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A comparison of transgenic rodent mutation and in vivo comet assay responses for 91 chemicals.

Kirkland, D; Levy, DD; LeBaron, MJ; Aardema, MJ; Beevers, C; Bhalli, J; Douglas, GR; Escobar, PA; Farabaugh, CS; Guerard, M; et al. Kirkland, D; Levy, DD; LeBaron, MJ; Aardema, MJ; Beevers, C; Bhalli, J; Douglas, GR; Escobar, PA; Farabaugh, CS; Guerard, M; Johnson, GE; Kulkarni, R; Le Curieux, F; Long, AS; Lott, J; Lovell, DP; Luijten, M; Marchetti, F; Nicolette, JJ; Pfuhler, S; Roberts, DJ; Stankowski, LF; Thybaud, V; Weiner, SK; Williams, A; Witt, KL; Young, R (2019) A comparison of transgenic rodent mutation and in vivo comet assay responses for 91 chemicals. Mutat Res, 839. pp. 21-35. ISSN 1873-135X https://doi.org/10.1016/j.mrgentox.2019.01.007
SGUL Authors: Lovell, David

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Abstract

A database of 91 chemicals with published data from both transgenic rodent mutation (TGR) and rodent comet assays has been compiled. The objective was to compare the sensitivity of the two assays for detecting genotoxicity. Critical aspects of study design and results were tabulated for each dataset. There were fewer datasets from rats than mice, particularly for the TGR assay, and therefore, results from both species were combined for further analysis. TGR and comet responses were compared in liver and bone marrow (the most commonly studied tissues), and in stomach and colon evaluated either separately or in combination with other GI tract segments. Overall positive, negative, or equivocal test results were assessed for each chemical across the tissues examined in the TGR and comet assays using two approaches: 1) overall calls based on weight of evidence (WoE) and expert judgement, and 2) curation of the data based on a priori acceptability criteria prior to deriving final tissue specific calls. Since the database contains a high prevalence of positive results, overall agreement between the assays was determined using statistics adjusted for prevalence (using AC1 and PABAK). These coefficients showed fair or moderate to good agreement for liver and the GI tract (predominantly stomach and colon data) using WoE, reduced agreement for stomach and colon evaluated separately using data curation, and poor or no agreement for bone marrow using both the WoE and data curation approaches. Confidence in these results is higher for liver than for the other tissues, for which there were less data. Our analysis finds that comet and TGR generally identify the same compounds (mainly potent mutagens) as genotoxic in liver, stomach and colon, but not in bone marrow. However, the current database content precluded drawing assay concordance conclusions for weak mutagens and non-DNA reactive chemicals.

Item Type: Article
Additional Information: © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
Keywords: DNA damage, Genotoxicity in vivo, Mutagens, Risk assessment, Transgenic rodents, Oncology & Carcinogenesis
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Mutat Res
ISSN: 1873-135X
Language: eng
Dates:
DateEvent
March 2019Published
18 January 2019Published Online
16 January 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
PubMed ID: 30744809
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110683
Publisher's version: https://doi.org/10.1016/j.mrgentox.2019.01.007

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