Grantee Research Project Results
2021 Progress Report: An in vitro-in silico hybrid approach for high-throughput estimation of trans-barrier permeability for chemical pollutants
EPA Grant Number: R840033Title: An in vitro-in silico hybrid approach for high-throughput estimation of trans-barrier permeability for chemical pollutants
Investigators: Li, Dingsheng , Bell, Thomas W , Earley, Yumei F , Li, Li
Institution: University of Nevada - Reno
EPA Project Officer: Spatz, Kyle
Project Period: August 1, 2020 through July 30, 2023 (Extended to July 30, 2024)
Project Period Covered by this Report: August 1, 2020 through July 31,2021
Project Amount: $799,997
RFA: Advancing Toxicokinetics for Efficient and Robust Chemical Evaluations (2019) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability
Objective:
This project aims to measure the trans-barrier permeability of a diverse body of environmental pollutants and build new models predicting the trans-barrier permeability for a greater chemical space. The goals of this project will be achieved by completing three work packages: in vitro permeability experiments, in silico permeability models, and a PBTK model.
Progress Summary:
In vitro permeability measurements. We have completed the solubility screening for 51 environmental pollutants and four pharmaceuticals as method controls, PAMPA-gut wall screening for 35 of these compounds, and PAMPA-BBB screening for 16 compounds of these compounds.
In silico permeability models. We have completed our seven-slab, process-based permeability model and evaluated it against measured effective permeabilities of 1,383 pharmaceutical chemicals documented in a PAMPA profiling database maintained by the National Center for Advancing Translational Sciences.
PBTK model. We have completed our PBTK model and verified the validity of its code.
The accomplishments so far have laid the foundation connecting the discoveries from in vitro and in silico to be integrate into new knowledge that can ultimately inform in vivo human exposure to environmental pollutants. Scholarly achievements in terms of papers and presentations are summarized below with the detailed list in the accompanied progress report.
Future Activities:
Our future activities are in accordance with our proposed project schedule:
In vitro permeability measurements. For Year 2 we aim to complete the solubility, PAMPA-gut wall, and PAMPA-BBB permeability tests for all the chemicals. The techniques have been refined in our Year 1 experiments and we do not anticipate new equipment will be needed. As mentioned earlier in this report, PFAS chemicals have presented some challenges for us, and we will explore collaborations with other researchers on these chemicals.
In silico permeability models. For Year 2 we will apply our process-based model to our measured effective permeability values for the environmental pollutants to assess its performance and adjust the model if needed. In addition, we will start the development of the QSAR model which could expand the coverage of chemicals beyond the ~90 chemicals to be tested in this project.
PBTK model. For Year 2 we will complete the TK conversion from effective permeability to bioavailability in body. Then the PBTK model will be parameterized by the in-house data generated.
Journal Articles:
No journal articles submitted with this report: View all 28 publications for this projectProgress and Final Reports:
Original AbstractThe 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.