Grantee Research Project Results
Final 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 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 applications to PBTK modeling.
Summary/Accomplishments (Outputs/Outcomes):
In vitro permeability measurements. We have completed the PAMPA methods simulating gastrointestinal (PAMPA-GIT) and blood-brain barrier (PAMPA-BBB) for 52 compounds. These results, along 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 is published. We found PAMPA showing potential to be utilized as a high-throughput method for providing screening-level permeability information for chemicals that lack such data. We also found that common PAMPA protocols may need to be modified for chemicals that have high volatility, low solubility, or unstable to gain robust data.
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 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 review. Another manuscript compiling comprehensive permeability data for predicting human intestinal absorption of organic chemicals is under development. These modeling efforts expanded the chemical coverage for permeability data and can offer insights on the mechanistic features and limitations of prevailing experimental methods for measuring permeability of chemicals.
PBTK modeling. 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 a PBTK model. 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 applied our new understanding from both the in vitro and in silico research activities to enhance PBTK modeling for gut absorption of chemicals. These efforts have been published in two papers and can be integrated by other PBTK models outside of this project to enhance the robustness of their results and application in in vitro in vivo extrapolation practices.
Conclusions:
The accomplishments 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.
Journal Articles on this Report : 7 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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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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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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Li D, Sangion A, Li L. Evaluating consumer exposure to disinfecting chemicals against coronavirus disease 2019 (COVID-19) and associated health risks. Environment International 2020;145:106108. |
R840033 (Final) |
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Wang S, Zhang Z, Li D, Illa SE, Li L. In silico model-based exploration of the applicability of parallel artificial membrane permeability assay (PAMPA) to screen chemicals of environmental concern. Environment International 2022;170:107589. |
R840033 (Final) |
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Intasiri A, Illa SE, Prertprawnon S, Wang S, Li L, Bell TW, Li D. Comparison of in vitro membrane permeabilities of diverse environmental chemicals with in silico predictions. Science of The Total Environment 2024;933:173244. |
R840033 (Final) |
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Wang S, Zhang Z, Saunders LJ, Li D, Li L. Understanding the impacts of presystemic metabolism on the human oral bioavailability of chemicals. Environmental Science & Technology 2024;58(32):14135-14145. |
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.