Isolated rat hepatocytes were used to investigate the biochemical mechanisms of hepatotoxicity of the insecticide lindane (γ-hexachlorocyclohexane) and the fungicide captan (N-(trichloromethylthio)tetra-hydrophthalimide).During the first 60 min of intoxication with 300 μM lindane, 45% of the hepatocytes were dead. This death was preceded by a significant decrease in oxygen uptake rate (75% of control) and GSH levels (44% of control value) and was accompanied by loss of MMP (68% retention of releaseable rhodamine 123 vs. 92% in controls) and reduction in ATP stores (down to 52% of controls). In contrast, at lower concentrations lindane was able to both enhance cellular oxygen consumption and decrease GSH levels although this was not necessarily followed by collapse of MMP, ATP depletion or loss of viability. Furthermore, captan-induced cytotoxicity (40% for 100 μM at 90 min) was exerted through acute depletion of GSH and oxygen uptake inhibition (80% and 71% of controls, respectively, for 100 μM at 30 min) followed by a 58% loss of ATP, collapse of MMP (77% retention of releaseable rhodamine 123 vs. 92% in controls) and ultimately cell death. Non-toxic concentrations of captan (50 μM) produced both oxygen consumption inhibition (82% of controls) and GSH depletion without further modification in MMP, ATP levels or cellular viability.The results indicate that lindane- and captan-induced oxidative stress produces biochemical effects leading to but not directly causing irreversible cell damage, and point to mitochondrial dysfunction as the ultimate cause of triggering the onset of hepatocyte death in this experimental model.