What is a cobalt allergy

The symptoms of metal hypersensitivity are caused when the body’s immune system starts to view metal ions as foreign threats. The cells that make up the immune system normally kill foreign bacteria and viruses by causing inflammation. If they start attacking metal ions that you touch, eat, inhale, or own implanted in you, they can produce a variety of symptoms (see the symptoms and complications section, below).

Potential metal allergens (triggers of allergic reactions) are extremely common in everyday life. Typical sources such as watches, coins, and jewellery come readily to mind.

However, there are also other less obvious sources of metal in our daily lives. For example, cosmetic products and contact lens solutions may also contain metals that can trigger a reaction at the area of contact.

Nickel is one of the most frequent allergens, causing significant local contact dermatitis (skin reddening and itching). Cobalt, copper, and chromium are also common culprits. These metals can be found in consumer items such as jewellery, cell phones, and clothing items.

Aside from everyday items, medical devices also contain possible allergens such as chromium and titanium.

Older dental implants and fillings are often made of metals. A few intra-uterine devices (IUDs) for birth control are made of copper and can also cause hypersensitivities. Implantable devices such as artificial knees, artificial hips, pacemakers, stents, and fracture plates, rods, or pins may contain metals that can cause metal hypersensitivity reactions. These reactions are often more severe in nature when the allergens own been implanted within the body for an extended period of time.

In addition, people who already own an autoimmune disorder (a disorder where the immune system is overactive) can own a higher risk of a metal hypersensitivity, as their immune system is in a constant state of activity.


Making the Diagnosis

Your doctor may suspect metal hypersensitivities based on a combination of your personal history and your signs and symptoms. To determine possible causes of metal exposure, your doctor may enquire if you own any type of implants, if you smoke, or if you regularly use any cosmetics.

Aside from a thorough personal history, your doctor may also order laboratory tests to confirm whether you own a metal hypersensitivity.

These tests generally involve giving a blood sample at a laboratory. The laboratory technicians will test the white blood cells for their activity against metal ions by using radioisotopes and microscopically observing physical changes within the cells. If the test shows that the white blood cells own increased activity when exposed to the metal ions, it indicates the presence of a metal hypersensitivity.

A dermatologist can also conduct an allergy test in which they expose various metal ions to your skin to test for a hypersensitivity reaction. This allergy test, which is similar to a regular "scratch test," is often done as a "patch test." The metal ions that are believed to be causing the allergic reaction are applied to a patch, which is then placed on the skin.

The patch is left in put for 48 hours, after which it is removed from the skin at a return visit to the doctor. Skin that is red or irritated under the patch may be an indication of an allergy.


Symptoms and Complications

Signs and symptoms of metal hypersensitivities can range from little and localized to more severe and generalized.

Limited reactions can appear as a contact dermatitis on the skin that has been exposed to the metal. The skin may appear red, swollen, and itchy. Hives and rashes may also develop.

More severe metal hypersensitivity reactions generally happen from prolonged exposure to a metal allergen through implants or metal ions that are inhaled or eaten.

These reactions often cause chronic joint or muscle pain, inflammation, and swelling, leading to generalized fatigue and lack of energy. In addition, fibromyalgia (pain without known cause) and chronic fatigue syndrome can also be seen in people with metal hypersensitivities.

Common symptoms of metal hypersensitivity include:

  1. reddening of skin
  2. cognitive impairment
  3. hives
  4. depression
  5. joint pain
  6. fibromyalgia
  7. chronic inflammation
  8. rash
  9. blistering of the skin
  10. chronic fatigue
  11. muscle pain
  12. swelling

Related conditions

The following symptoms and conditions own been linked to metal hypersensitivity.

If you own any of these conditions, you may wish to speak to your doctor about the possibility of a metal hypersensitivity:

  1. osteomyelitis
  2. chronic fatigue syndrome
  3. fibromyalgia
  4. eczema
  5. rheumatoid arthritis


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UKPID MONOGRAPHCOBALT SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Believe, 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 Toxbase summary Type of product Used in alloys, magnets, in the production of tungsten carbide, in catalysts, pigments and enamels. Toxicity Cobalt and its salts are relatively non toxic by ingestion.

Most cases of cobalt toxicity relate to occupational skin contact or inhalation. Features Topical — Cobalt is a topical irritant and a well recognised cause of occupational contact dermatitis. — Cobalt sensitivity may be the cause of metal prosthesis failure. — Simultaneous allergies to nickel and cobalt are frequent. — Orofacial granulomatosis has been described in association with delayed cobalt hypersensitivity. Ingestion — Nausea, vomiting, abdominal pain.

A transient neutropenia occurred in a six year ancient kid who ingested 2.5 g cobalt chloride. — Congestive cardiomyopathy has been reported after the consumption of large quantities of beer to which cobalt had been added as a foam stabiliser and in those receiving oral cobalt therapy in the treatment of anaemia. Inhalation — Pulmonary toxicity following chronic cobalt exposure is associated typically with the hard metal (tungsten carbide) industry. Symptoms generally arise after several years and may manifest as pneumoconiosis (with dyspnoea and cough secondary to interstitial fibrosis), an allergic alveolitis or occupational asthma.

— Corpulmonale may complicate hard metal pneumoconiosis. — There are occasional reports of cobalt cardiomyopathy following occupational exposure. Management Topical — Removal from exposure is the priority. Remember the cobalt source may not be immediately apparent e.g. in prostheses. Ingestion 1. Supportive care only. Replace fluids and electrolytes as necessary. 2. Gastrointestinal decontamination is not necessary. 3. Check the full blood count. 4. If chronic cobalt ingestion is suspected consider the possibility of cobalt cardiomyopathy and check thyroid function to exclude hypothyroidism. 5. Collect blood and urine for cobalt concentration determination in symptomatic patients.

Cobalt assays are not widely available. Check with NPIS. Inhalation Acute inhalation: 1. Remove from exposure and treat symptomatically. Chronic inhalation: 1. Asthmatic symptoms reply to conventional measures. 2. Established pulmonary fibrosis generally has a poor prognosis. Cyclophosphamide may own a role but seek specialist advice from the NPIS. References Alexander CS. Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty- eight cases. Am J Med 1972; 53: 395-417. 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. Manifold IH, Platts MM, Kennedy A. Cobalt cardiomyopathy in a patient on maintenance haemodialysis. BMJ 1978; 2: 1609. Mucklow ES, Griffin SJ, Delves HT, Suchak B. Cobalt poisoning in a 6-year-old. Lancet 1990; 335: 981. Pryce DW, King CM. Orofacial granulomatosis associated with delayed hypersensitivity to cobalt.

Clin Exp Dermatol 1990; 15: 384-6. 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 Origin of substance Naturally occurring in ores. (DOSE, 1993) Synonyms Aquacat Super cobalt Cobalt-59 (DOSE, 1993) Chemical group A transition metal (d block) element Reference numbers CAS 7440-48-4 (DOSE, 1993 RTECS GF8750000 (RTECS, 1996) UN NIF HAZCHEM CODE NIF Physico-chemical properties Chemical structure Cobalt, Co (DOSE, 1993) Molecular weight 58.93 (DOSE, 1993) Physical state at room temperature Solid Colour Silvery-grey (HSDB, 1996) Odour Odourless (HSDB, 1996) Viscosity NA pH NA Solubility Solubility in water:&lt1 mg/ml at 19°C.

(DOSE, 1993) Soluble in dimethyl sulphide, ethanol and acetone. (HSDB, 1996) Autoignition temperature NIF Chemical interactions Contact of cobalt dust with strong oxidizers may cause fire and explosions. Cobalt will react violently and sometimes explosively with fused ammonium nitrate. (HSDB, 1996) At ambient or slightly elevated temperatures cobalt powder will react violently with bromine pentafluoride, ignition often occurring. (NFPA, 1986) Pyrophoric cobalt decomposes acetylene in freezing and becomes incandescent. (NFPA, 1986) Glowing or white incandescence occurs when nitryl fluoride is passed over cobalt at mild warming temperatures. (HSDB, 1996) Major products of combustion NIF Explosive limits NA Flammability Fire potential moderate when exposed to heat of flame.

(HSDB, 1996) Boiling point 2870°C (DOSE, 1993) Density 8.92 at 20°C (DOSE, 1993) Vapour pressure 0 Pa at 20°C (HSDB, 1996) Relative vapour density NA Flash Point NA Reactivity NIF Uses Cobalt is used widely as an alloying ingredient together with nickel, chromium, molybdenum and other elements. These alloys are utilised in jet aircraft, gas turbines and other equipment operating at high temperatures. Cobalt is an significant constituent of magnets.

Cobalt is the binder employed in the production of tungsten carbide which, due to its toughness and shock resistance, is used in drill bits and machine tools. 60Co, the artificially produced radioisotope is sometimes used in put of x-rays to examine the internal structure of materials. Cobalt oxide is used in the glass and ceramic industries as a pigment, and for enamelling purposes.

