Cobalt - Toxicology of Metals - page 508

macrophages and hyperplasia of type II pneumocytes
were found after inhalation of cobalt chloride (0.5 mg/
m 3 for 1 month). Exposure to 0.4 and 2 mg/m 3 cobalt
chloride for 14-16 weeks (6 hours/day, 5 days/week)
induced a combination of lesions characterized by
nodular aggregation of type II cells; abnormal accumu-
lation of enlarged, vacuolated alveolar macrophages;
and interstitial infl ammation (Johansson et al ., 1987).
Camner et al . (1993) reported that the infl ammatory
reaction (BAL neutrophils and eosinophils) induced by
the inhalation of cobalt chloride (2.4 mg/m 3 , 6 hours/
day during 2 weeks) was more pronounced in guinea
pigs that had been presensitized to cobalt by repeated
application of cobalt chloride.
In Fischer 344/N rats and B6C3F 1 mice exposed to
cobalt sulfate heptahydrate aerosols of 0, 0.3, 1.0, 3.0,
10, or 30 mg/m 3 for 6 hours/day on 5 days/week for 13
weeks, the investigators found, in addition to lesions to
the upper respiratory tract (see earlier), histiocytic infi l-
trates, bronchiolar epithelial regeneration, and epithe-
lial hyperplasia in the lung alveoli. In rats, proteinosis,
alveolar epithelial metaplasia, granulomatous alveolar
infl ammation, and interstitial fi brosis were observed
at all dose levels. The nonneoplastic lesions were less
severe in mice and mainly consisted of cytoplasmic
vacuolization of the bronchi (Bucher et al . 1990; 1999).
The intratracheal instillation of cobalt chloride (1-
1000

other alloys) may cause interstitial disease (Linna et al .,
2003, Lison et al ., 1996; Swennen et al ., 1993).
The clinical presentation of hard metal lung dis-
ease is variable, with some patients presenting with
a picture of subacute alveolitis and others with that
of chronic interstitial fi brosis, and most studies have
found no relation between disease occurrence and
length of occupational exposure (Balmes, 1987; Cugell,
1992; Cugell et al ., 1990). In some cases, the outcome
of hard metal disease may be fatal (Ruokonen et al .,
1996). The high-resolution computed tomography
(HRCT) appearance of HM-ILD includes reticulation,
traction bronchiectasis, and large peripheral cystic
spaces in a mid and upper lung distribution (Gotway
et al ., 2002). Some aspects of this pathology such as
the lack of correlation with the intensity or duration
of exposure, the low frequency of the disease, and the
presence of T cells at the infl ammation site suggest
the existence of a genetic susceptibility. It has, indeed,
been reported that hard metal disease was associated
with a Glu-69 polymorphism of the HLA-DP beta
chain (Potolicchio et al ., 1997) but the strength of
this association was less than in berylliosis (Richeldi
et al., 1993).

7.2.3.3 Mechanisms of Toxicity
There is little doubt that cobalt plays a critical
role in the pathogenesis of hard metal lung disease.
As mentioned previously, experimental studies have
demonstrated that the mixture of Co and WC par-
ticles, which compose the hard metal dust, exhibits
a unique pulmonary toxicity compared with cobalt
particles alone. The toxicity can be explained, at least
in part, by the production of toxic oxygen species at
the surface of WC particles (Keane et al., 2002; Lison
et al ., 1995; Section 1).
The basis for individual susceptibility for the devel-
opment of hard metal lung disease is not known.
Cobalt is known to elicit allergic reactions in the skin,
but the relationship, if any, between allergy and hard
metal disease is unknown. Occasionally, patients
have been found to have both cobalt dermatitis and
interstitial lung disease (Cassina et al ., 1987; Demedts
et al ., 1984; Sjögren et al ., 1980). Immunological studies
(Kusaka et al ., 1989; 1991; Shirakawa et al ., 1988; 1989;
1990; 1992) have found specifi c antibodies and/or pos-
itive lymphocyte transformation tests against cobalt
(as well as nickel) in some patients with hard metal
asthma. The association of hard metal disease with the
presence of glutamate at position 69 in the HLA-DP
beta chain (Potolicchio et al ., 1997) probably refl ects a
higher affi nity of the mutated HLA-DP molecule for
cobalt, which may interfere with antigen presentation
(Potolicchio et al ., 1999).

g/kg) into hamster lungs induced biochemical
changes compatible with the development of oxidative
stress (decreased levels of reduced glutathione, increased
levels of oxidized glutathione, as well as stimulation of
the pentose phosphate pathway). Similar changes were
also observed in vitro after incubation of lung slices with
cobalt chloride (0.1-10 mmol/L); these manifestations
preceded the detection of cellular toxicity, indicating
their possible early involvement in the pulmonary tox-
icity of cobalt (II) ions (Lewis et al ., 1991).

µ

7.2.3.2 Human Data (Hard Metal Disease)
Interstitial (or parenchymal) lung disease caused by
cobalt-containing particles is a rare occupational lung
disease, generally called hard metal lung disease (Balmes,
1987; Bech et al ., 1962; Cugell, 1992; Hartung, 1986;
Lison, 1996). This disease affects a small percent of the
workforce at most (Lison, 1996). This lung disease gen-
erally presents as a giant-cell interstitial pneumonia that
is now accepted as being pathognomonic of hard metal
lung disease (Ohori et al ., 1989). It occurs mainly in
workers from the hard metal industry but has also been
reported in diamond polishers exposed to cobalt metal
powder associated with iron and diamond dust in the
apparent absence of tungsten carbide (Demedts et al .,
1984). There is no available evidence that exposure to
other cobalt species (cobalt metal alone, salts, oxide, or