UKPID MONOGRAPH
COPPER SULPHATE
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 SULPHATE
Toxbase summary
Type of product
Fungicide, herbicide, commercial chemical and found in some chemistry
and crystal growing sets. The anhydrous form is white, the
pentahydrate is blue.
Toxicity
Copper sulphate is a powerful oxidizing agent and irritant to mucous
membranes. A dose-response effect following ingestion is difficult to
define but approximately 10 g may be fatal in an adult (Akintonwa et
al, 1989).
Chronic inhalation of copper sulphate-containing pesticides produces
pulmonary and hepatic toxicity. Copper sulphate contact sensitivity is
recognized.
Features
Dermal
- Mild irritant to intact skin. Systemic copper uptake may
result from repeated application to broken skin. Contact
dermatitis is reported.
Ocular
- Irritant to the eye and my cause corneal necrosis and
opacification if crystals remain in the conjunctival sac.
Ingestion
- Very small ingestions (milligrams) are likely to cause only
nausea and vomiting.
Moderate/substantial ingestions:
- Nausea, vomiting and a metallic taste occur within minutes
followed by abdominal pain and diarrhoea. Secretions may be
blue/green. Severe gastrointestinal irritation may result in
haematemesis and/or melaena with hypovolaemic shock. Severe
poisoning is associated with the development of renal
failure, intravascular haemolysis (usually manifest 24-48
hours post-poisoning) and cellular and obstructive liver
damage. Methaemoglobinaemia, coma, convulsions,
rhabdomyolysis, muscle weakness and cardiac arrhythmias are
described. There is a high risk of aspiration of the gastric
contents in obtunded patients.
Inhalation
- Reported only as chronic occupational inhalation of copper
sulphate-containing fungicides, presenting as 'Vineyard
sprayer's lung' with progressive dyspnoea, cough, wheeze,
myalgia, malaise, micronodular and reticular opacities on
chest X-ray (which may coalesce) and a restrictive lung
function defect. Other features include hepatic copper-
containing granulomas and hypergammaglobulinaemia.
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 sulphate 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. Copper sulphate is a potent emetic and the absence of pontaneous
vomiting suggests the ingestion is small requiring only
supportive care.
2. Gastric lavage is contraindicated since copper sulphate is
corrosive.
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
glucose-6-phosphate dehydrogenase inhibition may reduce 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 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) are unlikely in those with whole blood copper
concentrations less than 4 mg/L but this is not universally true
(Wahal et al, 1976b; 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 and administer supplemental oxygen by
face-mask if there is evidence of respiratory distress.
2. Arrange a chest X-ray if there are abnormal findings on
respiratory examination.
3. Chronic occupational exposure to copper sulphate mists may
produce granulomas in several organs including the lung and
liver. Initial assessment involves chest X-ray and lung function
tests. Seek specialist advice 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 sulphate
Origin of substance
Occurs in nature as the mineral hydrocyanite. The pentahydrate
form occurs as the chalcanthite mineral. The commercial
preparation is the pentahydrate form.
(DOSE, 1993)
Synonyms
Copper (II) sulfate
Cupric sulfate
Bluestone
Blue vitriol
Roman vitriol
Salzburg vitriol (DOSE, 1993)
Chemical group
A compound of copper, a transition metal (d block) element.
Reference numbers
CAS 7758-98-7 (DOSE, 1993)
7758-99-8 (pentahydrate) (DOSE, 1993)
RTECS GL8900000 (RTECS, 1997)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
CuSO4 (DOSE, 1993)
Molecular weight
159.60 (DOSE, 1993)
Physical state at room temperature
Solid
Colour
Anhydrate: grey-white to green-white crystals or powder.
Pentahydrate: blue crystals or granules, or light blue powder.
