Population Life-course Exposure to Health Effects Model (PLETHEM): An R package for PBPK modeling

Abstract An outstanding challenge in the acceptance of alternatives to animal testing is the systematic incorporation of computational models into decision making pipelines. Fifteen years ago, the US EPA Office of Research and Development's framework for computational toxicology emphasized the need for computational methods to bridge the source-to-outcome continuum. This can be achieved by linking exposure estimation methods, physiologically based pharmacokinetic (PBPK) modeling, and computational systems biology pathway modeling tools into a standardized framework. To that end, we have developed the Population Life-course Exposure to Health Effects Model (PLETHEM) suite, a modular open source modeling platform that provides users the ability to create, run, share, and audit PBPK models. The platform consists of a database of chemicals, QSAR models, life-stage specific physiological and metabolic parameters needed to parameterize PBPK models, an R-based engine to perform model simulations, and an interactive user interface to define and select parameter sets for the models. PLETHEM implements easy to use interfaces for a generic PBPK model and a high-throughput IVIVE model. These model interfaces along with the included databases provide capabilities necessary for rapid analysis of chemicals using PBPK modeling. PLETHEM includes the ability to run Monte Carlo analyses to investigate population variance and a set of life-stage equations to investigate life-stage-based sensitivities. The PLETHEM database also incorporates ontogeny profiles for key metabolic enzymes that can be used to calculate in vivo metabolic clearance using measured in vitro clearance. In addition, PLETHEM has an ability to link to a number of EPA and OECD exposure estimation programs. These models, which estimate exposures in the workplace and the general populations, can be used to drive PBPK model-based estimates of resulting internal exposures to support risk assessments. PLETHEM is now freely available as an R package through the Bitbucket and GitHub open source repositories.