Green Trevor, Lee Robert, Farrar David, Hill James
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK.
Toxicol Lett. 2003 Feb 18;138(1-2):63-73. doi: 10.1016/s0378-4274(02)00372-7.
Hexachloro-1,3-butadiene (HCBD) has been reported to be toxic to the rat kidney in a 2 year study at doses higher than 0.2 mg/kg/day. The toxicity is known to be a consequence of the metabolism of HCBD by glutathione conjugation and the renal beta-lyase pathway. Neither toxicity data, nor data on the metabolism of HCBD, are available in humans. In the current work, the potential of HCBD to cause kidney damage in humans environmentally exposed to this chemical has been assessed quantitatively by comparing the key metabolic steps in rats and humans. To that end, the hepatic conjugation of HCBD with glutathione, the metabolism of the cysteine conjugate by renal beta-lyases and N-acetyltransferases, and the metabolism of the N-acetylcysteine conjugate by renal acylases has been compared in vitro in rat and human tissues. Rates for each metabolic step were lower in humans than in rats; 5-fold for glutathione conjugation, 3-fold for beta-lyase and 3.5-fold for N-acetyltransferase. Acylase activity could not be detected in human kidney cytosol. Use of these data in a physiologically based toxicokinetic model to quantify metabolism by the beta-lyase pathway demonstrated that metabolism in humans was an order of magnitude lower than that in rats. At the no effect level for kidney toxicity in the rat the concentration of beta-lyase metabolites was calculated by the model to be 137.7 mg/l. In humans the same concentration would be achieved following exposure to 1.41 ppm HCBD. This is in contrast to the figure of 0.6 ppb which is obtained when it is assumed that the risk is associated with the internal dose of HCBD itself rather than beta-lyase metabolites.
据报道，在一项为期两年的研究中，六氯-1,3-丁二烯（HCBD）在剂量高于0.2毫克/千克/天时对大鼠肾脏有毒性。已知这种毒性是HCBD通过谷胱甘肽结合和肾脏β-裂解酶途径代谢的结果。目前尚无关于HCBD在人体中的毒性数据或代谢数据。在当前的研究中，通过比较大鼠和人类的关键代谢步骤，定量评估了环境中接触这种化学物质的人类发生肾脏损伤的可能性。为此，在大鼠和人类组织中对HCBD与谷胱甘肽的肝脏结合、肾脏β-裂解酶和N-乙酰转移酶对半胱氨酸结合物的代谢以及肾脏酰基转移酶对N-乙酰半胱氨酸结合物的代谢进行了体外比较。人类每个代谢步骤的速率均低于大鼠；谷胱甘肽结合低5倍，β-裂解酶低3倍，N-乙酰转移酶低3.5倍。在人肾细胞溶胶中未检测到酰基转移酶活性。将这些数据用于基于生理学的毒代动力学模型以量化β-裂解酶途径的代谢，结果表明人类的代谢比大鼠低一个数量级。在大鼠肾脏毒性的无效应水平下，该模型计算出β-裂解酶代谢物的浓度为137.7毫克/升。在人类中，接触1.41 ppm的HCBD时将达到相同的浓度。这与假设风险与HCBD本身的内剂量而非β-裂解酶代谢物相关时得出的0.6 ppb的数字形成对比。
