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

Genes and Environment

Toshiyuki Shiragiku¹  Kenichi Masumura³  Takehiko Nohmi³  Hajime Sui⁵  Hiroyuki Hayashi²  Ayaka Akahori⁴  Madoka Nakajima⁴  Ryo Ohta⁵  Kenichiro Suzuki⁴ 

[1] Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd.;Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd.;Division of Genetics and Mutagenesis, National Institute of Health Sciences;Biosafety Research Center, Foods, Drugs and Pesticides;Division of Genetic Toxicology, Hatano Research Institute, Food and Drug Safety Center

关键词: F344 gpt delta transgenic rat;    diaminotoluenes;    28 consecutive daily treatment;    gpt assay;   

DOI  :  10.3123/jemsge.34.25

学科分类：分子生物学，细胞生物学和基因

来源: Japanese Environmental Mutagen Society / Nihon Kankyo Hen igen Gakkai

【 摘 要 】

References(31)Cited-By(2)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.

【 授权许可】

Unknown