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 REFERENCES Aaseth J, Norseth T. Copper. In: Friberg L, Nordberg GF, Vouk V, eds. Handbook on the toxicology of metals. Vol 2. 2nd ed. Amsterdam: Elsevier, 1986; 233-54. Agarwal BN, Bray SH, Bercz P, Plotzker R, Labovitz E. Ineffectiveness of hemodialysis in copper sulphate poisoning. Nephron 1975; 15: 74-7. 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. Allain P, Krari N. Diethyldithiocarbamate and brain copper. Res Commun Chem Pathol Pharmacol 1993; 80: 105-12. Aposhian HV. DMSA and DMPS - water soluble antidotes for heavy metal poisoning. Ann Rev Pharmacol Toxicol 1983; 23: 193-215. Ashraf I. Hepatic derangements (biochemical) in acute copper sulphate poisoning. J Indian Med Assoc 1970; 55: 341-2. Barash A, Shoham (Schwartz) Z, Borenstein R, Nebel L. Development of human embryos in the presence of a copper intrauterine device. Gynecol Obstet Invest 1990; 29: 203-6. Behl PN, Agarwal RS, Singh G. The role of copper in vitiligo. J Indian Med Assoc 1961; 37: 593-7. Bologa M, Pastuszak A, Shear NH, Koren G. Dermatologic drugs in pregnancy. Clin Dermatol 1992; 9: 435-51. Borthwick TR, Benson GD, Schugar HJ. Copper chelating agents. A comparison of cupruretic responses to various tetramines and D-penicillamine. J Lab Clin Med 1980; 95: 575-80. Botha CJ, Naude TW, Swan GE, Dauth J, Dreyer MJ, Williams MC. The cupruretic effect of two chelators following copper loading in sheep. Vet Hum Toxicol 1993; 35: 409-13. Britton RS. Metal-induced hepatotoxicity. Semin Liver Dis 1996; 16: 3-12. CHRIS/Chemical Hazard Response Information System. In: Tomes plus. Environmental Health and Safety Series I. Vol 32. United States Coast Guard, 1997. Chowdhury AKR, Ghosh S, Pal D. Acute copper sulphate poisoning. J Indian Med Assoc 1961; 36: 330-6. Chugh KS, Singhal PC, Sharma BK. Methemoglobinemia in acute copper sulfate poisoning. Ann Intern Med 1975; 82: 226-9. Chugh KS, Sharma BK, Singhal PC, Das KC, Datta BN. Acute renal failure following copper sulphate intoxication. Postgrad Med J 1977a; 53: 18-23. Chugh KS, Singhal PC, Sharma BK, Mahakur AC, Pal Y, Datta BN, Das KC. Acute renal failure due to intravascular hemolysis in the North Indian patients. Am J Med Sci 1977b; 274: 139-46. 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. Dash SC. Copper sulphate poisoning and acute renal failure. Int J Artif Organs 1989; 12: 610. Dash S, Dash RJ. Spectrum of haemolytic anaemias in Punjab, North India. Trop Geogr Med 1980; 32: 312-6. Deodhar LP, Deshpande CK. Acute copper sulphate poisoning. J Postgrad Med 1968; 14: 38-41. Dhir GG, Rao DS, Mehrotra MP. Contact dermatitis caused by copper sulfate used as coloring material in commercial alcohol. Ann Allergy 1977; 39: 204. DOSE/Dictionary of substances and their effects. Vol 3. Cambridge: Royal Society of Chemistry, 1993. Dubois RS, Rodgerson DO, Hambidge KM. Treatment of Wilson's disease with triethylene tetramine hydrochloride (Trientine). J Pediatr Gastroenterol Nutr 1990; 10: 77-81. Earl CJ, Moulton MJ, Selverstone B. Metabolism of copper in Wilson's disease and in normal subjects. Am J Med 1954; 17: 205-13. Epstein S. Cross-sensitivity between nickel and copper. With remarks on cross-sensitivity between nickel, cobalt and chromates. J Invest Dermatol 1955; 25: 269-74. Fairbanks VF. Copper sulfate-induced hemolytic anemia. Inhibition of glucose-6-phosphate dehydrogenase and other possible etiologic mechanisms. Arch Intern Med 1967; 120: 428-32. Gleason RP. Exposure to copper dust. Am Ind Hyg Assoc J 1968; 29: 461-2. Grant