What is a cobalt allergy

Cobalt catalysts are used in numerous industrial reactions; cobalt hydrocarbonyl may be used as a catalyst in organic reactions. (PATTY, 1994) Hazard/risk classification Index no. 027-001-00-9 Risk phrases R42/43 — May cause sensitisation by inhalation and skin contact. Safety phrases Xn; S(2-)22-24-37 — Harmful. Hold out of reach of children. Do not breathe dust. Avoid contact with the skin. Wear suitable gloves. EEC no.

231-158-0 (CHIP2, 1994) INTRODUCTION Cobalt is a relatively rare element that generally exists in association with nickel, silver, lead, copper and iron ores. Occupational exposure to cobalt dust occurs mainly in the tungsten carbide industry but has been reported also in diamond polishers (Lahaye et al, 1984) and dental technicians (Sherson et al, 1990). It is an essential dietary trace element as a component of vitamin B12 (cyanocobalamin), each molecule of the vitamin containing one atom of cobalt. Cigarettes contain cobalt but most of this is in the paper of the butt which contains approximately 4 µg cobalt compared to 0.4 µg in the cigarette.

Linnainmaa and Kiilunen (1997) estimated that the butt paper cobalt from 100 cigarettes would need to be absorbed to achieve cobalt uptake equivalent to eight hours exposure to 0.05 mgCo/m3. MECHANISM OF TOXICITY Cobalt interacts with sulphydryl groups to impair thiol-enzyme activities (Alexander, 1972). In in-vitro studies cobalt causes DNA damage and induces the formation of reactive oxygen species in the presence of hydrogen peroxide (Beyersman and Hartwig, 1992).

Cobalt is immunogenic and may act as a hapten in the induction of bronchial and dermal hypersensitivity (Sjögren et al, 1980). Evidence for an autoimmune mechanism in hard-metal lung disease 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 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).

This is probably related to cobalt-thiol group interaction causing citric acid cycle malfunction (Jarvis et al, 1992). The erythropoietic effect of cobalt is attributed to increased erythropoietin release from damaged renal cells (Alexander, 1972). In cobalt pneumoconiosis non-respiratory symptoms of constitutional upset are thought to be due to the release of a tumour necrosis factor (Rolfe et al, 1992).

TOXICOKINETICS Absorption Cobalt can be absorbed orally, by inhalation and dermal exposure (Domingo, 1989; Scansetti et al, 1994). Cobalt and iron share the same transport mechanism within the little intestine such that cobalt ingestion competitively inhibits iron uptake. The extent of intestinal cobalt absorption after ingestion depends on the dose with only some 20 per cent of a large ingestion being absorbed (Domingo, 1989). Some inhaled cobalt undergoes mucociliary clearance while particles which reach the distant pulmonary tree are taken up predominantly by macrophages (Evans et al, 1993).

Distribution The normal body burden of cobalt is about 1.1 mg. Approximately 43 per cent is in muscle with some 14 per cent in bone and the remainder in other soft tissues (Domingo, 1989). Excretion Cobalt which reaches the systemic circulation is eliminated predominantly in urine with a variable but little quantity excreted in bile (Domingo, 1989). Following acute occupational cobalt exposure the urinary elimination of cobalt is rapid for the first 24 hours followed by a slower excretion phase lasting several weeks (Alexandersson, 1988).

A little proportion of retained cobalt has a biological half-life of several years (Elinder and Friberg, 1986). CLINICAL FEATURES: ACUTE EXPOSURE Ingestion Cobalt salts are relatively non-toxic but ingestion may lead to gastrointestinal and rarely transient haematological disturbance (see below). Gastrointestinal toxicity A six year-old boy developed nausea and vomiting 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 serum cobalt concentration some seven hours post ingestion was 434 µg/L (normal range &lt1 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 a little (undetermined) quantity of cobalt chloride from her brother’s chemistry set. The serum cobalt concentration 12 hours post ingestion was 78 µg/L. Haemotoxicity A six year ancient boy who ingested 2.5 g cobalt chloride (Mucklow et al 1990) developed a transient neutropenia (1.7 x 109/L) but recovered fully.

CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Cobalt is a topical irritant (Fischer and Rystedt, 1985) and a well recognised cause of occupational contact dermatitis which has been described in hard metal workers (Cugell, 1992), printers, builders (Kiec-Swierczynska, 1990; Irvine et al, 1994) and employees in the rubber (Foussereau and Cavelier, 1988) and glass-fibre-reinforced plastics (Tarvainen et al, 1993) industries. Cobalt sensitivity may also be caused by exposure to jewellery, metal buttons, plastics and domestic detergents (Castiglioni et al, 1992). Photosensitization to cobalt has been reported (Camarasa and Alomar, 1981; Manciet et al, 1995).

Cobalt contact allergy is an significant cause of metal prosthesis failure with joint loosening and dislocation, local bone resorption and fractures (Jones et al, 1975). There may be an associated dermatitis which can spread beyond the primary irritation site (Merle et al, 1992). A widespread allergic vasculitis due to cobalt sensitivity from a cobalt alloy prosthesis has also been described (Munrow-Ashman and Miller, 1976). Dental prostheses containing cobalt also own caused local irritation with gingivitis and stomatitis in addition to a remote dermatitis (Hildebrand et al, 1989).

A 56 year-old lady developed intense pain and burning of the lips, with oedema and erosive lesions following implantation of a dental prosthesis in the superior dental arch. The prosthesis was mainly composed of a methylacrylate containing cobalt, chromium and nickel. A series of patch tests revealed an isolated strong positivity for cobalt chloride. This was the first report in which hypersensitivity to cobalt in a dental prosthesis was suggested as a possible cause of erosive oral lichen planus (Torresani et al, 1994).

Simultaneous allergies to nickel and cobalt are frequent (Burden and Eedy, 1991) and there is some evidence for a mutual enhancing effect of contact sensitization to one metal in the presence of the other (Domingo, 1989). The istration 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).

Pryce and King (1990) described a patient with orofacial granulomatosis in association with delayed cobalt hypersensitivity suggesting that this condition is allergy — based. The source of cobalt was traced to plastic pens and crayons which the patient sucked frequently. Tattoos containing cobalt own also initiated a granulomatous reaction (Ro and Lee, 1991). Ingestion Gastrointestinal toxicity Gastrointestinal symptoms similar to those occurring after acute cobalt salt ingestion own also complicated chronic therapy.

A 35 year-old lady with anaemia treated with cobalt chloride 25 mg qds complained of nausea, vomiting and weight loss in addition to the neurological symptoms described under (Schirrmacher, 1967). Cardiovascular toxicity Congestive cardiomyopathy has been reported in people who drank large quantities of beer to which cobalt 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 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 polycythemia 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 raised plasma cardiac enzyme concentrations.

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 little (up to 10 mg daily) (Kesteloot et al, 1968; Alexander, 1972).

What is a cobalt allergy

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 that renal failure haemodialysis patients treated with oral cobalt chloride had significantly higher (p=0.001) blood cobalt concentrations than patients who had not received cobalt thus identifying renal failure patients as an ‘at risk’ group for cobalt toxicity (see below).

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 lady developed limb paraesthesiae, an unsteady gait, impaired hearing and dizzy spells in addition to nausea, vomiting and weight loss (Schirrmacher, 1967).

What is a cobalt allergy

Clinical examination confirmed bilateral nerve deafness, absent ankle reflexes and impaired vibration sense which every resolved with four months of cobalt withdrawal. Haemotoxicity Chronic ingestion of excess cobalt causes polycythaemia which in the past led to its use in the treatment of anaemia (Manifold et al, 1978). A 13 month-old kid 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 finish 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 drop 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 recognised side-effect of cobalt therapy (Schirrmacher, 1967).

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). 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 own 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). Lung disease in the hard metal industry is more common among workers exposed to ionized cobalt (dissolved in machine coolants) than in those exposed to dry (non-ionized) cobalt dusts even though the dust-exposed group generally work in the highest ambient air cobalt concentrations (Cugell, 1992).

There is some debate concerning whether cobalt exposure alone is sufficient to cause pulmonary fibrosis. In-vitro and animal studies propose 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&lt0.05) 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. Patients generally present with exertional dyspnoea, cough and sometimes chest tightness (Bech et al, 1962). There may be associated constitutional 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 1 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 corpulmonale may ensue. Chest x-ray findings vary greatly (Cugell et al, 1990) but generally show increased linear markings and little nodular opacities in the lower (and mid) zones with later cardiomegaly and features of pulmonary hypertension (Bech et al, 1962). Numerous patients develop a form of pulmonary fibrosis complicated by atypical intraalveolar giant cells (Davison et al, 1983; Rochat et al, 1987; Cugell, 1992) which can be demonstrated in bronchoalveolar lavage fluid (Forni, 1994).

Forni (1994) suggested that a persistently high bronchoalveolar lavage eosinophil count despite steroid therapy and cessation of exposure carried an unfavourable prognosis in patients with hard metal lung disease. Several fatalities from hard metal pneumoconiosis own 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 own exacerbated this man’s deterioration via cobalt-induced hydroxyl free radical formation. Allergic alveolitis An allergic alveolitis has been described in hard-metal workers with cough, dyspnoea and flu-like symptoms associated with bilateral crackles, radiographic little 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 own 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 (&gt40 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).

