The current U.S chemical regulation framework was developed in an era when toxicology focused primarily on identifying acute hazards in controlled settings. A growing body of evidence demonstrates that such approaches struggle to capture cumulative exposures, chronic low-dose effects, microbial and ecological dynamics, and cross-species interactions that increasingly define real-world chemical risk. In recognition of these limitations, EPA recently issued updated Guidelines for Cumulative Risk Assessment Planning and Problem Formulation, which emphasize early identification of combined stressors and vulnerable populations. Yet, cumulative thinking remains unevenly translated into routine chemical-specific decisionmaking, particularly for antimicrobial compounds regulated under sector-specific statutes. This Comment argues that the future of science-based regulation requires a systems-based framework that integrates “New Approach Methodologies,” cumulative risk analysis, and a “One Health” perspective recognizing the interdependence of human, animal, and environmental health.