UKPID MONOGRAPH COPPER CARBONATE ST Beer BSc SM Bradberry BSc MB MRCP WN Harrison PhD CChem MRSC 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 CARBONATE/COPPER CARBONATE HYDROXIDE Toxbase summary Type of product Copper carbonate is produced commercially for veterinary use. Copper carbonate hydroxide is formed by the action of air and water on elemental copper. Variable amounts of copper carbonate hydroxide and copper sulphate are used in the fungicide "Burgundy mixture". Toxicity Direct copper carbonate poisoning is rare. Chronic inhalation of copper containing pesticides produces pulmonary and hepatic toxicity. Copper contact sensitivity is recognized. Features Dermal - May irritate skin. Contact dermatitis is recognized. Ocular - Copper carbonate is an eye irritant. Ingestion - There are no reports of copper carbonate poisoning following ingestion. - Very small ingestions (milligrams) are likely to cause only nausea and vomiting. Moderate/substantial ingestions: - Nausea, vomiting and a metallic taste followed by abdominal pain and diarrhoea may be expected. Secretions may be blue/green. Inhalation - Chronic occupational inhalation of copper-sulphate containing fungicides has caused 'Vineyard sprayer's lung' with progressive dyspnoea, cough and wheeze, micronodular and reticular opacities on chest X-ray (which may coalesce) and a restrictive lung function defect. Other features include hepatic copper-containing granulomas, hypergammaglobulinaemia, myalgia and profound malaise. Similar features might be expected among those working with "Burgundy mixture". Management Dermal 1. Irrigate with copious lukewarm water. 2. Copper irritant dermatitis and contact sensitivity are managed most effectively by discontinuing exposure. Ocular 1. Irrigate immediately with lukewarm water or preferably saline for at least 10 minutes. 2. Application of local anaesthetic may be required for pain relief and to overcome blepharospasm to allow thorough decontamination. 3. Ensure no particles remain lodged in the conjunctival recesses. 4. Corneal damage may be detected by the instillation of fluorescein. 5. If symptoms do not resolve rapidly or if there are abnormal examination findings, refer for an ophthalmological opinion. Ingestion 1. Symptomatic and supportive measures are usually all that are required. 2. Although based on cases of acute copper sulphate ingestions, whole blood copper concentrations correlate well with the severity of poisoning they should always be interpreted in conjunction with the clinical features. Chuttani et al (1965) suggested severe complications (liver or renal damage or hypovolaemic shock) were unlikely in those with whole blood copper concentrations less than 4 mg/L but this is not universally true (Wahal et al, 1976; Hantson et al, 1996). 3. Chelation therapy is unlikely to be appropriate and its value is unproven. Discussion with an NPIS physician is recommended. 4. Check full blood count and liver profile if chronic exposure is suspected. Inhalation - Acute copper salt inhalation will produce pulmonary irritation. There are no case reports specific to this compound. Chronic copper sulphate inhalation causes a granulomatous hypersensitivity response. Arrange for chest X-ray and lung function tests. Seek specialist advise from a NPIS physician. References Bentur T, Koren G, McGuigan M, Spielberg SP. An unusual skin exposure to copper; clinical and pharmacokinetic evaluation. Clin Toxicol 1988; 26: 371-80. Gleason RP. Exposure to copper dust. Am Ind Hyg Assoc J 1968; 29: 461-2. Knobeloch L, Ziarnik M, Howard J, Theis B, Farmer D, Anderson H, Proctor M. Gastrointestinal upsets associated with ingestion of copper- contaminated water. Environ Health Perspect 1994; 102: 958-61. Mülendahl KE, Lange H. Copper and childhood cirrhosis. Lancet 1994; 344: 1515-6. Spitalny KC, Brondum J, Vogt RL, Sargent HE, Kappel S. Drinking-water-induced copper intoxication in a Vermont family. Pediatrics 1984; 74: 1103-6. Terry RF. Excess copper in a local water supply. Med J Aust 1996; 165: 296. WHO/World Health Organization. Guidelines for drinking-water quality. 2nd ed. Vol 1. Recommendations. Geneva: World Health Organization, 1993. Wyllie J. Copper poisoning at a cocktail party. Am J Public Health 1957; 47: 617. Substance name Copper (II) carbonate Origin of substance Copper carbonate is manufactured commercially. (HSDB, 1997) Synonyms Carbonic acid, copper (II) salt Copper monocarbonate Cupric carbonate Xanthic acid, copper (II) salt (RTECS, 1997) Chemical group A compound of copper, a group 1B transition metal (d block) element. Reference numbers CAS 1184-64-1 RTECS FF9500000 (RTECS, 1997) UN NIF HAZCHEM CODE NIF Physicochemical properties Chemical structure CuCO3 (HSDB, 1997) Molecular weight 123.55 (RTECS, 1997) Physical state at room temperature NIF Colour NIF Odour Odourless (HSDB, 1997) Viscosity NIF pH NIF Solubility NIF Autoignition temperature NIF Chemical interactions Copper salts and