There was no significant difference in asthma prevalence between those exposed to the elemental (dust) or ionised (mist) metal (Kusaka et al, 1996a). Cobalt asthma is associated in some, but not every, cases with circulating cobalt-specific IgE and generalised 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 radiographic features of pulmonary hypertension and correct heart failure (Bech et al, 1962).

Cobalt cardiomyopathy is most frequently associated with chronic excess cobalt ingestion (see above) but an identical syndrome has been reported occasionally in those occupationally exposed (Barborik et al, 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). Neurotoxicity Jordan et al (1990) reported significantly impaired attention (p&lt0.05) and verbal (p&lt0.001) memory 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, every members of the study group had «pulmonary manifestations» of hard metal disease which may own affected performance.

A patient occupational exposed (mainly via inhalation) to cobalt dust for 20 months developed bilateral optic atrophy and bilateral nerve deafness. Fourteen months after stopping work visual activity 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.

MANAGEMENT Dermal exposure Removal from exposure is the priority. It is significant to remember that the cobalt source may not be immediately apparent, for example, when in a dental or other prosthesis. The role of chelation therapy in cobalt contact sensitivity is discussed under. Inhalation Removal from exposure is the principle requirement. The possibility of cobalt cardiotoxicity should be remembered in those in whom exposure is chronic. Asthmatic symptoms reply to conventional measures (Pisati and Zedda, 1994). Established pulmonary fibrosis has a generally poor prognosis although there are reports of substantial improvement following removal from the workplace (Zanelli et al, 1994).

The role of blood and urine cobalt concentration measurements is discussed under (Medical Surveillance). Ingestion Decontamination Gastric lavage is unnecessary as cobalt ingestion produces only low acute oral toxicity and there is no evidence that oral activated charcoal reduces gastrointestinal cobalt absorption. Supportive measures Following acute cobalt salt ingestion supportive care is generally every that is required with intravenous fluid replacement if vomiting is severe. 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 under (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 DMSA Aposhian (1983) reported early animal studies published in the Chinese literature in 1965 which showed that DMSA (4 mmol/kg, route not stated) increased the LD50 of cobalt chloride-poisoned mice some three times.

Four of ten mice istered 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 calcium EDTA or DTPA (diethylenetriamine- pentacetic acid) (see below). DTPA Llobet et al (1986) reported a 70 per cent two week survival rate in mice istered intraperitoneal DTPA (3.1 mmol/kg) immediately following intraperitoneal loading with 1.8 mmol/kg cobalt chloride (a dose in excess of the LD95). Calcium EDTA Every mice istered intraperitoneal cobalt chloride at doses approximating to the LD50-LD95 (0.6-1.8 mmol/kg), immediately followed by 4.3 mmol/kg intraperitoneal calcium EDTA (ethylenediamine tetraacetic acid) survived two weeks with significantly increased urine cobalt elimination in the 24 hours post antidote istration (Llobet et al, 1986).

Allenby and Basketter (1989) found that 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 EDTA solution. No cobalt was recovered in the urine of a patient with cobalt cardiomyopathy who received a one week course of calcium EDTA (and penicillamine, doses not stated) but treatment was not instituted until three years after cobalt ingestion (quantity not stated) (Alexander, 1972).

The use of topical EDTA in cobalt dermatitis is discussed above (dermal exposure). 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 of low-dose (25 mg bd) cyclophosphamide therapy. 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 drop 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 istered 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) and periodic assessment for pulmonary or dermatological symptoms are significant in the prevention of cobalt toxicity. The recommended maximum exposure limit (eight-hour time weighted average 1995) in the UK for cobalt is 0.1 mg/m3 (Health and Safety Executive, 1995).

Some studies propose that airborne cobalt concentrations are frequently underestimated (Auchincloss et al, 1992; Mosconi et al, 1994) and other workers recently own 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 own 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 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 specific 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 are frequently encountered in hard metal workers (Ichikawa et al, 1985; Stebbins et al, 1992) but are more useful as grouped rather than individual data (Sabbioni et al, 1994) and their significance requires careful interpretation. 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 while urine and blood cobalt concentrations correlate reasonably well with recent exposure to soluble forms of cobalt (as in hard metal powders) the same is not true following exposure to insoluble cobalt oxide.

No evidence of hard a metal pneumoconiosis or significantly excess heart disease was found in controlled study of 49 workers exposed to cobalt and cobalt oxides despite the presence of high urine cobalt concentrations (mean 340 g/L) (Morgan, 1983). OCCUPATIONAL DATA Maximum exposure limit Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1995). OTHER TOXICOLOGICAL DATA Carcinogenicity Animal studies propose cobalt and its compounds are carcinogenic.

While several studies own confirmed that hard metal workers exhibit excess lung cancer mortality, there is no strong evidence that cobalt or its compounds are carcinogenic in man (IARC, 1991). Assessment of human cancer risk is often confounded by simultaneous tobacco consumption, exposure to nickel and arsenic and little study population numbers (Mur et al, 1987; Jensen and Tüchsen, 1990). Mur et al (1987) observed an excess mortality form lung cancer (standardized mortality ratio = 4.66) in 1143 workers employed between 1950-1980 in a cobalt and sodium producing plant; smoking habits in the study population were not assessed.

Further follow-up from 1981-88 failed to show a relationship between lung cancer and cobalt exposure (Moulin et al, 1993). Lasfargues et al (1994) reported a significantly higher mortality from lung cancer among 709 hard metal workers (employed for at least one year) compared to controls, though the study was too little to be conclusive. Reprotoxicity There is no conclusive evidence regarding the reprotoxicity of cobalt (Reprotox, 1996). Ratto et al, (1988) reported a successful pregnancy in a 31 year-old lady despite severe cobalt pneumoconiosis requiring systemic steroids and cyclophosphamide.

Genotoxicity Salmonella typhimurium TA98, TA102, TA1535, TA1537 with metabolic activation negative; TA98, TA1537 without metabolic activation positive. Induced DNA strand breaks in human diploid fibroblasts and Chinese hamster ovary cells in vitro. In vivo rats 0.005 mg/kg cobalt metal in drinking water caused no mutagenic effects (DOSE, 1993). Fish toxicity LC50 (96 hr) fathead minnow 92 mg/L Rainbow trout tolerated 7 day exposure to 30 mg (Co)/L. Lethal limit 35 mg (Co)/L (DOSE, 1993). EC Directive on Drinking Water Quality 80/778/EEC NIF AUTHORS SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Believe, 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.

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Cobalt exposure and lung disease in tungsten carbide production. A cross-sectional study of current workers.

What is a cobalt allergy

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UKPID MONOGRAPHCOBALT SULPHATE 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 Believe, 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 SULPHATE Toxbase summary Type of product Used in manufacture of vitamin B12, storage batteries, varnishes, inks, pigments, enamels, glazes, in electroplating and removal of atmospheric pollutants in waste gases. Toxicity There are no case reports of acute cobalt sulphate poisoning over at least the final 30 years. Cobalt sensitization may happen following chronic dermal exposure. Features Dermal — Cobalt sulphate is a topical irritant and a recognized cause of occupational contact dermatitis.

— Simultaneous allergies to nickel and cobalt are frequent. Ocular — Cobalt sulphate 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 little ingestions. Nausea, vomiting and/or abdominal pain are likely after more substantial ingestions and there is a risk of gastrointestinal corrosion from concentrated solutions which are acidic. — Transient neutropenia occurred in a six year ancient kid who ingested 2.5 g cobalt chloride (Mucklow et al, 1990). — In the past congestive cardiomyopathy occurred after the consumption of large quantities of beer to which cobalt sulphate/chloride had been added as a foam stabilizer.

— Chronic cobalt (as chloride) ingestion has 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 generally arises after several years and may manifest as pneumoconiosis (with dyspnoea and cough secondary to interstitial fibrosis), an 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 happen spontaneously following significant ingestions and gastric lavage is contraindicated following ingestion of acidic solutions. 2. Supportive care is the priority. Replace fluids and electrolytes as necessary.

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 reply to conventional measures.

2. Established pulmonary fibrosis generally has a poor prognosis although cases own responded to high dose prednisolone (Rolfe et al, 1992) or cyclophosphamide (Balmes, 1987). Seek specialist advice from the NPIS. 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. Sertoli A, Fabbri P, Spallanzani P, Giannotti B. Unusual contact dermatitis to a cobalt salt. Contact Dermatitis 1978; 4: 314. 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) sulphate Origin of substance Hexahydrate occurs in nature as the mineral bieberite. (DOSE, 1993) Synonyms Cobaltous sulphate Cobalt monosulphate (DOSE, 1993) Sulphuric acid, cobalt(II) salt (RTECS, 1997) Chemical group A compound of cobalt, a group VIIIB element. Reference Numbers CAS 10124-43-3 (DOSE, 1993) RTECS GG 3100000 (RTECS, 1997) UN NIF HAZCHEM NIF Physicochemical properties Chemical structure CoSO4 (DOSE, 1993) Molecular weight 154.99 (DOSE, 1993) Physical state at room temperature Solid (HSDB, 1997) Colour Pink/Red (CHRIS, 1997) Odour None (CHRIS, 1997) Viscosity NA pH Forms acidic solution in water.

