Article ID Journal Published Year Pages File Type
2595575 Toxicology 2013 7 Pages PDF
Abstract
Transgenic rat gene mutation assays can be used to assess genotoxicity of chemicals in target organs for carcinogenicity. Mutations in transgenes are genetically neutral and accumulate during a treatment period; thus, the assays are suitable for assessment of the genotoxicity risk of chemicals using a repeated-dose treatment paradigm. However, few such studies have been conducted. To examine the utility of the transgenic rat assays in repeated-dose studies, we treated female F344 gpt delta rats with tamoxifen (TAM) at 20 and 40 mg/kg, or toremifene (TOR) at 40 mg/kg by gavage daily for 3 weeks. We also fed gpt delta rats with TAM at either 250 ppm (15.4-17.6 mg/kg) or 500 ppm (30.0-32.9 mg/kg) for 13 weeks. TAM is carcinogenic in the rat liver and TOR is not carcinogenic. TAM administration significantly increased gpt (point mutations) and Spi− (deletions) mutant frequencies (MFs) in the liver, the target organ of carcinogenesis; MFs were higher after treatment for 13 weeks than after treatment for 3 weeks. The MFs in the kidney did not increase in any of the TAM treatment groups. TOR had no effect on MFs (gpt and Spi−) in either the liver or the kidney. We conclude that the gpt delta rat assay in the repeated-dose treatment paradigm is sensitive enough to detect gene mutations induced by TAM in the target organ for carcinogenesis. Furthermore, the assay can be integrated into a 13-week dose-finding study for a 2-year cancer bioassay.
Related Topics
Life Sciences Environmental Science Health, Toxicology and Mutagenesis
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