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A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells

Julie Sanders Orcid Logo, Roel Anthonissen, George Johnson Orcid Logo, Tamara Vanhaecke Orcid Logo, Birgit Mertens Orcid Logo

Archives of Toxicology

Swansea University Author: George Johnson Orcid Logo

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DOI (Published version): 10.1007/s00204-025-03971-y

Abstract

Chemical risk assessment has historically focused on single compounds, neglecting the implications of combined exposures. To bridge this gap, several methodologies, such as concentration addition (CA) and independent action (IA), have been developed. However, a systematic, consistent, and integrated...

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Published in: Archives of Toxicology
ISSN: 0340-5761 1432-0738
Published: Springer Science and Business Media LLC 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa68888
first_indexed 2025-02-13T22:02:15Z
last_indexed 2025-03-26T05:31:05Z
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spelling 2025-03-25T16:26:08.2842460 v2 68888 2025-02-13 A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2025-02-13 MEDS Chemical risk assessment has historically focused on single compounds, neglecting the implications of combined exposures. To bridge this gap, several methodologies, such as concentration addition (CA) and independent action (IA), have been developed. However, a systematic, consistent, and integrated approach across various legislative frameworks is still lacking. The assessment of combined effects of genotoxicants is even more challenging, as genotoxicity data are typically evaluated qualitatively, without considering the effect size. This study aimed to develop a quantitative approach for evaluating the combined effects of genotoxic compounds with both similar and dissimilar modes of action (MoA), based on the benchmark concentration (BMC) principle. A proof-of-concept study was conducted using the in vitro micronucleus (MNvit) test to examine two types of binary mixtures: ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS), which share similar MoA, and MMS and etoposide (ETP), which have dissimilar MoA. The methodology involved collecting data for individual compounds, calculating BMC values, composing mixtures with different ratios and inducing various effect levels, testing these mixtures, and comparing the experimental results with the modelled data to verify additivity. The findings indicated that for both mixtures, the experimental responses aligned with the predicted additive effects, supporting the validity of the additivity principle. This study highlights the potential of an optimized BMC-based approach as a robust framework for testing chemical mixtures. It should be adopted in future studies to evaluate a wider range of genotoxic compounds, offering a more comprehensive and quantitative strategy for assessing combined chemical exposures. Journal Article Archives of Toxicology 0 Springer Science and Business Media LLC 0340-5761 1432-0738 In vitro micronucleus test; Mixtures; Genotoxicity; Benchmark dose approach; Principle of additivity 13 2 2025 2025-02-13 10.1007/s00204-025-03971-y COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This study was funded by internal budget of Sciensano. 2025-03-25T16:26:08.2842460 2025-02-13T18:40:00.6206778 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Julie Sanders 0000-0003-0276-2984 1 Roel Anthonissen 2 George Johnson 0000-0001-5643-9942 3 Tamara Vanhaecke 0000-0002-6685-7299 4 Birgit Mertens 0000-0001-8298-9104 5 68888__33884__963a428e2560405f983eca56c0d6b687.pdf 68888.VoR.pdf 2025-03-25T16:24:16.1069504 Output 960255 application/pdf Version of Record true © The Author(s) 2025. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells
spellingShingle A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells
George Johnson
title_short A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells
title_full A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells
title_fullStr A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells
title_full_unstemmed A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells
title_sort A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells
author_id_str_mv 37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv 37d0f121db69fd09f364df89e4405e31_***_George Johnson
author George Johnson
author2 Julie Sanders
Roel Anthonissen
George Johnson
Tamara Vanhaecke
Birgit Mertens
format Journal article
container_title Archives of Toxicology
container_volume 0
publishDate 2025
institution Swansea University
issn 0340-5761
1432-0738
doi_str_mv 10.1007/s00204-025-03971-y
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description Chemical risk assessment has historically focused on single compounds, neglecting the implications of combined exposures. To bridge this gap, several methodologies, such as concentration addition (CA) and independent action (IA), have been developed. However, a systematic, consistent, and integrated approach across various legislative frameworks is still lacking. The assessment of combined effects of genotoxicants is even more challenging, as genotoxicity data are typically evaluated qualitatively, without considering the effect size. This study aimed to develop a quantitative approach for evaluating the combined effects of genotoxic compounds with both similar and dissimilar modes of action (MoA), based on the benchmark concentration (BMC) principle. A proof-of-concept study was conducted using the in vitro micronucleus (MNvit) test to examine two types of binary mixtures: ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS), which share similar MoA, and MMS and etoposide (ETP), which have dissimilar MoA. The methodology involved collecting data for individual compounds, calculating BMC values, composing mixtures with different ratios and inducing various effect levels, testing these mixtures, and comparing the experimental results with the modelled data to verify additivity. The findings indicated that for both mixtures, the experimental responses aligned with the predicted additive effects, supporting the validity of the additivity principle. This study highlights the potential of an optimized BMC-based approach as a robust framework for testing chemical mixtures. It should be adopted in future studies to evaluate a wider range of genotoxic compounds, offering a more comprehensive and quantitative strategy for assessing combined chemical exposures.
published_date 2025-02-13T05:30:15Z
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