(582da) A Multi-Compartment Skin Penetration Model Coupled to a Physiology-Based Biokinetic Model for Chemical Exposure Assessment

Reliable predictions of chemical transport through skin are important for topical drug, transdermal drug and cosmetics design, as well as chemical risk and safety assessment. The skin is a complex organ and a living membrane. Mathematical models of skin have been developed in order to predict and measure the transportation of chemicals, drugs and cosmetics through the skin. These models have provided an essential contribution to the evaluation of dermal exposure as well as toxicity assessment. Moreover, they play a significant role in analyzing experimental data and in reducing the number of necessary toxicological experiments. In this study a multi-compartmental Physiology Based ToxicoKinetic (PBTK) model of skin has been developed that describes explicitly penetration, absorption and potential metabolism of chemical compounds under different realistic exposure scenarios. The model was applied in the case of BPA and to model its contact with human skin. The generic character of the model is supported by calculating input diffusion and partition coefficients from correlations with the octanol/water partition coefficient. The detailed skin absorption model was coupled to a generic human PBTK model, giving us the capability to capture the contribution of dermal route of exposure to the overall bioavailability of a toxic compound, under complex aggregate exposure scenarios.

The skin has been modeled with a two layer structure: Stratum corneum (SC) and viable epidermis (VE). The stratum corneum has been described as a “bricks and mortar” structure. Current understanding of solute binding to keratin and other corneocyte constituents of the SC encompasses mostly equilibrium binding, and macro-scale parameterizations of transient binding for a few solutes.  Our work leverages the latest and emerging results on homogenization theory and rates of binding to produce a broad mechanistic SC model that quantifies transient solute binding in terms of coexisting free and bound concentration fields, and is parameterized at the microscopic scale.  This is critical to realistically describe actual chemical exposure, in which most of the penetration often occurs before reaching steady state. 

The detailed skin model was coupled to a generic whole-body PBTK model, giving us the capability to capture the contribution of the dermal route of exposure to the overall bioavailability of toxic compounds, capturing complex aggregate exposure situations. The modeling framework was developed in the dynamic modelling environment acslX and applied to bisphenol A. Bisphenol A (BPA) is one of the highest industrial volume chemicals produced worldwide. The major volume of BPA is used for the production of polycarbonate plastic as well as a basic component in production of the epoxy resin. Various common consumer products contain or are made by polycarbonate plastic such as household electronics and baby bottles. Epoxy resin is used in the majority of food and beverage cans. Moreover, BPA is commonly used in paper industry and particularly as color developer in thermal and copy paper. Hence, BPA has been found in thermal paper of sale receipts and money at a mean concentration of 13.3 g/kg. BPA is characterized as an estrogen with endocrine disrupting properties mediated via multiple molecular mechanisms, which depend on its metabolism and, consequently, the possible exposure routes.  Additionally, recent studies have examined the neurotoxicity of BPA, highlighting that even low maternal exposure to BPA is associated to neurodevelopmental defects. Parameterization of the skin model for BPA was based on recent in vivo studies relevant to BPA skin metabolism and permeation. The results showed that BPA was extensively metabolized in viable epidermis, and the major BPA metabolites produced by the skin were BPA mono-glucuronide and BPA monosulfate, accounting together for 27% of the daily administered dose. Evaporation has also been calculated based on the REACH technical guidance. Hence, the effect of skin exposure scenarios compared to oral and inhalation exposure scenarios was investigated.

The major question related to skin absorption of BPA is the potential bioavailability differences that might arise compared to oral exposure, which is considered as the dominant exposure route for the majority of exposure scenarios considered by the competent regulatory authorities in the EU. This concern arises from the fact that oral intake of BPA is accompanied by an extensive and very rapid first-pass metabolism (phase II glucuronidation), resulting in very low bioavailability. On the contrary, our modelling analysis has indicated that inhalation exposure to BPA results in 6-fold higher bioavailability compared to oral exposure. To elucidate potential differences, we investigated the difference in steady state plasma concentration for a given dose, using the EFSA Tolerable Daily Intake (TDI) of 50 μg/kg_bw/d as the reference point. We also simulated the concentration time profile of an oral dose of 50 g/kg/day (which corresponds to the TDI) in blood and liver. In blood, the free plasma BPA concentration after oral dose of 50 μg/kg_bw/d is equal to 0.16 μg/L, while the corresponding free plasma concentration after the administration of the same dose dermally is up to 0.3 μg/L. In contrast, peak concentration in the liver is 14 fold higher after oral as compared to dermal administration of the same dose, due to the well-known first pass metabolism of BPA.

In terms of actual exposure scenarios, the case of thermal paper containing BPA deserves special attention, since it can be heavily loaded with BPA. Unlike in plastics and epoxy resins, BPA is present in this type of paper primarily as a free monomer, and is therefore directly available for skin uptake. In a relevant study of 13 samples analysed, they were found to contain between 8–17 g/kg (0.8–1.7%) BPA. In the same study, the average level of receipt and receipt-like papers amounted to 1.4% and 1.6%. Of these thermal papers, car park tickets and bus tickets were notable for levels as high as 3.2% and 2.3%, respectively. These results show that BPA is not only present in thermal printing papers but also that BPA is taken up on the surface of the fingers when receipts are handled by the cashier and the customer. Accordingly, exposure to BPA of cashiers, was estimated up to 71 μg/day. From an extensive literature review, this was found to be the worst case scenario regarding dermal exposure to BPA. Based on this assumption, we evaluated the intra-day time course of BPA between an exposed individual from the general population (assuming an oral daily intake of 1.5 μg/kg_bw/d) and a cashier receiving an additional dose of 71 μg/day during a 10-hour shift. When BPA is administered also dermally the corresponding quasi steady-state concentration is close to the oral exposure scenario, achieved in about three to four days. This is due to the long absorption half-life during which BPA is delivered from the skin into systemic circulation. In the case of dermal exposure, the lack of first pass metabolism is less important due to the slow rate of absorption and the respective metabolism occurring in skin. In this case, the diurnal peak concentrations are higher only by 60% than the exposure levels corresponding to the typical EFSA exposure scenario. However, the contribution of this exposure route to the area under the curve (AUC), i.e. the integrated quantity of bioavailable BPA, is more significant, since the slow rate of absorption contributes to continuous presence of BPA in plasma within the day. 

Additional investigation of the potential bioavailability differences that might exist because of dermal administration showed that BPA does not pose concern, since the lack of first-pass metabolism is decompensated by the slow rate of absorption, the extent of skin metabolism and more significantly to the low exposure. The above lead to the conclusion that dermal consumer exposure scenarios related to BPA arising from paper recycling (except in the case of thermal paper for cashiers), might be considered as negligible.