Physiologically based toxicokinetic modelling as a tool to support risk assessment: three case studies

Area of Science:

• Toxicology
• Risk Assessment
• Computational Modeling

Background:

• Physiologically-based toxicokinetic (PBTK) models are crucial for regulatory risk assessment.
• Understanding chemical exposure routes (oral, dermal) and age-dependent metabolic differences is vital for accurate risk evaluation.
• Bisphenol A (BPA) and coumarin are common chemicals with varying exposure pathways.

Purpose of the Study:

• To demonstrate the utility of PBTK modeling in regulatory risk assessment through three case studies.
• To evaluate the risk associated with oral and dermal exposure to BPA in different age groups.
• To assess the risk of coumarin exposure from cosmetic products.

Main Methods:

• Application of PBTK modeling to simulate chemical absorption, distribution, metabolism, and excretion (ADME) in humans.
• Analysis of age-dependent enzyme expression affecting BPA metabolism in newborns.
• Quantification of BPA exposure from dermal sources (e.g., receipts).
• Assessment of coumarin exposure from cosmetic products and its toxicological implications.

Main Results:

• Newborns exposed orally to BPA may reach near the tolerated daily intake (TDI) due to lower enzyme expression.
• Current levels of dermal BPA exposure pose no significant risk to adults.
• Dermal exposure to coumarin via cosmetics can lead to exposures twice the TDI.
• PBTK modeling identified liver peak concentration as a key metric for liver toxicity, showing lower levels after high dermal coumarin exposure compared to oral TDI exposure.

Conclusions:

• PBTK modeling provides a scientifically sound basis for regulatory decisions regarding chemical safety.
• Age and exposure route significantly influence the toxicological risk of chemicals like BPA.
• PBTK models are valuable tools for assessing risks from various exposure scenarios, including dermal contact with consumer products.