Bruckner J V, Kyle G M, Luthra R, Acosta D, Mehta S M, Sethuraman S, Muralidhara S
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602-2352, USA.
Toxicol Sci. 2001 Apr;60(2):363-72. doi: 10.1093/toxsci/60.2.363.
1,1,1-Trichloroethane (TRI) is a widely used solvent that has become a frequent contaminant of drinking water supplies in the U.S. There is very little information available on the potential for oral TRI to damage the liver or to alter its P450 metabolic capacity. Thus, a major objective of this investigation was to assess the acute, short-term, and subchronic hepatotoxicity of oral TRI. In the acute study, male Sprague-Dawley (S-D) rats were gavaged with 0, 0.5, 1, 2, or 4 g TRI/kg bw and killed 24 h later. No acute effects were apparent other than CNS depression. Other male S-D rats received 0, 0.5, 5, or 10 g TRI/kg po once daily for 5 consecutive days, rested for 2 days, and were dosed for 4 additional days. Groups of the animals were sacrificed for evaluation of hepatotoxicity 1, 5, and 12 days after initiation of the short-term experiment. This dosage regimen caused numerous fatalities at 5 and 10 g/kg, but no increases in serum enzymes or histopathological changes in the liver. For the subchronic study, male S-D rats were gavaged 5 times weekly with 0, 0.5, 2.5, or 5.0 g TRI/kg for 50 days. The 0 and 0.5 g/kg groups were dosed for 13 weeks. A substantial number of rats receiving 2.5 and 5.0 g/kg died, apparently due to effects of repeated, protracted CNS depression. There was evidence of slight hepatocytotoxicity at 10 g/kg, but no progression of injury nor appearance of adverse effects were seen during acute or short-term exposure. Ingestion of 0.5 g/kg over 13 weeks did not cause apparent CNS depression, body or organ weight changes, clinical chemistry abnormalities, histopathological changes in the liver, or fatalities. Additional experiments did reveal that 0.5 g/kg and higher doses induced hepatic microsomal cytochrome P450IIE1 (CYP2E1) in a dose- and time-dependent manner. Induction of CYP2E1 activity occurred sooner, but was of shorter duration than CYP2B1/2 induction. CYP1A1 activity was not enhanced. In summary, 0.5 g/kg po was the acute, short-term, and subchronic NOAEL for TRI, for effects other than transient CYP2E1 induction, under the conditions of this investigation. Oral TRI appears to have very limited capacity to induce P450s or to cause liver injury in male S-D rats, even when administered repeatedly by gavage in near-lethal or lethal dosages under conditions intended to maximize hepatic effects.
1,1,1-三氯乙烷（TRI）是一种广泛使用的溶剂，已成为美国饮用水供应中常见的污染物。关于口服TRI损害肝脏或改变其细胞色素P450代谢能力的可能性，目前几乎没有相关信息。因此，本研究的一个主要目标是评估口服TRI的急性、短期和亚慢性肝毒性。在急性研究中，给雄性Sprague-Dawley（S-D）大鼠经口灌胃给予0、0.5、1、2或4 g TRI/kg体重，并在24小时后处死。除中枢神经系统抑制外，未观察到明显的急性效应。其他雄性S-D大鼠连续5天每天经口给予0、0.5、5或10 g TRI/kg，休息2天，然后再给药4天。在短期实验开始后的第1、5和12天，处死各组动物以评估肝毒性。这种给药方案在5和10 g/kg剂量时导致大量死亡，但血清酶没有升高，肝脏也没有组织病理学变化。在亚慢性研究中，雄性S-D大鼠每周经口灌胃5次，给予0、0.5、2.5或5.0 g TRI/kg，持续50天。0和0.5 g/kg组给药13周。大量接受2.5和5.0 g/kg剂量的大鼠死亡，显然是由于反复、长期的中枢神经系统抑制作用。在10 g/kg剂量时有轻微肝细胞毒性的证据，但在急性或短期暴露期间未观察到损伤进展或不良反应出现。在13周内摄入0.5 g/kg未导致明显的中枢神经系统抑制、体重或器官重量变化、临床化学异常、肝脏组织病理学变化或死亡。额外的实验确实表明，0.5 g/kg及更高剂量以剂量和时间依赖性方式诱导肝微粒体细胞色素P450IIE1（CYP2E1）。CYP2E1活性的诱导发生得更快，但持续时间比CYP2B1/2诱导短。CYP1A1活性未增强。总之，在本研究条件下，对于除短暂的CYP2E1诱导外的其他效应，0.5 g/kg经口给药是TRI的急性、短期和亚慢性无观察到有害作用水平（NOAEL）。口服TRI似乎诱导细胞色素P450或导致雄性S-D大鼠肝损伤的能力非常有限，即使在旨在使肝脏效应最大化的条件下以接近致死或致死剂量反复经口给药也是如此。
