UKPID MONOGRAPH COBALT CHLORIDE SM Bradberry BSc MB MRCP P Sabatta MSc 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. COBALT CHLORIDE Toxbase summary Type of product Used in inks, varnishes, enamels, fertilizers, feed additives and humidity indicators. Toxicity Cobalt chloride is only moderately toxic by ingestion although a 19 month-old child died some six hours after allegedly drinking only 30 mL (Jacobziner and Raybin, 1961). In another report a six year-old developed only transient gastrointestinal upset after ingesting 2.5 g (Mucklow et al, 1990). Cobalt sensitization may occur following dermal exposure. Features Dermal - Cobalt chloride is a topical irritant and a recognized cause of occupational contact dermatitis. - Simultaneous allergies to nickel and cobalt are frequent. Ocular - Cobalt chloride is a potential eye irritant but there are no reports of acute eye toxicity in man. Ingestion - There may be no or minimal symptoms after small ingestions. Nausea, vomiting and/or abdominal pain are likely after more substantial ingestions (> 100 mg). Concentrated solutions are acidic (the pH of a 0.2 M solution is 4.6). There is an early case report of fatal cobalt chloride ingestion (30 mL) in which autopsy showed a blistered oesophageal mucosa and partially necrosed gastric mucosa (Jacobziner and Raybin, 1961). - Transient neutropenia occurred in a six year old child who ingested 2.5 g (Mucklow et al, 1990). - In the past congestive cardiomyopathy occurred after the consumption of large quantities of beer to which cobalt chloride/cobalt sulphate had been added as a foam stabilizer and in those receiving oral cobalt chloride therapy as treatment for anaemia. These presentations are now most unlikely in the UK. - Chronic cobalt chloride ingestion has also caused hypothyroidism (cobalt inhibits the iodination of tyrosine). Inhalation - Pulmonary toxicity following chronic cobalt exposure is associated typically with the hard metal industry in which elemental cobalt forms a matrix for tungsten carbide. Symptoms are most prevalent, however, among those working in 'wet' processes where cobalt is ionized. - Hard metal lung disease usually arises after several years and may manifest as pneumoconiosis (with dyspnoea and cough secondary to interstitial fibrosis), allergic alveolitis or occupational asthma. - Cor pulmonale may complicate hard metal pneumoconiosis. - There are occasional reports of cobalt cardiomyopathy following occupational exposure. Management Dermal 1. Removal from exposure is the priority. 2. Contact dermatitis responds to topical and/or systemic steroids. 3. There is no confirmed role for topical chelation therapy in cobalt dermatitis. Ocular 1. Irrigate for at least 15 minutes with lukewarm water. 2. Topical anaesthesia may be required. 3. Ensure particle removal from conjunctival recesses. 4. An ophthalmic opinion may be required. Ingestion 1. Gastrointestinal decontamination is not necessary. Vomiting will occur spontaneously following significant ingestions and gastric lavage is contraindicated following ingestion of acid solutions. 2. Supportive care is the priority. Replace fluids and electrolytes as required. 3. Check the full blood count. 4. If chronic cobalt ingestion is suspected consider the possibility of cobalt cardiomyopathy and check thyroid function. 5. Collect blood and urine for cobalt concentration determination in symptomatic patients to confirm diagnosis. Cobalt assays are not widely available. Check with NPIS. 6. There are no controlled clinical data regarding the use of chelating agents in cobalt poisoning. Discuss with an NPIS physician. Inhalation Acute inhalation: 1. Remove from exposure and treat symptomatically. Chronic inhalation: 1. Asthmatic symptoms respond to conventional measures. 2. Established pulmonary fibrosis generally has a poor prognosis. Some cases have responded to high dose prednisolone (Rolfe et al, 1992) or cyclophosphamide (Balmes, 1987). Discuss with an NPIS physician. References Alexander CS. Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty- eight cases. Am J Med 1972; 53: 395-417. Balmes JR. Respiratory effects of hard-metal dust exposure. Occup Med 1987; 2: 327-44. Cugell DW. The hard metal diseases. Clin Chest Med 1992; 13: 269-79. Curtis JR, Goode GC, Herrington J, Urdaneta LE. Possible cobalt toxicity in maintenance hemodialysis patients after treatment with cobaltous chloride: a study of blood and tissue cobalt concentrations in normal subjects and patients with terminal renal failure. Clin Nephrol 1976; 5: 61-5. Jacobziner H, Raybin HW. Accidental cobalt poisoning. Arch Pediatr 1961; 78: 200-5. Manifold IH, Platts MM, Kennedy A. Cobalt cardiomyopathy in a patient on maintenance haemodialysis. Br Med J 1978; 2: 1609. Mucklow ES, Griffin SJ, Delves HT, Suchak B. Cobalt poisoning in a 6-year-old. Lancet 1990; 335: 981. Rolfe MW, Paine R, Davenport RB, Strieter RM. Hard metal pneumoconiosis and the association of tumor necrosis factor-alpha. Am Rev Respir Dis 1992; 146: 1600-2. Sullivan JF, Egan JD, George RP. A distinctive myocardiopathy occurring in Omaha, Nebraska: Clinical aspects. Ann NY Acad Sci 1969; 156: 526-43. Substance name Cobalt (II) chloride Origin of substance Prepared commercially in hexahydrate, dihydrate and monohydrate forms. (DOSE, 1993) Synonyms Cobalt dichloride Cobaltous chloride (DOSE, 1993) Chemical group A compound of cobalt, a group VIIIB element. Reference numbers CAS 7646-79-9, (DOSE, 1993) 7791-13-1 (hexahydrate) RTECS GF 9800000 (RTECS, 1997) UN NIF HAZCHEM NIF Physicochemical properties Chemical structure CoCl2 (DOSE, 1993) Molecular weight 129.84 (DOSE, 1993) Physical state at room temperature Solid (DOSE, 1993) Colour Pale blue, turning pink on exposure to air. (OHM/TADS, 1997) Odour Very slight sharp odour. (CHRIS, 