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    UKPID MONOGRAPH




    COPPER SULPHATE




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

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


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

    Peer review group: Directors of the UK National Poisons Information
    Service.


    COPPER SULPHATE

    Toxbase summary

    Type of product

    Fungicide, herbicide, commercial chemical and found in some chemistry
    and crystal growing sets. The anhydrous form is white, the
    pentahydrate is blue.

    Toxicity

    Copper sulphate is a powerful oxidizing agent and irritant to mucous
    membranes. A dose-response effect following ingestion is difficult to
    define but approximately 10 g may be fatal in an adult (Akintonwa et
    al, 1989).

    Chronic inhalation of copper sulphate-containing pesticides produces
    pulmonary and hepatic toxicity. Copper sulphate contact sensitivity is
    recognized.

    Features

    Dermal

         -    Mild irritant to intact skin. Systemic copper uptake may
              result from repeated application to broken skin. Contact
              dermatitis is reported.

    Ocular

         -    Irritant to the eye and my cause corneal necrosis and
              opacification if crystals remain in the conjunctival sac.

    Ingestion

         -    Very small ingestions (milligrams) are likely to cause only
              nausea and vomiting.

    Moderate/substantial ingestions:
         -    Nausea, vomiting and a metallic taste occur within minutes
              followed by abdominal pain and diarrhoea. Secretions may be
              blue/green. Severe gastrointestinal irritation may result in
              haematemesis and/or melaena with hypovolaemic shock. Severe
              poisoning is associated with the development of renal
              failure, intravascular haemolysis (usually manifest 24-48
              hours post-poisoning) and cellular and obstructive liver
              damage. Methaemoglobinaemia, coma, convulsions,
              rhabdomyolysis, muscle weakness and cardiac arrhythmias are
              described. There is a high risk of aspiration of the gastric
              contents in obtunded patients.

    Inhalation

         -    Reported only as chronic occupational inhalation of copper
              sulphate-containing fungicides, presenting as 'Vineyard
              sprayer's lung' with progressive dyspnoea, cough, wheeze,
              myalgia, malaise, micronodular and reticular opacities on
              chest X-ray (which may coalesce) and a restrictive lung
              function defect. Other features include hepatic copper-
              containing granulomas and hypergammaglobulinaemia.

    Management

    Dermal

    1.   Irrigate with copious lukewarm water.
    2.   Consider the possibility of systemic copper uptake if there has
         been significant or repeated exposure to broken skin.
    3.   Copper sulphate irritant dermatitis and contact sensitivity are
         managed most effectively by discontinuing exposure.

    Ocular

    1.   Irrigate immediately with lukewarm water or preferably saline for
         at least 10 minutes.
    2.   Application of local anaesthetic may be required for pain relief
         and to overcome blepharospasm to allow thorough decontamination.
    3.   Ensure no particles remain lodged in the conjunctival recesses.
    4.   Corneal damage may be detected by the instillation of
         fluorescein.
    5.   If symptoms do not resolve rapidly or if there are abnormal
         examination findings, refer for an ophthalmological opinion.

    Ingestion

    1.   Copper sulphate is a potent emetic and the absence of pontaneous
         vomiting suggests the ingestion is small requiring only
         supportive care.
    2.   Gastric lavage is contraindicated since copper sulphate is
         corrosive.
    3.   There may be some benefit in attempting oral dilution if
         performed immediately, but fluids should not be offered if there
         is inadequate airway protection or severe abdominal pain.
    4.   Supportive measures are paramount. Ensure adequate fluid
         replacement and close observation of vital signs including
         cardiac monitoring.
    5.   Monitor biochemical and haematological profiles and acid-base
         status.
    6.   Intravascular haemolysis and renal failure are managed
         conventionally.
    7.   Symptomatic methaemoglobinaemia may be reversed by the
         intravenous administration of 2 mg/kg methylene blue (as a 1 per
         cent solution over five minutes) although copper induced
         glucose-6-phosphate dehydrogenase inhibition may reduce antidotal
         efficacy.

    8.   Early endoscopy is recommended if corrosive oesophageal or
         gastric damage is suspected.
    9.   An early surgical opinion should be sought if there are abdominal
         symptoms or signs or deep ulcers and/or areas of necrosis (grade
         3 burns) on endoscopy.
    10.  Although whole blood copper concentrations correlate well with
         the severity of poisoning, they should always be interpreted in
         conjunction with the clinical features. Chuttani et al (1965)
         suggested severe complications (liver or renal damage or
         hypovolaemic shock) are unlikely in those with whole blood copper
         concentrations less than 4 mg/L but this is not universally true
         (Wahal et al, 1976b; Hantson et al, 1996).
    11.  There are no controlled data regarding the use of chelating
         agents in copper poisoning. In severely poisoned patients the
         presence of acute renal failure often limits the potential for
         antidotes which enhance urinary copper elimination. Discuss with
         an NPIS physician.
    12.  Urine copper excretion is increased in copper poisoned patients
         who have not developed acute renal failure. The main role of 24
         hour urine copper excretion measurements is monitoring the effect
         of chelation therapy. Discuss with an NPIS physician.
    13.  The role of haemodialysis or peritoneal dialysis is restricted to
         patients with acute renal failure.

    Inhalation

    1.   Remove from exposure and administer supplemental oxygen by
         face-mask if there is evidence of respiratory distress.
    2.   Arrange a chest X-ray if there are abnormal findings on
         respiratory examination.
    3.   Chronic occupational exposure to copper sulphate mists may
         produce granulomas in several organs including the lung and
         liver. Initial assessment involves chest X-ray and lung function
         tests. Seek specialist advice from an NPIS physician.

    References

    Ahasan HAMN, Chowdhury MAJ, Azhar MA, Rafiqueuddin AKM.
    Copper sulphate poisoning.
    Trop Doct 1994; 24: 52-3.

    Akintonwa A, Mabadeje AFB, Odutola TA.
    Fatal poisonings by copper sulfate ingested from "spiritual water".
    Vet Hum Toxicol 1989; 31: 453-4.

    Chuttani HK, Gupta PS, Gulati S, Gupta DN.
    Acute copper sulfate poisoning.
    Am J Med 1965; 39: 849-54.

    Cole DEC, Lirenman DS.
    Role of albumin-enriched peritoneal dialysate in acute copper
    poisoning.
    J Pediatr 1978; 92: 955-7.

    Hantson P, Lievens M, Mahieu P.
    Accidental ingestion of a zinc and copper sulfate preparation.
    Clin Toxicol 1996; 34: 725-30.

    Isolauri J, Markkula H, Auvinen O.
    Copper sulfate corrosion and necrosis of the esophagus and stomach.
    Acta Chir Scand 1986; 152: 701-2.

    Jantsch W, Kulig K, Rumack BH.
    Massive copper sulfate ingestion resulting in hepatotoxicity.
    Clin Toxicol 1984/85; 22: 585-8.

    Stein RS, Jenkins D, Korns ME.
    Death after use of cupric sulfate as emetic
    JAMA 1976; 235: 801.

    Wahal PK, Mehrotra MP, Kishore B, Patney NL, Mital VP, Hazra DK,
    Raizada MN, Tiwari SR.
    Study of whole blood, red cell and plasma copper levels in acute
    copper sulphate poisoning and their relationship with complications
    and prognosis.
    J Assoc Physicians India 1976; 24: 153-8.

    Walsh FM, Crosson FJ, Bayley M, McReynolds J, Pearson BJ.
    Acute copper intoxication. Pathophysiology and therapy with a case
    report.
    Am J Dis Child 1977; 131: 149-51.

    Substance Name

         Copper sulphate

    Origin of substance

         Occurs in nature as the mineral hydrocyanite. The pentahydrate
         form occurs as the chalcanthite mineral. The commercial
         preparation is the pentahydrate form.
                                                      (DOSE, 1993)

    Synonyms

         Copper (II) sulfate
         Cupric sulfate
         Bluestone
         Blue vitriol
         Roman vitriol
         Salzburg vitriol                             (DOSE, 1993)

    Chemical group

         A compound of copper, a transition metal (d block) element.

