin. Systemic copper uptake may
result from repeated application to broken skin. Copper
contact dermatitis is recognized.
Ocular
- Irritant to the eye and may cause corneal necrosis and
opacification if crystals remain in conjunctival sac.
Ingestion
- Very small ingestions (milligrams) are likely to cause only
nausea and vomiting.
Moderate/substantial ingestions:
- Based on clinical reports of copper sulphate ingestion
nausea, vomiting and a metallic taste may occur within
minutes followed by abdominal pain and diarrhoea. Secretions
may be blue/green. Severe gastrointestinal irritation may
result in haematemesis and/or melaena and hypovolaemic
shock. Severe poisoning may precipitate renal failure,
intravascular haemolysis (usually manifest 12-24 hours
post-poisoning) and cellular and obstructive liver damage.
Methaemoglobinaemia, coma, convulsions, rhabdomyolysis,
muscle weakness and cardiac arrhythmias are possible. There
is a high risk of aspiration of the gastric contents in
obtunded patients.
Inhalation
- Acute copper chloride inhalation will produce pulmonary
irritation. There are no case reports specific to this
compound, though it is possible that chronic copper chloride
exposure will cause a granulomatous hypersensitivity
response as does copper sulphate.
Management
Dermal
1. Irrigate with copious lukewarm water.
2. Consider the possibility of systemic copper uptake if there has
been significant or repeated exposure to broken skin.
3. Copper irritant dermatitis and contact sensitivity are managed
most effectively by discontinuing exposure.
Ocular
1. Irrigate immediately with lukewarm water or preferably saline for
at least 10 minutes.
2. Application of local anaesthetic may be required for pain relief
and to overcome blepharospasm to allow thorough decontamination.
3. Ensure no particles remain lodged in the conjunctival recesses.
4. Corneal damage may be detected by the instillation of
fluorescein.
5. If symptoms do not resolve rapidly or if there are abnormal
examination findings, refer for an ophthalmological opinion.
Ingestion
1. The absence of spontaneous vomiting suggests the ingestion is
small requiring only supportive care.
2. Gastric lavage is contraindicated since copper chloride is an
oxidizing agent and irritant to mucous membranes.
3. There may be some benefit in attempting oral dilution if
performed immediately, but fluids should not be offered if there
is inadequate airway protection or severe abdominal pain.
4. Supportive measures are paramount. Ensure adequate fluid
replacement and close observation of vital signs including
cardiac monitoring.
5. Monitor biochemical and haematological profiles and acid-base
status.
6. Intravascular haemolysis and renal failure are managed
conventionally.
7. Symptomatic methaemoglobinaemia may be reversed by the
intravenous administration of 2 mg/kg methylene blue (as a 1 per
cent solution over five minutes) although copper induced
inhibition of glucose-6-phosphate dehydrogenase may impair
antidotal efficacy.
8. Early endoscopy is recommended if corrosive oesophageal or
gastric damage is suspected.
9. An early surgical opinion should be sought if there are abdominal
symptoms or signs or deep ulcers and/or areas of necrosis (grade
3 burns) on endoscopy.
10. Although based on cases of acute copper sulphate ingestions,
whole blood copper concentrations correlate well with the
severity of poisoning they should always be interpreted in
conjunction with the clinical features. Chuttani et al (1965)
suggested severe complications (liver or renal damage or
hypovolaemic shock) were unlikely in those with whole blood
copper concentrations less than 4 mg/L but this is not
universally true (Wahal et al, 1976; Hantson et al, 1996).
11. There are no controlled data regarding the use of chelating
agents in copper poisoning. In severely poisoned patients the
presence of acute renal failure often limits the potential for
antidotes which enhance urinary copper elimination. Discuss with
an NPIS physician.
12. Urine copper excretion is increased in copper poisoned patients
who have not developed acute renal failure. The main role of 24
hour urine copper excretion measurements is monitoring the effect
of chelation therapy. Discuss with an NPIS physician.
13. The role of haemodialysis or peritoneal dialysis is restricted to
patients with acute renal failure.
Inhalation
1. Remove from exposure.
2. Administer supplemental oxygen by face-mask if there is
respiratory distress.
3. Other symptomatic and supportive measures as dictated by
patient's condition.
4. If chronic copper chloride inhalation is suspected consider the
possibility of a pulmonary hypersensitivity response. Arrange for
chest X-ray and lung function tests. Seek specialist advise from
an NPIS physician.
References
Ahasan HAMN, Chowdhury MAJ, Azhar MA, Rafiqueuddin AKM.
Copper sulphate poisoning.
Trop Doct 1994; 24: 52-3.
Akintonwa A, Mabadeje AFB, Odutola TA.
Fatal poisonings by copper sulfate ingested from "spiritual water".
Vet Hum Toxicol 1989; 31: 453-4.
Chuttani HK, Gupta PS, Gulati S, Gupta DN.
Acute copper sulfate poisoning.
Am J Med 1965; 39: 849-54.
Cole DEC, Lirenman DS.
Role of albumin-enriched peritoneal dialysate in acute copper
poisoning.
J Pediatr 1978; 92: 955-7.
Hantson P, Lievens M, Mahieu P.
Accidental ingestion of a zinc and copper sulfate preparation.
Clin Toxicol 1996; 34: 725-30.
Isolauri J, Markkula H, Auvinen O.
Copper sulfate corrosion and necrosis of the esophagus and stomach.
Acta Chir Scand 1986; 152: 701-2.
Jantsch W, Kulig K, Rumack BH.
Massive copper sulfate ingestion resulting in hepatotoxicity.
Clin Toxicol 1984/85; 22: 585-8.
Stein RS, Jenkins D, Korns ME.
Death after use of cupric sulfate as emetic.
JAMA 1976; 235: 801.
Wahal PK, Mehrotra MP, Kishore B, Patney NL, Mital VP, Hazra DK,
Raizada MN, Tiwari SR.
Study of whole blood, red cell and plasma copper levels in acute
copper sulphate poisoning and their relationship with complications
and prognosis.
J Assoc Physicians India 1976; 24: 153-8.
Walsh FM, Crosson FJ, Bayley M, McReynolds J, Pearson BJ.
Acute copper intoxication. Pathophysiology and therapy with a case
report.
Am J Dis Child 1977; 131: 149-51.
Substance Name
Copper (II) chloride
Origin of substance
NIF
Synonyms
Cupric chloride (DOSE, 1993)
Eriocholcite (anhydrous) (CHRIS, 1997)
Copper bichloride (RTECS, 1997)
Cupric dichloride
Chemical group
A compound of copper, a group 1B transition metal (d block)
element.
Reference numbers
CAS 7447-39-4 (DOSE, 1993)
RTECS GL7000000 (RTECS, 1997)
UN 2802 (HAZARDTEXT, 1997)
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
CuCl2 (DOSE, 1993)
Molecular weight
134.45 (DOSE, 1993)
Physical state at room temperature
Solid (CHRIS, 1997)
Colour
Yellow to brown microcrystalline powder. The dihydrate is green
to blue. (MERCK, 1996)
Odour
Odourless (CHRIS, 1997)
Viscosity
NIF
pH
The aqueous solution is acid, a 0.2 M solution has a pH of 3.6.
(MERCK, 1996)
Solubility
Soluble in water 706 g/L at 0°C and methanol 680 g/L at 15°C.
Soluble in hot sulphuric acid. (HSDB, 1997)
Moderately soluble in acetone and ethyl acetate.
(MERCK, 1996)
Slightly soluble in ether.
Autoignition temperature
NIF
Chemical interactions
Copper chloride is corrosive to aluminium and may corrode other
metals in the presence of moisture.
