Authors: M Guérard G Johnson S Dertinger G DuranPacheco J Funk A Zeller
Publish Date: 2017/02/15
Volume: 91, Issue: 6, Pages: 2443-2453
Abstract
Temozolomide TMZ a monofunctional alkylating agent was selected as a model compound to determine its quantitative genotoxic dose–response relationship in different tissues blood liver and jejunum and endpoints Piga comet and micronucleus assay MNT in male rats TMZ was administered po over 5 consecutive days day 1–5 followed by a treatmentfree period of 50 days day 6–56 and a final administration prior to necropsy day 57–59 TMZ showed a dosedependent increase in DNA damage in all interrogated endpoints A statistically significant increase in Piga mutant phenotypes was observed on day 44 starting at 75 mg/kg/day for mutant reticulocytes for RETCD59− and at 375 mg/kg/day for mutant red blood cells RBCCD59− respectively In addition a statistically significant increase in cytogenetic damage as measured by micronucleated reticulocytes was observed starting at 375 mg/kg/day on day 3 and 15 mg/kg/day on day 59 DNA strand breaks as detected by the comet assay showed a dosedependent and statistically significant increase in liver blood and jejunum starting at doses of 375 375 and 75 mg/kg/day respectively The dose–response relationships of the Piga MNT and comet data were analyzed for possible points of departure PoD using the benchmarkdose BMD software PROAST with different critical effect sizes CES BMD01 BMD05 BMD1 and BMD1SD Overall PoD values show a high concordance between different tissues and endpoints underlining the suitability of this experimental design to explore quantitative dose–response relationships in a variety of different tissues and endpoints while minimizing animal use
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