Viluksela M, Stahl B U, Birnbaum L S, Rozman K K
Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7417, USA.
Toxicol Appl Pharmacol. 1997 Oct;146(2):217-26. doi: 10.1006/taap.1997.8240.
Groups of 20 male and 20 female rats were given five different oral doses of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) or one dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) divided into four daily loading doses and six biweekly maintenance doses. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest assigned to an off-dose period of another 13 weeks. At the end of the dosing period, liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased starting at the lowest dose (7- to 10-fold) with maximum induction (50- to 100-fold) at the middle or second highest dose. There was a slight reversibility of this effect in HpCDD-treated rats, particularly at lower doses, and a pronounced reversibility in TCDD-dosed rats, both in accordance with respective toxicokinetics. The activity of phosphoenolpyruvate carboxykinase in liver was dose-dependently decreased (up to 60%) at the two or three highest doses of HpCDD and also in the TCDD dosage group. Liver tryptophan 2,3-dioxygenase activity was decreased at the two highest doses of HpCDD (up to 41%), particularly in females. Serum tryptophan concentrations were elevated in rats found moribund due to wasting. There was a dose-dependent decrease in serum glucose concentrations (up to 30%) at the end of the dosing period. Serum thyroxin (T4) concentrations showed a dose-dependent decrease (78% at the highest dose) beginning in the middle dose for HpCDD and in the TCDD dosage group. Serum triiodothyronine (T3) concentrations were only slightly affected, except that they were somewhat decreased in moribund animals. The results demonstrate that similar biochemical changes occur in rats after single as after multiple dosing with HpCDD and TCDD. Based on these endpoints, the relative potency of HpCDD after subchronic exposure is in agreement with the international toxic equivalency factor (I-TEF) of 0.01 and, more specifically, with a TEF of 0.007 based on LD50 values in the same strain of rats.
将20只雄性和20只雌性大鼠分为几组，分别给予五种不同口服剂量的1,2,3,4,6,7,8 - 七氯二苯并 - p - 二噁英（HpCDD），或一剂2,3,7,8 - 四氯二苯并 - p - 二噁英（TCDD），分为四个每日负荷剂量和六个每两周维持剂量。给药期为13周，之后对一半的大鼠进行尸检，其余大鼠进入另一个13周的停药期。在给药期末，肝脏乙氧基异吩唑酮 - O - 脱乙基酶（EROD）活性从最低剂量开始呈剂量依赖性增加（7至10倍），在中等剂量或第二高剂量时诱导作用最大（50至100倍）。在HpCDD处理的大鼠中，这种效应有轻微的可逆性，尤其是在较低剂量时；而在TCDD给药的大鼠中，这种效应有明显的可逆性，这均与各自的毒代动力学一致。在HpCDD的两到三个最高剂量组以及TCDD剂量组中，肝脏磷酸烯醇丙酮酸羧激酶的活性呈剂量依赖性降低（高达60%）。在HpCDD的两个最高剂量时，肝脏色氨酸2,3 - 双加氧酶活性降低（高达41%），雌性大鼠中尤为明显。因消瘦而濒死的大鼠血清色氨酸浓度升高。在给药期末，血清葡萄糖浓度呈剂量依赖性降低（高达30%）。血清甲状腺素（T4）浓度从HpCDD的中等剂量组以及TCDD剂量组开始呈剂量依赖性降低（最高剂量时降低78%）。血清三碘甲状腺原氨酸（T3）浓度仅受到轻微影响，不过濒死动物中的T3浓度有所降低。结果表明，单次和多次给予HpCDD和TCDD后，大鼠体内会出现相似的生化变化。基于这些终点指标，亚慢性暴露后HpCDD的相对效力与国际毒性当量因子（I - TEF）0.01一致，更具体地说，与基于同一品系大鼠LD50值的毒性当量因子0.007一致。
