ICCVAM Biennial Report 2024-2025

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. In 2024 and 2025, ICCVAM agency scientists participated in the following HESI projects.

• tPODs for Chemical Risk Assessments Working Group: This working group is developing a comprehensive, multilayered methodological framework for deriving transcriptomic points-of-departure (tPODs) from short-term in vivo toxicity studies for ecological and human health chemical assessments. The goal is to develop tPODs that are stable, biologically meaningful, and suitable for use in chemical risk assessment. A 2025 workshop advanced this effort by addressing study design considerations, establishing upstream quality control practices to improve data harmonization, defining standardized approaches for transcriptomic benchmark dose modeling, and evaluating both gene level and gene set based summarization strategies for consistent tPOD derivation. Outcomes from the workshop are being prepared as several manuscripts. The working group has also emphasized opportunities to reduce and refine animal use by demonstrating how mechanistic studies that incorporate transcriptomics and other molecular data could help replace traditional animal-intensive developmental and reproductive toxicity (DART) studies. These concepts will be featured in a roundtable at the 2026 Society of Toxicology annual meeting, “Towards a New Paradigm: Can Mechanistic In Vivo Studies Replace Traditional DART Guideline Studies?” that will be summarized into a short communication for publication.
• Cell Painting - OASIS Consortium: The HESI-sponsored Omics for Assessing Signatures for Integrated Safety (OASIS) Consortium is advancing next-generation risk assessment by integrating multiomics technologies, including transcriptomics, proteomics, and high-content cell painting, across a range of human-relevant biological systems. With an initial focus on liver safety, the consortium is combining molecular and phenotypic data from rat and human cell line exposures to well-characterized reference chemicals to improve translation from in vitro findings to in vivo and clinical outcomes. Chemical testing and data acquisition have recently been completed, and analysis is now underway to compare transcriptomic responses with phenotypic profiles generated through cell painting. Through this work, the consortium aims to build more predictive, efficient, and human-relevant approaches to chemical safety assessment, while supporting reduced reliance on animal models and strengthening regulatory science across sectors.
• eSTAR MicroRNA Biomarkers Working Group: Previous work within the Emerging Systems Toxicology for the Assessment of Risk (eSTAR) MicroRNA Biomarkers Working Group identified candidate microRNA biomarkers for kidney toxicity (Chorley et al. 2021; Dasgupta et al. 2024). More recent work focused on NAMs development by measuring extracellular release of these biomarkers in human primary proximal tubule cell culture media after exposure to kidney toxicants. Results from the study, now in preparation for publication, are part of the working group’s long-term efforts to develop biomarkers based on extracellular microRNA released by region-specific nephron cells that are indicative of toxicity due to chemical or drug exposure. These biomarkers can be utilized as nondestructive, time-course measures in cell culture media.
• eSTAR Carcinogenomics Working Group: This working group is developing transcriptomic signatures to detect early molecular events that are associated with liver tumorigenic outcomes in short-term rodent studies. Using publicly available rat liver gene expression datasets, machine learning, expert biological review, and HESI-sponsored studies from wild-type and receptor-null rat models, the group is building concise gene sets that are sensitive and specific for the activation of key tumor-associated pathways, including AhR, CAR, PPARα, ER, PXR, p53, and cytotoxicity. In particular, the receptor-null rat models were leveraged to confirm signature gene responses that require the tumor-associated receptor. The goal is to support mechanistically informed, weight-of-evidence approaches for assessing carcinogenic potential in short-term studies and to help reduce the need for traditional two-year rodent carcinogenicity assays in alignment with guidance S1B(R1) issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.