Long‐Term Ambient Benzene Exposure and Brain Disorders Among Urban Adults: Effect Modification by Genetic Susceptibility and Potential Mediation by Plasma Proteins

ABSTRACT Benzene is a common urban air pollutant with potential neurotoxicity, yet the health effects of long‐term, low‐level ambient exposure and the underlying mechanisms remain poorly characterized. Here, we used data from 288,180 UK Biobank (UKB) participants to investigate associations between benzene exposure and brain disorders as well as related genetic susceptibility and potential protein‐mediated mechanisms. We found that benzene exposure was significantly associated with seven brain disorders, including anxiety disorders, dementia, epilepsy, major depressive disorder, migraine, sleep disorders, and schizophrenia spectrum disorders. Greater genetic susceptibility to benzene exposure was most apparent for epilepsy, migraine, sleep disorder, and schizophrenia spectrum disorders. Pathway‐level mediation analyses identified 40 pathways that may mediate the associations between benzene exposure and brain disorders, converging on pathways regulating cell survival and apoptosis, immune‐inflammatory signaling, cellular stress responses, and cell–cell or cell–matrix interactions, highlighting coordinated disruptions in cellular homeostasis and immune regulation. Overall, our findings suggest that even low‐level ambient benzene exposure may be linked to adverse brain health through multiple potential biological pathways, highlighting the need for further studies in diverse exposure settings, including rural populations with potentially higher benzene exposure.