title: Evaluation of the repeated-dose liver micronucleus assay using  2,4-dinitrotoluene: a report of a collaborative study by  CSGMT/JEMS.MMS.
abstract: The liver micronucleus assay using young adult rats has the potential to detect liver carcinogens by repeated dosing, and could be expected to be integrated into repeated-dose toxicity studies using a hepatocyte isolation method without the traditional in situ collagenase perfusion. In this study, to assess the performance of the repeated-dose liver micronucleus assay, 2,4-dinitrotoluene (DNT), which is a rodent liver carcinogen, was administered orally to male rats at doses of 50, 100 and 200 mg/kg/day once daily for 14 or 28 consecutive days, and the frequencies of micronucleated hepatocytes (MNHEPs) and micronucleated immature erythrocytes (MNIMEs) were examined. Significant increases in the MNHEPs were observed at 50 mg/kg/day or more in the 14-day treatment, and 50 and 100 mg/kg/day in the 28-day treatment. These increases were dependent on both the dose and the number of administrations, which indicates the possibility that the MNHEPs accumulate as a result of repeated dosing. In contrast, no increase in the MNIMEs was observed. In conclusion, the repeated-dose liver micronucleus assay using young adult rats is sufficiently sensitive to detect the genotoxicity of 2,4-DNT at a low dose.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Maeda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tsuchiyama
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Asaoka
authors.forename: Mikito
authors.initials: M
authors.lastname: Hirakata
authors.forename: Tomoya
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Keiyu
authors.initials: K
authors.lastname: Oshida
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000187:drug effects; D003299:Cooperative Behavior; D004136:Dinitrobenzenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007564:Japan; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D015162:Micronucleus Tests; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012156:Reticulocytes / Q000187:drug effects; D012957:Societies, Pharmaceutical
chemical_list: D002273:Carcinogens; D004136:Dinitrobenzenes; C016403:2,4-dinitrotoluene