UKPID MONOGRAPH
COBALT CHLORIDE
SM Bradberry BSc MB MRCP
P Sabatta MSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
COBALT CHLORIDE
Toxbase summary
Type of product
Used in inks, varnishes, enamels, fertilizers, feed additives and
humidity indicators.
Toxicity
Cobalt chloride is only moderately toxic by ingestion although a 19
month-old child died some six hours after allegedly drinking only 30
mL (Jacobziner and Raybin, 1961). In another report a six year-old
developed only transient gastrointestinal upset after ingesting 2.5 g
(Mucklow et al, 1990).
Cobalt sensitization may occur following dermal exposure.
Features
Dermal
- Cobalt chloride is a topical irritant and a recognized cause
of occupational contact dermatitis.
- Simultaneous allergies to nickel and cobalt are frequent.
Ocular
- Cobalt chloride is a potential eye irritant but there are no
reports of acute eye toxicity in man.
Ingestion
- There may be no or minimal symptoms after small ingestions.
Nausea, vomiting and/or abdominal pain are likely after more
substantial ingestions (> 100 mg). Concentrated solutions
are acidic (the pH of a 0.2 M solution is 4.6). There is an
early case report of fatal cobalt chloride ingestion (30 mL)
in which autopsy showed a blistered oesophageal mucosa and
partially necrosed gastric mucosa (Jacobziner and Raybin,
1961).
- Transient neutropenia occurred in a six year old child who
ingested 2.5 g (Mucklow et al, 1990).
- In the past congestive cardiomyopathy occurred after the
consumption of large quantities of beer to which cobalt
chloride/cobalt sulphate had been added as a foam stabilizer
and in those receiving oral cobalt chloride therapy as
treatment for anaemia. These presentations are now most
unlikely in the UK.
- Chronic cobalt chloride ingestion has also caused
hypothyroidism (cobalt inhibits the iodination of tyrosine).
Inhalation
- Pulmonary toxicity following chronic cobalt exposure is
associated typically with the hard metal industry in which
elemental cobalt forms a matrix for tungsten carbide.
Symptoms are most prevalent, however, among those working in
'wet' processes where cobalt is ionized.
- Hard metal lung disease usually arises after several years
and may manifest as pneumoconiosis (with dyspnoea and cough
secondary to interstitial fibrosis), allergic alveolitis or
occupational asthma.
- Cor pulmonale may complicate hard metal pneumoconiosis.
- There are occasional reports of cobalt cardiomyopathy
following occupational exposure.
Management
Dermal
1. Removal from exposure is the priority.
2. Contact dermatitis responds to topical and/or systemic steroids.
3. There is no confirmed role for topical chelation therapy in
cobalt dermatitis.
Ocular
1. Irrigate for at least 15 minutes with lukewarm water.
2. Topical anaesthesia may be required.
3. Ensure particle removal from conjunctival recesses.
4. An ophthalmic opinion may be required.
Ingestion
1. Gastrointestinal decontamination is not necessary. Vomiting will
occur spontaneously following significant ingestions and gastric
lavage is contraindicated following ingestion of acid solutions.
2. Supportive care is the priority. Replace fluids and electrolytes
as required.
3. Check the full blood count.
4. If chronic cobalt ingestion is suspected consider the possibility
of cobalt cardiomyopathy and check thyroid function.
5. Collect blood and urine for cobalt concentration determination in
symptomatic patients to confirm diagnosis. Cobalt assays are not
widely available. Check with NPIS.
6. There are no controlled clinical data regarding the use of
chelating agents in cobalt poisoning. Discuss with an NPIS
physician.
Inhalation
Acute inhalation:
1. Remove from exposure and treat symptomatically.
Chronic inhalation:
1. Asthmatic symptoms respond to conventional measures.
2. Established pulmonary fibrosis generally has a poor prognosis.
Some cases have responded to high dose prednisolone (Rolfe et al,
1992) or cyclophosphamide (Balmes, 1987). Discuss with an NPIS
physician.
References
Alexander CS.
Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty-
eight cases.
Am J Med 1972; 53: 395-417.
Balmes JR.
Respiratory effects of hard-metal dust exposure.
Occup Med 1987; 2: 327-44.
Cugell DW.
The hard metal diseases.
Clin Chest Med 1992; 13: 269-79.
Curtis JR, Goode GC, Herrington J, Urdaneta LE.
Possible cobalt toxicity in maintenance hemodialysis patients after
treatment with cobaltous chloride: a study of blood and tissue cobalt
concentrations in normal subjects and patients with terminal renal
failure.
Clin Nephrol 1976; 5: 61-5.
Jacobziner H, Raybin HW.
Accidental cobalt poisoning.
Arch Pediatr 1961; 78: 200-5.
Manifold IH, Platts MM, Kennedy A.
Cobalt cardiomyopathy in a patient on maintenance haemodialysis.
Br Med J 1978; 2: 1609.
Mucklow ES, Griffin SJ, Delves HT, Suchak B.
Cobalt poisoning in a 6-year-old.
Lancet 1990; 335: 981.
Rolfe MW, Paine R, Davenport RB, Strieter RM.
Hard metal pneumoconiosis and the association of tumor necrosis
factor-alpha.
Am Rev Respir Dis 1992; 146: 1600-2.
Sullivan JF, Egan JD, George RP.
A distinctive myocardiopathy occurring in Omaha, Nebraska: Clinical
aspects.
Ann NY Acad Sci 1969; 156: 526-43.
Substance name
Cobalt (II) chloride
Origin of substance
Prepared commercially in hexahydrate, dihydrate and monohydrate
forms. (DOSE, 1993)
Synonyms
Cobalt dichloride
Cobaltous chloride (DOSE, 1993)
Chemical group
A compound of cobalt, a group VIIIB element.
