A Dermal Absorption Model Validated By Linkage to a PBPK Model For Chloroform

Abstract

WM3-PD-11 Introduction: Dermal absorption is a significant contributor to chloroform concentrations in the body due to dermal exposure to chlorinated water during bathing and swimming. Because of the complexity of dermal exposure mechanisms and the skin absorption process, dermal exposure has only recently been studied more extensively. Most current mathematical absorption models of the skin take into account only one layer of the skin and/or allow for only a one-time deposition onto the skin. However, we have previously presented a dermal absorption model that accounts for 2 distinct layers of the skin (ie, stratum corneum and viable epidermis), time-series exposure events, previous concentration in the skin, and changes in skin concentration with time and depth. This 2-layer, time-variant dermal absorption model has been linked to a physiologically based pharmacokinetic (PBPK) model, allowing body burden estimates and validation of the dermal absorption component by comparison with experimental data. Methods: The PBPK model was constructed using parameters specific to the experimental subject and to chloroform. Chloroform concentrations in exhaled air from inhalation exposure experiments allowed a strong validation of the PBPK model without the dermal absorption component (experimental data and model output differences <20%). The 2-layer, time-variant dermal absorption model for chloroform was constructed and linked to the PBPK model. To validate the dermal absorption component, the combined dermal-PBPK model was used to simulate dermal absorption of aqueous chloroform, and exhaled air outputs were compared with the experimental data. Results: The combined dermal-PBPK model outputs were found to be highly dependent on parameters for the dermal absorption model that are difficult to estimate. Diffusivity and partitioning for chloroform in the 2 layers of the skin can be estimated using various equations based on the chemical characteristics of chloroform. However, each parameter can be estimated using multiple methods, often resulting in drastically different values. For instance, 2 methods for determining diffusivity in the stratum corneum resulted in a difference of a factor of 104. Such differences alter the shape and amplitude of the output curve. Discussion: Determining the optimal method for estimating the dermal parameters for our model will be important for a more accurate assessment of the impact of dermal exposure. This is especially important for chloroform, for which dermal exposure is a significant exposure route. The combined dermal-PBPK model can then be used to assess the impact of dermal and inhalation exposures simultaneously, in order to more accurately estimate body burden from bathing and swimming.