Integrated evidence supports a causal association between PHMG-P exposure and pneumonitis

Abstract

Polyhexamethylene guanidine phosphate (PHMG-P) is a guanidine-based disinfectant previously used in household humidifiers in Korea. This study evaluated whether PHMG-P exposure is causally linked to pneumonitis by integrating epidemiological, toxicological, and mechanistic evidence. We prespecified an evidence-integration framework aligned with the Office of Health Assessment and Translation/Grading of Recommendations Assessment, Development and Evaluation approaches, and applied the Organisation for Economic Cooperation and Development adverse outcome pathway (AOP) guidance to organize mechanistic evidence. We systematically identified studies and synthesized findings across 3 domains: epidemiology (age-period-cohort [APC], difference-in-differences [DID], and interrupted time-series [ITS] analyses), toxicology (animal and in vitro studies), and mechanism (mapping key events to an AOP). We assessed internal and external validity, coherence, and strength of evidence within and across domains. Epidemiological analyses showed that pneumonitis incidence rose during humidifier disinfectant use and declined after the 2011-2012 withdrawal, with higher risks in children and reproductive-age females. APC, DID, and ITS, including PHMG-P–specific time-series analysis, indicated increased pneumonitis incidence and mortality during exposure periods. Toxicological studies demonstrated that PHMG-P exposure resulted in epithelial injury, inflammation, fibrosis, and impaired lung function consistent with chemical pneumonitis. Mechanistic evidence linked PHMG-P exposure to epithelial damage, oxidative stress, macrophage polarization, and fibrotic changes. Multiple lines of evidence support a causal link between PHMG-P exposure and pneumonitis, underscoring the value of integrating epidemiology and toxicology to strengthen risk assessment and inform policy.