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A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens
Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biologic...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652818/ https://www.ncbi.nlm.nih.gov/pubmed/23675539 http://dx.doi.org/10.1371/journal.pone.0064532 |
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author | Hernández, Lya G. van Benthem, Jan Johnson, George E. |
author_facet | Hernández, Lya G. van Benthem, Jan Johnson, George E. |
author_sort | Hernández, Lya G. |
collection | PubMed |
description | Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E(2)). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E(2) and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment. |
format | Online Article Text |
id | pubmed-3652818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36528182013-05-14 A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens Hernández, Lya G. van Benthem, Jan Johnson, George E. PLoS One Research Article Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E(2)). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E(2) and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment. Public Library of Science 2013-05-13 /pmc/articles/PMC3652818/ /pubmed/23675539 http://dx.doi.org/10.1371/journal.pone.0064532 Text en © 2013 Hernández et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Hernández, Lya G. van Benthem, Jan Johnson, George E. A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens |
title | A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens |
title_full | A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens |
title_fullStr | A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens |
title_full_unstemmed | A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens |
title_short | A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens |
title_sort | mode-of-action approach for the identification of genotoxic carcinogens |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652818/ https://www.ncbi.nlm.nih.gov/pubmed/23675539 http://dx.doi.org/10.1371/journal.pone.0064532 |
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