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    COBALT CHLORIDE




    SM Bradberry BSc MB MRCP
    P Sabatta MSc
    JA Vale MD FRCP FRCPE FRCPG FFOM

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


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

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

    COBALT CHLORIDE

    Toxbase summary

    Type of product

    Used in inks, varnishes, enamels, fertilizers, feed additives and
    humidity indicators.

    Toxicity

    Cobalt chloride is only moderately toxic by ingestion although a 19
    month-old child died some six hours after allegedly drinking only 30
    mL (Jacobziner and Raybin, 1961). In another report a six year-old
    developed only transient gastrointestinal upset after ingesting 2.5 g
    (Mucklow et al, 1990).

    Cobalt sensitization may occur following dermal exposure.

    Features

    Dermal

         -    Cobalt chloride is a topical irritant and a recognized cause
              of occupational contact dermatitis.
         -    Simultaneous allergies to nickel and cobalt are frequent.

    Ocular

         -    Cobalt chloride is a potential eye irritant but there are no
              reports of acute eye toxicity in man.

    Ingestion

         -    There may be no or minimal symptoms after small ingestions.
              Nausea, vomiting and/or abdominal pain are likely after more
              substantial ingestions (> 100 mg). Concentrated solutions
              are acidic (the pH of a 0.2 M solution is 4.6). There is an
              early case report of fatal cobalt chloride ingestion (30 mL)
              in which autopsy showed a blistered oesophageal mucosa and
              partially necrosed gastric mucosa (Jacobziner and Raybin,
              1961).
         -    Transient neutropenia occurred in a six year old child who
              ingested 2.5 g (Mucklow et al, 1990).
         -    In the past congestive cardiomyopathy occurred after the
              consumption of large quantities of beer to which cobalt
              chloride/cobalt sulphate had been added as a foam stabilizer
              and in those receiving oral cobalt chloride therapy as
              treatment for anaemia. These presentations are now most
              unlikely in the UK.
         -    Chronic cobalt chloride ingestion has also caused
              hypothyroidism (cobalt inhibits the iodination of tyrosine).

    Inhalation

         -    Pulmonary toxicity following chronic cobalt exposure is
              associated typically with the hard metal industry in which
              elemental cobalt forms a matrix for tungsten carbide.
              Symptoms are most prevalent, however, among those working in
              'wet' processes where cobalt is ionized.
         -    Hard metal lung disease usually arises after several years
              and may manifest as pneumoconiosis (with dyspnoea and cough
              secondary to interstitial fibrosis), allergic alveolitis or
              occupational asthma.
         -    Cor pulmonale may complicate hard metal pneumoconiosis.
         -    There are occasional reports of cobalt cardiomyopathy
              following occupational exposure.

    Management

    Dermal

    1.   Removal from exposure is the priority.
    2.   Contact dermatitis responds to topical and/or systemic steroids.
    3.   There is no confirmed role for topical chelation therapy in
         cobalt dermatitis.

    Ocular

    1.   Irrigate for at least 15 minutes with lukewarm water.
    2.   Topical anaesthesia may be required.
    3.   Ensure particle removal from conjunctival recesses.
    4.   An ophthalmic opinion may be required.

    Ingestion

    1.   Gastrointestinal decontamination is not necessary. Vomiting will
         occur spontaneously following significant ingestions and gastric
         lavage is contraindicated following ingestion of acid solutions.
    2.   Supportive care is the priority. Replace fluids and electrolytes
         as required.
    3.   Check the full blood count.
    4.   If chronic cobalt ingestion is suspected consider the possibility
         of cobalt cardiomyopathy and check thyroid function.
    5.   Collect blood and urine for cobalt concentration determination in
         symptomatic patients to confirm diagnosis. Cobalt assays are not
         widely available. Check with NPIS.
    6.   There are no controlled clinical data regarding the use of
         chelating agents in cobalt poisoning. Discuss with an NPIS
         physician.

    Inhalation

    Acute inhalation:
    1.   Remove from exposure and treat symptomatically.

    Chronic inhalation:
    1.   Asthmatic symptoms respond to conventional measures.
    2.   Established pulmonary fibrosis generally has a poor prognosis.
         Some cases have responded to high dose prednisolone (Rolfe et al,
         1992) or cyclophosphamide (Balmes, 1987). Discuss with an NPIS
         physician.

    References

    Alexander CS.
    Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty-
    eight cases.
    Am J Med 1972; 53: 395-417.

    Balmes JR.
    Respiratory effects of hard-metal dust exposure.
    Occup Med 1987; 2: 327-44.

    Cugell DW.
    The hard metal diseases.
    Clin Chest Med 1992; 13: 269-79.

    Curtis JR, Goode GC, Herrington J, Urdaneta LE.
    Possible cobalt toxicity in maintenance hemodialysis patients after
    treatment with cobaltous chloride: a study of blood and tissue cobalt
    concentrations in normal subjects and patients with terminal renal
    failure.
    Clin Nephrol 1976; 5: 61-5.

    Jacobziner H, Raybin HW.
    Accidental cobalt poisoning.
    Arch Pediatr 1961; 78: 200-5.

    Manifold IH, Platts MM, Kennedy A.
    Cobalt cardiomyopathy in a patient on maintenance haemodialysis.
    Br Med J 1978; 2: 1609.

    Mucklow ES, Griffin SJ, Delves HT, Suchak B.
    Cobalt poisoning in a 6-year-old.
    Lancet 1990; 335: 981.

    Rolfe MW, Paine R, Davenport RB, Strieter RM.
    Hard metal pneumoconiosis and the association of tumor necrosis
    factor-alpha.
    Am Rev Respir Dis 1992; 146: 1600-2.

    Sullivan JF, Egan JD, George RP.
    A distinctive myocardiopathy occurring in Omaha, Nebraska: Clinical
    aspects.
    Ann NY Acad Sci 1969; 156: 526-43.

