Li X, Rozman K K
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Toxicology. 1995 Mar 31;97(1-3):133-40. doi: 10.1016/0300-483x(94)02938-q.
The hypothesis tested in this experiment is that effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) show identical dose-responses after subchronic as after acute exposure when the dose is corrected for toxicokinetics. Groups of male Sprague-Dawley (S-D) rats were administered orally a total dose of 0, 0.2, 2.3, 11.5, 35, 70 or 115 micrograms/kg of TCDD over a period of 10 weeks at 4 ml/kg of vehicle. Body weight was recorded weekly. One week after the last dose of TCDD one half of the rats was killed and tryptophan 2,3-dioxygenase (TdO), 7-ethoxyresorufin-O-deethylase (EROD) and phosphoenolpyruvate carboxykinase (PEPCK) activities were measured in livers, whereas tryptophan and total T4 (TT4) were determined in serum. The results show that the dose-response for decreased TdO and PEPCK activity and elevated serum tryptophan levels are similar if not the same as the dose-response for subchronic retardation of body weight increase. They also demonstrate that the dose-responses for the induction of EROD activity and the reduction of serum TT4 occurred at much lower doses than those for decreased TdO and PEPCK activities or elevated tryptophan levels and mortality. After a 6-week recovery period, PEPCK and TdO activities in liver as well as tryptophan in serum returned to near control values, whereas EROD activity and serum TT4 still displayed a dose-dependent induction and reduction, respectively, albeit both shifted to the right in accordance with toxicokinetics. These data support the notion that subchronic dose-responses of TCDD are similar to acute dose-responses when corrected for toxicokinetics and that at least some TCDD-induced effects are reversible also in accordance with toxicokinetics.
当根据毒代动力学对剂量进行校正后，2,3,7,8-四氯二苯并对二恶英（TCDD）在亚慢性暴露后的剂量反应与急性暴露后的剂量反应相同。将雄性Sprague-Dawley（S-D）大鼠分成几组，在10周内以4毫升/千克的赋形剂经口给予总量为0、0.2、2.3、11.5、35、70或115微克/千克的TCDD。每周记录体重。在最后一剂TCDD给药一周后，处死一半大鼠，测定肝脏中色氨酸2,3-双加氧酶（TdO）、7-乙氧基异吩恶唑酮-O-脱乙基酶（EROD）和磷酸烯醇式丙酮酸羧激酶（PEPCK）的活性，同时测定血清中的色氨酸和总T4（TT4）。结果表明，TdO和PEPCK活性降低以及血清色氨酸水平升高的剂量反应，如果与亚慢性体重增加迟缓的剂量反应不相同，也是相似的。这些结果还表明，诱导EROD活性和降低血清TT4的剂量反应发生时的剂量，比TdO和PEPCK活性降低、色氨酸水平升高及死亡率所对应的剂量要低得多。经过6周的恢复期后，肝脏中的PEPCK和TdO活性以及血清中的色氨酸恢复到接近对照值，而EROD活性和血清TT4仍分别表现出剂量依赖性的诱导和降低，尽管二者都根据毒代动力学向右移动。这些数据支持这样的观点，即当根据毒代动力学进行校正时，TCDD的亚慢性剂量反应与急性剂量反应相似，并且至少某些TCDD诱导的效应根据毒代动力学也是可逆的。
