Short-term inhalation and in vitro tests as predictors of fiber pathogenicity.
A wide range of fiber types was tested in two in vitro assays: toxicity to A549 epithelial cells, as detachment from substrate, and the production of the proinflammatory cytokine tumor necrosis factor (TNF) by rat alveolar macrophages. Three of the fibers were also studied in vivo, using short-term inhalation followed by a) bronchoalveolar lavage to assess the inflammatory response and b) measurement of cell proliferation in terminal bronchioles and alveolar ducts, using incorporation of bromodeoxyuridine (BrdU). The amount of TNF produced by macrophages in vitro depended on the fiber type, with the man-made vitreous fibers, and refractory ceramic fibers being least stimulatory and silicon carbide (SiC) whiskers providing the greatest stimulation. In the epithelial detachment assay there were dose-dependent differences in the toxicity of the various fibers, with long amosite being the most toxic. However, there was no clear relationship to known chronic pathogenicity. Fibers studied by short-term inhalation produced some inflammation, but there was no clear discrimination between the responses to code 100/475 glass fibers and the more pathogenic amosite and SiC. However, measurements of BrdU uptake into lung cells showed that amosite and SiC produced a greater reaction than code 100/475, which itself caused no more proliferation than that seen in untreated lungs. These results mirror the pathogenicity ranking of the fibers in long-term experiments. In conclusion, the only test to show potential as a predictive measure of pathogenicity was that of cell proliferation in lungs after brief inhalation exposure (BrdU assay). We believe that this assay should be validated with a wider range of fibers, doses, and time points.
Cullen
R T
RT
Institute of Occupational Medicine, Edinburgh, United Kingdom. rt_cullen@iomhq.org.uk
Miller
B G
BG
Davis
J M
JM
Brown
D M
DM
Donaldson
K
K
D000280:Administration, Inhalation; D000818:Animals; D017639:Asbestos, Amosite / Q000008:administration & dosage / Q000633:toxicity; D017638:Asbestos, Crocidolite / Q000008:administration & dosage / Q000633:toxicity; D001973:Bromodeoxyuridine; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D017554:Carbon Compounds, Inorganic / Q000008:administration & dosage / Q000633:toxicity; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002516:Ceramics / Q000633:toxicity; D004847:Epithelial Cells / Q000187:drug effects; D005898:Glass; D016676:Macrophages, Alveolar / Q000378:metabolism; D019016:Mineral Fibers / Q000633:toxicity*; D010316:Particle Size; D051381:Rats; D017655:Silicon Compounds / Q000008:administration & dosage / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D017554:Carbon Compounds, Inorganic; D002273:Carcinogens; D019016:Mineral Fibers; D017655:Silicon Compounds; D014409:Tumor Necrosis Factor-alpha; C009753:fiberglass; D017638:Asbestos, Crocidolite; D017639:Asbestos, Amosite; D001973:Bromodeoxyuridine; C022088:silicon carbide