Dermal and Multi-Route Exposure/Dose Analysis Using Physiologically Based Toxicokinetic Modeling. Panos G. Georgopoulos and Amit Roy, UMDNJ - Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute (EOHSI), Piscataway, NJ 08855-11 79
A modular, physiologically based, computational modeling system has been developed to support multimedia-multiroute-multipathway exposure analyses in a "bidirectional" framework. The computational scheme incorporates a hierarchy of alternative formulations describing dermal absorption of chemicals, ranging from a single "lumped" compartment representation of the skin, with absorption treated as a pseudo-kinetic step, to a detailed, fully "distributed," representation of the stratum corneum, with mass transport governed by partial differential diffusion-type equations. This modeling system is designed (a) to calculate internal---total and target tissue---dose, given exposure concentrations and contact patterns, as well as (b) to estimate exposure concentrations in different media using numerical optimization methods for the inverse formulation of the problem. In order to attain objective (b), suitable "response metrics," i.e. quantitative biomarker information, such as the time profiles of concentration levels of toxicants or their metabolites in body fluids, should be available. In addition to estimating--- and discriminating among---internal doses associated with different routes of exposure, such as inhalation, ingestion and dermal absorption, this approach in principle allows the reconstruction of exposure scenarios, when appropriate biomarker information is available, and the evaluation of exposure prediction methods that utilize environmental concentration and human activity pattern information. In practice, the usefulness and the robustness of the approach will depend on the chemical compound under consideration as well as on various environmental factors. The applicability and the potential use and implications of this approach forrisk analyses, as well as the performance of the modeling system that was developed to implement it, have been studied and evaluated using sensitivity-uncertainty analysis combined with measured time-concentration profiles in exhaled breath resulting from multimedia and multiroute exposures to volatile organic compounds (VOCs).