(OHM/TADS, 1997) Solubility 362 g/L at 20°C (DOSE, 1993) Autoignition temperature NA Chemical interactions Contact of dust with strong oxidizers may cause fire and explosions. (HSDB, 1997) Major products of combustion Toxic cobalt oxide fumes may form in fire. (HSDB, 1997) Explosive limits NA Flammability Not flammable (CHRIS, 1997) Boiling point Decomposes at 735°C. (OHM/TADS, 1997) Density 3.71 at 25°C (DOSE, 1993) Vapour pressure NA Relative vapour density NA Flash point NA Reactivity Cobalt sulphate heptahydrate dehydrates on heating (41.5°C) to the hexahydrate and to the monohydrate at 71°C. (HSDB, 1997) Uses Removal of atmospheric pollutants in waste gases Humidity indicator Manufacture of vitamin B12 Storage batteries and electroplating Drier for varnishes and lithographic inks Used in pigments, ceramics, enamels and glazes (DOSE, 1993) Hazard/risk classification NIF INTRODUCTION AND EPIDEMIOLOGY Cobalt sulphate is a water soluble bivalent cobalt salt.

Acute poisoning by ingestion is rare with no reported cases in at least the final 30 years. Outbreaks of chronic cobalt intoxication (manifest as cardiomyopathy) occurred in Belgium, Nebraska and Quebec in the 1960’s among heavy beer drinkers when a cobalt salt was added to beer as a foam stabilizer (Kesteloot et al, 1968). Occupational cobalt contact dermatitis has occurred from cobalt sulphate in varnishes, paints (Zenorola et al, 1994) and humidity indicators (Sertoli et al, 1978). 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). As discussed under (Chronic exposure) ionized cobalt (though not specifically cobalt sulphate) contributes significantly to the development of hard metal lung disease.

Evidence for an autoimmune mechanism in this condition 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 below haem to biliverdin (Taylor and Marks, 1978; Timbrell, 1994). TOXICOKINETICS Absorption Cobalt sulphate can be absorbed following inhalation, ingestion and dermal exposure (Domingo, 1989; Scansetti et al, 1994; Linnainmaa and Kiilunen, 1997).

Cobalt and iron share the same transport mechanism within the little 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 sulphate 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 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 little quantity 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 little proportion of retained cobalt has a biological half-life of several years (Elinder and Friberg, 1986). CLINICAL FEATURES: ACUTE EXPOSURE Dermal exposure Cobalt sulphate may cause skin irritation but dermal toxicity is associated primarily with contact sensitivity (see Chronic exposure). Ocular exposure Cobalt compounds cause 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 sulphate inhalation. Ingestion Acute cobalt sulphate ingestion has not been reported for at least 30 years but similar features to those reported after cobalt chloride ingestion would be anticipated. Gastrointestinal toxicity Jacobziner and Raybin (1961) reported a 19 month-old kid 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 kid was peripherally cyanosed and pale. The lips and tongue were oedematous. The child’s 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 propose the cobalt chloride solution was highly concentrated and corrosive. Cobalt was identified in the liver, kidney, spleen (89 mg entire 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 &lt 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 ancient 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 kid who ingested 30 mL of a cobalt chloride solution became restless and drowsy within two hours, in association with 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 when cobalt compounds are the primary allergen.

For example, cobalt sulphate used as a humidity indicator in shipment containers caused contact dermatitis in a 48 year-old labourer (Sertoli et al, 1978). A 71 year-old construction worker 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. Cobalt sulphate in the varnishes and paints with which he worked were potential sources of cobalt exposure. An initial irritant dermatitis, often involving operations traumatic to the hand, generally precedes cobalt allergy in industry (Fischer and Rystedt, 1983a). In addition , untrue positive cobalt patch tests may happen due to an irritant rather than delayed hypersensitivity response (Fischer and Rystedt, 1985).

Soluble cobalt salts are used widely in patch testing (Smith et al, 1975; Munro-Ashman and Miller, 1976; Veien and Svejgaard, 1978; Schmidt et al, 1980; Rae, 1981; Romaguera et al, 1982; Miyachi et al, 1985; Matsunaga et al, 1988; 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 people 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.

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 own 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 propose 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&lt0.05) 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.

Patients generally 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 generally show increased linear markings and little nodular opacities in the lower (and mid) zones with later cardiomegaly and features of pulmonary hypertension (Bech et al, 1962). Numerous 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 own 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 own exacerbated this man’s deterioration via cobalt-induced hydroxyl free radical formation. A 37 year-old female developed rapidly progressive pneumoconiosis after working for seven years, without respiratory protection, 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 cobalt concentration in bronchoalveolar lavage fluid was increased on presentation (2 µg/L, reference worth 0.6 µg/L) the lung 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 little 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 own 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 (&gt40 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 every, 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 correct 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&lt0.05) and verbal memory (p&lt0.001) 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, every members of the study group had «pulmonary manifestations» of hard metal disease which may own 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 There are no reports of cobalt sulphate ingestion during the final 35 years, though effects similar to those experienced following cobalt chloride ingestion may be expected.

Dermal toxicity There is some evidence that ingested cobalt sulphate can trigger a delayed cutaneous hypersensitivity reaction in those already sensitized, although the potential benefit of reduced dietary cobalt in these patients has not been clarified. In one study (Veien et al, 1987) 28 of 42 patients with a positive cobalt patch test experienced a dermatitis flare following 1 mg oral cobalt sulphate. The istration of oral 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 A 35 year-old lady 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 triglycleride concentrations own been noted in cobalt-treated anephric patients (Taylor and Marks, 1978). This is most probably related to cobalt-induced lipoprotein lipase inhibition. Cardiovascular toxicity Congestive cardiomyopathy has been reported in people who drank large quantities of beer to which a cobalt salt had been added as foam stabilizers (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 polycythemia 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 little (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 lady 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.

Every 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 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 kid 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 finish 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 drop 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 own 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 sulphate 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 reply to topical or systemic steroids.

The role of chelation therapy in cobalt contact sensitivity is discussed under. 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 reply 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 under (Medical Surveillance). Ingestion Decontamination Gastric lavage is unlikely to be helpful since if spontaneous vomiting does not happen the ingestion is almost certainly too little 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 sulphate ingestion supportive care is generally every 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, electrolytes and a 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 under (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 istered 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. Every mice istered 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 istration (Llobet et al, 1986). Llobet et al (1988) later demonstrated significantly increased (p&lt0.05) faecal but not urinary cobalt elimination during a five day course of chelation therapy in rats poisoned with intraperitoneal cobalt chloride (0.06 mmol/kg/day three days each week for four weeks).

Clinical studies Topical Allenby and Basketter (1989) found that a positive patch test 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 kid 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) reported early animal studies published in the Chinese literature (in 1965) which showed that DMSA (4 mmol/kg, route not stated) increased three fold the LD50 of cobalt chloride-poisoned mice.

Four of ten mice istered 1.8 mmol/kg intraperitoneal cobalt (as 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-pentaacetic acid) (see below). DMSA 1.2 mmol/kg/day intraperitoneally increased urine cobalt excretion significantly (p&lt0.01) only on the final (fifth) day of chelation in rats poisoned with intraperitoneal cobalt chloride (0.06 mmol/kg/day 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&lt0.05 days one, two and four, p&lt0.01 day three). DTPA Animal studies Llobet et al (1986) reported 70 per cent two week survival in mice istered 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&lt0.05) enhanced faecal and urinary cobalt elimination.

Other chelating agents Animal studies Intraperitoneal L-histidine 2.7 mmol/kg istered 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 rats given cobalt chloride only (Domingo et al, 1985a). Domingo et al (1985b) suggested that N-acetylcysteine (NAC) was ineffective in reducing experimental cobalt fatalities unless istered as a cobalt-NAC chelate.

What is a cobalt allergy

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&lt0.05 and p&lt0.01 respectively) increased urine and faecal cobalt excretion in cobalt-poisoned rats, with a significant (p&lt0.05) reduction in the spleen cobalt concentration compared to controls. Clinical studies Topical clioquinol one per cent significantly (p&lt0.001) 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 repeatedly and this 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 propose 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 worth of cobalt chelation may be limited where immunological mechanisms frolic an significant 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 drop 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 istered 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 significant in the prevention of cobalt toxicity.

