Cadmium-metallothionein (Cd-MT) is selectively distributed to the kidney, producing nephropathy similar to that seen following chronic exposure to Cd. The critical concentration of Cd after an injection of Cd-MT (about 10 micrograms/g) is much lower than that following chronic Cd exposure (130-200 micrograms/g). To investigate whether administration of Cd-MT at nonacute toxic dosages can induce chronic nephrotoxicity similar to inorganic Cd, i.e., renal accumulation of Cd and nephropathy, repeated injections of 109Cd-MT at two doses, 25 or 80 micrograms/kg/day, were given to rats. The concentration of 109Cd in kidney was 7-10 times higher than that in liver at each treatment level. Concentrations of 109Cd were highest in the kidney and reached a plateau following repeated injections of 109Cd-MT at both doses. The renal 109Cd levels found here (200 and 140 micrograms/g) were in the same range as the concentrations found at a plateau following repeated CdCl2 injection. Indications of nephrotoxicity following repeated injections of 109Cd-MT did not occur until renal Cd leveled off. The majority of intracellular Cd is sequestered by endogenous MT in the kidney. After renal Cd leveled off, the hepatic concentration of 109Cd did not markedly increase, but urinary excretion of 109Cd increased significantly. In addition both urinary protein and glucose also increased significantly, indicating that the appearance of nephrotoxicity is dependent on renal Cd saturation following long-term administration of Cd-MT. This is similar to what is seen following chronic inorganic cadmium exposure. These results support the suggestion that Cd-MT plays a major role in the initiation and development of Cd-induced renal damage.