Because limited histological information is available from clinical radiosurgical experience, animal investigations are needed to answer questions regarding the biological response of both normal and pathological tissues. To determine the radiosurgical dose-response relationship of normal brain, we irradiated the right frontal lobe of 18 rats with a single 4-mm isocenter of stereotactic irradiation using the 201-source 60Co gamma unit. Maximal single-fraction doses varied from 30 to 200 Gy (2 rats per dose). All animals were observed for 90 days, killed, and histologically examined. No animal developed neurological dysfunction during that interval, regardless of dose. Animals that received 30, 40, 50, or 60 Gy had no pathological changes. In those given 70 Gy, we found occasional shrunken neurons, and at 80 Gy, rare arteriolar wall thickening. One animal that received 100 Gy had marked capillary endothelial cell degeneration and protein extravasation in the target volume, and the other had a 4-mm diameter necrotic region. Circumscribed cerebral necrosis also was identified in all 4 rats treated with either 150 or 200 Gy; astrocytosis, edema, and microhemorrhage were noted within the surrounding 1 to 2 mm of adjacent brain, and tissue outside that volume had a more normal appearance. We constructed a dose-response relationship based on the cellular, spatial, and temporal effects of focused single-fraction irradiation of the rat brain. To determine the temporal evolution of a known necrotic lesion (200 Gy), 12 other animals were killed (2 each) 1, 7, 14, 21, 30, or 60 days after radiosurgery.(ABSTRACT TRUNCATED AT 250 WORDS)