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© 1996 Oxford University Press

research-article

Use of Lung Toxicity and Lung Particle Clearance to Estimate the Maximum Tolerated Dose (MTD) for a Fiber Glass Chronic Inhalation Study in the Rat

T. W. HESTERBERG*,1, E. E. MCCONNELL{dagger}, W. C. MULLER*, J. CHEVALIER{ddagger}, J. EVERITT§, P. THEVENAZ, H. FLEISSNER and G. OBERDöRSTER||

*Mountain Technical Center. Schuller International. Inc Littleton, Colorado 80162-5005 {dagger}Raleigh North Carolina {ddagger}Experimental Pathology Services Muttenz, Switzerland §Chemical Industry Institute of Toxicology, Research Triangle Park North Carolina Research and Consulting Company Füllinsdorf Switzerland ||University of Rochester, Department of Environmental Medicine Rochester New York

Received October 25, 1995; accepted March 27, 1996

Short–term toxicity and lung clearance were assessed in rats exposed by inhalation to size-selected fibrous glass (FG) for 13 weeks. Results from this study and from a recent FG chronic inhalation study are presented here as guidelines for the selection of a maximum tolerated dose (MTD) for chronic inhalation studies of fibers. Fischer 344 rats were exposed using nose–only inhalation chambers, 6 hr/day, 5 days/week, for 13 weeks to one of five concentrations of FG (36, 206, 316, 552, or 714 fibers/cc; expressed gravirnetrically, 3, 16, 30, 45, or 60 mg/m3) or to filtered air. Rats were then held for an additional 10 weeks of postexposure recovery. Test fiber was size–selected from glass wool having a chemical composition representative of building insulation. Rats were terminated at 7, 13, 19, and 23 weeks after the onset of exposure to evaluate pulmonary pathology, lung epithelium cell proliferation, lung fiber burden, and lung lavage cells and chemistry. The effect of fiber inhalation on lung clearance of innocuous microspheres was also evaluated: following fiber exposure, six rats/group were exposed to 85Sr–labeled 3.0-µm polystyrene microspheres by intratracheal inhalation and then monitored for whole–body radioactivity during the 10–week recovery period. Data from the short–term study support the choice of 30 mg/m3 as the MTD for the previous chronic FG study and also provide indicators of long–term lung toxicity and functional impairment that can be used to estimate the MTD for future chronic fiber inhalation studies.


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