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dc.contributor.authorKuo, Byron
dc.contributor.authorBeal, Marc A
dc.contributor.authorWills, John W
dc.contributor.authorWhite, Paul A
dc.contributor.authorMarchetti, Francesco
dc.contributor.authorNong, Andy
dc.contributor.authorBarton-Maclaren, Tara S
dc.contributor.authorHouck, Keith
dc.contributor.authorYauk, Carole L
dc.date.accessioned2022-06-07T08:10:34Z
dc.date.available2022-06-07T08:10:34Z
dc.date.issued2022-07
dc.date.submitted2021-11-03
dc.identifier.issn0340-5761
dc.identifier.others00204-022-03286-2
dc.identifier.other3286
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337738
dc.descriptionFunder: Canada Research Chairs; doi: http://dx.doi.org/10.13039/501100001804
dc.description.abstractRisk assessments are increasingly reliant on information from in vitro assays. The in vitro micronucleus test (MNvit) is a genotoxicity test that detects chromosomal abnormalities, including chromosome breakage (clastogenicity) and/or whole chromosome loss (aneugenicity). In this study, MNvit datasets for 292 chemicals, generated by the US EPA's ToxCast program, were evaluated using a decision tree-based pipeline for hazard identification. Chemicals were tested with 19 concentrations (n = 1) up to 200 µM, in the presence and absence of Aroclor 1254-induced rat liver S9. To identify clastogenic chemicals, %MN values at each concentration were compared to a distribution of batch-specific solvent controls; this was followed by cytotoxicity assessment and benchmark concentration (BMC) analyses. The approach classified 157 substances as positives, 25 as negatives, and 110 as inconclusive. Using the approach described in Bryce et al. (Environ Mol Mutagen 52:280-286, 2011), we identified 15 (5%) aneugens. IVIVE (in vitro to in vivo extrapolation) was employed to convert BMCs into administered equivalent doses (AEDs). Where possible, AEDs were compared to points of departure (PODs) for traditional genotoxicity endpoints; AEDs were generally lower than PODs based on in vivo endpoints. To facilitate interpretation of in vitro MN assay concentration-response data for risk assessment, exposure estimates were utilized to calculate bioactivity exposure ratio (BER) values. BERs for 50 clastogens and two aneugens had AEDs that approached exposure estimates (i.e., BER < 100); these chemicals might be considered priorities for additional testing. This work provides a framework for the use of high-throughput in vitro genotoxicity testing for priority setting and chemical risk assessment.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectGenotoxicity and Carcinogenicity
dc.subjectMicronucleus
dc.subjectGenotoxicity
dc.subjectBenchmark dose
dc.subjectToxicokinetics
dc.subjectIVIVE
dc.subjectPoint of departure
dc.titleComprehensive interpretation of in vitro micronucleus test results for 292 chemicals: from hazard identification to risk assessment application.
dc.typeArticle
dc.date.updated2022-06-07T08:10:33Z
prism.endingPage2085
prism.issueIdentifier7
prism.publicationNameArch Toxicol
prism.startingPage2067
prism.volume96
dc.identifier.doi10.17863/CAM.85147
dcterms.dateAccepted2022-02-23
rioxxterms.versionofrecord10.1007/s00204-022-03286-2
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidYauk, Carole L [0000-0002-6725-3454]
dc.identifier.eissn1432-0738
cam.issuedOnline2022-04-21


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