nitromethane may spontaneously form explosive materials. Dangerous acetylides may be formed from copper salts. Salts of copper promote the decomposition of hydrazine. Solutions of sodium hypobromite are decomposed by the powerful catalytic action of cupric ions. (HSDB, 1997) Major products of combustion NIF Explosive limits NIF Flammability NIF Boiling point NIF Density NIF Vapour pressure NIF Relative vapour density NIF Flash point NIF Reactivity NIF Uses In poultry and animal feeds as an absorbable source of copper. Anthelmintic aid in sheep. (HSDB, 1997) Hazard/risk classification NIF Substance name Copper (II) carbonate hydroxide Origin of substance Occurs in nature as the mineral malachite. Prepared by adding CuSO4 solution to Na2CO3solution. Another form of basic copper carbonate, 2CuCO3.Cu(OH)2, occurs in nature as the mineral azurite or chessylite. In hard water copper carbonate hydroxide is the final precipitation product of dissolved copper. (MERCK, 1996; DOSE, 1993) Synonyms Basic copper carbonate Cupric subcarbonate Bremen blue Bremen green (MERCK, 1996) Chemical group A compound of copper, a group 1B transition metal (d block) element. Reference numbers CAS 12069-69-1 RTECS GL6910000 (RTECS, 1997) UN NIF HAZCHEM CODE NIF Physicochemical properties Chemical structure CuCO3.Cu(OH)2 (MERCK, 1996) Molecular weight 221.11 (SAX'S, 1996) Physical state at room temperature Solid (MERCK, 1996) Colour Green to blue powder or dark green crystals (MERCK, 1996) Odour NIF Viscosity NA pH NIF Solubility Soluble in dilute acids and ammonia. Practically insoluble in alcohol and water. (MERCK, 1996) Autoignition temperature NIF Chemical interactions NIF Major products of combustion Acrid smoke and fumes. (SAX'S, 1996) Explosive limits NIF Flammability NIF Boiling point Decomposes at 200°C (SAX'S, 1996) Density 4.0 at 20°C (SAX'S, 1996) Vapour pressure NIF Relative vapour density NIF Flash point NIF Reactivity NIF Uses In the manufacture of other copper salts. As a fungicide. In pyrotechnics. In sweetening of petrol sour crude stock. As paint and varnish pigment. In animal and poultry feeds. As a treatment for copper deficiency in ruminants. (MERCK, 1996) Hazard/risk classification NIF INTRODUCTION AND EPIDEMIOLOGY Copper forms two divalent carbonates, copper carbonate (CuCO3) and copper carbonate hydroxide (CuCO3.Cu (OH)2). Copper carbonate is a commercially manufactured copper salt. There are no reports of intoxication from exposure to copper carbonate. Copper carbonate hydroxide, commonly known as verdigris, is formed naturally by the action of moist air on elemental copper (MERCK, 1996). It is also a constituent of fungicides, such as Burgundy mixture, formed by the reaction of aqueous copper sulphate and sodium carbonate. In hard water areas copper carbonate hydroxide is the final precipitation product of dissolved copper ions. MECHANISM OF TOXICITY 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 Cu(I) (from Cu(II) reduction) binds to intracellular sulphydryl groups and inactivates enzymes such as glucose-6-phosphate dehydrogenase and glutathione reductase (Dash, 1989). In addition copper may interact with oxygen species (e.g. superoxide anions and hydrogen peroxide) and catalyze the production of reactive toxic hydroxyl radicals. Copper(II) ions can oxidize haem iron to form methaemoglobin. TOXICOKINETICS Absorption and distribution There are no toxicokinetic data specific to copper carbonate. Although copper carbonate hydroxide is practically insoluble in water its solubility in dilute acid may facilitate gastrointestinal absorption. 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 within some two hours after oral copper chloride administration (1.5-12 mg copper) (Earl et al, 1954). Copper transport across the intestinal mucosa following ingestion is facilitated by cytosolic metallothionein. In blood, copper is initially albumin-bound and transported via the hepatic portal circulation to the liver where it is incorporated into caeruloplasmin (an alpha globulin synthesized in hepatic microsomes) (Britton, 1996). Some authors have noted a secondary rise in the serum copper concentration following acute copper sulphate ingestion (Singh and Singh, 1968) and this may be due to release of the copper-caeruloplasmin complex from the liver. Ninety-eight per cent of copper in the systemic circulation is caeruloplasmin-bound. Copper is distributed to all tissues with the highest concentrations in liver, heart, brain, kidneys and muscle. Intracellular copper is predominantly metallothionein-bound. Kurisaki et al (1988) reported copper in the lungs, liver, kidney, blood, bile and stomach (33.7, 35.1, 41.4, 13.8, 2.8, and 2988 µg/g wet weight respectively) following ingestion of some 10 g copper sulphate in a 58 year-old male. Although copper in the liver and kidneys was metallothionein bound, pulmonary copper was not, possibly because copper had entered the lung via aspiration. 