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Title: Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds

Abstract

Genetic toxicology data have traditionally been utilized for hazard identification to provide a binary call for a compound's risk. Recent advances in the scientific field, especially with the development of high‐throughput methods to quantify DNA damage, have influenced a change of approach in genotoxicity assessment. The in vitro MultiFlow® DNA Damage Assay is one such method which multiplexes γH2AX, p53, phospho‐histone H3 biomarkers into a single‐flow cytometric analysis (Bryce et al., [2016]: Environ Mol Mutagen 57:546–558). This assay was used to study human TK6 cells exposed to each of eight topoisomerase II poisons for 4 and 24 hr. Using PROAST v65.5, the Benchmark Dose approach was applied to the resulting flow cytometric datasets. With “compound” serving as covariate, all eight compounds were combined into a single analysis, per time point and endpoint. The resulting 90% confidence intervals, plotted in Log scale, were considered as the potency rank for the eight compounds. The in vitro MultiFlow data showed a maximum confidence interval span of 1Log, which indicates data of good quality. Patterns observed in the compound potency rank were scrutinized by using the expert rule‐based software program Derek Nexus, developed by Lhasa Limited. Compound sub‐classification and structural alerts were considered contributory tomore » the potencies observed for the topoisomerase II poisons studied herein. The Topo II poison Adverse Outcome Pathway was evaluated with MultiFlow endpoints serving as Key Events. The step‐wise approach described herein can be considered as a foundation for risk assessment of compounds within a specific mode of action of interest. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc.« less

Authors:
ORCiD logo [1];  [2];  [2];  [2];  [2]; ORCiD logo [1]
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  1. Institute of Life Science, Swansea University Medical School, Swansea University Wales United Kingdom
  2. Litron Laboratories Rochester New York
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1598725
Resource Type:
Publisher's Accepted Manuscript
Journal Name:
Environmental and Molecular Mutagenesis
Additional Journal Information:
Journal Name: Environmental and Molecular Mutagenesis Journal Volume: 61 Journal Issue: 4; Journal ID: ISSN 0893-6692
Publisher:
Wiley Blackwell (John Wiley & Sons)
Country of Publication:
United States
Language:
English

Citation Formats

Wheeldon, Ryan P., Bernacki, Derek T., Dertinger, Stephen D., Bryce, Steven M., Bemis, Jeffrey C., and Johnson, George E. Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds. United States: N. p., 2020. Web. doi:10.1002/em.22360.
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Wheeldon, Ryan P., Bernacki, Derek T., Dertinger, Stephen D., Bryce, Steven M., Bemis, Jeffrey C., & Johnson, George E. Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds. United States. https://doi.org/10.1002/em.22360
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Wheeldon, Ryan P., Bernacki, Derek T., Dertinger, Stephen D., Bryce, Steven M., Bemis, Jeffrey C., and Johnson, George E. Mon . "Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds". United States. https://doi.org/10.1002/em.22360.
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@article{osti_1598725,
title = {Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds},
author = {Wheeldon, Ryan P. and Bernacki, Derek T. and Dertinger, Stephen D. and Bryce, Steven M. and Bemis, Jeffrey C. and Johnson, George E.},
abstractNote = {Genetic toxicology data have traditionally been utilized for hazard identification to provide a binary call for a compound's risk. Recent advances in the scientific field, especially with the development of high‐throughput methods to quantify DNA damage, have influenced a change of approach in genotoxicity assessment. The in vitro MultiFlow® DNA Damage Assay is one such method which multiplexes γH2AX, p53, phospho‐histone H3 biomarkers into a single‐flow cytometric analysis (Bryce et al., [2016]: Environ Mol Mutagen 57:546–558). This assay was used to study human TK6 cells exposed to each of eight topoisomerase II poisons for 4 and 24 hr. Using PROAST v65.5, the Benchmark Dose approach was applied to the resulting flow cytometric datasets. With “compound” serving as covariate, all eight compounds were combined into a single analysis, per time point and endpoint. The resulting 90% confidence intervals, plotted in Log scale, were considered as the potency rank for the eight compounds. The in vitro MultiFlow data showed a maximum confidence interval span of 1Log, which indicates data of good quality. Patterns observed in the compound potency rank were scrutinized by using the expert rule‐based software program Derek Nexus, developed by Lhasa Limited. Compound sub‐classification and structural alerts were considered contributory to the potencies observed for the topoisomerase II poisons studied herein. The Topo II poison Adverse Outcome Pathway was evaluated with MultiFlow endpoints serving as Key Events. The step‐wise approach described herein can be considered as a foundation for risk assessment of compounds within a specific mode of action of interest. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc.},
doi = {10.1002/em.22360},
journal = {Environmental and Molecular Mutagenesis},
number = 4,
volume = 61,
place = {United States},
year = {Mon Feb 10 00:00:00 EST 2020},
month = {Mon Feb 10 00:00:00 EST 2020}
}
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https://doi.org/10.1002/em.22360
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