Reference numbers
CAS 7646-79-9, (DOSE, 1993)
7791-13-1 (hexahydrate)
RTECS GF 9800000 (RTECS, 1997)
UN NIF
HAZCHEM NIF
Physicochemical properties
Chemical structure
CoCl2 (DOSE, 1993)
Molecular weight
129.84 (DOSE, 1993)
Physical state at room temperature
Solid (DOSE, 1993)
Colour
Pale blue, turning pink on exposure to air.
(OHM/TADS, 1997)
Odour
Very slight sharp odour. (CHRIS, 1997)
Viscosity
NA
pH
Forms acid solution in water (0.2 M aqueous solution has pH 4.6).
(MERCK, 1996; OHM/TADS, 1997)
Solubility
450 g/L in water at 7°C
385 g/L in methanol (HSDB, 1997)
Autoignition temperature
NA
Chemical interactions
A mixture of potassium and cobalt chloride is sensitive to
mechanical shock and may cause a violent explosion.
Sodium dispersions will reduce cobalt chloride exothermically,
resulting in a temperature increase of 50°C. Very violent
explosions may occur.
Contact of dust with strong oxidizers may cause fire and
explosion. (HSDB, 1997)
Major products of combustion
Cobalt oxide (HSDB, 1997)
Explosive limits
NA
Flammability
Not flammable (HSDB, 1997)
Boiling point
1049°C (DOSE, 1993)
Density
3.367 at 25°C (DOSE, 1993)
Vapour pressure
5333 Pa at 770°C (DOSE, 1993)
Relative vapour density
NA
Flash point
NA
Reactivity
Cobalt chloride decomposes at 400°C on heating in air.
Cobalt chloride hydrolyzes in aqueous solution.
(HSDB, 1997)
Uses
Invisible ink
Humidity indicator
Glass and porcelain painting
Production of vitamin B12
Fertilizer and feed additive
Stabilizer in beer
Absorbant for poisonous gases and ammonia
(DOSE, 1993)
Hazard/risk classification
NIF
INTRODUCTION AND EPIDEMIOLOGY
Cobalt chloride is a water soluble bivalent cobalt salt. Cobalt
chloride poisoning is now rare with only isolated case reports of
accidental or intentional ingestion, usually from chemistry sets or
crystal growing kits (Jacobziner and Raybin, 1961; Everson et al,
1988; Mucklow et al, 1990).
Outbreaks of cobalt cardiomyopathy occurred in Belgium, Nebraska and
Quebec in the 1960's among heavy beer drinkers when cobalt
chloride/sulphate was added to beer to act as a foam stabilizer
(Kesteloot et al, 1968). Chronic cobalt intoxication also occurred
when oral cobalt chloride was used to treat anaemia (Duckham and Lee,
1976; Manifold et al, 1978) but this is no longer a licensed
indication in the UK.
Cobalt is an important cause of occupational contact dermatitis and
cobalt chloride is widely used in patch testing. However, reports in
which cobalt chloride specifically is the allergen are rare (Zenorola
et al, 1994).
MECHANISM OF TOXICITY
Cytotoxic hydroxy radicals may form when cobalt ions interact with
reactive oxygen species. Hydroxy radicals may then cause the
production of further free radicals which reduce cellular glutathione
concentrations and NADPH activity. The resulting oxidative stress
leads to DNA and cellular protein damage (Timbrell, 1994).
Cobalt is immunogenic and acts as a hapten in the induction of
bronchial and dermal hypersensitivity (Sjögren et al, 1980). Ionized
cobalt, though not specifically cobalt chloride, is an important
contributing factor in the aetiology of hard metal lung disease.
Evidence for an autoimmune mechanism in this disorder is suggested by
the recurrence of disease in a single transplanted lung despite no
evidence of cobalt in the donated organ (Frost et al, 1993). In cobalt
pneumoconiosis non-respiratory symptoms may be due to cobalt-induced
release of a tumour necrosis factor from sensitized pulmonary
lymphocytes (Rolfe et al, 1992).
In a dog model cobalt myocardial toxicity was characterized by
vacuolation and loss of myofibers (Sandusky et al, 1981a) with
histochemical evidence of severe mitochondrial damage (Sandusky et al,
1981b). Alexander (1972) suggested cobalt depresses mitochondrial
oxygen uptake in the myocardium by complexing with sulphydryl groups
and preventing the oxidation of pyruvate in the citric acid cycle.
Tissue hypoxia is the probable stimulus also of erythropoietin
secretion in cobalt-induced polycythaemia (Taylor and Marks, 1978).
In animal studies, cobalt decreases synthesis of several enzymes
including cellular cytochrome P450 (Timbrell, 1994). Cobalt inhibits
aminolaevulinic acid synthetase and increases the activity of haem
oxygenase which breaks down haem to biliverdin (Taylor and Marks,
1978; Timbrell, 1994).
TOXICOKINETICS
Absorption
Cobalt chloride can be absorbed following ingestion, inhalation and
dermal exposure (Domingo, 1989; Scansetti et al, 1994; Linnainmaa and
Kiilunen, 1997). Cobalt and iron share the same transport mechanism
within the small intestine such that cobalt ingestion competitively
inhibits iron uptake. The extent of intestinal cobalt absorption
depends on the dose with only some 20 per cent of a large ingestion
being absorbed (Domingo, 1989).
Some inhaled cobalt chloride is swallowed following mucociliary
clearance while particles which reach the distant pulmonary tree are
taken up predominantly by macrophages (Taylor and Marks, 1978; Evans
et al, 1993). Systemic uptake is confirmed by increased blood and
urine cobalt concentrations in those occupationally exposed to
cobalt-containing dusts and mists (Della Torre et al, 1990).
Distribution
The normal body burden of cobalt is about 1.1 mg. Approximately 43 per
cent of this is in muscle with some 14 per cent in bone and the
remainder in other soft tissues (Taylor and Marks, 1978; Domingo,
1989).
