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Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation / RYAN WHEELDON

Swansea University Author: RYAN WHEELDON

DOI (Published version): 10.23889/SUthesis.59193

Abstract

Genotoxic risk from exposure to pharmaceutical compounds has historically been focussed on dichotomous hazard characterisation, with little regulatory acceptance of risk assessment paradigms. The regulations focus on testing novel compounds with outdated genotoxicity test systems. Recent overwhelmin...

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Published: Swansea 2022
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Johnson, George E.
URI: https://cronfa.swan.ac.uk/Record/cronfa59193
first_indexed 2022-01-17T10:28:24Z
last_indexed 2022-01-18T04:28:45Z
id cronfa59193
recordtype RisThesis
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spelling 2022-01-17T11:52:27.9319609 v2 59193 2022-01-17 Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation cf05218cbb78b94d71e701a745645f7c RYAN WHEELDON RYAN WHEELDON true false 2022-01-17 Genotoxic risk from exposure to pharmaceutical compounds has historically been focussed on dichotomous hazard characterisation, with little regulatory acceptance of risk assessment paradigms. The regulations focus on testing novel compounds with outdated genotoxicity test systems. Recent overwhelming support of the Benchmark Dose (BMD) methodology provides the baseline for advanced exposure risk assessments. Novel flow cytometric in vitro DNA damage response assays (MultiFlow and ToxTracker) have been developed that provide quantitative dose-response information that can be used in a high-throughput screening environment. In the following work, BMD modelling is applied to the MultiFlow and ToxTracker biomarker dose-response datasets. This work demonstrates that the MultiFlow dose-response biomarker datasets are amenable to BMD analysis for a set of clastogens and aneugens, and that the biomarker dose-responses correlate with dose-responses from the gold-standard in vitro micronucleus assay. A detailed appraisal of BMD confidence intervals (CIs) is provided for a selection of 10 clastogens requiring metabolic activation (with S9), demonstrating the criticality of using BMD uncertainty measures in comparative potency analysis. A comparative potency algorithm is developed and utilised in machine learning to distinguish four S9-dependent groupings: high and low-level potentiation, no effect, and diminution. A deep dive case study is presented for MultiFlow and ToxTracker analysis of Topoisomerase II Poisons, where BMD CI potency ranks are shown to correlate broadly with compound structural information. The Adverse Outcome Pathway (AOP) for Topoisomerase-II Poisoning is developed upon, and the Lhasa Derek Nexus alerts are mapped to the AOP. A Quantitative Structural Activity Relationship model is developed using Topoisomerase-II Poison molecular descriptors and BMD measurements from MultiFlow and ToxTracker biomarkers that correspond to Key Events relative to the Topoisomerase-II Poison AOP. This thesis provides an all-encompassing report of in vitro DNA damage response biomarker BMD analysis for compound potency ranking and read across. E-Thesis Swansea Genotoxicity, DNA Damage, BMD Analysis, Potency, QSAR, AOP 17 1 2022 2022-01-17 10.23889/SUthesis.59193 A selection of third party content is redacted or is partially redacted from this thesis due to copyright restrictions.ORCiD identifier: https://orcid.org/0000-0002-4893-246X COLLEGE NANME COLLEGE CODE Swansea University Johnson, George E. Doctoral Ph.D Baxter Healthcare 2022-01-17T11:52:27.9319609 2022-01-17T10:24:26.5041780 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine RYAN WHEELDON 1 59193__22157__7e1a7e8d7a73458ca2da8089bd3170e9.pdf Wheeldon_Ryan_PhD_Thesis_Final_Redacted.pdf 2022-01-17T11:05:06.7447068 Output 43704403 application/pdf E-Thesis – open access true Copyright: The author, Ryan P. Wheeldon, 2022. true eng
title Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation
spellingShingle Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation
RYAN WHEELDON
title_short Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation
title_full Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation
title_fullStr Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation
title_full_unstemmed Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation
title_sort Application of Benchmark Dose Analysis to in vitro Genotoxicity Data for Compound Risk Characterisation
author_id_str_mv cf05218cbb78b94d71e701a745645f7c
author_id_fullname_str_mv cf05218cbb78b94d71e701a745645f7c_***_RYAN WHEELDON
author RYAN WHEELDON
author2 RYAN WHEELDON
format E-Thesis
publishDate 2022
institution Swansea University
doi_str_mv 10.23889/SUthesis.59193
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Genotoxic risk from exposure to pharmaceutical compounds has historically been focussed on dichotomous hazard characterisation, with little regulatory acceptance of risk assessment paradigms. The regulations focus on testing novel compounds with outdated genotoxicity test systems. Recent overwhelming support of the Benchmark Dose (BMD) methodology provides the baseline for advanced exposure risk assessments. Novel flow cytometric in vitro DNA damage response assays (MultiFlow and ToxTracker) have been developed that provide quantitative dose-response information that can be used in a high-throughput screening environment. In the following work, BMD modelling is applied to the MultiFlow and ToxTracker biomarker dose-response datasets. This work demonstrates that the MultiFlow dose-response biomarker datasets are amenable to BMD analysis for a set of clastogens and aneugens, and that the biomarker dose-responses correlate with dose-responses from the gold-standard in vitro micronucleus assay. A detailed appraisal of BMD confidence intervals (CIs) is provided for a selection of 10 clastogens requiring metabolic activation (with S9), demonstrating the criticality of using BMD uncertainty measures in comparative potency analysis. A comparative potency algorithm is developed and utilised in machine learning to distinguish four S9-dependent groupings: high and low-level potentiation, no effect, and diminution. A deep dive case study is presented for MultiFlow and ToxTracker analysis of Topoisomerase II Poisons, where BMD CI potency ranks are shown to correlate broadly with compound structural information. The Adverse Outcome Pathway (AOP) for Topoisomerase-II Poisoning is developed upon, and the Lhasa Derek Nexus alerts are mapped to the AOP. A Quantitative Structural Activity Relationship model is developed using Topoisomerase-II Poison molecular descriptors and BMD measurements from MultiFlow and ToxTracker biomarkers that correspond to Key Events relative to the Topoisomerase-II Poison AOP. This thesis provides an all-encompassing report of in vitro DNA damage response biomarker BMD analysis for compound potency ranking and read across.
published_date 2022-01-17T08:08:45Z
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