Bridging Toxicological Silos with Organoids: A Systems Approach to Human-Relevant Risk Assessment

Human-relevant toxic assessment of environmental contaminants remains a critical challenge, as conventional animal models and 2D cell cultures often fail to capture systemic complexity and interindividual variability. Organoid technology, by recapitulating 3D organ architecture, cellular heterogeneity, and donor-specific features, offers a mechanistically rich and ethically superior platform for investigating environmental toxicity. This perspective highlights the use of organoids in developmental and organ-specific toxicity (e.g., liver, brain, and thyroid) as well as patient-derived organoids (PDOs) for personalized susceptibility assessment, enabling the identification of vulnerable cell populations, elucidation of gene-environment interactions, and mechanistic mapping of adverse outcomes. Meanwhile, emerging strategies, including vascularized and unified multiorgan platforms, coculture systems, high-throughput organoid screening, and incorporation with single-cell omics analyses, which enable the mapping of pollutant effects from molecular to tissue and organ levels, were further discussed. Essential challenges, including standardization, scalability, and predictive modeling, are addressed, and we propose that coupling organoid-based approaches with computational and systems-level frameworks can bridge traditional toxicological silos, advancing predictive, mechanistic, and human-relevant environmental health assessment. Collectively, organoid technology is poised to transform environmental toxicology by providing a fully human-relevant, integrative, and predictive platform for chemical risk assessment and regulatory decision-making.