title: The JaCVAM international validation study on the in vivo comet assay: Selection of test chemicals.
abstract: The Japanese Center for the Validation of Alternative Methods (JaCVAM) sponsored an international prevalidation and validation study of the in vivo rat alkaline pH comet assay. The main objective of the study was to assess the sensitivity and specificity of the assay for correctly identifying genotoxic carcinogens, as compared with the traditional rat liver unscheduled DNA synthesis assay. Based on existing carcinogenicity and genotoxicity data and chemical class information, 90 chemicals were identified as primary candidates for use in the validation study. From these 90 chemicals, 46 secondary candidates and then 40 final chemicals were selected based on a sufficiency of carcinogenic and genotoxic data, differences in chemical class or genotoxic or carcinogenic mode of action (MOA), availability, price, and ease of handling. These 40 chemicals included 19 genotoxic carcinogens, 6 genotoxic non-carcinogens, 7 non-genotoxic carcinogens and 8 non-genotoxic non-carcinogens. "Genotoxicity" was defined as positive in the Ames mutagenicity test or in one of the standard in vivo genotoxicity tests (primarily the erythrocyte micronucleus assay). These chemicals covered various chemicals classes, MOAs, and genotoxicity profiles and were considered to be suitable for the purpose of the validation study. General principles of chemical selection for validation studies are discussed.
authors.affiliation: 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: Safety Research Laboratories, Mitsubishi Tanabe Pharma Co., Chiba 292-0818, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Uno
authors.affiliation: National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
authors.affiliation: National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; Japanese Center for the Validation of Alternative Methods (JaCVAM), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Public Interest Incorporated Foundation, BioSafety Research Center, 582-2 Shioshinden, Iwata, Shizuoka 437-1213, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Division of National Toxicology Program, National Institute of Environmental Health Sciences, Mail Code K2-17, P.O. Box 12233 Research Triangle Park, NC 27709, USA.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
authors.affiliation: European Union Reference Laboratory for Alternative Methods to Animal testing (EURL ECVAM), Institute for Health and Consumer Protection, European Commission Joint Research Centre, Via E. Fermi 2749, I-21027 Ispra, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Corvi
authors.affiliation: Innovative Toxicology Consulting, LLC, Lake Worth, FL 33467, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Schechtman
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D020552:Comet Assay / Q000379:methods* / Q000592:standards*; D004249:DNA Damage / Q000187:drug effects; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009153:Mutagens / Q000633:toxicity; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D023382:Toxicity Tests, Acute
chemical_list: D002273:Carcinogens; D009153:Mutagens
keywords: Chemical selection; In vivo comet assay; JaCVAM; Validation study