Integrating tissue chips, rapid untargeted analytical methods and molecular modeling for toxicokinetic screening of chemicals, their metabolites and mixtures

EPA Grant Number: RD840032
Title: Integrating tissue chips, rapid untargeted analytical methods and molecular modeling for toxicokinetic screening of chemicals, their metabolites and mixtures
Investigators: Rusyn, Ivan , Chiu, Weihsueh A , Baker, Erin D.
Institution: Texas A & M University , North Carolina State University
EPA Project Officer: Klieforth, Barbara I
Project Period: August 1, 2020 through July 30, 2023
Project Amount: $799,993
RFA: Advancing Toxicokinetics for Efficient and Robust Chemical Evaluations (2019) RFA Text |  Recipients Lists
Research Category: Safer Chemicals

Description:

Current in vitro-to-in vivo (IVIVE) approaches rely on simplistic modeling assumptions and rudimentary assays to estimate equivalent oral doses from test concentrations. While numerous limitations of current approaches have been recognized, only in the past 3-5 years have advances in biomedical engineering and analytical chemistry acquired sufficient throughput and reproducibility to enhance IVIVE. First, microphysiological systems of the liver, kidney and gut have been developed and validated for medium-throughput capacity, enabling toxicokinetic properties of environmental chemicals to be estimated in a more physiologically relevant manner. Second, rapid multi-dimensional characterization of chemicals, their metabolites, and mixtures has been demonstrated using ion mobility spectrometry-mass spectrometry (IMS-MS) coupled with a recently developed database of thousands of environmental chemicals. 

Objective:

Therefore, the long-term objective of this project is to support risk-based decisions with new approach methodologies (NAMs) data by demonstrating integration of new biological (i.e., tissue chips), analytical (i.e., IMS-MS), and modeling methods for high fidelity, data-driven IVIVE.

Approach:

This proposal integrates the two research areas specified in the Funding Opportunity through three Aims. Aim 1 will use tissue chips that are already commercially available and that have been validated by Texas A&M Tissue Chip Testing Center to generate physiologically relevant toxicokinetic data. Aim 2 will couple a computational pipeline and database of thousands of environmental chemicals with IMS-MS to demonstrate high-throughput detection, identification, and quantification of multiple chemicals, their metabolites, and mixtures. Aim 3 will integrate the results of Aims 1 and 2 by extending traditional IVIVE approaches to incorporate both tissue chip-based toxicokinetic data and IMS-MS analytical data into high throughput PBPK modeling of both parent chemicals and metabolites. Specifically, refinement of the estimates for absorption (gut chip), distribution (plasma protein binding), metabolism (a multi-cellular liver chip), and elimination (kidney chip), coupled with high-resolution analytical data, will enable a more comprehensive characterization of toxicokinetics and metabolite formation, thereby reducing the uncertainty of traditional IVIVE approaches and improving the basis for decision-making with NAMs data. 

Expected Results:

 The main outcome of this project will be a novel approach and a framework to support risk-based decisions on environmental chemicals and mixtures by demonstrating how an integrated set of novel biological assays (i.e., tissue chips), analytical techniques (i.e., IMS-MS) and computational methods can be used to enable high-fidelity, data-driven toxicokinetic modeling. 

Supplemental Keywords:

risk assessment, cellular, chemicals, modeling, dose-response.