A comparison of transgenic rodent mutation and in vivo comet assay responses for 91 chemicals
- DOI
- Language of the publication
- English
- Date
- 2019-01-18
- Type
- Article
- Author(s)
- Kirkland, David
- Levy, Dan D.
- LeBaron, Matthew J.
- Aardema, Marilyn J.
- Beevers, Carol
- Bhalli, Javed
- Douglas, George R.
- Escobar, Patricia A.
- Farabaugh, Christopher S.
- Guerard, Melanie
- Johnson, George E.
- Kulkarni, Rohan
- Le Curieux, Frank
- Long, Alexandra S.
- Lott, Jasmin
- Lovell, David P.
- Luijten, Mirjam
- Marchetti, Francesco
- Nicolette, John J.
- Pfuhler, Stefan
- Roberts, Daniel J.
- Stankowski Jr., Leon F.
- Thybaud, Veronique
- Weiner, Sandy K.
- Williams, Andrew
- Witt, Kristine L.
- Young, Robert
- Publisher
- Elsevier
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.
Plain language summary
Health Canada supports the development, validation and improvement of test guidelines for the Organisation for the Economic Co-operation and Development (OECD). These guidelines are routinely used for assessing chemicals for mutagenicity (changes in the sequence of the DNA) or clastogenicity (induction of breaks in the DNA). However, guidelines are not yet available to properly assess the ability of chemicals to induce changes in chromosome number, a condition called aneuploidy and that is associated with cancer development and hereditary diseases such as Down syndrome. To address this gap, a group of international experts from various governments, industry and academia met in Tokyo, Japan in November 2017 as part of the International Workshops on Genotoxicity Testing, to discuss the role of aneugens (chemicals that induce aneuploidy) in human health risk assessment. The work from the group is summarized in three companion papers. In this first paper, the group conducted a review of the scientific literature and developed scientific consensus on the biological mechanisms by which chemicals can induce aneuploidy, identified the best methodologies that can be used to measure aneuploidy, and explored the use of the OECD Adverse Outcome Pathway approach, which is an effort to describe all molecular events that take place from the initial interaction of a chemical with a biological structure to an adverse outcome, to document mechanisms of chemically induced aneuploidy. The group concluded that the tests that are currently used to generated data for regulatory submission, while not ideal for a comprehensive risk assessment, are sufficient for the identification of chemicals that may be capable of inducing aneuploidy. The comprehensive review presented in this paper should help regulators in the identification and risk management of aneugens.
Subject
- Health,
- Health and safety