    Reference numbers

         CAS            7758-98-7                     (DOSE, 1993)
                        7758-99-8 (pentahydrate)      (DOSE, 1993)
         RTECS          GL8900000                     (RTECS, 1997)
         UN             NIF
         HAZCHEM CODE   NIF

    Physicochemical properties

    Chemical structure
         CuSO4                                        (DOSE, 1993)

    Molecular weight
         159.60                                       (DOSE, 1993)

    Physical state at room temperature
         Solid

    Colour
         Anhydrate: grey-white to green-white crystals or powder.
         Pentahydrate: blue crystals or granules, or light blue powder.
                                                      (MERCK,1996)

    Odour
         Odourless                                    (HSDB, 1997)

    Viscosity
         NA

    pH
         A 0.2 molar aqueous solution has a pH of 4.  (MERCK, 1996)

    Solubility
         Soluble in water: 230 g/L at 25C. Soluble in glycerol, methanol
         and ethanol.                                 (DOSE, 1993)

    Autoignition temperature
         NIF

    Chemical interactions
         Copper sulphate solution is strongly corrosive to iron and
         galvanized iron.                             (HSDB, 1997)

         Copper salts and nitromethane spontaneously form explosive
         materials.                                   (NFPA, 1986)

         Dangerous acetylides may be formed from many copper salts. The
         copper acetylides formed in ammonical or caustic solutions with
         cupric Cu(II) salts and acetylene are more explosive than those
         derived from cuprous Cu(I) salts. Copper salts promote the
         decomposition of hydrazine.                  (NFPA, 1986)

         Anhydrous copper sulphate will cause hydroxylamine to ignite and
         the hydrated salt is vigorously reduced.     (NFPA, 1986)

    Major products of combustion
         NIF

    Explosive limits
         NIF

    Flammability
         Non-flammable                                (HSDB, 1997)

    Boiling point
         Copper sulphate pentahydrate decomposes above 150C (with -5H2O)
                                                      (HSDB, 1997)

    Density
         3.6 at 20C                                  (MERCK, 1996)

    Vapour pressure
         NA

    Relative vapour density
         NA

    Flash point
         NA

    Reactivity
         NIF

    Uses

         The pentahydrate is used agriculturally as a fungicide,
         herbicide, algicide and bactericide, and as a fertilizer
         additive. In industry it is used in the manufacture of other
         copper salts; as a mordant in textile dyeing; in the preparation
         of azo dyes; for preserving hides and wood; tanning leather;
         electroplating; as a battery electrolyte; in laundry and
         metal-marking inks; as a paint pigment; in photography and in
         antirusting compositions for radiator and heating systems.

         The anhydrous salt is used for detection and removal of trace
         amounts of water from organic compounds including alcohol.

         Therapeutically copper sulphate has been used as a topical
         antifungal agent, and as an antidote in phosphorus poisoning (via
         phosphide formation). In veterinary practice it is used as an
         anthelmintic, emetic and fungicide and for treating copper
         deficiency in ruminants.
                                                 (MERCK, 1996; DOSE, 1993)

    Hazard/risk classification

    Index no.  029-004-00-0
    Risk phrases
         Xn; R22. Xi; R36/38 - Harmful if swallowed. Irritant; Irritating
         to eyes and skin.
    Safety phrases
         S(2-) 22 - Keep out of reach of children. Do not breathe dust.
     EEC no.  231-847-6 (CHIP2, 1994)

    INTRODUCTION

    Copper plays an important role as a co-factor in several
    metalloproteins, including cytochrome oxidase and superoxide dismutase
    and is essential for the utilization of iron and haemoglobin
    formation.

    The richest food sources of copper are shellfish, 'organ' meats,
    seeds, nuts and grains where it is bound to specific proteins. Copper
    tends to exist in the cupric Cu(II) state in biological systems
    including water although it may also be found as Cu(I) (Linder and
    Hazegh-Azam, 1996).

    Copper deficiency is associated with neurological dysfunction and
    manifests as "Swayback" in lambs and calves born to sheep and cows
    grazing on copper deficient pastures.

    Wilson's disease is an inborn error of metabolism inherited as an
    autosomal recessive trait whereby there is reduced biliary copper
    excretion associated with decreased or absent circulating
    caeruloplasmin (Schilsky, 1996). The disease is characterized by
    excessive copper accumulation in the liver, brain, kidneys and cornea.
    Basal ganglia degeneration and cirrhosis are the principle
    complications.

    Copper sulphate solution, used as an antiseptic on open wounds and to
    treat yellow phosphorus skin burns (via phosphide formation) (Zong-yue
    et al, 1985; Eldad and Simon, 1991), may be absorbed and give rise to
    systemic toxicity (Holtzman et al, 1966). Ahasan et al (1994) recently
    reported farmers and fishermen in southern Bangladesh still treating
    tinea pedis and other skin diseases with copper sulphate.

    Copper sulphate is an effective emetic and historically was advocated
    routinely (250 mg dissolved in water) following toxic non-corrosive
    ingestions in paediatric patients (Mellencamp, 1966). This practice
    was discontinued when the inherent toxicity of copper sulphate was
    recognized.

    Acute copper sulphate poisoning usually results from accidental or
    deliberate ingestion (Aaseth and Norseth, 1986).

    EPIDEMIOLOGY

    Until recently accidental and intentional paediatric and adult acute
    copper sulphate poisoning was particularly common in India (Mital et
    al, 1966; Singh et al, 1984) where it was cheap and readily available
    as an antiseptic. The amount ingested in suicidal attempts was often
    in excess of the lethal dose since copper sulphate does not have a
    particularly unpleasant smell or taste.

    In 1961 copper sulphate poisoning constituted 33.6 per cent of all
    (n=238) poisoning cases admitted to the Irwin Hospital, New Delhi
    (Chuttani et al, 1965). Forty-eight of these were studied, including
    nine fatalities. Amounts ingested varied from 1 g to 112 g. In another
    study Wahal et al (1965) estimated that in 1965 acute copper sulphate
    poisoning represented 64.7 per cent of the total poisoning cases
    admitted to Sarojini Naidu Hospital, Agra, India.

    By contrast, of 203 accidental paediatric poisoning cases admitted to
    King George's Medical College, Lucknow, India over a four year period
    only 12 (5.9 per cent) involved copper sulphate and all patients made
    a full recovery (Sharma et al, 1967).

    Chugh et al (1989) reported a decrease in the number of cases of acute
    renal failure attributed to intentional copper sulphate ingestion
    among patients admitted to a renal unit in Northern India over a
    period of three decades. The decline, from five per cent in the 1960s
    to one per cent in the 1980s was attributed to easier access to
    quicker, less painful methods of suicide (Chugh et al, 1989).

    MECHANISM OF TOXICITY

    Copper sulphate is a powerful oxidizing agent which is corrosive to
    mucous membranes. Concentrated solutions are acidic (a 0.2 M aqueous
    solution has pH 4). Cellular damage and cell death may result from
    excess copper accumulation. This is likely when copper-metallothionein
    binding and copper clearance from the cell are blocked.

    Metallothionein is a cysteine rich low molecular weight (6500 Da)
    metal-binding protein which is important in heavy metal
    detoxification, metal ion storage, and in the regulation of normal
    cellular Cu(II) (and Zn(II)) metabolism. It is also thought to be a
    free radical scavenger, playing a protective role in oxidative stress.
    Metallothionein is found in both intra- and extracellular
    compartments. It is known to bind zinc, cadmium, copper, mercury and
    silver (in increasing order of affinity) and its gene transcription is
    greatly enhanced upon exposure of cells to these metals. High
    metallothionein concentrations are also induced in the liver by
    physical and chemical stress, infection and glucocorticoids.

    It is proposed that free reduced Cu(I) in the cell binds to sulfhydryl
    groups and inactivates enzymes such as glucose-6-phosphate
    dehydrogenase and glutathione reductase (Dash, 1989). In addition
    copper may interact with oxygen species (e.g. superoxide anions and

    hydrogen peroxide) and catalyze the production of reactive toxic
    hydroxyl radicals.

    Copper sulphate can penetrate the erythrocyte membrane. Haemolytic
    anaemia, a common complication of copper sulphate poisoning, is caused
    either by direct red cell membrane damage (Chuttani et al, 1965) or
    indirectly as a result of the inactivation of enzymes (including
    glutathione reductase) which protect against oxidative stress (Mital
    et al, 1966; Walsh et al, 1977). Intracellular glutathione is believed
    to chelate Cu(I) as soon as it enters the cell as a "first-line"
    defence mechanism. In addition superoxide dismutase and glutathione
    may serve to remove physiologically generated toxic radicals
    (Steinebach and Wolterbeek, 1994).

    Copper(II) ions can oxidize haem iron to form methaemoglobin.

    TOXICOKINETICS

    Absorption and distribution

    Strickland et al (1972) suggested a mean copper absorption of 57 per
    cent (range 40 to 70 per cent) following oral administration of 0.4 -
    4.5 mg copper (as copper acetate) to four volunteers. An early human
    study suggested a maximum blood copper concentration was reached some
    two hours after oral copper chloride administration (1.5 - 12 mg
    copper) (Earl et al, 1954).

    Copper transport across the intestinal mucosa following ingestion is
    facilitated by cytosolic metallothionein. In blood, copper is
    initially albumin-bound and transported via the hepatic portal
    circulation to the liver where it is incorporated into caeruloplasmin
    (an alpha globulin synthesized in hepatic microsomes) (Britton, 1996).
    Some authors have noted a secondary rise in the serum copper
    concentration following acute copper sulphate ingestion (Singh and
    Singh, 1968) and this may be due to release of the
    copper-caeruloplasmin complex from the liver. Ninety-eight per cent of
    copper in the systemic circulation is caeruloplasmin-bound.

