title: A proposal for a novel rationale for critical effect size in dose-response analysis based on a multi-endpoint in vivo study with methyl methanesulfonate.
abstract: Methyl methanesulfonate, a well-known direct-acting genotoxicant, was assessed in a multi-endpoint study in rats using six closely spaced dose levels. The main goal of the study was to investigate the genotoxic response at very low doses and to analyse this response with dedicated statistical tools in order to find a Point of Departure (PoD) and related metrics. Software packages like PROAST or EPA-BMDS require the toxicologist to define a so-called critical effect size (CES) or benchmark response (BMR) and this choice has a large impact on the result of the PoD calculation. Currently, increases of 5%, 10% or 1 standard deviation over concurrent vehicle controls have been proposed for CES/BMR, values that may or may not be suited for all genotoxicity endpoints. Based on the data obtained in this study, we propose an endpoint specific CES approach that reflects the typical evaluation process of a regulatory acceptable genotoxicology study. However, we are aware that this ratio-based CES strategy will need to be more fully developed with additional experimentation and should be mainly seen as a starting point for scientific discussion.
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland and andreas.zeller@roche.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zeller
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland and Present address: Qiagen Instruments, CH-8634 Hombrechtikon, Switzerland.
authors.forename: Leilei
authors.initials: L
authors.lastname: Tang
authors.affiliation: Litron Laboratories, Rochester, NY, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Dertinger
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland and.
authors.forename: Juergen
authors.initials: J
authors.lastname: Funk
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland and.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Duran-Pacheco
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland and.
authors.forename: Melanie
authors.initials: M
authors.lastname: Guérard
mesh_terms: D000818:Animals; D004247:DNA / Q000187:drug effects; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D008297:Male; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012107:Research Design; D018401:Sample Size
chemical_list: D018736:DNA Adducts; D009153:Mutagens; D004247:DNA; D008741:Methyl Methanesulfonate