Development of additional workflows for risk assessment and prioritization for the PLETHEM R Package

March 19, 2020

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Authors: Kevin A. Bronson, Jeremy Fitzpatrick, Marjory Moreau, Patrick D. McMullen, Salil N. Pendse

Over the past three years we have been developing the population life-course exposure to health effects model (PLETHEM) – the open source R package that is designed to provide tools that can be used to bridge the source-to-outcome continuum. Pharmacokinetic modeling is becoming increasingly important in chemical safety decision making, with applications in prioritizing risk assessment by establishing margins of exposure for chemicals and extrapolating hazard across different ages, population cohorts, or occupational classes. As a part of our effort to provide the community with an easy-to-use yet capable modeling tool, we have continued to develop the PLETHEM package. We have created workflows for automated reverse dosimetry and route to route extrapolation, modeling for ecotoxicology applications, and kinetically derived maximum tolerated dose estimation. The automated reverse dosimetry module implements the Discretized Bayesian Approach as described by Tan et al. (2007) along with an easy-to-use interface to run the workflow. Simulation results from existing PBPK models or from models parameterized within PLETHEM can be imported for dose reconstruction. We have also added the ability to perform automated route-to-route extrapolations within PLETHEM. The user can parameterize the model for a given route of exposure using the existing forward dosimetry interface within PLETHEM and use this parameterized model to estimate exposure along a different route using this workflow. Next, as a part of this update, we have added a fish PBPK model described by Krishnan et al. (2009), physiological datasets for this model and an easy to use modeling interface to help stakeholders address ecotoxicology concerns.  Lastly, we are incorporating into PLETHEM additional features to make kinetically derived maximum tolerated dose (KMD) modeling more accessible. KMD makes use of kinetic modeling to identify dose ranges that avoid saturating ADME processes, which would convolute the interpretation of the study. McFadden et al. (2012) described a statistical method to determine KMD values for toxicokinetic studies. We are adding to PLETHEM an interface that allows users to import their own toxicokinetic datasets or simulated PBPK models from PLETHEM to estimate a KMD. PLETHEM is freely available via the Comprehensive R Archive Network (CRAN). We are also hosting some of these workflows as standalone apps online to provide users with easy access to them.