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    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 0C and methanol 680 g/L at 15C.
         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
         993C                                   (DOSE, 1993)

    Density
         3.39 at 25C/4C                        (HSDB, 1997)

    Vapour pressure
         2666.4 Pa at 1970C                     (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 g/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 g/g wet weight (control value of
    1.3 g/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 mol/L
    creatinine) than in the 13 who survived (15.6  3.2 mmol/L urea, 235 
    143 mol/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 g/g wet weight, compared to a control value of
    2.6 g/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 g/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 mol/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 g,
    with a maximum value of 2000 g/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 g (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 g/L on the second day, increasing to 3000 g/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 g/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 g/L at source of
    supply; 3000 g/L after standing in piping for 12 hours (DOSE, 1993).

    WHO Guidelines for Drinking Water Quality

    Copper: Provisional guideline value 2 mg/L (WHO, 1993).

    AUTHORS

    ST Beer BSc
    SM Bradberry BSc MB MRCP
    JA Vale MD FRCP FRCPE FRCPG FFOM

    National Poisons Information Service (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    Birmingham
    B18 7QH
    UK

    This monograph was produced by the staff of the Birmingham Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Date of last revision
    28/1/98

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    See Also:
       Toxicological Abbreviations