title: Using in vitro structural alerts for chromosome damage to predict in vivo activity and direct future testing.
abstract: While the in vivo genotoxicity of a compound may not always correlate well with its activity in in vitro test systems, for certain compound classes a good overlap may exist between the two endpoints. The difficulty, however, lies in establishing the cases where this relationship holds true and selecting the most appropriate protocol to highlight any potential in vivo hazard. With this in mind, a project was initiated in which existing structural alerts for in vitro chromosome damage in the expert system Derek Nexus were assessed for their relevance to in vivo activity by assessing their predictivity against an in vivo chromosome damage data set. An expert assessment was then made of selected alerts. Information regarding the findings from specific in vivo tests was added to the alert along with any significant correlations between activity and test protocol or mechanism. A total of 32 in vitro alerts were updated using this method resulting in a significant improvement in the coverage of in vivo chromosome damage in Derek Nexus against a data set compiled by the mammalian mutagenicity study group of Japan. The detailed information relating to in vivo activity and protocol added to the alerts in combination with the mechanistic information provided will prove useful in directing the further testing of compounds of interest.
authors.forename: Steven
authors.initials: S
authors.lastname: Canipa
authors.forename: Alex
authors.initials: A
authors.lastname: Cayley
authors.forename: William C
authors.initials: WC
authors.lastname: Drewe
authors.forename: Richard V
authors.initials: RV
authors.lastname: Williams
authors.affiliation: Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan, and.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hamada
authors.affiliation: Division of Risk Assessment, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hirose
authors.affiliation: Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan, and.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
authors.affiliation: Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan, and.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morita
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000187:drug effects; D003198:Computer Simulation; D004249:DNA Damage; D006801:Humans; D008322:Mammals / Q000235:genetics; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D012984:Software
chemical_list: D009153:Mutagens