Expanded Decision Tree: FDA’s Food Chemical Toxicity Screening Tool

If not evaluated or used properly, some chemicals in food may have toxic properties that could pose a risk to human health. The FDA helps to safeguard the food supply by evaluating the safe use of chemicals as food ingredients and food contact substances. The FDA also monitors the food supply for chemical contaminants and takes action to limit them when we find that the level of a contaminant causes a food to be unsafe. To do this, the FDA uses scientific and regulatory tools to assess the safety of chemicals in food while continually updating its methods to incorporate new approaches.

The Expanded Decision Tree (EDT) is one example of New Approach Methods, which leverage large data sets to achieve faster, less expensive, and informative new approaches to chemical assessments that can inform risk management decisions and actions. The EDT has gained widespread international support in recent years, and this approach to evaluating the safety of chemicals takes science to a new level. The EDT is a modernized version of the original Cramer Decision Tree tool and can be used to screen chemicals based on their structural features. The Cramer Decision Tree tool, which is a scientific tool that sorts chemicals into classes of chronic toxic potential using a series of mainly chemical structure-based questions, has been widely used by scientists to provide a quick, preliminary estimate of a new chemical’s toxic potential, especially when the testing data about a chemical is limited. The updated, expanded, and greatly refined fully structure-based questions of the FDA’s EDT allow classification of chemicals with greater specificity and precision than the Cramer Decision Tree.

The EDT, once fully operational and automated, will enable fast screenings of chemicals, will help to identify data gaps in information about chemicals, will help support the agency’s assessment of chemicals submitted through premarket programs, will help screen and prioritize chemicals for further evaluation through the post-market assessment program, and will inform assessments of cumulative toxicity and mixtures of chemicals.

Development of the EDT

Every year, the FDA receives hundreds of submissions to evaluate chemicals intended for use in food, or that may come into contact with food, and the agency receives numerous reports of unknown or unexpected chemicals detected in food. As research continues and new data become available, it is increasingly challenging for the agency to prioritize chemicals for which new data suggests there may be a benefit to further assessment. And, for some chemicals, no data are available. Knowing the estimated toxicity of a chemical is a part of understanding its safety profile and whether the FDA needs to further assess a chemical’s safety.

When the FDA evaluates if a substance can be safely used in food or come into contact with food, we consider all relevant information, including:

Safety data and other information regarding whether the substance is safe at the calculated exposure levels.
Information on the identity of the substance, including its chemical structure and what is known about similar substances.
The amount of the substance that we expect people may be exposed to based on how the substance will be used and its use level in food.

The FDA evaluates chemicals in food on a case-by-case basis through submissions to our programs or when addressing reports about emerging information about chemicals in the food supply. To improve this process, the FDA has developed the EDT as a support tool on predictive toxicity in safety evaluations of chemicals. The EDT was first validated and then evaluated through external peer-review.

The FDA also engaged a broad spectrum of stakeholders as part of developing the EDT, receiving input from experts of the European Food Safety Authority, U.S. Environmental Protection Agency, Western University of Canada, Liverpool John Moores University, National Institutes of Health’s National Toxicology Program (NTP), and industry.

In addition, FDA scientists developing the tool engaged representatives from FDA’s various medical product centers and the Center for Tobacco Products to create internal agency awareness of this tool and to enable a dialogue that can maximize the EDT’s regulatory usefulness across the FDA. Beyond this internal engagement, our scientists are also engaging other federal agencies that may have an interest in utilizing the EDT for Threshold of Toxicological Concern (TTC) levels-based approaches to safety reviews. The FDA also continues to engage with the NTP and representatives of other federal public health agencies.

Strong Toxicology Data is the Foundation for the EDT

The EDT database contains toxicity studies, metabolism data, and chemical data for a diverse set of chemicals present in food. These include nutrients, other substances intentionally added to food or used in food packaging, and some contaminants present in food because of where food is sourced, prepared, or processed. The EDT database also contains data on chemicals other than those found in food, such as those present in cosmetics, tobacco products, and pharmaceutical preparations, as well as known environmental toxins.

The FDA used the chemicals found in the Munro database as the starting point for the EDT database and added toxicological, metabolic, and chemical data about a large number of new chemicals. The FDA added data from online databases and reports from authoritative bodies such as the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives, the Joint FAO/WHO Meeting on Pesticide Residues, the U.S. Environmental Protection Agency’s (EPA) Integrated Risk Information System, the U.S. EPA’s High Production Volume Information System, the U.S. EPA’s Pesticides: Reregistration, the California Environmental Protection Agency, the European Chemicals Agency, and the European Food Safety Authority. The FDA also added chemicals to the database for which animal safety studies were available in the published literature; chemicals found in the FDA’s Office of Food Chemical Safety, Dietary Supplements and Innovation (formerly the Office of Food Additive Safety) records on food and color additives, Generally Recognized As Safe (GRAS) substances, and food contact substances; and chemicals included in NTP study reports.

Automating the EDT

Currently, using the EDT to screen a chemical is a manual process that requires organic chemistry and metabolism expertise to evaluate a chemical efficiently and reproducibly. Automation of the EDT is necessary to fully realize its capabilities and for the tool to be more broadly used. The FDA is working to develop an automated version of the EDT to harness its fullest potential.

