Comprehensive analysis of adverse outcome pathway, potency, human exposure supports carcinogenicity of polyhexamethylene guanidine phosphate in lung cancer

In this study, we investigated the potential mechanisms by which polyhexamethylene guanidine phosphate (PHMG-p), a known respiratory irritant, may contribute to lung cancer development. Using the adverse outcome pathway (AOP) framework, we analyzed established databases (such as AOP-Wiki) and employed AI tools (AOP-helpFinder) to identify key events (KEs) associated with lung carcinogenesis. Our analysis indicates that chronic inhalation of PHMG-p triggers a non-genotoxic pathway, characterized by cell membrane disruption, inflammation, and oxidative stress, with a point of departure (POD) of 0.0018 mg/m³, suggesting carcinogenic potential. Additionally, a human exposure assessment revealed that most claimants were exposed to PHMG-p levels exceeding the estimated inhalation reference concentration (RfC) of 0.018 µg/m³. While downstream KEs, such as DNA damage, mutation, and cell proliferation, require further investigation, our findings, supported by the AOP framework and potency and exposure assessments, strongly suggest that PHMG-p exposure could induce lung cancer in individuals affected by humidifier disinfectants. These results underscore the importance of a comprehensive risk assessment approach for evaluating the carcinogenicity of PHMG-p.