Physiologically based pharmacokinetic model parameter estimation and sensitivity and variability analyses for...

Area of Science:

• Toxicology and Environmental Health
• Pharmacokinetics and Metabolism
• Computational Modeling

Background:

• Acrylonitrile (ACN) and its metabolite cyanoethylene oxide (CEO) are industrial chemicals with potential health risks.
• Understanding their disposition in the human body is crucial for accurate risk assessment.

Purpose of the Study:

• To develop a physiologically based pharmacokinetic (PBPK) model for ACN and CEO disposition in humans.
• To apply the model for risk assessment by simulating human exposure scenarios.

Main Methods:

• Developed a human PBPK model incorporating biotransformation and reactivity pathways of ACN and CEO.
• Utilized human in vitro data and scaled parameters from a rat model.
• Conducted simulations for inhalation and oral exposure routes, followed by sensitivity and variability analyses.

Main Results:

• Predicted similar blood and brain ACN and CEO concentrations in rats and humans exposed via inhalation.
• Simulations showed higher predicted blood ACN concentrations in rats than humans exposed to ACN via drinking water.
• Identified key parameters influencing variability in ACN and CEO concentrations, including reaction rates, partition coefficients, and ventilation rates.

Conclusions:

• The PBPK model provides a valuable tool for assessing human health risks associated with ACN exposure.
• Exposure route significantly influences predicted ACN concentrations, with inhalation and oral routes yielding different results between species.
• Variability analyses highlight critical parameters for refining future risk assessments and targeted research.