INITIATING THE RISK ASSESSMENT PROCESS FOR INHALED PARTICULATE MATERIALS - DEVELOPMENT OF SHORT-TERM INHALATION BIOASSAYS

This study describes a short term inhalation bioassay in rats to predi ct the potential for inhaled particles to produce chronic lung disease in humans (e.g., pulmonary fibrosis). To validate the method, rats we re exposed for 6 h or 3 days to various concentrations of two referenc e materials: (1) a known fibrogenic material (i.e., aerosolized alpha- quartz silica particles in the form of Berkeley Min-U-Sil(R) (Pennsylv ania Glass and Sand Company, Pittsburgh, PA), or (2) carbonyl iron (Cl ) particles, as a negative control. Cells and fluids from groups of sh am and dust exposed animals were recovered by bronchoalveolar lavage ( BAL). Alkaline phosphatase, lactate dehydrogenase and protein values w ere measured in BAL fluids at several times postexposure. Cells were i dentified, counted, and evaluated for viability. The lungs of addition al exposed animals were processed for histopathology. Although particl e deposition patterns for the two dusts were similar brief exposures t o silica particles produced a persistent pulmonary inflammatory respon se characterized by neutrophil recruitment at sites of particle deposi tion and consistently elevated biomarkers of cytotoxicity in BAL fluid s. In addition, alveolar macrophage clearance functions were impaired. Progressive histopathologic lesions were observed within 1 mo after a 3-day exposure. Light and electron microscopy of silica exposed lung tissue revealed a chronically active pulmonary inflammatory response c haracterized by hyperplasia of Type II alveolar epithelial cells and t he infiltration of macrophages and neutrophils into alveoli and inters titial compartments. The lesions were progressive, leaning to the deve lopment of a multifocal, granulomatoustype pneumonitis within 2 mo pos texposure. In contrast to the observed effects of silica, 3-day exposu res to CI particles produced no significant adverse biochemical or his topathological effects on pulmonary tissues. These results demonstrate that short term, high dose inhalation exposures of silica produce eff ects similar to those previously observed using intratracheal instilla tion or chronic inhalation models and lend support to this method as a reliable short term bioassay for evaluating the pulmonary toxicity an d mechanisms associated with exposure to new and untested respirable m aterials.