Some studies propose airborne cobalt concentrations frequently are underestimated (Auchincloss et al, 1992; Mosconi et al, 1994) and other workers recently own 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 own 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 specific 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 propose cobalt and its compounds are carcinogenic. While several studies own 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 little study population numbers (Mur et al, 1987; Jensen and Tüchsen, 1990). Mur et al (1987) observed increased 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 little to be conclusive. Reprotoxicity Soluble cobalt salts damage the testis in rats when istered 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 Soluble cobalt salts own 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 (as cobalt) LC50 (96 hr) fathead minnow 92 mg/L. Rainbow trout tolerated 7 day exposure to 30 mg (Co)/L. Lethal limit 35 mg (Co)/L (DOSE, 1993).

EC Directive on Drinking Water Quality 80/778/EEC NIF 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 Believe, 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.

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Keywords

metal implant allergy — metal hypersensitivity — titanium allergy

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UKPID MONOGRAPHCOBALT SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Believe, 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 Toxbase summary Type of product Used in alloys, magnets, in the production of tungsten carbide, in catalysts, pigments and enamels. Toxicity Cobalt and its salts are relatively non toxic by ingestion. Most cases of cobalt toxicity relate to occupational skin contact or inhalation. Features Topical — Cobalt is a topical irritant and a well recognised cause of occupational contact dermatitis.

— Cobalt sensitivity may be the cause of metal prosthesis failure. — Simultaneous allergies to nickel and cobalt are frequent. — Orofacial granulomatosis has been described in association with delayed cobalt hypersensitivity. Ingestion — Nausea, vomiting, abdominal pain. A transient neutropenia occurred in a six year ancient kid who ingested 2.5 g cobalt chloride. — Congestive cardiomyopathy has been reported after the consumption of large quantities of beer to which cobalt had been added as a foam stabiliser and in those receiving oral cobalt therapy in the treatment of anaemia. Inhalation — Pulmonary toxicity following chronic cobalt exposure is associated typically with the hard metal (tungsten carbide) industry.

Symptoms generally arise after several years and may manifest as pneumoconiosis (with dyspnoea and cough secondary to interstitial fibrosis), an allergic alveolitis or occupational asthma. — Corpulmonale may complicate hard metal pneumoconiosis. — There are occasional reports of cobalt cardiomyopathy following occupational exposure. Management Topical — Removal from exposure is the priority. Remember the cobalt source may not be immediately apparent e.g. in prostheses.

Ingestion 1. Supportive care only. Replace fluids and electrolytes as necessary. 2. Gastrointestinal decontamination is not necessary. 3. Check the full blood count. 4. If chronic cobalt ingestion is suspected consider the possibility of cobalt cardiomyopathy and check thyroid function to exclude hypothyroidism. 5. Collect blood and urine for cobalt concentration determination in symptomatic patients. Cobalt assays are not widely available. Check with NPIS. Inhalation Acute inhalation: 1. Remove from exposure and treat symptomatically.

Chronic inhalation: 1. Asthmatic symptoms reply to conventional measures. 2. Established pulmonary fibrosis generally has a poor prognosis. Cyclophosphamide may own a role but seek specialist advice from the NPIS. References Alexander CS. Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty- eight cases. Am J Med 1972; 53: 395-417. 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. Manifold IH, Platts MM, Kennedy A. Cobalt cardiomyopathy in a patient on maintenance haemodialysis. BMJ 1978; 2: 1609. Mucklow ES, Griffin SJ, Delves HT, Suchak B. Cobalt poisoning in a 6-year-old. Lancet 1990; 335: 981. Pryce DW, King CM. Orofacial granulomatosis associated with delayed hypersensitivity to cobalt. Clin Exp Dermatol 1990; 15: 384-6. 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 Origin of substance Naturally occurring in ores. (DOSE, 1993) Synonyms Aquacat Super cobalt Cobalt-59 (DOSE, 1993) Chemical group A transition metal (d block) element Reference numbers CAS 7440-48-4 (DOSE, 1993 RTECS GF8750000 (RTECS, 1996) UN NIF HAZCHEM CODE NIF Physico-chemical properties Chemical structure Cobalt, Co (DOSE, 1993) Molecular weight 58.93 (DOSE, 1993) Physical state at room temperature Solid Colour Silvery-grey (HSDB, 1996) Odour Odourless (HSDB, 1996) Viscosity NA pH NA Solubility Solubility in water:&lt1 mg/ml at 19°C.

(DOSE, 1993) Soluble in dimethyl sulphide, ethanol and acetone. (HSDB, 1996) Autoignition temperature NIF Chemical interactions Contact of cobalt dust with strong oxidizers may cause fire and explosions. Cobalt will react violently and sometimes explosively with fused ammonium nitrate. (HSDB, 1996) At ambient or slightly elevated temperatures cobalt powder will react violently with bromine pentafluoride, ignition often occurring. (NFPA, 1986) Pyrophoric cobalt decomposes acetylene in freezing and becomes incandescent. (NFPA, 1986) Glowing or white incandescence occurs when nitryl fluoride is passed over cobalt at mild warming temperatures.

(HSDB, 1996) Major products of combustion NIF Explosive limits NA Flammability Fire potential moderate when exposed to heat of flame. (HSDB, 1996) Boiling point 2870°C (DOSE, 1993) Density 8.92 at 20°C (DOSE, 1993) Vapour pressure 0 Pa at 20°C (HSDB, 1996) Relative vapour density NA Flash Point NA Reactivity NIF Uses Cobalt is used widely as an alloying ingredient together with nickel, chromium, molybdenum and other elements. These alloys are utilised in jet aircraft, gas turbines and other equipment operating at high temperatures.

Cobalt is an significant constituent of magnets. Cobalt is the binder employed in the production of tungsten carbide which, due to its toughness and shock resistance, is used in drill bits and machine tools. 60Co, the artificially produced radioisotope is sometimes used in put of x-rays to examine the internal structure of materials. Cobalt oxide is used in the glass and ceramic industries as a pigment, and for enamelling purposes. Cobalt catalysts are used in numerous industrial reactions; cobalt hydrocarbonyl may be used as a catalyst in organic reactions.

(PATTY, 1994) Hazard/risk classification Index no. 027-001-00-9 Risk phrases R42/43 — May cause sensitisation by inhalation and skin contact. Safety phrases Xn; S(2-)22-24-37 — Harmful. Hold out of reach of children. Do not breathe dust. Avoid contact with the skin. Wear suitable gloves. EEC no. 231-158-0 (CHIP2, 1994) INTRODUCTION Cobalt is a relatively rare element that generally exists in association with nickel, silver, lead, copper and iron ores. Occupational exposure to cobalt dust occurs mainly in the tungsten carbide industry but has been reported also in diamond polishers (Lahaye et al, 1984) and dental technicians (Sherson et al, 1990).

It is an essential dietary trace element as a component of vitamin B12 (cyanocobalamin), each molecule of the vitamin containing one atom of cobalt. Cigarettes contain cobalt but most of this is in the paper of the butt which contains approximately 4 µg cobalt compared to 0.4 µg in the cigarette. Linnainmaa and Kiilunen (1997) estimated that the butt paper cobalt from 100 cigarettes would need to be absorbed to achieve cobalt uptake equivalent to eight hours exposure to 0.05 mgCo/m3. MECHANISM OF TOXICITY Cobalt interacts with sulphydryl groups to impair thiol-enzyme activities (Alexander, 1972).

In in-vitro studies cobalt causes DNA damage and induces the formation of reactive oxygen species in the presence of hydrogen peroxide (Beyersman and Hartwig, 1992). Cobalt is immunogenic and may act as a hapten in the induction of bronchial and dermal hypersensitivity (Sjögren et al, 1980). Evidence for an autoimmune mechanism in hard-metal lung disease 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 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).

This is probably related to cobalt-thiol group interaction causing citric acid cycle malfunction (Jarvis et al, 1992). The erythropoietic effect of cobalt is attributed to increased erythropoietin release from damaged renal cells (Alexander, 1972). In cobalt pneumoconiosis non-respiratory symptoms of constitutional upset are thought to be due to the release of a tumour necrosis factor (Rolfe et al, 1992).

TOXICOKINETICS Absorption Cobalt can be absorbed orally, by inhalation and dermal exposure (Domingo, 1989; Scansetti et al, 1994). Cobalt and iron share the same transport mechanism within the little intestine such that cobalt ingestion competitively inhibits iron uptake. The extent of intestinal cobalt absorption after ingestion depends on the dose with only some 20 per cent of a large ingestion being absorbed (Domingo, 1989). Some inhaled cobalt undergoes mucociliary clearance while particles which reach the distant pulmonary tree are taken up predominantly by macrophages (Evans et al, 1993). Distribution The normal body burden of cobalt is about 1.1 mg.

Approximately 43 per cent is in muscle with some 14 per cent in bone and the remainder in other soft tissues (Domingo, 1989). Excretion Cobalt which reaches the systemic circulation is eliminated predominantly in urine with a variable but little quantity excreted in bile (Domingo, 1989). Following acute occupational cobalt exposure the urinary elimination of cobalt is rapid for the first 24 hours followed by a slower excretion phase lasting several weeks (Alexandersson, 1988).

