Olson J R
Toxicol Appl Pharmacol. 1986 Sep 15;85(2):263-73. doi: 10.1016/0041-008x(86)90121-3.
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 microgram/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.
2,3,7,8-四氯二苯并对二恶英（TCDD）的急性毒性存在显著的种间差异，豚鼠是对TCDD急性毒性最敏感的哺乳动物物种。在单次腹腔注射纯化的[3H]TCDD（0.56微克/千克）后，对豚鼠进行了45天的TCDD代谢和处置研究。纳入毒代动力学研究的豚鼠体重增加，维持正常的相对身体组成，并且在45天的研究期间未表现出明显的毒性迹象。在暴露于[3H]TCDD后45天，约36%的TCDD衍生的3H剂量保留在脂肪组织中，而肝脏、皮毛、骨骼肌和胴体各自含有约7%的给药剂量。尽管肝脏、肾脏、肾周脂肪组织和骨骼肌中大部分TCDD衍生的放射性代表未变化的TCDD，但3H的4%至28%与TCDD的代谢产物相关。这一意外发现表明TCDD代谢产物不能有效地从豚鼠体内排出。TCDD衍生放射性的尿排泄和粪排泄遵循明显的一级动力学，消除半衰期为93.7±15.5天（平均值±标准差）。对[3H]TCDD处理的豚鼠的尿液和胆汁进行HPLC分析表明，所有放射性均代表TCDD的代谢产物，表明这些排泄途径依赖于TCDD的先前代谢。然而，在整个45天排泄研究中，发现粪便样品中70%至90%的放射性代表未代谢的TCDD。粪便中存在TCDD而胆汁中不存在TCDD表明未变化的TCDD的粪便排泄是由于亲脂性毒素的直接肠道排泄。此外，45天内TCDD衍生放射性的累积排泄表明，3H的74.3%以未变化的TCDD形式排泄在粪便中，而3H的25.7%以TCDD代谢产物的形式排泄在尿液和粪便中。因此，TCDD主要以未变化的形式在豚鼠粪便中消除，表明TCDD的代谢在豚鼠体内毒素的最终消除中不发挥主要作用。这可能部分解释了豚鼠中TCDD相对较长的排泄半衰期，并可能导致豚鼠对TCDD急性毒性的显著敏感性。