(HSDB, 1997; CHRIS, 1997)
Major products of combustion
Irritating hydrogen chloride gas may form in fire.
(HSDB, 1997)
Explosive limits
NIF
Flammability
Not flammable (CHRIS, 1997)
Boiling point
993°C (DOSE, 1993)
Density
3.39 at 25°C/4°C (HSDB, 1997)
Vapour pressure
2666.4 Pa at 1970°C (OHM/TADS, 1997)
Relative vapour density
NIF
Flash point
NA
Reactivity
Deliquescent, forms dihydrate in moist air. There is no reaction
with water. (HSDB, 1997; CHRIS, 1997)
Uses
Electroplating baths, for plating aluminium and copper.
Feed additive.
Desulphurizing and deodorizing agent for the petroleum industry.
In invisible, indelible and laundry marking inks and hair dyes.
Catalyst.
Mordant for dying and printing textiles.
In refining of silver, gold and copper ores.
Adsorbent for carbon monoxide.
To produce colour in pyrotechnic compositions.
Oxidizing agent for aniline dyestuffs.
In photography as a reagent, fixer and desensitizer.
Pigment for ceramics and glass.
Disinfectant and wood preservative.
In acrylonitrile and melanin manufacture.
(DOSE, 1993)
Hazard/risk classification
NIF
INTRODUCTION AND EPIDEMIOLOGY
Copper plays an important role as a co-factor in several
metalloproteins, including cytochrome oxidase and superoxide dismutase
and is essential for the utilization of iron and haemoglobin
formation.
The richest food sources of copper are shellfish, 'organ' meats,
seeds, nuts and grains where it is bound to specific proteins. Copper
tends to exist in the cupric Cu(II) state in biological systems
including water, although it may also be found as Cu(I) (Linder and
Hazegh-Azam, 1996).
Copper deficiency is associated with neurological dysfunction and
manifests as "Swayback" in lambs and calves born to sheep and cows
grazing on copper deficient pastures.
Wilson's disease is an inborn error of metabolism inherited as an
autosomal recessive trait whereby there is reduced biliary copper
excretion associated with decreased or absent circulating
caeruloplasmin (Schilsky, 1996). The disease is characterized by
excessive accumulation of copper in the liver, brain, kidneys and
cornea. Basal ganglia degeneration and cirrhosis are the principle
complications.
Copper chloride has many industrial applications (see Physicochemical
data) and historically has been used in the treatment of leucoderma
(Behl et al, 1961) but toxicity attributed directly to copper chloride
is extremely rare. Copper chloride has similar physicochemical
properties to copper sulphate so they might be expected to share a
similar toxicity profile; both salts are water soluble oxidizing
agents. The pH of 0.2 M solutions are 3.6 and 4 for copper chloride
and copper sulphate respectively.
MECHANISM OF TOXICITY
Copper chloride is an oxidizing agent which is corrosive to mucous
membranes. Concentrated solutions are acidic (a 0.2 M aqueous solution
has pH 3.6). Cellular damage and cell death may result from excess
copper accumulation. This is particularly likely when
copper-metallothionein binding and copper clearance from the cell are
blocked.
Metallothionein is a cysteine rich low molecular weight (6500 Da)
metal-binding protein which is important in heavy metal
detoxification, metal ion storage, and in the regulation of normal
cellular Cu(II) (and Zn(II)) metabolism. It is also thought to be a
free radical scavenger, playing a protective role in oxidative stress.
Metallothionein is found in both intra- and extracellular
compartments. It is known to bind zinc, cadmium, copper, mercury and
silver (in increasing order of affinity) and its gene transcription is
greatly enhanced upon exposure of cells to these metals. High
metallothionein concentrations are also induced in the liver by
physical and chemical stress, infection and glucocorticoids.
It is proposed that free Cu(I) (from Cu(II) reduction) binds to
intracellular sulphydryl groups and inactivates enzymes such as
glucose-6-phosphate dehydrogenase and glutathione reductase (Dash,
1989). In addition copper may interact with oxygen species (e.g.
superoxide anions and hydrogen peroxide) and catalyze the production
of reactive toxic hydroxyl radicals (Ribarov and Bochev, 1984).
Copper salts can penetrate the erythrocyte membrane. Haemolytic
anaemia is a common complication of copper sulphate poisoning, caused
either by direct red cell membrane damage (Chuttani et al, 1965) or
indirectly as a result of the inactivation of enzymes (including
glutathione reductase) which protect against oxidative stress (Mital
et al, 1966; Walsh et al, 1977). Intracellular glutathione is believed
to chelate Cu(I) as soon as it enters the cell as a "first-line"
defence mechanism. In addition superoxide dismutase and glutathione
may serve to remove physiologically generated toxic radicals
(Steinebach and Wolterbeek, 1994).
Copper(II) ions can oxidize haem iron to form methaemoglobin.
TOXICOKINETICS
Absorption and distribution
Strickland et al (1972) suggested a mean copper absorption of 57 per
cent (range 40 to 70 per cent) following oral administration of 0.4 -
4.5 mg copper (as copper acetate) to four volunteers. An early human
study suggested a maximum blood copper concentration was reached some
two hours after oral copper chloride administration (1.5 - 12 mg
copper) (Earl et al, 1954).
Copper transport across the intestinal mucosa following ingestion is
facilitated by cytosolic metallothionein. In blood, copper is
initially albumin-bound and transported via the hepatic portal
circulation to the liver where it is incorporated into caeruloplasmin
(an alpha globulin synthesized in hepatic microsomes) (Britton, 1996).
Some authors have noted a secondary rise in the serum copper
concentration following acute copper sulphate ingestion (Singh and
Singh, 1968) and this may be due to release of the
copper-caeruloplasmin complex from the liver. Ninety-eight per cent of
copper in the systemic circulation is caeruloplasmin-bound.
Copper is distributed to all tissues with the highest concentrations
in liver, heart, brain, kidneys and muscle. Intracellular copper is
predominantly metallothionein-bound. Kurisaki et al (1988) reported
copper in the lungs, liver, kidney, blood, bile and stomach (33.7,
35.1, 41.4, 13.8, 2.8, and 2988 µg/g wet weight respectively)
following ingestion of some 10 g copper sulphate in a 58 year-old
male. Although copper in the liver and kidneys was metallothionein
bound, pulmonary copper was not, possibly because copper had entered
the lung via aspiration.
Ionized copper can penetrate the erythrocyte membrane. In acute copper
sulphate poisoning this occurs quite rapidly as indicated by the
markedly higher whole blood than serum copper concentration within the
first few hours after ingestion (Singh and Singh, 1968). In a series
of 40 cases of acute copper sulphate ingestion Singh and Singh (1968)
noted that haemolysis (secondary to erythrocyte copper uptake)
occurred typically 12-24 hours post poisoning, suggesting that red
cell copper accumulation is maximal around this time.
Studies among vineyard sprayers provide evidence of haematogenous
dissemination of inhaled copper sulphate (Villar, 1974; Pimentel and
Menezes, 1977). Copper sulphate can also be absorbed through the skin
giving rise to systemic effects (Holtzman et al, 1966; Pande and
Gupta, 1969). Similar toxicokinetic properties are anticipated for
copper chloride.
Copper can cross the placenta.
Excretion
Caeruloplasmin renders free copper innocuous with subsequent excretion
via a lysosome-to-bile pathway. This process is essential to normal
copper homeostasis and provides a protective mechanism in acute copper
sulphate poisoning. An impaired or overloaded biliary copper excretion
system results in hepatic copper accumulation, as occurs in patients
with Wilson's disease and in copper poisoning.
