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 toxicokinetics. 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® 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 concentrations. 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.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sebastian Polak and Zofia Bielecka are Certara UK (Simcyp Division) employees. Certara is a developer of the Simcyp platform which was used in the current study. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.