title: Validation study of the combined repeated-dose toxicity and genotoxicity assay using gpt delta rats.
abstract: Transgenic rodents carrying reporter genes to detect organ-specific in vivo genetic alterations are useful for risk assessment of genotoxicity that causes cancer. Thus, the Organization for Economic Co-operation and Development has established the guideline for genotoxicity tests using transgenic animals, which may be combined with repeated-dose toxicity studies. Here, we provide evidence to support equivalence of gpt delta and wild type (WT) rats in terms of toxicological responses to a genotoxic hepatocarcinogen, N-nitrosodiethylamine (DEN), and a non-genotoxic hepatocarcinogen, di(2-ethylhexyl)phthalate (DEHP). gpt delta rats treated with DEHP showed similar increases in liver and kidney weights, serum albumin, albumin/globulin ratios, and incidence of diffuse hepatocyte hypertrophy compared to WT F344 and Sprague-Dawley (SD) rats. DEN-treated gpt delta rats showed equivalent increases in the number and area of precancerous GST-P-positive foci in the liver compared to WT rats. The livers of DEN-treated gpt delta rats also showed increased frequencies of gpt and Spi(-) mutations; such changes were not observed in DEHP-treated gpt delta rats. These results indicated that gpt delta rats (both F344 and SD backgrounds) showed comparable DEHP-induced toxicity and DEN-induced genotoxicity to those observed in WT rats. With regard to the administration period, the general toxicity of 1.2% DEHP was evident throughout the experimental period, and the genotoxicity of 10 p.p.m. DEN could be detected after 2 weeks of administration and further increased at 4 weeks. These results suggested that combined assays using gpt delta rats could detect both general toxicity and genotoxicity by the canonical 4-week administration protocol. Therefore, this assay using gpt delta rats would be applicable for risk assessment including early detection of genotoxic carcinogens and ultimately serve to reduce cancer risks in humans from environmental chemicals.
authors: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors: Jun-Ichi
authors: J
authors: Akagi
authors: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors: Takeshi
authors: T
authors: Toyoda
authors: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors: Young-Man
authors: YM
authors: Cho
authors: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors: Yasuko
authors: Y
authors: Mizuta
authors: Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.|Center for Innovative Drug Discovery and Development, National Institute of Biomedical Innovation, Tokyo, Japan.
authors: Takehiko
authors: T
authors: Nohmi
authors: Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
authors: Akiyoshi
authors: A
authors: Nishikawa
authors: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors: Kumiko
authors: K
authors: Ogawa
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000633:toxicity; D004052:Diethylnitrosamine / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods*; D009154:Mutation; D009929:Organ Size / Q000187:drug effects; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
chemical_list: D002273:Carcinogens; D004052:Diethylnitrosamine; D004051:Diethylhexyl Phthalate
keywords: Genotoxicity; gpt delta; mutation; reduction of animal use; repeated-dose toxicity