WM, Schuman JS. Toxicology of the eye, 4th ed. Springfield, Illinois: Charles C Thomas, 1993. Gulliver JM. A fatal copper sulfate poisoning. J Anal Toxicol 1991; 15: 341-2. Hantson P, Lievens M, Mahieu P. Accidental ingestion of a zinc and copper sulfate preparation. Clin Toxicol 1996; 34: 725-30. HAZARDTEXT. In: Tomes plus. Environmental Health and Safety Series 1. Vol 33. Colorado: Micromedex, Inc., 1997. Health and Safety Executive. EH40/97. Occupational exposure limits 1997. Sudbury: Health and Safety Executive, 1997. Heilmaier HE, Jiang JL, Greim H, Schramel P, Summer KH. d-Penicillamine induces rat hepatic metallothionein. Toxicology 1986; 42: 23-31. Henderson P, Hale TW, Shum S, Habersang RW. N-acetylcysteine therapy of acute heavy metal poisoning in mice. Vet Hum Toxicol 1985; 27: 522-5. Holleran RS. Copper sulfate overdose. J Emerg Nurs 1981; 7: 136-7. Holtzman NA, Elliott DA, Heller RH. Copper intoxication. Report of a case with observations on ceruloplasmin. N Engl J Med 1966; 275: 347-52. Hoogenraad TU, Van den Hamer CJA. 3 years of continuous oral zinc therapy in 4 patients with Wilson's disease. Acta Neurol Scand 1983; 67: 356-64. HSDB/Hazardous Substances Data Bank. In: Tomes plus. Environmental Health and Safety Series I. Vol 33. National Library of Medicine, 1997. IPCS. Copper and copper salts. Poisons Information Monographs (Chemicals). In: IPCS Chemical Information CD Rom (Inchem). Geneva: WHO, 1997 and Ontario: Canadian Centre for Occupational Health and Safety, 1997. Ishikawa A, Minami H. Kinky hair disease with suspected Pseudo-Bartter syndrome. Brain Dev 1985; 7: 454-5. Isolauri J, Markkula H, Auvinen O. Copper sulfate corrosion and necrosis of the esophagus and stomach. Acta Chir Scand 1986; 152: 701-2. Iwata H, Watanabe K, Miichi H, Matsui Y. Accumulation of copper in the central nervous system on prolonged administration of sodium diethyldithiocarbamate to rats. Pharmacol Res Commun 1970; 2: 213-20. Jantsch W, Kulig K, Rumack BH. Massive copper sulfate ingestion resulting in hepatotoxicity. Clin Toxicol 1984/85; 22: 585-8. Jasim S, Danielsson BRG, Tjälve H, Dencker L. Distribution of 64Cu in foetal and adult tissues in mice: Influence of sodium diethyldithiocarbamate treatment. Acta Pharmacol Toxicol 1985; 57: 262-70. Jones MM, Basinger MA, Tarka MP. The relative effectiveness of some chelating agents in acute copper intoxication in the mouse. Res Commun Chem Pathol Pharmacol 1980; 27: 571-7. Karlberg A-T, Boman A, Wahlberg JE. Copper - a rare sensitizer. Contact Dermatitis 1983; 9: 134-9. Kurisaki E, Kuroda Y, Sato M. Copper-binding protein in acute copper poisoning. Forensic Sci Int 1988; 38: 3-11. Lamont DL, Duflou ALC. Copper sulfate. Not a harmless chemical. Am J Forensic Med Pathol 1988; 9: 226-7. Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr 1996; 63: 797-811. Maehashi H, Yamaguchi Y, Tsutsumi S. Arsenic and copper excretion after treatment of arsenic poisoning in rats with heavy-metal antagonists. Dev Sci Pract Toxicol 1983; 11: 325-8. Mehta A, Patney NL, Bhati DPS, Singh SP. Copper sulphate poisoning - its impact on kidneys. J Indian Med Assoc 1985; 83: 108-10. MERCK/The Merck Index. Cupric chloride. In: Budavari S, ed. An encyclopedia of chemicals, drugs, and biologicals. 