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 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 is likely to increase in acute copper poisoning. For example, a child who ingested three grams copper sulphate had increased urine copper concentrations (maximum 2.8 - 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 reports of acute dermal copper carbonate exposure. Copper contact and irritant dermatitis are recognized (see Copper monograph). Ocular exposure Verdigris dropped or dusted on the eye caused immediate irritation and conjunctival inflammation. The reaction subsided following irrigation of the eye with no permanent damage (Grant and Schuman, 1993). Ingestion There are no reports of acute copper carbonate ingestion. Abdominal pain, diarrhoea, nausea and vomiting, headaches and dizziness have been reported following ingestion of copper contaminated water (Spitalny et al, 1984; Knobeloch et al, 1994). This is discussed in detail in the Copper monograph. Inhalation Occupational exposure to copper fumes may cause upper respiratory tract irritation and sometimes symptoms of metal fume fever. These complaints are, however, typically encountered in those working in the copper industry for prolonged periods (see Copper monograph). CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure A number of cases of green staining of the hair have been reported following exposure to water containing high copper concentrations, presumably due to the precipitation of copper carbonate hydroxide on exposure to air. Parish (1975) noted that cases of green hair among copper workers have been reported since 1882. In these cases it was generally accepted that the copper staining was "from without and not within the hair" (Parish, 1975). Cooper and Goodman (1975) reported a "minor epidemic" of green hair in girls from a state college following the introduction of fluoride to the town water supply. Low pH water leaching copper from piping was a possible cause of the colouration. The authors noted that individuals with blonde hair were affected mainly, although green discolouration would not be as apparent in dark haired individuals. However, Goldsmith and Holmes (1975) noted that, independent of any copper effect, artificial hair bleaching may lead to green discolouration on exposure to chlorinated water. A hair copper concentration of 466 mg/kg (normal 4-128 mg/kg) was measured in a six year-old boy who developed green hair following repeated bathing in a swimming pool (Lampe et al, 1977). In another case of "green hair" in a five year-old girl (Lampe et al, 1977), water analysis revealed a copper concentration of 0.9 mg/L. Hair returned to normal following daily alternate washing with acidic and basic shampoos. The source of small amounts of copper in the swimming pool water was likely to be algicide residue or copper leached from pipes. Nordlund et al (1977) described two nursing students who acquired green discolouration to blonde hair following a four to six week stay in a university dormitory where they washed their hair daily. Analysis of one student's hair revealed a copper concentration of 1042 ppm (normal 17-38 ppm) and the copper concentration from the dormitory water source was noted to range from 0.41 to 4 ppm (normal 0.25 ppm). A faulty electrical connection to the copper water pipes was thought to have resulted in increased amounts of dissolved copper in the water supply. Copper contact sensitivity has been described and is discussed in the Copper monograph. Ingestion Gastrointestinal toxicity A 15 month-old infant who presented with failure to thrive and diarrhoea was found to have a serum copper concentration increased to 2.9 mg/L which was attributed to the consumption of contaminated domestic water (copper concentration 0.8 mg/L) for three months. Resolution of symptoms and substantial weight gain accompanied removal from exposure. The child also received a five week course of oral d-penicillamine 75 mg tds which was associated initially with an increased urine copper concentration (Salmon and Wright, 1971). The water copper concentration reported in this case is well below the provisional guideline value for drinking water of 2 mg/L (WHO, 1993) which is defined as "the concentration of a constituent that does not result in any significant risk to health ........ over a lifetime of consumption" (IPCS, 1996). This child must have had "abnormal sensitivity to the metal" as the authors emphasized for copper intoxication to occur. Wilson's disease was excluded by serum caeruloplasmin assay and liver biopsy but another defect of copper metabolism is possible. Hepatotoxicity Indian childhood cirrhosis (ICC) is a frequently fatal disease affecting children (mean age 18 months) in rural areas of India and is caused by massive hepatic copper accumulation (Pandit and Bhave, 1983; Pandit and Bhave, 1996). A high dietary copper intake, due to copper leaching into milk from brass cooking vessels, is the most important aetiological factor (Pandit and Bhave, 1983; Pandit and Bhave, 1996). The milk protein casein has been shown to avidly bind copper and serve as an effective metal ion carrier from brass to the infant (O'Neill and Tanner, 1989). Fortunately the previously high incidence of ICC, accounting for 10 per cent paediatric mortality in some Indian hospitals (Pandit and Bhave, 1983), has been reduced dramatically by an effective health education campaign aimed at maximizing breast feeding and avoiding the use of copper-containing cooking utensils (Pandit and Bhave, 1996). ICC is now rare. Although a high dietary copper intake is undoubtedly the main cause of ICC, the observed male preponderance and familial occurrence suggests an inherited predisposition (Pandit and Bhave, 1996). Further support for a genetic component in at least some cases of paediatric copper-induced cirrhosis comes from reports of an ICC-like condition among children in Western countries who have had a high, but not massive, dietary copper intake (Mühlendahl and Lange, 1994). A large-scale epidemiological survey in Massachusetts in 1993 concluded that a moderately increased domestic water copper concentration alone does not cause liver disease (Scheinberg and Sternlieb, 1994). In this study none of the 135 deaths occurring between 1969 and 1991 in children under six years-old in three towns with the highest tapwater copper concentration (8.5-8.8 mg/L) of any "medium size" USA town, were attributed to any form of liver disease. In conclusion it appears that idiopathic childhood cirrhosis is a multifactorial disease which requires increased copper ingestion superimposed on an inherited defect of copper metabolism to be manifest fully. A 15 month-old infant fed with copper-contaminated water (copper concentration 0.8 mg/L) for three months developed transiently increased liver enzyme activities in association with features of gastrointestinal and neurological toxicity (Salmon and Wright, 1971). As discussed above this child must have been predisposed to copper toxicity since the water copper concentration was not particularly high. Walker-Smith and Blomfield (1973) described a 14 month-old infant who died six weeks after presenting with clinical and histopathological features of cirrhosis. The child had been bottle fed with copper-contaminated water from an acidic private supply running through domestic copper pipes (water copper concentration 6.75 mg/L). A slightly low plasma caeruloplasmin concentration and raised urinary copper excretion were consistent with Wilson's disease although the acute presentation at such a young age suggested concomitant abnormally high copper exposure was aetiologically significant. Neurotoxicity Hypotonia, photophobia and "behaviour change" were noted in a young child who presented with failure to thrive and was found to have an increased serum copper concentration (2.9 mg/L) attributed to chronic copper intoxication from a domestic water supply (Salmon and Wright, 1971). Inhalation "Burgundy mixture" is a fungicide containing variable amounts of copper carbonate hydroxide and copper sulphate. Although there are no reports of adverse effects from the use of this mixture, features similar to those from exposure to copper sulphate in "Bordeaux mixture" may be expected (see Copper sulphate monograph). Copper poisoning due to occupational inhalation of such fungicides presents as "Vineyard sprayers lung" which, although primarily a pulmonary disease, may involve systemic granuloma formation. 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 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 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). Occupational exposure to dusts and fumes of copper salts has been reported to cause nasal mucosal congestion and occasionally nasal septum perforation but no original data have been identified (Scheinberg, 1983). Although upper respiratory tract irritation and metal fume fever are cited as "common complaints" of copper workers (Cohen, 1979) original case data are scarce. Metal fume fever is more typically associated with zinc oxide inhalation (see Zinc monograph). Employees complained of head stuffiness, "common cold" symptoms and "sensations of chills or warmth" a few weeks after commencing copper plate polishing (Gleason, 1968). Analysis of settled dust revealed "major" amounts of copper and "minor" amounts of aluminium; air copper concentrations ranged from 0.030 - 0.120 mg/m3. Following dust control via exhaust ventilation copper concentrations were reduced to less than 0.008 mg/m3 air, and symptoms resolved. 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 cause of 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). A recent population based case control study among 144 Parkinsonian patients and 464 controls in Detroit identified a significant (p<0.05) association between Parkinson's disease and more than 20 years occupational exposure to copper (Gorell et al, 1977). Chronic manganese exposure was independently significantly associated with this disorder. The neurological hazards of chronic metal exposure require further clarification. 