    Copper is distributed to all tissues with the highest concentrations
    in liver, heart, brain, kidneys and muscle. Intracellular copper is
    predominantly metallothionein-bound. Kurisaki et al (1988) reported
    copper in the lungs, liver, kidney, blood, bile and stomach (33.7,
    35.1, 41.4, 13.8, 2.8, and 2988 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, probably because copper had entered
    the lung via aspiration.

    Copper can penetrate the erythrocyte membrane. In acute copper
    sulphate poisoning this occurs quite rapidly as indicated by the
    markedly higher whole blood than serum copper concentration within the
    first few hours after ingestion (Singh and Singh, 1968). In a series
    of 40 cases of acute copper sulphate ingestion Singh and Singh (1968)

    noted that haemolysis (secondary to erythrocyte copper uptake)
    occurred typically 12-24 hours post poisoning, suggesting that red
    cell copper accumulation is maximal around this time.

    Studies among vineyard sprayers provide evidence of haematogenous
    dissemination of inhaled copper sulphate (Villar, 1974; Pimentel and
    Menezes, 1977). Copper sulphate can also be absorbed through the skin
    giving rise to systemic effects (Holtzman et al, 1966; Pande and
    Gupta, 1969).

    Copper can cross the placenta.

    Excretion

    Caeruloplasmin renders free copper innocuous with subsequent excretion
    via a lysosome-to-bile pathway. This process is essential to normal
    copper homeostasis and provides a protective mechanism in acute copper
    sulphate poisoning. An impaired or overloaded biliary copper excretion
    system results in hepatic copper accumulation, as occurs in patients
    with Wilson's disease and in copper poisoning.

    Renal copper elimination is normally low (Tauxe et al (1966) retrieved
    less than one per cent of an injected dose in the urine over 72 hours)
    but will increase in acute copper sulphate poisoning. For example, a
    child who ingested 3 g copper sulphate had increased urine copper
    concentrations (maximum 3.0 mg/L) for three weeks post poisoning
    (Walsh et al, 1977).

    In a series of 40 cases of acute copper sulphate ingestion increased
    whole blood copper concentrations were noted up to ten days post
    poisoning with values returning to normal over 17 hours to seven days
    (Singh and Singh, 1968). The whole-body half-life of copper has been
    estimated as approximately four weeks (Strickland et al, 1972).

    CLINICAL FEATURES: ACUTE EXPOSURE

    Dermal exposure

    There are no clinical reports of acute copper sulphate dermal exposure
    although it is mildly irritant to intact skin. There is a risk of
    greater tissue damage and systemic copper uptake if large amounts of
    copper sulphate are in contact with open wounds and burns but this is
    encountered typically in the context of acute-on-chronic topical
    copper sulphate application (see Chronic exposure).

    Ocular exposure

    Copper sulphate is an eye irritant (Grant and Schuman, 1993). Corneal
    necrosis and opacification may occur if particles remain in the
    conjunctival sac (see Chronic exposure).

    Ingestion

    Gastrointestinal toxicity

    Copper sulphate is a powerful oxidizing agent and corrosive to mucous
    membranes. Copper sulphate is also a potent emetic and vomiting is
    likely to occur within minutes of ingesting any significant amount
    (Holleran, 1981). Other early features include abdominal pain,
    diarrhoea (Kurisaki et al, 1988), hypersalivation (Ahasan et al, 1994)
    and a metallic taste (Jantsch et al, 1984/85; Nagaraj et al, 1985).
    Body secretions may be green or blue (Kurisaki et al, 1988; Gulliver,
    1991) with blue staining of the mouth, lips and oesophageal mucosa
    (Deodhar and Deshpande, 1968).

    Gastric and duodenal ulceration have been described in association
    with erosive oesophagitis and gastritis (Schwartz and Schmidt, 1986).
    There may be gastrointestinal bleeding with haematemesis and melaena
    (Chugh et al, 1977 a and b); fatalities have occurred (Chuttani et al,
    1965; Deodhar and Deshpande, 1968; Papadoyanakis et al, 1969; Nagaraj
    et al, 1985; Kurisaki et al, 1988; Lamont and Duflou, 1988; Gulliver,
    1991).

    There is some disagreement regarding the dose/effect relationship
    following copper sulphate ingestion. In a review of 123 cases Ahasan
    et al (1994) observed an "unpredictable" outcome in those consuming
    less than 50 g while 100 g was "invariably fatal". By contrast
    Akintonwa et al (1989) claimed 10-20 g copper sulphate to be a
    "definitely fatal" dose and Stein et al (1976) reported a fatality
    after ingestion of only 2 g copper sulphate as an emetic. The latter
    case is complicated because although the patient developed features
    typical of copper poisoning (haemolysis, gastrointestinal haemorrhage,
    hepatic and renal failure), benzodiazepine and alcohol overdose
    undoubtedly contributed to coma. The patient also had undergone a
    previous gastrectomy which is likely to have increased copper-induced
    gastrointestinal toxicity.

    Twenty workmen developed symptoms including nausea, vomiting and
    diarrhoea within a few minutes of ingesting tea brewed with copper
    sulphate - contaminated water from an unserviced gas hot-water geyser
    (Nicholas, 1968). Copper content of the tea drunk was thought to be
    greater than 30 ppm.

    Ingestion of some 20-30 mL copper sulphate/methanol/ethylene
    glycol-containing fluid by a 31 year-old male resulted in severe
    corrosive necrosis of the oesophagus and stomach necessitating total
    gastrectomy and oesophagectomy (Isolauri et al, 1986). This case was
    unusual in that the patient did not develop significant hepatic or
    renal damage. Four months later reconstruction was performed between
    the pharynx and duodenum using a colon segment. At follow-up 2 years
    later the patient had no dysphagia, and had returned to his original
    occupation.

    An 86 year-old patient vomited blue/green liquid and developed watery
    diarrhoea within 30 minutes of ingesting a mixture of zinc sulphate
    and copper sulphate (3 g of each). Early endoscopy demonstrated a
    normal oesophagus and diffusely inflamed gastric mucosa with several
    areas of bleeding. Plasma copper and zinc concentrations obtained
    approximately 90 minutes after ingestion were 2.1 mg/L (normal range
    0.8-1.4 mg/L) and 19.8 mg/L (normal range 0.9-1.2 mg/L) respectively.
    Treatment included prompt resuscitation with intravenous fluids and
    chelation therapy with dimercaprol and d-penicillamine. The patient
    developed acute renal failure, cardiac failure and aspiration
    pneumonitis but made a full recovery with no abnormality identified on
    an upper gastrointestinal endoscopy "a few days later" (Hantson et al,
    1996).

    Hepatotoxicity

    Hepatic copper accumulation produces cellular and obstructive damage.
    There may be jaundice, tender hepatomegaly (Chuttani et al, 1965),
    increased transaminase and alkaline phosphatase activities (Ashraf,
    1970) and possibly prolongation of the prothrombin time (Chuttani et
    al, 1965; Agarwal et al, 1975).

    Jaundice may be cholestatic, haemolytic (see Haemotoxicity) or both
    (Papadoyanakis et al, 1969). Jaundice was observed in 11 of 48 cases
    of acute copper sulphate ingestion reported by Chuttani et al (1965).
    In six cases this was attributed mainly to haemolysis (there was no
    hepatomegaly, liver enzyme activities were normal and the reticulocyte
    count and urine urobilinogen concentrations were raised). The
    remaining five patients exhibited tender hepatomegaly, marked
    progressive jaundice, grossly deranged liver enzyme activities and a
    prolonged prothrombin time (mean 35 seconds) with histological
    evidence of centrilobular necrosis and biliary stasis on liver biopsy.
    One of these patients died. Reliable information regarding the
    quantity of copper sulphate ingested by these patients was not
    available.

    In another series of 100 copper sulphate-poisoned patients 36 cases
    exhibited jaundice which was hepatocellular, haemolytic or mixed in
    16, 16, and four cases respectively (Wahal et al, 1965).

    Serum caeruloplasmin concentrations are increased in acute copper
    sulphate poisoning. In a series of 50 cases (Wahal et al, 1978) mean
    (SD) peak caeruloplasmin concentrations were significantly higher
    (p<0.001) in 28 uncomplicated cases (48.1  9.7 mg/dL) than in 22
    complicated cases (37.2  6.0 mg/dL) of poisoning suggesting increased
    caeruloplasmin offered some protection against copper toxicity.
    Complicated cases were defined by the presence of jaundice, renal
    impairment, gastrointestinal haemorrhage, delirium or coma. Serum
    caeruloplasmin concentrations in 30 healthy controls (29.4  7.4
    mg/dL) were significantly lower (p<0.001) than in both the
    complicated and uncomplicated poisoned cases. A progressive increase
    in serum caeruloplasmin concentrations was observed in all copper

    sulphate-poisoned patients until the third day post poisoning before
    gradually decreasing to normal by day seven.

