Wildland Urban Interface Exposure Toxicity in Cells, Animals, and Humans

ABSTRACT Wildfires are a threat to public health worldwide, growing in both intensity and prevalence year-by-year, particularly in regions at the Wildland Urban Interface (WUI). The health impacts associated with exposures to wildfire smoke include those relevant to the pulmonary system, including asthma, bronchitis, dyspnea, chronic

obstructive pulmonary disease, and respiratory infections; however, the impacts and quantified health risks at the WUI remain understudied. This research gap likely exists due to the inherent difficulties surrounding the evaluation of these complex and variable atmospheric exposures. The team brought together by the PI has

established methods and recent data measuring harmful chemicals in simulated wildfire scenarios, including conditions that incorporate anthropogenic materials indicative of the WUI environment. We have also demonstrated through vigorous pilot experimentation that different wildfire smoke conditions converge upon

biological changes in the lung relevant to lung cell stress and hypoxia. Recent molecular-based experimentation has also uncovered novel mediation of pulmonary toxicity through extracellular vesicle mechanisms coinciding with incidences of cell stress and hypoxia. This study set out to test the innovative hypothesis that forest and

WUI burn scenarios will initiate MOAs with shared components across in vitro, in vivo animal, and human systems, facilitating health risk predictions in humans for exposure conditions that need health guidances. We will address this hypothesis through aims designed to carry out the following: First, we will use in vitro lung

models derived from human donors to evaluate biological responses across multiple forest and WUI-relevant exposures, including conditions that are difficult to evaluate in vivo, particularly in humans due to feasibility limitations and ethical considerations. Second, we will evaluate in vivo responses to select burn scenarios in

mice and humans, with analyses focusing on the prototypical burn scenario of smoldering red oak, without WUI- relevant materials in humans and +/- WUI-relevant materials in mice. Biological responses that will be characterized across systems include lung cell transcriptional and protein-level responses relevant to cell stress

and hypoxia, emphasizing hypoxia inducible factor 1 subunit alpha (HIF1A) and connected pathways. Functional responses will include changes in lung function in vivo and markers of tissue injury/stress/inflammation. Pulmonary secreted signals that are known to coincide with cell stress and hypoxia include extracellular vesicles,

which will also be evaluated for changes in physical characteristics, count, and molecular cargo. All aims incorporate advanced computational toxicology approaches, paralleling strengths of the PI, and pave the way for health risk estimates across a wide domain of wildfire exposures. This cross-cutting approach aligns with

many NIEHS goals and will serve as a solid foundation for the PI’s laboratory, to support future research efforts aimed at improving environmental and public health.