Excretion
Cobalt which reaches the systemic circulation is eliminated
predominantly in urine with a variable but small amount excreted in
bile (Taylor and Marks, 1978; Domingo, 1989).
Following acute occupational cobalt inhalation urinary elimination is
rapid for the first 24 hours followed by a slower excretion phase
lasting several weeks (Alexandersson, 1988). A small proportion of
retained cobalt has a biological half-life of several years (Elinder
and Friberg, 1986).
CLINICAL FEATURES: ACUTE EXPOSURE
Dermal exposure
Cobalt chloride may cause skin irritation but dermal toxicity is
associated primarily with contact sensitivity (see Chronic exposure).
Ocular exposure
Cobalt chloride causes corneal damage when directly applied to the
eyes of experimental animals (Grant and Schuman, 1993) but there are
no reports of acute eye toxicity in man.
Inhalation
There are no reports of acute cobalt chloride inhalation.
Ingestion
Most reports of cobalt chloride ingestion involve only modest
gastrointestinal upset although Jacobziner and Raybin (1961) described
a fatality in a 19 month-old child (see below).
Gastrointestinal toxicity
Jacobziner and Raybin (1961) reported a 19 month-old child who
ingested approximately 30 mL of a cobalt chloride solution. Vomiting
was induced immediately and gastric lavage performed on arrival at
hospital two hours later. On examination the child was pale and
peripherally cyanosed. The lips and tongue were oedematous. The
clinical condition deteriorated rapidly with death following a cardiac
arrest some six hours post ingestion. Autopsy revealed a blistered
oesophageal mucosa with coagulative necrosis involving one third the
thickness of the gastric mucosa. The precise cause of death was not
clear but these findings suggest the solution was highly concentrated
and corrosive. Cobalt was identified in the liver, kidney, spleen (89
mg total in these organs) and stomach.
A six year-old boy developed nausea, vomiting and abdominal pain after
swallowing a drink to which he had added about 2.5 g cobalt chloride
from a crystal growing set (Mucklow et al, 1990). The whole blood
cobalt concentration some seven hours post ingestion was 241 µg/L
(normal range < 1 µg/L) but he made a full recovery.
Everson et al (1988) reported a 14 year-old female who vomited but was
otherwise asymptomatic following ingestion of approximately 130 mg
cobalt chloride from her brother's chemistry set. The serum cobalt
concentration 12 hours post ingestion was 78 µg/L.
Haemotoxicity
A six year old boy who ingested 2.5 g cobalt chloride developed a
transient neutropenia (1.7 x 109/L) but recovered fully (Mucklow et
al, 1990).
Neurotoxicity
A 19 month-old child who ingested 30 mL of a cobalt chloride solution
became restless and drowsy within two hours in association with severe
respiratory distress, cyanosis and pallor. He died some six hours
later (Jacobziner and Raybin, 1961). Cerebral oedema was evident at
autopsy.
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Cobalt is a well recognized cause of contact dermatitis (Smith et al,
1975), a delayed hypersensitivity reaction characterized by vesicles,
itchy maculopapular lesions, scaling and/or fissuring (Miyachi et al,
1985; Foussereau and Cavelier, 1988; Illuminati et al, 1988). These
features are seen commonly on the hands, face and neck and sometimes
the eyelids and chest.
Cobalt contact dermatitis primarily occurs following exposure to the
elemental form, which subsequently is ionized in sweat, although there
are situations where cobalt compounds are the primary allergen. For
example, a 71 year-old construction labourer developed contact
dermatitis induced by cobalt and chromium ions present in cement
(Miyachi et al, 1985). Cobalt dermatitis is also described in those
handling or manufacturing rubber. In the rubber industry cobalt is
used as lipid soluble (cobalt naphthenates and stearates) rather than
water soluble salts (Bedello et al, 1984; Foussereau and Cavelier,
1988).
Zenorola et al (1994) described atypical dermatitis in a 23 year-old
plumber. The clinical appearance was highly suggestive of "Ashy
dermatitis" or erythema dyschromicum perstans, a disorder of uncertain
aetiology characterized by asymptomatic, ash-like grey macular
pigmentation of the skin. The patient patch tested positive to cobalt
chloride for which there were several sources in his workplace
including varnishes and paints. However a causative association
between ashy dermatitis and cobalt allergy could not be confirmed.
An initial irritant dermatitis, often involving operations traumatic
to the hand, usually precedes cobalt allergy in industry (Fischer and
Rystedt, 1983a). In addition false positive cobalt patch tests may
occur due to an irritant rather than delayed hypersensitivity response
(Fischer and Rystedt, 1985).
Cobalt chloride is used widely in patch testing (James and Smith,
1975; Munro-Ashman and Miller, 1976; Veien and Svejgaard, 1978;
Schmidt et al, 1980; Rae, 1981; Romaguera et al, 1982; Miyachi et al,
1985; Shirakawa et al 1988; Allenby and Basketter, 1989; Pryce and
King, 1990; Zhang et al, 1991; Castiglioni et al, 1992; Torresani et
al, 1994). Lantinga et al (1984) invited 2800 members of the general
population in a geographically defined area of the Netherlands to be
examined for skin disorders of the hands and forearms. Patch testing
was performed in 141 persons with eczema. Contact allergy was detected
in 50 (35 per cent) of these. Cobalt chloride was the allergen in five
cases with nickel sulphate in 28 and potassium dichromate in nine
cases.
Among 4721 consecutive patients at a patch test clinic, six per cent
had a positive reaction to cobalt chloride (compared to nickel
sensitivity in 18.5 per cent) (Shehade et al, 1991). These authors
emphasized the importance of not reading the patch test before day
four; 69 of 271 (24 per cent) patients with a positive reaction to
cobalt chloride on day four had a negative result on day two.
