The role of estradiol in sex differences in hepatic and renal cadmium accumulation and metallothionein (MT) induction was investigated. Male and female rats and castrated males pretreated with estradiol were injected either i.v. or s.c. with 10 mumol CdCl2/kg. Sex differences in cadmium accumulation and MT induction were apparent after s.c. but not i.v. administration. The female rats accumulated a significantly greater concentration of cadmium in their liver than did the males, as early as 1 hr after the s.c. injection. The elevated levels of cadmium in the females were maintained for at least 10 days. Pretreatment of castrated males with estradiol caused a similarly greater accumulation of cadmium in the liver. Hepatic MT levels peaked in the females at 24 hr and in males 48-72 hr after the cadmium injection and then declined to lower levels. This superinduction of MT occurred only after the s.c. administration of cadmium. MT levels in both sexes plateaued 5 days after the s.c. injection to the levels that were similar to those seen in male and female rats 24 hr after an i.v. injection. In animals injected s.c. with cadmium the renal cadmium levels continued to rise for 5-10 days; however, in animals injected i.v. the levels stabilized within 2 hr. The renal MT levels in the females were significantly higher than in the males. Estradiol pretreatment induced renal MT but did not affect renal cadmium accumulation. Thus, the sex differences in hepatic cadmium accumulation and MT induction are affected by the route and time after the administration of cadmium. Furthermore, estradiol causes a more rapid uptake of cadmium by the liver and also an enhanced induction of MT in both the liver and kidney.