STRESS AS A BIOLOGICAL VARIABLE: INTEGRATING ALLOSTATIC LOAD INTO RESEARCH ON WILDFIRE SMOKE EXPOSURE

Air pollution is widely recognized as a driver of global disease, yet less is known about how chronic psychosocial stress interacts with environmental exposures to influence health outcomes. Prolonged stress contributes to allostatic load (AL), a measure of cumulative physiological strain across immune, cardiovascular, and metabolic systems. Elevated AL has been linked to impaired stress recovery, immune imbalance, and greater vulnerability to toxicants. Communities facing structural disadvantage often experience both higher pollutant burdens and heightened psychosocial stress, creating conditions for amplified health risks. Framing stress as a biological variable may help capture these compounded effects in risk assessment. To explore these interactions, we evaluated AL as a modifier of responses to wildfire smoke (WS), a major source of fine particulate matter and toxic combustion byproducts. We developed a novel framework for deriving AL scores from small serum samples, which revealed race- and sex-related disparities in stress burdens within a human cohort. Applying this scoring approach in a controlled human exposure study, we found that individuals with higher AL exhibited elevated baseline inflammation but blunted systemic responses following WS exposure. These findings suggest that chronic stress primes the body toward an inflammatory state under resting conditions while impairing adaptability to acute environmental challenges. Sex differences were also evident, with women displaying stronger baseline responses yet weaker adaptability after exposure, consistent with stress-immune interactions observed in broader health contexts. Our controlled mouse studies reinforced these findings. Animals housed in depleted conditions, designed to model social disadvantage, developed higher AL and greater cardiopulmonary dysfunction following WS, whereas enriched environments reduced susceptibility. Taken together, these studies highlight AL as an important determinant of biological responses to wildfire smoke and a contributor to disparities in pollution-related health outcomes. Integrating stress biology into toxicological frameworks can improve risk assessments, enhance prediction of vulnerable groups, and guide protective strategies for at-risk populations.