A General Physiological and Toxicokinetic (GPAT) Model for Simulating Complex Toluene Exposure Scenarios in Humans

Abstract

Realistic simulation of environmental exposure scenarios requires dynamic methods in which exposures and human activities vary continuously as a function of time. Simulation of such complex scenarios is, with conventional physiologically based methods, a complex and programming-intensive task. The goal of the present effort was to simplify this task by combining a commercially available general whole-body human physiological model (QCP2004) with a slightly extended physiologically based toxicokinetic (PBTK) model from the literature. The QCP2004 model is a differential equation-based model similar to PBTK models except that normal organ function is simulated and the body organs are appropriately interlinked. Here QCP2004 provided estimates of physiological parameters required by the PBTK model. These were updated as the model was iteratively executed appropriate to the varying activity of the human subject. The combined general physiological model and the PBTK model was called a general physiological and toxicokinetic (GPAT) model.The GPAT model was tested and (within the constraints of available toluene exposure experiments in the literature) found to predict toluene blood concentrations, even in dynamic situations. A model of the structure used in the present work is capable of expansion as new knowledge is developed and greater detail is desired. Similarly, multiple toxicant PBTK models can be developed and incorporated for applications to mixtures risk assessment. Additionally, toxicant effects on organ systems can be achieved by altering organ function during a simulation as a function of the internal dose of toxicants. By cumulatively adding detail to the model as new physiological and chemical-specific information becomes available, the model can become a repository of knowledge for increasingly sophisticated risk-assessment applications.