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dc.contributor.authorBoobis, Alan
dc.contributor.authorBrown, Paul
dc.contributor.authorCronin, Mark Timothy David
dc.contributor.authorEdwards, James
dc.contributor.authorGalli, Corrado Lodovico
dc.contributor.authorGoodman, Jay
dc.contributor.authorJacobs, Abigail
dc.contributor.authorKirkland, David
dc.contributor.authorLuijten, Mirjam
dc.contributor.authorMarsaux, Cyril
dc.contributor.authorMartin, Matthew
dc.contributor.authorYang, Chihae
dc.contributor.authorHollnagel, Heli Miriam
dc.date.accessioned2018-01-24T13:46:19Z
dc.date.accessioned2018-01-24T13:48:07Z
dc.date.available2018-01-24T13:46:19Z
dc.date.available2018-01-24T13:48:07Z
dc.date.issued2017-09
dc.identifier.citationOrigin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation. 2017, 47 (8):705-727 Crit. Rev. Toxicol.en
dc.identifier.issn1547-6898
dc.identifier.pmid28510487
dc.identifier.doi10.1080/10408444.2017.1318822
dc.identifier.urihttp://hdl.handle.net/10029/621247
dc.description.abstractThe threshold of toxicological concern (TTC) approach is a resource-effective de minimis method for the safety assessment of chemicals, based on distributional analysis of the results of a large number of toxicological studies. It is being increasingly used to screen and prioritize substances with low exposure for which there is little or no toxicological information. The first step in the approach is the identification of substances that may be DNA-reactive mutagens, to which the lowest TTC value is applied. This TTC value was based on the analysis of the cancer potency database and involved a number of assumptions that no longer reflect the state-of-the-science and some of which were not as transparent as they could have been. Hence, review and updating of the database is proposed, using inclusion and exclusion criteria reflecting current knowledge. A strategy for the selection of appropriate substances for TTC determination, based on consideration of weight of evidence for genotoxicity and carcinogenicity is outlined. Identification of substances that are carcinogenic by a DNA-reactive mutagenic mode of action and those that clearly act by a non-genotoxic mode of action will enable the protectiveness to be determined of both the TTC for DNA-reactive mutagenicity and that applied by default to substances that may be carcinogenic but are unlikely to be DNA-reactive mutagens (i.e. for Cramer class I-III compounds). Critical to the application of the TTC approach to substances that are likely to be DNA-reactive mutagens is the reliability of the software tools used to identify such compounds. Current methods for this task are reviewed and recommendations made for their application.
dc.language.isoenen
dc.rightsArchived with thanks to Critical reviews in toxicologyen
dc.subject.meshCarcinogens
dc.subject.meshDatabases, Chemical
dc.subject.meshHumans
dc.subject.meshMutagens
dc.subject.meshRisk Assessment
dc.subject.meshSoftware
dc.titleOrigin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation.en
dc.typeArticleen
dc.identifier.journalCrit Rev Toxicol 2017; 47(8):705-27en
html.description.abstractThe threshold of toxicological concern (TTC) approach is a resource-effective de minimis method for the safety assessment of chemicals, based on distributional analysis of the results of a large number of toxicological studies. It is being increasingly used to screen and prioritize substances with low exposure for which there is little or no toxicological information. The first step in the approach is the identification of substances that may be DNA-reactive mutagens, to which the lowest TTC value is applied. This TTC value was based on the analysis of the cancer potency database and involved a number of assumptions that no longer reflect the state-of-the-science and some of which were not as transparent as they could have been. Hence, review and updating of the database is proposed, using inclusion and exclusion criteria reflecting current knowledge. A strategy for the selection of appropriate substances for TTC determination, based on consideration of weight of evidence for genotoxicity and carcinogenicity is outlined. Identification of substances that are carcinogenic by a DNA-reactive mutagenic mode of action and those that clearly act by a non-genotoxic mode of action will enable the protectiveness to be determined of both the TTC for DNA-reactive mutagenicity and that applied by default to substances that may be carcinogenic but are unlikely to be DNA-reactive mutagens (i.e. for Cramer class I-III compounds). Critical to the application of the TTC approach to substances that are likely to be DNA-reactive mutagens is the reliability of the software tools used to identify such compounds. Current methods for this task are reviewed and recommendations made for their application.


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