Grantee Research Project Results
Wildfire Smoke Mixtures Toxicity Testing
EPA Grant Number: R840458Title: Wildfire Smoke Mixtures Toxicity Testing
Investigators: Rager, Julia , Jaspers, Ilona , Rebuli, Meghan E , Kim, Yong Ho , Reif, David
Current Investigators: Rager, Julia , Reif, David , Jaspers, Ilona , Rebuli, Meghan E , Kim, Yong Ho
Institution: University of North Carolina at Chapel Hill , North Carolina State University
EPA Project Officer: Aja, Hayley
Project Period: October 1, 2022 through May 9, 2025
Project Amount: $599,999
RFA: Development of Innovative Approaches to Assess the Toxicity of Chemical Mixtures Request for Applications (RFA) (2022) RFA Text | Recipients Lists
Research Category: Air , CSS , Chemical Safety for Sustainability , Early Career Awards , Endocrine Disruptors , Health Effects , Human Health , Mixtures , New Approach Methods (NAMs) , Safer Chemicals , Wildfires
Description:
This proposal hypothesizes that individual chemicals in wildfire smoke induce in vitro responses that group according to biological pathways, informing mixturesbased joint toxicities that overlap with in vivo pulmonary responses and disease outcomes.
Objective:
The hypothesis will be tested through three objectives: (1) Establish qualitative membership of wildfire mixture components into pathway groupings through in vitro transcriptomic screening; (2) Quantify joint toxicities across pathway groupings and compare to whole biomass smoke mixture effects through in silico modeling; and (3) Relate in vitro wildfire chemical-induced signatures to similarly exposed mice and human pulmonary disease tissues to evaluate events along adverse outcome pathways (AOPs).
Approach:
We leverage our existing chemical characterization results from variable biomass burn scenarios, representing wildfire events, to prioritize chemicals that co-occur in wildfire smoke to test for chemical groupings and joint toxicities. Lung cells from human donors will be exposed to individual chemicals. Transcriptomic signatures from exposed cells will be used to group chemicals based on transcriptomic similarity scoring. These chemical groups will then be tested using the same in vitro model, alongside the full chemical mixture and whole biomass smoke mixtures to compare individual chemicals vs. chemical groups vs. whole mixture effects on pathwaylevel responses in vitro. In silico approaches will then be used to quantify joint toxicities between chemicals using dose-additivity, response-additivity, and methods to quantify any observed interactions (greater-than-additive (aka synergistic) or less-than-additive (aka antagonistic)). All findings will be anchored to data from mice previously exposed to the same biomass smoke samples, including lung transcriptomics and pulmonary toxicity phenotypes. In vitro signatures will also be compared against human pulmonary disease signatures through query of publicly available repositories, further translating in vitro findings to human health outcomes through these new approach methodologies (NAMs).
Expected Results:
This project will address the need to improve mixtures toxicity methods leveraging primary cells that better capture in vivo response variability. In vitro molecular signatures will inform chemical groupings, and data reduction approaches will be used to incorporate high dimensional molecular data into mixtures modeling. In vitro findings will be strengthened through comparisons against mouse and human data to result in improved mechanistic understanding and health risk quantifications on wildfires.
Publications and Presentations:
Publications have been submitted on this project: View all 8 publications for this projectJournal Articles:
Journal Articles have been submitted on this project: View all 2 journal articles for this projectSupplemental Keywords:
In vitro, Joint Toxicity, Mixtures, Wildfire, Risk assessmentProgress and Final Reports:
The 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.