Tyl R W, Price C J, Marr M C, Myers C B, Seely J C, Heindel J J, Schwetz B A
Center for Life Sciences and Toxicology, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194.
Fundam Appl Toxicol. 1993 May;20(4):402-12. doi: 10.1006/faat.1993.1052.
Artificially inseminated New Zealand white (NZW) rabbits were administered ethylene glycol (EG) by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. EG resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity, mice >> rats >> rabbits.
在妊娠第6天至19天，通过灌胃给人工授精的新西兰白兔（NZW）施用乙二醇（EG），剂量分别为0、100、500、1000或2000毫克/千克/天，每组有23 - 24只授精动物。记录临床症状，每天测量饮水量；在妊娠第0天、6 - 19天、25天和30天对母兔称重。在尸检时（妊娠第30天），记录母体肝脏、肾脏和妊娠子宫的重量。对每个剂量组的10只母兔的肾脏以及所有意外死亡的母兔进行组织病理学检查。计算卵巢黄体数量，并记录子宫着床部位（总着床数、吸收数、死胎和活胎数）。对所有活胎进行称重、性别鉴定，并检查其外部、内脏和骨骼的畸形及变异情况。在2000毫克/千克/天的剂量下，EG导致严重的母体毒性（死亡率42%；3例早产和1例自然流产），伴有肾脏病变，且无其他母体毒性指标。2000毫克/千克/天剂量下的肾脏病变累及皮质肾小管，包括管腔内草酸钙结晶、上皮坏死以及肾小管扩张和变性。在100 - 1000毫克/千克/天的剂量下未出现与剂量相关的母体毒性。在任何测试剂量下均未显示出发育毒性，包括对着床前或着床后损失、胎儿数量、胎儿体重或每窝胎儿性别比例（雄性胎儿百分比）均无影响，也没有致畸性证据。因此，在本研究中，母体毒性的“无观察到有害作用水平”（NOAEL）为1000毫克/千克/天，发育毒性的NOAEL至少为2000毫克/千克/天。对于器官形成期经灌胃给予EG后的母体和发育毒性，可确定NZW兔相对于Sprague - Dawley大鼠和瑞士小鼠的敏感性：就母体毒性而言：兔＞小鼠＞大鼠；就发育毒性而言，小鼠＞＞大鼠＞＞兔。
