A Detailed Multi-compartmental Skin Penetration Model Coupled to a Physiologically Based Pharmacokinetic Model for Assessing Exposure to Chemical Compounds: the Case of Bisphenol A

摘要

The study deals with the development of a multi-compartmental model of skin for explicit description of penetration, absorption and metabolism of chemical compounds under different realistic exposure scenarios. The generic character of the model is supported by calculating input diffusion and partition coefficients from Abraham's equation. The detailed skin model was coupled to a generic PBPK model, giving us the capability to capture the contribution of dermal route of exposure to the overall bioavailabilty of a toxic compound, under complex aggregate exposure scenarios. The model was applied on bisphenol A, a common plasticizer found in many consumer products (mainly food conduct materials), as well as to thermal printing paper and money, thus coming into contact with human skin. Parameterization of the model was based on recent in vivo studies relevant to BPA permeation through the skin. Among several typical exposure scenarios examined, of particular interest is the one of a cashier who receives an additional daily intake of BPA up to 71 μg during a ten-hour work shift from dermal contact with thermal paper that is used commonly for receipts. It was found that the extent of metabolism to inactive BPA-glucuronide was only 2% within the first 24 h, the time in which 90% of the dermal dose is absorbed. Thus, although BPA penetrates slowly the layers of the skin to enter systemic circulation, its contribution to the overall bioavailability is significant, since derm ally absorbed BPA is not subjected to 1st pass metabolism (as it is the case of oral exposure) occurring at the liver. For the same normalized bodyweight dose, absorbed BPA through the skin corresponds to a dose twice as high to the one taken orally. However, even in the worst-case exposure scenario of skin exposure to BPA (71 μg/day), internal exposure is one order of magnitude lower than the equivalent internal dose corresponding to the revised EFSA TDI of 5 μg/kg_bw/day.