Defining EMS and ENU dose¨Cresponse relationships using the Pig-a mutation assay in rats
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- 作者：Krista L. Dobo ; ; ; krista.l.dobo@pfizer.com ; Ronald D. Fiedler ; William C. Gunther ; Catherine J. Thiffeault ; Zoryana Cammerer ; Stephanie L. Coffing ; Thomas Shutsky ; Maik Schuler
- 关键词：Ethyl methane sulfonate ; Ethylnitrosourea ; Point mutation ; Rats ; Dose&ndash ; response ; RETs
- 刊名：Mutation Research/Genetic Toxicology and Environmental Mutagenesis
- 出版年：2011
- 出版时间：9 October 2011
- 年：2011
- 卷：725
- 期：1-2
- 页码：13-21
- 全文大小：704 K
文摘
In recent years, experimental evidence has accumulated that supports the existence of sublinear dose¨Cresponse relationships at low doses of DNA reactive mutagens. However, creating the in vivo data necessary to allow for a more detailed dose¨Cresponse modeling with the currently available tools might not always be practical. The purpose of the current work was to evaluate the utility of the Pig-a gene mutation assay to rapidly identify dose¨Cresponse relationships for direct acting genotoxicants. The induction of mutations in the peripheral blood of rats was evaluated following 28 days of exposure down to low doses of the direct acting alkylating agents ethyl methane sulfonate (EMS) and ethylnitrosourea (ENU). Using statistical modeling based on the 28-day studies, a threshold for mutation induction for EMS was estimated to be 21.9 mg/kg, whereas for the more potent ENU, the threshold was estimated to be 0.88 mg/kg. Comparing mutation frequencies from acute and sub-chronic dosing indicated less than additive dose¨Cresponse relationships, further confirming the possibility of a threshold dose¨Cresponse relationship for both compounds. In conclusion, the work presented provides evidence that the Pig-a assay might be a practical alternative to other in vivo mutation assays when assessing dose¨Cresponse relationships for direct acting mutagens and that an experimental approach using fractionated dosing could be used to substantiate a biological mechanism responsible for the observation of a sublinear dose¨Cresponse relationship.