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Towards replacing the two-year bioassay with short-term NAMs: genomic and nongenomic thresholds can identify rat liver tumorigens
Citation:
Corton, C. Towards replacing the two-year bioassay with short-term NAMs: genomic and nongenomic thresholds can identify rat liver tumorigens. Society of Toxicology Virtual 2021 Annual Meeting, NA, Virtual, March 12 - 26, 2021. https://doi.org/10.23645/epacomptox.14474145
Impact/Purpose:
New approach methods (NAMs) are rapidly emerging as cutting edge tools to modernize cancer risk assessment. Such tools offer the promise of mechanistic insight to support structured frameworks for regulatory decision-making. Traditional apical endpoints, such as those measured in the rodent cancer bioassay(s), are used to identify potential human carcinogens for agrochemicals, food additives, and pharmaceuticals; however, decades of research has underscored limitations in the rodent cancer bioassays. These limitations provide opportunities to develop and refine NAMs for targeted use to support cancer risk assessment. Experts are working to modernize carcinogenicity testing with mechanistic approaches that reduce testing on animals and may provide more human health protective information. This session has been modified from a previously accepted SOT2020 proposal to focus regulatory, industry, and NGO expert discussion toward current opportunities and lessons learned in the development and utilization of NAMs for human-relevant cancer risk and safety assessment. A representative from the Division of the National Toxicology Program will discuss their ongoing Health Effects Innovation Initiative that is working towards modernizing their carcinogenicity testing program. An investigator from the U.S. Environmental Protection Agency (EPA) will give a presentation highlighting the use of gene expression endpoints in short-term animal studies as a NAM to replace the use of the two-year rodent bioassay. Methods developers will discuss utility of NAMs for carcinogenicity assessment through expert-driven in silico systems, small model organisms providing mechanistic insights, and complex organotypic model tumor systems that recapitulate human cancer. Presentations from these cross-sector experts will provide thought-provoking discussion on paradigm-shifting opportunities to implement NAMs for regulatory cancer risk assessment, and will be of interest to a wide range of stakeholders, including regulators, cancer toxicologists, systems modelers, and industry scientists.
Description:
Traditional data sources for cancer hazard assessment are resource-intensive, retrospective, and not feasible for the vast majority of environmental chemicals. Incorporation of quantitative genomic and nongenomic data from short-term rodent studies may adequately define protective thresholds for potential tumorigens as a bridge to move from current testing to greater reliance on in vitro assays. We hypothesized that gene expression biomarkers that measure the activation of the major molecular initiating events (MIEs) in rodent liver cancer adverse outcome pathways as well as liver weight to body weight (LW/BW) and clinical chemistry (ClinChem) endpoints exhibit chemical-independent thresholds beyond which cancer occurs, and the thresholds could be used together as a NAM to predict liver cancer. The hypothesis was tested by defining thresholds of gene expression biomarkers of liver cancer MIEs using training sets from the 77 and 86 chemicals in the TG-GATES and DrugMatrix datasets, respectively and testing them in a number of contexts. The biomarkers tested consisting of 7-113 genes included those that predict genotoxicity, cytotoxicity, and activation of AhR, CAR, ER, or PPARa. Thresholds were calculated as the maximum values derived from exposures that do not lead to liver cancer. In all cases, clear threshold values could be identified that were consistent across training and test sets. Thresholds derived from the TG-GATES study were not very predictive of liver tumorigens in the DrugMatrix study (77-81%). In contrast, thresholds derived from the DrugMatrix study were predictive in the TG-GATES study (84-100%). The DrugMatrix-derived thresholds were most predictive when applied to test sets of 7d and 14d treatments (100% and 99%, respectively). In addition, thresholds derived from just 12 genes (2/biomarker) as well as LW/BW and ClinChem endpoints exhibited high predictive accuracy (up to 94%). These findings support the idea that genomic and nongenomic changes measured after short-term exposures can be used to establish threshold estimates or “molecular tipping points” that are predictive of later-life outcomes. This abstract does not reflect US EPA policy.
URLs/Downloads:
DOI: Towards replacing the two-year bioassay with short-term NAMs: genomic and nongenomic thresholds can identify rat liver tumorigens
CORTON_SOT_SYMPOSIUM_02_21_21V3.PDF (PDF, NA pp, 1469.057 KB, about PDF)