Liver organoids for chemical risk assessment: biological fidelity, standardization, and context-of-use frameworks.

Liver organoids are emerging as human-relevant three-dimensional in vitro systems for chemical safety assessment, however, their application value depends on their ability to generate decision-ready evidence within clearly defined context-of-use (CoU). Here, we review the biological fidelity, quality assessment, exposure characterization, and validation requirements of liver organoids across three CoUs: (1) hazard screening and identification, (2) mechanistic elucidation of hazard, and (3) quantitative risk assessment support. Within this CoU framework, we review recent advances in liver organoids and their applications to chemical safety assessment, highlighting models that already provide useful evidence and those where implementation remains partial or inconsistent. Based on this review, we discuss the major barriers to broader regulatory adoption, which include insufficient biological implementation, limited reproducibility, insufficient exposure characterization, and a lack of harmonized performance criteria and standardization frameworks. By evaluating liver organoids in relation to clearly defined decision questions rather than generalized technological promise, this review clarifies their current contributions, explains why their contributions remain CoU-dependent, and outlines key priorities for developing decision-ready liver organoid platforms for next-generation chemical safety assessment.