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Towards Reduction and Replacement of the 2-year Rodent Bioassay Using Genomic Approaches: Update From eSTAR and Impact on ICH S1
Citation:
Corton, C. Towards Reduction and Replacement of the 2-year Rodent Bioassay Using Genomic Approaches: Update From eSTAR and Impact on ICH S1. Environmental Mutagenesis and Genomics Society meeting (EMGS) 2021, NA, September 22 - 25, 2021. https://doi.org/10.23645/epacomptox.17317859
Impact/Purpose:
Presentation to the Environmental Mutagenesis & Genomics Society (EMGS) Virtual Annual Meeting to be held September 2021.
Description:
Traditional data sources for cancer hazard assessment are resource-intensive, retrospective, and not feasible for the vast majority of chemicals. The HESI Emerging Systems Toxicology in the Assessment of Risk (eSTAR) Committee launched the Carcinogenomics Workgroup to implement genomic strategies within the ICH framework for cancer risk assessment. Transcriptional biomarkers provide a clear example of viable opportunities for immediate use driven by imminent changes in ICH S1 carcinogenicity testing guidance for pharmaceuticals, and analogous changes evolving for evaluating industrial and agrochemicals. The availability of quantitative, predictive transcriptional biomarkers predictive of changes in cancer-outcome AOPs will have many applications in risk assessment in both the pharmaceutical and chemical sectors. This talk will provide an update of the activities of the Carcinogenomics Workgroup as well as present examples of how gene expression biomarkers are built and used in short-term (≤ 28d) testing of the ability of chemicals to induce liver tumors. Six gene expression biomarkers have been built in the author’s lab that predict the major molecular initiating events (MIEs) of liver tumor induction including genotoxicity, cytotoxicity, and activation of the xenobiotic receptors aryl hydrocarbon receptor (AhR), constitutive activated receptor (CAR), estrogen receptor (ER), and peroxisome proliferator-activated receptor α (PPARα). Using full-genome microarrays, these biomarkers can be used to predict chemicals that activate these events with accuracy of 91-98%. Chemical-independent thresholds for the individual biomarkers when used together were up to 100% accurate at identifying doses that were tumorigenic. These results show that a MIE-directed approach using only gene expression biomarkers and their thresholds could be applied to short-term assays to identify chemicals and their doses that cause tumors. (This abstract does not reflect EPA policy.)
URLs/Downloads:
DOI: Towards Reduction and Replacement of the 2-year Rodent Bioassay Using Genomic Approaches: Update From eSTAR and Impact on ICH S1
EMGS_09_25_21.PDF (PDF, NA pp, 1655.267 KB, about PDF)