    A 42 year-old male who allegedly ingested 250 g copper sulphate
    developed epigastric pain, vomiting and a metallic taste within
    minutes but no signs of severe gastrointestinal inflammation,
    hypovolaemia, haemolysis or oliguria. Serum copper concentration was
    14.2 mg/L one day post ingestion. Liver function became markedly but
    transiently abnormal with a serum bilirubin concentration of 110
    mol/L and liver enzyme activities (lactate dehydrogenase and
    aspartate transaminase) increased some one hundred fold, three days
    after ingestion. These abnormalities were not accompanied by clinical
    deterioration and resolved by day seven. The patient received
    dimercaprol and d-penicillamine but increased urine copper elimination
    was not confirmed (Jantsch et al, 1984/85).

    Autopsy findings following ingestion of a copper sulphate-containing
    witch doctor's remedy by a 30 year-old female included centrilobular
    congestion and hydropic hepatocyte swelling (Lamont and Duflou, 1988).
    The blood copper concentration at autopsy was 42 mg/L.

    Another patient (Kurisaki et al, 1988) who died some 24 hours post
    copper sulphate ingestion had centrilobular necrosis and a liver
    copper concentration of 35.1 g/g wet weight compared to 5.3 g/g wet
    weight in a non-exposed autopsy patient. Most of the copper was
    metallothionein bound.

    Other autopsy findings include central vein dilatation, fatty liver
    degeneration (Deodhar and Deshpande, 1968), inflammatory cell
    infiltration and cholestasis (Papadoyanakis et al, 1969). Copper
    deposits have been noted also in the spleen (Agarwal et al, 1975).

    Nephrotoxicity

    Acute renal failure is a common complication of severe copper sulphate
    poisoning (Hantson et al, 1996). This may occur via a direct toxic
    effect on the proximal tubules and/or reduced renal perfusion
    secondary to hypovolaemic shock plus intravascular haemolysis.

    Renal complications generally carry a poor prognosis. Of 10 fatalities
    in a series of 100 cases of acute copper sulphate ingestion eight had
    "evidence of severe renal failure" (Wahal et al, 1965).

    Nineteen cases of copper sulphate-induced acute renal failure were
    investigated by Mehta et al (1985) over a two year period. Seventeen
    patients were reported to have ingested more than 25 g copper sulphate
    and all were admitted to hospital six to 96 hours post ingestion.
    Renal complications were observed most frequently three to four days
    post poisoning and presenting features included dysuria, "dark-reddish
    coloured urine" and oliguria. Albuminuria, haematuria and
    haemoglobinuria were present in 100, 84 and 58 per cent of cases
    respectively. Mean (SD) "blood" urea and serum creatinine
    concentrations were elevated in all cases and to a greater extent in

    the six patients who died (26.8  7 mmol/L urea, 696  152 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).

    Haemotoxicity

    Haemolytic anaemia is a common complication of copper sulphate
    intoxication (Dash and Dash, 1980) and may be caused by direct
    erythrocyte membrane damage (Chuttani et al, 1965) or indirectly by
    copper-mediated inhibition of enzymes important in protecting against
    oxidative stress, including glucose-6-phosphate dehydrogenase (Mital
    et al, 1966; Fairbanks, 1967; Wahal et al, 1976a; Walsh et al, 1977)
    and glutathione reductase (Wahal et al, 1976a). In a study by Wahal et
    al (1976a) the high frequency of reduced erythrocyte
    glucose-6-phosphate dehydrogenase activity and its return to normal in
    surviving patients confirmed that impaired enzyme activity in copper
    sulphate-poisoned patients was a direct toxic effect of copper rather
    than a genetic phenomenon.

    Mital et al (1966) observed red cell glutathione instability in 13 of
    24 copper sulphate-poisoned patients with evidence of intravascular
    haemolysis in nine of the 13. Glutathione is necessary for erythrocyte
    integrity and its stability is directly related to glucose-6-phosphate
    dehydrogenase and glutathione reductase activities.

    Intravascular haemolysis following copper sulphate ingestion is
    accompanied typically by hyperbilirubinaemia (Mittal, 1972),
    reticulocytosis, haemo- globinaemia and a fall in haematocrit
    (Papadoyanakis et al, 1969). Acute renal failure is a common
    complication and is contributed to by renal tubular obstruction by
    haemolysis products, disseminated intravascular coagulation and
    possibly renal vasoconstriction (Chugh et al, 1977b).

    Copper sulphate is a powerful oxidizing agent and methaemoglobinaemia
    has been reported frequently following ingestion (Chugh et al, 1975;
    Patel et al, 1976; Chugh et al, 1977a; Thirumalaikolundusubramanian et
    al, 1984; Nagaraj et al, 1985). Although methaemoglobin concentrations
    are typically moderate (33 to 38 per cent) concurrent acute renal
    failure frequently contributes to a poor outcome (Patel et al, 1976;
    Nagaraj et al, 1985).

    A 27 year-old male died 16 hours post ingestion of 50 g copper
    sulphate despite peritoneal dialysis, ascorbic acid and methylene blue
    therapy. Peak blood copper concentration was 82.7 mg/L (normal 2.1 
    0.5 mg/L). His methaemoglobin concentration was 36 per cent five hours
    post poisoning although the concentration immediately prior to death
    was not stated. Any beneficial effect of methylene blue would have
    been limited by the observed low glucose-6-phosphate dehydrogenase
    activity. It is not known whether this patient had a pre-existing
    deficiency of this enzyme (Chugh et al, 1975).

    A prolonged prothrombin time may be observed in acute copper sulphate
    poisoning and reflects hepatotoxicity (see above) (Agarwal et al,
    1975).

    Pulmonary toxicity

    Features of pulmonary toxicity following copper sulphate ingestion
    usually reflect secondary complications, most significantly aspiration
    of the gastric contents in an obtunded patient (Lamont and Duflou,
    1988; Hantson et al, 1996). Profound hypovolaemic shock may be
    accompanied by pulmonary oedema (Schwartz and Schmidt, 1986). Direct
    corrosive damage to the hypopharynx and larynx at the time of
    ingestion may produce respiratory embarrassment requiring mechanical
    ventilation (Isolauri et al, 1986).

    An 86 year-old female who ingested a mixture of zinc sulphate and
    copper sulphate (3 g of each) was found 15 minutes later coughing and
    vomiting a blue/green liquid. She developed respiratory failure three
    days later requiring mechanical ventilation. Bronchoscopy demonstrated
    an ulcerated bronchial mucosa suggesting aspiration and subsequent
    corrosive pneumonitis. The patient's clinical course was complicated
    also by cardiac and renal failure, but she made a full recovery
    (Hantson et al, 1996).

    A 30 year-old female died approximately 48 hours after ingesting a
    witch doctor's tonic containing salt, vinegar, sugar, alcohol and
    copper sulphate (Lamont and Duflou, 1988). Following ingestion the
    woman lapsed into a coma, during which time she was administered
    further copper sulphate-containing "medication". Post-mortem revealed
    bronchopneumonia, thought to be secondary to aspiration and a blood
    copper concentration of 42 mg/L. Two friends who also ingested the
    tonic vomited immediately and survived.

    A lung copper concentration of 33.7 g/g wet weight (control value 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).

    Neurotoxicity

    Following copper sulphate ingestion neurological complications usually
    occur in association with hypovolaemic shock, hepatic and/or renal
    failure. Headache, drowsiness, coma, convulsions, depressed or absent
    deep reflexes, and equivocal plantar responses have been reported
    (Papadoyanakis et al, 1969; Patel et al, 1976; Wahal et al, 1976b). In
    one series of 100 cases coma and convulsions were observed in 10
    patients (Wahal et al, 1965).

    "Toxic psychosis" has been reported in association with
    gastrointestinal toxicity and acute renal failure in two patients who
    ingested 200-400 mL "spiritual water" containing copper sulphate (100-
    150 g/L) and nickel (50 mg/L). Further details of the psychosis were
    not given, but both patients died (despite haemodialysis) within nine
    days of poisoning (Akintonwa et al, 1989).

    Copper deposits were found at autopsy in the brain of a 41 year-old
    female who drank some 280 mL dissolved copper sulphate and died on the
    fifth hospital day following development of hepatorenal failure,
    haemolysis and gram-negative septicaemia (Agarwal et al, 1975).

    Cardiovascular toxicity

    Peripheral cyanosis and other features of hypovolaemic shock
    frequently accompany substantial copper sulphate ingestion
    (Papadoyanakis et al, 1969; Schwartz and Schmidt, 1986). In severe
    cases cardiopulmonary arrest may ensue rapidly. For example, an 11
    year-old female died following a cardiac arrest (in association with
    gastrointestinal features) two hours after ingesting a "jam jar full"
    of copper sulphate solution from a crystal growing set, which she had
    mistaken for fruit juice. A post-mortem blood sample revealed a copper
    concentration of 66 mg/L. The cause of death was identified as
    "cardio-respiratory arrest due to copper sulfate poisoning" but no
    further details of the post-mortem findings were given (Gulliver,
    1991).

