Abstract
The Threshold of Toxicological Concern (TTC) is a risk assessment tool for evaluating low-level exposure to chemicals with limited toxicological data. A next step in the ongoing development of TTC is to extend this concept further so that it can be applied to internal exposures. This refinement of TTC based on plasma concentrations, referred to as internal TTC (iTTC), attempts to convert the chemical-specific external NOAELs (in mg/kg/day) in the TTC database to an estimated internal exposure. A multi-stakeholder collaboration formed, with the aim of establishing an iTTC suitable for human safety risk assessment. Here, we discuss the advances and future directions for the iTTC project, including: (1) results from the systematic literature search for metabolism and pharmacokinetic data for the 1,251 chemicals in the iTTC database; (2) selection of ~350 chemicals that will be included in the final iTTC; (3) an overview of the in vitro caco-2 and in vitro hepatic metabolism studies currently being generated for the iTTC chemicals; (4) demonstrate how PBPK modeling is being utilized to convert a chemical-specific external NOAEL to an internal exposure; (5) perspective on the next steps in the iTTC project.
Highlights
Industries and regulatory agencies across the world are challenged with performing human health safety assessments, risk-based prioritizations, and evaluations of thousands of chemicals
ADME properties are collected for each chemical in Abbreviations: ADME, Absorption, Distribution, Metabolism and Excretion; CosEu, Cosmetics Europe; fraction absorbed (Fa), Fraction absorbed; internal TTC (iTTC), Internal Threshold of Toxicological Concern; LOAEL, Lowest Observable Adverse Effect Level; NOAEL, No Observable Adverse Effect Levels; PK, Pharmacokinetic; physiologically based pharmacokinetic (PBPK), Physiologically based pharmacokinetic; PLETHEM, Population Life-course Exposure to Health Effects Model; RIFM, Research Institute for Fragrance Materials; TTC, Threshold of Toxicological Concern
The large dataset derived when merging the Munro, COSMOS, and RIFM databases creates a practical challenge for the iTTC project because of the resources needed to generate new in vitro ADME data and complete PBPK modeling for such a diverse group of chemicals
Summary
Industries and regulatory agencies across the world are challenged with performing human health safety assessments, risk-based prioritizations, and evaluations of thousands of chemicals. This refinement of TTC based on plasma concentrations, referred to as an “internal TTC” (iTTC), attempts to convert external NOAELs in mg/kg/day of chemicals in the TTC database to an estimated corresponding internal exposure.
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