    Substance name

         Cobalt (II) chloride

    Origin of substance

         Prepared commercially in hexahydrate, dihydrate and monohydrate
         forms.                                  (DOSE, 1993)

    Synonyms

         Cobalt dichloride
         Cobaltous chloride                      (DOSE, 1993)

    Chemical group

         A compound of cobalt, a group VIIIB element.

    Reference numbers

         CAS            7646-79-9,               (DOSE, 1993)
                        7791-13-1 (hexahydrate)
         RTECS          GF 9800000               (RTECS, 1997)
         UN             NIF
         HAZCHEM        NIF

    Physicochemical properties

    Chemical structure
         CoCl2                                   (DOSE, 1993)

    Molecular weight
         129.84                                  (DOSE, 1993)

    Physical state at room temperature
         Solid                                   (DOSE, 1993)

    Colour
         Pale blue, turning pink on exposure to air.
                                                 (OHM/TADS, 1997)

    Odour
         Very slight sharp odour.                (CHRIS, 1997)

    Viscosity
         NA

    pH
         Forms acid solution in water (0.2 M aqueous solution has pH 4.6).
                                            (MERCK, 1996; OHM/TADS, 1997)

    Solubility
         450 g/L in water at 7C  
         385 g/L in methanol                     (HSDB, 1997)

    Autoignition temperature
         NA

    Chemical interactions
         A mixture of potassium and cobalt chloride is sensitive to
         mechanical shock and may cause a violent explosion.
         Sodium dispersions will reduce cobalt chloride exothermically,
         resulting in a temperature increase of 50C. Very violent
         explosions may occur.
         Contact of dust with strong oxidizers may cause fire and
         explosion.                              (HSDB, 1997)

    Major products of combustion
         Cobalt oxide                            (HSDB, 1997)

    Explosive limits
         NA

    Flammability
         Not flammable                           (HSDB, 1997)

    Boiling point
         1049C                                  (DOSE, 1993)

    Density
         3.367 at 25C                           (DOSE, 1993)

    Vapour pressure
         5333 Pa at 770C                        (DOSE, 1993)

    Relative vapour density
         NA

    Flash point
         NA

    Reactivity
         Cobalt chloride decomposes at 400C on heating in air.
         Cobalt chloride hydrolyzes in aqueous solution.
                                                 (HSDB, 1997)

    Uses

         Invisible ink
         Humidity indicator
         Glass and porcelain painting
         Production of vitamin B12
         Fertilizer and feed additive
         Stabilizer in beer
         Absorbant for poisonous gases and ammonia
                                                 (DOSE, 1993)

    Hazard/risk classification

         NIF

    INTRODUCTION AND EPIDEMIOLOGY

    Cobalt chloride is a water soluble bivalent cobalt salt. Cobalt
    chloride poisoning is now rare with only isolated case reports of
    accidental or intentional ingestion, usually from chemistry sets or
    crystal growing kits (Jacobziner and Raybin, 1961; Everson et al,
    1988; Mucklow et al, 1990).

    Outbreaks of cobalt cardiomyopathy occurred in Belgium, Nebraska and
    Quebec in the 1960's among heavy beer drinkers when cobalt
    chloride/sulphate was added to beer to act as a foam stabilizer
    (Kesteloot et al, 1968). Chronic cobalt intoxication also occurred
    when oral cobalt chloride was used to treat anaemia (Duckham and Lee,
    1976; Manifold et al, 1978) but this is no longer a licensed
    indication in the UK.

    Cobalt is an important cause of occupational contact dermatitis and
    cobalt chloride is widely used in patch testing. However, reports in
    which cobalt chloride specifically is the allergen are rare (Zenorola
    et al, 1994).

    MECHANISM OF TOXICITY

    Cytotoxic hydroxy radicals may form when cobalt ions interact with
    reactive oxygen species. Hydroxy radicals may then cause the
    production of further free radicals which reduce cellular glutathione
    concentrations and NADPH activity. The resulting oxidative stress
    leads to DNA and cellular protein damage (Timbrell, 1994).

    Cobalt is immunogenic and acts as a hapten in the induction of
    bronchial and dermal hypersensitivity (Sjgren et al, 1980). Ionized
    cobalt, though not specifically cobalt chloride, is an important
    contributing factor in the aetiology of hard metal lung disease.
    Evidence for an autoimmune mechanism in this disorder is suggested by
    the recurrence of disease in a single transplanted lung despite no
    evidence of cobalt in the donated organ (Frost et al, 1993). In cobalt
    pneumoconiosis non-respiratory symptoms may be due to cobalt-induced

    release of a tumour necrosis factor from sensitized pulmonary
    lymphocytes (Rolfe et al, 1992).

    In a dog model cobalt myocardial toxicity was characterized by
    vacuolation and loss of myofibers (Sandusky et al, 1981a) with
    histochemical evidence of severe mitochondrial damage (Sandusky et al,
    1981b). Alexander (1972) suggested cobalt depresses mitochondrial
    oxygen uptake in the myocardium by complexing with sulphydryl groups
    and preventing the oxidation of pyruvate in the citric acid cycle.
    Tissue hypoxia is the probable stimulus also of erythropoietin
    secretion in cobalt-induced polycythaemia (Taylor and Marks, 1978).

    In animal studies, cobalt decreases synthesis of several enzymes
    including cellular cytochrome P450 (Timbrell, 1994). Cobalt inhibits
    aminolaevulinic acid synthetase and increases the activity of haem
    oxygenase which breaks down haem to biliverdin (Taylor and Marks,
    1978; Timbrell, 1994).

    TOXICOKINETICS

    Absorption

    Cobalt chloride can be absorbed following ingestion, inhalation and
    dermal exposure (Domingo, 1989; Scansetti et al, 1994; Linnainmaa and
    Kiilunen, 1997). Cobalt and iron share the same transport mechanism
    within the small intestine such that cobalt ingestion competitively
    inhibits iron uptake. The extent of intestinal cobalt absorption
    depends on the dose with only some 20 per cent of a large ingestion
    being absorbed (Domingo, 1989).

