Exposure to silica, a cytotoxic and fibrogenic mineral dust, has been demonstrated to cause pulmonary inflammation and damage to the lung tissue. In contrast to the longterm consequences, little information exists on the sequence of inflammatory/damaging events occurring acutely after exposure to silica. The purpose of this study was to determine the minimum time after the administration of silica that the inflammatory/damage response is detectable and the temporal relationship of these processes. Male Fischer 344 rats were dosed intratracheally with silica (2.5 or 10 m g/100 g body weight) or saline vehicle. At 2 and 4 h after instillation, both cellular (total cell count and neutrophil count) and biochemical (total protein, albumin, and-glucuronidase and lactate dehydrogenase activities) parameters of inflammation and damage were evaluated in the bronchoalveolar lavage fluid. At 2 h, total protein levels were elevated at both silica doses, but all other parameters were unchanged; however, 4 h after silica exposure all parameters were elevated over those of the saline control. In a further attempt to characterize the inflammatory/ damage processes, luminol-dependent chemiluminescence (LDCL) was performed on aliquots of chopped lung. At 2 h after silica instillation, phorbol myristate acetate-stimulated lung tissue from silica-treated rats had no increase in light production when compared to controls, whereas after 4 h there were significant increases in LDCL activity in both dose groups when compared to controls. The addition of superoxide dismutase (SOD) decreased LDCL activity of the 2.5 m g/100 g group by 59% (2 h) and 66% (4 h), and of the 10 m g/100 g group by 49% (2 h) and 73% (4 h). Alternatively, the addition of N--nitro-Larginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, decreased the 2.5 mg/ 100 g group by 52% (2 h) and 60% (4 h). The 10 m g/100 g group was decreased by 67% (2 h), but only exhibited a 12% reduction at 4 h. SOD and L-NAME also inhibited the background LDCL in saline-treated rats. These reductions in LDCL activity indicate that reactive oxygen and nitrogen species play a role in the acute phase pulmonary response from silica. The results of this study indicate that the initial stages of damage begin to appear by 2 h, but damage and inflammation are definitive by 4 h after administration of silica in rats.