Renal copper elimination is normally low (Tauxe et al (1966) retrieved
less than one per cent of an injected dose in the urine over 72 hours)
but will increase in acute copper/copper salt poisoning. For example,
a child who ingested 3 grams copper sulphate had increased urine
copper concentrations (maximum 3.0 mg/L) for three weeks post
poisoning (Walsh et al, 1977).
In a series of 40 cases of acute copper sulphate ingestion increased
whole blood copper concentrations were noted up to ten days post
poisoning with values returning to normal over 17 hours to seven days
(Singh and Singh, 1968). The whole-body half-life of copper has been
estimated as approximately four weeks (Strickland et al, 1972).
CLINICAL FEATURES: ACUTE EXPOSURE
There are no clinical reports regarding copper chloride toxicity
although it is anticipated that copper chloride exposure would produce
clinical features similar to those observed following copper sulphate
poisoning. These are summarized below. Copper sulphate toxicity is
considered in detail in a separate monograph.
Dermal exposure
Copper chloride is mildly irritant to intact skin. There is a risk of
tissue damage and systemic copper uptake if large amounts of copper
chloride are in contact with open wounds and burns.
Ocular exposure
Copper salts are eye irritants (Grant and Schuman, 1993). Corneal
necrosis and opacification may occur if particles remain in the
conjunctival sac (see Chronic exposure).
Ingestion
Gastrointestinal toxicity
Copper chloride is an oxidizing agent and corrosive to mucous
membranes. Vomiting is likely to occur within minutes of ingesting any
significant amount. Based on reports of copper sulphate ingestion
other early features include abdominal pain, diarrhoea (Kurisaki et
al, 1988), hypersalivation (Ahasan et al, 1994) and a metallic taste
(Jantsch et al, 1984/85; Nagaraj et al, 1985). Body secretions may be
green or blue (Kurisaki et al, 1988; Gulliver, 1991) with blue
staining of the mouth, lips and oesophageal mucosa (Deodhar and
Deshpande, 1968).
Gastric and duodenal ulceration have been described in association
with erosive oesophagitis and gastritis following copper sulphate
ingestion (Schwartz and Schmidt, 1986). There may be gastrointestinal
bleeding with haematemesis and melaena (Chugh et al, 1977 a and b);
fatalities have occurred (Chuttani et al, 1965; Deodhar and Deshpande,
1968; Papadoyanakis et al, 1969; Gulliver, 1991; Nagaraj et al, 1985;
Kurisaki et al, 1988; Lamont and Duflou, 1988).
There is no available information regarding an anticipated fatal
copper chloride dose and despite extensive clinical reports of copper
sulphate poisoning disagreement remains regarding the dose/effect
relationship following ingestion. In a review of 123 cases of copper
sulphate ingestion Ahasan et al (1994) observed an "unpredictable"
outcome in those consuming less than 50 g while 100 g was "invariably
fatal". By contrast Akintonwa et al (1989) claimed 10-20 g copper
sulphate to be a "definitely fatal" dose and Stein et al (1976)
reported a fatality after ingestion of only 2 g copper sulphate as an
emetic. The latter case is complicated because although the patient
developed features typical of copper poisoning (haemolysis,
gastrointestinal haemorrhage, hepatic and renal failure),
benzodiazepine and alcohol overdose undoubtedly contributed to coma.
The patient also previously had undergone a gastrectomy which is
likely to have increased copper-induced gastrointestinal toxicity.
Twenty workmen developed symptoms including nausea, vomiting and
diarrhoea within a few minutes of ingesting tea brewed with copper
sulphate - contaminated water from an unserviced gas hot-water geyser
(Nicholas, 1968). Copper content of the tea drunk was thought to be
greater than 30 ppm.
Ingestion of some 20-30 mL copper sulphate/methanol/ethylene
glycol-containing fluid by a 31 year-old male resulted in severe
corrosive necrosis of the oesophagus and stomach necessitating total
gastrectomy and oesophagectomy (Isolauri et al, 1986). This case was
unusual in that the patient did not develop significant hepatic or
renal damage. Four months later reconstruction was performed between
the pharynx and duodenum using a colon segment. At follow-up 2´ years
later the patient had no dysphagia, and had returned to his original
occupation.
An 86 year-old patient vomited blue/green liquid and developed watery
diarrhoea within 30 minutes of ingesting a mixture of zinc sulphate
and copper sulphate (3 g of each). Early endoscopy demonstrated a
normal oesophagus and diffusely inflamed gastric mucosa with several
areas of bleeding. Plasma copper and zinc concentrations obtained
approximately 90 minutes after ingestion were 2.1 mg/L (normal range
0.8-1.4 mg/L) and 19.8 mg/L (normal range 0.9-1.2 mg/L) respectively.
Treatment included prompt resuscitation with intravenous fluids and
chelation therapy with dimercaprol and d-penicillamine. The patient
developed acute renal failure, cardiac failure and aspiration
pneumonitis but made a full recovery with no abnormality identified on
an upper gastrointestinal endoscopy "a few days later" (Hantson et al,
1996).
Pulmonary toxicity
Features of pulmonary toxicity following copper salt ingestion usually
reflect secondary complications, most significantly aspiration of the
gastric contents in an obtunded patient (Lamont and Duflou, 1988;
Hantson et al, 1996). Profound hypovolaemic shock may be accompanied
by pulmonary oedema (Schwartz and Schmidt, 1986). Direct corrosive
damage to the hypopharynx and larynx at the time of ingestion may
produce respiratory embarrassment requiring mechanical ventilation
(Isolauri et al, 1986).
An 86 year-old female who ingested a mixture of zinc sulphate and
copper sulphate (3 g of each) was found 15 minutes later coughing and
vomiting a blue/green liquid. She developed respiratory failure three
days later requiring mechanical ventilation. Bronchoscopy demonstrated
an ulcerated bronchial mucosa suggesting aspiration and subsequent
corrosive pneumonitis. The patient's clinical course was complicated
also by cardiac and renal failure, but she made a full recovery
(Hantson et al, 1996).
A 30 year-old female died approximately 48 hours after ingesting a
witch doctor's tonic containing salt, vinegar, sugar, alcohol and
copper sulphate (Lamont and Duflou, 1988). Following ingestion the
woman lapsed into a coma, during which time she was administered
further copper sulphate-containing "medication". Post-mortem revealed
bronchopneumonia, thought to be secondary to aspiration and a blood
copper concentration of 42 mg/L. Two friends who also ingested the
"tonic" vomited immediately and survived.
A lung copper concentration of 33.7 µg/g wet weight (control value of
1.3 µg/g wet weight) was reported at autopsy following copper sulphate
ingestion in a 58 year-old male. Again, this most probably reflected
aspiration. No copper was identified in the metallothionein fraction
(Kurisaki et al, 1988).
Musculoskeletal toxicity
Muscle weakness has been reported following acute copper sulphate
ingestion (Chowdhury et al, 1961).
A 42 year-old man who ingested 250 g copper sulphate developed
rhabdomyolysis (peak creatine kinase activity 5620 iu/L on day three)
in addition to features of gastrointestinal and hepatotoxicity. Renal
function was not impaired (Jantsch et al, 1984/85).
Hepatotoxicity
Hepatic copper accumulation produces cellular and obstructive damage.
There may be jaundice, tender hepatomegaly (Chuttani et al, 1965),
increased transaminase and alkaline phosphatase activities (Ashraf,
1970) and prolongation of the prothrombin time (Chuttani et al, 1965;
Agarwal et al, 1975).
Jaundice may be cholestatic, haemolytic (see Haemotoxicity) or both
(Papadoyanakis et al, 1969). Jaundice was observed in 11 of 48 cases
of acute copper sulphate ingestion reported by Chuttani et al (1965).