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 noted frequently 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). Oral toxicity Superficial green staining of the teeth was reported in a 21 year-old brass foundry worker after 10 months exposure to fumes containing approximately 75 per cent copper (Donoghue and Ferguson, 1996). The authors suggested the staining was attributed to copper adherence from the brass fume and its subsequent conversion to copper carbonate. MANAGEMENT Dermal exposure Following acute exposure irrigate the affected area with lukewarm water. Particular care is required if copper carbonate has been in prolonged contact, with broken skin since systemic copper uptake is then possible. Copper contact sensitivity or irritant dermatitis are managed most effectively by discontinuing exposure. Ocular exposure Irrigate immediately with lukewarm water or preferably saline for at least 10 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. Seek ophthalmological advice if there are any significant findings on examination and in those whose symptoms do not resolve rapidly. Ingestion Effective management of copper carbonate ingestion primarily involves symptomatic and supportive care. Gastrointestinal decontamination is most unlikely to favourably influence outcome and should only be considered within the first hour after a potentially life threatening ingestion. Liver function assessment is important, especially in children, if chronic excess copper ingestion is suspected. In these circumstances the serum copper concentration is likely to be increased. The role of chelating agents is discussed below. Inhalation The priority following copper salt inhalation is removal from exposure and administration of oxygen by face-mask if there is respiratory distress. A chest X-ray should be performed if there are abnormal examination findings; metal fume fever may be accompanied by transient ill-defined opacities which typically resolve uneventfully. The possibility of a granulomatous pulmonary and possibly systemic reaction should be considered following chronic exposure. Antidotes Animal studies The application of dimercaprol-containing ointments or the injection of aqueous dimercaprol into the eyes of animals with experimentally induced copper injury was of no benefit (Grant and Schuman, 1993). d-Penicillamine, triethylenetetramine dihydrochloride (trien) and DMPS each administered in a dose of 50 µmol/kg intraperitoneally daily for five days were the most effective chelating agents in increasing copper excretion in the urine (p<0.01) in copper-poisoned rats fed a high copper diet for 20 days prior to chelation (Planas-Bohne, 1979). Faecal copper excretion was unaffected. Other workers have demonstrated enhanced renal copper elimination following parenteral DMPS and DMSA (Maehashi et al, 1983). Rana and Kumar (1983) suggested oral sodium calciumedetate (1g/kg daily for ten days) could limit histopathological renal damage in rats fed oral copper sulphate 0.1 g/kg daily for 20 days prior to chelation therapy. Protection against copper-induced hepatic and renal lesions was observed also in mice administered intraperitoneal DMPS 132 mg/kg 20 minutes after intraperitoneal copper sulphate 10 mg/kg (approximately the LD50) (Mitchell et al, 1982). DMPS was the most effective antidote in protecting against copper-induced mortality in copper sulphate-intoxicated mice (10 mg/kg intraperitoneally, LD50 8.7 mg/kg) administered intraperitoneal antidotes 20 minutes post dosing at a 10:1 molar ratio antidote: copper sulphate. Mice were observed for two weeks or until death. The survival ratio following DMPS was 25/30, compared to 7/30, 5/15, 4/15, 3/15, 3/15 for d-penicillamine, triethylene- tetramine, sodium calciumedetate, DMSA and dimercaprol respectively (p <0.0001 for DMPS compared to all chelating agents except triethylenetetramine, p<0.0005) (Jones et al, 1980). Henderson et al (1985) investigated the effect of single and repeated doses of chelating agents on copper toxicity. Copper intoxicated mice (10-130 mg/kg subcutaneously) were given single doses of dimercaprol 10 mg/kg or N-acetylcysteine 200 mg/kg, 30 minutes post dosing. With a single dose of chelating agent, the calculated LD50 (± SE) was significantly (p<0.05) increased from 54.7 ± 10 mg/kg in control mice to 95.2 ± 22 mg/kg and 87 ± 14 mg/kg in mice treated with dimercaprol or NAC respectively. The chelating agents were even more effective (p<0.05) in copper-poisoned mice (40-170 mg/kg subcutaneously) treated with repeated doses of chelating agent: dimercaprol 10 mg/kg, N-acetylcysteine 200 mg/kg or d-penicillamine 50 mg/kg every hour for five hours, with calculated LD50 values of 60.5 ± 12 mg/kg, 150.3 ± 35 mg/kg, 139.4 ± 8 mg/kg and 91.4 ± 16 mg/kg for controls, dimercaprol, NAC