    On presentation to a Poisons Centre some 16 hours after ingesting 30
    mL of a supersaturated copper sulphate solution a two year-old child
    was noted to have a pulse rate of 150 beats/minute with multiple
    ventricular extrasystoles and occasional runs of bigeminy on
    electrocardiogram (Cole and Lirenman, 1978). He also had profuse
    vomiting and diarrhoea plus renal failure (treated with peritoneal
    dialysis), haemolysis and impaired consciousness but made a full
    recovery over four weeks.

    An 86 year-old lady who ingested a mixture of zinc sulphate and copper
    sulphate (3 g of each) rapidly developed features of gastrointestinal
    and renal toxicity. Cardiac failure (confirmed on echocardiogram)
    developed within 48 hours and the patient required inotropic support
    for several days. The precise aetiology of the cardiac complications
    was unclear but the patient made a full recovery (Hantson et al,
    1996).

    Muthusethupathi et al (1988) reported toxic myocarditis as a cause of
    death following copper sulphate poisoning although this information is
    poorly referenced.

    Copper deposits have been noted in the heart at autopsy following
    ingestion of some 280 mL copper sulphate solution (Agarwal et al,
    1975).

    Musculoskeletal toxicity

    Muscle weakness has been reported following acute copper sulphate
    ingestion (Chowdhury et al, 1961).

    A 42 year-old man who ingested 250 g copper sulphate developed
    transient rhabdomyolysis (peak creatine kinase activity 5620 iu/L on
    day three) in addition to features of gastrointestinal and
    hepatotoxicity. Renal function was not impaired (Jantsch et al,
    1984/85).

    Endocrine toxicity

    Copper deposits were found at autopsy in the adrenal glands of a woman
    who ingested some 280 mL dissolved copper sulphate (Agarwal et al,
    1975).

    Metabolic disturbances

    Electrolyte disturbances are likely in severe copper sulphate
    poisoning and are contributed to by gastrointestinal fluid loss,
    haemolysis and renal failure. A 36 year-old man admitted to hospital
    in coma following copper sulphate ingestion was noted to have serum
    potassium and sodium concentrations of 7.7 mmol/L and 126 mmol/L
    respectively, in association with gastrointestinal haemorrhage and
    haemolysis (Papadoyanakis et al, 1969).

    Inhalation

    There are no reports of acute copper sulphate inhalation, although
    inhalation of copper fumes may cause 'metal fume fever' (Gleason,
    1968) (see Copper/Copper oxide monographs).

    CLINICAL FEATURES: CHRONIC EXPOSURE

    Dermal exposure

    Dermal toxicity

    Despite its widespread use, the sensitizing potential of copper has
    been described as "extremely low" (Walton, 1983a). In patch tests
    among 354 eczema patients, six tested positive to copper sulphate (5
    per cent solution) and 39 to nickel sulphate (2.5 per cent solution)
    (Walton, 1983a). All patients positive to copper sulphate were also
    nickel sulphate positive. None of the subjects positive to copper

    sulphate were occupationally exposed to copper or had a history of
    atopy; all were females with hand eczema. The authors postulated
    nickel- and copper- containing coins as the source of exposure.
    Interpretation of these results was complicated by the possibility
    that patients were sensitive to the nickel sulphate trace (0.01 per
    cent) in the copper sulphate test solution. The author subsequently
    demonstrated (Walton, 1983b) that the six copper sensitive patients
    were patch test negative to nickel sulphate (0.01 per cent),
    suggesting true copper sensitivity.

    Further evidence of true copper allergy was presented by Van Joost et
    al (1988) who described two females patch test positive to copper (as
    sulphate 5 per cent) and nickel (as sulphate 2.5 per cent) in whom the
    possibility of nickel contamination of the copper test solution was
    largely excluded by the observation that 11 "control" nickel sensitive
    patients each gave no positive reaction to the copper solution.

    Epstein (1955) described combined nickel/copper sensitivity in 38 per
    cent of 32 patients patch tested, and emphasized that many
    nickel-containing alloys also contain copper. The author suggested the
    frequency of cross-sensitivity reactions, the close chemical
    relationship between copper and nickel (in adjacent positions in the
    transition metal series of the periodic table) and evidence for a true
    cross-sensitivity between nickel and cobalt as reasons to assume a
    true cross-sensitivity between copper and nickel rather than a
    coincidental occurrence of separate sensitivities (Epstein, 1955).

    In 30 patients known to be contact sensitive to nickel but patch-test
    negative to copper, the severity of patch test reaction to a
    copper/nickel mixture was greater (p <0.001) than to nickel alone,
    suggesting copper ions somehow enhanced the sensitivity reaction to
    nickel (Santucci et al, 1993). The authors proposed that the presence
    of copper ions facilitated the formation of nickel protein complexes
    in the skin although the precise mechanism remains obscure.

    In a study by Karlberg et al (1983), 13 of 1190 eczema patients showed
    a patch test reaction to two per cent copper sulphate. However, these
    patients had concomitant reactions to other known contact allergens
    and serial dilution tests with copper sulphate provided no confirmed
    cases of copper sulphate contact sensitivity. The authors recommended
    a serial dilution test in cases of suspected copper sulphate allergy
    to eliminate the possibility of an irritant effect and confirm whether
    true copper sulphate sensitivity is present (Karlberg et al, 1983).

    Indurated erythematous areas of the face, neck, chest and forearms,
    periungual telangiectasia and nail changes were noted in a group of
    female labourers occupationally exposed to fertilizers, weedkillers
    and a copper sulphate-containing fungicide (Bordeaux mixture). The
    aetiological agent was not identified (Narahari et al, 1990).

    Contact dermatitis was reported in 10 furniture polishers using
    commercial spirit (ethyl/methyl alcohol) coloured blue with copper
    sulphate (Dhir et al, 1977). All patients developed erythema, itching
    and vesiculopustular areas on the skin of the hands, improving on
    removal from contact with the spirit. Positive patch tests with copper
    sulphate (5 per cent solution) were reported in all patients and were
    negative in 15 non-exposed controls.

    In conclusion, available evidence regarding copper contact sensitivity
    suggests that while a true copper contact allergy exists, cross
    sensitivity between nickel and copper contributes to many cases.
    Copper also may cause an irritant dermatitis.

    Haemotoxicity

    A five year-old girl with 40 per cent second and third degree burns
    had copper sulphate crystals rubbed onto granulated areas of skin (as
    an antiseptic) during debridement seven times over a nine week period.
    A decrease in haematocrit of eight to ten per cent requiring
    transfusion was observed after each treatment, though this may have
    been due to blood loss. Twenty four hours after the last debridement
    there was evidence of haemolytic anaemia with a fall in haematocrit to
    18.5 per cent and a reticulocytosis (8.6 per cent). Total serum copper
    was 5.4 mg/L; caeruloplasmin 86 mg/dL. The child received
    d-penicillamine therapy and made a full recovery (Holtzman et al,
    1966). Six months later "moderately increased" serum copper and
    caeruloplasmin concentrations persisted.

    Nephrotoxicity

    Acute renal failure in association with haemolytic anaemia developed
    in a five year-old with 40 per cent burns who was treated with topical
    copper sulphate crystals over a nine week period during debridement.
    Urine was dark brown and haematuria, albuminuria, urobilinogenuria,
    and biliuria were present with evidence of erythrocyte casts. Urine
    copper concentration was 2.2 mg/L. Renal function improved following
    d-penicillamine therapy (1 g daily for 12 days) with some evidence of
    increased urine copper clearance. The patient made a full recovery
    (Holtzman et al, 1966).

    Ocular exposure

    Ocular toxicity

    Copper sulphate applied topically to the conjunctivae was used
    historically in the treatment of trachoma. This resulted in temporary
    inflammation and pustular formation, leading to corneal discolouration
    with little or no visual interference. Corneal discolouration has also
    been described following chronic use of copper sulphate-containing
    eyedrops. Local inflammation, necrosis and corneal opacification may
    occur if copper sulphate particles are left in the conjunctival sac
    (Grant and Schuman, 1993).

    Ingestion

    A 17 year-old male treated for leucoderma with oral copper sulphate
    (one per cent solution, 2 mg/day for two months) developed purpuric
    spots in association with bleeding gums and epistaxis. Investigations
    revealed anaemia (7g/dL, possibly due to co-existing iron deficiency)
    and thrombocytopenia. Treatment with copper sulphate was discontinued
    and following blood transfusion, ferrous sulphate and steroid therapy
    the patient made a full recovery (Pande and Gupta, 1969).

    Inhalation

    Occupational inhalational exposure to copper sulphate-containing
    fungicides may result in "Vineyard sprayer's lung" (Pimentel and
    Marques, 1969; Villar, 1974; Pimentel and Menezes, 1975; Pimentel and
    Menezes, 1977; Stark, 1981; Plamenac et al, 1985). Although copper
    sulphate-containing fungicides are manufactured in the UK, this
    condition is particularly common in Portugal where Bordeaux mixture, a
    1-2.5 per cent copper sulphate solution neutralized with hydrated
    lime, is sprayed on grape vines to prevent mildew. This treatment is
    necessary between two and twelve times per year, exposing labourers to
    the pesticide at intervals for up to three months annually. Although
    the lung is the primary target organ, there is evidence that "Vineyard
    sprayer's lung" is a systemic granulomatous disorder (see below).

