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ICCVAM Biennial Report 2020-2021

Biennial Progress Report 2020-2021 Interagency Coordinating Committee on the Validation of Alternative Methods

In Silico Approaches in Organ Toxicity Hazard Assessment: Current Status and Future Needs for Predicting Heart, Kidney, and Lung Toxicities

The kidneys, heart, and lungs are vital organ systems evaluated as part of acute or chronic toxicity assessments. New methodologies are being developed to predict adverse effects based on in vitro and in silico approaches. A review coauthored by ATSDR, FDA, and NIEHS scientists considered the current state of the art in predicting these organ toxicities (Bassan et al. 2021). The review outlines the biological basis, processes, and endpoints for kidney toxicity, pulmonary toxicity, respiratory irritation and sensitization, and functional and structural cardiac toxicities. The review also covers current experimental approaches, including off-target panels from secondary pharmacology batteries. Current in silico approaches for prediction of these effects and mechanisms are described as well as obstacles to the use of in silico methods. Ultimately, a commonly accepted protocol for performing in silico assessments would be a valuable resource to expand the use of such approaches across different regulatory and industrial applications. The review identifies factors impeding the widespread deployment of in silico approaches, including lack of a comprehensive understanding of the mechanisms of toxicity, limited in vitro testing approaches, limited in vivo databases suitable for modeling, a limited understanding of how to incorporate ADME considerations into the overall process, a lack of in silico models designed to predict a safe dose, and a need for an accepted framework for organizing the key characteristics of these organ toxicants.