1997) Viscosity NA pH Forms acid solution in water (0.2 M aqueous solution has pH 4.6). (MERCK, 1996; OHM/TADS, 1997) Solubility 450 g/L in water at 7°C 385 g/L in methanol (HSDB, 1997) Autoignition temperature NA Chemical interactions A mixture of potassium and cobalt chloride is sensitive to mechanical shock and may cause a violent explosion. Sodium dispersions will reduce cobalt chloride exothermically, resulting in a temperature increase of 50°C. Very violent explosions may occur. Contact of dust with strong oxidizers may cause fire and explosion. (HSDB, 1997) Major products of combustion Cobalt oxide (HSDB, 1997) Explosive limits NA Flammability Not flammable (HSDB, 1997) Boiling point 1049°C (DOSE, 1993) Density 3.367 at 25°C (DOSE, 1993) Vapour pressure 5333 Pa at 770°C (DOSE, 1993) Relative vapour density NA Flash point NA Reactivity Cobalt chloride decomposes at 400°C on heating in air. Cobalt chloride hydrolyzes in aqueous solution. (HSDB, 1997) Uses Invisible ink Humidity indicator Glass and porcelain painting Production of vitamin B12 Fertilizer and feed additive Stabilizer in beer Absorbant for poisonous gases and ammonia (DOSE, 1993) Hazard/risk classification NIF INTRODUCTION AND EPIDEMIOLOGY Cobalt chloride is a water soluble bivalent cobalt salt. Cobalt chloride poisoning is now rare with only isolated case reports of accidental or intentional ingestion, usually from chemistry sets or crystal growing kits (Jacobziner and Raybin, 1961; Everson et al, 1988; Mucklow et al, 1990). Outbreaks of cobalt cardiomyopathy occurred in Belgium, Nebraska and Quebec in the 1960's among heavy beer drinkers when cobalt chloride/sulphate was added to beer to act as a foam stabilizer (Kesteloot et al, 1968). Chronic cobalt intoxication also occurred when oral cobalt chloride was used to treat anaemia (Duckham and Lee, 1976; Manifold et al, 1978) but this is no longer a licensed indication in the UK. Cobalt is an important cause of occupational contact dermatitis and cobalt chloride is widely used in patch testing. However, reports in which cobalt chloride specifically is the allergen are rare (Zenorola et al, 1994). MECHANISM OF TOXICITY Cytotoxic hydroxy radicals may form when cobalt ions interact with reactive oxygen species. Hydroxy radicals may then cause the production of further free radicals which reduce cellular glutathione concentrations and NADPH activity. The resulting oxidative stress leads to DNA and cellular protein damage (Timbrell, 1994). Cobalt is immunogenic and acts as a hapten in the induction of bronchial and dermal hypersensitivity (Sjögren et al, 1980). Ionized cobalt, though not specifically cobalt chloride, is an important contributing factor in the aetiology of hard metal lung disease. Evidence for an autoimmune mechanism in this disorder is suggested by the recurrence of disease in a single transplanted lung despite no evidence of cobalt in the donated organ (Frost et al, 1993). In cobalt pneumoconiosis non-respiratory symptoms may be due to cobalt-induced release of a tumour necrosis factor from sensitized pulmonary lymphocytes (Rolfe et al, 1992). In a dog model cobalt myocardial toxicity was characterized by vacuolation and loss of myofibers (Sandusky et al, 1981a) with histochemical evidence of severe mitochondrial damage (Sandusky et al, 1981b). Alexander (1972) suggested cobalt depresses mitochondrial oxygen uptake in the myocardium by complexing with sulphydryl groups and preventing the oxidation of pyruvate in the citric acid cycle. Tissue hypoxia is the probable stimulus also of erythropoietin secretion in cobalt-induced polycythaemia (Taylor and Marks, 1978). In animal studies, cobalt decreases synthesis of several enzymes including cellular cytochrome P450 (Timbrell, 1994). Cobalt inhibits aminolaevulinic acid synthetase and increases the activity of haem oxygenase which breaks down haem to biliverdin (Taylor and Marks, 1978; Timbrell, 1994). TOXICOKINETICS Absorption Cobalt chloride can be absorbed following ingestion, inhalation and dermal exposure (Domingo, 1989; Scansetti et al, 1994; Linnainmaa and Kiilunen, 1997). Cobalt and iron share the same transport mechanism within the small intestine such that cobalt ingestion competitively inhibits iron uptake. The extent of intestinal cobalt absorption depends on the dose with only some 20 per cent of a large ingestion being absorbed (Domingo, 1989). Some inhaled cobalt chloride is swallowed following mucociliary clearance while particles which reach the distant pulmonary tree are taken up predominantly by macrophages (Taylor and Marks, 1978; Evans et al, 1993). Systemic uptake is confirmed by increased blood and urine cobalt concentrations in those occupationally exposed to cobalt-containing dusts and mists (Della Torre et al, 1990). Distribution The normal body burden of cobalt is about 1.1 mg. Approximately 43 per cent of this is in muscle with some 14 per cent in bone and the remainder in other soft tissues (Taylor and Marks, 1978; Domingo, 1989). Excretion Cobalt which reaches the systemic circulation is eliminated predominantly in urine with a variable but small amount excreted in bile (Taylor and Marks, 1978; Domingo, 1989). Following acute occupational cobalt inhalation urinary elimination is rapid for the first 24 hours followed by a slower excretion phase lasting several weeks (Alexandersson, 1988). A small proportion of retained cobalt has a biological half-life of several years (Elinder and Friberg, 1986). CLINICAL FEATURES: ACUTE EXPOSURE Dermal exposure Cobalt chloride may cause skin irritation but dermal toxicity is associated primarily with contact sensitivity (see Chronic exposure). Ocular exposure Cobalt chloride causes corneal damage when directly applied to the eyes of experimental animals (Grant and Schuman, 1993) but