System Toxicological Approaches to Define Flame Retardant Adverse Outcome PathwaysEPA Grant Number: R835796
Title: System Toxicological Approaches to Define Flame Retardant Adverse Outcome Pathways
Investigators: Tanguay, Robert L. , Du, Jane La , Reif, David , Simonich, Mike , Sullivan, Chris
Institution: Oregon State University , North Carolina State University at Raleigh
EPA Project Officer: Lasat, Mitch
Project Period: July 1, 2014 through June 30, 2017
Project Amount: $798,661
RFA: Systems-Based Research for Evaluating Ecological Impacts of Manufactured Chemicals (2014) RFA Text | Recipients Lists
Research Category: Ecological Indicators/Assessment/Restoration , Ecosystems , Safer Chemicals
A team of researchers from Oregon State University and North Carolina State University proposes to conduct the first comprehensive in vivo,structure-activity based toxicity studies of flame retardant chemicals (FRCs), including FRCs that EPA has phased out, FRCs that companies manufacture now, and FRCs that companies have proposed as replacements. We will test the hypothesis that the toxicity of FRCs will be highly dependent on their chemical structure.
We will expose embryonic zebrafish to FRCs and observe their morphology and behavior for signs of toxicity. We will also grow exposed zebrafish to adulthood and observe their morphology, behavior and respiratory fitness for signs of toxicity. We plan to discover which FRCs have the lowest hazard potential and to rank the others according to their toxicity. With the identified phenotypic anchors, we will conduct whole-transcriptome analyses to define the early expression changes and pathways underlying the adverse outcomes to the toxic FRCs. We will cluster FRC outcomes across the levels of biological organization, i.e, chemical structure, similarity of gene expression profiles, early and adult life stage adverse outcomes, and thereby define adverse outcome pathways (AOP) for mechanistic FRC hazard prediction. We will bin FRCs according to their mode of action to discover how it depends chemical structure, thereby gaining the ability to predict the toxicity of new compounds. We will develop new tools that enable manufacturers and risk assessors to determine the likelihood that a new compound is safe.
The toxicity screening results will help prioritize chemicals for further testing and may also alert chemical manufacturers that some of their commercial products may be toxic. The identified AOPs will improve the research community's ability to translate zebrafish results to other species. The proposed work will help to establish a base of knowledge that will lead to novel cell-based assays that can reliably predict chemical toxicity without in vivo testing.