In six cases this was attributed mainly to haemolysis (there was no
hepatomegaly, liver enzyme activities were normal and the reticulocyte
count and urine urobilinogen concentrations were raised). The
remaining five patients exhibited tender hepatomegaly, marked
progressive jaundice, grossly deranged liver enzyme activities and a
prolonged prothrombin time (mean 35 seconds) with histological
evidence of centrilobular necrosis and biliary stasis on liver biopsy.
One of these patients died. Reliable information regarding the
quantity of copper sulphate ingested by these patients was not
available.
Serum caeruloplasmin concentrations are increased in acute
copper/copper salt poisoning. In a series of 50 cases of copper
sulphate ingestion (Wahal et al, 1978) mean (±SD) peak caeruloplasmin
concentrations were significantly higher (p<0.001) in 28
uncomplicated cases (48.1 ± 9.7 mg/dL) than in 22 complicated cases
(37.2 ± 6.0 mg/dL) of poisoning suggesting increased caeruloplasmin
offered some protection against copper toxicity. Complicated cases
were defined by the presence of jaundice, renal impairment,
gastrointestinal haemorrhage, delirium or coma. Serum caeruloplasmin
concentrations in 30 healthy controls (29.4 ± 7.4 mg/dL) were
significantly lower (p<0.001) than in both the complicated and
uncomplicated poisoned cases. A progressive increase in serum
caeruloplasmin concentrations was observed in all copper
sulphate-poisoned patients until the third day post poisoning before
gradually decreasing to normal by day seven.
Autopsy findings following copper sulphate ingestion include
centrilobular congestion and hydropic hepatocyte swelling (Lamont and
Duflou, 1988), centrilobular necrosis (Kurisaki et al, 1988), central
vein dilatation, fatty liver degeneration (Deodhar and Deshpande,
1968), inflammatory cell infiltration and cholestasis (Papadoyanakis
et al, 1969). The liver copper content is usually increased (Kurisaki
et al, 1988). Copper deposits have also been noted in the spleen
(Agarwal et al, 1975).
Nephrotoxicity
Acute renal failure is a common complication of severe copper salt
poisoning and generally carries a poor prognosis (Wahal, et al, 1965;
Hantson et al, 1996). This may occur via a direct toxic effect on the
proximal tubules and/or reduced renal perfusion secondary to
hypovolaemic shock plus intravascular haemolysis.
Nineteen cases of copper sulphate-induced acute renal failure were
investigated by Mehta et al (1985) over a two year period. Seventeen
of these patients were reported to have ingested more than 25 g copper
sulphate and all were admitted to hospital six to 96 hours post
ingestion. Renal complications were observed most frequently three to
four days post poisoning and presenting features included dysuria,
"dark-reddish coloured urine" and oliguria. Albuminuria, haematuria
and haemoglobinuria were present in 100, 84 and 58 per cent of cases
respectively. Mean (±SD) blood urea and serum creatinine
concentrations were elevated in all cases and to a greater extent in
the six patients who died (26.8 ± 7 mmol/L urea, 696 ± 152 µmol/L
creatinine) than in the 13 who survived (15.6 ± 3.2 mmol/L urea, 235 ±
143 µmol/L creatinine).
Necrotic tubular epithelium, an oedematous medulla and eosinophilic
casts were identified at post-mortem following copper sulphate
ingestion by a 58 year-old male (Kurisaki et al, 1988). Kidney copper
concentration was 41.4 µg/g wet weight, compared to a control value of
2.6 µg/g wet weight, and the majority of renal copper was
metallothionein bound. Other post-mortem findings include enlarged
congested kidneys, glomerular capillary dilatation, interstitial
lymphocyte infiltration, haemoglobin/leucocyte/bile casts in the
proximal and distal tubules, and proliferative changes with hyaline
glomerular thickening (Deodhar and Deshpande, 1968; Papadoyanakis et
al, 1969).
Neurotoxicity
Following copper salt ingestion neurological complications usually
occur in association with hypovolaemic shock, hepatic and/or renal
failure. Headache, drowsiness, coma, convulsions, depressed or absent
deep reflexes, and equivocal plantar responses have been reported
(Papadoyanakis et al, 1969; Patel et al, 1976; Wahal et al, 1976b).
"Toxic psychosis" has been reported in association with
gastrointestinal toxicity and acute renal failure in two patients who
ingested 200-400 mL "spiritual water" containing copper sulphate
(100-150 g/L) and nickel (50 mg/L). Further details of the psychosis
were not given, but both patients died (despite haemodialysis) within
nine days of poisoning (Akintonwa et al, 1989).
Copper deposits were found at autopsy in the brain of a 41 year-old
female who drank some 280 mL dissolved copper sulphate and died on the
fifth hospital day following development of hepatorenal failure,
haemolysis and gram-negative septicaemia (Agarwal et al, 1975).
Cardiovascular toxicity
Peripheral cyanosis and other features of hypovolaemic shock
frequently accompany substantial copper salt ingestion (Papadoyanakis
et al, 1969; Schwartz and Schmidt, 1986). In severe cases
cardiopulmonary arrest may ensue rapidly. An 11 year-old female died
following a cardiac arrest (in association with gastrointestinal
features) two hours after ingesting a "jam jar full" of copper
sulphate solution from a crystal growing set, which she had mistaken
for fruit juice. A post-mortem blood sample revealed a copper
concentration of 66 mg/L. The cause of death was identified as
"cardio-respiratory arrest due to copper sulfate poisoning" but no
further details of the post-mortem findings were given (Gulliver,
1991).
On presentation to a Poisons Centre some 16 hours after ingesting 30
mL of a supersaturated copper sulphate solution a two year-old child
was noted to have a pulse rate of 150 beats/minute with multiple
ventricular extrasystoles and occasional runs of bigeminy on
electrocardiogram (Cole and Lirenman, 1978). He also had profuse
vomiting and diarrhoea plus renal failure (treated with peritoneal
dialysis), haemolysis and impaired consciousness but made a full
recovery over four weeks.
An 86 year-old lady who ingested a mixture of zinc sulphate and copper
sulphate (3 g of each) rapidly developed features of gastrointestinal
and renal toxicity. Cardiac failure (confirmed on echocardiogram)
developed within 48 hours and the patient required inotropic support
for several days. The precise aetiology of the cardiac complications
was unclear but the patient fully recovered (Hantson et al, 1996).
Copper deposits have been noted in the heart at autopsy following
ingestion of some 280 mL copper sulphate solution (Agarwal et al,
1975).
Muthusethupathi et al (1988) reported toxic myocarditis as a cause of
death following copper sulphate poisoning although this information is
poorly referenced.
Haemotoxicity
Haemolytic anaemia is a common complication of systemic copper
intoxication (Dash and Dash, 1980) and may be caused by direct
erythrocyte membrane damage (Chuttani et al, 1965) or indirectly by
copper-mediated inhibition of enzymes important in protecting against
oxidative stress, including glucose-6-phosphate dehydrogenase (Mital
et al, 1966; Fairbanks, 1967; Wahal et al, 1976a; Walsh et al, 1977)
and glutathione reductase (Wahal et al, 1976a). In a study by Wahal et
al (1976a) the high frequency of reduced erythrocyte
glucose-6-phosphate dehydrogenase activity and its return to normal in
surviving patients confirmed that impaired enzyme activity in copper
sulphate-poisoned patients was a direct toxic effect of copper rather
than a genetic phenomenon.