Simultaneous allergies to nickel and cobalt are frequent (Burden and
Eedy, 1991; Kanerva and Estlander, 1995) and there is some evidence
for a mutual enhancing effect of contact sensitization to one metal in
the presence of the other (Domingo, 1989).
Inhalation
Pulmonary toxicity
Pulmonary toxicity following chronic cobalt exposure is associated
typically with the hard metal (tungsten carbide in a cobalt matrix)
industry (Auchincloss et al, 1992) but similar problems have been
reported in diamond polishers using cobalt-coated discs (Lahaye et al,
1984; Nemery et al, 1990) and in a dental technician (Sherson et al,
1990). Hard metal lung disease is discussed here since employees are
exposed both to elemental and ionized cobalt (the latter in 'wet'
grinding processes where cobalt is dissolved in machine coolants).
Cugell (1992) suggested ionized cobalt is more likely than elemental
cobalt to cause occupational pulmonary disease although this may not
be true of hard metal asthma (Kusaka et al, 1996a).
There is some debate concerning whether cobalt exposure alone is
sufficient to cause pulmonary fibrosis. In-vitro and animal studies
suggest there is no relationship between cellular cobalt uptake and
cellular toxicity (Lison and Lauwerys, 1994) and cobalt workers
frequently are exposed to several other potential toxins (including
tungsten carbide, iron, silica and diamond) (Swennen et al, 1993).
While Gennart and Lauwerys (1990) observed a significantly increased
incidence (p<0.05) of restrictive spirometry and respiratory symptoms
in workers exposed for more than five years to cobalt dust in a plant
producing diamond-cobalt circular saws compared to non cobalt-exposed
factory workers, Swennen et al (1993) found no difference in
ventilatory performance, lung volumes or carbon monoxide diffusion
capacity between 82 cobalt refinery workers and controls even though
the cobalt workers complained more frequently of wheeze and dyspnoea.
Hard metal pneumoconiosis
Chronic cobalt (and tungsten carbide) inhalation is associated
typically with "hard metal" pneumoconiosis characterized by
interstitial fibrosis (primarily of the lower zones) and a restrictive
ventilatory defect (Bech et al, 1962). Patients usually present with
exertional dyspnoea, cough and sometimes chest tightness (Bech et al,
1962). There may be associated symptoms of fever, weight loss or
general malaise (Coates and Watson, 1971; Balmes, 1987; Migliori et
al, 1994). In one study of 12 tungsten carbide workers the mean
duration of exposure before the onset of respiratory symptoms was 12
years with a range of one month to 28 years (Coates and Watson, 1971).
Inspiratory crackles are the earliest physical sign (Rochat et al,
1987) but finger clubbing, cyanosis and eventually cor pulmonale may
ensue. Chest X-ray findings vary greatly (Cugell et al, 1990) but
usually show increased linear markings and small nodular opacities in
the lower (and mid) zones with later cardiomegaly and features of
pulmonary hypertension (Bech et al, 1962).
Many patients develop a form of pulmonary fibrosis complicated by
atypical intraalveolar giant cells (Davison et al, 1983; Rochat et al,
1987; Cugell, 1992; Frost et al, 1993) which can be demonstrated in
bronchoalveolar lavage fluid (Forni, 1994) and transbronchial biopsies
(Rolfe et al, 1992). Pulmonary eosinophilia is also a feature of hard
metal lung disease (Della Torre et al, 1990). Forni (1994) suggested
that a persistently high bronchoalveolar lavage eosinophil count
despite steroid therapy and cessation of exposure carried an
unfavourable prognosis.
Several fatalities from hard metal pneumoconiosis have been reported
(Della Torre et al, 1990; Figueroa et al, 1992). Nemery et al (1990)
described a 52 year-old diamond polisher who died less than one year
after a diagnosis of interstitial lung disease. He continued work
without specific treatment until three months before death when he
required continuous oxygen and systemic steroids. At autopsy there was
evidence of extensive fibrosis with interstitial giant cells. The lung
cobalt concentration was 2.1 µg/g. The authors suggested that oxygen
therapy may have exacerbated this man's deterioration via
cobalt-induced hydroxyl free radical formation.
A 37 year-old female developed rapidly progressive pneumoconiosis
after working, without respiratory protection, for seven years in
sharpening and grinding operations with hard metal tools (Della Torre
et al, 1990). There was no response to steroid therapy and she died
from respiratory failure less than one year after presentation.
Interestingly, although the lung cobalt concentration in
bronchoalveolar lavage fluid was increased on presentation (2 µg/L,
reference value 0.6 µg/L) the cobalt concentration at open biopsy four
months later was not raised significantly, supporting the hypothesis
that cobalt-induced lung damage is immunologically mediated rather
than a direct effect.
Allergic alveolitis
An allergic alveolitis has been described in hard-metal workers with
cough, dyspnoea and flu-like symptoms associated with bilateral
crackles, radiographic small nodular infiltrates and a restrictive
lung function defect (Sjögren et al, 1980; Cugell, 1992). These
abnormalities may reverse if exposure ceases but with continued cobalt
inhalation irreversible fibrosis is likely (Cugell, 1992).
Occupational asthma
Hard metal workers may develop occupational asthma with cough, wheeze
and dyspnoea that characteristically improves during week-ends and
holidays (Sprince et al, 1988; Cugell, 1992). Similar symptoms have
been described in diamond workers exposed to cobalt in polishing discs
(Gheysens et al, 1985).
In a study of 703 hard metal workers Kusaka et al (1996a) identified
age (>40 years), atopy and cobalt exposure as risk factors for
asthma. Surprisingly, low airborne cobalt concentrations (below 50
µg/m3) posed a greater risk of hard metal asthma than did higher air
cobalt concentrations (Kusaka et al, 1996a) although the observed
deterioration in ventilatory function seemed to be related to duration
of cobalt exposure (Kusaka et al, 1996b). In this study there was no
significant difference in asthma prevalence between those exposed to
the elemental (dust) or ionized (mist) metal (Kusaka et al, 1996a).
