title: Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).
abstract: The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan; National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-0098, Japan; University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka-shi, Shizuoka 422-8526, Japan. Electronic address: Hamada.Shuuichi@mh.medience.co.jp.
authors.forename: Shuichi
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authors.lastname: Hamada
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authors.forename: Wakako
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authors.lastname: Ohyama
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Rie
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authors.lastname: Takashima
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authors.forename: Satoru
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authors.lastname: Kawakami
authors.affiliation: Public Interest Incorporated Foundation, Biosafety Research Center, 582-2 Shioshinden, Iwata-shi, Shizuoka 437-1213, Japan.
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authors.forename: Yasushi
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authors.forename: Shigeharu
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authors.lastname: Takayanagi
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authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ogiwara
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authors.forename: Akihisa
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authors.lastname: Maeda
authors.affiliation: Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan.
authors.forename: Emiko
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authors.lastname: Okada
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authors.forename: Yukari
authors.initials: Y
authors.lastname: Terashima
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Hironao
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authors.lastname: Takasawa
authors.affiliation: Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan.
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authors.lastname: Narumi
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Yumi
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authors.lastname: Wako
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Kazufumi
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authors.lastname: Kawasako
authors.affiliation: Public Interest Incorporated Foundation, Biosafety Research Center, 582-2 Shioshinden, Iwata-shi, Shizuoka 437-1213, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Sano
authors.affiliation: Public Interest Incorporated Foundation, Biosafety Research Center, 582-2 Shioshinden, Iwata-shi, Shizuoka 437-1213, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ohashi
authors.affiliation: National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-0098, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morita
authors.affiliation: National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-0098, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kojima
authors.affiliation: National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-0098, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
authors.affiliation: Public Interest Incorporated Foundation, Biosafety Research Center, 582-2 Shioshinden, Iwata-shi, Shizuoka 437-1213, Japan.
authors.forename: Makoto
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mesh_terms: D000367:Age Factors; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000187:drug effects; D003299:Cooperative Behavior; D004249:DNA Damage; D004334:Drug Administration Schedule; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects*; D015386:Hazardous Substances / Q000633:toxicity*; 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; D015203:Reproducibility of Results; D012156:Reticulocytes / Q000187:drug effects; D012680:Sensitivity and Specificity; D012957:Societies, Pharmaceutical
chemical_list: D002273:Carcinogens; D015386:Hazardous Substances
keywords: Gastrointestinal tract; Hepatocarcinogen; Integration; Liver; Micronucleus; Repeated-dose