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. 2021 Jan 15:2:621541.
doi: 10.3389/ftox.2020.621541. eCollection 2020.

Internal Threshold of Toxicological Concern (iTTC): Where We Are Today and What Is Possible in the Near Future

Corie A Ellison  1 , Anne Marie Api  2 , Richard A Becker  3 , Alina Y Efremenko  4 , Sanket Gadhia  2 , C Eric Hack  4 , Nicola J Hewitt  5 , Mustafa Varcin  5 , Andreas Schepky  6
Affiliations

Internal Threshold of Toxicological Concern (iTTC): Where We Are Today and What Is Possible in the Near Future

Corie A Ellison et al. Front Toxicol. .

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.

Keywords: ITTC; IVIVE; PBPK; TTC; in vitro to in vivo; metabolism; physiologically based pharmacokinetic modeling; threshold of toxicological concern.

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Conflict of interest statement

CE was employed by The Procter and Gamble Company, AA and SG were employed by the Research Institute for Fragrance Materials, RB was employed by the American Chemistry Council, AE and CH were employed by ScitoVation LLC, NH and MV were employed by Cosmetic Europe, AS was employed by Beiersdorf AG.

Figures

Figure 1
Figure 1
Framework for deriving iTTC values. Chemicals from key TTC databases were combined and the chemical space was mapped using structural and ADME descriptors for the chemicals. Each chemical has undergone a literature search for existing pharmacokinetic (PK) and in vitro metabolism data. Results of the chemical space assessment and literature search were used to guide chemical selection for the iTTC project (see Figure 2). The external dose NOAEL for chemicals included in the iTTC project are converted to an internal exposure by using PBPK modeling. The distribution of chemical specific internal exposures is then used to identify iTTC thresholds.
Figure 2
Figure 2
Decision tree for chemical selection for the iTTC project.
See this image and copyright information in PMC

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