(MERCK,1996)
Odour
Odourless (HSDB, 1997)
Viscosity
NA
pH
A 0.2 molar aqueous solution has a pH of 4. (MERCK, 1996)
Solubility
Soluble in water: 230 g/L at 25°C. Soluble in glycerol, methanol
and ethanol. (DOSE, 1993)
Autoignition temperature
NIF
Chemical interactions
Copper sulphate solution is strongly corrosive to iron and
galvanized iron. (HSDB, 1997)
Copper salts and nitromethane spontaneously form explosive
materials. (NFPA, 1986)
Dangerous acetylides may be formed from many copper salts. The
copper acetylides formed in ammonical or caustic solutions with
cupric Cu(II) salts and acetylene are more explosive than those
derived from cuprous Cu(I) salts. Copper salts promote the
decomposition of hydrazine. (NFPA, 1986)
Anhydrous copper sulphate will cause hydroxylamine to ignite and
the hydrated salt is vigorously reduced. (NFPA, 1986)
Major products of combustion
NIF
Explosive limits
NIF
Flammability
Non-flammable (HSDB, 1997)
Boiling point
Copper sulphate pentahydrate decomposes above 150°C (with -5H2O)
(HSDB, 1997)
Density
3.6 at 20°C (MERCK, 1996)
Vapour pressure
NA
Relative vapour density
NA
Flash point
NA
Reactivity
NIF
Uses
The pentahydrate is used agriculturally as a fungicide,
herbicide, algicide and bactericide, and as a fertilizer
additive. In industry it is used in the manufacture of other
copper salts; as a mordant in textile dyeing; in the preparation
of azo dyes; for preserving hides and wood; tanning leather;
electroplating; as a battery electrolyte; in laundry and
metal-marking inks; as a paint pigment; in photography and in
antirusting compositions for radiator and heating systems.
The anhydrous salt is used for detection and removal of trace
amounts of water from organic compounds including alcohol.
Therapeutically copper sulphate has been used as a topical
antifungal agent, and as an antidote in phosphorus poisoning (via
phosphide formation). In veterinary practice it is used as an
anthelmintic, emetic and fungicide and for treating copper
deficiency in ruminants.
(MERCK, 1996; DOSE, 1993)
Hazard/risk classification
Index no. 029-004-00-0
Risk phrases
Xn; R22. Xi; R36/38 - Harmful if swallowed. Irritant; Irritating
to eyes and skin.
Safety phrases
S(2-) 22 - Keep out of reach of children. Do not breathe dust.
EEC no. 231-847-6 (CHIP2, 1994)
INTRODUCTION
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 copper accumulation in the liver, brain, kidneys and cornea.
Basal ganglia degeneration and cirrhosis are the principle
complications.
Copper sulphate solution, used as an antiseptic on open wounds and to
treat yellow phosphorus skin burns (via phosphide formation) (Zong-yue
et al, 1985; Eldad and Simon, 1991), may be absorbed and give rise to
systemic toxicity (Holtzman et al, 1966). Ahasan et al (1994) recently
reported farmers and fishermen in southern Bangladesh still treating
tinea pedis and other skin diseases with copper sulphate.
Copper sulphate is an effective emetic and historically was advocated
routinely (250 mg dissolved in water) following toxic non-corrosive
ingestions in paediatric patients (Mellencamp, 1966). This practice
was discontinued when the inherent toxicity of copper sulphate was
recognized.
Acute copper sulphate poisoning usually results from accidental or
deliberate ingestion (Aaseth and Norseth, 1986).
EPIDEMIOLOGY
Until recently accidental and intentional paediatric and adult acute
copper sulphate poisoning was particularly common in India (Mital et
al, 1966; Singh et al, 1984) where it was cheap and readily available
as an antiseptic. The amount ingested in suicidal attempts was often
in excess of the lethal dose since copper sulphate does not have a
particularly unpleasant smell or taste.
In 1961 copper sulphate poisoning constituted 33.6 per cent of all
(n=238) poisoning cases admitted to the Irwin Hospital, New Delhi
(Chuttani et al, 1965). Forty-eight of these were studied, including
nine fatalities. Amounts ingested varied from 1 g to 112 g. In another
study Wahal et al (1965) estimated that in 1965 acute copper sulphate
poisoning represented 64.7 per cent of the total poisoning cases
admitted to Sarojini Naidu Hospital, Agra, India.
By contrast, of 203 accidental paediatric poisoning cases admitted to
King George's Medical College, Lucknow, India over a four year period
only 12 (5.9 per cent) involved copper sulphate and all patients made
a full recovery (Sharma et al, 1967).
Chugh et al (1989) reported a decrease in the number of cases of acute
renal failure attributed to intentional copper sulphate ingestion
among patients admitted to a renal unit in Northern India over a
period of three decades. The decline, from five per cent in the 1960s
to one per cent in the 1980s was attributed to easier access to
quicker, less painful methods of suicide (Chugh et al, 1989).