    Some inhaled cobalt chloride is swallowed following mucociliary
    clearance while particles which reach the distant pulmonary tree are
    taken up predominantly by macrophages (Taylor and Marks, 1978; Evans
    et al, 1993). Systemic uptake is confirmed by increased blood and
    urine cobalt concentrations in those occupationally exposed to
    cobalt-containing dusts and mists (Della Torre et al, 1990).

    Distribution

    The normal body burden of cobalt is about 1.1 mg. Approximately 43 per
    cent of this is in muscle with some 14 per cent in bone and the
    remainder in other soft tissues (Taylor and Marks, 1978; Domingo,
    1989).

    Excretion

    Cobalt which reaches the systemic circulation is eliminated
    predominantly in urine with a variable but small amount excreted in
    bile (Taylor and Marks, 1978; Domingo, 1989).

    Following acute occupational cobalt inhalation urinary elimination is
    rapid for the first 24 hours followed by a slower excretion phase
    lasting several weeks (Alexandersson, 1988). A small proportion of
    retained cobalt has a biological half-life of several years (Elinder
    and Friberg, 1986).

    CLINICAL FEATURES: ACUTE EXPOSURE

    Dermal exposure

    Cobalt chloride may cause skin irritation but dermal toxicity is
    associated primarily with contact sensitivity (see Chronic exposure).

    Ocular exposure

    Cobalt chloride causes corneal damage when directly applied to the
    eyes of experimental animals (Grant and Schuman, 1993) but there are
    no reports of acute eye toxicity in man.

    Inhalation

    There are no reports of acute cobalt chloride inhalation.

    Ingestion

    Most reports of cobalt chloride ingestion involve only modest
    gastrointestinal upset although Jacobziner and Raybin (1961) described
    a fatality in a 19 month-old child (see below).

    Gastrointestinal toxicity

    Jacobziner and Raybin (1961) reported a 19 month-old child who
    ingested approximately 30 mL of a cobalt chloride solution. Vomiting
    was induced immediately and gastric lavage performed on arrival at
    hospital two hours later. On examination the child was pale and
    peripherally cyanosed. The lips and tongue were oedematous. The
    clinical condition deteriorated rapidly with death following a cardiac
    arrest some six hours post ingestion. Autopsy revealed a blistered
    oesophageal mucosa with coagulative necrosis involving one third the
    thickness of the gastric mucosa. The precise cause of death was not
    clear but these findings suggest the solution was highly concentrated
    and corrosive. Cobalt was identified in the liver, kidney, spleen (89
    mg total in these organs) and stomach.

    A six year-old boy developed nausea, vomiting and abdominal pain after
    swallowing a drink to which he had added about 2.5 g cobalt chloride
    from a crystal growing set (Mucklow et al, 1990). The whole blood
    cobalt concentration some seven hours post ingestion was 241 g/L
    (normal range < 1 g/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 g/L.

    Haemotoxicity

    A six year old boy who ingested 2.5 g cobalt chloride developed a
    transient neutropenia (1.7 x 109/L) but recovered fully (Mucklow et
    al, 1990).

    Neurotoxicity

    A 19 month-old child who ingested 30 mL of a cobalt chloride solution
    became restless and drowsy within two hours in association with severe
    respiratory distress, cyanosis and pallor. He died some six hours
    later (Jacobziner and Raybin, 1961). Cerebral oedema was evident at
    autopsy.

    CLINICAL FEATURES: CHRONIC EXPOSURE

    Dermal exposure

    Cobalt is a well recognized cause of contact dermatitis (Smith et al,
    1975), a delayed hypersensitivity reaction characterized by vesicles,
    itchy maculopapular lesions, scaling and/or fissuring (Miyachi et al,
    1985; Foussereau and Cavelier, 1988; Illuminati et al, 1988). These
    features are seen commonly on the hands, face and neck and sometimes
    the eyelids and chest.

    Cobalt contact dermatitis primarily occurs following exposure to the
    elemental form, which subsequently is ionized in sweat, although there
    are situations where cobalt compounds are the primary allergen. For
    example, a 71 year-old construction labourer developed contact
    dermatitis induced by cobalt and chromium ions present in cement
    (Miyachi et al, 1985). Cobalt dermatitis is also described in those
    handling or manufacturing rubber. In the rubber industry cobalt is
    used as lipid soluble (cobalt naphthenates and stearates) rather than
    water soluble salts (Bedello et al, 1984; Foussereau and Cavelier,
    1988).

    Zenorola et al (1994) described atypical dermatitis in a 23 year-old
    plumber. The clinical appearance was highly suggestive of "Ashy
    dermatitis" or erythema dyschromicum perstans, a disorder of uncertain
    aetiology characterized by asymptomatic, ash-like grey macular
    pigmentation of the skin. The patient patch tested positive to cobalt
    chloride for which there were several sources in his workplace
    including varnishes and paints. However a causative association
    between ashy dermatitis and cobalt allergy could not be confirmed.

    An initial irritant dermatitis, often involving operations traumatic
    to the hand, usually precedes cobalt allergy in industry (Fischer and
    Rystedt, 1983a). In addition false positive cobalt patch tests may
    occur due to an irritant rather than delayed hypersensitivity response
    (Fischer and Rystedt, 1985).

    Cobalt chloride is used widely in patch testing (James and Smith,
    1975; Munro-Ashman and Miller, 1976; Veien and Svejgaard, 1978;
    Schmidt et al, 1980; Rae, 1981; Romaguera et al, 1982; Miyachi et al,
    1985; Shirakawa et al 1988; Allenby and Basketter, 1989; Pryce and
    King, 1990; Zhang et al, 1991; Castiglioni et al, 1992; Torresani et
    al, 1994). Lantinga et al (1984) invited 2800 members of the general
    population in a geographically defined area of the Netherlands to be
    examined for skin disorders of the hands and forearms. Patch testing
    was performed in 141 persons with eczema. Contact allergy was detected
    in 50 (35 per cent) of these. Cobalt chloride was the allergen in five
    cases with nickel sulphate in 28 and potassium dichromate in nine
    cases.