Mital et al (1966) observed red cell glutathione instability in 13 of
24 copper sulphate-poisoned patients with evidence of intravascular
haemolysis in nine of the 13. Glutathione is necessary for erythrocyte
integrity and its stability is directly related to glucose-6-phosphate
dehydrogenase and glutathione reductase concentrations.
Intravascular haemolysis is accompanied by hyperbilirubinaemia
(Mittal, 1972), reticulocytosis, haemoglobinaemia and a fall in
haematocrit (Papadoyanakis et al, 1969). Acute renal failure is a
common complication and is contributed to by renal tubular obstruction
by haemolysis products, disseminated intravascular coagulation and
possibly renal vasoconstriction (Chugh et al, 1977b).
Copper chloride may oxidize haemoglobin but there are no case reports
of copper chloride-induced methaemoglobinaemia. By contrast
methaemo-globinaemia has been reported frequently following copper
sulphate ingestion (Chugh et al, 1975; Patel et al, 1976; Chugh et al,
1977a; Nagaraj et al, 1985). Although methaemoglobin concentrations
are typically moderate (33 to 38 per cent) concurrent acute renal
failure frequently contributes to a poor outcome (Patel et al, 1976;
Nagaraj et al, 1985).
A 27 year-old male died 16 hours post ingestion of 50 g copper
sulphate despite peritoneal dialysis, ascorbic acid and methylene blue
therapy. Peak blood copper concentration was 82.7 mg/L (normal 2.1 ±
0.5 mg/L). His methaemoglobin concentration was 36 per cent five hours
post poisoning although the concentration immediately prior to death
was not stated. Any beneficial effect of methylene blue would have
been limited by an observed low glucose-6-phosphate dehydrogenase
activity. It is not known whether this patient had a pre-existing
deficiency of this enzyme (Chugh et al, 1975).
A prolonged prothrombin time may be observed in acute copper sulphate
poisoning and reflects hepatotoxicity (see above) (Agarwal et al,
1975).
Endocrine toxicity
Copper deposits were found at autopsy in the adrenal glands of a woman
who ingested some 280 mL dissolved copper sulphate (Agarwal et al,
1975).
Metabolic disturbances
Electrolyte disturbances are likely in severe copper chloride
poisoning and are contributed to by gastrointestinal fluid loss,
haemolysis and renal failure.
Inhalation
There are no reports of acute copper chloride inhalation, although
inhalation of copper fumes may cause 'metal fume fever' (Gleason,
1968) (see Copper/Copper oxide monographs).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
There are no reports specific to copper chloride. The following
discussion is based on experience with copper sulphate.
Dermal toxicity
Despite its widespread use, the sensitizing potential of copper has
been described as "extremely low" (Walton, 1983a). In patch tests
among 354 eczema patients, six tested positive to copper sulphate (5
per cent solution) and 39 to nickel sulphate (2.5 per cent solution)
(Walton, 1983a). All patients positive to copper sulphate were also
nickel sulphate positive. None of the subjects positive to copper
sulphate were occupationally exposed to copper or had a history of
atopy; all were females with hand eczema. The authors postulated
nickel- and copper-containing coins as the source of exposure.
Interpretation of these results was complicated by the possibility
that patients were sensitive to the nickel sulphate trace (0.01 per
cent) in the copper sulphate test solution. The author subsequently
demonstrated (Walton, 1983b) that the six copper sensitive patients
were patch test negative to nickel sulphate (0.01 per cent),
suggesting true copper sensitivity.
Further evidence of true copper allergy was presented by Van Joost et
al (1988) who described two females patch test positive to copper (as
sulphate 5 per cent) and nickel (as sulphate 2.5 per cent) in whom the
possibility of nickel contamination of the copper test solution was
largely excluded by the observation that 11 "control" nickel sensitive
patients each gave no positive reaction to the copper solution.
Epstein (1955) described combined nickel/copper sensitivity in 38 per
cent of 32 patients patch tested, and emphasized that many
nickel-containing alloys also contain copper. The author suggested the
frequency of cross-sensitivity reactions, the close chemical
relationship between copper and nickel (in adjacent positions in the
transition metal series of the periodic table) and evidence for a true
cross-sensitivity between nickel and cobalt as reasons to assume a
true cross-sensitivity between copper and nickel rather than a
coincidental occurrence of separate sensitivities (Epstein, 1955).
In 30 patients known to be contact sensitive to nickel but patch-test
negative to copper, the severity of patch test reaction to a
copper/nickel mixture was greater (p <0.001) than to nickel alone,
suggesting copper ions somehow enhanced the sensitivity reaction to
nickel (Santucci et al, 1993). The authors proposed that the presence
of copper ions facilitated the formation of nickel protein complexes
in the skin although the mechanism was not clear.
In a study by Karlberg et al (1983), 13 of 1190 eczema patients showed
a patch test reaction to two per cent copper sulphate. However, these
patients had concomitant reactions to other known contact allergens
and serial dilution tests with copper sulphate provided no confirmed
cases of copper sulphate contact sensitivity. The authors recommended
a serial dilution test in cases of suspected copper sulphate allergy
to eliminate the possibility of an irritant effect and confirm whether
true copper sulphate sensitivity is present (Karlberg et al, 1983).
Indurated erythematous areas of the face, neck, chest and forearms,
periungual telangiectasia and other nail changes were noted in a group
of female labourers occupationally exposed to fertilizers, weedkillers
and copper sulphate-containing Bordeaux mixture. The aetiological
agent was not identified (Narahari et al, 1990).
Contact dermatitis was reported in 10 furniture polishers using
commercial spirit (ethyl/methyl alcohol) coloured blue with copper
sulphate (Dhir et al, 1977). All patients developed erythema, itching
and vesiculopustular areas on the skin of the hands, improving on
removal from contact with the spirit. Positive patch tests with copper
sulphate (5 per cent solution) were reported in all patients and were
negative in 15 non-exposed controls.
In conclusion, available evidence regarding copper contact sensitivity
suggests that while a true copper contact allergy exists, cross
sensitivity between nickel and copper contributes to many cases.
Irritant dermatitis also occurs.
Haemotoxicity
A five year-old girl with 40 per cent second and third degree burns
had copper sulphate crystals rubbed onto granulated areas of skin (as
an antiseptic) during debridement seven times over a nine week period.
A decrease in haematocrit of eight to ten per cent requiring
transfusion was observed after each treatment, though this may have
been due to blood loss. Twenty four hours after the last debridement
there was evidence of haemolytic anaemia with a fall in haematocrit to
18.5 per cent and a reticulocytosis (8.6 per cent). Total serum copper
was 5.4 mg/L; caeruloplasmin 86 mg/dL. The child received
d-penicillamine therapy and made a full recovery (Holtzman et al,
1966). Six months later "moderately increased" serum copper and
caeruloplasmin concentrations persisted.
Nephrotoxicity
Acute renal failure in association with haemolytic anaemia developed
in a five year-old with 40 per cent burns who was treated with topical
copper sulphate crystals over a nine week period during debridement.
Urine was dark brown and haematuria, albuminuria, urobilinogenuria,
and biliuria were present with evidence of erythrocyte casts. Urine
copper concentration was 2.2 mg/L. Renal function improved following
d-penicillamine therapy (1 g daily for 12 days) with some evidence of
increased urine copper clearance. The patient made a full recovery
(Holtzman et al, 1966).
Ocular exposure
Corneal inflammation, necrosis and scarring opacification may occur if
copper salt particles remain in the conjunctival sac (Grant and
Schuman, 1993). Historically, copper sulphate eye drops were used in
the treatment of trachoma. This resulted in temporary inflammation and
pustular formation, leading to corneal discoloration with little or no
visual interference.