MECHANISM OF TOXICITY
Copper sulphate is a powerful oxidizing agent which is corrosive to
mucous membranes. Concentrated solutions are acidic (a 0.2 M aqueous
solution has pH 4). Cellular damage and cell death may result from
excess copper accumulation. This is 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 reduced Cu(I) in the cell binds to sulfhydryl
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.
Copper sulphate can penetrate the erythrocyte membrane. Haemolytic
anaemia, a common complication of copper sulphate poisoning, is 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, probably because copper had entered
the lung via aspiration.
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).
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 sulphate poisoning. For example, a
child who ingested 3 g 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
Dermal exposure
There are no clinical reports of acute copper sulphate dermal exposure
although it is mildly irritant to intact skin. There is a risk of
greater tissue damage and systemic copper uptake if large amounts of
copper sulphate are in contact with open wounds and burns but this is
encountered typically in the context of acute-on-chronic topical
copper sulphate application (see Chronic exposure).
Ocular exposure
Copper sulphate is an eye irritant (Grant and Schuman, 1993). Corneal
necrosis and opacification may occur if particles remain in the
conjunctival sac (see Chronic exposure).
Ingestion
Gastrointestinal toxicity
Copper sulphate is a powerful oxidizing agent and corrosive to mucous
membranes. Copper sulphate is also a potent emetic and vomiting is
likely to occur within minutes of ingesting any significant amount
(Holleran, 1981). 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 (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; Nagaraj
et al, 1985; Kurisaki et al, 1988; Lamont and Duflou, 1988; Gulliver,
1991).
There is some disagreement regarding the dose/effect relationship
following copper sulphate ingestion. In a review of 123 cases 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 had undergone a
previous 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).
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 possibly 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.
In another series of 100 copper sulphate-poisoned patients 36 cases
exhibited jaundice which was hepatocellular, haemolytic or mixed in
16, 16, and four cases respectively (Wahal et al, 1965).
Serum caeruloplasmin concentrations are increased in acute copper
sulphate poisoning. In a series of 50 cases (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.
A 42 year-old male who allegedly ingested 250 g copper sulphate
developed epigastric pain, vomiting and a metallic taste within
minutes but no signs of severe gastrointestinal inflammation,
hypovolaemia, haemolysis or oliguria. Serum copper concentration was
14.2 mg/L one day post ingestion. Liver function became markedly but
transiently abnormal with a serum bilirubin concentration of 110
µmol/L and liver enzyme activities (lactate dehydrogenase and
aspartate transaminase) increased some one hundred fold, three days
after ingestion. These abnormalities were not accompanied by clinical
deterioration and resolved by day seven. The patient received
dimercaprol and d-penicillamine but increased urine copper elimination
was not confirmed (Jantsch et al, 1984/85).
Autopsy findings following ingestion of a copper sulphate-containing
witch doctor's remedy by a 30 year-old female included centrilobular
congestion and hydropic hepatocyte swelling (Lamont and Duflou, 1988).
The blood copper concentration at autopsy was 42 mg/L.
Another patient (Kurisaki et al, 1988) who died some 24 hours post
copper sulphate ingestion had centrilobular necrosis and a liver
copper concentration of 35.1 µg/g wet weight compared to 5.3 µg/g wet
weight in a non-exposed autopsy patient. Most of the copper was
metallothionein bound.
Other autopsy findings include central vein dilatation, fatty liver
degeneration (Deodhar and Deshpande, 1968), inflammatory cell
infiltration and cholestasis (Papadoyanakis et al, 1969). Copper
deposits have been noted also in the spleen (Agarwal et al, 1975).
Nephrotoxicity
Acute renal failure is a common complication of severe copper sulphate
poisoning (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.
Renal complications generally carry a poor prognosis. Of 10 fatalities
in a series of 100 cases of acute copper sulphate ingestion eight had
"evidence of severe renal failure" (Wahal et al, 1965).
Nineteen cases of copper sulphate-induced acute renal failure were
investigated by Mehta et al (1985) over a two year period. Seventeen
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).
Haemotoxicity
Haemolytic anaemia is a common complication of copper sulphate
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 activities.
