Grantee Research Project Results
Integrated blood brain barrier computational model development to predict doses of concern for compound linked neurotoxicity
EPA Grant Number: R840027Title: Integrated blood brain barrier computational model development to predict doses of concern for compound linked neurotoxicity
Investigators: Knipp, Gregory , Stratford, Robert
Current Investigators: Knipp, Gregory , Sluka, James
Institution: Purdue University
EPA Project Officer: Spatz, Kyle
Project Period: August 1, 2020 through May 8, 2025
Project Amount: $790,441
RFA: Advancing Toxicokinetics for Efficient and Robust Chemical Evaluations (2019) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability
Description:
Reports of xenobiotic-induced neurotoxicity have significantly increased in the literature over the last few decades. There currently exist a number of in vitro neurotoxicity screens utilizing neuronal cell cultures to assess specific phenotypic neuronal responses, however the cells are often exposed to concentrations that far exceed levels that may traverse the restrictive Blood-Brain Barrier (BBB).
Objective:
The overarching objective of this project is to extend the current High Throughput Toxicokinetic (HTTK) prediction of steady-state systemic exposure (Css) of environmental chemicals for predicting doses of concern to an assessment of brain extracellular fluid (ECF) exposure at steady-state (Css,brain). The investigators have recently developed a novel BBB model that mimics the physiologically relevant in vivo barrier. In the model, astrocytes, pericytes and brain micro-vessel endothelial cells (BMECs) are layered in direct contact to enable cell-cell signaling that acts synergistically to restrict permeation across the barrier. Utilizing this model, the bidirectional permeability of paracellular, passive transcellular, and transporter-substrate marker compounds will be determined to rank order the permeation of known environmental toxicants. Integration of a human cell-based in vitro BBB permeation rates across the triculture assay will be linked with physiological-based pharmacokinetic (PBPK) modeling to the drive attainment of this objective.
Approach:
Two approaches will be implemented to test the central hypothesis that the integrated system for prediction of compound Css,brain will improve accuracy in predicting doses of concern of chemicals that cause perturbations in brain cell-based assays.
1. Adapt a presently available low-throughput triculture assay of the human BBB to a higher throughput screen that measures bi-directional compound permeability (in vitro physiological-based model);
2. Integrate permeability measures with human-based physiological parameters and compound properties relevant to their disposition in the brain to predict Css,brain of compounds (in silico physiological-based model).
Expected Results:
Accomplishment of these aims will define a novel integrated in vitro and in silico system that builds on current approaches for prediction of systemic exposure to prediction of brain exposure. Integration of systemic-to-brain with dose-to-systemic exposure prediction will improve accuracy, and thereby confidence, for assessment of brain toxicity potential, and ultimately improve the ability to protect human health.
Publications and Presentations:
Publications have been submitted on this project: View all 10 publications for this projectJournal Articles:
Journal Articles have been submitted on this project: View all 6 journal articles for this projectSupplemental Keywords:
Pharmacokinetic Modeling, In Vitro-In Vivo Extrapolation, Toxicity, Neurodevelopment, Neurodegenerative, chemicals, toxics, PAHs, PNAs, PCBs, Organics, Exposure, Risk, Risk Assessment, Effects, Health Effects, Human Health, Bayesian, and Modeling.Progress and Final Reports:
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.