title: Comprehensive retrospective evaluation of existing in vitro chromosomal aberration test data by cytotoxicity index transformation.
abstract: New OECD test guidelines have been issued, in which the cytotoxicity index relative cell count (RCC) is replaced with a new index, RICC or RPD (relative increase in cell count/relative population doubling), with the goal of reducing the high proportion of false positive results in in vitro chromosomal aberration tests. Using a mathematical approach to estimate new indices from the RCC, we constructed an evaluation flow that quantitatively estimates how often the previous test conclusions change when applying the updated cytotoxicity criteria. The new evaluation flow was applied to a retrospective evaluation of 285 chemicals in two databases. The effects of the employment of new cytotoxicity indices are investigated at a large scale. Using the new evaluation flow, 90 chemicals were estimated as positive, 39 were designated as estimated negative (13 probably negative and 26 possibly negative), and 140 were designated as negative. Moreover, we also applied a prioritization index to indicate the likelihood of a chemical being re-evaluated as negative and assigned priorities for testing. Most of the chemicals that were designated as estimated negative and had negative results in the in vivo micronucleus tests were considered as false-positives that would be correctly judged under the new test guideline. Furthermore, statistical analysis of the frequency of estimated negatives revealed that the results for Ames-positive chemicals, especially those with a strong response, are unlikely to change. Therefore, we concluded that the new indices would likely reduce the proportion of false positive results and not increase the proportion of false negative results. This study is the first report of a comprehensive re-evaluation of test results in terms of new cytotoxicity indices. The evaluation flow we have developed facilitates efficient retrospective evaluation of genotoxicity.
authors.affiliation: R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: National Institute of Health Sciences, Division of Risk Assessment, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morita
authors.affiliation: R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ito
authors.affiliation: R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan. Electronic address: honda.hiroshi@kao.co.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Honda
mesh_terms: D000818:Animals; D016466:CHO Cells; D002869:Chromosome Aberrations / Q000139:chemically induced*; D003412:Cricetulus; D004249:DNA Damage / Q000187:drug effects; D015162:Micronucleus Tests; D009152:Mutagenicity Tests / Q000592:standards*; D009153:Mutagens / Q000633:toxicity*; D012189:Retrospective Studies
chemical_list: D009153:Mutagens
keywords: Cytotoxicity index; In vitro chromosomal aberration test; In vitro micronucleus test; OECD test guidelines; RICC (relative increase in cell count); RPD (relative population doubling)