there are no reports of acute eye toxicity in man. Inhalation There are no reports of acute cobalt chloride inhalation. Ingestion Most reports of cobalt chloride ingestion involve only modest gastrointestinal upset although Jacobziner and Raybin (1961) described a fatality in a 19 month-old child (see below). Gastrointestinal toxicity Jacobziner and Raybin (1961) reported a 19 month-old child who ingested approximately 30 mL of a cobalt chloride solution. Vomiting was induced immediately and gastric lavage performed on arrival at hospital two hours later. On examination the child was pale and peripherally cyanosed. The lips and tongue were oedematous. The clinical condition deteriorated rapidly with death following a cardiac arrest some six hours post ingestion. Autopsy revealed a blistered oesophageal mucosa with coagulative necrosis involving one third the thickness of the gastric mucosa. The precise cause of death was not clear but these findings suggest the solution was highly concentrated and corrosive. Cobalt was identified in the liver, kidney, spleen (89 mg total in these organs) and stomach. A six year-old boy developed nausea, vomiting and abdominal pain after swallowing a drink to which he had added about 2.5 g cobalt chloride from a crystal growing set (Mucklow et al, 1990). The whole blood cobalt concentration some seven hours post ingestion was 241 µg/L (normal range < 1 µg/L) but he made a full recovery. Everson et al (1988) reported a 14 year-old female who vomited but was otherwise asymptomatic following ingestion of approximately 130 mg cobalt chloride from her brother's chemistry set. The serum cobalt concentration 12 hours post ingestion was 78 µg/L. Haemotoxicity A six year old boy who ingested 2.5 g cobalt chloride developed a transient neutropenia (1.7 x 109/L) but recovered fully (Mucklow et al, 1990). Neurotoxicity A 19 month-old child who ingested 30 mL of a cobalt chloride solution became restless and drowsy within two hours in association with severe respiratory distress, cyanosis and pallor. He died some six hours later (Jacobziner and Raybin, 1961). Cerebral oedema was evident at autopsy. CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Cobalt is a well recognized cause of contact dermatitis (Smith et al, 1975), a delayed hypersensitivity reaction characterized by vesicles, itchy maculopapular lesions, scaling and/or fissuring (Miyachi et al, 1985; Foussereau and Cavelier, 1988; Illuminati et al, 1988). These features are seen commonly on the hands, face and neck and sometimes the eyelids and chest. Cobalt contact dermatitis primarily occurs following exposure to the elemental form, which subsequently is ionized in sweat, although there are situations where cobalt compounds are the primary allergen. For example, a 71 year-old construction labourer developed contact dermatitis induced by cobalt and chromium ions present in cement (Miyachi et al, 1985). Cobalt dermatitis is also described in those handling or manufacturing rubber. In the rubber industry cobalt is used as lipid soluble (cobalt naphthenates and stearates) rather than water soluble salts (Bedello et al, 1984; Foussereau and Cavelier, 1988). Zenorola et al (1994) described atypical dermatitis in a 23 year-old plumber. The clinical appearance was highly suggestive of "Ashy dermatitis" or erythema dyschromicum perstans, a disorder of uncertain aetiology characterized by asymptomatic, ash-like grey macular pigmentation of the skin. The patient patch tested positive to cobalt chloride for which there were several sources in his workplace including varnishes and paints. However a causative association between ashy dermatitis and cobalt allergy could not be confirmed. An initial irritant dermatitis, often involving operations traumatic to the hand, usually precedes cobalt allergy in industry (Fischer and Rystedt, 1983a). In addition false positive cobalt patch tests may occur due to an irritant rather than delayed hypersensitivity response (Fischer and Rystedt, 1985). Cobalt chloride is used widely in patch testing (James and Smith, 1975; Munro-Ashman and Miller, 1976; Veien and Svejgaard, 1978; Schmidt et al, 1980; Rae, 1981; Romaguera et al, 1982; Miyachi et al, 1985; Shirakawa et al 1988; Allenby and Basketter, 1989; Pryce and King, 1990; Zhang et al, 1991; Castiglioni et al, 1992; Torresani et al, 1994). Lantinga et al (1984) invited 2800 members of the general population in a geographically defined area of the Netherlands to be examined for skin disorders of the hands and forearms. Patch testing was performed in 141 persons with eczema. Contact allergy was detected in 50 (35 per cent) of these. Cobalt chloride was the allergen in five cases with nickel sulphate in 28 and potassium dichromate in nine cases. Among 4721 consecutive patients at a patch test clinic, six per cent had a positive reaction to cobalt chloride (compared to nickel sensitivity in 18.5 per cent) (Shehade et al, 1991). These authors emphasized the importance of not reading the patch test before day four; 69 of 271 (24 per cent) patients with a positive reaction to cobalt chloride on day four had a negative result on day two. Simultaneous allergies to nickel and cobalt are frequent (Burden and Eedy, 1991; Kanerva and Estlander, 1995) and there is some evidence for a mutual enhancing effect of contact sensitization to one metal in the presence of the other (Domingo, 1989). Inhalation Pulmonary toxicity Pulmonary toxicity following chronic cobalt exposure is associated typically with the hard metal (tungsten carbide in a cobalt matrix) industry (Auchincloss et al, 1992) but similar problems have been reported in diamond polishers using cobalt-coated discs (Lahaye et al, 1984; Nemery et al, 1990) and in a dental technician (Sherson et al, 1990). Hard metal lung