Grantee Research Project Results
2023 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, 2022 through July 31,2023
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 PBTK model. A manuscript including the results from the PAMPA experiments with additional analysis on the results considering physicochemical properties, using the results to evaluate the previously developed process-based PAMPA model, and comparing the results with existing relevant literature has been completed and will be submitted to the journal Environmental Science & Technology soon.
Progress Summary:
In vitro permeability measurements. We have completed the PAMPA experiments for 52 compounds and conducted Caco-2 experiments for four compounds. Two PFAS chemicals remain to be evaluated by the PAMPA method.
In silico permeability models. The seven-slab, process-based permeability model for PAMPA has been published. It was further evaluated with our own PAMPA results and showed good performance. A quantitative structure-activity relationship (QSAR) model to predict the effective permeability of chemicals, based on a dataset comprising literature-reported measurements for pharmaceuticals and our measurements for environmental pollutants is currently under development.
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. This PBTK model is currently being evaluated after being re-coded to be integrated with the HTTK model developed by the US EPA. In addition, we are using fitted brain permeability from the reverse calculations on the collected biodistribution data with a three-compartment PBTK model to evaluate the PAMPA-BBB results from both in vitro experimental results and in silico model predictions.
The accomplishments so far have laid the foundation connecting the discoveries from in vitro and in silico to be integrated 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. We aim to complete the PAMPA permeability tests for the two PFAS chemicals in collaboration with the University of Nevada, Las Vegas. We will also compare our PAMPA results with cell culture permeability test results with other scientists.
In silico permeability models. We will finish developing the QSAR model which could expand the coverage of chemicals beyond the chemicals tested in this project.
PBTK model. We will complete the TK conversion from effective permeability to bioavailability in the body. The parameterized PBTK model with in-house data will be evaluated against collected biodistribution data.
Journal Articles on this Report : 3 Displayed | Download in RIS Format
| Other project views: | All 28 publications | 9 publications in selected types | All 9 journal articles |
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Intasiri A, Illa S, Prertprawnon S, Wang S, Bell T, Li L, Li D. Comparison of in vitro membrane permeabilities of diverse environmental chemicals with in silico predictions. SCIENCE OF THE TOTAL ENVIRONMENT 2024;933 |
R840033 (2023) |
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Wang S, Zhang Z, Saunders L, Li D, Li L. Understanding the Impacts of Presystemic Metabolism on the Human Oral Bioavailability of Chemicals. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; |
R840033 (2023) |
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Wang S, Zhang Z, Li D. Elucidating impacts of partitioning and transmembrane permeability on absorption of chemicals in human gastrointestinal tract. Environment International 2024;193. |
R840033 (2023) R840033 (Final) |
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Supplemental Keywords:
high-throughput, toxicokinetics, blood-brain barrier, bioavailability, in vitro, QSAR, modeling
Progress 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.