Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits.
Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits.
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新西兰白兔灌胃乙二醇的发育毒性评价。
DOI：
10.1006/faat.1993.1052
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Schwetz,BA
中科院分区：
文献类型：
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作者：
Tyl,RW;Price,CJ;Marr,MC;Myers,CB;Seely,JC;Heindel,JJ;Schwetz,BA
在妊娠第6 - 19天（GD），以0、100、500、1000或2000 mg/kg/天的剂量，通过管饲法对人工授精的新西兰白色（NZW）家兔给予乙二醇（EG），每组23-24只授精动物。每天记录临床体征并测量饮水量;在GD 0、6-19、25和30对雌兔称重。尸检时（GD 30），记录母体肝脏、肾脏和妊娠子宫重量。对10只母兔/剂和所有计划外死亡的肾脏进行组织学检查。计数卵巢黄体并记录子宫着床部位（总部位、吸收、死胎和活胎）。对所有活胎进行称重、性别鉴定，并检查外部、内脏和骨骼畸形和变异。在2000 mg/kg/天剂量下，EG导致严重的母体毒性（42%死亡率; 3例早产和1例自然流产），与肾脏病理学相关，且不伴有任何其他母体毒性指标。2000 mg/kg/天剂量组的肾脏病变涉及皮质肾小管，包括管腔内草酸盐晶体、上皮坏死和肾小管扩张和变性。在100-1000 mg/kg/天剂量下未发生剂量相关的母体毒性。在任何试验剂量下均无发育毒性迹象，包括对着床前或着床后丢失、胎仔数量、胎仔体重或每窝性别比（雄性胎仔%）无影响，且无致畸性证据。因此，在本研究中，母体毒性的“无明显不良作用水平”（NOAEL）为1000 mg/kg/天，发育毒性的NOAEL至少为2000 mg/kg/天。相对于Sprague-Dawley大鼠和Swiss小鼠，NZW兔对器官形成期间EG灌胃给药的母体和发育毒性的敏感性可确定为母体毒性：兔>小鼠>大鼠，发育毒性：小鼠>大鼠>兔。
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.