INTEGRA will establish a next-generation, animal-free platform for the systemic, physiology-informed safety and exposure assessment, combining integrated organ-on-chip (OoC) technologies, Digital Twin (DT) and AI tools. Current New Approach Methodologies (NAMs) model single organs or weakly connected systems and do not adequately capture the dynamic interplay between gut absorption, liver metabolism, kidney clearance, barrier function, systemic redistribution, and distal effects on the brain. INTEGRA addresses this gap through a modular, physiology-based NAM linking gut, brain, liver, and kidney modules in a recirculating microfluidic architecture with real-time sensing. The project will validate this framework using pesticides and advanced (nano)materials selected for their regulatory relevance significance. INTEGRA follows a staged translational strategy. It will establish and validate standalone murine OoC modules and their single-organ DT, integrating them into a multi-organ murine platform benchmarked against targeted in vivo data. Thus, the project will develop a human multi-organ platform based on iPSC-derived OoC modules, organoids, and 3D-bioprinted tissues, coupled to a human DT calibrated with project-generated multimodal data and anchored to biomarkers from exposed human cohorts. This approach will deliver predictive, mechanistically interpretable, and transferable tools for evidence integration and prioritisation. Generating validated modules, reusable SOPs, benchmark datasets, FAIR data assets and uncertainty-aware DT workflows, INTEGRA will strengthen regulatory confidence, support faster and more human-relevant safety assessment, and contribute to reducing reliance on animal testing. Beyond its demonstration case, the platform is designed for broader use in chemical safety, biomaterials assessment, and preclinical research.