12th ed. New Jersey: Merck and Co., Inc., 1989; 445. Mital VP, Wahal PK, Bansal OP. A study of erythrocytic glutathione in acute copper sulphate poisoning. Indian J Pathol Bacteriol 1966; 9: 155-62. Mittal SR. Oxyhaemoglobinuria following copper sulphate poisoning: A case report and a review of the literature. Forensic Sci 1972; 1: 245-8. Mitchell WM, Basinger MA, Jones MM. Antagonism of acute copper(II)-induced renal lesions by sodium 2,3-dimercaptopropanesulfonate. John Hopkins Med J 1982; 151: 283-5. Morita J, Yoshino M, Watari H, Yoshida I, Motohiro T, Yamashita F, Okano Y, Hashimoto T. Wilson's disease treatment by triethylene tetramine dihydrochloride (Trientine, 2HCI): Long-term observations. Dev Pharmacol Ther 1992; 19: 6-9. Musicco M, Sant M, Molinari S, Filippini G, Gatta G, Berrino F. A case-control study of brain gliomas and occupational exposure to chemical carcinogens: The risk to farmers. Am J Epidemiol 1988; 128: 778-85. Muthusethupathi MA, Selvaraj AM, Shivakumar S, Chenthil S. Forced alkaline diuresis in acute copper sulphate poisoning. J Assoc Physicians India 1988; 36: 459-60. Nagaraj MV, Rao PV, Susarala S. Copper sulphate poisoning, hemolysis and methaemoglobinemia. J Assoc Physicians India 1985; 33: 308-9. Narahari SR, Srinivas CR, Kelkar SK. LE-like erythema and periungual telangiectasia among coffee plantation workers. Contact Dermatitis 1990; 22: 296-7. Nicholas PO. Food-poisoning due to copper in the morning tea. Lancet 1968; 1: 40-42. OHM/TADS-Oil and hazardous Materials/Technical Assistance Data System. In: Tomes plus. Environmental Health and Safety Series 1. Vol 32. United States Environmental Protection Agency, 1997. Pande RS, Gupta YN. Thrombocytopenic purpura following copper sulphate therapy. J Indian Med Assoc 1969; 52: 227-8. Papadoyanakis N, Katsilambros N, Patsourakos B. Acute copper sulfate poisoning with jaundice. J Irish Med Assoc 1969; 62: 99-100. Patel KC, Kulkarni BS, Acharya VN. Acute renal failure and methaemoglobinaemia due to copper sulphate poisoning. J Postgrad Med 1976; 22: 180-4. Perry AR, Pagliuca A, Fitzsimons EJ, Mufti GJ, Williams R. Acquired sideroblastic anaemia induced by a copper-chelating agent. Int J Hematol 1996; 64: 69-72. Pimentel JC, Marques F. 'Vineyard sprayer's lung': a new occupational disease. Thorax 1969; 24: 678-88. Pimentel JC, Menezes AP. Liver granulomas containing copper in vineyard sprayer's lung. A new etiology of hepatic granulomatosis. Am Rev Respir Dis 1975; 111: 189-95. Pimentel JC, Menezes AP. Liver disease in vineyard sprayers. Gastroenterology 1977; 72: 275-83. Plamenac P, Santic Z, Nikulin A, Serdarevic H. Cytologic changes of the respiratory tract in vineyard spraying workers. Eur J Respir Dis 1985; 67: 50-5. Planas-Bohne F. Influence of several chelating agents on the excretion and organ concentration of copper in the rat. Toxicol Appl Pharmacol 1979; 50: 337-45. Rana SVS, Kumar A. The protective effects of EDTA against copper poisoning in rats with special reference to the kidney. Int J Tissue React 1983; 2: 187-92. Ribarov SR, Bochev PG. The interaction of copper chloride with erythrocyte membrane as a source of activated oxygen species. A chemiluminescent study. Gen Physiol Biophys 1984; 5: 431-5. RTECS/Registry of Toxic Effects of Chemical Substances. In: Tomes plus. Environmental Health and Safety Series I. Vol 33. National Institute for Occupational Safety and Health (NIOSH), 1997. Santucci B, Cannistraci C, Cristaudo A, Picardo M. Interaction of metals in nickel-sensitive patients. Contact Dermatitis 1993; 29: 251-3. Scheinberg HI. Copper, alloys and compounds. In: Parmeggiani L, ed. Encyclopaedia of occupational heath and safety. 