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The Internal Threshold of Toxicological Concern (iTTC) combines the Threshold of Toxicological Concern (TTC) concept from toxicology with the internal dose from pharmacokinetics/pharmacodynamics (PBPK). Combining these approaches makes rapid prioritization and risk assessment possible while reducing animal use and protecting human health. However, more research is required before the benefits of these combined approaches can be realized. To this end, an international collaboration has been established.

The collaborative research activities to develop the iTTC – a safe level representative of internal exposures – are progressing. Once developed, these iTTC values can be used in advanced safety evaluations as part of a New Approach Methodologies (NAMs) toolbox to interpret results from in vitro test systems in a risk context.
With increasing interest in non-animal alternatives and NAMs, many researchers in academia, government, and the private sector have increased their focus on the potential to use the TTC and iTTC in tiered risk-based applications for commodity and consumer chemicals. For example, the TTC can help establish acceptable low-level exposure values for risk-based prioritization and safety evaluations for chemicals with limited toxicological data. (Read the ACC LRI TTC Q & A document and view the ACC LRI TTC web video to learn more about the derivation and application of TTCs.)

The scientific studies needed to generate the data and conduct pharmacokinetic modeling to establish iTTC values are being realized through the Research Institute for Fragrance Materials (RIFM), the American Chemistry Council’s Long-range Research Initiative (ACC LRI), and within the framework of the Cosmetics Europe Long Range Science Strategy (LRSS) Programme.

A key milestone in developing iTTC values has been reached: The in vitro permeability and metabolism studies have been completed. However, as described in Ellison et al. (2019),  to derive iTTC values, new in vitro data need to be generated for liver metabolism and gastrointestinal (oral) absorption. These data are necessary for the PBPK modeling component to convert external NOAELs to estimates of internal plasma concentration.

• The derivation of iTTC values requires the conversion of chemical-specific external NOAELs (in mg/kg/day) in the TTC database to estimated internal plasma concentrations. This conversion requires in vitro data and PBPK modeling.
• These in vitro laboratory studies, which have recently been completed, involved determining the permeability and hepatocyte metabolism of ~200 chemicals.
• The data developed from these in vitro results are now used to conduct the PBPK (using PLETHEM PBPK open source software) modeling to derive the iTTC values.
• A list of the compounds studied in the in vitro hepatocyte metabolism assays is available here.
• Once the PBPK modeling has been completed, the derived iTTCs, PBPK modeling results, and underlying in vitro data will be submitted to a peer-reviewed scientific journal.
• This research has increased the chemical space covered by such in vitro assays. In addition to deriving iTTC values, these results will inform future research, such as ground-truthing high throughput toxicokinetic models or the design of new studies to address underrepresented chemistries.