Incorporating a dermal absorption route into high throughput toxicokinetic modeling

Area of Science:

• Environmental Science
• Toxicology
• Computational Chemistry

Background:

• Dermal absorption is a key exposure route for pharmaceuticals, occupational, and environmental chemicals.
• Limited toxicokinetic (TK) data exists for many chemicals, despite available in vitro bioactivity data.
• In vivo TK data collection is often infeasible, necessitating high-throughput estimation methods.

Purpose of the Study:

• Develop a generalized physiologically-based toxicokinetic (PBTK) dermal exposure model for in vitro-in vivo extrapolation (IVIVE).
• Estimate dermal exposures leading to systemic concentrations comparable to in vitro bioactivity.
• Facilitate rapid risk assessment for chemicals via dermal contact in occupational settings.

Main Methods:

• Simulated dermal exposures using a PBTK model for 22 scenarios across 12 chemicals with in vivo TK data.
• Evaluated two skin permeability estimation methods: Potts-Guy and Surrey.
• Calculated root mean squared log10 errors (RMSLE) to assess model performance.

Main Results:

• A single optimal dermal permeability prediction method could not be identified due to limited chemical data.
• In vitro-in vivo extrapolation (IVIVE) was performed for 561 chemicals using both permeability methods.
• Administered Equivalent Doses (AEDs) were calculated, indicating that many chemicals did not reach achievable concentrations for bioactivity via dermal exposure.

Conclusions:

• The PBTK model integrates with a database of over a thousand industrial chemicals and pesticides.
• IVIVE suggests only a small fraction of chemicals with in vitro bioactivity data may lead to bioactive plasma concentrations through dermal exposure.
• Handling chemicals with potential for dermal bioactivity may require protective gloves.