Bilateral adrenalectomy or adrenal demedullation was performed on male Sprague-Dawley rats by established surgical techniques. Subsequently, the dose-response (mortality and mean time to death) to TCDD was determined in adrenalectomized (10, 20, 40 micrograms/kg TCDD ip in 95:5 corn oil:acetone) or demedullated (15, 30, 60 micrograms/kg TCDD) rats. Adrenalectomy drastically increased mortality and greatly shortened mean time to death after dosing with TCDD. More importantly, adrenalectomized TCDD-treated rats died of hypoglycemic shock without losing much body weight. Conversely, adrenal demedullation had no effect on mortality or mean time to death caused by TCDD when compared to nondemedullated TCDD-treated controls. Thus, it was concluded that the factor(s) modulating the acute toxicity of TCDD resides in the adrenal cortex and not in the medulla. Administration of corticosterone (25 micrograms/ml in drinking water) to adrenalectomized rats returned the toxicity of TCDD to levels seen in nonadrenalectomized rats suggesting that this hormone is another key factor (in addition to the thyroid hormones) in the modulation of the acute toxicity of TCDD. Corticosterone supplementation (25, 50, or 100 micrograms/ml) to nonadrenalectomized rats, or to thyroidectomized-adrenalectomized rats (25 micrograms/ml), resulted in no additional beneficial effect indicating that a factor(s) other than thyroid hormones and corticosterone is also involved in the acute toxicity of TCDD.