disease is discussed here since employees are exposed both to elemental and ionized cobalt (the latter in 'wet' grinding processes where cobalt is dissolved in machine coolants). Cugell (1992) suggested ionized cobalt is more likely than elemental cobalt to cause occupational pulmonary disease although this may not be true of hard metal asthma (Kusaka et al, 1996a). There is some debate concerning whether cobalt exposure alone is sufficient to cause pulmonary fibrosis. In-vitro and animal studies suggest there is no relationship between cellular cobalt uptake and cellular toxicity (Lison and Lauwerys, 1994) and cobalt workers frequently are exposed to several other potential toxins (including tungsten carbide, iron, silica and diamond) (Swennen et al, 1993). While Gennart and Lauwerys (1990) observed a significantly increased incidence (p<0.05) of restrictive spirometry and respiratory symptoms in workers exposed for more than five years to cobalt dust in a plant producing diamond-cobalt circular saws compared to non cobalt-exposed factory workers, Swennen et al (1993) found no difference in ventilatory performance, lung volumes or carbon monoxide diffusion capacity between 82 cobalt refinery workers and controls even though the cobalt workers complained more frequently of wheeze and dyspnoea. Hard metal pneumoconiosis Chronic cobalt (and tungsten carbide) inhalation is associated typically with "hard metal" pneumoconiosis characterized by interstitial fibrosis (primarily of the lower zones) and a restrictive ventilatory defect (Bech et al, 1962). Patients usually present with exertional dyspnoea, cough and sometimes chest tightness (Bech et al, 1962). There may be associated symptoms of fever, weight loss or general malaise (Coates and Watson, 1971; Balmes, 1987; Migliori et al, 1994). In one study of 12 tungsten carbide workers the mean duration of exposure before the onset of respiratory symptoms was 12 years with a range of one month to 28 years (Coates and Watson, 1971). Inspiratory crackles are the earliest physical sign (Rochat et al, 1987) but finger clubbing, cyanosis and eventually cor pulmonale may ensue. Chest X-ray findings vary greatly (Cugell et al, 1990) but usually show increased linear markings and small nodular opacities in the lower (and mid) zones with later cardiomegaly and features of pulmonary hypertension (Bech et al, 1962). Many patients develop a form of pulmonary fibrosis complicated by atypical intraalveolar giant cells (Davison et al, 1983; Rochat et al, 1987; Cugell, 1992; Frost et al, 1993) which can be demonstrated in bronchoalveolar lavage fluid (Forni, 1994) and transbronchial biopsies (Rolfe et al, 1992). Pulmonary eosinophilia is also a feature of hard metal lung disease (Della Torre et al, 1990). Forni (1994) suggested that a persistently high bronchoalveolar lavage eosinophil count despite steroid therapy and cessation of exposure carried an unfavourable prognosis. Several fatalities from hard metal pneumoconiosis have been reported (Della Torre et al, 1990; Figueroa et al, 1992). Nemery et al (1990) described a 52 year-old diamond polisher who died less than one year after a diagnosis of interstitial lung disease. He continued work without specific treatment until three months before death when he required continuous oxygen and systemic steroids. At autopsy there was evidence of extensive fibrosis with interstitial giant cells. The lung cobalt concentration was 2.1 µg/g. The authors suggested that oxygen therapy may have exacerbated this man's deterioration via cobalt-induced hydroxyl free radical formation. A 37 year-old female developed rapidly progressive pneumoconiosis after working, without respiratory protection, for seven years in sharpening and grinding operations with hard metal tools (Della Torre et al, 1990). There was no response to steroid therapy and she died from respiratory failure less than one year after presentation. Interestingly, although the lung cobalt concentration in bronchoalveolar lavage fluid was increased on presentation (2 µg/L, reference value 0.6 µg/L) the cobalt concentration at open biopsy four months later was not raised significantly, supporting the hypothesis that cobalt-induced lung damage is immunologically mediated rather than a direct effect. Allergic alveolitis An allergic alveolitis has been described in hard-metal workers with cough, dyspnoea and flu-like symptoms associated with bilateral crackles, radiographic small nodular infiltrates and a restrictive lung function defect (Sjögren et al, 1980; Cugell, 1992). These abnormalities may reverse if exposure ceases but with continued cobalt inhalation irreversible fibrosis is likely (Cugell, 1992). Occupational asthma Hard metal workers may develop occupational asthma with cough, wheeze and dyspnoea that characteristically improves during week-ends and holidays (Sprince et al, 1988; Cugell, 1992). Similar symptoms have been described in diamond workers exposed to cobalt in polishing discs (Gheysens et al, 1985). In a study of 703 hard metal workers Kusaka et al (1996a) identified age (>40 years), atopy and cobalt exposure as risk factors for asthma. Surprisingly, low airborne cobalt concentrations (below 50 µg/m3) posed a greater risk of hard metal asthma than did higher air cobalt concentrations (Kusaka et al, 1996a) although the observed deterioration in ventilatory function seemed to be related to duration of cobalt exposure (Kusaka et al, 1996b). In this study there was no significant difference in asthma prevalence between those exposed to the elemental (dust) or ionized (mist) metal (Kusaka et al, 1996a). Cobalt asthma is associated in some, but not all, cases with circulating cobalt-specific IgE and generalized bronchial hyperresponsiveness (Coates and Watson 1971; Sjögren et al, 1980; Kusaka