BK/TD models for analyzing in vitro impedance data on cytotoxicity

Area of Science:

• Toxicology
• In vitro toxicology
• Computational toxicology

Background:

• The ban on animal testing drives innovation in in vitro methods for cosmetics safety.
• Impedance metrics offer real-time cell viability monitoring but require dynamic toxicity assessment.
• Current methods often lack the ability to fully capture chronic exposure effects.

Purpose of the Study:

• To develop and apply mechanistic biokinetic/toxicodynamic (BK/TD) models for analyzing time-course cell viability in impedance-based cytotoxicity assays.
• To assess the predictive power of BK/TD models for both single and repeated exposures to hepatotoxic compounds.
• To establish a framework for coupling in vitro models with human biokinetic models for dose-response extrapolation.

Main Methods:

• Construction of mechanistic biokinetic/toxicodynamic (BK/TD) models incorporating compound fate during assays.
• Application of BK/TD models to HepaRG cell viability data following single (48h) and repeated (4-week) exposures.
• Calibration and validation of models using experimental data from three known hepatotoxic compounds: coumarin, isoeugenol, and benzophenone-2.

Main Results:

• BK/TD models demonstrated a good fit to the calibration data for both single and repeated exposure scenarios.
• Models calibrated with single exposure data could only predict repeated exposure outcomes for one of the three tested compounds.
• The study highlights the limitations of single-exposure data for predicting chronic effects.

Conclusions:

• Mechanistic BK/TD models provide a dynamic approach to analyzing in vitro cytotoxicity data from impedance monitoring.
• Long-term in vitro exposure data are crucial for accurately assessing chronic hepatotoxicity.
• The proposed BK/TD models offer potential for integration with human biokinetic models to predict human hepatotoxicity from dose exposure.