A proposal for a novel rationale for critical effect size in dose–response analysis based on a multi-endpointin vivostudy 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.

Predictions of genotoxic potential, mode of action, molecular targets, and potency via a tiered multiflow® assay data analysis strategy

“…Traditionally, the BMD approach is utilized to estimate a Point of Departure (PoD) value from in vivo studies and thereby derive compound‐specific reference values in human health safety assessment; in these cases, the choice of BMR value should be justified. There is much debate over the appropriate BMR value to be selected, with several expert groups suggesting that an endpoint‐specific effect size approach is necessary (Slob ; Zeller et al , ). Briefly, a “one‐size‐fits‐all” BMR in the range of 1–10% is suggested to be inappropriate to apply to all endpoints.…”

Measuring reproducibility of dose response data for the Pig-a assay using covariate benchmark dose analysis

“…Supplementary Figure 5 also shows the analyses carried out without data from Zeller et al, (2016), in which the BMDL 10 -BMDU 10 are wider and less precise which leads to more overlap between laboratories. Figs.…”

“…As presented in Wills et al 2016, historical dose-responses for the same endpoint but with a different chemical can be used to increase precision of the BMD estimate [7]. An extensive Pig-a MF data set containing 6 dose levels of alkylating agent methyl methanesulfonate [17] was therefore used to improve the BMD analysis in which 2 dose groups were tested for ENU. This approach allows any differences in BMDL-BMDU to be more clearly observed, by reducing the width of these BMD confidence intervals, as observed in Figures 1 and 2, which include the Zeller et al (2016) data, compared to Supplementary Figure 5 which does not.…”

“…Pig-a MF dose response data following exposure to ENU from the different laboratories was analysed using the BMD covariate approach, using BMRs of (a) 10% and (b) 100%. One MMS dose response data set from Zeller et al 2016 [17] was used to increase the precision of the BMD estimates [7]. The 4 parameter exponential (top horizontal line) and Hill (bottom horizontal line) models provided a suitable fit to the data, with 'laboratory' used as covariate.…”

Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds

“…For continuous dose–response data, the CES is described as the quantitative change in response considered as non‐adverse or acceptable at the level of the individual organism (Slob, ). Methods for selecting the appropriate CES specific to the endpoint being studied have been evaluated in the literature (Zeller et al, , ; Slob, ); however, a lengthy discussion is beyond the scope of this report. The interested reader is directed to publications by Bemis et al (2016) and Dertinger et al (), which discuss the implications of choosing different CES.…”