Ingestion
A 17 year-old male treated for leucoderma with oral copper sulphate
(one per cent solution, 2 mg/day for two months) developed purpuric
spots in association with bleeding gums and epistaxis. Investigations
revealed anaemia (7g/dL, possibly due to co-existing iron deficiency)
and thrombocytopenia. Treatment with copper sulphate was discontinued
and following blood transfusion, ferrous sulphate and steroid therapy
the patient made a full recovery (Pande and Gupta, 1969).
Inhalation
Occupational exposure to dusts and fumes of copper salts have been
reported to cause nasal mucosal congestion and occasionally nasal
septum perforation but no original case data have been identified
(Scheinberg, 1983).
Occupational inhalational exposure to copper sulphate-containing
fungicides may result in "Vineyard sprayer's lung" (Pimentel and
Marques, 1969; Villar, 1974; Pimentel and Menezes, 1975; Pimentel and
Menezes, 1977; Stark, 1981; Plamenac et al, 1985). Although copper
sulphate-containing fungicides are manufactured in the UK, this
condition is particularly common in Portugal where Bordeaux mixture, a
1-2.5 per cent copper sulphate solution neutralized with hydrated
lime, is sprayed on grape vines to prevent mildew. This treatment is
necessary between two and twelve times per year, exposing labourers to
the pesticide at intervals for up to three months annually.
The lung is the primary target organ in "Vineyard sprayer's" disease
but there is evidence this is a systemic granulomatous disorder. In
addition to pulmonary fibrosis with copper-containing granulomas,
hepatic and renal copper granulomas and increased IgA and IgG
concentrations are widely recognized (Villar, 1974; Pimentel and
Menezes, 1975; Pimentel and Menezes, 1977).
"Vineyard sprayer's lung" is reviewed in detail in the Copper sulphate
monograph.
Injection
Nephrotoxicity
Ishikawa and Minami (1985) reported pseudo-Bartter syndrome (with
hyperreninaemia, polyuria and hypokalaemia) following 12 months
intravenous copper sulphate therapy (providing 130 µg/kg copper
weekly) to a child with Kinky-hair disease (inherited copper
deficiency). The authors suggested renal copper accumulation as the
cause of renal tubular damage.
MANAGEMENT
Dermal exposure
Following acute exposure irrigate the affected area with lukewarm
water. Particular care is required if copper chloride has been in
contact with broken skin since corrosive damage and systemic copper
uptake are then possible.
Copper contact sensitivity or irritant dermatitis are managed most
effectively by discontinuing exposure.
Ocular exposure
Irrigate immediately with lukewarm water or preferably saline for at
least 10-15 minutes. A local anaesthetic may be indicated for pain
relief and to overcome blepharospasm. Ensure removal of any particles
lodged in the conjunctival recesses. The instillation of fluorescein
allows detection of corneal damage. Specialist ophthalmological advice
should be sought if any significant abnormality is detected on
examination and in those whose symptoms do not resolve rapidly.
Ingestion
Copper chloride is an oxidizing agent and causes corrosive damage to
mucous membranes. Concentrated solutions are acidic; a 0.2 M aqueous
solution has a pH of 3.6.
Effective management primarily involves rapid appropriate symptomatic
and supportive care. The role of chelating agents is discussed below.
Decontamination and dilution
Vomiting is likely to occur spontaneously following significant copper
chloride ingestion. Gastric lavage is contraindicated since copper
chloride is irritant to mucous membranes. There may be some benefit in
attempting oral dilution with milk or water, if performed immediately,
though this is controversial. The administration of egg white as a
demulcent or potassium ferrocyanide ("600 mg in a glass of water") to
precipitate copper, have been advocated (IPCS, 1997), but there is no
clinical evidence to support these measures.
Fluids should not be offered if the patient has a depressed level of
consciousness, is unable to swallow or protect his/her own airway, has
respiratory difficulty or severe abdominal pain. Possible
complications of fluid administration include vomiting, aspiration,
perforation of the gastrointestinal tract and worsening of oesophageal
or gastric injuries.
Supportive and symptomatic measures
If corrosive oesophageal or gastric damage is suspected panendoscopy
should be carried out, ideally within 12-24 hours, to gauge the
severity of injury. A severity score based on acid ingestions may be
useful:
Grade 0: Normal examination
1: Oedema, hyperaemia of mucosa
2a: Superficial, localized ulcerations, friability, blisters
2b: Grade 2a findings and circumferential ulceration
3: Multiple, deep ulceration, areas of necrosis (Zargar et al,
1989)
Zargar et al (1989) described the important prognostic value of this
grading system in the management of acid ingestions. Following copper
chloride ingestion the presence and severity of gastrointestinal
injury is important in predicting outcome but must be considered in
the light of other complications, particularly haematological, hepatic
and renal damage.
An early surgical opinion should be sought if there is any suspicion
of pending gastrointestinal perforation or where endoscopy reveals
evidence of grade 3 burns.
Airway support and analgesia should be provided as required. Treat
hypovolaemic shock with intravenous colloid/crystalloid and/or blood.
Monitor biochemical and haematological profiles and acid/base status.
Intravascular haemolysis and renal failure should be managed
conventionally.
Symptomatic methaemoglobinaemia requires correction with intravenous
methylene blue 2 mg/kg body weight (as a one per cent solution over
five minutes). The efficacy of this antidote may be impaired if there
is copper-induced inhibition of glucose-6-phosphate dehydrogenase
activity (Chugh et al, 1975).
There is no evidence to suggest any role for corticosteroid therapy in
the management of copper chloride ingestion. Antibiotics should be
reserved for established infection only.
Inhalation
The priority following copper salt inhalation is removal from exposure
and administration of oxygen by face-mask if there is respiratory
distress. A chest X-ray should be performed if there are abnormal
examination findings; metal fume fever may be accompanied by transient
ill-defined opacities which typically resolve uneventfully. The
possibility of a granulomatous pulmonary and possibly systemic
reaction should be considered following chronic exposure (see Copper
sulphate monograph).
Antidotes
Animal Studies
d-Penicillamine, triethylenetetramine dihydrochloride (trien) and DMPS
each administered in a dose of 50 µmol/kg intraperitoneally daily for
five days were the most effective chelating agents in increasing
copper excretion in the urine (p <0.01) in copper-poisoned rats fed a
high copper diet for 20 days prior to chelation (Planas-Bohne, 1979).
Faecal copper excretion was unaffected. Other workers have
demonstrated enhanced renal copper elimination following parenteral
DMPS and DMSA (Maehashi et al, 1983).
Rana and Kumar (1983) suggested oral sodium calciumedetate (1g/kg
daily for ten days) could limit histopathological renal damage in rats
fed oral copper sulphate 0.1 g/kg daily for 20 days prior to chelation
therapy. Protection against copper-induced hepatic and renal lesions
was observed also in mice administered intraperitoneal DMPS 132 mg/kg
20 minutes after intraperitoneal copper sulphate 10 mg/kg
(approximately the LD50) (Mitchell et al, 1982).
DMPS was the most effective antidote in protecting against
copper-induced mortality in copper sulphate-intoxicated mice (10 mg/kg
intraperitoneally, LD5050 8.7 mg/kg) administered intraperitoneal
antidotes 20 minutes post dosing at a 10:1 molar ratio antidote:copper
sulphate. Mice were observed for two weeks or until death. The
survival ratio following DMPS was 25/30, compared to 7/30, 5/15, 4/15,
3/15, 3/15 for d-penicillamine, triethylene- tetramine, sodium
calciumedetate, DMSA and dimercaprol respectively (p <0.0001 for DMPS
compared to all chelating agents except triethylenetetramine,
p <0.0005) (Jones et al, 1980).
