Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo- p-dioxin in guinea pigs

Abstract

Marked interspecies variability exists in the acute toxicity of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), with the guinea pig being the mammalian species most sensitive to the acute toxicity of TCDD. The metabolism and disposition of TCDD was investigated in guinea pigs for 45 days following a single exposure to purified [ 3H]TCDD (0.56 μg/kg, ip). Guinea pigs included in the toxicokinetic study gained body weight, maintained a normal relative body composition, and exhibited no gross signs of toxicity during the 45-day study. Approximately 36% of the dose of TCDD-derived 3H remained in the adipose tissue at 45 days following exposure to [ 3H]TCDD, while the liver, pelt, and skeletal muscle and carcass each contained about 7% of the administered dose. Although most of the TCDD-derived radioactivity in liver, kidney, perirenal adipose tissue, and skeletal muscle represented unchanged TCDD, from 4 to 28% of the 3H was associated with metabolites of TCDD. This unexpected finding suggests that TCDD metabolites are not efficiently excreted from guinea pigs. The urinary and fecal excretion of TCDD-derived radioactivity followed apparent first-order kinetics, with an elimination half-life of 93.7 ± 15.5 days (mean ± SD). HPLC analysis of urine and bile from [ 3H]TCDD-treated guinea pigs showed that all of the radioactivity represented metabolites of TCDD, indicating that these routes of elimination are dependent on prior metabolism of TCDD. However, 70 to 90% of the radioactivity in fecal samples was found to represent unmetabolized TCDD throughout the 45-day excretion study. The presence of TCDD in feces and its absence in bile suggest that the fecal excretion of unchanged TCDD resulted from the direct intestinal elimination of the lipophilic toxin. Furthermore, the cumulative excretion of TCDD-derived radioactivity over 45 days indicated that 74.3% of the 3H was excreted in feces as unchanged TCDD, while 25.7% of the 3H was excreted in urine and feces as TCDD metabolites. Thus, TCDD is primarily eliminated unchanged in the feces of guinea pigs, indicating that the metabolism of TCDD does not play a major role in the ultimate elimination of the toxin from the guinea pig. This may in part explain the relatively long excretion half-life for TCDD in the guinea pig and may contribute to the remarkable sensitivity of the guinea pig to the acute toxicity of TCDD.