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Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their revaluation

Boobis, AR and Brown, P and Cronin, MTD and Edwards, J and Galli, CL and Goodman, J and Jacobs, A and Kirkland, D and Luijten, M and Marsaux, CFM and Martin, M and Yang, C and Hollnagel, HM (2017) Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their revaluation. Critical Reviews in Toxicology. ISSN 1547-6898

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Abstract

The threshold of toxicological concern (TTC) approach is a resource-effective de minimismethod 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 prioritise 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 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 mutagenicmode 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 mutagenicityand 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.

Item Type: Article
Additional Information: This is an Accepted Manuscript of an article published by Taylor & Francis in Critical Reviews in Toxicology on 16th May 2017, available online: http://www.tandfonline.com/10.1080/10408444.2017.1318822
Uncontrolled Keywords: 1115 Pharmacology And Pharmaceutical Sciences
Subjects: R Medicine > RA Public aspects of medicine > RA1190 Toxicology. Poisions
R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Taylor & Francis
Date Deposited: 13 Apr 2017 09:15
Last Modified: 07 Sep 2017 12:36
DOI or Identification number: 10.1080/10408444.2017.1318822
URI: http://researchonline.ljmu.ac.uk/id/eprint/6250

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