RECONSTRUCTION OF SHORT-TERM MULTIROUTE EXPOSURE TO VOLATILE ORGANIC-COMPOUNDS USING PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELS

An approach has been developed for implementing physiologically based pharmacokinetic (PBPK) models in an ''inverse'' mode to reconstruct sh ort-term exposure concentrations and internal dose for multiroute and multimedia exposures to toxic volatile organic compounds. It has been applied to chloroform inhalation and dermal absorption. This modeling approach estimates exposure concentrations in different media through statistical optimization methods for the solutions of the PBPK models, such as likelihood maximization. The necessary input is a suitable ph ysiological response metric, such as the time profile of concentration levels of toxicants or their metabolites in body fluids. Two PBPK mod els of different sophistication - the DP-PBPKM, which employs a partia l differential equation description of dermal transport (i.e. based on Fick's second law for diffusive transport), and LP2S-PBPKM, which use s an ordinary differential equation description of transport (i.e. bas ed on Fick's first law, which assumes steady state for mass fluxes) - have been utilized in this study. The model performance was evaluated using available ambient and exhaled breath chloroform concentration da ta from previously conducted shower and swimming pool studies, corresp onding to inhalation only, and combined inhalation and dermal exposure s. The exposure/dose reconstruction results were in agreement with obs ervations when critical data, such as the peak exhaled concentration a nd the shape of the immediate post-exposure exhaled concentration prof ile, were available.