The FDA's Expanded Decision Tree (EDT) – A New Era for Food Chemical Safety Screening

The U.S. Food and Drug Administration (FDA) has unveiled its Expanded Decision Tree (EDT), a significant modernization of the classic Cramer Decision Tree. As toxicologists, we understand the increasing need for efficient, structure-based methods to screen the vast number of chemicals in the food supply, especially those with limited existing safety data. The EDT is the FDA's new tool for this, marking a step forward in the use of computational toxicology (also known as in silico methods) for risk assessment.

This development underscores the growing necessity for toxicologists to become proficient in computational toxicology tools.

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What is the Expanded Decision Tree (EDT)?

The EDT is a chemical structure-based classification system designed to estimate the potential for chronic oral toxicity of food-related chemicals.

It works by putting a chemical through a series of refined, systematic questions about its molecular structure and chemical features. Based on the answers, the chemical is assigned to one of six toxicity classes (the original Cramer Decision Tree had three). This increased specificity allows for more nuanced risk estimations.

• Modernized Classification: The EDT moves beyond the original Cramer Tree's three classes to six more granular classes, improving the precision of the toxic potential estimate.

• Threshold of Toxicological Concern (TTC): Each of the six EDT classes is associated with a specific Threshold of Toxicological Concern (TTC) level. For toxicologists unfamiliar with the TTC concept, it defines an exposure level below which there is a negligible probability of adverse health effects, even for chemicals lacking comprehensive toxicity data. The EDT leverages these TTC values for preliminary risk screening.

• A "New Approach Method" (NAM): The EDT is part of a growing suite of New Approach Methods (NAMs) that aim to leverage large datasets and predictive modeling to assess chemical safety more efficiently, inform decision-making, and reduce the need for animal testing.

Why is this important for Toxicologists?

1. Prioritization Tool: The FDA intends to use the EDT to help screen and prioritize chemicals for further pre-market and post-market review. For the industry, understanding a substance's predicted EDT class will be crucial for regulatory strategy.

2. Addressing Data Gaps: For the many low-exposure, data-poor substances, the EDT provides a scientifically defensible method to get an initial safety estimate and inform whether more extensive testing is warranted.

3. Efficiency and Cost Savings: By leveraging the principles of in silico toxicology, the EDT allows for chemical classification in minutes (once the fully automated software is released), offering a cost-effective and rapid initial screening step compared to traditional in vivo studies.

4. Regulatory Alignment: Although currently a support tool, the EDT reflects the FDA's commitment to modernizing its food chemical safety program and increasing the use of NAMs—a trend that is gaining international support.