Chronic exposure of cadmium (Cd) to rats (6 mg/kg body weight/day) led to a significant accumulation of Cd in brain and other organs. Calmodulin (CaM) isolated from brains of Cd exposed rats showed a decreased ability to stimulate CaM-dependent phosphodiesterase (PDE) as compared to that purified from unexposed animals. There was a dose dependent inhibition of CaM activity when CaM (from normal and Cd exposed rats) was incubated with different molar ratios of aluminium (Al3+), lead (Pb2+), manganese (Mn2+) and vanadium (V5+). Regression analysis of rat brain CaM activity versus varying metal ion concentration demonstrated negative slopes. However, CaM from the brains of Cd exposed rats was less sensitive to these metals in comparison to the normal rat brain CaM. These data suggest that CaM inhibition may be used as a biological marker of neurotoxicity and for elucidating the possible mechanism by which neurotoxic metals manifest toxic effects.