Physiologically based modelling of dermal absorption and kinetics of consumer-relevant chemicals: A case study with exposure to bisphenol A from thermal paper

Bisphenol A (BPA) is one of the best studied industrial chemicals in terms of exposure, toxicity, and tox-icokinetics. This renders it an ideal candidate to exploit the recent advancements in physiologically based pharmacokinetic (PBPK) modelling to support risk assessment of BPA specifically, and of other consumer-relevant hazardous chemicals in general. Using the exposure from thermal paper as a case scenario, this study employed the multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model available in the Simcyp (R) Simulator to simulate the dermal toxicokinetics of BPA at local and systemic levels. Sensitivity analysis helped to identify physicochemical and physiological factors influencing the systemic exposure to BPA. The iterative modelling process was as follows: (i) development of compound files for BPA and its conjugates, (ii) setting-up of a PBPK model for intravenous administration, (iii) extension for oral administration, and (iv) extension for exposure via skin (i.e., hand) contact. A toxicokinetic study involving hand contact to BPA-containing paper was used for model refinement. Cumulative urinary excretion of total BPA had to be employed for dose reconstruction. PBPK model performance was verified using the observed serum BPA con-centrations. The predicted distribution across the skin compartments revealed a depot of BPA in the stratum corneum (SC). These findings shed light on the role of the SC to act as temporary reservoir for lipophilic chemicals prior to systemic absorption, which inter alia is relevant for the interpretation of human biomonitoring data and for establishing the relationship between external and internal measures of exposure.

Automated summary

This study used a physiologically based pharmacokinetic (PBPK) model to simulate the dermal toxicokinetics of BPA and investigate its absorption through skin contact. Sensitivity analysis revealed factors influencing systemic exposure to BPA. The PBPK model was validated using serum BPA concentrations and revealed the temporary storage of BPA in the stratum corneum, providing insights for interpreting biomonitoring data and understanding the relationship between external and internal exposure measures.