title: The delayed lung responses to single and repeated intratracheal administration of pure cobalt and hard metal powder in the rat.
abstract: Epidemiological and clinical studies suggest that inhalation of cobalt metal dust (Co) mixed with tungsten carbide particles (WC), but not of cobalt dust alone, may cause interstitial pulmonary lesions (hard metal disease). In previous experimental studies in the rat, we have demonstrated the greater acute pulmonary toxicity of a WC-Co mixture compared to Co or WC alone. The present study was undertaken to compare in the same animal model the delayed lung response after intratracheal administration of Co or WC-Co particles (cobalt particle 6.3 wt%). The responses were also compared with those obtained after treatment with arsenic trioxide and crystalline silica used a reference materials producing an acute toxic insult and a progressive fibrogenic response, respectively. Cellular (total and differential counts) and biochemical parameters (LDH, N-acetyl-beta-D-glucosaminidase, total protein, albumin, fibronectin, and hyaluronic acid) were measured in bronchoalveolar lavage fluid following single and repeated intratracheal instillations. The results indicate that the delayed lung response observed after WC-Co is different from that after cobalt metal alone. A single intratracheal dose of WC-Co (1, 5, or 10 mg/100 g body wt) induced an acute alveolitis which persisted for at least 1 month. Four months after a single instillation of WC-Co, no clear histological lung fibrosis could however be evidenced, indicating a reversibility of the lesions. The effects of cobalt (0.06, 0.3, or 0.6 mg/100 g body wt) or tungsten carbide alone (1, 5, 10 mg/ 100 g body wt) were very modest, if any. Following repeated intratracheal instillations (four administrations at 1-month interval), increased lung hydroxyproline content and histopathological evidence of interstitial fibrosis were observed after WC-Co (4 x 1 mg/100 g body wt), but not after administration of each component separately, i.e., Co (4 x 0.06 mg/100 g body wt) or WC (4 x 1 mg/100 g body wt). The mechanism of the fibrotic reaction induced by WC-Co seems different from the progressive inflammatory reaction induced by crystalline silica. We suggest that it might result from a scarring reaction elicited by repeated acute insults as observed after repeated administration of arsenic trioxide.
authors.affiliation: Industrial Toxicology and Occupational Medicine Unit, School of Medicine, Catholic University of Louvain, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Lasfargues
authors.forename: C
authors.initials: C
authors.lastname: Lardot
authors.forename: M
authors.initials: M
authors.lastname: Delos
authors.forename: R
authors.initials: R
authors.lastname: Lauwerys
authors.forename: D
authors.initials: D
authors.lastname: Lison
mesh_terms: D000118:Acetylglucosaminidase / Q000378:metabolism; D000418:Albumins / Q000378:metabolism; D000818:Animals; D020261:Arsenic Poisoning; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003035:Cobalt / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage / Q000633:toxicity; D011208:Powders; D011506:Proteins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000633:toxicity; D013194:Staining and Labeling; D014132:Trachea / Q000187:drug effects / Q000378:metabolism; D017973:Tungsten Compounds / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000418:Albumins; D001152:Arsenicals; D005353:Fibronectins; D010087:Oxides; D011208:Powders; D011506:Proteins; D017973:Tungsten Compounds; C002802:tungsten carbide; D003035:Cobalt; D012822:Silicon Dioxide; D006820:Hyaluronic Acid; D007770:L-Lactate Dehydrogenase; D000118:Acetylglucosaminidase; D000077237:Arsenic Trioxide