The threshold of toxicological concern (TTC) is a science-based concept that categorizes chemicals with low-level exposures. No appreciable human health risk for a lifetime of 70 years is expected for exposure values below the TTC. The US Food and Drug Administration (US FDA) Threshold of Regulation for indirect food additives was the scientific basis for the TTC concept. This approach has been accepted by various global regulatory agencies for assessment of impurities, cosmetic ingredients, chemicals food packaging materials, etc. With the ever-changing landscape of risk assessment, the TTC concept has evolved, with a diverse range of applications. The developments in this concept were presented in a Workshop Session titled “Thresholds of Toxicological Concern: Reassessing the Basis and Expanding the Horizon” during 2021 SOT Annual Meeting and ToxExpo.
Dr. Grace Patlewicz from the US Environmental Protection Agency provided a brief introduction to the TTC. She spoke about the two main types of TTC, viz “general TTC” and “structural-based TTC.” The general TTC is based on a predicted tumor risk of one in a million, derived through an analysis of cancer data, and the structural-based TTC are based on frequency distribution (fifth percentile) of no-observed-adverse/effect levels, NO(A)ELs, of noncancer endpoints. Dr. Patlewicz also explained how chemicals are classified based on the Cramer decision tree. She also provided a brief overview of the current ongoing work in TTC to expand its application in different areas of risk assessment.
Dr. Mark Cronin from Liverpool John Moores University spoke about the updated Cancer Potency Database (CPDB). He explained the need for an update to the original database because of availability of new data and information and the requirement of full curation of chemical structures, as well as to ensure consistency in calculation of the point of departure (PoD). Dr. Cronin explained that datasets were extracted from the original database to ensure quality of the data to evaluate mode of action of carcinogens and to compare toxic doses (TDx) with benchmark dose limits (BMDL) to derive PoD values. He explained the process of how the data were compiled to create a new cancer TTC dataset.
Dr. Szabina Stice from US FDA provided updates to the expanded Cramer decision tree (CDT). She briefly discussed some of the shortcomings of the original CDT, which was published in 1978. Because of availability of new safety data in addition to deciphering modes of toxic action, US FDA has updated the CDT. Dr. Stice provided updates related to this work in the past six years and the application of the expanded decision tree (EDT).
Dr. Chihae Yang from MN-AM spoke about a new database to derive highly curated datasets for the TTC approach. The objective of working on this database was to expand the applicability of the TTC in the risk assessment of antimicrobials by utilizing subchronic toxicity data. She explained how the antimicrobial TTC datasets were created and the multiple data sources used in the process. New cheminformatics methods for the grouping of chemicals and chemotype categories associated with potency, based on the highly curated dataset, were developed. Dr. Yang presented new case studies using the new datasets for potential assessment of chronic toxicity.
Dr. Corie Ellison from Procter & Gamble spoke about working toward development of an internal TTC (iTTC), or how internal exposures can be represented by refining the TTC based on plasma concentrations, which were termed as iTTC. Dr. Ellison explained how computational tools are being employed to convert NOAELs in the TTC database to an estimated internal exposure. He also spoke about the multiple databases that are being used to generate the iTTC values. Systematic literature reviews of pharmacokinetic data combined with chemical space analysis were utilized to narrow down the number of chemicals in the final inclusion. The PBPK modeling approach also is being used to convert NOAELs in the existing TTC database to iTTC. Dr. Ellison described how this body of work also will be applicable to broader issues, like creation of a PK and ADME database, for increased acceptance of PBPK modeling, and for route-to-route extrapolation.
Dr. Heli Hollnagel from Dow spoke about characterizing uncertainty in TTC. She explained the sources of uncertainty in each step of the hazard characterization process. The methods employed and the results from the work of the ILSI Europe Expert Group, which characterized and quantified the uncertainties, were put forth. Dr. Hollnagel also spoke about how to improve the hazard characterization process.
Data-poor chemicals require the application of the TTC concept to enable risk assessments. However, there are limitations and uncertainties in this concept, which were put forth and adequately answered in this Workshop Session. New developments in this area are increasing the transparency in this concept, and with the application of next-generation methodologies, the TTC concept is here to stay.
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