Grantee Research Project Results
2022 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, 2021 through July 31,2022
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 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 physiologically-based toxicokinetic (PBTK) model.
Progress Summary:
In vitro permeability measurements. We have completed the Parallel Artificial Membrane Permeability Assay (PAMPA) -gut wall screening for 39 compounds and the PAMPA-BBB screening for 38 compounds. Detection methods are being validated for 16 other compounds before carrying out the actual PAMPA tests. We are currently finalizing the conditions for the transwell experiments.
In silico permeability models. We have developed a seven-slab, process-based permeability model for PAMPA and evaluated it against measured effective permeabilities of 1,383 pharmaceutical chemicals. Overall, the model provided reasonable or conservative estimates for 91% of chemicals in the evaluation set, indicating that the model is protective of risks associated with human gastrointestinal absorption of chemical substances.
PBTK model. We have completed our PBTK model and verified the validity of its code. We have collected 37 studies over the past four decades with adequate biodistribution data with blood, brain, and at least one other major organ as a database to evaluate the performance of the PBTK model after the permeability data (both in vitro measurement and predicted by the in silico model) becomes available.
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 3 we aim to complete the PAMPA permeability tests for the remaining chemicals. Some of which will be done in collaboration with researchers at the University of Nevada, Las Vegas. We will also carry out the transwell experiments for a subgroup of compound with good detection and solubility and compare results with PAMAP tests.
In silico permeability models. For Year 3 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 finish developing the QSAR model which could expand the coverage of chemicals beyond the chemicals to be tested in this project.
PBTK model. For Year 3 we will complete the TK conversion from effective permeability to bioavailability in body. The parameterized PBTK model with in-house data will be evaluated against collected biodistribution data.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
| Other project views: | All 28 publications | 9 publications in selected types | All 9 journal articles |
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Li D, Li L. Human chemical exposure from background emissions in the United States and the implication for quantifying risks from marginal emission increase. Toxics 2021;9(11):308. |
R840033 (2022) R840033 (Final) |
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Zhang Z, Wang S, Li L. Emerging investigator series:the role of chemical properties in human exposure to environmental chemicals. Environmental Sciences: Process Impacts 2021;23(12):1839-1862. |
R840033 (2022) R840033 (Final) |
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Supplemental Keywords:
high-throughput, toxicokinetics, blood-brain barrier, bioavailability, in vitro, QSAR, modelingProgress 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.