    Among 4721 consecutive patients at a patch test clinic, six per cent
    had a positive reaction to cobalt chloride (compared to nickel
    sensitivity in 18.5 per cent) (Shehade et al, 1991). These authors
    emphasized the importance of not reading the patch test before day
    four; 69 of 271 (24 per cent) patients with a positive reaction to
    cobalt chloride on day four had a negative result on day two.

    Simultaneous allergies to nickel and cobalt are frequent (Burden and
    Eedy, 1991; Kanerva and Estlander, 1995) and there is some evidence
    for a mutual enhancing effect of contact sensitization to one metal in
    the presence of the other (Domingo, 1989).

    Inhalation

    Pulmonary toxicity

    Pulmonary toxicity following chronic cobalt exposure is associated
    typically with the hard metal (tungsten carbide in a cobalt matrix)
    industry (Auchincloss et al, 1992) but similar problems have been
    reported in diamond polishers using cobalt-coated discs (Lahaye et al,
    1984; Nemery et al, 1990) and in a dental technician (Sherson et al,
    1990). Hard metal lung disease is discussed here since employees are
    exposed both to elemental and ionized cobalt (the latter in 'wet'
    grinding processes where cobalt is dissolved in machine coolants).
    Cugell (1992) suggested ionized cobalt is more likely than elemental
    cobalt to cause occupational pulmonary disease although this may not
    be true of hard metal asthma (Kusaka et al, 1996a).

    There is some debate concerning whether cobalt exposure alone is
    sufficient to cause pulmonary fibrosis.  In-vitro and animal studies
    suggest there is no relationship between cellular cobalt uptake and
    cellular toxicity (Lison and Lauwerys, 1994) and cobalt workers
    frequently are exposed to several other potential toxins (including
    tungsten carbide, iron, silica and diamond) (Swennen et al, 1993).

    While Gennart and Lauwerys (1990) observed a significantly increased
    incidence (p<0.05) of restrictive spirometry and respiratory symptoms
    in workers exposed for more than five years to cobalt dust in a plant
    producing diamond-cobalt circular saws compared to non cobalt-exposed
    factory workers, Swennen et al (1993) found no difference in
    ventilatory performance, lung volumes or carbon monoxide diffusion
    capacity between 82 cobalt refinery workers and controls even though
    the cobalt workers complained more frequently of wheeze and dyspnoea.

    Hard metal pneumoconiosis

    Chronic cobalt (and tungsten carbide) inhalation is associated
    typically with "hard metal" pneumoconiosis characterized by
    interstitial fibrosis (primarily of the lower zones) and a restrictive
    ventilatory defect (Bech et al, 1962). Patients usually present with
    exertional dyspnoea, cough and sometimes chest tightness (Bech et al,
    1962). There may be associated symptoms of fever, weight loss or
    general malaise (Coates and Watson, 1971; Balmes, 1987; Migliori et
    al, 1994). In one study of 12 tungsten carbide workers the mean
    duration of exposure before the onset of respiratory symptoms was 12
    years with a range of one month to 28 years (Coates and Watson, 1971).
    Inspiratory crackles are the earliest physical sign (Rochat et al,
    1987) but finger clubbing, cyanosis and eventually cor pulmonale may
    ensue. Chest X-ray findings vary greatly (Cugell et al, 1990) but
    usually show increased linear markings and small nodular opacities in
    the lower (and mid) zones with later cardiomegaly and features of
    pulmonary hypertension (Bech et al, 1962).

    Many patients develop a form of pulmonary fibrosis complicated by
    atypical intraalveolar giant cells (Davison et al, 1983; Rochat et al,
    1987; Cugell, 1992; Frost et al, 1993) which can be demonstrated in
    bronchoalveolar lavage fluid (Forni, 1994) and transbronchial biopsies
    (Rolfe et al, 1992). Pulmonary eosinophilia is also a feature of hard
    metal lung disease (Della Torre et al, 1990). Forni (1994) suggested
    that a persistently high bronchoalveolar lavage eosinophil count
    despite steroid therapy and cessation of exposure carried an
    unfavourable prognosis.

    Several fatalities from hard metal pneumoconiosis have been reported
    (Della Torre et al, 1990; Figueroa et al, 1992). Nemery et al (1990)
    described a 52 year-old diamond polisher who died less than one year
    after a diagnosis of interstitial lung disease. He continued work
    without specific treatment until three months before death when he
    required continuous oxygen and systemic steroids. At autopsy there was
    evidence of extensive fibrosis with interstitial giant cells. The lung
    cobalt concentration was 2.1 g/g. The authors suggested that oxygen
    therapy may have exacerbated this man's deterioration via
    cobalt-induced hydroxyl free radical formation.

    A 37 year-old female developed rapidly progressive pneumoconiosis
    after working, without respiratory protection, for seven years in
    sharpening and grinding operations with hard metal tools (Della Torre
    et al, 1990). There was no response to steroid therapy and she died
    from respiratory failure less than one year after presentation. 
    Interestingly, although the lung cobalt concentration in
    bronchoalveolar lavage fluid was increased on presentation (2 g/L,
    reference value 0.6 g/L) the cobalt concentration at open biopsy four
    months later was not raised significantly, supporting the hypothesis
    that cobalt-induced lung damage is immunologically mediated rather
    than a direct effect.

    Allergic alveolitis

    An allergic alveolitis has been described in hard-metal workers with
    cough, dyspnoea and flu-like symptoms associated with bilateral
    crackles, radiographic small nodular infiltrates and a restrictive
    lung function defect (Sjgren et al, 1980; Cugell, 1992). These
    abnormalities may reverse if exposure ceases but with continued cobalt
    inhalation irreversible fibrosis is likely (Cugell, 1992).

    Occupational asthma

    Hard metal workers may develop occupational asthma with cough, wheeze
    and dyspnoea that characteristically improves during week-ends and
    holidays (Sprince et al, 1988; Cugell, 1992). Similar symptoms have
    been described in diamond workers exposed to cobalt in polishing discs
    (Gheysens et al, 1985).

