Measuring Toxicokinetics for Organ-on-Chip Devices

EPA Grant Number: RD840031
Title: Measuring Toxicokinetics for Organ-on-Chip Devices
Investigators: Hutson, Michael Shane , McCawley, Lisa J. , Markov, Dmitry
Institution: Vanderbilt University
EPA Project Officer: Spatz, Kyle
Project Period: August 1, 2020 through July 30, 2023
Project Amount: $790,352
RFA: Advancing Toxicokinetics for Efficient and Robust Chemical Evaluations (2019) RFA Text |  Recipients Lists
Research Category: Chemical Safety for Sustainability

Objective:

As a way to reduce the need for animal testing, EPA and other regulatory agencies have funded investigations of organotypic culture models and organ-on-chip devices. These new approach methodologies place multiple human cell types in appropriate 3D geometries under continuous microfluidic perfusion to better approximate in vivo cellular microenvironments – and thus yield more predictive responses to potential toxicants. Nonetheless, translating organ-on-chip results to predict human health effects still requires in-vitro-to-in-vivo extrapolation. Such extrapolation is always difficult, but becomes even more complicated for organ-on-chip devices because their high surface-to-volume ratios and permeable materials such as PDMS can sequester hydrophobic compounds. Using results from these devices thus requires two calculations: (1) from nominal inlet concentration to in-device cellular dose; and (2) from that dose to equivalent organismal exposure. The latter has been the subject of decades of work, but the former is just beginning to be explored. Our primary objective is to establish methods, measurements and models for the toxicokinetics of PDMS-based organ-on-chip devices.

Approach:

We will pursue this objective using UV/Vis and FTIR spectroscopy to measure (a) the time-dependent depletion of chemicals of interest from solutions in contact with PDMS surfaces, (b) the return of these chemicals from the PDMS surfaces to fresh solutions, and (c) the ability of chemicals to diffuse through thin PDMS layers. From these measurements, we will quantify the key chemical-PDMS reaction parameters – on-rate, off-rate, carrying capacity, partition coefficient and PDMS diffusion coefficient – that will enable toxicokinetic modeling of in-device cellular dose. We will determine these parameters for a set of 54 chemicals: 48 TSCA Work Plan chemicals that were also screened in ToxCast Phase 1 or 2; three organophosphates being investigated in a blood-brain-barrier-on-a-chip model; and three AhR agonists that are being investigated in an endometrium-on-a-chip model. We will the use these results to build a QSPR model to predict sequestration into PDMS for a wider set of chemicals, and we will investigate how the chemical-PDMS interaction parameters are altered by plasma treatment and oxidation of PDMS surfaces.

Expected Results:

Project outputs/outcomes will include: (i) quantified PDMS-chemical interaction parameters for a priority list of 54 chemicals; (ii) toxicokinetic models for organs-on-chips that use these parameters to predict in-device cellular dose; (iii) a QSPR model for predicting PDMS-chemical interaction parameters; and (iv) a determination of the degree to which plasma treatment of PDMS reduces chemical sequestration. These outcomes will improve our ability to use new organ-on-chip methodologies to predict human health risks. 

Supplemental Keywords:

adsorption, risk assessment, bioavailability, dose-response, mammalian, PAH, dioxin, innovative technology, decision making, biology, chemistry, physics, engineering, modeling, analytical, measurement methods, Tennessee, TN

Progress and Final Reports:

  • 2021 Progress Report