Cobalt asthma is associated in some, but not all, cases with
circulating cobalt-specific IgE and generalized bronchial
hyperresponsiveness (Coates and Watson 1971; Sjögren et al, 1980;
Kusaka et al, 1989; Shirakawa et al, 1989; Cugell, 1992). Respiratory
cross-reactivity between cobalt and nickel has also been described
(Shirakawa et al, 1990).
Cardiovascular toxicity
Patients with fulminant hard metal pneumoconiosis may, after several
years, develop cor pulmonale with clinical and radiological features
of pulmonary hypertension and right heart failure (Bech et al, 1962).
Cobalt cardiomyopathy is associated most frequently with chronic
excess cobalt chloride or cobalt sulphate ingestion (see above) but an
identical syndrome has been reported occasionally in those exposed
occupationally (Barborik and Dusek, 1972; Jarvis et al, 1992).
Kennedy et al (1981) reported fatal cardiogenic shock in a 48 year-old
hard metal worker following routine vagotomy and pyloroplasty for
duodenal ulceration. The patient, who had handled tungsten carbide and
cobalt dust for four years, initially developed signs of
cardiovascular compromise during the operation and gradually
deteriorated without evidence of ischaemic heart disease. At
post-mortem the heart was dilated with extensive myocardial fibrosis
and a myocardial cobalt concentration of 7 µg/g (normal range
0.1-0.4).
There is limited evidence that hard metal workers may develop
electrocardiographic abnormalities and/or impaired left ventricular
function after chronic cobalt exposure (Horowitz et al, 1988; Evans et
al, 1993) but the significance of these studies is uncertain.
Neurotoxicity
Jordan et al (1990) reported significantly impaired attention
(p<0.05) and verbal memory (p<0.001) in 12 hard metal workers
exposed to tungsten carbide and cobalt (as dust and dissolved in an
organic solvent) compared to healthy unexposed controls. However, all
members of the study group had "pulmonary manifestations" of hard
metal disease which may have affected performance.
A patient exposed occupationally (mainly via inhalation) to cobalt
dust for 20 months developed bilateral optic atrophy and bilateral
nerve deafness. Fourteen months after stopping work visual acuity
improved and hearing returned to normal (Meecham and Humphrey, 1991).
Nephrotoxicity
Lechleitner et al (1993) reported Goodpasture's syndrome in a 26
year-old hard metal worker with severe interstitial lung disease and
fulminant glomerulonephritis. The role of heavy metal exposure in the
aetiology of this case is not known though the authors proposed
cobalt-induced ß-cell activation or exposure of pulmonary basement
membrane antigens as possible disease mechanisms.
Ocular toxicity
Optic atrophy occurring in association with chronic cobalt inhalation
is discussed above (Neurotoxicity).
Ingestion
Dermal toxicity
The administration of disulfiram in the treatment of ethanol abuse has
led to an exacerbation of cobalt dermatitis presumably via
diethyldithiocarbamate (a disulfiram metabolite) chelation and
mobilization of cobalt in a manner similar to that reported in nickel
sensitive subjects (Menné, 1985).
Gastrointestinal toxicity
Gastrointestinal symptoms similar to those occurring after acute
cobalt chloride ingestion have also complicated chronic therapy. A 35
year-old woman with anaemia treated with cobalt chloride 25 mg qds
complained of nausea, vomiting and weight loss in addition to
neurological symptoms (Schirrmacher, 1967).
One of 12 renal failure patients on haemodialysis treated with cobalt
chloride 25-50 mg daily had to discontinue therapy after ten days due
to nausea and constipation. Symptoms resolved on withdrawal of cobalt
supplements (Duckham and Lee, 1976).
Increased serum triglyceride concentrations have been noted in
cobalt-treated anephric patients and although hepatic glucagon
resistance was postulated as the cause this has not been confirmed
(Taylor and Marks, 1978). Cobalt-induced inhibition of lipoprotein
lipase is now thought likely to be relevant (Taylor and Marks, 1978).
Cardiovascular toxicity
Congestive cardiomyopathy has been reported in people who drank large
quantities of beer to which cobalt chloride/sulphate had been added as
a foam stabilizer (Morin et al, 1967; Kesteloot et al, 1968; Sullivan
et al, 1969) and in those receiving oral cobalt chloride therapy
(Manifold et al, 1978).
In a study of 28 cases of cobalt beer cardiomyopathy (Alexander, 1972)
symptoms of cardiac failure were of fairly abrupt onset (mean duration
at presentation 10 weeks) and variable severity with five deaths from
cardiogenic shock and a full physical recovery in only 11 patients.
Cardiomegaly, a pericardial effusion and polycythaemia were present in
the majority with pleural effusion in 11 cases though radiological
evidence of pulmonary oedema "characteristically ..... was absent".
Profound lactic acidosis was a prominent feature in severe cases.
Electrocardiographic abnormalities included p pulmonale or p mitrale,
axis (usually right) deviation and acute ischaemic changes in the
precordial leads typically associated with increased plasma cardiac
enzyme activities. Electron microscopy of myocardial tissue from these
patients showed extensive myofibril degeneration with abnormal
mitochondria containing electron-dense bodies believed to incorporate
cobalt. It is probable that alcohol and malnutrition contributed to
the cardiotoxicity observed in these and other cases since the
absolute quantities of cobalt ingested often were small (up to 10 mg
daily) (Kesteloot et al, 1968; Alexander, 1972).
