Yamasaki Kanji, Sawaki Masakuni, Noda Shuji, Imatanaka Nobuya, Takatsuki Mineo
Chemicals Assessment Center, Chemicals Evaluation and Research Institute, 3-822 Ishii, Hita, Oita 877-0061, Japan.
Arch Toxicol. 2002 Mar;76(2):65-74. doi: 10.1007/s00204-001-0319-1. Epub 2002 Feb 6.
We performed a 28-day repeated-dose toxicity study of ethynylestradiol (EE) and bisphenol A (BPA) based on the draft protocol of the "Enhanced OECD Test Guideline no. 407", and assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine disruption. Doses of EE at 0, 10, 50 or 200 microg/kg per day, or BPA at 0, 40, 200 or 1000 mg/kg per day were orally administered to Sprague-Dawley rats. The highest dose of BPA was decreased to 600 mg/kg per day from the second week of administration because a male rat given 1000 mg/kg BPA had died within 1 week with toxic clinical signs. In the assay using EE, the decrease of prostate, seminal vesicle and pituitary weights, increase of the testis weight, atrophic changes of the prostate, seminal vesicle and mammary gland, and degenerative changes in the testes were detected in male rats in the 50 and/or 200 microg/kg groups. In females of the 200 microg/kg group, decrease of the ovary weight, increase of the uterine weight, atrophy of the ovary, hypertrophy or squamous metaplasia of the uterine epithelial cells and mucification in the vagina were observed. Furthermore, diestrous, estrous or the unknown stage was prolonged in the 50 and 200 microg/kg groups of rats. Endocrine-mediated effects of EE were not detected in general observations, hematology, serum biochemistry, or hormonal or spermatological examinations. In the assay using BPA, the diestrous stages were prolonged at the highest dose, but changes related to endocrine effects were not detected in other examinations. Thus, among the parameters tested, the weight of endocrine-linked organs and their histopathological assessment and estrous cycle stage allowed the detection of the endocrine-related effect of EE, whereas the estrous cycle stage was only a useful parameter to detect the effect of BPA.
我们根据“经合组织第407号强化试验指南”草案方案，对乙炔雌二醇（EE）和双酚A（BPA）进行了为期28天的重复剂量毒性研究，并评估了一系列用于检测内分泌干扰物内分泌相关效应参数的敏感性。将EE剂量分别设定为每天0、10、50或200微克/千克，或BPA剂量分别设定为每天0、40、200或1000毫克/千克，经口给予斯普拉格-道利大鼠。由于一只给予1000毫克/千克BPA的雄性大鼠在1周内出现中毒临床症状死亡，从给药第二周起，BPA的最高剂量降至每天600毫克/千克。在使用EE的试验中，在50和/或200微克/千克组的雄性大鼠中，检测到前列腺、精囊和垂体重量减轻，睾丸重量增加，前列腺、精囊和乳腺出现萎缩性变化，以及睾丸出现退行性变化。在200微克/千克组的雌性大鼠中，观察到卵巢重量减轻，子宫重量增加，卵巢萎缩，子宫上皮细胞肥大或鳞状化生，以及阴道黏液化。此外，在50和200微克/千克组的大鼠中，间情期、发情期或未知阶段延长。在一般观察、血液学、血清生物化学、激素或精子学检查中未检测到EE的内分泌介导效应。在使用BPA的试验中，最高剂量组间情期延长，但在其他检查中未检测到与内分泌效应相关的变化。因此，在所测试的参数中，与内分泌相关器官的重量及其组织病理学评估以及发情周期阶段能够检测到EE的内分泌相关效应，而发情周期阶段仅是检测BPA效应的一个有用参数。
