title: Evaluation of a repeated dose liver micronucleus assay in rats treated with two genotoxic hepatocarcinogens, dimethylnitrosamine and 2-acetylaminofluorene: the possibility of integrating micronucleus tests with multiple tissues into a repeated dose general toxicity study.
abstract: As part of a collaborative study by the Collaborative Study Group for Micronucleus Test (CSGMT) of the Mammalian Mutagenicity Study Group (MMS) in the Japanese Environmental Mutagen Society (JEMS), the present study evaluated the effectiveness of the repeated dose liver micronucleus (RDLMN) assay. Two genotoxic hepatocarcinogens, dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF), were administered orally to male rats (6 weeks old at the initial dosing) once daily for 14 and 28 days to evaluate the micronucleus (MN) inducibility in the liver. In addition, these chemicals were evaluated for MN inducibility in the bone marrow (BM) and gastrointestinal (GI) tract, i.e. glandular stomach and colon of the same animals used in the RDLMN assay. As a result, both chemicals produced positive results in the liver, although a weak positive response was given by 2-AAF. DMN gave negative results in the tissues other than the liver. 2-AAF produced positive responses in the BM and glandular stomach, and a prominent response was particularly observed in the glandular stomach, which is directly exposed to the test chemicals by gavage. The present results suggest that the RDLMN assay is a useful method for detecting genotoxic hepatocarcinogens, and that it is especially effective for evaluating test chemicals, such as DMN, undetectable by the BM and GI tract MN assay. Moreover, the results in this investigation indicate that the use of multiple tissues in the study integrating the MN tests is more effective than using a single tissue, for detection of the MN induction produced by chemical exposure to rats, and helps to determine the characteristics of the test chemicals.
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan. Electronic address: Takashima.Rie@ma.medience.co.jp.
authors.forename: Rie
authors.initials: R
authors.lastname: Takashima
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Takasawa
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kawasako
authors.affiliation: Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Ohyama
authors.affiliation: Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Okada
authors.affiliation: Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Narumi
authors.affiliation: Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Fujiishi
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Wako
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Yasunaga
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hattori
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kawabata
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Nakadate
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hamada
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000187:drug effects; D003299:Cooperative Behavior; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D041981:Gastrointestinal Tract / Q000187:drug effects*; 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; D012957:Societies, Pharmaceutical
chemical_list: D002273:Carcinogens; D015073:2-Acetylaminofluorene; D004128:Dimethylnitrosamine
keywords: GI tract micronucleus assay; Genotoxic hepatocarcinogens; Integration into toxicity study; Liver micronucleus assay; Repeated dosing