et al, 1989; Shirakawa et al, 1989; Cugell, 1992). Respiratory cross-reactivity between cobalt and nickel has also been described (Shirakawa et al, 1990). Cardiovascular toxicity Patients with fulminant hard metal pneumoconiosis may, after several years, develop cor pulmonale with clinical and radiological features of pulmonary hypertension and right heart failure (Bech et al, 1962). Cobalt cardiomyopathy is associated most frequently with chronic excess cobalt chloride or cobalt sulphate ingestion (see above) but an identical syndrome has been reported occasionally in those exposed occupationally (Barborik and Dusek, 1972; Jarvis et al, 1992). Kennedy et al (1981) reported fatal cardiogenic shock in a 48 year-old hard metal worker following routine vagotomy and pyloroplasty for duodenal ulceration. The patient, who had handled tungsten carbide and cobalt dust for four years, initially developed signs of cardiovascular compromise during the operation and gradually deteriorated without evidence of ischaemic heart disease. At post-mortem the heart was dilated with extensive myocardial fibrosis and a myocardial cobalt concentration of 7 µg/g (normal range 0.1-0.4). There is limited evidence that hard metal workers may develop electrocardiographic abnormalities and/or impaired left ventricular function after chronic cobalt exposure (Horowitz et al, 1988; Evans et al, 1993) but the significance of these studies is uncertain. Neurotoxicity Jordan et al (1990) reported significantly impaired attention (p<0.05) and verbal memory (p<0.001) in 12 hard metal workers exposed to tungsten carbide and cobalt (as dust and dissolved in an organic solvent) compared to healthy unexposed controls. However, all members of the study group had "pulmonary manifestations" of hard metal disease which may have affected performance. A patient exposed occupationally (mainly via inhalation) to cobalt dust for 20 months developed bilateral optic atrophy and bilateral nerve deafness. Fourteen months after stopping work visual acuity improved and hearing returned to normal (Meecham and Humphrey, 1991). Nephrotoxicity Lechleitner et al (1993) reported Goodpasture's syndrome in a 26 year-old hard metal worker with severe interstitial lung disease and fulminant glomerulonephritis. The role of heavy metal exposure in the aetiology of this case is not known though the authors proposed cobalt-induced ß-cell activation or exposure of pulmonary basement membrane antigens as possible disease mechanisms. Ocular toxicity Optic atrophy occurring in association with chronic cobalt inhalation is discussed above (Neurotoxicity). Ingestion Dermal toxicity The administration of disulfiram in the treatment of ethanol abuse has led to an exacerbation of cobalt dermatitis presumably via diethyldithiocarbamate (a disulfiram metabolite) chelation and mobilization of cobalt in a manner similar to that reported in nickel sensitive subjects (Menné, 1985). Gastrointestinal toxicity Gastrointestinal symptoms similar to those occurring after acute cobalt chloride ingestion have also complicated chronic therapy. A 35 year-old woman with anaemia treated with cobalt chloride 25 mg qds complained of nausea, vomiting and weight loss in addition to neurological symptoms (Schirrmacher, 1967). One of 12 renal failure patients on haemodialysis treated with cobalt chloride 25-50 mg daily had to discontinue therapy after ten days due to nausea and constipation. Symptoms resolved on withdrawal of cobalt supplements (Duckham and Lee, 1976). Increased serum triglyceride concentrations have been noted in cobalt-treated anephric patients and although hepatic glucagon resistance was postulated as the cause this has not been confirmed (Taylor and Marks, 1978). Cobalt-induced inhibition of lipoprotein lipase is now thought likely to be relevant (Taylor and Marks, 1978). Cardiovascular toxicity Congestive cardiomyopathy has been reported in people who drank large quantities of beer to which cobalt chloride/sulphate had been added as a foam stabilizer (Morin et al, 1967; Kesteloot et al, 1968; Sullivan et al, 1969) and in those receiving oral cobalt chloride therapy (Manifold et al, 1978). In a study of 28 cases of cobalt beer cardiomyopathy (Alexander, 1972) symptoms of cardiac failure were of fairly abrupt onset (mean duration at presentation 10 weeks) and variable severity with five deaths from cardiogenic shock and a full physical recovery in only 11 patients. Cardiomegaly, a pericardial effusion and polycythaemia were present in the majority with pleural effusion in 11 cases though radiological evidence of pulmonary oedema "characteristically ..... was absent". Profound lactic acidosis was a prominent feature in severe cases. Electrocardiographic abnormalities included p pulmonale or p mitrale, axis (usually right) deviation and acute ischaemic changes in the precordial leads typically associated with increased plasma cardiac enzyme activities. Electron microscopy of myocardial tissue from these patients showed extensive myofibril degeneration with abnormal mitochondria containing electron-dense bodies believed to incorporate cobalt. It is probable that alcohol and malnutrition contributed to the cardiotoxicity observed in these and other cases since the absolute quantities of cobalt ingested often were small (up to 10 mg daily) (Kesteloot et al, 1968; Alexander, 1972). Curtis et al (1976) described a haemodialysis patient who died three months after "a course" of cobalt chloride. At post mortem the myocardial cobalt concentration was 1.65 µg/g, some 25-80 times greater than myocardial cobalt concentrations in haemodialysis patients who had not received cobalt. These authors noted also that patients treated with oral cobalt chloride had significantly higher (p=0.001) blood cobalt concentrations than