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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 Orcid Logo, Paul Rees Orcid Logo, George Johnson Orcid Logo

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

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

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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
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URI: https://cronfa.swan.ac.uk/Record/cronfa57940
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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 &#x2018;standard battery&#x2019; 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&#x2013;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&#x2013;in vivo correlation, albeit with marked scatter across compounds. No evidence for distinct differences in the sensitivity of the three ToxTracker endpoints was found. 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spelling 2021-10-18T13:20:42.3129331 v2 57940 2021-09-17 Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay 9f113236244f4f54d584f1fb3278061b John Wills John Wills true false a61c15e220837ebfa52648c143769427 0000-0002-0898-5612 Huw Summers Huw Summers true false 537a2fe031a796a3bde99679ee8c24f5 0000-0002-7715-6914 Paul Rees Paul Rees true false 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2021-09-17 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. Journal Article Mutagenesis 36 4 311 320 Oxford University Press (OUP) 0267-8357 1464-3804 7 8 2021 2021-08-07 10.1093/mutage/geab020 COLLEGE NANME COLLEGE CODE Swansea University SU Library paid the OA fee (TA Institutional Deal) UK Engineering and Physical Sciences Research Council; UK Biotechnology and Biological Sciences Research Council EP/N013506/1; BB/P026818/1 2021-10-18T13:20:42.3129331 2021-09-17T14:47:34.0540676 Faculty of Science and Engineering School of Engineering and Applied Sciences - Uncategorised John Wills 1 Elias Halkes-Wellstead 2 Huw Summers 0000-0002-0898-5612 3 Paul Rees 0000-0002-7715-6914 4 George Johnson 0000-0001-5643-9942 5 57940__21010__7b2a246ede004b0bb311e8a667ac04f4.pdf 57940.pdf 2021-09-27T10:46:20.6049015 Output 1686853 application/pdf Version of Record true © The Author(s) 2021. This is an Open Access article distributed under the terms of the Creative Commons Attribution License true eng https://creativecommons.org/licenses/by/4.0/
title Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay
spellingShingle Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay
John Wills
Huw Summers
Paul Rees
George Johnson
title_short Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay
title_full Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay
title_fullStr Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay
title_full_unstemmed Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay
title_sort Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay
author_id_str_mv 9f113236244f4f54d584f1fb3278061b
a61c15e220837ebfa52648c143769427
537a2fe031a796a3bde99679ee8c24f5
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author_id_fullname_str_mv 9f113236244f4f54d584f1fb3278061b_***_John Wills
a61c15e220837ebfa52648c143769427_***_Huw Summers
537a2fe031a796a3bde99679ee8c24f5_***_Paul Rees
37d0f121db69fd09f364df89e4405e31_***_George Johnson
author John Wills
Huw Summers
Paul Rees
George Johnson
author2 John Wills
Elias Halkes-Wellstead
Huw Summers
Paul Rees
George Johnson
format Journal article
container_title Mutagenesis
container_volume 36
container_issue 4
container_start_page 311
publishDate 2021
institution Swansea University
issn 0267-8357
1464-3804
doi_str_mv 10.1093/mutage/geab020
publisher Oxford University Press (OUP)
college_str Faculty of Science and Engineering
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hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Uncategorised{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Uncategorised
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description 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.
published_date 2021-08-07T04:14:03Z
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