    In a study of 703 hard metal workers Kusaka et al (1996a) identified
    age (>40 years), atopy and cobalt exposure as risk factors for
    asthma. Surprisingly, low airborne cobalt concentrations (below 50
    g/m3) posed a greater risk of hard metal asthma than did higher air
    cobalt concentrations (Kusaka et al, 1996a) although the observed
    deterioration in ventilatory function seemed to be related to duration
    of cobalt exposure (Kusaka et al, 1996b). In this study there was no
    significant difference in asthma prevalence between those exposed to
    the elemental (dust) or ionized (mist) metal (Kusaka et al, 1996a).

    Cobalt asthma is associated in some, but not all, cases with
    circulating cobalt-specific IgE and generalized bronchial
    hyperresponsiveness (Coates and Watson 1971; Sjgren et al, 1980;
    Kusaka et al, 1989; Shirakawa et al, 1989; Cugell, 1992). Respiratory
    cross-reactivity between cobalt and nickel has also been described
    (Shirakawa et al, 1990).

    Cardiovascular toxicity

    Patients with fulminant hard metal pneumoconiosis may, after several
    years, develop cor pulmonale with clinical and radiological features
    of pulmonary hypertension and right heart failure (Bech et al, 1962).

    Cobalt cardiomyopathy is associated most frequently with chronic
    excess cobalt chloride or cobalt sulphate ingestion (see above) but an
    identical syndrome has been reported occasionally in those exposed
    occupationally (Barborik and Dusek, 1972; Jarvis et al, 1992).

    Kennedy et al (1981) reported fatal cardiogenic shock in a 48 year-old
    hard metal worker following routine vagotomy and pyloroplasty for
    duodenal ulceration. The patient, who had handled tungsten carbide and
    cobalt dust for four years, initially developed signs of
    cardiovascular compromise during the operation and gradually
    deteriorated without evidence of ischaemic heart disease. At
    post-mortem the heart was dilated with extensive myocardial fibrosis
    and a myocardial cobalt concentration of 7 g/g (normal range
    0.1-0.4).

    There is limited evidence that hard metal workers may develop
    electrocardiographic abnormalities and/or impaired left ventricular
    function after chronic cobalt exposure (Horowitz et al, 1988; Evans et
    al, 1993) but the significance of these studies is uncertain.

    Neurotoxicity

    Jordan et al (1990) reported significantly impaired attention
    (p<0.05) and verbal memory (p<0.001) in 12 hard metal workers
    exposed to tungsten carbide and cobalt (as dust and dissolved in an
    organic solvent) compared to healthy unexposed controls. However, all
    members of the study group had "pulmonary manifestations" of hard
    metal disease which may have affected performance.

    A patient exposed occupationally (mainly via inhalation) to cobalt
    dust for 20 months developed bilateral optic atrophy and bilateral
    nerve deafness. Fourteen months after stopping work visual acuity
    improved and hearing returned to normal (Meecham and Humphrey, 1991).

    Nephrotoxicity

    Lechleitner et al (1993) reported Goodpasture's syndrome in a 26
    year-old hard metal worker with severe interstitial lung disease and
    fulminant glomerulonephritis. The role of heavy metal exposure in the
    aetiology of this case is not known though the authors proposed
    cobalt-induced -cell activation or exposure of pulmonary basement
    membrane antigens as possible disease mechanisms.

    Ocular toxicity

    Optic atrophy occurring in association with chronic cobalt inhalation
    is discussed above (Neurotoxicity).

    Ingestion

    Dermal toxicity

    The administration of disulfiram in the treatment of ethanol abuse has
    led to an exacerbation of cobalt dermatitis presumably via
    diethyldithiocarbamate (a disulfiram metabolite) chelation and
    mobilization of cobalt in a manner similar to that reported in nickel
    sensitive subjects (Menn, 1985).

    Gastrointestinal toxicity

    Gastrointestinal symptoms similar to those occurring after acute
    cobalt chloride ingestion have also complicated chronic therapy. A 35
    year-old woman with anaemia treated with cobalt chloride 25 mg qds
    complained of nausea, vomiting and weight loss in addition to
    neurological symptoms (Schirrmacher, 1967).

    One of 12 renal failure patients on haemodialysis treated with cobalt
    chloride 25-50 mg daily had to discontinue therapy after ten days due
    to nausea and constipation. Symptoms resolved on withdrawal of cobalt
    supplements (Duckham and Lee, 1976).

    Increased serum triglyceride concentrations have been noted in
    cobalt-treated anephric patients and although hepatic glucagon
    resistance was postulated as the cause this has not been confirmed
    (Taylor and Marks, 1978). Cobalt-induced inhibition of lipoprotein
    lipase is now thought likely to be relevant (Taylor and Marks, 1978).

    Cardiovascular toxicity

    Congestive cardiomyopathy has been reported in people who drank large
    quantities of beer to which cobalt chloride/sulphate had been added as
    a foam stabilizer (Morin et al, 1967; Kesteloot et al, 1968; Sullivan
    et al, 1969) and in those receiving oral cobalt chloride therapy
    (Manifold et al, 1978).

    In a study of 28 cases of cobalt beer cardiomyopathy (Alexander, 1972)
    symptoms of cardiac failure were of fairly abrupt onset (mean duration
    at presentation 10 weeks) and variable severity with five deaths from
    cardiogenic shock and a full physical recovery in only 11 patients.
    Cardiomegaly, a pericardial effusion and polycythaemia were present in
    the majority with pleural effusion in 11 cases though radiological
    evidence of pulmonary oedema "characteristically ..... was absent".
    Profound lactic acidosis was a prominent feature in severe cases.
    Electrocardiographic abnormalities included p pulmonale or p mitrale,
    axis (usually right) deviation and acute ischaemic changes in the
    precordial leads typically associated with increased plasma cardiac
    enzyme activities. Electron microscopy of myocardial tissue from these
    patients showed extensive myofibril degeneration with abnormal
    mitochondria containing electron-dense bodies believed to incorporate
    cobalt. It is probable that alcohol and malnutrition contributed to

    the cardiotoxicity observed in these and other cases since the
    absolute quantities of cobalt ingested often were small (up to 10 mg
    daily) (Kesteloot et al, 1968; Alexander, 1972).

