Student Research: Anayi Norman
MS, , 2004
Use of PBPK Models to Characterize Dermal Absorption of Volatile Organic Compounds from Water
Recently, results have been reported from human in vivo trials conducted to assess dermal absorption of volatile organic compounds (VOCs) from aqueous solution (Gordon and Wallace, 1998; Corley et al., 2000; Gordon et al., 2002; Thrall et al., 2002). Because these experiments utilized VOC concentration in exhaled breath as the indicator of exposure, estimation of VOC absorption and distribution in the body is facilitated by the use of physiologically-based pharmacokinetic (PBPK) models. Dermal absorption is typically characterized by a permeability coefficient (KD). By using KD as a fitting parameter to match PBPK model predictions to breath data, results from the in vivo experiments noted above can be employed to estimate Kp. Values of Kp calculated in this manner can be compared to values obtained using the modified Potts-Guy equation recommended by the U.S. Environmental Protection Agency (EPA) in current guidance (EPA, 2001). The modified Potts-Guy equation is based on results obtained in vitro.
Traditional PBPK models have often not included a skin compartment. In order to evaluate dermal exposure, the investigators cited above modified PBPK models by adding skin compartments. There are several ways that the skin can be represented in a PBPK model. Common foRMS of the skin component of a PBPK model include the one-compartment model (in which the skin is represented as one layer), the two-compartment model (in which the skin is represented as two layers), or a hybrid of the two. Many versions of a one-compartment model have been proposed, as discussed in McCarley and Bunge (2001). In one variety of the one-compartment model, the stratum corneum or the viable epidermis alone represents both the barrier function and the storage capacity of the skin. This type of model assumes the other layers of the skin insignificant to the storage capacity and overall resistance to transport. Another type of one-compartment model represents the skin with composite skin layers. The skin compartment may be composed of the stratum corneum, the viable epidermis, the dermis, or a combination of any of these skin layers (whole thickness skin). In the third type of one-compartment model commonly used, the penetration rate of the skin is limited by the stratum corneum and the storage capacity is controlled by the viable epidermis. In each of the above models, the skin compartment is assumed to have the same concentration at all locations. The term Continuously Stirred Tank Reactor (CSTR) is generally used in chemical engineering to describe this type of model. The term CSTR will be utilized in this paper to describe a one-compartment skin model in which the compartment composed of stratum corneum and has the same concentration of chemical compounds at all points.
Although many current models represent the skin as having the same concentration at all points, experiments have shown that the skin behaves like a membrane (Scheuplein, 1972). Mathematical models treating the skin as a membrane require more cumbersome mathematics and intensive computing resources. By modifying the CSTR rate constants to give the same predictions as a membrane model for specific matching criteria, an approximate membrane model that is amenable to traditional PBPK foRMS can be created. This type of model will be referred to as the Simplified Time Lag model (STL) as in McCarley and Bunge (1998).
The objective of this paper is to demonstrate the difference in outcomes when using the CSTR and STL models. A difference in outcome values from the two models would suggest that any parameters that are back-fit are dependent on the model used and must be used with caution. The present effort uses trichloroethylene (TCE) as the test compound and Poet et al. (2000) values for parameters for the models. Poet et al. (2000) did experiments in which subjects immersed either one hand in water with TCE or had two exposure cells attached per arm for two hours while breathing purified air. Exhaled breath concentration of TCE was monitored during the exposure period and for two hours post-exposure.
Taken from the beginning of thesis.