https://ntp.niehs.nih.gov/go/n464426

Collaborations with HESI

ICCVAM agency scientists participate in programs coordinated by the Health and Environmental Sciences Institute (HESI). HESI collaboratively identifies and helps to resolve global health and environmental challenges through the engagement of scientists from academia, government, industry, nongovernmental organizations, and other strategic partners. During 2022 and 2023, ICCVAM agency scientists participated in these HESI projects.

  • The Emerging Systems Toxicology for the Assessment of Risk (eSTAR) Committee was established to develop and deliver innovative systems toxicology approaches for risk assessment. In 2023, this committee launched the Omics for Assessing Signatures for Integrated Safety Consortium to increase confidence in the use of techniques such as imaging-based phenomics, transcriptomics, and proteomics for chemical safety assessment. The consortium has assembled a list of over 1000 candidate molecules for testing in Cell Painting, high-throughput transcriptomics and high-throughput proteomics assays. These molecules have liver toxicity data from traditional animal studies and/or human clinical studies. Data generation from in vitro screening studies is scheduled to begin in summer of 2024.
  • The eSTAR Committee is also coordinating an effort to develop and qualify biomarker gene expression panels that measure widely accepted molecular pathways linked to tumorigenesis and their activation levels to predict tumorigenic doses of chemicals from short-term exposures (Corton et al. 2022). Success from these efforts will facilitate the transition from current heavy reliance on conventional two-year rodent carcinogenicity studies to more rapid animal- and resource-sparing approaches for mechanism-based carcinogenicity evaluation supporting internal and regulatory decision-making.
  • The HESI eSTAR Molecular Point-of-Departure workgroup published a paper that establishes the scientific principles underpinning the genomic dose-response approach being investigated by the group (Johnson et al. 2022). Ongoing efforts are focused on a manuscript that describes the current standards for data analysis and identifies points of uncertainty in relation to analysis pipeline parameter selections and definition of terms (e.g., concerted molecular change). The data analysis standards paper will provide background information and a starting point for a workshop, tentatively planned for late 2025, with the goal of codifying best practices in genomic dose-response analysis and molecular POD determination.
  • The HESI eSTAR microRNA biomarkers workgroup continued to develop biomarkers based on extracellular microRNA released by region-specific nephron cells that are indicative of toxicity due to chemical or drug exposure. The current project builds on foundational work in a rat model that established kidney microRNA release into urine corresponding to subregion-specific expression that indicated nephrotoxicity due to drug exposure (Chorley et al. 2021). A manuscript currently in review describes a project started in 2022 studying temporal modulation of primate urinary microRNA biomarkers after mild nephrotoxicity. NAMs development work has focused on proximal tubule microRNA release in a human primary cell culture media after nephrotoxicant exposure.
  • The Genetic Toxicology Technical Committee is working to improve the scientific basis of the interpretation of results from genetic toxicology tests for more accurate hazard identification and assessment of human risk and develop follow-up strategies for determining the relevance of test results to human health. The committee’s In Vitro Working Group is critically evaluating NAMs for in vitro genotoxicity testing and envisioning how NAMs could expand current in vitro genetic toxicology testing strategies. A recent publication reports on a case study on 31 reference chemicals to evaluate the performance of IVIVE application to genotoxicity data (Beal et al. 2023). The group will make recommendations for creating an “in vitro only” approach for genetic toxicology testing that would meet the needs of various regulatory decision-makers.
  • The Transforming the Evaluation of Agrochemicals Committee seeks to develop fit-for-purpose safety evaluation for agrochemicals that is applicable to changing global, as well as local, needs for evaluation and regulatory decisions that can incorporate relevant evolving science inputs. The group has been assessing the use of various test guidelines across different regulatory agencies in the context of agrochemical safety assessment and compiling information from industry members on the types of NAMs typically used.
  • The HESI PBPK Models Committee aims to address key needs related to PBPK modeling practices and applications that could facilitate use of PBPK models more consistently within the risk assessment context. The group has been working to develop PBPK templates and frameworks, as well as evaluate and address commonly raised technical and scientific issues related to the use of toxicokinetic data for dose selection and/or interpretation of results in toxicity testing. The PBPK Models Committee is also collaborating with the Transforming the Evaluation of Agrochemicals Committee to evaluate the utility of the subchronic dog study for agrochemical safety evaluation.