Henderson et al (1985) investigated the effect of single and repeated
doses of chelating agents on copper toxicity. Copper intoxicated mice
(10-130 mg/kg subcutaneously) were given single doses of dimercaprol
10 mg/kg or N-acetylcysteine 200 mg/kg, 30 minutes post dosing. With a
single dose of chelating agent, the calculated LD50 (± SE) was
significantly (p<0.05) increased from 54.7 ± 10 mg/kg in control mice
to 95.2 ± 22 mg/kg and 87 ± 14 mg/kg in mice treated with dimercaprol
or NAC respectively. The chelating agents were even more effective
(p<0.05) in copper-poisoned mice (40-170 mg/kg subcutaneously)
treated with repeated doses of chelating agent: dimercaprol 10 mg/kg,
N-acetylcysteine 200 mg/kg or d-penicillamine 50 mg/kg every hour for
five hours, with calculated LD50 values of 60.5 ± 12 mg/kg, 150.3 ±
35 mg/kg, 139.4 ± 8 mg/kg and 91.4 ± 16 mg/kg for controls,
dimercaprol, NAC and d-penicillamine treated mice respectively.
d-Penicillamine, 52 mg/kg daily for six days, significantly (p<0.05)
enhanced urinary copper excretion in four copper-poisoned sheep (given
20 mg/kg copper sulphate intraruminally daily for 35 days) (Botha et
al, 1993). Under the same conditions triethylenetetramine failed to
increase urinary copper excretion although the authors suggested this
might have been related to specific features of ruminant metabolism.
There is some evidence that polyamines structurally related to
triethylenetetramine (e.g. 2,3,2-tetramine) have a more potent
cupruretic action (Borthwick et al, 1980) but experience with these
agents is limited (Twedt et al, 1988).
Diethyldithiocarbamate (DDC) chelates copper but the lipophilic
chelate accumulates in tissues, especially the brain (Iwata et al,
1970; Jasim et al, 1985), suggesting it may be an unsuitable antidote
in copper poisoning. It has been suggested that DDC modifies the
permeability of cell membranes and the blood brain barrier to copper
(Allain and Krari, 1993).
Clinical studies
Wilson's disease
Wilson's disease, characterized by decreased biliary copper excretion
traditionally has been treated with d-penicillamine which serves to
increase urinary copper elimination (Scheinberg et al, 1987). Adverse
reactions to d-penicillamine are not uncommon and frequently are
immunologically rather than toxicologically-induced including
nephrotic syndrome, systemic lupus erythematosus (Walshe, 1982), white
cell dyscrasias, thrombocytopenia, haemolytic anaemia (Walshe, 1982)
and urticaria (Walshe, 1968). Anorexia, nausea and vomiting are
described (Walshe, 1968). In animal studies penicillamine induces
hepatic metallothionein (Heilmaier et al, 1986) which may disrupt the
body distribution of other trace elements. Adverse effects occur in up
to 10 per cent of patients receiving penicillamine and may necessitate
treatment withdrawal (Walshe, 1982). Thus, in recent years,
alternative agents have been investigated.
Sunderman et al (1963) advocated parenteral and/or oral DDC in the
management of Wilson's disease but evidence that this antidote
enhances cerebral copper uptake limits its usefulness (see above).
Walshe (1982) demonstrated increased urine copper elimination,
symptomatic improvement and resolution of basal-ganglia abnormalities
on CT brain scan among 20 patients with Wilson's disease treated with
triethylenetetramine. These authors suggested triethylenetetramine as
an effective drug for the treatment and maintenance of patients with
Wilson's disease at all stages of the illness. Others concur with this
view (Dubois et al, 1990; Morita et al, 1992) although there are
potential hazards of triethylenetetramine therapy, notably
sideroblastic anaemia (Perry et al, 1996).
Although zinc sulphate has been utilized as alternative therapy to
penicillamine in patients with Wilson's disease (Hoogenraad and Van
den Hamer, 1983; Van Caillie-Bertrand et al, 1985; Veen et al, 1991),
this treatment is unsuitable for acute copper poisoning as the
mechanism of benefit is reduced gastrointestinal copper absorption.
DMPS 200 mg bd increased urine copper elimination in a patient with
Wilson's disease (Walshe, 1985).
Acute poisoning
There are no controlled data regarding the use of any chelating agent
in acute copper poisoning. In severely poisoned patients the presence
of acute renal failure often limits the potential for antidotes which
enhance urinary copper elimination.
d-Penicillamine, the standard therapy for Wilson's disease, has been
utilized in copper poisoning (Holtzman et al, 1966; Jantsch et al,
1984/85; Hantson et al, 1996) but without confirmed evidence of
enhanced urinary copper excretion. Intramuscular dimercaprol
(Fairbanks, 1967; Jantsch et al, 1984/85; Schwartz and Schmidt, 1986;
Hantson et al, 1996) and intravenous sodium calciumedetate (Holleran,
1981; Agarwal et al, 1975) have also been employed but again without
confirmed benefit.
A five year-old child with copper intoxication following repeated
application of copper sulphate crystals to skin burns received a 12
day course of d-penicillamine 250 mg qds (Holtzman et al, 1966). Six
hour urine copper excretion on the first day of chelation was 1000 µg,
with a maximum value of 2000 µg/6h some 24 hours later. No pre- or
post-chelation copper excretion data were given.
Jantsch et al (1984/85) advocated the use of chelation therapy with
dimercaprol and d-penicillamine following their experience with a
patient who survived the alleged ingestion of 250 g copper sulphate. A
single intramuscular dimercaprol dose 4 mg/kg was administered within
the first ten hours (time not specified) followed by oral
d-penicillamine 250 mg qds for at least seven days. The only 24 hour
urine copper excretion measured "after initiation of chelation
therapy" was 8160 µg (time not specified) with no pre- or
post-chelation data presented. This case was unusual in that despite
massive copper sulphate ingestion the patient developed no features of
severe gastrointestinal irritation (save initial vomiting), no
haemolysis or oliguria.
Walsh et al (1977) administered intramuscular dimercaprol 2.5 g/kg
(?2.5 mg/kg) plus 12.5 g/kg (?12.5 mg/kg) "edetic acid" four hourly to
an 18 month-old child, commencing five hours after ingestion of 3 g
copper sulphate. The urine copper concentration from a two hour
collection was 500 µg/L on the second day, increasing to 3000 µg/L on
day 12. The chelating agent was then switched to d-penicillamine 250
mg daily for one month with a gradual fall in urine copper excretion.
Unfortunately urine volumes were not stated and no pre-chelation
measurements were possible.
Hantson et al (1996) recently treated an 86 year-old woman with acute
copper sulphate poisoning with intramuscular dimercaprol 4 mg/kg qds
and oral d-penicillamine 250 mg qds, both commenced within four hours
of poisoning. Urine copper elimination was not enhanced and chelation
was discontinued after 48 hours following onset of renal failure.
These authors concluded that "available clinical and toxicokinetic
data do not support the benefits of chelation in addition to
supportive therapy" in acute copper (and zinc) sulphate poisoning.
Alkaline diuresis
Muthusethupathi et al (1988) advocated forced alkaline diuresis in
copper sulphate poisoning. In 103 copper sulphate-poisoned patients in
whom gastric lavage followed by forced alkaline diuresis were
instituted immediately, the incidence of renal failure was claimed to
be substantially lower (14.6 per cent) than in other similar series.
However, no copper excretion data were reported, and it is possible
that prompt fluid resuscitation with correction of hypovolaemia played
an important role in patient recovery (Muthusethupathi et al, 1988).
