The mammalian central nervous system is composed of a large and diverse array of its two principle cell types, neurons and glia. Given this extreme cellular heterogeneity, it is not surprising that targets of neurotoxic insult often are diverse and unprepredictable. In devising strategies to assess neurotoxicity, one must overcome the obstacle posed by not knowing where to look for damage. The study's approach to the detection and localization of sites of toxicant-induced damage has been to take advantage of two general responses to nervous system insult, astrogliosis and argyrophilia. Assays of GFAP, the principle intermediate filament protein of astrocytes, have been devised to quantify astrogliosis and a modified cupric silver degeneration stain has been employed to examine patterns of argyrophilia. Using these methods, it was found that increases in GFAP and the occurrence of argyrophilia are consistent responses to neurotoxic insults. Moreover, increments in these two indicators reveal dose-, time-, and region-dependent patterns of neurotoxicity at toxicant dosages below those that cause light microscopic evidence of cell loss or damage. The rapid onset of astrogliosis and argyrophilia following specific toxicant exposures suggests that the signals underlying these events are among the earliest that can be linked to the neurotoxic state.