Evaluation of In Vivo Mutagenicity by 2,4-Diaminotoluene and 2,6-Diaminotoluene in Liver of F344 gpt delta Transgenic Rat Dosed for 28 Days : A Collaborative Study of the gpt delta Transgenic Rat Mutation Assay

DOI Web Site 被引用文献3件 参考文献52件
  • Sui Hajime
    Division of Genetic Toxicology, Hatano Research Institute, Food and Drug Safety Center
  • Ohta Ryo
    Division of Genetic Toxicology, Hatano Research Institute, Food and Drug Safety Center
  • Shiragiku Toshiyuki
    Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd.
  • Akahori Ayaka
    Biosafety Research Center, Foods, Drugs and Pesticides
  • Suzuki Kenichiro
    Biosafety Research Center, Foods, Drugs and Pesticides
  • Nakajima Madoka
    Biosafety Research Center, Foods, Drugs and Pesticides
  • Hayashi Hiroyuki
    Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd.
  • Masumura Kenichi
    Division of Genetics and Mutagenesis, National Institute of Health Sciences
  • Nohmi Takehiko
    Division of Genetics and Mutagenesis, National Institute of Health Sciences

書誌事項

タイトル別名
  • Evaluation of <i>In Vivo</i> Mutagenicity by 2,4-Diaminotoluene and 2,6-Diaminotoluene in Liver of F344 <i>gpt</i> delta Transgenic Rat Dosed for 28 Days: A Collaborative Study of the <i>gpt</i> delta Transgenic Rat Mutation Assay

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説明

The transgenic rodent (TGR) assay has been widely used to study in vivo gene mutations by chemicals or radiation; however, an optimal protocol has not yet been established to assess unknown genotoxic potential. The International Workshop on Genotoxicity Testing (IWGT) strongly recommends a repeated-dose regimen for the TGR assay protocol for regulatory safety assessment as follows: a treatment period of 28 days and a sampling time of 3 days following the final treatment. In this study, TGR assays using F344 gpt delta transgenic rats were conducted at three laboratories to evaluate the validity of the IWGT protocol, as part of a collaborative study of the transgenic rat mutation assay. Male F344 gpt delta transgenic rats were orally treated with 2,4-diaminotoluene (2,4-DAT; hepatic carcinogen in rodents; 10 and 30 mg/kg/day) or 2,6-diaminotoluene (2,6-DAT; non-carcinogen in rodents; 60 mg/kg/day) once daily for 28 days. Rats were euthanized 3 days after the last dosing, and then mutant frequencies (MFs) of the gpt gene in the livers were studied. As a result, a significant increase in the MF was observed at 30 mg/kg in the 2,4-DAT-treated group, but not in the 2,6-DAT-treated group. These results were commonly observed among the three laboratories. In addition, the overall results from the three laboratories were in general agreement. These results indicate that 2,4-DAT induces gene mutation in the liver of gpt delta rats, but 2,6-DAT does not. These results also indicate that the F344 gpt delta transgenic rat mutation assay can distinguish differences in the in vivo mutagenic potential between a hepatic carcinogen and a non-carcinogen. Results from one laboratory showed more variability than those from the other two laboratories, and this appearance was due to the smaller number of colonies scored. Thus, these results demonstrate that the IWGT protocol for the TGR assays is valid, and show that consistent results are obtained among different laboratories.<br>

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