    Pulmonary toxicity

    Characteristic presenting features of "Vineyard sprayer's lung"
    include weakness, anorexia, fever, myalgia, progressive dyspnoea,
    wheeze and a dry productive cough (Pimentel and Marques, 1969; Villar,
    1974; Pimentel and Menezes, 1975; Stark, 1981). Symptoms may resolve
    following prolonged absence from work, reappearing on return to work
    (Pimentel and Marques, 1969; Villar, 1974). Examination findings
    include cyanosis, finger clubbing and diffuse crackles and wheeze on
    auscultation of the lung fields (Villar, 1974; Pimentel and Menezes,
    1975; Stark, 1981).

    Chest X-ray findings typically include increased pulmonary markings
    with diffuse bilateral micronodular and reticular opacities sometimes
    with areas of consolidation (Pimentel and Marques, 1969; Villar, 1974;
    Pimentel and Menezes, 1975). Enlarged hilae, pleural effusion and
    areas of calcification have been noted (Villar, 1974; Stark, 1981).
    These findings initially are mainly in the lower lung fields, but may
    progress to the upper zones with formation of large opacities from
    confluence of the shadows (Villar, 1974; Stark, 1981).

    Lung function tests usually reveal a restrictive ventilatory defect
    (Pimentel and Marques, 1969; Villar, 1974; Pimentel and Menezes,
    1975). Arterial blood gases may show a respiratory alkalosis and
    hypoxia (Pimentel and Menezes, 1975).

    In a study by Plamenac et al (1985) copper containing macrophages were
    identified in the sputum of 64 and 42 per cent respectively of smoking
    (n=9) and non-smoking (n=16) vineyard workers (all with normal chest
    X-rays) compared to none of 51 controls (smokers n=21, non-smokers
    n=30, all non-vineyard workers). Morning expectoration was more common
    among vineyard workers than controls suggesting an effect on the
    respiratory epithelium as well as the lung parenchyma. Eosinophilia
    (not defined) was present in the sputum samples from 42 per cent of
    vineyard workers compared to ten per cent of controls, suggesting an
    allergic reaction to the Bordeaux mixture (Plamenac et al, 1985).

    Lung biopsies from vineyard sprayers have revealed non-specific
    inflammation and intra-alveolar copper-containing macrophages,
    copper-containing granulomas of the alveolar septum with fibro-hyaline
    nodules, which sometimes also contain copper (Pimentel and Marques,
    1969; Villar, 1974; Stark, 1981). A notable similarity between
    copper-induced nodules and silicotic nodules has been emphasized
    (Pimentel and Marques, 1969; Stark, 1981). Thoracotomy may show
    characteristic blue-green patchy colouration of the visceral pleura (a
    phenomenon not observed in any other pathological lung condition)
    which often coalesce (Pimentel and Marques, 1969; Villar, 1974;
    Plamenac et al, 1985).

    Established "Vineyard sprayer's lung" carries a poor long-term
    prognosis although there may be partial resolution of radiological
    abnormalities following removal from exposure (Pimentel and Marques,
    1969). More typically progressive respiratory failure ensues (Pimentel
    and Menezes, 1975), often associated with cor pulmonale (see below)
    (Stark, 1981). Pimentel and Menezes (1975) reported fatal spontaneous
    bilateral pneumothoraces in a 57 year-old man who developed "Vineyard
    sprayer's lung" after using Bordeaux mixture for three years. Autopsy
    revealed pulmonary fibrosis with numerous copper-containing blue
    nodules and lower lobe emphysema (Pimentel and Menezes, 1975).

    Stark (1981) suggested that the duration of copper sulphate exposure
    before the clinical disease is produced is usually at least five
    years, though most workers are occupationally exposed for far longer.
    Diagnosis is complicated by the fact that the disease may remain
    subclinical for several years following removal from exposure (Villar,
    1974). Progression may be accelerated by the presence of pulmonary
    infection. Moreover, presenting features are not dissimilar to those
    of tuberculosis which itself may predispose to "Vineyard sprayer's
    lung".

    It is proposed that the incidence of bronchial carcinoma is increased
    among those with "Vineyard sprayer's lung" (Villar, 1974; Stark, 1981)
    (see Carcinogenicity).

    Hepatotoxicity

    Biopsy and autopsy findings from patients with "Vineyard sprayer's
    lung" in association with pulmonary lesions include hepatomegaly,
    copper-containing granulomas (histiocytic or sarcoid-type), Kupffer
    cell proliferation with copper inclusions, peri/intralobular fibrosis
    and idiopathic portal hypertension (Pimentel and Menezes, 1975;
    Pimentel and Menezes, 1977). Micronodular cirrhosis (sometimes
    complicated by oesophageal varices and splenomegaly) and "fatty
    change" have also been observed but may be at least partly
    alcohol-induced (Pimentel and Menezes, 1975; Pimentel and Menezes,
    1977). Copper sulphate is proposed as the aetiological agent for the
    lesions observed following deposition in the reticuloendothelial cells
    of the liver (Pimentel and Menezes, 1977). Copper accumulation in
    hepatocytes and abnormal liver function tests do not typically
    accompany these histological findings (Pimentel and Menezes, 1975).

    Haemotoxicity

    Increased erythrocyte sedimentation rates, IgA and IgG concentrations
    have been reported in association with the pulmonary features of
    "Vineyard sprayer's lung" (Villar, 1974). Hypergammaglobulinaemia is
    consistent with the likely immunological basis for this condition.

    Cardiovascular toxicity

    Cor pulmonale may ensue as a complication of "Vineyard sprayer's lung"
    with typical features of tachycardia, a raised jugular venous
    pressure, cardiomegaly, a right ventricular heave and summation
    gallop, and evidence of right heart strain on the electrocardiogram
    (Stark, 1981).

    Neurotoxicity

    Severe pulmonary manifestations of "Vineyard sprayer's lung" with
    fever may be accompanied by confusion (Pimentel and Menezes, 1975).

    Musculoskeletal toxicity

    Joint and muscle pain with weakness has been described in association
    with the characteristic pulmonary features of "Vineyard sprayer's
    lung" (Pimentel and Marques, 1969; Villar, 1974; Pimentel and Menezes,
    1975).

    Metabolic disturbances

    Hypoalbuminaemia is frequently noted in patients chronically
    debilitated with "Vineyard sprayer's lung" (Villar, 1974; Pimentel and
    Menezes, 1975).

    Nephrotoxicity

    Copper-containing renal granulomas have been reported at autopsy in a
    patient with "Vineyard sprayer's lung" (Villar, 1974).

    Injection

    Nephrotoxicity

    Ishikawa and Minami (1985) reported a pseudo-Bartter syndrome (with
    hypereninaemia, polyuria and hypokalaemia) following 12 months
    intravenous copper sulphate therapy (providing 130 g/kg copper
    weekly) to a child with Kinky-hair disease (an inherited copper
    deficiency). The authors suggested renal copper accumulation as the
    most likely cause of renal tubular damage.

    MANAGEMENT

    Dermal exposure

    Following acute exposure irrigate the affected area with lukewarm
    water. Particular care is required if copper sulphate has been in
    contact with broken skin since corrosive damage and systemic copper
    uptake are then possible.

    Copper sulphate contact sensitivity or irritant dermatitis are managed
    most effectively by discontinuing exposure.

    Ocular exposure

    Irrigate immediately with lukewarm water or preferably saline for at
    least 10-15 minutes. A local anaesthetic may be indicated for pain
    relief and to overcome blepharospasm. Ensure removal of any particles
    lodged in the conjunctival recesses. The instillation of fluorescein
    allows detection of corneal damage. Specialist ophthalmological advice
    should be sought if any significant abnormality is detected on
    examination and in those whose symptoms do not resolve rapidly.

    Ingestion

    Copper sulphate is a powerful oxidizing agent and causes corrosive
    damage to mucous membranes. Concentrated solutions are acidic; a 0.2 M
    aqueous solution has a pH of 4.

    Effective management primarily involves symptomatic and supportive
    care. The role of chelating agents is discussed below.

    Decontamination and dilution

    Vomiting is likely to occur spontaneously following significant copper
    sulphate ingestion. Gastric lavage is contraindicated since copper
    sulphate is corrosive. There may be some benefit in attempting oral
    dilution with milk or water, if performed immediately, though this is

    controversial. The administration of egg white as a demulcent or
    potassium ferrocyanide ("600 mg in a glass of water") to precipitate
    copper, have been advocated (IPCS, 1997), but there is no clinical
    evidence to support these measures.

