Cadmium (Cd) is known to have a long biological half-life in the body, possibly due to its binding to metallothionein (MT). This study was designed to determine the role of MT in the tissue distribution and retention of Cd using MT-I and -II null (MT-null) mice. Mice were given 109CdCl(2) (15 mumol/kg, 25 microCi/kg, i.p.), and radioactivity was quantified in 14 major organs at 2 hr, 1, 2, 3, 7 and 15 days thereafter. The lack of MT in MT-null mice 2 hr after Cd administration (74% vs 72% of the dose, respectively). However, the elimination of Cd was much faster in MT-null mice than in control mice. In control mice, approximately 40% of Cd administered was found in liver 24 hr after administration, and the majority was bound to MT. In contrast, only 20% of Cd was found in liver of MT-null mice, which was not bound to MT. Cd concentrations in kidney, pancreas, and spleen were also lower in MT-null than in control mice 1 week after administration. No apparent difference in Cd retention in other organs was noted between control and MT-null mice over the 15-day period. Cd concentration in kidney continued to increase with time in control but not in MT-null mice, indicating that an important source of Cd in the kidney is the uptake of CdMT. In conclusion, the present data indicate that MT does not play a role in the initial distribution of Cd to tissues, but does play a major role in the elimination of Cd, especially from liver, kidney, and pancreas. These data support the conclusion that the persistence of Cd in the body is at least partially due to Cd binding to MT in tissues.