Haemodialysis
Haemodialysis for five hours in a 41 year-old female failed to remove
copper when instituted 12 hours after the ingestion of 280 mL
dissolved copper sulphate (Agarwal et al, 1975). The patient had
already undergone gastric lavage, had received intravenous sodium
calciumedetate (1g) and a blood transfusion but died on the sixth
hospital day after developing septicaemia, hepatic and renal failure.
Peritoneal dialysis
Cole and Lirenman (1978) reported a two year old child who had
ingested some 30 mL super-saturated copper sulphate solution and
underwent peritoneal dialysis for the management of renal failure.
Copper extraction into the dialysate was enhanced markedly by the
addition of salt-poor albumin 25 g/L. Over a 40 hour dialysis period
(between 17 and 57 hours post ingestion) 0.7 mg copper was removed in
17 litres dialysate compared to 9.1 mg copper removed in 24 litres
during dialysis with added albumin between 57 and 117 hours. The
authors advocated albumin-enriched peritoneal dialysis in the
management of copper poisoning complicated by acute renal failure. It
should be noted, however, that the child consumed at least 2.7 g
copper so that the amount removed by dialysis, even with albumin, was
small.
Enhancing elimination: Conclusions and recommendations
1. There are no controlled clinical data regarding the use of
chelating agents in copper chloride poisoning.
2. Animal data suggest DMPS may be the most effective antidote in
copper poisoning, though DMPS was administered within 20 minutes
of copper dosing in these studies. DMPS has a more favourable
adverse effect profile than dimercaprol and d-penicillamine
although these are alternatives if DMPS is not available. DMPS
usually is given orally or parenterally in a dose of 30 mg/kg
body weight per day. Side effects are infrequent but have
included allergic skin reactions, nausea and vertigo (Aposhian,
1983). Discussion of individual cases with an NPIS physician is
recommended.
3. There is insufficient evidence to advocate alkaline diuresis in
the management of acute copper poisoning.
4. The role of haemodialysis and peritoneal dialysis is limited to
the management of renal failure.
Management of copper and caeruloplasmin concentrations in
biological fluids
Although whole blood copper concentrations correlate well with the
severity of poisoning following acute ingestion, they should always be
interpreted in conjunction with the clinical features. Serum copper
concentrations are less useful in acute intoxications (Chuttani et al,
1965). In 20 patients who ingested copper sulphate, mean (± SD) whole
blood copper concentrations were markedly lower (2.9 ± 1.3 mg/L) in
those with only gastrointestinal symptoms compared to those who
developed jaundice, renal failure or shock (mean whole blood copper
8.0 ± 4.0 mg/L). The number of patients in each group was not stated.
Among 65 cases of acute copper sulphate poisoning, Wahal et al (1976b)
observed that although patients who developed complications had higher
whole blood, red cell and plasma copper concentrations than
uncomplicated cases, the difference was not statistically significant
(p>0.05). No correlation was found between plasma copper
concentrations and prognosis. However, whole blood copper
concentrations greater than 1.2 mg/L were associated generally with
the development of complications. The four fatalities reported, who
were admitted within 6-8 hours of ingestion, had whole blood
concentrations of at least 2.1 mg/L.
Serum caeruloplasmin concentration estimation has been suggested as a
useful prognostic indicator in cases of acute copper sulphate
poisoning. Wahal et al (1978) observed significantly higher (p<0.001)
serum caeruloplasmin concentrations in uncomplicated cases of copper
sulphate poisoning than in those with complications (gastrointestinal
haemorrhage, jaundice, renal impairment, delirium or coma). Values
less than 35 mg/dL within 24 hours of poisoning or less than 44 mg/dL
beyond 72 hours post ingestion were associated with the development of
complications.
Increased urine copper excretion (preferably as a 24 hour collection)
will be present in any moderate or severe case of copper chloride
poisoning. The main value of this measurement is to monitor the effect
of chelation therapy.
MEDICAL SURVEILLANCE
Close attention to personal hygiene and the appropriate use of
protective equipment are the most important measures in limiting
occupational copper exposure.
Twenty-four hour urine copper excretion is a useful screening
procedure if copper intoxication is suspected but the source of
exposure is unclear. However, when collected in an occupational
setting great care must be taken to avoid sample contamination. Serum
or whole blood copper concentrations may be useful if exogenous copper
contamination of urine samples is suspected (Cohen, 1979). It should
be remembered that impaired biliary copper excretion from any cause
will lead to increased renal copper elimination.
Pre-employment screening for Wilson's disease may be indicated in
those occupationally exposed to copper.
Normal copper concentrations in biological fluids
Plasma/serum: 0.7-1.3 mg/L (Weatherall et al, 1996).
Whole blood: 1.6-2.7 mg/L (Chuttani et al, 1965).
Urine: Less than 60 µg/24h (Weatherall et al, 1996).
OCCUPATIONAL DATA
Occupational exposure standard
Copper: Long-term exposure limit (8 hour TWA reference period) fume
0.2 mg/m3; dusts and mists 1 mg/m3 (Health and Safety Executive,
1997).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
There are no carcinogenicity data for copper chloride.
There is no conclusive evidence that copper is carcinogenic in humans
(Aaseth and Norseth, 1986). However, it is proposed that patients with
"Vineyard sprayer's lung" are at a greater risk than the general
population of developing bronchial carcinoma (Villar, 1974; Stark,
1981). When originally reported in Europe, lung cancers in vineyard
workers were attributed to the arsenic content of some fungicides, but
in Portugal arsenic fungicides have never been used in the vineyards
(Villar, 1974).
Among 14 smoking vineyard workers Plamenac et al (1985) noted atypical
squamous metaplasia in four cases and suggested copper as an
aetiologic agent.
In a review of liver disease among 30 vineyard sprayers who had used
Bordeaux mixture for three to 45 years (mean 18 years), Pimentel and
Menezes (1977) observed one case of hepatic angiosarcoma. The authors
suggested copper-induced sinusoidal cell proliferation as a possible
trigger of tumour development.
Musicco et al (1988) reported a significant (p = 0.006) increase in
the incidence of brain gliomas among farmers occupationally exposed to
insecticides or fungicides (often commercial copper sulphate
preparations), but concluded these were associated probably with
exposure to alkyl urea (known neurogenic carcinogens) in the
pesticides.
Reprotoxicity
There are no reprotoxicity data for copper chloride.
In a controlled study Barash et al (1990) investigated the teratogenic
potential of copper releasing intrauterine devices (IUD) on the
developing human embryo. No malformations or copper deposits were
observed in the organs/placentae of copper IUD-exposed embryos (n=11)
examined between seven and 12 weeks gestation. The results from the
small study suggest that copper releasing IUDs have no observed
negative effects on the developing embryo.
Copper sulphate is teratogenic in several animal species (Bologa et
al, 1992).
Genotoxicity (for copper)
Copper induced sister chromatid exchanges in human peripheral
lymphocytes (DOSE, 1993).
Fish Toxicity
Bridgelip sucker exposed to 3 mg/L (CuCl2) died within 12-18 hours.
Stickleback exposed to 2 mg/L (CuCl2) died within 16-24 hours,
steelhead trout and sockeye salmon died in 12-16 hours (DOSE, 1993).
EC Directive on Drinking Water Quality 80/778/EEC
Copper: EC advisory level for drinking water, 100 µg/L at source of
supply; 3000 µg/L after standing in piping for 12 hours (DOSE, 1993).
WHO Guidelines for Drinking Water Quality
Copper: Provisional guideline value 2 mg/L (WHO, 1993).
AUTHORS
ST Beer BSc
SM Bradberry BSc MB MRCP
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Date of last revision
28/1/98
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