Curtis et al (1976) described a haemodialysis patient who died three
months after "a course" of cobalt chloride. At post mortem the
myocardial cobalt concentration was 1.65 µg/g, some 25-80 times
greater than myocardial cobalt concentrations in haemodialysis
patients who had not received cobalt. These authors noted also that
patients treated with oral cobalt chloride had significantly higher
(p=0.001) blood cobalt concentrations than haemodialysis patients who
had not received cobalt. In another report a 17 year-old girl on
maintenance haemodialysis died from rapidly progressive dilated
cardiomyopathy after nine months cobalt chloride therapy (25 mg bd)
for anaemia. At necropsy the myocardial cobalt concentration was 8.9
µg/g (Manifold et al, 1978).
Neurotoxicity
After six months treatment with cobalt chloride 25 mg qds for anaemia
a 35 year-old woman developed limb paraesthesiae, an unsteady gait,
impaired hearing and dizzy spells in addition to nausea, vomiting and
weight loss (Schirrmacher, 1967). Clinical examination confirmed
bilateral nerve deafness, absent ankle reflexes and impaired vibration
sense. All symptoms and signs resolved with four months of cobalt
chloride withdrawal.
A haemodialysis patient developed polyarthralgia and muscle weakness
after three weeks cobalt chloride therapy (25-50 mg daily). Weakness
improved following cobalt withdrawal but polyarthralgia persisted; the
patient died eight months later after renal transplantation failure
(Duckham and Lee, 1976).
Haemotoxicity
Chronic excess cobalt chloride ingestion causes polycythaemia which in
the past led to its use in the treatment of anaemia (Manifold et al,
1978). A 13 month-old child developed persistent anaemia with
polycythaemia and cardiomegaly in addition to hypothyroidism (see
below) and hypertrichosis following treatment of iron deficiency for
one year with a commercial iron-cobalt preparation. At the end of the
treatment period the serum cobalt concentration was 59 µg/L. The
haematological abnormalities and hypothyroidism resolved when the
treatment was stopped, with some improvement in cardiac size and a
fall in the serum cobalt concentration to 6.8 µg/L and 1.4 µg/L at
four and 12 months respectively (Bianchi et al, 1989).
Endocrine toxicity
Cobalt inhibits the iodination of tyrosine and goitre is a recognized
side-effect of cobalt therapy (Schirrmacher, 1967). A four year-old
boy with sickle cell anaemia admitted for tonsillectomy was noted to
have a large goitre. For seven months prior to admission the patient
had taken 60-80 mg cobalt chloride daily. The thyroid gland was
bilaterally and asymmetrically enlarged, firm, nodular, painless and
mobile (Kriss et al, 1955). The goitre disappeared one month after
cobalt chloride withdrawal.
A 13 month-old baby developed clinical and biochemical hypothyroidism
after treatment of iron deficiency for one year with a commercial
iron-cobalt preparation. The endocrine abnormality resolved when
treatment was withdrawn (Bianchi et al, 1989).
Ocular toxicity
Following treatment of pancytopenia with 73 g oral cobalt chloride
over two and a half years, a patient developed abnormal choroidal
perfusion and optic atrophy. Vision did not deteriorate further
following cessation of therapy (Licht et al, 1972).
MANAGEMENT
Dermal exposure
Removal from exposure is the priority. Most barrier creams do not
prevent the penetration of cobalt chloride through the skin (Fischer
and Rystedt, 1983b) although Fischer and Rystedt (1990) demonstrated
that polyethylene glycol effectively reduced cobalt contact
reactivity. Exacerbations of cobalt contact dermatitis respond to
topical or systemic steroids. The role of chelation therapy in cobalt
contact sensitivity is discussed below.
Ocular exposure
Decontamination with copious lukewarm water (eg via drip tubing) is
the priority. Topical anaesthesia may be necessary, particularly to
ensure removal of particles from the conjunctival recesses. Seek an
ophthalmic opinion if symptoms persist or there are abnormal
examination findings.
Inhalation
Exposure must be discontinued if occupational cobalt lung disease is
suspected or confirmed. Asthmatic symptoms respond to conventional
measures (Pisati and Zedda, 1994). Established pulmonary fibrosis has
a generally poor prognosis although there are reports of substantial
improvement following high dose steroids (prednisolone 60 mg daily
(Rolfe et al, 1992) and/or removal from the workplace (Zanelli et al,
1994). The possibility of cobalt cardiotoxicity should be remembered.
The role of blood and urine cobalt concentration measurements is
discussed below (Medical Surveillance).
Ingestion
Decontamination
Gastric lavage is unlikely to be helpful since if spontaneous vomiting
does not occur the ingestion is almost certainly too small to cause
significant toxicity. Concentrated solutions are acidic and gastric
lavage is contraindicated if corrosive damage is a possibility. There
is no evidence that oral activated charcoal reduces gastrointestinal
cobalt absorption.
Supportive measures
Following acute cobalt chloride ingestion supportive care is usually
all that is required with intravenous fluid replacement if vomiting is
severe. Concentrated solutions are acidic and the possibility of
corrosive damage should be considered. Plasma creatinine, urea and
electrolytes and full blood count should be measured. If chronic
cobalt toxicity is suspected a thorough cardiovascular and
neurological (including fundoscopy) assessment should be undertaken.
Thyroid function tests should be performed. The role of chelation
therapy is discussed below (Antidotes). The presence of cobalt in
blood and urine confirms exposure but blood and urine concentrations
require careful interpretation (see Medical Surveillance) and these
assays are not widely available.
Antidotes
Sodium calciumedetate
Animal studies
Post (1955) observed that rats administered sodium calciumedetate
subcutaneously following intraperitoneal cobalt chloride injection did
not show the polycythaemic response induced in controls (treated with
cobalt only). Subsequent studies (Domingo et al, 1983; Llobet et al,
1985; Llobet et al, 1986) provided further evidence for sodium
calciumedetate as an effective cobalt chelator.
