Human organoids to assess environmental contaminants toxicity and mode of action: towards New Approach Methodologies

The global rise of environmental contaminants (ECs), including microplastics, heavy metals, pesticides, and drugs, poses an urgent threat to human health. Traditional toxicological models often fail to replicate human-specific responses, delaying effective risk assessment and regulation. Conversely, human organoid models represent a breakthrough in environmental health research by offering unprecedented physiological relevance. Hence, this review highlights the potential role of human organoids in ECs toxicity assessment. Results showed that current studies primarily focus on drugs, while perfluorinated compounds, solvents and dietary toxicants remain understudied. A major shortcoming is the overreliance on acute, high-dose exposure models that fail to mimic real-world situations. Thus, incorporating chronic, low-dose exposures is essential for ecological and regulatory relevance. Regarding the model, induced pluripotent stem cell derived organoids are the most used, while adult stem cell- and patient-derived models remain underutilized despite their potential for clinical research. Also, standardization challenges, especially variability in organoid architecture, cellular diversity, and reproducibility, continue to limit their broad application. Mechanistic insights reveal that ECs disrupt key signaling pathways (Wnt/β-catenin, MAPK, Notch, BMP, p53) inducing altered cell differentiation, inflammation, structural changes and apoptosis. As regards the assays, reliance on the conventional ones restricts molecular depth. Indeed, advanced multi-omics and AI-driven analyses remain underexploited, despite their promise for environmental toxicology. To accelerate progress, future efforts must integrate low and chronic exposure with multi-organoid platforms and AI-based profiling to better capture systemic and tissue specific responses to ECs. Doing so will revolutionize hazard assessment and support more effective environmental health policies worldwide.