The effects of lead on Ca2+ homeostasis in nerve terminals was studied. Incubation with lead in vitro stimulated the activity of calmodulin and the maximum effect was observed at 30 microM lead, higher concentrations had an inhibitory effect. In vivo exposure to lead increased the activity of calmodulin by 45%. Lead had an inhibitory effect on Ca2+ ATPase activity in both calmodulin-rich and calmodulin-depleted synaptic plasma membranes, the IC50 values for inhibition being 13.34 and 16.69 microM respectively. Exogenous addition of calmodulin (5 micrograms) and glutathione (1 mM) to calmodulin rich synaptic plasma membranes reversed the inhibition by IC50 concentration of lead. In vivo exposure of lead also significantly reduced the Ca2+ ATPase activity, resulting in an increase in intrasynaptosomal calcium. Concomitant with the increase in intrasynaptosomal calcium, lipid peroxidation values also increased significantly in lead-treated animals. In addition lead also had an inhibitory effect on depolarization induced Ca2+ uptake and the inhibition was found to be a competitive one. The results suggest that lead exerts its toxic effects by modifications of the intracellular calcium messenger system which would have serious consequences on neuronal functioning.