All mice administered intraperitoneal cobalt chloride at doses
approximating to the LD50 - LD95 (0.6-1.8 mmol/kg), immediately
followed by 4.3 mmol/kg intraperitoneal sodium calciumedetate survived
two weeks with significantly increased urine cobalt elimination in the
24 hours post antidote administration (Llobet et al, 1986). Llobet et
al (1988) later demonstrated significantly increased (p<0.05) faecal
but not urinary cobalt elimination during a five day course of
chelation therapy in cobalt-poisoned rats (administration details as
below).
Clinical studies
Topical
Allenby and Basketter (1989) found a positive patch test reaction to
one per cent aqueous cobalt chloride was abolished in five out of six
subjects by the concomitant application of an equimolar sodium
calciumedetate solution.
Systemic
A 14 year-old female who ingested approximately 130 mg cobalt chloride
was asymptomatic but treated with intravenous sodium calciumedetate 1g
tds for three doses on the basis of a raised serum cobalt
concentration (78 µg/L 12 hours post ingestion) (Everson et al, 1988).
No cobalt excretion data were presented. The serum cobalt
concentration had fallen to 7 µg/L 22 hours post ingestion and the
child remained well.
No cobalt was recovered in the urine of a patient with cobalt
cardiomyopathy who received a one week course of sodium calciumedetate
(and penicillamine, doses not stated) but treatment was not instituted
until three years after cobalt ingestion (quantity not stated)
(Alexander, 1972).
DMSA
Animal studies
Aposhian (1983) cited early animal studies published in the Chinese
literature (in 1965) which showed that DMSA 4 mmol/kg (route not
stated) increased threefold the LD50 of cobalt chloride-poisoned
mice.
Four of ten mice administered 1.8 mmol/kg intraperitoneal cobalt
chloride (a dose exceeding the LD95) immediately followed by
intraperitoneal DMSA 3.4 mmol/kg, survived two weeks (Llobet et al,
1986). Under these experimental conditions DMSA was a less effective
cobalt chelator than sodium calciumedetate or DTPA
(diethylenetriamine-pentacetic acid) (see below).
DMSA 1.2 mmol/kg/day intraperitoneally increased urine cobalt
excretion significantly (p<0.01) only on the final (fifth) day of
chelation in rats poisoned with cobalt chloride (0.06 mmol/kg/day
intraperitoneally three days per week for four weeks) (Llobet et al,
1988). In the same study faecal cobalt elimination was increased
significantly during the first four days of chelation therapy (p<0.05
days one, two and four, p<0.01 day three).
DTPA
Animal studies
Llobet et al (1986) reported 70 per cent two week survival in mice
administered intraperitoneal DTPA 3.1 mmol/kg immediately following
intraperitoneal loading with 1.8 mmol/kg cobalt chloride (a dose in
excess of the LD95). In a later study (Llobet et al, 1988) DTPA 1.2
mmol/kg/day significantly (p<0.05) enhanced faecal and urine cobalt
elimination.
Other chelating agents
Animal studies
Intraperitoneal L-histidine 2.7 mmol/kg administered immediately after
oral cobalt chloride (4.2 mmol/kg, approximately the oral LD95)
resulted in 90 per cent seven day survival compared to 15 per cent
survival in animals treated with cobalt chloride only (Domingo et al,
1985a).
Domingo et al (1985b) suggested that N-acetylcysteine (NAC) was
ineffective in reducing experimental cobalt fatalities unless
administered as a cobalt-NAC chelate. However, Llobet et al (1985)
demonstrated that glutathione and NAC (each 3.5 mmol/kg
intraperitoneally) immediately after intraperitoneal cobalt chloride
(0.70 mmol/kg, the LD50) improved survival. In a later study (Llobet
et al, 1988) glutathione and NAC (both 1.2 mmol/kg/day
intraperitoneally) significantly (p<0.05 and p<0.01 respectively)
increased urine and faecal cobalt excretion in cobalt poisoned rats,
with a significant (p<0.05) reduction in the spleen cobalt
concentration compared to controls.
Clinical studies
Topical clioquinol one per cent significantly (p<0.001) reduced patch
test reactions to cobalt in 29 cobalt-sensitive individuals. However
the authors emphasized this chelating agent is not suitable for
regular application since it is itself an allergen (Fischer and
Rystedt, 1990). There is also a risk of systemic uptake if clioquinol
is topically applied chronically. Clioquinol absorption may be
associated with neurological side-effects including peripheral
neuropathy and delirium (Rose, 1986).
Antidotes: Conclusions and recommendations
1. There are no human controlled data regarding the use of chelating
agents in cobalt(II) poisoning.
2. Animal studies suggest sodium calciumedetate and DTPA are the
most effective cobalt chelators although NAC and glutathione are
less toxic alternatives.
3. Following severe cobalt poisoning by ingestion the use of
chelation therapy may be considered; discussion of individual
cases with an NPIS physician is recommended.
4. There is no evidence that chelation therapy reduces the pulmonary
cobalt burden following chronic inhalation. Moreover, the value
of cobalt chelation my be limited where immunological mechanisms
play an important part in cobalt toxicity.
5. The role of topical chelating agents in cobalt dermatitis remains
unproven and is likely to be limited by practical difficulties.
Chemotherapy
Balmes (1987) reported a 28 year-old lady with aggressive hard metal
pneumoconiosis unresponsive to prednisolone (40-60 mg daily) who
clinically improved significantly after two months low-dose
cyclophosphamide therapy (25 mg bd).
Haemodialysis
In a patient with uraemic cardiomyopathy and a high serum cobalt
concentration (0.24 ppb), Lins and Pehrsson (1976) reported reduced
cardiac size in association with a fall in the serum cobalt
concentration to 0.07 ppb during haemodialysis. However no cobalt
dialysis clearance data or details of dialysis duration were given.