haemodialysis patients who had not received cobalt. In another report a 17 year-old girl on maintenance haemodialysis died from rapidly progressive dilated cardiomyopathy after nine months cobalt chloride therapy (25 mg bd) for anaemia. At necropsy the myocardial cobalt concentration was 8.9 µg/g (Manifold et al, 1978). Neurotoxicity After six months treatment with cobalt chloride 25 mg qds for anaemia a 35 year-old woman developed limb paraesthesiae, an unsteady gait, impaired hearing and dizzy spells in addition to nausea, vomiting and weight loss (Schirrmacher, 1967). Clinical examination confirmed bilateral nerve deafness, absent ankle reflexes and impaired vibration sense. All symptoms and signs resolved with four months of cobalt chloride withdrawal. A haemodialysis patient developed polyarthralgia and muscle weakness after three weeks cobalt chloride therapy (25-50 mg daily). Weakness improved following cobalt withdrawal but polyarthralgia persisted; the patient died eight months later after renal transplantation failure (Duckham and Lee, 1976). Haemotoxicity Chronic excess cobalt chloride ingestion causes polycythaemia which in the past led to its use in the treatment of anaemia (Manifold et al, 1978). A 13 month-old child developed persistent anaemia with polycythaemia and cardiomegaly in addition to hypothyroidism (see below) and hypertrichosis following treatment of iron deficiency for one year with a commercial iron-cobalt preparation. At the end of the treatment period the serum cobalt concentration was 59 µg/L. The haematological abnormalities and hypothyroidism resolved when the treatment was stopped, with some improvement in cardiac size and a fall in the serum cobalt concentration to 6.8 µg/L and 1.4 µg/L at four and 12 months respectively (Bianchi et al, 1989). Endocrine toxicity Cobalt inhibits the iodination of tyrosine and goitre is a recognized side-effect of cobalt therapy (Schirrmacher, 1967). A four year-old boy with sickle cell anaemia admitted for tonsillectomy was noted to have a large goitre. For seven months prior to admission the patient had taken 60-80 mg cobalt chloride daily. The thyroid gland was bilaterally and asymmetrically enlarged, firm, nodular, painless and mobile (Kriss et al, 1955). The goitre disappeared one month after cobalt chloride withdrawal. A 13 month-old baby developed clinical and biochemical hypothyroidism after treatment of iron deficiency for one year with a commercial iron-cobalt preparation. The endocrine abnormality resolved when treatment was withdrawn (Bianchi et al, 1989). Ocular toxicity Following treatment of pancytopenia with 73 g oral cobalt chloride over two and a half years, a patient developed abnormal choroidal perfusion and optic atrophy. Vision did not deteriorate further following cessation of therapy (Licht et al, 1972). MANAGEMENT Dermal exposure Removal from exposure is the priority. Most barrier creams do not prevent the penetration of cobalt chloride through the skin (Fischer and Rystedt, 1983b) although Fischer and Rystedt (1990) demonstrated that polyethylene glycol effectively reduced cobalt contact reactivity. Exacerbations of cobalt contact dermatitis respond to topical or systemic steroids. The role of chelation therapy in cobalt contact sensitivity is discussed below. Ocular exposure Decontamination with copious lukewarm water (eg via drip tubing) is the priority. Topical anaesthesia may be necessary, particularly to ensure removal of particles from the conjunctival recesses. Seek an ophthalmic opinion if symptoms persist or there are abnormal examination findings. Inhalation Exposure must be discontinued if occupational cobalt lung disease is suspected or confirmed. Asthmatic symptoms respond to conventional measures (Pisati and Zedda, 1994). Established pulmonary fibrosis has a generally poor prognosis although there are reports of substantial improvement following high dose steroids (prednisolone 60 mg daily (Rolfe et al, 1992) and/or removal from the workplace (Zanelli et al, 1994). The possibility of cobalt cardiotoxicity should be remembered. The role of blood and urine cobalt concentration measurements is discussed below (Medical Surveillance). Ingestion Decontamination Gastric lavage is unlikely to be helpful since if spontaneous vomiting does not occur the ingestion is almost certainly too small to cause significant toxicity. Concentrated solutions are acidic and gastric lavage is contraindicated if corrosive damage is a possibility. There is no evidence that oral activated charcoal reduces gastrointestinal cobalt absorption. Supportive measures Following acute cobalt chloride ingestion supportive care is usually all that is required with intravenous fluid replacement if vomiting is severe. Concentrated solutions are acidic and the possibility of corrosive damage should be considered. Plasma creatinine, urea and electrolytes and full blood count should be measured. If chronic cobalt toxicity is suspected a thorough cardiovascular and neurological (including fundoscopy) assessment should be undertaken. Thyroid function tests should be performed. The role of chelation therapy is discussed below (Antidotes). The presence of cobalt in blood and urine confirms exposure but blood and urine concentrations require careful interpretation (see Medical Surveillance) and these assays are not widely available. Antidotes Sodium calciumedetate Animal studies Post (1955) observed that rats administered sodium calciumedetate subcutaneously following intraperitoneal cobalt chloride injection did not show the polycythaemic response induced in controls (treated with cobalt only). Subsequent studies (Domingo et al, 1983; Llobet et al, 1985; Llobet et al, 1986) provided further evidence for sodium calciumedetate as an effective cobalt chelator. All mice