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Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay / John Wills, Elias Halkes-Wellstead, Huw Summers, Paul Rees, George Johnson

Mutagenesis, Volume: 36, Issue: 4, Pages: 311 - 320

Swansea University Authors: John Wills, Huw Summers, Paul Rees, George Johnson

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DOI (Published version): 10.1093/mutage/geab020

Abstract

Genetic toxicology is an essential component of compound safety assessment. In the face of a barrage of new compounds, higher throughput, less ethically divisive in vitro approaches capable of effective, human-relevant hazard identification and prioritisation are increasingly important. One such app...

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Published in: Mutagenesis
ISSN: 0267-8357 1464-3804
Published: Oxford University Press (OUP) 2021
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa57940
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Abstract: Genetic toxicology is an essential component of compound safety assessment. In the face of a barrage of new compounds, higher throughput, less ethically divisive in vitro approaches capable of effective, human-relevant hazard identification and prioritisation are increasingly important. One such approach is the ToxTracker assay, which utilises murine stem cell lines equipped with green fluorescent protein (GFP)-reporter gene constructs that each inform on distinct aspects of cellular perturbation. Encouragingly, ToxTracker has shown improved sensitivity and specificity for the detection of known in vivo genotoxicants when compared to existing ‘standard battery’ in vitro tests. At the current time however, quantitative genotoxic potency correlations between ToxTracker and well-recognised in vivo tests are not yet available. Here we use dose–response data from the three DNA-damage-focused ToxTracker endpoints and from the in vivo micronucleus assay to carry out quantitative, genotoxic potency estimations for a range of aromatic amine and alkylating agents using the benchmark dose (BMD) approach. This strategy, using both the exponential and the Hill BMD model families, was found to produce robust, visually intuitive and similarly ordered genotoxic potency rankings for 17 compounds across the BSCL2-GFP, RTKN-GFP and BTG2-GFP ToxTracker endpoints. Eleven compounds were similarly assessed using data from the in vivo micronucleus assay. Cross-systems genotoxic potency correlations for the eight matched compounds demonstrated in vitro–in vivo correlation, albeit with marked scatter across compounds. No evidence for distinct differences in the sensitivity of the three ToxTracker endpoints was found. The presented analyses show that quantitative potency determinations from in vitro data enable more than just qualitative screening and hazard identification in genetic toxicology.
College: College of Engineering
Funders: UK Engineering and Physical Sciences Research Council; UK Biotechnology and Biological Sciences Research Council
Issue: 4
Start Page: 311
End Page: 320