论文部分内容阅读
Genotoxicity assays were conducted on male Sprague Dawley rats treated with 5-? uorouracil (5-FU), melamine and 4-nitroquinoline-1-oxide (4NQO) as part of Stage IV of the international validation study on the Pig-a gene mutation assay.Rats were orally given 3 daily doses of 0, 11.5, 23 and 46 mg/kg 5-FU and doses of 0,500, 1000, 2000 mg/kg melamine;In 5-FU study, blood was sampled on Days-1, 4, 15, 29, and 45.Pig-a mutant frequencies were determined on Days-1, 15, 29, and 45 in total red blood cells (RBCs) and reticulocytes (RETs) as RBCCD59-and RETCD59-frequencies;percent micronucleated-RETs (% MN-RET) were measured on Days 4.In melamine study, peripheral blood were sampled for RBCCD59 and RETCD59-frequencies on Days-1, 15,29, and 60;and for MN-RET on Day 4.Rats were treated with 4NQO for 28 consecutive days by oral gavage, at doses of 1.5, 3 and 6 mg/kg/day.Reticulocytes were evaluated for Pig-a phenotypic mutation, RBCCD59-and RETCD59-on Days-1, 15 and 29, and for MN-RET on Day 29.5-FU was found to increase MN-RET frequencies, but no significant increases were observed for RBCCD59-or RETCD59-frequencies in 3-day study design.Neither the mean RBCCD59-frequency and RETCD59-frequency nor the mean MN-RET frequencies induced by melamine were significant increases above negative control.RBCCD59-and RETCD59-significant increased only at 4NQO 6 mg/kg/day and the responses for RETs were stronger than those for RBCs.MN-RET showed 2 fold-increase compared to control, where significant, still at 4NQO 6 mg/kg/day on Day 29 in 28-day study design.The results provide a useful way of integrating the Pig-a RET and RBC assay into an acute micronucleus test or else incorporating two genotoxicity assays into 28-day repeat-dose studies.