Correlation of In Vivo Versus In Vitro Benchmark Doses (BMDs) Derived From Micronucleus Test Data: A Proof of Concept Study.

Lya G Soeteman-Hernández,Mick D Fellows,Wout Slob,George E Johnson

doi:10.1093/toxsci/kfv189

Abstract

In this study, we explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information. Nineteen chemicals covering a broad spectrum of genotoxic modes of action were tested in an in vitro MN test using TK6 cells using the same study protocol. Several of these chemicals were considered to need metabolic activation, and these were administered in the presence of S9. The Benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST to estimate the genotoxic potency from the in vitro data. The resulting in vitro BMDs were compared with previously derived BMDs from in vivo MN and carcinogenicity studies. A proportional correlation was observed between the BMDs from the in vitro MN and the BMDs from the in vivo MN assays. Further, a clear correlation was found between the BMDs from in vitro MN and the associated BMDs for malignant tumors. Although these results are based on only 19 compounds, they show that genotoxicity potencies estimated from in vitro tests may result in useful information regarding in vivo genotoxic potency, as well as expected cancer potency. Extension of the number of compounds and further investigation of metabolic activation (S9) and of other toxicokinetic factors would be needed to validate our initial conclusions. However, this initial work suggests that this approach could be used for in vitro to in vivo extrapolations which would support the reduction of animals used in research (3Rs: replacement, reduction, and refinement).

Highlights

We explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information
These results are based on only 19 compounds, they show that genotoxicity potencies estimated from in vitro tests may result in useful information regarding in vivo genotoxic potency, as well as expected cancer potency
Short-term genotoxicity tests are generally utilized in cancer risk assessment in a qualitative manner for hazard identification, but here we explored their applicability for quantitative analysis and prediction of cancer potency

Summary

Introduction

Short-term genotoxicity tests are generally utilized in cancer risk assessment in a qualitative manner for hazard identification, but here we explored their applicability for quantitative analysis and prediction of cancer potency. Several efforts are exploring the possibility of quantitatively using data from genetic toxicology studies for use in human health risk assessment (Gollapudi et al, 2013; Hernandez et al, 2011, 2012; Johnson et al, 2014a,b; MacGregor et al, 2014a,b; Soeteman-Hernandez et al, 2015) These studies showed that in vivo genotoxicity studies provide more information than just the presence or absence of genotoxic potential for a given compound. If BMDs from in vitro genotoxicity tests could provide information on the carcinogenic potency of compounds, this might be highly useful in improving test strategies and in supporting the reduction of animals used in research (3Rs: replacement, reduction, and refinement)

Methods

Results

Conclusion