Abstract
The Benchmark Dose (BMD) method is the favored approach for quantitative dose-response analysis where uncertainty measurements are delineated between the upper (BMDU) and lower (BMDL) confidence bounds, or confidence intervals (CIs). Little has been published on the accurate interpretation of uncertainty measurements for potency comparative analyses between different test conditions. We highlight this by revisiting a previously published comparative in vitro genotoxicity dataset for human lymphoblastoid TK6 cells that were exposed to each of 10 clastogens in the presence and absence (+/-) of low concentration (0.25%) S9, and scored for p53, γH2AX and Relative Nuclei Count (RNC) responses at two timepoints (Tian et al., 2020). The researchers utilized BMD point estimates in potency comparative analysis between S9 treatment conditions. Here we highlight a shortcoming that the use of BMD point estimates can mischaracterize potency differences between systems. We reanalyzed the dose responses by BMD modeling using PROAST v69.1. We used the resulting BMDL and BMDU metrics to calculate "S9 potency ratio confidence intervals" that compare the relative potency of compounds +/- S9 as more statistically robust metrics for comparative potency measurements compared to BMD point estimate ratios. We performed unsupervised hierarchical clustering that identified four S9-dependent groupings: high and low-level potentiation, no effect, and diminution. This work demonstrates the importance of using BMD uncertainty measurements in potency comparative analyses between test conditions. Irrespective of the source of the data, we propose a stepwise approach when performing BMD modeling in comparative potency analyses between test conditions.
Highlights
An appreciation of dose–response analysis of genotoxicity data has accompanied a shift from a hazard identification testing approach, toward quantitative assessment of genotoxicity for risk assessment purposes (Macgregor et al, 2015; Dearfield et al, 2017)
The benchmark dose (BMD) point estimates and associated “S9 potentiation ratio” comparison metrics did not convey information about the uncertainty of the measurements that are consistent with the BMD uncertainty measurement approach that is advocated in the scientific literature
The BMD point estimates are included in the comparative potency plots to aid in graphical representation of the BMD point estimate relative to the corresponding BMDL and BMDU
Summary
An appreciation of dose–response analysis of genotoxicity data has accompanied a shift from a hazard identification testing approach, toward quantitative assessment of genotoxicity for risk assessment purposes (Macgregor et al, 2015; Dearfield et al, 2017). We stress that the use of a BMD point estimate value does not provide an accurate representation of the likely potency range of the test compound Said another way, the BMD point estimates and associated “S9 potentiation ratio” comparison metrics did not convey information about the uncertainty of the measurements that are consistent with the BMD uncertainty measurement approach that is advocated in the scientific literature. The BMD point estimates and associated “S9 potentiation ratio” comparison metrics did not convey information about the uncertainty of the measurements that are consistent with the BMD uncertainty measurement approach that is advocated in the scientific literature This current report focuses on reanalysis and augmentation of the previously published Tian et al (2020) dataset. Readers are encouraged to refer to the original Tian and colleagues' article for further context (Tian et al, 2020)
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