Chadwick R W, George S E, Kohan M J, Williams R W, Allison J C, Hayes Y O, Chang J
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Toxicology. 1993 Jun 11;80(2-3):153-71. doi: 10.1016/0300-483x(93)90178-u.
Pretreatment of Fischer 344 rats for 5 weeks with Aroclor 1254, a commercial mixture of polychlorinated biphenyls, potentiated the genotoxicity of 2,6-dinitrotoluene (DNT), a component of an industrial chemical used in the production of polyurethane foams. This interaction resulted from Aroclor 1254-mediated bioactivation of DNT to markedly greater levels of the genotoxic metabolites, that were excreted in urine and formed DNA adducts in the liver. A significant increase in the excretion of mutagenic urinary DNT metabolites was observed after the first week of Aroclor 1254 treatment, peaked at week 2 and then declined by nearly 25% at week 4. Nevertheless, by week 5, there was almost a 4-fold increase in the formation of hepatic DNA adducts. Significantly elevated hepatic metabolism and increased beta-glucuronidase in the small intestine and cecum, at 4 weeks, may account for the increased adducts and decreased urinary mutagens. Altered nitroreductase activity, reduced pH, and changes in the microfloral population may also play a role in the effect of Aroclor 1254 on the bioactivation of DNT. Such chemical interactions could be important to predictive risk assessment because the overall cancer risk of the mixture would exceed that determined by the current guidelines for chemical mixtures.
用多氯联苯的商业混合物Aroclor 1254对Fischer 344大鼠进行为期5周的预处理，可增强2,6-二硝基甲苯（DNT）的遗传毒性，DNT是用于生产聚氨酯泡沫的一种工业化学品的成分。这种相互作用是由于Aroclor 1254介导的DNT生物活化，使其产生了水平明显更高的遗传毒性代谢产物，这些代谢产物经尿液排出，并在肝脏中形成DNA加合物。在Aroclor 1254处理的第一周后，观察到诱变尿液中DNT代谢产物的排泄量显著增加，在第2周达到峰值，然后在第4周下降了近25%。然而，到第5周时，肝脏DNA加合物的形成几乎增加了4倍。在第4周时，肝脏代谢显著增强，小肠和盲肠中的β-葡萄糖醛酸酶增加，这可能是加合物增加和尿液诱变剂减少的原因。硝基还原酶活性的改变、pH值降低以及微生物群落的变化也可能在Aroclor 1254对DNT生物活化的影响中起作用。这种化学相互作用对于预测性风险评估可能很重要，因为混合物的总体癌症风险将超过当前化学混合物指南所确定的风险。
