Abstract
The limited ability of animal and cancer cell-based models to recapitulate human-specific responses underscores the need for human-relevant in vitro systems in toxicology. Here, we present a scalable platform for generating human lung organoids from induced pluripotent stem cells (iLOs), providing a physiologically relevant model for respiratory toxicity assessment. To evaluate this model, iLOs were exposed to polyhexamethylene guanidine phosphate (PHMG-p), a disinfectant associated with lung injury. PHMG-p treatment induced fibrotic responses, including upregulation of α-smooth muscle actin and fibronectin. Transcriptomic profiling revealed a coordinated cellular stress response marked by robust induction of metallothionein (MT) genes. Among them, MT1H was highly sensitive and strongly induced, highlighting its potential as an early biomarker of chemically induced lung injury. This human-specific organoid platform enables mechanistic toxicology, early biomarker discovery, and hazard assessment, offering a compelling alternative to animal-based models for evaluating respiratory toxicants.