    Fluids should not be offered if the patient has a depressed level of
    consciousness, is unable to swallow or protect his/her own airway, has
    respiratory difficulty or severe abdominal pain. Possible
    complications of fluid administration include vomiting, aspiration,
    perforation of the gastrointestinal tract and worsening of oesophageal
    or gastric injuries.

    Supportive and symptomatic measures

    If corrosive oesophageal or gastric damage is suspected panendoscopy
    should be carried out, ideally within 12-24 hours, to gauge the
    severity of injury. A severity score based on acid ingestions may be
    useful:

    Grade 0:  Normal examination
          1:  Oedema, hyperaemia of mucosa
          2a: Superficial, localized ulcerations, friability, blisters
          2b: Grade 2a findings and circumferential ulceration
          3:  Multiple, deep ulceration, areas of necrosis (Zargar et al,
              1989)

    Zargar et al (1989) described the important prognostic value of this
    grading system in the management of acid ingestions. Following copper
    sulphate ingestion the presence and severity of gastrointestinal
    injury is important in predicting outcome but must be considered in
    the light of other complications, particularly haematological, hepatic
    and renal damage.

    An early surgical opinion should be sought if there is any suspicion
    of pending gastrointestinal perforation or where endoscopy reveals
    evidence of grade 3 burns.

    Airway support and analgesia should be provided as required. Treat
    hypovolaemic shock with intravenous colloid/crystalloid and/or blood.
    Monitor biochemical and haematological profiles and acid/base status.
    Intravascular haemolysis and renal failure should be managed
    conventionally.

    Symptomatic methaemoglobinaemia requires correction with intravenous
    methylene blue 2 mg/kg body weight (as a one per cent solution over
    five minutes). The efficacy of this antidote may be impaired if there
    is copper-induced inhibition of glucose-6-phosphate dehydrogenase
    activity (Chugh et al, 1975).

    There is no evidence to suggest any role for corticosteroid therapy in
    the management of copper sulphate ingestion. Antibiotics should be
    reserved for established infection only.

    Inhalation

    Acute pulmonary irritation following copper sulphate inhalation
    requires only appropriate symptomatic and supportive measures plus
    investigation of any abnormal findings. If chronic granulomatous
    pulmonary disease ("Vineyard sprayer's lung") is suspected,
    appropriate investigations include chest X-ray, lung function tests,
    biochemical, haematological and immunological profiles. There is no
    established role for steroid therapy.

    Antidotes

    Animal Studies

    d-Penicillamine, triethylenetetramine dihydrochloride (trien) and DMPS
    each administered in a dose of 50 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, LD50 8.7 mg/kg) administered intraperitoneal
    antidotes 20 minutes post dosing at a 10:1 molar ratio antidote:
    copper sulphate. Mice were observed for two weeks or until death. The
    survival ratio following DMPS was 25/30, compared to 7/30, 5/15, 4/15,
    3/15, 3/15 for d-penicillamine, triethylene- tetramine, sodium
    calciumedetate, DMSA and dimercaprol respectively (p <0.0001 for DMPS
    compared to all chelating agents except triethylenetetramine,
    p <0.0005) (Jones et al, 1980).

    Henderson et al (1985) investigated the effect of single and repeated
    doses of chelating agents on copper toxicity. Copper intoxicated mice
    (10-130 mg/kg subcutaneously) were given single doses of dimercaprol
    10 mg/kg or N-acetylcysteine 200 mg/kg, 30 minutes post dosing. With a
    single dose of chelating agent, the calculated LD50 ( SE) was
    significantly (p< 0.05) increased from 54.7  10 mg/kg in control
    mice to 95.2  22 mg/kg and 87  14 mg/kg in mice treated with
    dimercaprol or NAC respectively. The chelating agents were even more
    effective (p< 0.05) in copper-poisoned mice (40-170 mg/kg
    subcutaneously) treated with repeated doses of chelating agent:
    dimercaprol 10 mg/kg, N-acetylcysteine 200 mg/kg or d-penicillamine 50

    mg/kg every hour for five hours, with calculated LD50 values of 60.5
     12 mg/kg, 150.3  35 mg/kg, 139.4  8 mg/kg and 91.4  16 mg/kg for
    controls, dimercaprol, NAC and d-penicillamine treated mice
    respectively.

    d-Penicillamine, 52 mg/kg daily for six days, significantly (p <0.05)
    enhanced urinary copper excretion in four copper-poisoned sheep (given
    20 mg/kg copper sulphate intraruminally daily for 35 days) (Botha et
    al, 1993). Under the same conditions triethylenetetramine failed to
    increase urinary copper excretion although the authors suggested this
    might have been related to specific features of ruminant metabolism.
    There is some evidence that polyamines structurally related to
    triethylenetramine (e.g. 2,3,2-tetramine) have a more potent
    cupruretic action (Borthwick et al, 1980) but experience with these
    agents is limited (Twedt et al, 1988).

    Diethyldithiocarbamate (DDC) chelates copper but the lipophilic
    chelate accumulates in tissues, especially the brain (Iwata et al,
    1970; Jasim et al, 1985), suggesting it may be an unsuitable antidote
    in copper poisoning. It has been suggested that DDC modifies the
    permeability of cell membranes and the blood brain barrier to copper
    (Allain and Krari, 1993).

    Clinical studies

    Wilson's disease

    Wilson's disease, characterized by decreased biliary copper excretion
    traditionally has been treated with d-penicillamine which serves to
    increase urinary copper elimination (Scheinberg et al, 1987). Adverse
    reactions to d-penicillamine are not uncommon and frequently are
    immunologically rather than toxicologically-induced including
    nephrotic syndrome, systemic lupus erythematosus (Walshe, 1982), white
    cell dyscrasias, thrombocytopenia, haemolytic anaemia (Walshe, 1982)
    and urticaria (Walshe, 1968). Anorexia, nausea and vomiting are
    described (Walshe, 1968). In animal studies penicillamine induces
    hepatic metallothionein (Heilmaier et al, 1986) which may disrupt the
    body distribution of other trace elements. Adverse effects occur in up
    to 10 per cent of patients receiving penicillamine and may necessitate
    treatment withdrawal (Walshe, 1982). Thus, in recent years,
    alternative agents have been investigated.

    Sunderman et al (1963) advocated parenteral and/or oral DDC in the
    management of Wilson's disease but evidence that this antidote
    enhances cerebral copper uptake limits its usefulness (see above).

    Walshe (1982) demonstrated increased urine copper elimination,
    symptomatic improvement and resolution of basal-ganglia abnormalities
    on CT brain scan among 20 patients with Wilson's disease treated with
    triethylenetetramine. These authors suggested triethylenetetramine as
    an effective drug for the treatment and maintenance of patients with
    Wilson's disease at all stages of the illness. Others concur with this
    view (Dubois et al, 1990; Morita et al, 1992) although there are

    potential hazards of triethylenetetramine therapy, notably
    sideroblastic anaemia (Perry et al, 1996).

    Although zinc sulphate has been utilized as alternative therapy to
    penicillamine in patients with Wilson's disease (Hoogenraad and Van
    den Hamer, 1983; Van Caillie-Bertrand et al, 1985; Veen et al, 1991),
    this treatment is unsuitable for acute copper poisoning as the
    mechanism of benefit is reduced gastrointestinal copper absorption.

    DMPS 200 mg bd increased urine copper elimination in a patient with
    Wilson's disease (Walshe, 1985).

    Acute poisoning

    There are no controlled data regarding the use of any chelating agent
    in acute copper sulphate poisoning. In severely poisoned patients the
    presence of acute renal failure often limits the potential for
    antidotes which enhance urinary copper elimination.

    d-Penicillamine, the standard therapy for Wilson's disease, has been
    utilized in copper poisoning (Holtzman et al, 1966; Jantsch et al,
    1984/85; Hantson et al, 1996) but without confirmed evidence of
    enhanced urinary copper excretion. Intramuscular dimercaprol
    (Fairbanks, 1967; Jantsch et al, 1984/85; Schwartz and Schmidt, 1986;
    Hantson et al, 1996) and intravenous sodium calciumedetate (Holleran,
    1981; Agarwal et al, 1975) have also been employed but again without
    confirmed benefit.

    A five year-old child with copper intoxication following repeated
    application of copper sulphate crystals to skin burns received a 12
    day course of d-penicillamine 250 mg qds (Holtzman et al, 1966). Six
    hour urine copper excretion on the first day of chelation was 1000 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 sulphate poisoning.

    2.   Animal data suggest DMPS may be the most effective antidote in
         copper poisoning, though DMPS was administered within 20 minutes
         of copper dosing in these studies. DMPS has a more favourable
         adverse effect profile than dimercaprol and d-penicillamine
         although these are alternatives if DMPS is not available. DMPS
         usually is given orally or parenterally in a dose of 30 mg/kg
         body weight per day. Side effects are infrequent but have
         included allergic skin reactions, nausea and vertigo (Aposhian,
         1983). Discussion of individual cases with an NPIS physician is
         recommended.