3rd ed. Vol 1. Geneva: International Labour Office, 1983; 546-8. Scheinberg IH, Sternlieb I, Schilsky M, Stockert RJ. Penicillamine may detoxify copper in Wilson's disease. Lancet 1987; 2: 95. Schilsky ML. Wilson disease: Genetic basis of copper toxicity and natural history. Semin Liver Dis 1996; 16: 83-95. Schwartz E, Schmidt E. Refractory shock secondary to copper sulfate ingestion. Ann Emerg Med 1986; 15: 952-4. Singh MM, Singh GS. Biochemical changes in blood in cases of acute copper sulphate poisoning. J Indian Med Assoc 1968; 50: 549-54. Stark P. Vineyard sprayer's lung - a rare occupational disease. J Can Assoc Radiologists 1981; 32: 183-4. Stein RS, Jenkins D, Korns ME. Death after use of cupric sulfate as emetic. JAMA 1976; 235: 801. Steinebach OM, Wolterbeek HTh. Role of cytosolic copper, metallothionein and glutathione in copper toxicity in rat hepatoma tissue culture cells. Toxicology 1994; 92: 75-90. Strickland GT, Beckner WM, Leu ML. Absorption of copper in homozygotes and heterozygotes for Wilson's disease and controls: isotope tracer studies with 67Cu and 64Cu. Clin Sci 1972; 43: 617-25. Sunderman FW Jr , White JC, Sunderman FW, Lucyszyn GW. Metabolic balance studies in hepatolenticular degeneration treated with diethyldithiocarbamate. Am J Med 1963; 34: 875-87. Tauxe WN, Goldstein NP, Randall RV, Gross JB. Radiocopper studies in patients with Wilson's disease and their relatives. Am J Med 1966; 41: 375-80. Twedt DC, Hunsaker HA, Allen KGD. Use of 2,3,2-tetramine as a hepatic copper chelating agent for treatment of copper hepatotoxicosis in Bedlington Terriers. J Am Vet Med Assoc 1988; 192: 52-56. Van Caillie-Bertrand M, Degenhart HJ, Visser HKA, Sinaasappel M, Bouquet J. Oral zinc sulphate for Wilson's disease. Arch Dis Child 1985; 60: 656-9. Van Joost Th, Habets JMW, Stolz E, Naafs B. The meaning of positive patch tests to copper sulphate in nickel allergy. Contact Dermatitis 1988; 18: 101-2. Veen C, Van Den Hamer CJA, De Leeuw PW. Zinc sulphate therapy for Wilson's disease after acute deterioration during treatment with low-dose D-penicillamine. J Intern Med 1991; 229: 549-52. Villar TG. Vineyard sprayer's lung. Clinical aspects. Am Rev Respir Dis 1974; 110: 545-55. Wahal PK, Mittal VP, Bansal OP. Renal complications in acute copper sulphate poisoning. The Indian Practitioner 1965; 18: 807-12. Wahal PK, Mehrotra MP, Patney NL, Saraswat RL, Sharma RD, Tiwari SR. A study of haemolytic jaundice in acute copper sulphate poisoning. J Assoc Physicians India 1976a; 24: 103-8. 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 1976b; 24: 153-8. Wahal PK, Mehrotra MP, Kishore B, Goyal SP, Gupta MC, Patney NL, Raizada SN, Singh R. A study of serum ceruloplasmin levels in acute copper sulphate poisoning. J Assoc Physicians India 1978; 26: 983-7. 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. Walshe JM. Toxic reactions to penicillamine in patients with Wilson's disease. Postgrad Med J 1968; PSuppl: 6-8. Walshe JM. Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride. Lancet 1982; 1: 643-7. Walshe JM. Unithiol in Wilson's disease. Br Med J 1985; 290: 673-4. Walton S. Investigation into patch testing with copper sulphate. Contact Dermatitis 1983a; 9: 89-90. Walton S. Patch testing with copper sulphate. Contact Dermatitis 1983b; 9: 337. Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford Textbook of Medicine. 3rd ed. New York: Oxford University Press Inc., 1996. WHO/World Health Organization. Guidelines for drinking-water quality. 2nd ed. Vol 1. Recommendations. Geneva: World Health Organization, 1993. Zargar SA, Kochhar R, Nagi B, Mehta S, Mehta SK. Ingestion of corrosive acids. Spectrum of injury to upper gastrointestinal tract and natural history. Gastroenterology 1989; 97: 702-7.