    Curtis et al (1976) described a haemodialysis patient who died three
    months after "a course" of cobalt chloride. At post mortem the
    myocardial cobalt concentration was 1.65 g/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
    g/g (Manifold et al, 1978).

    Neurotoxicity

    After six months treatment with cobalt chloride 25 mg qds for anaemia
    a 35 year-old woman developed limb paraesthesiae, an unsteady gait,
    impaired hearing and dizzy spells in addition to nausea, vomiting and
    weight loss (Schirrmacher, 1967). Clinical examination confirmed
    bilateral nerve deafness, absent ankle reflexes and impaired vibration
    sense. All symptoms and signs resolved with four months of cobalt
    chloride withdrawal.

    A haemodialysis patient developed polyarthralgia and muscle weakness
    after three weeks cobalt chloride therapy (25-50 mg daily). Weakness
    improved following cobalt withdrawal but polyarthralgia persisted; the
    patient died eight months later after renal transplantation failure
    (Duckham and Lee, 1976).

    Haemotoxicity

    Chronic excess cobalt chloride ingestion causes polycythaemia which in
    the past led to its use in the treatment of anaemia (Manifold et al,
    1978).  A 13 month-old child developed persistent anaemia with
    polycythaemia and cardiomegaly in addition to hypothyroidism (see
    below) and hypertrichosis following treatment of iron deficiency for
    one year with a commercial iron-cobalt preparation. At the end of the
    treatment period the serum cobalt concentration was 59 g/L. The
    haematological abnormalities and hypothyroidism resolved when the
    treatment was stopped, with some improvement in cardiac size and a
    fall in the serum cobalt concentration to 6.8 g/L and 1.4 g/L at
    four and 12 months respectively (Bianchi et al, 1989).

    Endocrine toxicity

    Cobalt inhibits the iodination of tyrosine and goitre is a recognized
    side-effect of cobalt therapy (Schirrmacher, 1967). A four year-old
    boy with sickle cell anaemia admitted for tonsillectomy was noted to
    have a large goitre. For seven months prior to admission the patient

    had taken 60-80 mg cobalt chloride daily. The thyroid gland was
    bilaterally and asymmetrically enlarged, firm, nodular, painless and
    mobile (Kriss et al, 1955). The goitre disappeared one month after
    cobalt chloride withdrawal.

    A 13 month-old baby developed clinical and biochemical hypothyroidism
    after treatment of iron deficiency for one year with a commercial
    iron-cobalt preparation. The endocrine abnormality resolved when
    treatment was withdrawn (Bianchi et al, 1989).

    Ocular toxicity

    Following treatment of pancytopenia with 73 g oral cobalt chloride
    over two and a half years, a patient developed abnormal choroidal
    perfusion and optic atrophy. Vision did not deteriorate further
    following cessation of therapy (Licht et al, 1972).

    MANAGEMENT

    Dermal exposure

    Removal from exposure is the priority. Most barrier creams do not
    prevent the penetration of cobalt chloride through the skin (Fischer
    and Rystedt, 1983b) although Fischer and Rystedt (1990) demonstrated
    that polyethylene glycol effectively reduced cobalt contact
    reactivity. Exacerbations of cobalt contact dermatitis respond to
    topical or systemic steroids. The role of chelation therapy in cobalt
    contact sensitivity is discussed below.

    Ocular exposure

    Decontamination with copious lukewarm water (eg via drip tubing) is
    the priority. Topical anaesthesia may be necessary, particularly to
    ensure removal of particles from the conjunctival recesses. Seek an
    ophthalmic opinion if symptoms persist or there are abnormal
    examination findings.

    Inhalation

    Exposure must be discontinued if occupational cobalt lung disease is
    suspected or confirmed. Asthmatic symptoms respond to conventional
    measures (Pisati and Zedda, 1994). Established pulmonary fibrosis has
    a generally poor prognosis although there are reports of substantial
    improvement following high dose steroids (prednisolone 60 mg daily
    (Rolfe et al, 1992) and/or removal from the workplace (Zanelli et al,
    1994). The possibility of cobalt cardiotoxicity should be remembered.
    The role of blood and urine cobalt concentration measurements is
    discussed below (Medical Surveillance).

    Ingestion

    Decontamination

    Gastric lavage is unlikely to be helpful since if spontaneous vomiting
    does not occur the ingestion is almost certainly too small to cause
    significant toxicity. Concentrated solutions are acidic and gastric
    lavage is contraindicated if corrosive damage is a possibility. There
    is no evidence that oral activated charcoal reduces gastrointestinal
    cobalt absorption.

    Supportive measures

    Following acute cobalt chloride ingestion supportive care is usually
    all that is required with intravenous fluid replacement if vomiting is
    severe. Concentrated solutions are acidic and the possibility of
    corrosive damage should be considered. Plasma creatinine, urea and
    electrolytes and full blood count should be measured. If chronic
    cobalt toxicity is suspected a thorough cardiovascular and
    neurological (including fundoscopy) assessment should be undertaken.
    Thyroid function tests should be performed. The role of chelation
    therapy is discussed below (Antidotes). The presence of cobalt in
    blood and urine confirms exposure but blood and urine concentrations
    require careful interpretation (see Medical Surveillance) and these
    assays are not widely available.

    Antidotes

    Sodium calciumedetate

    Animal studies

    Post (1955) observed that rats administered sodium calciumedetate
    subcutaneously following intraperitoneal cobalt chloride injection did
    not show the polycythaemic response induced in controls (treated with
    cobalt only). Subsequent studies (Domingo et al, 1983; Llobet et al,
    1985; Llobet et al, 1986) provided further evidence for sodium
    calciumedetate as an effective cobalt chelator.

