The REU 2012 group consisted of three undergraduates, myself, and two mentors from the US EPA (Dr. Marina Evans and Christopher Eklund). We explored extrapolation of in vivo and in vitro rat studies to in vivo human data using physiologically-based pharmacokinetic (PBPK) modeling using dermal exposure data for lindane.
The undergraduates were:
The following project description was taken from the NCSU 2012 REU site:
Title: Application of physiologically based pharmacokinetic (PBPK) modeling to estimate internal dose in the brain after exposure to lindane (pesticide).
Description: The application of mathematical models that take into account physiological and chemical information is now well established as a risk assessment tool, especially for extrapolation across species and different exposure scenarios. These PBPK models are usually calibrated using data collected in rodents and used to predict internal dose to humans, for which we usually have very little or no data. In this project, the students will make use of rodent data to develop a PBPK model that describes the clearance of a pesticide from the body. The pesticide lindane has different effects throughout the body, but the brain is well studied and documented in humans. The rodent PBPK model will then be translated to predict human brain concentrations. The model in the brain will be further refined to describe the specific areas of the brain that lead to toxicity, such as seizures. The mechanism used to explain the seizures involves a specific neuron having GABA receptors. This mechanistic information has not yet been incorporated into previous mathematical models. The human model can be further refined using children parameters and explore issues of potential susceptibility at different ages. The students involved in this project will make use of mathematics to develop models similar to those currently applied in risk assessments and used to help support environmental decision based on scientific principles.
Our paper describing this work was published in the Toxicology Letters and can be found here.
Sawyer, M.E., Evans, M.V., Wilson, C.A., Beesley, L.J., Leon, L.S., Eklund, C.R., Croom, E.L., Pegram, R.A. (2016). Development of a human physiologically based pharmacokinetic (PBPK) model for dermal permeability for lindane. Toxicology Letters, 245, 106-109. DOI:10.1016/j.toxlet.2016.01.008
Lindane is a neurotoxicant used for the treatment of lice and scabies present on human skin. Due to its pharmaceutical application, an extensive pharmacokinetic database exists in humans. Mathematical diffusion models allow for calculation of lindane skin permeability coefficients using human kinetic data obtained from in vitro and in vivo experimentation as well as a default compound-specific calculation based on physicochemical characteristics used in the absence of kinetic data. A dermal model was developed to describe lindane diffusion into the skin, where the skin compartment consisted of homogeneous dermal tissue. This study utilized Fick's law of diffusion along with chemical binding to protein and lipids to determine appropriate dermal absorption parameters which were then incorporated into a physiologically based pharmacokinetic (PBPK) model to describe in vivo kinetics. The estimation of permeability coefficients using chemical binding in combination with in vivo data demonstrates the advantages of combining physiochemical properties with a PBPK model to predict dermal absorption.
This work was presented at several conferences in the form of posters and presentations.