An in vitro-in silico hybrid approach for high-throughput estimation of trans-barrier permeability for chemical pollutants

EPA Grant Number: RD840033
Title: 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
Project Amount: $799,997
RFA: Advancing Toxicokinetics for Efficient and Robust Chemical Evaluations (2019) RFA Text |  Recipients Lists
Research Category: Chemical Safety for Sustainability

Description:

Understanding the toxicokinetics (TK) of chemical pollutants is critical in assessing the biological significance of public exposure. High-throughput approaches that provide efficient evaluation are vital due to the many chemicals exist. The current lack of information on trans-barrier permeability of chemical pollutants makes accurate estimations of certain kinetics of chemicals in the body, such as oral bioavailability and blood-brain barrier penetration, challenging.Understanding the toxicokinetics (TK) of chemical pollutants is critical in assessing the biological significance of public exposure. High-throughput approaches that provide efficient evaluation are vital due to the many chemicals exist. The current lack of information on trans-barrier permeability of chemical pollutants makes accurate estimations of certain kinetics of chemicals in the body, such as oral bioavailability and blood-brain barrier penetration, challenging.

Objective:

The overall objective is to develop and characterize a high-throughput approach for estimating trans-barrier permeability for chemical pollutants. Our Specific Aims are: (1) Employ transwell in vitro methods to simulate trans-barrier permeability of diverse chemical pollutants; (2) Develop process-based in vitro permeability models to understand the mass transfer processes in in vitro tests and a quantitative structure-activity relationship (QSAR) model that links permeability with molecular structures; (3) Integrate the new TK permeability parameters into a parsimonious physiologically based toxicokinetic (PBTK) model and evaluate its performance against in vivo biodistribution data to characterize the uncertainty of our approach. These Aims are to test four hypotheses: (1) The proposed high-throughput capable experiment design can measure permeability more efficiently and cost-effectively than conventional  but low-throughput designs; (2) The measured apparent permeability of a chemical pollutant is dependent on its physicochemical properties and the features of the in vitro test system; (3) The trans-barrier permeability for most chemical pollutants is dominated by passive diffusion, and (4) the TK parameters from our approach can provide accurate predictions of in vivo biodistribution.

Approach:

First, we will use high-throughput in vitro models to measure the permeability through gut and blood-brain barrier of nearly 100 chemical pollutants with diverse properties. Second, we will build a six-compartment model describing the trans-barrier transport governed mainly by passive diffusion and evaluate its performance against experimental-determined apparent permeability. The experimental-derived values will also be used to build the QSAR model with the Genetic Algorithm Variable Subset Selection method. Finally, we will parameterize an eight-compartment PBTK model with the new TK parameters via in vitro in vivo extrapolation and evaluate the model’s robustness by comparing its outputs with existing in vivo biodistribution data.

Expected Results:

The results of this study will advance the development of high-throughput exposure models by providing new TK parameters, expanding coverage of chemical pollutants, and characterizing the models’ uncertainty. These results will advance robust and efficient tools for exposure and risk assessments that enable knowledge-based management decisions for the protection of human health. These results are directly addressing the call to address unmet need of “TK parameters not currently available via in vitro approaches” to achieve the goal that will “enable knowledge-based decisions that protect human health” in the solicitation.

Supplemental Keywords:

chemicals, exposure, toxicokinetics, blood-brain barrier, bioavailability, cellular, modeling, QSAR, high-throughput

Progress and Final Reports:

  • 2021 Progress Report