A fully automated EDT would allow for the agency and the public to systematically examine information about chemicals and would help focus the agency’s post-market safety reviews on the chemicals that have the greatest potential for public health impact. A fully automated EDT will also enhance our work on food chemical safety in a variety of ways:

Reduce burden on FDA staff. The tool would allow for a chemical to be classified in minutes, the results of which could then be considered with other data as part of the chemical’s safety evaluation.
Reduce and refine the use of animal testing for chemical safety. The FDA has had a long-standing commitment to promote the development and use of innovative technologies to better predict human and animal responses to substances. The EDT leverages existing toxicological data obtained from animal testing to help reduce and refine future animal testing.
Provide a greater level of transparency on the agency’s decision-making when evaluating the safety of chemicals in the U.S. food supply.

In the longer term, as resources permit, the FDA envisions linking the automated EDT to existing databases on food composition and consumption. Integrating these databases would allow the agency to better monitor food chemical exposures as the market changes or as new intake data become available. This will also position the FDA to begin to use artificial intelligence and machine learning tools to identify potential safety concerns stemming from changes in food-consumption patterns or food composition.

Using EDT to Screen Chemicals

The EDT can be used by the FDA, other regulators, and industry to sort chemicals into classes of estimated toxicity using a series of structure-based questions. The open-source nature of the tool fosters collaboration among stakeholders to advance food chemical safety.

Using the EDT

The FDA issued the manual version of the EDT with the peer-review response. The EDT was designed to predict the chronic oral toxicity of structurally defined organic compounds that may have limited or no safety data available. Therefore, the applicability domain of the EDT does not include toxic elements (for example, lead, mercury, cadmium, and arsenic), non-hydrolyzable polymers (for example, low-density polyethylene), large peptides (for example, insulin), nanomaterials, and proteins.

The EDT does not replace the review and approval processes required by statute, such as the Federal Food, Drug, and Cosmetic Act’s pre-market authorization process for food additives. The EDT is just one of any number of tools and data that could be used to help assess the safety of a substance used in food or that comes into contact with food.

The FDA is now publicly releasing the EDT to the scientific community for technical consideration. At a later date, FDA intends to release additional information regarding the EDT and provide opportunities for public input.

EDT Tiers of Toxicity

Compared to the original Cramer Tree, the EDT classifies chemicals into twice as many classes of toxic potential, allowing for more refined predictions of a chemical’s toxic potential. The EDT uses a series of interconnected questions about chemical structure to systematically predict toxic potential. The EDT predicts both the chronic oral toxic potential of a chemical and a safe level of exposure, known as the Threshold of Toxicological Concern (TTC level). These are essential pieces of information when evaluating chemical safety. TTC levels are reported in micrograms per kilogram body weight per day (μg /kg bw/d). Currently, the EDT has only been evaluated for the oral exposure route and has not been validated for other routes of chemical exposure.

Users of the EDT can consider the tool’s prediction of a chemical’s estimated toxicity together with an assessment of consumers’ real-world exposure to the chemical to evaluate whether the current exposure level raises concerns or whether the chemical should be prioritized for additional review. This may involve considering other data, such as compound specific Absorption, Distribution, Metabolism, and Excretion (ADME), toxicology and/or epidemiology data, or determining whether additional research is needed. It is important to note that even if a chemical is classified by the EDT in the lowest estimated toxicity category, it could be unsafe when used at a level higher than its class TTC. Researchers should never ignore quality data and should always consider all relevant information related to a specific chemical when evaluating safety regardless of the results of the EDT classification.

Informing Possible FDA Actions

The FDA is still considering all of the potential applications of the EDT tool for the agency’s various regulatory responsibilities. However, the FDA is already piloting use of the EDT to inform the FDA’s pre- and post-market programs.

Once a chemical is classified based on the EDT, the FDA might use the output from the EDT together with other available data on the chemical, such as an assessment of current exposure levels from consumption of food containing the chemical, to help determine whether the chemical poses safety concerns. This will also help inform whether the FDA should prioritize that chemical for additional data collection, toxicity testing, or analyses.

In the context of submissions to the FDA, the agency might use the classifications from the EDT to inform decisions on what information may be needed to evaluate a new food contact material or food additive submission. In addition, anyone developing a new ingredient or making a GRAS conclusion might run a substance or impurity through the EDT to help evaluate potential safety concerns and identify targeted testing needs. Use of the EDT may therefore help to streamline submissions to the FDA and make FDA's review process more efficient .

In the post-market context, the EDT might be used to inform reevaluation of substances that were evaluated at the time of their approval—in some cases, 40 to 50 years ago—to help evaluate whether further study on a compound is necessary.

For some chemical contaminants for which little to no safety information exists, the FDA might use the EDT to help analyze these substances and classify them according to their toxic potential, allowing the FDA and other stakeholders to prioritize future research.

Engage with the FDA on the EDT

The FDA plans to further refine the EDT over time with access to more information about chemicals in the food supply and in response to public input. The FDA encourages interested parties to engage with the agency on the EDT and will provide opportunities for public engagement:

Informational video – Expanded Decision Tree: The FDA plans to release an informational video to explain the development and function of the EDT.
Listening Sessions: The FDA plans to hold listening sessions with technical, scientific, and trade groups to learn about how the tool may impact their work.

Announcements

Constituent Update: FDA Releases New Tool for Toxicity Screening of Chemicals in Food

Related FDA Programs on Chemicals in Food and Food Packaging

Contact

If you have questions about the EDT, email EDT@FDA.HHS.GOV