Revisiting the approaches to DNA damage detection in genetic toxicology: insights and regulatory implications

Genetic toxicology is crucial for evaluating the potential risks of chemicals and drugs to human health and the environment. The emergence of high-throughput technologies has transformed this field, providing more efficient, cost-effective, and ethically sound methods for genotoxicity testing. It utilizes advanced screening techniques, including automated in vitro assays and computational models to rapidly assess the genotoxic potential of thousands of compounds simultaneously. This review explores the transformation of traditional in vitro and in vivo methods into computational models for genotoxicity assessment. By leveraging advances in machine learning, artificial intelligence, and high-throughput screening, computational approaches are increasingly replacing conventional methods. Coupling conventional screening with artificial intelligence (AI) and machine learning (ML) models has significantly enhanced their predictive capabilities, enabling the identification of genotoxicity signatures tied to molecular structures and biological pathways. Regulatory agencies increasingly support such methodologies as humane alternatives to traditional animal models, provided they are validated and exhibit strong predictive power. Standardization efforts, including the establishment of common endpoints across testing approaches, are pivotal for enhancing comparability and fostering consensus in toxicological assessments. Initiatives like ToxCast exemplify the successful incorporation of HTS data into regulatory decision-making, demonstrating that well-interpreted in vitro results can align with in vivo outcomes. Innovations in testing methodologies, global data sharing, and real-time monitoring continue to refine the precision and personalization of risk assessments, promising a transformative impact on safety evaluations and regulatory frameworks.