administered intraperitoneal cobalt chloride at doses approximating to the LD50 - LD95 (0.6-1.8 mmol/kg), immediately followed by 4.3 mmol/kg intraperitoneal sodium calciumedetate survived two weeks with significantly increased urine cobalt elimination in the 24 hours post antidote administration (Llobet et al, 1986). Llobet et al (1988) later demonstrated significantly increased (p<0.05) faecal but not urinary cobalt elimination during a five day course of chelation therapy in cobalt-poisoned rats (administration details as below). Clinical studies Topical Allenby and Basketter (1989) found a positive patch test reaction to one per cent aqueous cobalt chloride was abolished in five out of six subjects by the concomitant application of an equimolar sodium calciumedetate solution. Systemic A 14 year-old female who ingested approximately 130 mg cobalt chloride was asymptomatic but treated with intravenous sodium calciumedetate 1g tds for three doses on the basis of a raised serum cobalt concentration (78 µg/L 12 hours post ingestion) (Everson et al, 1988). No cobalt excretion data were presented. The serum cobalt concentration had fallen to 7 µg/L 22 hours post ingestion and the child remained well. No cobalt was recovered in the urine of a patient with cobalt cardiomyopathy who received a one week course of sodium calciumedetate (and penicillamine, doses not stated) but treatment was not instituted until three years after cobalt ingestion (quantity not stated) (Alexander, 1972). DMSA Animal studies Aposhian (1983) cited early animal studies published in the Chinese literature (in 1965) which showed that DMSA 4 mmol/kg (route not stated) increased threefold the LD50 of cobalt chloride-poisoned mice. Four of ten mice administered 1.8 mmol/kg intraperitoneal cobalt chloride (a dose exceeding the LD95) immediately followed by intraperitoneal DMSA 3.4 mmol/kg, survived two weeks (Llobet et al, 1986). Under these experimental conditions DMSA was a less effective cobalt chelator than sodium calciumedetate or DTPA (diethylenetriamine-pentacetic acid) (see below). DMSA 1.2 mmol/kg/day intraperitoneally increased urine cobalt excretion significantly (p<0.01) only on the final (fifth) day of chelation in rats poisoned with cobalt chloride (0.06 mmol/kg/day intraperitoneally three days per week for four weeks) (Llobet et al, 1988). In the same study faecal cobalt elimination was increased significantly during the first four days of chelation therapy (p<0.05 days one, two and four, p<0.01 day three). DTPA Animal studies Llobet et al (1986) reported 70 per cent two week survival in mice administered intraperitoneal DTPA 3.1 mmol/kg immediately following intraperitoneal loading with 1.8 mmol/kg cobalt chloride (a dose in excess of the LD95). In a later study (Llobet et al, 1988) DTPA 1.2 mmol/kg/day significantly (p<0.05) enhanced faecal and urine cobalt elimination. Other chelating agents Animal studies Intraperitoneal L-histidine 2.7 mmol/kg administered immediately after oral cobalt chloride (4.2 mmol/kg, approximately the oral LD95) resulted in 90 per cent seven day survival compared to 15 per cent survival in animals treated with cobalt chloride only (Domingo et al, 1985a). Domingo et al (1985b) suggested that N-acetylcysteine (NAC) was ineffective in reducing experimental cobalt fatalities unless administered as a cobalt-NAC chelate. However, Llobet et al (1985) demonstrated that glutathione and NAC (each 3.5 mmol/kg intraperitoneally) immediately after intraperitoneal cobalt chloride (0.70 mmol/kg, the LD50) improved survival. In a later study (Llobet et al, 1988) glutathione and NAC (both 1.2 mmol/kg/day intraperitoneally) significantly (p<0.05 and p<0.01 respectively) increased urine and faecal cobalt excretion in cobalt poisoned rats, with a significant (p<0.05) reduction in the spleen cobalt concentration compared to controls. Clinical studies Topical clioquinol one per cent significantly (p<0.001) reduced patch test reactions to cobalt in 29 cobalt-sensitive individuals. However the authors emphasized this chelating agent is not suitable for regular application since it is itself an allergen (Fischer and Rystedt, 1990). There is also a risk of systemic uptake if clioquinol is topically applied chronically. Clioquinol absorption may be associated with neurological side-effects including peripheral neuropathy and delirium (Rose, 1986). Antidotes: Conclusions and recommendations 1. There are no human controlled data regarding the use of chelating agents in cobalt(II) poisoning. 2. Animal studies suggest sodium calciumedetate and DTPA are the most effective cobalt chelators although NAC and glutathione are less toxic alternatives. 3. Following severe cobalt poisoning by ingestion the use of chelation therapy may be considered; discussion of individual cases with an NPIS physician is recommended. 4. There is no evidence that chelation therapy reduces the pulmonary cobalt burden following chronic inhalation. Moreover, the value of cobalt chelation my be limited where immunological mechanisms play an important part in cobalt toxicity. 