An appraisal of critical effect sizes for the benchmark dose approach to assess dose-response relationships in genetic toxicology.

The benchmark dose (BMD) concept is increasingly utilized to analyze quantitative dose-response relationships in genetic toxicology. This methodology requires the user (i.e. the toxicologist) to a priori define a small increase over controls that is "acceptable" to be induced by a genotoxic test substance. The increase is called benchmark response (BMR) or critical effect size (CES), depending on the software used. To render the metrics calculated from the data of animals treated with the test substance applicable for risk assessment, the BMR or CES must represent biologically relevant changes of parameters measured in in vivo genotoxicity assays such as the Micronucleus, Comet, Transgenic rodent or Pig-a assay. Current recommendations for CES in genotoxicology are arbitrary (10% increase over mean vehicle controls) or based on limited, usually 5-6, data points (i.e. the standard deviation of the concurrent vehicle control group). We have, therefore, analyzed historical vehicle control data of standard in vivo genotoxicity test systems with statistical methods. Based on this evaluation, we illustrate limitations of the currently recommended CES values and propose a pragmatic approach that may contribute to better defining endpoint-specific CES values for BMD software like PROAST.