A little proportion of retained cobalt has a biological half-life of several years (Elinder and Friberg, 1986). CLINICAL FEATURES: ACUTE EXPOSURE Ingestion Cobalt salts are relatively non-toxic but ingestion may lead to gastrointestinal and rarely transient haematological disturbance (see below). Gastrointestinal toxicity A six year-old boy developed nausea and vomiting 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 serum cobalt concentration some seven hours post ingestion was 434 µg/L (normal range &lt1 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 a little (undetermined) quantity of cobalt chloride from her brother’s chemistry set.

The serum cobalt concentration 12 hours post ingestion was 78 µg/L. Haemotoxicity A six year ancient boy who ingested 2.5 g cobalt chloride (Mucklow et al 1990) developed a transient neutropenia (1.7 x 109/L) but recovered fully. CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Cobalt is a topical irritant (Fischer and Rystedt, 1985) and a well recognised cause of occupational contact dermatitis which has been described in hard metal workers (Cugell, 1992), printers, builders (Kiec-Swierczynska, 1990; Irvine et al, 1994) and employees in the rubber (Foussereau and Cavelier, 1988) and glass-fibre-reinforced plastics (Tarvainen et al, 1993) industries.

Cobalt sensitivity may also be caused by exposure to jewellery, metal buttons, plastics and domestic detergents (Castiglioni et al, 1992). Photosensitization to cobalt has been reported (Camarasa and Alomar, 1981; Manciet et al, 1995). Cobalt contact allergy is an significant cause of metal prosthesis failure with joint loosening and dislocation, local bone resorption and fractures (Jones et al, 1975). There may be an associated dermatitis which can spread beyond the primary irritation site (Merle et al, 1992).

A widespread allergic vasculitis due to cobalt sensitivity from a cobalt alloy prosthesis has also been described (Munrow-Ashman and Miller, 1976). Dental prostheses containing cobalt also own caused local irritation with gingivitis and stomatitis in addition to a remote dermatitis (Hildebrand et al, 1989). A 56 year-old lady developed intense pain and burning of the lips, with oedema and erosive lesions following implantation of a dental prosthesis in the superior dental arch. The prosthesis was mainly composed of a methylacrylate containing cobalt, chromium and nickel.

A series of patch tests revealed an isolated strong positivity for cobalt chloride. This was the first report in which hypersensitivity to cobalt in a dental prosthesis was suggested as a possible cause of erosive oral lichen planus (Torresani et al, 1994). Simultaneous allergies to nickel and cobalt are frequent (Burden and Eedy, 1991) and there is some evidence for a mutual enhancing effect of contact sensitization to one metal in the presence of the other (Domingo, 1989). The istration 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).

Pryce and King (1990) described a patient with orofacial granulomatosis in association with delayed cobalt hypersensitivity suggesting that this condition is allergy — based. The source of cobalt was traced to plastic pens and crayons which the patient sucked frequently. Tattoos containing cobalt own also initiated a granulomatous reaction (Ro and Lee, 1991). Ingestion Gastrointestinal toxicity Gastrointestinal symptoms similar to those occurring after acute cobalt salt ingestion own also complicated chronic therapy. A 35 year-old lady with anaemia treated with cobalt chloride 25 mg qds complained of nausea, vomiting and weight loss in addition to the neurological symptoms described under (Schirrmacher, 1967).

Cardiovascular toxicity Congestive cardiomyopathy has been reported in people who drank large quantities of beer to which cobalt 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 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 polycythemia 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 raised plasma cardiac enzyme concentrations.

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 little (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 that renal failure haemodialysis patients treated with oral cobalt chloride had significantly higher (p=0.001) blood cobalt concentrations than patients who had not received cobalt thus identifying renal failure patients as an ‘at risk’ group for cobalt toxicity (see below). 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 lady 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 which every resolved with four months of cobalt withdrawal.

Haemotoxicity Chronic ingestion of excess cobalt causes polycythaemia which in the past led to its use in the treatment of anaemia (Manifold et al, 1978). A 13 month-old kid 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 finish 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 drop 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 recognised side-effect of cobalt therapy (Schirrmacher, 1967). 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). 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 own 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).

Lung disease in the hard metal industry is more common among workers exposed to ionized cobalt (dissolved in machine coolants) than in those exposed to dry (non-ionized) cobalt dusts even though the dust-exposed group generally work in the highest ambient air cobalt concentrations (Cugell, 1992). There is some debate concerning whether cobalt exposure alone is sufficient to cause pulmonary fibrosis. In-vitro and animal studies propose 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&lt0.05) 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.

Patients generally present with exertional dyspnoea, cough and sometimes chest tightness (Bech et al, 1962). There may be associated constitutional 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 1 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 corpulmonale may ensue.

Chest x-ray findings vary greatly (Cugell et al, 1990) but generally show increased linear markings and little nodular opacities in the lower (and mid) zones with later cardiomegaly and features of pulmonary hypertension (Bech et al, 1962). Numerous patients develop a form of pulmonary fibrosis complicated by atypical intraalveolar giant cells (Davison et al, 1983; Rochat et al, 1987; Cugell, 1992) which can be demonstrated in bronchoalveolar lavage fluid (Forni, 1994).

Forni (1994) suggested that a persistently high bronchoalveolar lavage eosinophil count despite steroid therapy and cessation of exposure carried an unfavourable prognosis in patients with hard metal lung disease. Several fatalities from hard metal pneumoconiosis own 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 own exacerbated this man’s deterioration via cobalt-induced hydroxyl free radical formation. Allergic alveolitis An allergic alveolitis has been described in hard-metal workers with cough, dyspnoea and flu-like symptoms associated with bilateral crackles, radiographic little 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 own 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 (&gt40 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). There was no significant difference in asthma prevalence between those exposed to the elemental (dust) or ionised (mist) metal (Kusaka et al, 1996a).

Cobalt asthma is associated in some, but not every, cases with circulating cobalt-specific IgE and generalised 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 radiographic features of pulmonary hypertension and correct heart failure (Bech et al, 1962). Cobalt cardiomyopathy is most frequently associated with chronic excess cobalt ingestion (see above) but an identical syndrome has been reported occasionally in those occupationally exposed (Barborik et al, 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). Neurotoxicity Jordan et al (1990) reported significantly impaired attention (p&lt0.05) and verbal (p&lt0.001) memory 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, every members of the study group had «pulmonary manifestations» of hard metal disease which may own affected performance. A patient occupational exposed (mainly via inhalation) to cobalt dust for 20 months developed bilateral optic atrophy and bilateral nerve deafness. Fourteen months after stopping work visual activity 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.

MANAGEMENT Dermal exposure Removal from exposure is the priority. It is significant to remember that the cobalt source may not be immediately apparent, for example, when in a dental or other prosthesis. The role of chelation therapy in cobalt contact sensitivity is discussed under. Inhalation Removal from exposure is the principle requirement. The possibility of cobalt cardiotoxicity should be remembered in those in whom exposure is chronic. Asthmatic symptoms reply to conventional measures (Pisati and Zedda, 1994). Established pulmonary fibrosis has a generally poor prognosis although there are reports of substantial improvement following removal from the workplace (Zanelli et al, 1994).

The role of blood and urine cobalt concentration measurements is discussed under (Medical Surveillance). Ingestion Decontamination Gastric lavage is unnecessary as cobalt ingestion produces only low acute oral toxicity and there is no evidence that oral activated charcoal reduces gastrointestinal cobalt absorption. Supportive measures Following acute cobalt salt ingestion supportive care is generally every that is required with intravenous fluid replacement if vomiting is severe.

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 under (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 DMSA Aposhian (1983) reported early animal studies published in the Chinese literature in 1965 which showed that DMSA (4 mmol/kg, route not stated) increased the LD50 of cobalt chloride-poisoned mice some three times. Four of ten mice istered 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 calcium EDTA or DTPA (diethylenetriamine- pentacetic acid) (see below). DTPA Llobet et al (1986) reported a 70 per cent two week survival rate in mice istered intraperitoneal DTPA (3.1 mmol/kg) immediately following intraperitoneal loading with 1.8 mmol/kg cobalt chloride (a dose in excess of the LD95). Calcium EDTA Every mice istered intraperitoneal cobalt chloride at doses approximating to the LD50-LD95 (0.6-1.8 mmol/kg), immediately followed by 4.3 mmol/kg intraperitoneal calcium EDTA (ethylenediamine tetraacetic acid) survived two weeks with significantly increased urine cobalt elimination in the 24 hours post antidote istration (Llobet et al, 1986).

Allenby and Basketter (1989) found that 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 EDTA solution. No cobalt was recovered in the urine of a patient with cobalt cardiomyopathy who received a one week course of calcium EDTA (and penicillamine, doses not stated) but treatment was not instituted until three years after cobalt ingestion (quantity not stated) (Alexander, 1972). The use of topical EDTA in cobalt dermatitis is discussed above (dermal exposure).

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 of low-dose (25 mg bd) cyclophosphamide therapy. 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 drop 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 istered 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) and periodic assessment for pulmonary or dermatological symptoms are significant in the prevention of cobalt toxicity.