and d-penicillamine treated mice respectively. d-Penicillamine, 52 mg/kg daily for six days, significantly (p<0.05) enhanced urinary copper excretion in four copper-poisoned sheep (given 20 mg/kg copper sulphate intraruminally daily for 35 days) (Botha et al, 1993). Under the same conditions triethylenetetramine failed to increase urinary copper excretion although the authors suggested this might have been related to specific features of ruminant metabolism. There is some evidence that polyamines structurally related to triethylenetetramine (e.g. 2,3,2-tetramine) have a more potent cupruretic action (Borthwick et al, 1980) but experience with these agents is limited (Twedt et al, 1988). Diethyldithiocarbamate (DDC) chelates copper but the lipophilic chelate accumulates in tissues, especially the brain (Iwata et al, 1970; Jasim et al, 1985), suggesting it may be an unsuitable antidote in copper poisoning. It has been suggested that DDC modifies the permeability of cell membranes and the blood brain barrier to copper (Allain and Krari, 1993). Clinical studies Wilson's disease Wilson's disease, characterized by decreased biliary copper excretion traditionally has been treated with d-penicillamine which serves to increase urinary copper elimination (Scheinberg et al, 1987). Adverse reactions to d-penicillamine are not uncommon and frequently are immunologically rather than toxicologically-induced including nephrotic syndrome, systemic lupus erythematosus (Walshe, 1982), white cell dyscrasias, thrombocytopenia, haemolytic anaemia (Walshe, 1982) and urticaria (Walshe, 1968). Anorexia, nausea and vomiting are described (Walshe, 1968). In animal studies penicillamine induces hepatic metallothionein (Heilmaier et al, 1986) which may disrupt the body distribution of other trace elements. Adverse effects occur in up to 10 per cent of patients receiving penicillamine and may necessitate treatment withdrawal (Walshe, 1982). Thus, in recent years, alternative agents have been investigated. Sunderman et al (1963) advocated parenteral and/or oral DDC in the management of Wilson's disease but evidence that this antidote enhances cerebral copper uptake limits its usefulness (see above). Walshe (1982) demonstrated increased urine copper elimination, symptomatic improvement and resolution of basal-ganglia abnormalities on CT brain scan among 20 patients with Wilson's disease treated with triethylenetetramine. These authors suggested triethylenetetramine as an effective drug for the treatment and maintenance of patients with Wilson's disease at all stages of the illness. Others concur with this view (Dubois et al, 1990; Morita et al, 1992) although there are potential hazards of triethylenetetramine therapy, notably sideroblastic anaemia (Perry et al, 1996). Although zinc sulphate has been utilized as alternative therapy to penicillamine in patients with Wilson's disease (Hoogenraad and Van den Hamer, 1983; Van Caillie-Bertrand et al, 1985; Veen et al, 1991), this treatment is unsuitable for acute copper poisoning as the mechanism of benefit is reduced gastrointestinal copper absorption. DMPS 200 mg bd increased urine copper elimination in a patient with Wilson's disease (Walshe, 1985). Acute poisoning There are no clinical data regarding the use of any chelating agent in copper carbonate poisoning. d-Penicillamine, the standard therapy for Wilson's disease, has been utilized in copper poisoning (Holtzman et al, 1966; Jantsch et al, 1984/85; Hantson et al, 1996) but without confirmed evidence of enhanced urinary copper excretion. Intramuscular dimercaprol (Fairbanks, 1967; Jantsch et al, 1984/85; Schwartz and Schmidt, 1986; Hantson et al, 1996) and intravenous sodium calciumedetate (Holleran, 1981; Agarwal et al, 1975) have also been employed but again without confirmed benefit. A five year-old child with copper intoxication following repeated application of copper sulphate crystals to skin burns received a 12 day course of d-penicillamine 250 mg qds (Holtzman et al, 1966). Six hour urine copper excretion on the first day of chelation was 1000 µg, with a maximum value of 2000 µg/6h some 24 hours later. No pre- or post-chelation copper excretion data were given. Jantsch et al (1984/85) advocated the use of chelation therapy with dimercaprol and d-penicillamine following their experience with a patient who survived the alleged ingestion of 250 g copper sulphate. A single intramuscular dimercaprol dose 4 mg/kg was administered within the first ten hours (time not specified) followed by oral d-penicillamine 250 mg qds for at least seven days. The only 24 hour urine copper excretion measured "after initiation of chelation therapy" was 8160 µg (time not specified) with no pre- or post-chelation data presented. This case was unusual in that despite massive copper sulphate ingestion the patient developed no features of severe gastrointestinal irritation (save initial vomiting), no haemolysis or oliguria. Walsh et al (1977) administered intramuscular dimercaprol 2.5 g/kg (?2.5 mg/kg) plus 12.5 g/kg (?12.5 mg/kg) "edetic acid" four hourly to an 18 month-old child, commencing five hours after ingestion of 3 g copper sulphate. The urine copper concentration from a two hour collection was 500 µg/L on the second day, increasing to 3000 µg/L on day 12. The chelating agent was then switched to d-penicillamine 250 mg daily for one month with a gradual fall in urine copper excretion. Unfortunately urine volumes were not stated and no pre-chelation measurements were possible. Hantson et al (1996) recently treated an 86 year-old woman with acute copper sulphate poisoning with intramuscular dimercaprol 4 mg/kg qds and oral d-penicillamine 250 mg qds, both commenced within four hours of poisoning. Urine copper elimination was not enhanced and chelation was discontinued after 48 hours following onset of renal failure. These authors concluded that "available clinical and toxicokinetic data do not support the benefits of chelation in addition to supportive therapy" in acute copper (and zinc) sulphate poisoning. Alkaline diuresis Muthusethupathi et al (1988) advocated forced alkaline diuresis in copper sulphate poisoning. In 103 copper sulphate-poisoned patients in whom gastric lavage followed by forced alkaline diuresis were instituted immediately, the incidence of renal failure was claimed to be substantially lower (14.6 per cent) than in other similar series. However, no copper excretion data were reported, and it is possible that prompt fluid resuscitation with correction of hypovolaemia played an important role in patient recovery (Muthusethupathi et al, 1988). Haemodialysis Haemodialysis for five hours in a 41 year-old female failed to remove copper when instituted 12 hours after the ingestion of 280 mL dissolved copper sulphate (Agarwal et al, 1975). The patient had already undergone gastric lavage, had received intravenous sodium calciumedetate (1g) and a blood transfusion but died on the sixth hospital day after developing septicaemia, hepatic and renal failure. Peritoneal dialysis Cole and Lirenman (1978) reported a two year old child who had ingested some 30 mL super-saturated copper sulphate solution and underwent peritoneal dialysis for the management of renal failure. Copper extraction into the dialysate was enhanced markedly by the addition of salt-poor albumin 25 g/L. Over a 40 hour dialysis period (between 17 and 57 hours post ingestion) 0.7 mg copper was removed in 17 litres dialysate compared to 9.1 mg copper removed in 24 litres during dialysis with added albumin between 57 and 117 hours. The authors advocated albumin-enriched peritoneal dialysis in the management of copper poisoning complicated by acute renal failure. It should be noted, however, that the child consumed at least 2.7 g copper so that the amount removed by dialysis, even with albumin, was small. Enhancing elimination: Conclusions and recommendations 1. There are no controlled clinical data regarding the use of chelating agents in copper carbonate 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. Measurement of copper and caeruloplasmin concentrations in biological fluids Although whole blood copper concentrations correlate well with the severity of copper poisoning following acute ingestion, they should always be interpreted in conjunction with the clinical features. Serum copper concentrations are less useful in acute intoxication (Chuttani et al, 1965). In 20 patients who ingested copper sulphate, mean (± SD) whole blood copper concentrations were 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 (1976) 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 betwen 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. There are no data for copper carbonate. 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 poisoning. The main value of this measurement is to monitor the effect of chelation therapy. AT RISK GROUPS Infants are at increased risk of excess copper accumulation during the first three months of life since their hepatic copper stores are significantly higher than in adults. This is due to the presence of fetal copper-binding protein which enables the fetal liver to accumulate sufficient copper to maintain body stores despite the relatively lower copper content of breast milk (Walker-Smith and Blomfield, 1973). MEDICAL SURVEILLANCE Close attention to personal hygiene and the use of appropriate protective equipment are of primary importance among those occupationally exposed to copper. Twenty-four hour urine copper excretion is a useful screening procedure if copper intoxication is suspected but the source of exposure is unclear. However, when collected in an occupational setting great care must be taken to avoid sample contamination. Serum or whole blood copper concentrations may be useful if exogenous copper contamination of urine samples is suspected (Cohen, 1979). It should be remembered that impaired biliary copper excretion