    All mice administered intraperitoneal cobalt chloride at doses
    approximating to the LD50 - LD95 (0.6-1.8 mmol/kg), immediately
    followed by 4.3 mmol/kg intraperitoneal sodium calciumedetate survived
    two weeks with significantly increased urine cobalt elimination in the
    24 hours post antidote administration (Llobet et al, 1986). Llobet et
    al (1988) later demonstrated significantly increased (p<0.05) faecal
    but not urinary cobalt elimination during a five day course of
    chelation therapy in cobalt-poisoned rats (administration details as
    below).

    Clinical studies

    Topical

    Allenby and Basketter (1989) found a positive patch test reaction to
    one per cent aqueous cobalt chloride was abolished in five out of six
    subjects by the concomitant application of an equimolar sodium
    calciumedetate solution.

    Systemic

    A 14 year-old female who ingested approximately 130 mg cobalt chloride
    was asymptomatic but treated with intravenous sodium calciumedetate 1g
    tds for three doses on the basis of a raised serum cobalt
    concentration (78 g/L 12 hours post ingestion) (Everson et al, 1988).
    No cobalt excretion data were presented. The serum cobalt
    concentration had fallen to 7 g/L 22 hours post ingestion and the
    child remained well.

    No cobalt was recovered in the urine of a patient with cobalt
    cardiomyopathy who received a one week course of sodium calciumedetate
    (and penicillamine, doses not stated) but treatment was not instituted
    until three years after cobalt ingestion (quantity not stated)
    (Alexander, 1972).

    DMSA

    Animal studies

    Aposhian (1983) cited early animal studies published in the Chinese
    literature (in 1965) which showed that DMSA 4 mmol/kg (route not
    stated) increased threefold the LD50 of cobalt chloride-poisoned
    mice.

    Four of ten mice administered 1.8 mmol/kg intraperitoneal cobalt
    chloride (a dose exceeding the LD95) immediately followed by
    intraperitoneal DMSA 3.4 mmol/kg, survived two weeks (Llobet et al,
    1986). Under these experimental conditions DMSA was a less effective
    cobalt chelator than sodium calciumedetate or DTPA
    (diethylenetriamine-pentacetic acid) (see below).

    DMSA 1.2 mmol/kg/day intraperitoneally increased urine cobalt
    excretion significantly (p<0.01) only on the final (fifth) day of
    chelation in rats poisoned with cobalt chloride (0.06 mmol/kg/day
    intraperitoneally three days per week for four weeks) (Llobet et al,
    1988). In the same study faecal cobalt elimination was increased
    significantly during the first four days of chelation therapy (p<0.05
    days one, two and four, p<0.01 day three).

    DTPA

    Animal studies

    Llobet et al (1986) reported 70 per cent two week survival in mice
    administered intraperitoneal DTPA 3.1 mmol/kg immediately following
    intraperitoneal loading with 1.8 mmol/kg cobalt chloride (a dose in
    excess of the LD95). In a later study (Llobet et al, 1988) DTPA 1.2
    mmol/kg/day significantly (p<0.05) enhanced faecal and urine cobalt
    elimination.

    Other chelating agents

    Animal studies

    Intraperitoneal L-histidine 2.7 mmol/kg administered immediately after
    oral cobalt chloride (4.2 mmol/kg, approximately the oral LD95)
    resulted in 90 per cent seven day survival compared to 15 per cent
    survival in animals treated with cobalt chloride only (Domingo et al,
    1985a).

    Domingo et al (1985b) suggested that N-acetylcysteine (NAC) was
    ineffective in reducing experimental cobalt fatalities unless
    administered as a cobalt-NAC chelate. However, Llobet et al (1985)
    demonstrated that glutathione and NAC (each 3.5 mmol/kg
    intraperitoneally) immediately after intraperitoneal cobalt chloride
    (0.70 mmol/kg, the LD50) improved survival. In a later study (Llobet
    et al, 1988) glutathione and NAC (both 1.2 mmol/kg/day
    intraperitoneally) significantly (p<0.05 and p<0.01 respectively)
    increased urine and faecal cobalt excretion in cobalt poisoned rats,
    with a significant (p<0.05) reduction in the spleen cobalt
    concentration compared to controls.

    Clinical studies

    Topical clioquinol one per cent significantly (p<0.001) reduced patch
    test reactions to cobalt in 29 cobalt-sensitive individuals. However
    the authors emphasized this chelating agent is not suitable for
    regular application since it is itself an allergen (Fischer and
    Rystedt, 1990). There is also a risk of systemic uptake if clioquinol
    is topically applied chronically. Clioquinol absorption may be
    associated with neurological side-effects including peripheral
    neuropathy and delirium (Rose, 1986).

    Antidotes: Conclusions and recommendations

    1.   There are no human controlled data regarding the use of chelating
         agents in cobalt(II) poisoning.

    2.   Animal studies suggest sodium calciumedetate and DTPA are the
         most effective cobalt chelators although NAC and glutathione are
         less toxic alternatives.

    3.   Following severe cobalt poisoning by ingestion the use of
         chelation therapy may be considered; discussion of individual
         cases with an NPIS physician is recommended.

    4.   There is no evidence that chelation therapy reduces the pulmonary
         cobalt burden following chronic inhalation. Moreover, the value
         of cobalt chelation my be limited where immunological mechanisms
         play an important part in cobalt toxicity.

    5.   The role of topical chelating agents in cobalt dermatitis remains
         unproven and is likely to be limited by practical difficulties.

    Chemotherapy

    Balmes (1987) reported a 28 year-old lady with aggressive hard metal
    pneumoconiosis unresponsive to prednisolone (40-60 mg daily) who
    clinically improved significantly after two months low-dose
    cyclophosphamide therapy (25 mg bd).

    Haemodialysis

    In a patient with uraemic cardiomyopathy and a high serum cobalt
    concentration (0.24 ppb), Lins and Pehrsson (1976) reported reduced
    cardiac size in association with a fall in the serum cobalt
    concentration to 0.07 ppb during haemodialysis. However no cobalt
    dialysis clearance data or details of dialysis duration were given.

    AT RISK GROUPS

    Patients with renal failure are at risk of cobalt toxicity if
    administered oral cobalt containing pharmaceuticals (Curtis et al,
    1976); these preparations are not available in the UK.

