SOT FDA Colloquium: State of the Art in the Cramer Classification Scheme and Threshold of Toxicological Concern - March 29, 2016

The Society of Toxicology in conjunction with the US FDA Center for Food Safety and Applied Nutrition (CFSAN) have partnered to provide this colloquia series. The series presents scientific information that is high-quality, cutting-edge, future-oriented toxicological science to provide a well-grounded foundation to inform the work of US FDA employees.

On March 29, 2016, SOT and US FDA co-hosted a colloquium that included a review of the evolution of the Cramer Decision Tree and TTC approach, presentation of possible revisions to the original Cramer Decision Tree and its impact on TTC levels for other routes of exposure, and a discussion of the possible expansion of the Cramer Decision Tree or other computational approaches to more diverse chemicals, multiple structural classes, and the chemical specificity of questions.

The Threshold of Toxicological Concern (TTC) is a risk assessment approach aimed at deriving a level of human intake or exposure to a chemical that is perceived to be of negligible risk, despite the absence of chemical-specific toxicity data. The original Cramer Decision Tree was proposed in 1978 for the classification of chemical substances of concern and was the basis for the subsequent adoption of the TTC approach. TTC has been originally developed to qualitatively assess the risk of low-level substances in the diet, but is now used frequently to determine whether a comprehensive risk assessment is required for a broad range of chemicals. It also has been a major advance in the prioritization and evaluation of food substances with low exposure scenarios. The application of the TTC approach to a broader universe of chemicals and routes of exposure has been the main focus of recent research, along with a number of proposals for the revision of the Cramer Decision Tree. However, an updated Cramer Decision Tree would require collection and integration of a database of information on species- and sex-specific toxicology, chemistry, dose-dependent metabolism, pharmacokinetics, and mechanism of action for a chemical space related to food exposure.