5. The role of topical chelating agents in cobalt dermatitis remains unproven and is likely to be limited by practical difficulties. Chemotherapy Balmes (1987) reported a 28 year-old lady with aggressive hard metal pneumoconiosis unresponsive to prednisolone (40-60 mg daily) who clinically improved significantly after two months low-dose cyclophosphamide therapy (25 mg bd). Haemodialysis In a patient with uraemic cardiomyopathy and a high serum cobalt concentration (0.24 ppb), Lins and Pehrsson (1976) reported reduced cardiac size in association with a fall in the serum cobalt concentration to 0.07 ppb during haemodialysis. However no cobalt dialysis clearance data or details of dialysis duration were given. AT RISK GROUPS Patients with renal failure are at risk of cobalt toxicity if administered oral cobalt containing pharmaceuticals (Curtis et al, 1976); these preparations are not available in the UK. MEDICAL SURVEILLANCE Regular monitoring of workplace airborne cobalt concentrations (Sala et al, 1994), strict attention to personal hygiene (Scansetti et al, 1994; Linnainmaa and Kiilunen, 1997) and periodic assessment for pulmonary or dermatological symptoms are important in the prevention of cobalt toxicity. Some studies suggest airborne cobalt concentrations frequently are underestimated (Auchincloss et al, 1992; Mosconi et al, 1994) and other workers recently have reported average cobalt airborne concentrations in a hard metal factory greatly exceeding the recommended occupational exposure limit (Kumagai et al, 1996). Furthermore, significant reductions in FEV1 and FVC have been observed in workers exposed to airborne cobalt concentrations lower than 50 µg/m3 (Nemery et al, 1992). Sjögren et al (1980) noted that the development of cobalt contact dermatitis among hard metal workers often preceded pulmonary disease and suggested that those with a positive cobalt patch test should be removed immediately from exposure. However, in another study, only two of nine hard metal workers sensitive to inhaled cobalt had a positive cobalt patch test (Kusaka et al, 1986). Abnormal clinical findings should be investigated conventionally with particular attention to establishing a temporal relationship to workplace exposure in those with possible occupational asthma or alveolitis. The presence of cobalt-specific IgE in plasma or cobalt particles in bronchoalveolar lavage fluid or lung biopsy tissue may be useful. Increased blood and urine cobalt concentrations frequently are encountered in hard metal workers (Ichikawa et al, 1985; Della Torre et al, 1990; Stebbins et al, 1992; Linnainmaa and Kiilunen, 1997) but are more useful as grouped rather than individual data (Sabbioni et al, 1994) and their significance requires careful interpretation. A potential role for hair and nail cobalt concentrations as indicators of chronic exposure has not been substantiated (Della Torre et al, 1990). In workers exposed to cobalt dust in a plant producing diamond-cobalt saws urine cobalt concentrations reflected recent rather than cumulative cobalt exposure (Gennart and Lauwerys, 1990). Lison et al (1994) concluded that urine and blood cobalt concentrations correlated reasonably well with recent occupational exposure to soluble forms of cobalt. Normal concentrations in biological fluids In unexposed individuals normal cobalt concentrations are 0.1-1.2 µg/L in blood (and serum) and 0.1-2.3 µg/L in urine (spot samples) (Alexandersson, 1988). OCCUPATIONAL DATA Maximum exposure limit Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1997). OTHER TOXICOLOGICAL DATA Carcinogenicity Animal studies suggest cobalt and its compounds are carcinogenic. While several studies have shown that hard metal workers exhibit excess lung cancer mortality, there is inadequate evidence for cobalt or its compounds to be classed as carcinogenic in man (IARC, 1991). Assessment of human cancer risk is often confounded by simultaneous tobacco consumption, exposure to nickel and arsenic and small study population numbers (Mur et al, 1987; Jensen and Tüchsen, 1990). Mur et al (1987) observed excess lung cancer mortality (standardized mortality ratio = 4.66) in 1143 workers employed between 1950 and 1980 in a cobalt and sodium producing plant; smoking habits in the study population were not assessed. A follow-up study from 1981-88 failed to show a relationship between lung cancer and cobalt exposure (Moulin et al, 1993). Lasfargues et al (1994) reported significantly higher lung cancer mortality among 709 hard metal workers (employed for at least one year) compared to controls, though the study was too small to be conclusive. Reprotoxicity Cobalt chloride induced hypoxic testicular damage in rats when administered orally (Mollenhauer et al, 1985). Pedigo and Vernon (1993) observed reversible infertility in male mice exposed to 400 ppm cobalt chloride for 10 weeks. Reduced sperm function led to increased preimplantation embryo loss when these animals were mated. There are no data confirming human reprotoxicity in association with cobalt or cobalt compounds although occupational cobalt exposure has been linked to miscarriages in Finland (Reprotox, 1997; Reprotext, 1997). Genotoxicity Cobalt chloride induced gene conversions in the yeast S cerevisiae (DOSE, 1993). Kasprzak et al (1994) observed oxidative DNA base damage in renal, hepatic and pulmonary chromatin of rats after intraperitoneal injection of cobalt salts. Fish toxicity LC50 (96 hr) carp embryo 96 mg/L. Static bioassay in freshwater, pH 7.5, temperature 16°C, water hardness 360 mg/L CaCO3. The common carp hatching process was impaired by cobalt chloride in a dose related manner. Adult giant gourami exposed to 232.8 mg/L for 24, 72 and 96 hr (freshwater static bioassay, pH 7.5, temperature 23.6°C, water oxygen content 7.6 mg/L and water hardness 164 mg/L CaCO3) showed blood pyruvate concentrations increased by 22, 75 and 47 per cent respectively. LC50 (96 hr) fathead minnow 48 mg/L; lakewater static bioassay, pH 6.5-8.5, temperature 20°C, water hardness 130 mg/L CaCO3. LC50 (48 hr) Olyzias latipes 620 ppm (DOSE, 1993). EC Directive on Drinking Water Quality 80/778/EEC Chlorides: Maximum admissible concentration 25 mg/L. Concentration above which effects might occur 200 mg/L (DOSE, 1993). WHO Guidelines for Drinking Water Quality NIF AUTHORS SM Bradberry BSc MB MRCP P Sabatta MSc 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 Alexander CS. Cobalt-beer cardiomyopathy. 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