    MEDICAL SURVEILLANCE

    Regular monitoring of workplace airborne cobalt concentrations (Sala
    et al, 1994), strict attention to personal hygiene (Scansetti et al,
    1994; Linnainmaa and Kiilunen, 1997) and periodic assessment for
    pulmonary or dermatological symptoms are important in the prevention
    of cobalt toxicity.

    Some studies suggest airborne cobalt concentrations frequently are
    underestimated (Auchincloss et al, 1992; Mosconi et al, 1994) and
    other workers recently have reported average cobalt airborne
    concentrations in a hard metal factory greatly exceeding the
    recommended occupational exposure limit (Kumagai et al, 1996).
    Furthermore, significant reductions in FEV1 and FVC have been
    observed in workers exposed to airborne cobalt concentrations lower
    than 50 g/m3 (Nemery et al, 1992).

    Sjgren et al (1980) noted that the development of cobalt contact
    dermatitis among hard metal workers often preceded pulmonary disease
    and suggested that those with a positive cobalt patch test should be
    removed immediately from exposure. However, in another study, only two
    of nine hard metal workers sensitive to inhaled cobalt had a positive
    cobalt patch test (Kusaka et al, 1986).

    Abnormal clinical findings should be investigated conventionally with
    particular attention to establishing a temporal relationship to
    workplace exposure in those with possible occupational asthma or
    alveolitis. The presence of cobalt-specific IgE in plasma or cobalt
    particles in bronchoalveolar lavage fluid or lung biopsy tissue may be
    useful.

    Increased blood and urine cobalt concentrations frequently are
    encountered in hard metal workers (Ichikawa et al, 1985; Della Torre
    et al, 1990; Stebbins et al, 1992; Linnainmaa and Kiilunen, 1997) but
    are more useful as grouped rather than individual data (Sabbioni et
    al, 1994) and their significance requires careful interpretation. A
    potential role for hair and nail cobalt concentrations as indicators
    of chronic exposure has not been substantiated (Della Torre et al,
    1990).

    In workers exposed to cobalt dust in a plant producing diamond-cobalt
    saws urine cobalt concentrations reflected recent rather than
    cumulative cobalt exposure (Gennart and Lauwerys, 1990). Lison et al
    (1994) concluded that urine and blood cobalt concentrations correlated
    reasonably well with recent occupational exposure to soluble forms of
    cobalt.

    Normal concentrations in biological fluids

    In unexposed individuals normal cobalt concentrations are 0.1-1.2 g/L
    in blood (and serum) and 0.1-2.3 g/L in urine (spot samples)
    (Alexandersson, 1988).

    OCCUPATIONAL DATA

    Maximum exposure limit

    Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3
    (Health and Safety Executive, 1997).

    OTHER TOXICOLOGICAL DATA

    Carcinogenicity

    Animal studies suggest cobalt and its compounds are carcinogenic.
    While several studies have shown that hard metal workers exhibit
    excess lung cancer mortality, there is inadequate evidence for cobalt
    or its compounds to be classed as carcinogenic in man (IARC, 1991).
    Assessment of human cancer risk is often confounded by simultaneous

    tobacco consumption, exposure to nickel and arsenic and small study
    population numbers (Mur et al, 1987; Jensen and Tchsen, 1990).

    Mur et al (1987) observed excess lung cancer mortality (standardized
    mortality ratio = 4.66) in 1143 workers employed between 1950 and 1980
    in a cobalt and sodium producing plant; smoking habits in the study
    population were not assessed. A follow-up study from 1981-88 failed to
    show a relationship between lung cancer and cobalt exposure (Moulin et
    al, 1993).

    Lasfargues et al (1994) reported significantly higher lung cancer
    mortality among 709 hard metal workers (employed for at least one
    year) compared to controls, though the study was too small to be
    conclusive.

    Reprotoxicity

    Cobalt chloride induced hypoxic testicular damage in rats when
    administered orally (Mollenhauer et al, 1985). Pedigo and Vernon
    (1993) observed reversible infertility in male mice exposed to 400 ppm
    cobalt chloride for 10 weeks. Reduced sperm function led to increased
    preimplantation embryo loss when these animals were mated.

    There are no data confirming human reprotoxicity in association with
    cobalt or cobalt compounds although occupational cobalt exposure has
    been linked to miscarriages in Finland (Reprotox, 1997; Reprotext,
    1997).

    Genotoxicity

    Cobalt chloride induced gene conversions in the yeast  S cerevisiae 
    (DOSE, 1993).

    Kasprzak et al (1994) observed oxidative DNA base damage in renal,
    hepatic and pulmonary chromatin of rats after intraperitoneal
    injection of cobalt salts.

    Fish toxicity

    LC50 (96 hr) carp embryo 96 mg/L. Static bioassay in freshwater, pH
    7.5, temperature 16C, water hardness 360 mg/L CaCO3.

    The common carp hatching process was impaired by cobalt chloride in a
    dose related manner.

    Adult giant gourami exposed to 232.8 mg/L for 24, 72 and 96 hr
    (freshwater static bioassay, pH 7.5, temperature 23.6C, water oxygen
    content 7.6 mg/L and water hardness 164 mg/L CaCO3) showed blood
    pyruvate concentrations increased by 22, 75 and 47 per cent
    respectively.

    LC50 (96 hr) fathead minnow 48 mg/L; lakewater static bioassay, pH
    6.5-8.5, temperature 20C, water hardness 130 mg/L CaCO3.

    LC50 (48 hr)  Olyzias latipes 620 ppm (DOSE, 1993).

    EC Directive on Drinking Water Quality 80/778/EEC

    Chlorides: Maximum admissible concentration 25 mg/L. Concentration
    above which effects might occur 200 mg/L (DOSE, 1993).

    WHO Guidelines for Drinking Water Quality

    NIF

    AUTHORS

    SM Bradberry BSc MB MRCP
    P Sabatta MSc
    JA Vale MD FRCP FRCPE FRCPG FFOM

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

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

    Date of last revision
    28/1/98

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