title: Lung toxicity of hard metal particles and production of interleukin-1, tumor necrosis factor-alpha, fibronectin, and cystatin-c by lung phagocytes.
abstract: Hard metal alloys (WC-Co) are made of a mixture of cobalt (Co; 6%) and tungsten carbide (WC; 94%) particles. Chronic inhalation of hard metal dust can lead to the development of a fibrosing alveolitis, the pathogenesis of which is still undefined. The present investigation was undertaken to assess the effect of Co, WC, and WC-Co particles on the release by lung phagocytes of interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), fibronectin, and cystatin-c. The responses were compared with those induced by two other lung toxicants, i.e., crystalline silica (DQ12) and arsenic trioxide (As2O3). IL-1 and TNF-alpha activities produced in the presence and absence of LPS stimulation were measured with the aid of bioassays while fibronectin and cystatin-c were determined by latex immunoassays. In vitro, maximal noncytotoxic doses of As2O3, Co, WC, or WC-Co did not significantly affect the production of these mediators by rat alveolar macrophages. In contrast, DQ12 enhanced the production of TNF-alpha (with and without LPS stimulation) and IL-1 (after LPS stimulation) and decreased cystatin-c release (in the absence of LPS). Following a single intratracheal instillation of the different test preparations in the rat, the response of the lung phagocytes obtained by bronchoalveolar lavage (BAL) 24 hr later was examined. We were unable to detect any consistent effect of Co (0.06 mg/100 g body wt), WC (1 mg/100 g body wt), or WC-Co treatment (1 mg/100 g body wt) on the production of the above mediators. In contrast, after LPS stimulation, As2O3 (0.5 mg/100 g body wt) and DQ12 (1 mg/100 g body wt) stimulated the production of TNF-alpha and IL-1. In the absence of LPS, As2O3 stimulated fibronectin and cystatin-c production and DQ12 stimulated cystatin-c release. Since the dose of WC-Co used in vivo (1 mg/100 g body wt) caused pronounced lung inflammation (increased LDH, protein, and albumin levels in BAL fluid), we conclude that the acute lung toxicity of WC-Co particles is not mediated through enhanced production of the examined mediators by lung phagocytes.
authors.affiliation: Industrial Toxicology and Occupational Medicine Unit, School of Medicine, Catholic University of Louvain, Brussels, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Huaux
authors.forename: G
authors.initials: G
authors.lastname: Lasfargues
authors.forename: R
authors.initials: R
authors.lastname: Lauwerys
authors.forename: D
authors.initials: D
authors.lastname: Lison
mesh_terms: D000497:Alloys / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003035:Cobalt / Q000633:toxicity; D055316:Cystatin C; D015891:Cystatins / Q000096:biosynthesis; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012822:Silicon Dioxide / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D017973:Tungsten Compounds / Q000633:toxicity
chemical_list: D000497:Alloys; C525032:Cst3 protein, rat; D055316:Cystatin C; D015891:Cystatins; D005353:Fibronectins; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D017973:Tungsten Compounds; C002802:tungsten carbide; D003035:Cobalt; D012822:Silicon Dioxide