Intravascular haemolysis following copper sulphate ingestion is
accompanied typically by hyperbilirubinaemia (Mittal, 1972),
reticulocytosis, haemo- globinaemia 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 sulphate is a powerful oxidizing agent and methaemoglobinaemia
has been reported frequently following ingestion (Chugh et al, 1975;
Patel et al, 1976; Chugh et al, 1977a; Thirumalaikolundusubramanian et
al, 1984; 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 the 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).
Pulmonary toxicity
Features of pulmonary toxicity following copper sulphate 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 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).
Neurotoxicity
Following copper sulphate 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). In
one series of 100 cases coma and convulsions were observed in 10
patients (Wahal et al, 1965).
"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 sulphate ingestion
(Papadoyanakis et al, 1969; Schwartz and Schmidt, 1986). In severe
cases cardiopulmonary arrest may ensue rapidly. For example, 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 made a full recovery (Hantson et al,
1996).
Muthusethupathi et al (1988) reported toxic myocarditis as a cause of
death following copper sulphate poisoning although this information is
poorly referenced.
Copper deposits have been noted in the heart at autopsy following
ingestion of some 280 mL copper sulphate solution (Agarwal et al,
1975).
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
transient 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).
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 sulphate
poisoning and are contributed to by gastrointestinal fluid loss,
haemolysis and renal failure. A 36 year-old man admitted to hospital
in coma following copper sulphate ingestion was noted to have serum
potassium and sodium concentrations of 7.7 mmol/L and 126 mmol/L
respectively, in association with gastrointestinal haemorrhage and
haemolysis (Papadoyanakis et al, 1969).
Inhalation
There are no reports of acute copper sulphate inhalation, although
inhalation of copper fumes may cause 'metal fume fever' (Gleason,
1968) (see Copper/Copper oxide monographs).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
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 precise mechanism remains obscure.
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 nail changes were noted in a group of
female labourers occupationally exposed to fertilizers, weedkillers
and a copper sulphate-containing fungicide (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.
Copper also may cause an irritant dermatitis.
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
Ocular toxicity
Copper sulphate applied topically to the conjunctivae was used
historically in the treatment of trachoma. This resulted in temporary
inflammation and pustular formation, leading to corneal discolouration
with little or no visual interference. Corneal discolouration has also
been described following chronic use of copper sulphate-containing
eyedrops. Local inflammation, necrosis and corneal opacification may
occur if copper sulphate particles are left in the conjunctival sac
(Grant and Schuman, 1993).
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 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. Although
the lung is the primary target organ, there is evidence that "Vineyard
sprayer's lung" is a systemic granulomatous disorder (see below).
Pulmonary toxicity
Characteristic presenting features of "Vineyard sprayer's lung"
include weakness, anorexia, fever, myalgia, progressive dyspnoea,
wheeze and a dry productive cough (Pimentel and Marques, 1969; Villar,
1974; Pimentel and Menezes, 1975; Stark, 1981). Symptoms may resolve
following prolonged absence from work, reappearing on return to work
(Pimentel and Marques, 1969; Villar, 1974). Examination findings
include cyanosis, finger clubbing and diffuse crackles and wheeze on
auscultation of the lung fields (Villar, 1974; Pimentel and Menezes,
1975; Stark, 1981).
Chest X-ray findings typically include increased pulmonary markings
with diffuse bilateral micronodular and reticular opacities sometimes
with areas of consolidation (Pimentel and Marques, 1969; Villar, 1974;
Pimentel and Menezes, 1975). Enlarged hilae, pleural effusion and
areas of calcification have been noted (Villar, 1974; Stark, 1981).
These findings initially are mainly in the lower lung fields, but may
progress to the upper zones with formation of large opacities from
confluence of the shadows (Villar, 1974; Stark, 1981).
Lung function tests usually reveal a restrictive ventilatory defect
(Pimentel and Marques, 1969; Villar, 1974; Pimentel and Menezes,
1975). Arterial blood gases may show a respiratory alkalosis and
hypoxia (Pimentel and Menezes, 1975).
In a study by Plamenac et al (1985) copper containing macrophages were
identified in the sputum of 64 and 42 per cent respectively of smoking
(n=9) and non-smoking (n=16) vineyard workers (all with normal chest
X-rays) compared to none of 51 controls (smokers n=21, non-smokers
n=30, all non-vineyard workers). Morning expectoration was more common
among vineyard workers than controls suggesting an effect on the
respiratory epithelium as well as the lung parenchyma. Eosinophilia
(not defined) was present in the sputum samples from 42 per cent of
vineyard workers compared to ten per cent of controls, suggesting an
allergic reaction to the Bordeaux mixture (Plamenac et al, 1985).