from any cause will lead to increased renal copper elimination. Pre-employment screening for Wilson's disease may be indicated in those occupationally exposed to copper. Normal copper concentrations in biological fluids Plasma/serum: 0.7-1.3 mg/L (Weatherall et al, 1996). Whole blood: 1.6-2.7 mg/L (Chuttani et al, 1965). Urine: Less than 60 µg/24h (Weatherall et al, 1996). OCCUPATIONAL DATA Occupational exposure standard Copper: Long-term exposure limit (8 hour TWA reference period) fume 0.2 mg/m3; dusts and mists 1 mg/m3 (Health and Safety Executive, 1997). OTHER TOXICOLOGICAL DATA Carcinogenicity There are no human carcinogenicity data for copper carbonate. There is no conclusive evidence that copper is carcinogenic in humans (Aaseth and Norseth, 1986). However, it is proposed that patients with "Vineyard sprayer's lung" are at a greater risk than the general population of developing bronchial carcinoma (Villar, 1974; Stark, 1981). When originally reported in Europe, lung cancers in vineyard workers were attributed to the arsenic content of some fungicides, but in Portugal arsenic fungicides have never been used in the vineyards (Villar, 1974). Among 14 smoking vineyard workers Plamenac et al (1985) noted atypical squamous metaplasia in four cases and suggested copper as an aetiologic agent. In a review of liver disease among 30 vineyard sprayers who had used Bordeaux mixture for three to 45 years (mean 18 years), Pimentel and Menezes (1977) observed one case of hepatic angiosarcoma. The authors suggested copper-induced sinusoidal cell proliferation as a possible trigger of tumour development. Musicco et al (1988) reported a significant (p=0.006) increase in the incidence of brain gliomas among farmers occupationally exposed to insecticides or fungicides (often commercial copper sulphate preparations), but concluded these were associated probably with exposure to alkyl urea (known neurogenic carcinogens) in the pesticides. Reprotoxicity There are no reprotoxicity data for copper carbonate. In a controlled study Barash et al (1990) investigated the teratogenic potential of copper releasing intrauterine devices (IUD) on the developing human embryo. No malformations or copper deposits were observed in the organs/placentae of copper IUD-exposed embryos (n=11) examined between seven and 12 weeks gestation. The results from the small study suggest that copper releasing IUDs have no observed negative effects on the developing embryo. Copper sulphate is teratogenic in several animal species (Bologa et al, 1992). Genotoxicity (for copper) Copper induced sister chromatid exchanges in human peripheral lymphocytes (DOSE, 1993). Fish toxicity (for copper) Chronic, partial chronic and early life stage toxicity tests were carried out on bluegill sunfish, bluntnose minnow, king salmon, fathead minnow and brook trout. The study duration was 30-60 days post-hatch. Under hard water conditions for fat head minnow the lowest observed effect concentration (LOEC) - no observed effect concentration (NOEC) was 33-15 µg/L and for the bluntnose minnow 18-4 µg/L. The reproduction part of the life cycle gave the most sensitive responses. In a chronic study (30-60 days post-hatch) with fathead minnow and bluegill sunfish, in soft water conditions LOEC-NOEC range was 40-11 µg/L, fry survival was the most sensitive response. A partial chronic study (30-60 days post-hatch) the LOEC-NOEC for brook trout was 17-9 µg/L, fry growth and survival were the most sensitive responses. LC50 (96 hr) Oreochromis niloticus 1.06 mg/L. LC50 (96 hr) rainbow trout 0.253 mg/L. LC50 (48 hr) larvae of flat fish Paralichthys olivaceus 0.36 mg/L (Cu2+). The fertilized eggs of Cyprinus carpio (108 hr) were exposed to 10, 50, 70 and 100 ppb copper. Survival of developing eggs, hatchlings, hatching and hatchability percentage decreased with increasing concentration. Deformities observed were formation of blisters, curved tail, stunted growth, circulatory failure, enlargement of the pericardial sac, deformed head region, underdeveloped fins and deformed vertebral column. Rainbow trout exposed to a number of combinations of copper, water hardness and pH showed reduced growth rate during the first 10 days, followed by partial or complete recovery. The lethal concentration of copper to rainbow trout was not affected by alkalinity at 10-50 ppm in soft water, however, the toxicity doubled by the same alkalinity change in hard water. Synergism between pH value and copper toxicity was observed (DOSE, 1993). EC Directive on Drinking Water Quality 80/778/EEC Copper: EC advisory level for drinking water, 100 µg/L at source of supply; 3000 µg/L after standing in piping for 12 hours (DOSE, 1993). WHO Guidelines for Drinking Water Quality Copper: Provisional guideline value 2 mg/L (WHO, 1993). AUTHORS ST Beer BSc SM Bradberry BSc MB MRCP WN Harrison PhD CChem MRSC 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. 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