The recommended maximum exposure limit (eight-hour time weighted average 1995) in the UK for cobalt is 0.1 mg/m3 (Health and Safety Executive, 1995). Some studies propose that airborne cobalt concentrations are frequently underestimated (Auchincloss et al, 1992; Mosconi et al, 1994) and other workers recently own 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 own 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 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 specific 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 are frequently encountered in hard metal workers (Ichikawa et al, 1985; Stebbins et al, 1992) but are more useful as grouped rather than individual data (Sabbioni et al, 1994) and their significance requires careful interpretation. 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 while urine and blood cobalt concentrations correlate reasonably well with recent exposure to soluble forms of cobalt (as in hard metal powders) the same is not true following exposure to insoluble cobalt oxide. No evidence of hard a metal pneumoconiosis or significantly excess heart disease was found in controlled study of 49 workers exposed to cobalt and cobalt oxides despite the presence of high urine cobalt concentrations (mean 340 g/L) (Morgan, 1983).

OCCUPATIONAL DATA Maximum exposure limit Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1995). OTHER TOXICOLOGICAL DATA Carcinogenicity Animal studies propose cobalt and its compounds are carcinogenic. While several studies own confirmed that hard metal workers exhibit excess lung cancer mortality, there is no strong evidence that cobalt or its compounds are carcinogenic in man (IARC, 1991). Assessment of human cancer risk is often confounded by simultaneous tobacco consumption, exposure to nickel and arsenic and little study population numbers (Mur et al, 1987; Jensen and Tüchsen, 1990).

Mur et al (1987) observed an excess mortality form lung cancer (standardized mortality ratio = 4.66) in 1143 workers employed between 1950-1980 in a cobalt and sodium producing plant; smoking habits in the study population were not assessed. Further follow-up from 1981-88 failed to show a relationship between lung cancer and cobalt exposure (Moulin et al, 1993). Lasfargues et al (1994) reported a significantly higher mortality from lung cancer among 709 hard metal workers (employed for at least one year) compared to controls, though the study was too little to be conclusive. Reprotoxicity There is no conclusive evidence regarding the reprotoxicity of cobalt (Reprotox, 1996).

Ratto et al, (1988) reported a successful pregnancy in a 31 year-old lady despite severe cobalt pneumoconiosis requiring systemic steroids and cyclophosphamide. Genotoxicity Salmonella typhimurium TA98, TA102, TA1535, TA1537 with metabolic activation negative; TA98, TA1537 without metabolic activation positive. Induced DNA strand breaks in human diploid fibroblasts and Chinese hamster ovary cells in vitro. In vivo rats 0.005 mg/kg cobalt metal in drinking water caused no mutagenic effects (DOSE, 1993). Fish toxicity LC50 (96 hr) fathead minnow 92 mg/L Rainbow trout tolerated 7 day exposure to 30 mg (Co)/L.

Lethal limit 35 mg (Co)/L (DOSE, 1993). EC Directive on Drinking Water Quality 80/778/EEC NIF AUTHORS SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Believe, 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.

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UKPID MONOGRAPHCOBALT SULPHATE 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 Believe, 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 SULPHATE Toxbase summary Type of product Used in manufacture of vitamin B12, storage batteries, varnishes, inks, pigments, enamels, glazes, in electroplating and removal of atmospheric pollutants in waste gases.

Toxicity There are no case reports of acute cobalt sulphate poisoning over at least the final 30 years. Cobalt sensitization may happen following chronic dermal exposure. Features Dermal — Cobalt sulphate is a topical irritant and a recognized cause of occupational contact dermatitis. — Simultaneous allergies to nickel and cobalt are frequent. Ocular — Cobalt sulphate 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 little ingestions. Nausea, vomiting and/or abdominal pain are likely after more substantial ingestions and there is a risk of gastrointestinal corrosion from concentrated solutions which are acidic.

— Transient neutropenia occurred in a six year ancient kid who ingested 2.5 g cobalt chloride (Mucklow et al, 1990). — In the past congestive cardiomyopathy occurred after the consumption of large quantities of beer to which cobalt sulphate/chloride had been added as a foam stabilizer. — Chronic cobalt (as chloride) ingestion has 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 generally arises after several years and may manifest as pneumoconiosis (with dyspnoea and cough secondary to interstitial fibrosis), an 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 happen spontaneously following significant ingestions and gastric lavage is contraindicated following ingestion of acidic solutions. 2. Supportive care is the priority. Replace fluids and electrolytes as necessary. 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 reply to conventional measures. 2. Established pulmonary fibrosis generally has a poor prognosis although cases own responded to high dose prednisolone (Rolfe et al, 1992) or cyclophosphamide (Balmes, 1987).

Seek specialist advice from the NPIS. 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. Sertoli A, Fabbri P, Spallanzani P, Giannotti B. Unusual contact dermatitis to a cobalt salt. Contact Dermatitis 1978; 4: 314. 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) sulphate Origin of substance Hexahydrate occurs in nature as the mineral bieberite. (DOSE, 1993) Synonyms Cobaltous sulphate Cobalt monosulphate (DOSE, 1993) Sulphuric acid, cobalt(II) salt (RTECS, 1997) Chemical group A compound of cobalt, a group VIIIB element. Reference Numbers CAS 10124-43-3 (DOSE, 1993) RTECS GG 3100000 (RTECS, 1997) UN NIF HAZCHEM NIF Physicochemical properties Chemical structure CoSO4 (DOSE, 1993) Molecular weight 154.99 (DOSE, 1993) Physical state at room temperature Solid (HSDB, 1997) Colour Pink/Red (CHRIS, 1997) Odour None (CHRIS, 1997) Viscosity NA pH Forms acidic solution in water.

(OHM/TADS, 1997) Solubility 362 g/L at 20°C (DOSE, 1993) Autoignition temperature NA Chemical interactions Contact of dust with strong oxidizers may cause fire and explosions. (HSDB, 1997) Major products of combustion Toxic cobalt oxide fumes may form in fire. (HSDB, 1997) Explosive limits NA Flammability Not flammable (CHRIS, 1997) Boiling point Decomposes at 735°C. (OHM/TADS, 1997) Density 3.71 at 25°C (DOSE, 1993) Vapour pressure NA Relative vapour density NA Flash point NA Reactivity Cobalt sulphate heptahydrate dehydrates on heating (41.5°C) to the hexahydrate and to the monohydrate at 71°C.

(HSDB, 1997) Uses Removal of atmospheric pollutants in waste gases Humidity indicator Manufacture of vitamin B12 Storage batteries and electroplating Drier for varnishes and lithographic inks Used in pigments, ceramics, enamels and glazes (DOSE, 1993) Hazard/risk classification NIF INTRODUCTION AND EPIDEMIOLOGY Cobalt sulphate is a water soluble bivalent cobalt salt. Acute poisoning by ingestion is rare with no reported cases in at least the final 30 years. Outbreaks of chronic cobalt intoxication (manifest as cardiomyopathy) occurred in Belgium, Nebraska and Quebec in the 1960’s among heavy beer drinkers when a cobalt salt was added to beer as a foam stabilizer (Kesteloot et al, 1968).

Occupational cobalt contact dermatitis has occurred from cobalt sulphate in varnishes, paints (Zenorola et al, 1994) and humidity indicators (Sertoli et al, 1978). 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). As discussed under (Chronic exposure) ionized cobalt (though not specifically cobalt sulphate) contributes significantly to the development of hard metal lung disease.

Evidence for an autoimmune mechanism in this condition 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 below haem to biliverdin (Taylor and Marks, 1978; Timbrell, 1994).

TOXICOKINETICS Absorption Cobalt sulphate can be absorbed following inhalation, ingestion and dermal exposure (Domingo, 1989; Scansetti et al, 1994; Linnainmaa and Kiilunen, 1997). Cobalt and iron share the same transport mechanism within the little 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 sulphate 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 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 little quantity 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 little proportion of retained cobalt has a biological half-life of several years (Elinder and Friberg, 1986). CLINICAL FEATURES: ACUTE EXPOSURE Dermal exposure Cobalt sulphate may cause skin irritation but dermal toxicity is associated primarily with contact sensitivity (see Chronic exposure).

Ocular exposure Cobalt compounds cause 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 sulphate inhalation. Ingestion Acute cobalt sulphate ingestion has not been reported for at least 30 years but similar features to those reported after cobalt chloride ingestion would be anticipated. Gastrointestinal toxicity Jacobziner and Raybin (1961) reported a 19 month-old kid 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 kid was peripherally cyanosed and pale. The lips and tongue were oedematous. The child’s 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 propose the cobalt chloride solution was highly concentrated and corrosive.

Cobalt was identified in the liver, kidney, spleen (89 mg entire 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 &lt 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 ancient 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 kid who ingested 30 mL of a cobalt chloride solution became restless and drowsy within two hours, in association with 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 when cobalt compounds are the primary allergen. For example, cobalt sulphate used as a humidity indicator in shipment containers caused contact dermatitis in a 48 year-old labourer (Sertoli et al, 1978). A 71 year-old construction worker 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.

