Acute, subacute, and subchronic oral toxicity studies of 1,1-dichloroethane in rats: application to risk evaluation.
Acute, subacute, and subchronic oral toxicity studies of 1,1-dichloroethane in rats: application to risk evaluation.
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DOI：
10.1093/toxsci/64.1.135
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发表时间：
2001-11
期刊：
影响因子：
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通讯作者：
S. Muralidhara;R. Ramanathan;S. M. Mehta;L. H. Lash;Daniel Acosta;James V. Bruckner
中科院分区：
文献类型：
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作者：
S. Muralidhara;R. Ramanathan;S. M. Mehta;L. H. Lash;Daniel Acosta;James V. Bruckner
1，1-二氯乙烷(DCE)是一种经常被发现的饮用水污染物和危险废物场所的污染物。有关其短期和长期毒性的信息非常有限，以至于美国环保局和ATSDR尚未确定这种挥发性有机化合物(VOC)的口服参考剂量或最低风险水平。本文估算了S-D雄性大鼠的急性经口LD(50)为8.2g/kg体重(BW)。死亡似乎是由于中枢神经系统抑郁和呼吸衰竭。在急性/亚急性实验中，雄性S-D大鼠分别给予0、1、2、4和8gDCE/kg玉米油灌胃，连续灌胃1、5和10d。这些动物被关在代谢笼中收集尿液，并在最后一次服药后24小时处死取血和组织标本。2和4g/kg剂量组小鼠第5天和第10天的体重增长和肝脏相对重量均有所下降，肾脏非蛋白巯基水平有所升高。血清酶水平升高、组织病理学改变和尿液分析异常均不明显。在亚慢性实验中，成年雄性S-D大鼠以0.5g、1g、2g或4gDCE/kg灌胃，每周5次，持续13周。注射4g/kg的大鼠表现出明显的中枢神经系统抑制，超过一半的动物在第11周死亡。2g/kg的大鼠表现出中度的中枢神经系统抑制。一只2g/kg的大鼠在6周内死亡。无论是死亡的动物还是存活的动物，在任何剂量水平下都很少有器官损伤的表现。在2和4g/kg剂量下，体重增加减少，尿酶一过性增加。血清酶水平和血尿素氮水平没有升高，也没有出现糖尿或蛋白尿。在肝、肾、肺、脑、肾上腺、脾、胃、附睾或睾丸中未见化学诱导的组织学改变。肝微粒体细胞色素P450实验表明，单次、高剂量口服DCE不改变总P450水平，但可诱导细胞色素P2E1的水平和活性，并抑制细胞色素P1A1的活性。这些影响是可逆的，并随着重复接触DCE而消退。在为期13周的亚慢性研究中，没有明显的器官损害进展，也没有出现短期暴露中看不到的不良反应。在本研究条件下，口服1g/kg为DCE的急性、亚急性和亚慢性LOAEL。在每种情况下，0.5g/kg为NOAEL。
1,1-Dichloroethane (DCE) is a solvent that is often found as a contaminant of drinking water and a pollutant at hazardous waste sites. Information on its short- and long-term toxicity is so limited that the U.S. EPA and ATSDR have not established oral reference doses or minimal risk levels for the volatile organic chemical (VOC). The acute oral LD(50) in male Sprague-Dawley (S-D) rats was estimated in the present study to be 8.2 g/kg of body weight (bw). Deaths appeared to be due to CNS depression and respiratory failure. In an acute/subacute experiment, male S-D rats were given 0, 1, 2, 4, or 8 g DCE/kg in corn oil by gavage for 1, 5, or 10 consecutive days. The animals were housed in metabolism cages for collection of urine and sacrificed for blood and tissue sampling 24 h after their last dose. There were decreases in body weight gain and relative liver weight at all dosage levels, as well as increased renal nonprotein sulfhydryl levels at 2 and 4 g/kg after 5 and 10 days. Elevated serum enzyme levels, histopathological changes, and abnormal urinalyses were not manifest. For the subchronic study, adult male S-D rats were gavaged with 0.5, 1, 2, or 4 g DCE/kg 5 times weekly for up to 13 weeks. Animals receiving 4 g/kg exhibited pronounced CNS depression, with more than one-half dying by week 11. The 2-g/kg rats exhibited moderate CNS depression. One 2-g/kg rat died during week 6. There were very few manifestations of organ damage in animals that succumbed or in survivors at any dosage level. Decreases in bw gain and transient increases in enzymuria were noted at 2 and 4 g/kg. Serum enzyme levels and blood urea nitrogen were not elevated, nor were glycosuria or proteinuria present. Chemically induced histological changes were not seen in the liver, kidney, lung, brain, adrenal, spleen, stomach, epididymis, or testis. Hepatic microsomal cytochrome P450 experiments revealed that single, high oral doses of DCE did not alter total P450 levels, but did induce CYP2E1 levels and activity and inhibit CYP1A1 activity. These effects were reversible and regressed with repeated DCE exposure. There was no apparent progression of organ damage during the 13-week subchronic study, nor appearance of adverse effects not seen in the short-term exposures. One g/kg orally (po) was found to be the acute, subacute, and subchronic LOAEL for DCE, under the conditions of this investigation. In each instance, 0.5 g/kg was the NOAEL.