den Besten C, Vet J J, Besselink H T, Kiel G S, van Berkel B J, Beems R, van Bladeren P J
Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
Toxicol Appl Pharmacol. 1991 Oct;111(1):69-81. doi: 10.1016/0041-008x(91)90135-2.
The acute toxicity of a number of chlorinated benzenes, ranging from monosubstituted to pentasubstituted benzenes, was studied in rats. Toxic effects on the liver, the kidneys, and the thyroid were monitored after a single ip administration of 1, 2, or 4 mmol/kg monochlorobenzene (MCB), 1,2-dichlorobenzene (1,2-DICB), 1,4-dichlorobenzene (1,4-DICB), 1,2,4-trichlorobenzene (1,2,4-TRCB), and pentachlorobenzene (PECB). Due to its low solubility, 1,2,4,5-tetrachlorobenzene (1,2,4,5-TECB) was tested at a highest dose of 0.8 mmol/kg. 1,2-DICB and 1,2,4-TRCB produced the most severe hepatotoxic effects when compared with an equimolar dose of the other chlorinated benzenes, as determined by plasma ALT profile and histopathological changes after 72 hr. MCB was considerably less hepatotoxic. Severe degenerative damage to the kidney was only observed in a few rats treated with 1,2,4-TRCB. However, protein droplets in the tubular epithelial cells were observed at 72 hr after administration of 1,4-DICB, 1,2,4-TRCB, 1,2,4,5-TECB, and PECB. In the latter two groups, these protein droplets were still observed 9 days after administration. All chlorinated benzenes tested excluding MCB induced a reduction in plasma thyroxine levels. The extent of decrease in plasma thyroxine was more severe in rats treated with 1,2,4-TRCB or PECB and correlated well with the relative binding affinities of the phenolic metabolites to the plasma transport protein for thyroxine, i.e., transthyretin. The present study indicates that the establishment of a structure-activity relationship with regard to toxicity depends on the sensitivity of the respective target organs. In the series of (poly)chlorinated benzenes studied, ranging from mono- to pentachlorobenzene, the most severe effects on liver, kidney, and thyroid were observed for 1,2,4-substitution.
研究了一系列氯化苯（从单取代到五取代苯）对大鼠的急性毒性。在腹腔注射1、2或4 mmol/kg的一氯苯（MCB）、1,2-二氯苯（1,2-DICB）、1,4-二氯苯（1,4-DICB）、1,2,4-三氯苯（1,2,4-TRCB）和五氯苯（PECB）后，监测对肝脏、肾脏和甲状腺的毒性作用。由于1,2,4,5-四氯苯（1,2,4,5-TECB）溶解度低，其最高测试剂量为0.8 mmol/kg。与等摩尔剂量的其他氯化苯相比，1,2-DICB和1,2,4-TRCB产生的肝毒性作用最为严重，这是通过72小时后的血浆谷丙转氨酶（ALT）水平和组织病理学变化确定的。MCB的肝毒性要小得多。仅在少数用1,2,4-TRCB处理的大鼠中观察到严重的肾脏退行性损伤。然而，在给予1,4-DICB、1,2,4-TRCB、1,2,4,5-TECB和PECB 72小时后，在肾小管上皮细胞中观察到蛋白滴。在后面两组中，给药9天后仍观察到这些蛋白滴。除MCB外，所有测试的氯化苯均导致血浆甲状腺素水平降低。在用1,2,4-TRCB或PECB处理的大鼠中，血浆甲状腺素降低的程度更严重，并且与酚类代谢物与甲状腺素血浆转运蛋白（即甲状腺素转运蛋白）的相对结合亲和力密切相关。本研究表明，关于毒性的构效关系的建立取决于各个靶器官的敏感性。在所研究的从单氯苯到五氯苯的一系列（多）氯化苯中，观察到1,2,4-取代对肝脏、肾脏和甲状腺的影响最为严重。
