Challenges and opportunities for validation of AI-based new approach methods

Abstract

The integration of artificial intelligence (AI) into new approach methods (NAMs) for toxicology rep­resents a paradigm shift in chemical safety assessment. Harnessing AI appropriately has enormous potential to streamline validation efforts. This review explores the challenges, opportunities, and future directions for validating AI-based NAMs, highlighting their transformative potential while acknowledging the complexities involved in their implementation and acceptance. We discuss key hurdles such as data quality, model interpretability, and regulatory acceptance, alongside opportunities including enhanced predictive power and efficient data integration. The concept of e-validation, an AI-powered framework for streamlining NAM validation, is presented as a comprehensive strategy to overcome limitations of traditional validation approaches, leveraging AI-powered modules for reference chemical selection, study simulation, mechanistic validation, and model training and evaluation. We propose robust validation strategies, including tiered approaches, performance benchmarking, uncertainty quantification, and cross-validation across diverse datasets. The importance of ongoing monitoring and refinement post-implementation is emphasized, addressing the dynamic nature of AI models. We consider ethical implications and the need for human oversight in AI-driven toxicology and outline the impact of trends in AI devel­opment, research priorities, and a vision for the integration of AI-based NAMs in toxicological practice, calling for collaboration among researchers, regulators, and industry stakeholders. We describe the vision of companion AI post-validation agents to keep methods and their validity status current. By addressing these challenges and opportunities, the scientific community can harness the potential of AI to enhance predictive toxicology while reducing reliance on traditional animal testing and increasing human relevance and translational capabilities.