Cobalt sulphate in the varnishes and paints with which he worked were potential sources of cobalt exposure. An initial irritant dermatitis, often involving operations traumatic to the hand, generally precedes cobalt allergy in industry (Fischer and Rystedt, 1983a). In addition , untrue positive cobalt patch tests may happen due to an irritant rather than delayed hypersensitivity response (Fischer and Rystedt, 1985). Soluble cobalt salts are used widely in patch testing (Smith et al, 1975; Munro-Ashman and Miller, 1976; Veien and Svejgaard, 1978; Schmidt et al, 1980; Rae, 1981; Romaguera et al, 1982; Miyachi et al, 1985; Matsunaga et al, 1988; 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 people 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. 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 own 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 propose 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&lt0.05) 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.

Patients generally 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 generally show increased linear markings and little nodular opacities in the lower (and mid) zones with later cardiomegaly and features of pulmonary hypertension (Bech et al, 1962). Numerous 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 own 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 own exacerbated this man’s deterioration via cobalt-induced hydroxyl free radical formation. A 37 year-old female developed rapidly progressive pneumoconiosis after working for seven years, without respiratory protection, 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 cobalt concentration in bronchoalveolar lavage fluid was increased on presentation (2 µg/L, reference worth 0.6 µg/L) the lung 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 little 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 own 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 (&gt40 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 every, 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 correct 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&lt0.05) and verbal memory (p&lt0.001) 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, every members of the study group had «pulmonary manifestations» of hard metal disease which may own 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 There are no reports of cobalt sulphate ingestion during the final 35 years, though effects similar to those experienced following cobalt chloride ingestion may be expected. Dermal toxicity There is some evidence that ingested cobalt sulphate can trigger a delayed cutaneous hypersensitivity reaction in those already sensitized, although the potential benefit of reduced dietary cobalt in these patients has not been clarified.

In one study (Veien et al, 1987) 28 of 42 patients with a positive cobalt patch test experienced a dermatitis flare following 1 mg oral cobalt sulphate. The istration of oral 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 A 35 year-old lady 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 triglycleride concentrations own been noted in cobalt-treated anephric patients (Taylor and Marks, 1978). This is most probably related to cobalt-induced lipoprotein lipase inhibition. Cardiovascular toxicity Congestive cardiomyopathy has been reported in people who drank large quantities of beer to which a cobalt salt had been added as foam stabilizers (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 polycythemia 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 little (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 lady 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. Every 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 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 kid 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 finish 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 drop 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 own 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 sulphate 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 reply to topical or systemic steroids. The role of chelation therapy in cobalt contact sensitivity is discussed under. 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 reply 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 under (Medical Surveillance). Ingestion Decontamination Gastric lavage is unlikely to be helpful since if spontaneous vomiting does not happen the ingestion is almost certainly too little 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 sulphate ingestion supportive care is generally every 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, electrolytes and a 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 under (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 istered 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.

Every mice istered 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 istration (Llobet et al, 1986). Llobet et al (1988) later demonstrated significantly increased (p&lt0.05) faecal but not urinary cobalt elimination during a five day course of chelation therapy in rats poisoned with intraperitoneal cobalt chloride (0.06 mmol/kg/day three days each week for four weeks).

Clinical studies Topical Allenby and Basketter (1989) found that a positive patch test 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 kid 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) reported early animal studies published in the Chinese literature (in 1965) which showed that DMSA (4 mmol/kg, route not stated) increased three fold the LD50 of cobalt chloride-poisoned mice. Four of ten mice istered 1.8 mmol/kg intraperitoneal cobalt (as 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-pentaacetic acid) (see below). DMSA 1.2 mmol/kg/day intraperitoneally increased urine cobalt excretion significantly (p&lt0.01) only on the final (fifth) day of chelation in rats poisoned with intraperitoneal cobalt chloride (0.06 mmol/kg/day 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&lt0.05 days one, two and four, p&lt0.01 day three). DTPA Animal studies Llobet et al (1986) reported 70 per cent two week survival in mice istered 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&lt0.05) enhanced faecal and urinary cobalt elimination.

Other chelating agents Animal studies Intraperitoneal L-histidine 2.7 mmol/kg istered 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 rats given cobalt chloride only (Domingo et al, 1985a). Domingo et al (1985b) suggested that N-acetylcysteine (NAC) was ineffective in reducing experimental cobalt fatalities unless istered 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&lt0.05 and p&lt0.01 respectively) increased urine and faecal cobalt excretion in cobalt-poisoned rats, with a significant (p&lt0.05) reduction in the spleen cobalt concentration compared to controls. Clinical studies Topical clioquinol one per cent significantly (p&lt0.001) 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 repeatedly and this 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 propose 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 worth of cobalt chelation may be limited where immunological mechanisms frolic an significant 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 drop 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 istered 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 significant in the prevention of cobalt toxicity.

Some studies propose airborne cobalt concentrations frequently are underestimated (Auchincloss et al, 1992; Mosconi et al, 1994) and other workers recently own 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 own 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 specific 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 propose cobalt and its compounds are carcinogenic. While several studies own 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 little study population numbers (Mur et al, 1987; Jensen and Tüchsen, 1990). Mur et al (1987) observed increased 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 little to be conclusive. Reprotoxicity Soluble cobalt salts damage the testis in rats when istered 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 Soluble cobalt salts own 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 (as cobalt) LC50 (96 hr) fathead minnow 92 mg/L. Rainbow trout tolerated 7 day exposure to 30 mg (Co)/L. Lethal limit 35 mg (Co)/L (DOSE, 1993). EC Directive on Drinking Water Quality 80/778/EEC NIF 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 Believe, 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.

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Abstract

Background With the growing use of metallic implants, increased research has focused on metal hypersensitivity. The purpose of this case report is to describe a patient with a suspected metal allergy to a titanium plate and to review the literature behind this controversial topic.

Case Description A 45-year-old lady underwent ulnar shortening osteotomy for ulnocarpal abutment.

One year later, the patient continued to own chronic pain at the site of the implant, with negative work-up for infection, hardware loosening, or failure. During hardware removal, intraoperative findings revealed titanium particle wear in the surrounding tissues, and subsequent allergy testing revealed a new diagnosis of nickel allergy. Following hardware removal, the patient had finish resolution of her symptoms at 3 months without any recurrence after 12 months from the date of surgery.

Discussion Metals are the most common cause of allergic contact dermatitis.

With the increased use of metallic implants, it is no surprise that metal implant allergies own become a cause for concern. While there are multiple tests to attempt and diagnose a metal implant allergy, there is no gold standard, and results are often hard to interpret. Physicians need to be cognizant of metal allergies with there often vague symptoms as we continue to search for more dependable and affordable testing.

Clinical Relevance Metal implant allergies can be hard to diagnose. It is often a diagnosis of exclusion but requires a heightened sense of awareness in the face of a negative work-up with persistent symptoms.

Note

Investigation was performed at the Hand & Upper Extremity Middle of Georgia, Atlanta, GA.


Treatment and Prevention

Treatment of metal hypersensitivity is highly individualized, as the allergens and reactions can be extremely diverse from person to person.

Skin hypersensitivities can often be resolved by avoiding the item that causes the reaction. If the dermatitis is more significant, the doctor can also prescribe corticosteroid creams and ointments to reduce the local inflammation. The doctor can also prescribe oral antihistamines to further reduce the allergic reaction. Oral corticosteroids can also be used, but they can cause problematic side effects.

Systemic reactions are more hard to resolve, as they are often caused by implants. Removal of the implant is sometimes considered when a non-metal replacement is available and may be used.

For example, a plastic-based dental filling material may be used to replace a previous metal dental filling. However, if the allergy is caused by an artificial knee or hip, replacement with a non-metal option is rarely done due to the difficulty of replacement. For these situations, treatment generally involves both topical (surface-applied) and oral medications to reduce the allergic reaction. Due to the hard nature of treating systemic metal allergies, doctors sometimes recommend a hypersensitivity test before an implant is chosen.

All material copyright MediResource Inc. 1996 – 2020.

Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may own regarding a medical condition. Source: www.medbroadcast.com/condition/getcondition/Metal-Hypersensitivity

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The Facts

Metal hypersensitivity is a disorder of the immune system. It is a common condition that affects 10% to 15% of the population.

It can produce a variety of symptoms, including rashes, swelling, or pain due to contact with certain metals (see the symptoms and complications section, below).

In addition to the local skin reactions, metal hypersensitivity can also manifest itself as more chronic conditions such as fibromyalgia and chronic fatigue syndrome. There are numerous local and systemic symptoms that, when considered together, can be caused by metal hypersensitivities.

It is estimated that up to 17% of women and 3% of men are allergic to nickel and that 1% to 3% of people are allergic to cobalt and chromium. These types of reactions can be localized reactions that are limited to one area, but they can also be more generalized and affect other more distant parts of the body.


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