AT RISK GROUPS
Patients with renal failure are at risk of cobalt toxicity if
administered oral cobalt containing pharmaceuticals (Curtis et al,
1976); these preparations are not available in the UK.
MEDICAL SURVEILLANCE
Regular monitoring of workplace airborne cobalt concentrations (Sala
et al, 1994), strict attention to personal hygiene (Scansetti et al,
1994; Linnainmaa and Kiilunen, 1997) and periodic assessment for
pulmonary or dermatological symptoms are important in the prevention
of cobalt toxicity.
Some studies suggest airborne cobalt concentrations frequently are
underestimated (Auchincloss et al, 1992; Mosconi et al, 1994) and
other workers recently have reported average cobalt airborne
concentrations in a hard metal factory greatly exceeding the
recommended occupational exposure limit (Kumagai et al, 1996).
Furthermore, significant reductions in FEV1 and FVC have been
observed in workers exposed to airborne cobalt concentrations lower
than 50 µg/m3 (Nemery et al, 1992).
Sjögren et al (1980) noted that the development of cobalt contact
dermatitis among hard metal workers often preceded pulmonary disease
and suggested that those with a positive cobalt patch test should be
removed immediately from exposure. However, in another study, only two
of nine hard metal workers sensitive to inhaled cobalt had a positive
cobalt patch test (Kusaka et al, 1986).
Abnormal clinical findings should be investigated conventionally with
particular attention to establishing a temporal relationship to
workplace exposure in those with possible occupational asthma or
alveolitis. The presence of cobalt-specific IgE in plasma or cobalt
particles in bronchoalveolar lavage fluid or lung biopsy tissue may be
useful.
Increased blood and urine cobalt concentrations frequently are
encountered in hard metal workers (Ichikawa et al, 1985; Della Torre
et al, 1990; Stebbins et al, 1992; Linnainmaa and Kiilunen, 1997) but
are more useful as grouped rather than individual data (Sabbioni et
al, 1994) and their significance requires careful interpretation. A
potential role for hair and nail cobalt concentrations as indicators
of chronic exposure has not been substantiated (Della Torre et al,
1990).
In workers exposed to cobalt dust in a plant producing diamond-cobalt
saws urine cobalt concentrations reflected recent rather than
cumulative cobalt exposure (Gennart and Lauwerys, 1990). Lison et al
(1994) concluded that urine and blood cobalt concentrations correlated
reasonably well with recent occupational exposure to soluble forms of
cobalt.
Normal concentrations in biological fluids
In unexposed individuals normal cobalt concentrations are 0.1-1.2 µg/L
in blood (and serum) and 0.1-2.3 µg/L in urine (spot samples)
(Alexandersson, 1988).
OCCUPATIONAL DATA
Maximum exposure limit
Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3
(Health and Safety Executive, 1997).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
Animal studies suggest cobalt and its compounds are carcinogenic.
While several studies have shown that hard metal workers exhibit
excess lung cancer mortality, there is inadequate evidence for cobalt
or its compounds to be classed as carcinogenic in man (IARC, 1991).
Assessment of human cancer risk is often confounded by simultaneous
tobacco consumption, exposure to nickel and arsenic and small study
population numbers (Mur et al, 1987; Jensen and Tüchsen, 1990).
Mur et al (1987) observed excess lung cancer mortality (standardized
mortality ratio = 4.66) in 1143 workers employed between 1950 and 1980
in a cobalt and sodium producing plant; smoking habits in the study
population were not assessed. A follow-up study from 1981-88 failed to
show a relationship between lung cancer and cobalt exposure (Moulin et
al, 1993).
Lasfargues et al (1994) reported significantly higher lung cancer
mortality among 709 hard metal workers (employed for at least one
year) compared to controls, though the study was too small to be
conclusive.
Reprotoxicity
Cobalt chloride induced hypoxic testicular damage in rats when
administered orally (Mollenhauer et al, 1985). Pedigo and Vernon
(1993) observed reversible infertility in male mice exposed to 400 ppm
cobalt chloride for 10 weeks. Reduced sperm function led to increased
preimplantation embryo loss when these animals were mated.
There are no data confirming human reprotoxicity in association with
cobalt or cobalt compounds although occupational cobalt exposure has
been linked to miscarriages in Finland (Reprotox, 1997; Reprotext,
1997).
Genotoxicity
Cobalt chloride induced gene conversions in the yeast S cerevisiae
(DOSE, 1993).
Kasprzak et al (1994) observed oxidative DNA base damage in renal,
hepatic and pulmonary chromatin of rats after intraperitoneal
injection of cobalt salts.
Fish toxicity
LC50 (96 hr) carp embryo 96 mg/L. Static bioassay in freshwater, pH
7.5, temperature 16°C, water hardness 360 mg/L CaCO3.
The common carp hatching process was impaired by cobalt chloride in a
dose related manner.
Adult giant gourami exposed to 232.8 mg/L for 24, 72 and 96 hr
(freshwater static bioassay, pH 7.5, temperature 23.6°C, water oxygen
content 7.6 mg/L and water hardness 164 mg/L CaCO3) showed blood
pyruvate concentrations increased by 22, 75 and 47 per cent
respectively.
LC50 (96 hr) fathead minnow 48 mg/L; lakewater static bioassay, pH
6.5-8.5, temperature 20°C, water hardness 130 mg/L CaCO3.
LC50 (48 hr) Olyzias latipes 620 ppm (DOSE, 1993).
EC Directive on Drinking Water Quality 80/778/EEC
Chlorides: Maximum admissible concentration 25 mg/L. Concentration
above which effects might occur 200 mg/L (DOSE, 1993).
WHO Guidelines for Drinking Water Quality
NIF
AUTHORS
SM Bradberry BSc MB MRCP
P Sabatta MSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Date of last revision
28/1/98
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