Lung biopsies from vineyard sprayers have revealed non-specific
inflammation and intra-alveolar copper-containing macrophages,
copper-containing granulomas of the alveolar septum with fibro-hyaline
nodules, which sometimes also contain copper (Pimentel and Marques,
1969; Villar, 1974; Stark, 1981). A notable similarity between
copper-induced nodules and silicotic nodules has been emphasized
(Pimentel and Marques, 1969; Stark, 1981). Thoracotomy may show
characteristic blue-green patchy colouration of the visceral pleura (a
phenomenon not observed in any other pathological lung condition)
which often coalesce (Pimentel and Marques, 1969; Villar, 1974;
Plamenac et al, 1985).
Established "Vineyard sprayer's lung" carries a poor long-term
prognosis although there may be partial resolution of radiological
abnormalities following removal from exposure (Pimentel and Marques,
1969). More typically progressive respiratory failure ensues (Pimentel
and Menezes, 1975), often associated with cor pulmonale (see below)
(Stark, 1981). Pimentel and Menezes (1975) reported fatal spontaneous
bilateral pneumothoraces in a 57 year-old man who developed "Vineyard
sprayer's lung" after using Bordeaux mixture for three years. Autopsy
revealed pulmonary fibrosis with numerous copper-containing blue
nodules and lower lobe emphysema (Pimentel and Menezes, 1975).
Stark (1981) suggested that the duration of copper sulphate exposure
before the clinical disease is produced is usually at least five
years, though most workers are occupationally exposed for far longer.
Diagnosis is complicated by the fact that the disease may remain
subclinical for several years following removal from exposure (Villar,
1974). Progression may be accelerated by the presence of pulmonary
infection. Moreover, presenting features are not dissimilar to those
of tuberculosis which itself may predispose to "Vineyard sprayer's
lung".
It is proposed that the incidence of bronchial carcinoma is increased
among those with "Vineyard sprayer's lung" (Villar, 1974; Stark, 1981)
(see Carcinogenicity).
Hepatotoxicity
Biopsy and autopsy findings from patients with "Vineyard sprayer's
lung" in association with pulmonary lesions include hepatomegaly,
copper-containing granulomas (histiocytic or sarcoid-type), Kupffer
cell proliferation with copper inclusions, peri/intralobular fibrosis
and idiopathic portal hypertension (Pimentel and Menezes, 1975;
Pimentel and Menezes, 1977). Micronodular cirrhosis (sometimes
complicated by oesophageal varices and splenomegaly) and "fatty
change" have also been observed but may be at least partly
alcohol-induced (Pimentel and Menezes, 1975; Pimentel and Menezes,
1977). Copper sulphate is proposed as the aetiological agent for the
lesions observed following deposition in the reticuloendothelial cells
of the liver (Pimentel and Menezes, 1977). Copper accumulation in
hepatocytes and abnormal liver function tests do not typically
accompany these histological findings (Pimentel and Menezes, 1975).
Haemotoxicity
Increased erythrocyte sedimentation rates, IgA and IgG concentrations
have been reported in association with the pulmonary features of
"Vineyard sprayer's lung" (Villar, 1974). Hypergammaglobulinaemia is
consistent with the likely immunological basis for this condition.
Cardiovascular toxicity
Cor pulmonale may ensue as a complication of "Vineyard sprayer's lung"
with typical features of tachycardia, a raised jugular venous
pressure, cardiomegaly, a right ventricular heave and summation
gallop, and evidence of right heart strain on the electrocardiogram
(Stark, 1981).
Neurotoxicity
Severe pulmonary manifestations of "Vineyard sprayer's lung" with
fever may be accompanied by confusion (Pimentel and Menezes, 1975).
Musculoskeletal toxicity
Joint and muscle pain with weakness has been described in association
with the characteristic pulmonary features of "Vineyard sprayer's
lung" (Pimentel and Marques, 1969; Villar, 1974; Pimentel and Menezes,
1975).
