From concept to regulation: OECD’s role in the development of the DNT in vitro battery

Chemical exposure during critical stages of nervous system development can lead to adverse neurotoxic effects, known as developmental neurotoxicity (DNT). Although standardized in vivo test guidelines (TGs) are required under various regulatory frameworks, compared to other TGs few in vivo DNT studies have been conducted. The complexity, interpretative limitations, high cost and resource demands of these studies have prompted regulatory agencies and stakeholders to emphasize the need for developing and standardizing NAMs (New Approach Methodologies) that capture relevant endpoints and biomarkers of DNT effects. Recent advances in in vitro neural models and high throughput analytical technologies have enabled the creation of a battery of assays -the DNT In Vitro Battery (DNT-IVB)- designed to rapidly assess chemicals for their impact on critical neurodevelopmental processes in in vitro test systems. In response to the regulatory needs and the scientific advancements, an international collaboration led by regulatory agencies from both sides of the Atlantic under the auspices of OECD was initiated about a decade ago. Since then, substantial progress has been made. The DNT-IVB provides a structured approach for integrating human-relevant in vitro assay data into chemical DNT assessments. Its application is supported by guidance in the OECD Initial Recommendations for evaluating DNT-IVB data, along with case examples that apply the IATA (Integrated Approaches to Testing and Assessment) framework. Ongoing efforts aim to address remaining challenges and consolidate the guidance needed for standardizing and expanding the application of NAMs to assess DNT across various regulatory contexts. The DNT-IVB now represents a flagship OECD project, testing the paradigm of applying NAMs and IATA in risk assessment and paving the way for broader worldwide alignment on NAMs standardization and use.