Grantee Research Project Results
2021 Progress Report: System toxicological approaches to define and predict the toxicity of Per and Polyfluoroalkyl Substances
EPA Grant Number: R839481Title: System toxicological approaches to define and predict the toxicity of Per and Polyfluoroalkyl Substances
Investigators: Tanguay, Robyn L. , Field, Jennifer , Reif, David , Truong, Lisa , Ng, Carla , DeWitt, Jamie
Institution: Oregon State University , North Carolina State University
EPA Project Officer: Packard, Benjamin H
Project Period: May 1, 2019 through April 30, 2022 (Extended to April 30, 2025)
Project Period Covered by this Report: May 1, 2021 through April 30,2022
Project Amount: $1,981,500
RFA: National Priorities: Per- and Polyfluoroalkyl Substances (2018) RFA Text | Recipients Lists
Research Category: Water Quality
Objective:
1. Study the toxicity of a large collection of volatile and non-volatile PFASs and PFAS mixtures with the zebrafish assay. Hypothesis: PFAS compounds with similar structures will bind to the same biomolecular targets, induce expression of the same or highly overlapping gene sets, and induce similar toxic responses.
2. Conduct developmental immunotoxicity (DIT) studies in mice. Hypotheses: Developmental exposure to PFASs will compromise antigen-specific antibody responses (a measure of adaptive immunity) and natural killer cell cytotoxicity (a measure of innate immunity). Developmental findings in the mouse will accord with developmental findings in the zebrafish.
3. Create pharmacokinetic models that can explain and predict the concentrations of PFASs in the organs of mice and adult zebrafish as a function of exposure dose and chemical structure. Hypotheses: The bioaccumulation and internal distribution of PFASs depend on passive diffusion, transporter-mediated membrane uptake and efflux, and protein binding. The interaction of PFASs with proteins and membranes will depend on i) the presence of polar or charged functional groups and on ii) the length of the linear fluorinated alkyl chain.
Progress Summary:
We have secured, validate and tested the toxicity of an ever-growing library of PFAS compounds. These include 58 Wellington Laboratories PFAS analytical standards, a 139 member US EPA PFAS Library, an additional 25 commercial reference standards and a series of PFAS mixtures. We also completed three adult zebrafish dietary studies by contaminating a commercial diet with PFAS. These were 43-day dietary exposure studies at several exposure levels starting at 17-dpf. We investigated the toxicity and transcriptional responses following exposure to a series of short-chain compounds and determined that the sulfonamide head group was the most biologically active. We completed a quantitative assessment of laboratory animal diets for PFAS contamination and found that some commercial sources have background levels that could interfere with toxicological data interpretation. We completed developmental immunotoxicity (DIT) studies in mice with “PFMOAA” (perfluoro-2-methoxyacetic acid), a three carbon perfluoroether carboxylic acid. We have evaluated three different PFAS (PFMOAA, Nafion Byproduct 2, and FHxSA). We advanced two physiologically based toxicokinetic (PBTK) models for PFAS: a zebrafish model (for PFOA in adult zebrafish) and a new mouse model (for several different PFAS in adult mice). The major improvements of the zebrafish model include a better physiological parameterization that includes more fish-specific and zebrafish-specific data, and a refinement of the description of protein binding in the different compartments. The mouse model was developed from the framework of the rat model originally published by Cheng & Ng in 2017, re-parameterized to reflect the physiology of the mouse. The major contribution of this model is the inclusion of a new mechanistic description of PFAS associating with phospholipids within the cell membrane and the impact of this interaction on both the kinetics of PFAS inter-compartment transport and the tissue. The new model captures the different distribution kinetics and tissue accumulation patterns of PFOA and PFBS (with chemical-specific parameterization), illustrating the model’s robustness and flexibility.
Journal Articles on this Report : 1 Displayed | Download in RIS Format
Other project views: | All 22 publications | 10 publications in selected types | All 10 journal articles |
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Rericha Y, Simonich M, Truong L, Tanguay R. Review of the zebrafish as a model to investigate per- and polyfluoroalkyl substance toxicity. TOXICOLOGICAL SCIENCES 2023;online ahead of print |
R839481 (2021) |
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Supplemental Keywords:
zebrafish, toxicity, development, modeling, bioaccumulation, dietary, pharmacokinetic,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.