Human iPSC Models at the Nexus of Environmental Exposures and Human Health: Advancements, Applications, and Future Directions

Human induced pluripotent stem cells (iPSCs) have emerged as transformative platforms for investigating environmental toxicant effects on human health. This comprehensive review synthesizes recent advancements (2022–2025) in iPSC-based environmental toxicology, with particular emphasis on the integration of artificial intelligence (AI), multi-omics technologies, and the emerging "digital twin" concept for personalized risk assessment. A systematic literature search was conducted across PubMed, Scopus, and Web of Science using standardized keywords and predefined inclusion criteria to ensure methodological transparency and reproducibility. The review examines iPSC-derived cellular models encompassing hepatic, neural, cardiac, pulmonary, and renal systems, evaluating their applications in elucidating mechanisms of toxicity for diverse environmental hazards including heavy metals, persistent organic pollutants (POPs), per- and polyfluoroalkyl substances (PFAS), microplastics, and emerging contaminants. Critical comparisons with traditional animal models, primary human cells, and immortalized cell lines highlight iPSC advantages in predictive capability, cost-efficiency, and ethical considerations, alongside persistent limitations in scalability, immune-component representation, and vascularization. The manuscript proposes that coupling iPSC platforms with AI-driven predictive modeling and comprehensive multi-omics profiling offers a transformative pathway toward digital-twin systems capable of simulating individualized and population-level responses to environmental exposures. Current regulatory landscape and standardization efforts are reviewed. Remaining knowledge gaps and future research priorities required for achieving widespread regulatory acceptance and implementation in environmental health risk assessment frameworks are comprehensively discussed.