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dc.contributor.authorWills, John W
dc.contributor.authorJohnson, George E
dc.contributor.authorBattaion, Hannah L
dc.contributor.authorSlob, Wout
dc.contributor.authorWhite, Paul A
dc.date.accessioned2018-03-08T12:47:19Z
dc.date.available2018-03-08T12:47:19Z
dc.date.issued2017
dc.identifier.citationComparing BMD-derived genotoxic potency estimations across variants of the transgenic rodent gene mutation assay. 2017, 58 (9):632-643 Environ. Mol. Mutagen.en
dc.identifier.issn1098-2280
dc.identifier.pmid28945287
dc.identifier.doi10.1002/em.22137
dc.identifier.urihttp://hdl.handle.net/10029/621571
dc.description.abstractThere is growing interest in quantitative analysis of in vivo genetic toxicity dose-response data, and use of point-of-departure (PoD) metrics such as the benchmark dose (BMD) for human health risk assessment (HHRA). Currently, multiple transgenic rodent (TGR) assay variants, employing different rodent strains and reporter transgenes, are used for the assessment of chemically-induced genotoxic effects in vivo. However, regulatory issues arise when different PoD values (e.g., lower BMD confidence intervals or BMDLs) are obtained for the same compound across different TGR assay variants. This study therefore employed the BMD approach to examine the ability of different TGR variants to yield comparable genotoxic potency estimates. Review of over 2000 dose-response datasets identified suitably-matched dose-response data for three compounds (ethyl methanesulfonate or EMS, N-ethyl-N-nitrosourea or ENU, and dimethylnitrosamine or DMN) across four commonly-used murine TGR variants (Muta™Mouse lacZ, Muta™Mouse cII, gpt delta and BigBlue® lacI). Dose-response analyses provided no conclusive evidence that TGR variant choice significantly influences the derived genotoxic potency estimate. This conclusion was reliant upon taking into account the importance of comparing BMD confidence intervals as opposed to directly comparing PoD values (e.g., comparing BMDLs). Comparisons with earlier works suggested that with respect to potency determination, tissue choice is potentially more important than choice of TGR assay variant. Scoring multiple tissues selected on the basis of supporting toxicokinetic information is therefore recommended. Finally, we used typical within-group variances to estimate preliminary endpoint-specific benchmark response (BMR) values across several TGR variants/tissues. We discuss why such values are required for routine use of genetic toxicity PoDs for HHRA. Environ. Mol. Mutagen. 58:632-643, 2017. © 2017 Her Majesty the Queen in Right of Canada. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.
dc.language.isoenen
dc.rightsArchived with thanks to Environmental and molecular mutagenesisen
dc.subject.meshAnimals
dc.subject.meshAnimals, Genetically Modified
dc.subject.meshBenchmarking
dc.subject.meshDNA Damage
dc.subject.meshDimethylnitrosamine
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshEthyl Methanesulfonate
dc.subject.meshEthylnitrosourea
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshMutagenicity Tests
dc.subject.meshMutation
dc.subject.meshRisk Assessment
dc.subject.meshRodentia
dc.subject.meshTransgenes
dc.titleComparing BMD-derived genotoxic potency estimations across variants of the transgenic rodent gene mutation assay.en
dc.typeArticleen
dc.identifier.journalEnviron Mol Mutagen 2017; 58(9):632-43en
html.description.abstractThere is growing interest in quantitative analysis of in vivo genetic toxicity dose-response data, and use of point-of-departure (PoD) metrics such as the benchmark dose (BMD) for human health risk assessment (HHRA). Currently, multiple transgenic rodent (TGR) assay variants, employing different rodent strains and reporter transgenes, are used for the assessment of chemically-induced genotoxic effects in vivo. However, regulatory issues arise when different PoD values (e.g., lower BMD confidence intervals or BMDLs) are obtained for the same compound across different TGR assay variants. This study therefore employed the BMD approach to examine the ability of different TGR variants to yield comparable genotoxic potency estimates. Review of over 2000 dose-response datasets identified suitably-matched dose-response data for three compounds (ethyl methanesulfonate or EMS, N-ethyl-N-nitrosourea or ENU, and dimethylnitrosamine or DMN) across four commonly-used murine TGR variants (Muta™Mouse lacZ, Muta™Mouse cII, gpt delta and BigBlue® lacI). Dose-response analyses provided no conclusive evidence that TGR variant choice significantly influences the derived genotoxic potency estimate. This conclusion was reliant upon taking into account the importance of comparing BMD confidence intervals as opposed to directly comparing PoD values (e.g., comparing BMDLs). Comparisons with earlier works suggested that with respect to potency determination, tissue choice is potentially more important than choice of TGR assay variant. Scoring multiple tissues selected on the basis of supporting toxicokinetic information is therefore recommended. Finally, we used typical within-group variances to estimate preliminary endpoint-specific benchmark response (BMR) values across several TGR variants/tissues. We discuss why such values are required for routine use of genetic toxicity PoDs for HHRA. Environ. Mol. Mutagen. 58:632-643, 2017. © 2017 Her Majesty the Queen in Right of Canada. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.


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