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

Abstract

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.

Genotoxicity of Aluminum and Aluminum Oxide Nanomaterials in Rats Following Oral Exposure

“…The mean of the median tail intensity value of each slide was calculated for each animal, prior to the calculation of the mean value of each group. When DNA damage was too high to score, the cells were counted as hedgehogs [30,31].…”

Re: Gi et al. 2018, In vivo positive mutagenicity of 1,4-dioxane and quantitative analysis of its mutagenicity and carcinogenicity in rats, Archives of Toxicology 92:3207–3221

“…Thus, as already indicated above, it is critically important to (1) examine complete BMD confidence intervals (i.e., BMDL to BMDU), and (2) select a CES that is appropriate for the endpoint under consideration. With respect to the latter, recent analyses indicate that a CES of 10% is too low for the genetic toxicity endpoint examined; moreover, that a CES in the range of 40-50% is more appropriate for the interpretation of transgenic rodent mutagenicity dose-response data (Zeller et al 2017). Reanalysis of the Gi et al data with a CES of 50% yields BMDL and BMDU values of 23 and 2030 ppm for the exponential model, and 171 and 2490 ppm for the hill model; resultant BMDL to BMDU ratios for the exponential and hill models are 88.3 and 14.6, respectively.…”

Influencing factors and health risk assessment of microcystins in the Yongjiang river (China) by Monte Carlo simulation

“…Recent studies have gradually established superior methods, such as benchmark dose (BMD) and chemical-specific adjustment factor (CSAF), to address and reduce the uncertainty in the risk assessment ( Ibelings et al, 2015 ). The USEPA and Health Canada have gradually started utilizing the BMD and CSAF methods to develop the health guidance values ( Zeller, Duran-Pacheco & Guerard, 2017 ).…”