The expanded decision tree: Predicting chronic toxic potential and safe intake levels

The Expanded Decision Tree (EDT) was developed by the U.S. Food and Drug Administration (FDA) to address the significant limitations of the original Cramer Decision Tree (CDT), a tool historically used for estimating the relative oral toxic potential of chemicals based on their structure. Over the past four decades, scientific understanding of structure-toxicity relationships has advanced significantly, exposing the CDT's limitations in logic, reliance on some ambiguous and non-structure-based questions, and limited ability to classify substances with high specificity. The EDT was designed as a science-forward, structure-based revision of the CDT that leverages contemporary toxicology data, metabolism insights, and mechanistic knowledge to assess a broader array of chemical substances. This article provides a high-level summary of the EDT's development, the construction and use of its underlying database, the logic and structure of its expanded classification framework, the scientific rationale for its updates, and the findings from its extensive external validation and peer review. The EDT represents a robust, transparent, and scientifically defensible tool for regulatory toxicology, especially in the context of threshold of toxicological concern (TTC) screening.