title: Strategies in case of positive in vivo results in genotoxicity testing.
abstract: At the 2009 International Workshop on Genotoxicity Testing in Basel, an expert group gathered to provide guidance on suitable follow-up tests to describe risk when basic in vivo genotoxicity tests have yielded positive results. The working group agreed that non-linear dose-response curves occur in vivo with at least some DNA-reactive agents. Quantitative risk assessment in such cases requires the use of (1) adequate data, i.e., the use of all available data for the selection of reliable in vivo models to be used for quantitative risk assessment, (2) appropriate mathematical models and statistical analysis for characterizing the dose-response relationships and allowing the use of quantitative and dose-response information in the interpretation of results, (3) mode of action (MOA) information for the evaluation and analysis of risk, and (4) reliable assessments of the internal dose across species for deriving acceptable margins of exposure and risk levels. Hence, the elucidation of MOA and understanding of the mechanism underlying the dose-response curve are important components of risk assessment. The group agreed on the need for (i) the development of in vivo assays, especially multi-endpoint, multi-species assays, with emphasis on those applicable to humans, and (ii) consensus about the most appropriate mathematical models and statistical analyses for defining non-linear dose-responses and exposure levels associated with acceptable risk.
authors.affiliation: Sanofi-Aventis, Disposition-Safety and Animal Research, Vitry sur Seine, France. Veronique.thybaud@sanofi-aventis.com
authors.forename: Véronique
authors.initials: V
authors.lastname: Thybaud
authors.forename: James T
authors.initials: JT
authors.lastname: Macgregor
authors.forename: Lutz
authors.initials: L
authors.lastname: Müller
authors.forename: Riccardo
authors.initials: R
authors.lastname: Crebelli
authors.forename: Kerry
authors.initials: K
authors.lastname: Dearfield
authors.forename: George
authors.initials: G
authors.lastname: Douglas
authors.forename: Peter B
authors.initials: PB
authors.lastname: Farmer
authors.forename: Elmar
authors.initials: E
authors.lastname: Gocke
authors.forename: Makoto
authors.initials: M
authors.lastname: Hayashi
authors.forename: David P
authors.initials: DP
authors.lastname: Lovell
authors.forename: Werner K
authors.initials: WK
authors.lastname: Lutz
authors.forename: Daniel
authors.initials: D
authors.lastname: Marzin
authors.forename: Martha
authors.initials: M
authors.lastname: Moore
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Jan
authors.initials: J
authors.lastname: Van Benthem
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008433:Mathematics; D008962:Models, Theoretical; D009152:Mutagenicity Tests / Q000379:methods*; D018570:Risk Assessment; D013223:Statistics as Topic