    3.   There is insufficient evidence to advocate alkaline diuresis in
         the management of acute copper poisoning.

    4.   The role of haemodialysis and peritoneal dialysis is limited to
         the management of renal failure.

    Management of copper and caeruloplasmin concentrations in
    biological fluids

    Although whole blood copper concentrations correlate well with the
    severity of poisoning following acute ingestion, they should always be
    interpreted in conjunction with the clinical features.  Serum copper
    concentrations are less useful in acute intoxications (Chuttani et al,
    1965). In 20 patients who ingested copper sulphate, mean ( SD) whole
    blood copper concentrations were markedly lower (2.9  1.3 mg/L) in
    those with only gastrointestinal symptoms compared to those who
    developed jaundice, renal failure or shock (mean whole blood copper
    8.0  4.0 mg/L). The number of patients in each group was not stated.

    Among 65 cases of acute copper sulphate poisoning, Wahal et al (1976b)
    observed that although patients who developed complications had higher
    whole blood, red cell and plasma copper concentrations than
    uncomplicated cases, the difference was not statistically significant
    (p>0.05). No correlation was found between plasma copper
    concentrations and prognosis. However, whole blood copper
    concentrations greater than 1.2 mg/L were associated generally with
    the development of complications. The four fatalities reported, who
    were admitted within 6-8 hours of ingestion, had whole blood
    concentrations of at least 2.1 mg/L.

    Serum caeruloplasmin concentration estimation has been suggested as a
    useful prognostic indicator in cases of acute copper sulphate
    poisoning. Wahal et al (1978) observed significantly higher (p<0.001)
    serum caeruloplasmin concentrations in uncomplicated cases of copper
    sulphate poisoning than in those with complications (gastrointestinal
    haemorrhage, jaundice, renal impairment, delirium or coma). Values
    less than 35 mg/dL within 24 hours of poisoning or less than 44 mg/dL

    beyond 72 hours post ingestion were associated with the development of
    complications.

    Increased urine copper excretion (preferably as a 24 hour collection)
    will be present in any moderate or severe case of copper sulphate
    poisoning. The main value of this measurement is to monitor the effect
    of chelation therapy.

    MEDICAL SURVEILLANCE

    Appropriate occupational hygiene and safety measures should be ensured
    for those potentially chronically exposed to copper sulphate sprays
    with monitoring for pulmonary complications if necessary.

    Twenty-four hour urine copper excretion is a useful screening
    procedure if copper intoxication is suspected but the source of
    exposure is unclear. However, when collected in an occupational
    setting great care must be taken to avoid sample contamination. Serum
    or whole blood copper concentrations may be useful if exogenous copper
    contamination of urine samples is suspected (Cohen, 1979). It should
    be remembered that impaired biliary copper excretion from any cause
    will lead to increased renal copper elimination.

    Pre-employment screening for Wilson's disease may be indicated in
    those occupationally exposed to copper.

    Normal copper concentrations in biological fluids

    Plasma/serum: 0.7-1.3 mg/L (Weatherall et al, 1996).
    Whole blood: 1.6-2.7 mg/L (Chuttani et al, 1965).
    Urine: Less than 60 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 is no conclusive evidence that copper is carcinogenic in humans
    (Aaseth and Norseth, 1986). However, it is proposed that patients with
    "Vineyard sprayer's lung" are at a greater risk than the general
    population of developing bronchial carcinoma (Villar, 1974; Stark,
    1981). When originally reported in Europe, lung cancers in vineyard
    workers were attributed to the arsenic content of some fungicides, but
    in Portugal arsenic fungicides have never been used in vineyards
    (Villar, 1974).

    Among 14 smoking vineyard workers Plamenac et al (1985) noted atypical
    squamous metaplasia in four cases and suggested copper as an
    aetiologic agent.

    In a review of liver disease among 30 vineyard sprayers who had used
    Bordeaux mixture for three to 45 years (mean 18 years), Pimentel and
    Menezes (1977) observed one case of hepatic angiosarcoma. The authors
    suggested copper-induced sinusoidal cell proliferation as a possible
    trigger of tumour development.

    Musicco et al (1988) reported a significant (p = 0.006) increase in
    the incidence of brain gliomas among farmers occupationally exposed to
    insecticides or fungicides (often commercial copper sulphate
    preparations). The authors concluded the gliomas were probably
    associated with exposure to alkyl ureas (known neurogenic carcinogens)
    in the pesticides.

    Reprotoxicity

    Copper sulphate is teratogenic in several animal species (Bologa et
    al, 1992).

    In a controlled study Barash et al (1990) investigated the teratogenic
    potential of copper releasing intrauterine devices (IUD) on the
    developing human embryo. No malformations or copper deposits were
    observed in the organs/placentae of copper IUD-exposed embryos (n=11)
    examined between seven and 12 weeks gestation. The results from the
    small study suggest that copper releasing IUDs have no observed
    negative effects on the developing embryo.

    Genotoxicity

     Escherichia coli PQ37, PQ35 SOS chromotest - negative.
     In vivo mouse bone marrow micronuclei test - negative (DOSE, 1993).

    Fish toxicity

    Indian catfish exposed to 0.25 mg/L for up to 30 days became lethargic
    and frequently surfaced to gulp air. Numerous immature and fragmented
    blood corpuscles were evident.

    Threespine stickleback exposed to 10 mg/L died within 16-24 hr.

    LC50 (96 hr) rainbow trout, harlequin fish, goldfish, eel 0.1-2.5
    mg/L.

    Exposed carp (concentration and duration unspecified) had increased
    serum cholinesterase and transaminase activities and adrenaline and
    noradrenaline concentrations.

    A static bioassay was conducted on Indian carp using low dose (0.05
    ppm) copper sulphate. Erythrocyte count and haematocrit decreased 34.1
    per cent and 14.6 per cent respectively. Morphological study of
    erythrocytes showed slight anisocytosis, cell membrane degeneration
    and cell clumping. Thus copper sulphate caused a direct or indirect
    effect on the cell membrane leading to haemolysis.

    The order of the concentrations of copper sulfate taken up by carp
    organs was skeletal muscle>liver>gills>intestine>kidney>heart> brain.
    With the exception of the brain, greater copper accumulation was
    measurable in every organ at 20C compared to 4C. Considerable
    acetylcholinesterase inhibition measurable only in the first 24 hours,
    was exhibited in carp exposed to 5 ppm for two weeks (DOSE, 1993).

    EC Directive on Drinking Water Quality 80/778/EEC.

    Copper: Guide level 100 g/L at pumping/substation outlets; 3 mg/L
    after water has been standing 12 hours in the piping (DOSE, 1993).

    WHO Guidelines for Drinking Water Quality

    Guideline value 2 mg/L (provisional value), as copper (WHO, 1993).

    AUTHORS

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

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

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

    Date of last revision
    28/1/98

    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.

    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.

    CHIP2/Chemicals (Hazard Information and Packaging for Supply)
    Regulations 1994.
    Health and Safety Commission.
    Sudbury: Health and Safety Executive, 1994.

    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.

    Chugh KS, Sakhuja V, Malhotra HS, Pereira BJG.
    Changing trends in acute renal failure in Third-world countries -
    Chandigarh study.
    Q J Med 1989; 73: 1117-23.

    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 2.
    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.

    Eldad A, Simon GA.
    The phosphorous burn - a preliminary comparative experimental study of
    various forms of treatment.
    Burns 1991; 17: 198-200.

    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.

    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: World Health Organization, 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, Tjlve 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.

    Mellencamp F.
    Copper sulfate as an emetic.
    Appl Therapeutics 1966; 18: 233-4.

    MERCK/The Merck Index.
    Cupric sulphate. In Budavari S, ed. An encyclopedia of chemicals,
    drugs, and biologicals. 12th ed.
    New Jersey: Merck and Co., Inc., 1989; 447.

    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.

    NFPA/National Fire Protection Association.
    Fire protection guide on hazardous materials. 9th Ed.
    Boston: National Fire Protection Association, 1986.

    Nicholas PO.
    Food-poisoning due to copper in the morning tea.
    Lancet 1968; 1: 40-42.

    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.

    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 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.

    Sharma NL, Singh RN, Natu NK.
    Accidental poisoning in infancy and childhood.
    J Indian Med Assoc 1967; 48: 20-5.

    Singh MM, Singh GS.
    Biochemical changes in blood in cases of acute copper sulphate
    poisoning.
    J Indian Med Assoc 1968; 50: 549-54.

    Singh S, Sharma BK , Wahi PL, Anand BS, Chugh KS.
    Spectrum of acute poisoning in adults (10 year experience).
    J Assoc Physicians India 1984; 32: 561-3.

    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.

    Thirumalaikolundusubramanian P, Chandramohan M, Johnson ES.
    Copper sulphhate poisoning.
    J Indian Med Assoc 1984; 82: 6-8.

    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.
    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.

    Zong-yue S, Yao-ping L, Xue-qi G.
    Treatment of yellow phosphorus skin burns with silver nitrate instead
    of copper sulfate.
    Scand J Work Environ Health 1985; 11: 33.