Comprehensive interpretation of in vitro micronucleus test results for 292 chemicals: from hazard identification to risk assessment application
- DOI
- Language of the publication
- English
- Date
- 2022-04-21
- Type
- Article
- Author(s)
- Kuo, Byron
- Beal, Marc A.
- Wills, John W.
- White, Paul A.
- Marchetti, Francesco
- Nong, Andy
- Barton‑Maclaren, Tara S.
- Houck, Keith
- Yauk, Carole L.
- Publisher
- Springer Link
Abstract
Risk 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.
Plain language summary
Health Canada is responsible for the assessment of health risks to Canadians associated with chemical exposures in the environment. Every day, Canadians are exposed to a variety of chemicals at home, outdoors and even at work. New alternative methods are investigated to help predict the potential harm from existing chemicals in Canada. These new methods allow to screen rapidly for various toxic effects over a large numbers of chemicals. Assessment and research efforts can then be prioritized to chemicals of high health risks that can affect the population. One such laboratory technology detects for toxic effects on genes known as in vitro micronucleus test (MNvit). In collaboration with the US EPA, 292 chemicals were analyzed using the micronucleus test. Mathematical and computer models helped translate the laboratory results into daily intake levels that can then be compared against exposure levels in the population. The tests and models were able to classify 157 positive, 25 negative, and 110 inconclusive chemicals to potentially harm human genes. Among the positives with complete exposure data, 50 chemicals were identified to alter genes directly whereas only 2 chemicals can alter indirectly the genetic apparatus. The last set of chemicals identified for greater health concern would be immediately prioritized for in depth follow-up. The present study demonstrates the use of new advance scientific tools to improve assessment strategies at screening existing chemicals in our daily lives from potential harm.
Subject
- Health,
- Health and safety