title: Evaluation of the sensitivity and specificity of in vivo erythrocyte micronucleus and transgenic rodent gene mutation tests to detect rodent carcinogens.
abstract: Sensitivity and/or specificity of the in vivo erythrocyte micronucleus (MN) and transgenic rodent mutation (TGR) tests to detect rodent carcinogens and non-carcinogens were investigated. The Carcinogenicity and Genotoxicity eXperience (CGX) dataset created by Kirkland et al. was used for the carcinogenicity and in vitro genotoxicity data, i.e., Ames and chromosome aberration (CA) tests. Broad literature surveys were conducted to gather in vivo MN or TGR test data to add to the CGX dataset. Genotoxicity data in vitro were also updated slightly. Data on 379 chemicals (293 carcinogens and 86 non-carcinogens) were available for the in vivo MN test; sensitivity, specificity or concordances were calculated as 41.0%, 60.5% or 45.4%, respectively. For the TGR test, data on 80 chemicals (76 carcinogens and 4 non-carcinogens) were available; sensitivity was calculated as 72.4%. Based on the recent guidance on genotoxicity testing strategies, performance (sensitivity/specificity) of the following combinations was calculated; Ames+in vivo MN (68.7%/45.3%), Ames+TGR (83.8%/not calculated (nc)), Ames+in vitro CA+in vivo MN (80.8%/21.3%), Ames+in vitro CA+TGR (89.1%/nc), Ames+in vivo MN+TGR (87.5%/nc), Ames+in vitro CA+in vivo MN+TGR (89.3%/nc). Relatively good balance in performance was shown by the Ames+in vivo MN in comparison with Ames+in vitro CA (74.3%/37.5%). Ames+TGR and Ames+in vivo MN+TGR gave even higher sensitivity, but the specificity could not be calculated (too few TGR data on non-carcinogens). This indicates that in vivo MN and TGR tests are both useful as in vivo tests to detect rodent carcinogens.
authors.affiliation: Division of Risk Assessment, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. Electronic address: morita-tk@nihs.go.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morita
authors.affiliation: Nonclinical Research Center, LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hamada
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Masumura
authors.affiliation: Drug Safety Research Laboratories., Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Wakata
authors.affiliation: Clinical Science Division, Research & Development, AstraZeneca KK, 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011 Japan, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Maniwa
authors.affiliation: Nonclinical Research Center, LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Takasawa
authors.affiliation: Nonclinical Research Center, LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Yasunaga
authors.affiliation: Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Hashizume
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects*; D051379:Mice; D015162:Micronucleus Tests / Q000592:standards*; D051381:Rats; D012377:Rodentia; D012680:Sensitivity and Specificity
chemical_list: D002273:Carcinogens
keywords: Genotoxicity in vivo; Rodent erythrocyte micronucleus test; Sensitivity; Specificity; Transgenic rodent mutation assay