title: Evaluation of the repeated dose liver micronucleus assay using young  adult rats with cyclophosphamide monohydrate: a report of a  collaborative study by CSGMT/JEMS.MMS.
abstract: The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect liver carcinogens, and this assay could be integrated into general toxicological studies. In this study, in order to assess the performance of the assay, cyclophosphamide monohydrate (CP) was tested in a 14-day RDLMN assay. Based on the results of the 4-day repeated dose-finding study, 10 mg/kg/day of CP was selected as the highest dose and the lower doses were set at 5, 2.5, 1.25, and 0.625 mg/kg/day for the 14-day RDLMN assay. On the day after the completion of the dosing period, specimens of hepatocytes and bone marrow cells were prepared and the induction of micronuclei was assessed. No changes were observed in the incidences of micronucleated hepatocytes. Nevertheless, the incidences of micronucleated immature erythrocytes in the bone marrow were increased significantly at CP doses of 1.25 mg/kg/day or more. These findings are consistent with reports that CP induces tumors in various tissues but it does not induce liver tumors.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Zaizen
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyamoto
authors.forename: Yumi
authors.initials: Y
authors.lastname: Wako
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kawasako
authors.forename: Hisao
authors.initials: H
authors.lastname: Ishida
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000187:drug effects; D003299:Cooperative Behavior; D003520:Cyclophosphamide / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007564:Japan; D008099:Liver / Q000187:drug effects; D008297:Male; D015162:Micronucleus Tests; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012156:Reticulocytes / Q000187:drug effects* / Q000473:pathology; D012957:Societies, Pharmaceutical
chemical_list: D002273:Carcinogens; D003520:Cyclophosphamide