Viluksela M, Stahl B U, Birnbaum L S, Rozman K K
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, 66160-7417, USA.
Toxicol Appl Pharmacol. 1998 Jul;151(1):70-8. doi: 10.1006/taap.1998.8412.
Groups of 20 male and 20 female rats were given five different oral doses of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1, 2,3,7,8-pentaCDD, (PCDD) 1,2,3,4,7,8-hexaCDD (HxCDD), and 1,2,3,4,6, 7,8-heptaCDD (HpCDD) divided into four daily loading doses and six biweekly maintenance doses. PCDD and HxCDD were used as positive controls. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest provided with an off-dose period of another 13 weeks. Liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased in rats dosed with the mixture starting at the lowest dose (13- to 16-fold increase), with the effect reaching maximum at the middle dosage (74- to 112-fold increase), as well as in the positive control groups. There was some indication of reversibility at the lower doses and in positive controls during the off-dose period. The activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver was dose-dependently decreased (maximally by 51%). This effect was more distinct in males than in females. Liver tryptophan 2,3-dioxygenase (TdO) activity decreased maximally by 53% at the two highest doses. This effect was more distinct in females than in males. Serum tryptophan concentrations were increased in rats moribund due to wasting. Some reversibility was apparent by the end of the off-dose period regarding all three biochemical markers of CDD toxicity. Serum glucose concentrations were decreased at the three highest doses of the mixture and in positive controls, maximally by 30%, with some reversibility during the off-dose period. There was a dose-dependent decrease of serum thyroxine (T4) concentrations in rats given the mixture and in the PCDD and HxCDD dosage groups (maximally by 69%), with some reversibility in males during the off-dose period. Serum triiodothyronine (T3) levels were not much affected, except that they tended to be decreased in rats moribund with hemorrhage or anemia. The results demonstrate that comparable biochemical changes occur after multiple as after single dosing with CDDs and that TEFs derived from acute studies can be used to predict the toxicity of mixtures of CDDs regardless whether they are administered as single compounds or as a mixture. This study supports the validity of the toxic equivalency factor (TEF) method and the notion of additive toxicity for CDDs as currently used in the risk assessment of these compounds.
将20只雄性和20只雌性大鼠分为几组，给予五种不同口服剂量的2,3,7,8-四氯二苯并 - 对 - 二噁英（TCDD）、1,2,3,7,8-五氯二苯并二噁英（PCDD）、1,2,3,4,7,8-六氯二苯并二噁英（HxCDD）和1,2,3,4,6,7,8-七氯二苯并二噁英（HpCDD）混合物，分为四个每日负荷剂量和六个每两周维持剂量。PCDD和HxCDD用作阳性对照。给药期为13周，之后对一半大鼠进行尸检，其余大鼠给予另外13周的停药期。从最低剂量开始给予混合物的大鼠肝脏乙氧基异吩唑酮 - O - 脱乙基酶（EROD）活性呈剂量依赖性增加（增加13至16倍），在中等剂量时效果达到最大值（增加74至112倍），阳性对照组也是如此。在较低剂量组和阳性对照组的停药期有一些可逆性迹象。肝脏磷酸烯醇丙酮酸羧激酶（PEPCK）活性呈剂量依赖性降低（最大降低51%）。这种效应在雄性大鼠中比在雌性大鼠中更明显。肝脏色氨酸2,3 - 双加氧酶（TdO）活性在两个最高剂量时最大降低53%。这种效应在雌性大鼠中比在雄性大鼠中更明显。濒死消瘦大鼠的血清色氨酸浓度升高。关于CDD毒性的所有三个生化指标，在停药期末期都有明显的可逆性。混合物的三个最高剂量组和阳性对照组的血清葡萄糖浓度降低，最大降低30%，在停药期有一定的可逆性。给予混合物的大鼠以及PCDD和HxCDD剂量组的血清甲状腺素（T4）浓度呈剂量依赖性降低（最大降低69%），雄性大鼠在停药期有一定的可逆性。血清三碘甲状腺原氨酸（T3）水平受影响不大，只是在濒死的出血或贫血大鼠中往往降低。结果表明，多次给药后与单次给药后CDDs引起的生化变化相当，并且来自急性研究的毒性当量因子（TEF）可用于预测CDDs混合物的毒性，无论它们是作为单一化合物还是作为混合物给药。本研究支持毒性当量因子（TEF）方法的有效性以及目前在这些化合物风险评估中使用的CDDs相加毒性的概念。