Metabolic disturbances
Hypoalbuminaemia is frequently noted in patients chronically
debilitated with "Vineyard sprayer's lung" (Villar, 1974; Pimentel and
Menezes, 1975).
Nephrotoxicity
Copper-containing renal granulomas have been reported at autopsy in a
patient with "Vineyard sprayer's lung" (Villar, 1974).
Injection
Nephrotoxicity
Ishikawa and Minami (1985) reported a pseudo-Bartter syndrome (with
hypereninaemia, polyuria and hypokalaemia) following 12 months
intravenous copper sulphate therapy (providing 130 µg/kg copper
weekly) to a child with Kinky-hair disease (an inherited copper
deficiency). The authors suggested renal copper accumulation as the
most likely cause of renal tubular damage.
MANAGEMENT
Dermal exposure
Following acute exposure irrigate the affected area with lukewarm
water. Particular care is required if copper sulphate has been in
contact with broken skin since corrosive damage and systemic copper
uptake are then possible.
Copper sulphate 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 sulphate is a powerful oxidizing agent and causes corrosive
damage to mucous membranes. Concentrated solutions are acidic; a 0.2 M
aqueous solution has a pH of 4.
Effective management primarily involves symptomatic and supportive
care. The role of chelating agents is discussed below.
Decontamination and dilution
Vomiting is likely to occur spontaneously following significant copper
sulphate ingestion. Gastric lavage is contraindicated since copper
sulphate is corrosive. 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
sulphate 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 sulphate ingestion. Antibiotics should be
reserved for established infection only.
Inhalation
Acute pulmonary irritation following copper sulphate inhalation
requires only appropriate symptomatic and supportive measures plus
investigation of any abnormal findings. If chronic granulomatous
pulmonary disease ("Vineyard sprayer's lung") is suspected,
appropriate investigations include chest X-ray, lung function tests,
biochemical, haematological and immunological profiles. There is no
established role for steroid therapy.
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, LD50 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
triethylenetramine (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 sulphate 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 sulphate 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 sulphate
poisoning. The main value of this measurement is to monitor the effect
of chelation therapy.
MEDICAL SURVEILLANCE
Appropriate occupational hygiene and safety measures should be ensured
for those potentially chronically exposed to copper sulphate sprays
with monitoring for pulmonary complications if necessary.
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 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 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). The authors concluded the gliomas were probably
associated with exposure to alkyl ureas (known neurogenic carcinogens)
in the pesticides.
Reprotoxicity
Copper sulphate is teratogenic in several animal species (Bologa et
al, 1992).
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.
Genotoxicity
Escherichia coli PQ37, PQ35 SOS chromotest - negative.
In vivo mouse bone marrow micronuclei test - negative (DOSE, 1993).
Fish toxicity
Indian catfish exposed to 0.25 mg/L for up to 30 days became lethargic
and frequently surfaced to gulp air. Numerous immature and fragmented
blood corpuscles were evident.
Threespine stickleback exposed to 10 mg/L died within 16-24 hr.
LC50 (96 hr) rainbow trout, harlequin fish, goldfish, eel 0.1-2.5
mg/L.
Exposed carp (concentration and duration unspecified) had increased
serum cholinesterase and transaminase activities and adrenaline and
noradrenaline concentrations.
A static bioassay was conducted on Indian carp using low dose (0.05
ppm) copper sulphate. Erythrocyte count and haematocrit decreased 34.1
per cent and 14.6 per cent respectively. Morphological study of
erythrocytes showed slight anisocytosis, cell membrane degeneration
and cell clumping. Thus copper sulphate caused a direct or indirect
effect on the cell membrane leading to haemolysis.
The order of the concentrations of copper sulfate taken up by carp
organs was skeletal muscle>liver>gills>intestine>kidney>heart> brain.
With the exception of the brain, greater copper accumulation was
measurable in every organ at 20°C compared to 4°C. Considerable
acetylcholinesterase inhibition measurable only in the first 24 hours,
was exhibited in carp exposed to 5 ppm for two weeks (DOSE, 1993).
EC Directive on Drinking Water Quality 80/778/EEC.
Copper: Guide level 100 µg/L at pumping/substation outlets; 3 mg/L
after water has been standing 12 hours in the piping (DOSE, 1993).
WHO Guidelines for Drinking Water Quality
Guideline value 2 mg/L (provisional value), as copper (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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