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Systematic Review
Integrated evidence supports a causal association between PHMG-P exposure and pneumonitis
Yong Joo Park, Hye-Jin Kim, Youngmee Lee, Haewon Kim, Ha Ryong Kim, Jaiyong Kim, Hae-Kwan Cheong, Mina Ha, Kyu Hyuck Chung
Epidemiol Health. 2025;47:e2025073.   Published online December 14, 2025
DOI: https://doi.org/10.4178/epih.e2025073
  • 873 View
  • 62 Download
AbstractAbstract AbstractSummary PDF
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.
Summary
Korean summary
인구집단 기반 역학 연구와 독성발현경로(AOP) 기반 기전 독성학적 증거를 통합 분석한 결과, 폴리헥사메틸렌구아니딘 인산염(PHMG-P) 노출과 화학성 폐렴 간의 인과관계가 과학적으로 입증되었다.
Key Message
Population-based epidemiological analyses, including age–period–cohort, difference-in-differences, and interrupted time series approaches, demonstrated increases in pneumonia diagnoses during periods of PHMG-P use and subsequent declines following its market withdrawal. Toxicological evidence, structured through adverse outcome pathway mapping, provided mechanistic support for PHMG-P–induced chemical pneumonitis, collectively establishing a causal association between PHMG-P exposure and chemical pneumonitis.
Original Article
Toxicological evidence integration to confirm the biological plausibility of the association between humidifier disinfectant exposure and respiratory diseases using the AEP-AOP framework
Ha Ryong Kim, Jun Woo Kim, Jong-Hyeon Lee, Younghee Kim, Jungyun Lim, Yong-Wook Baek, Sunkyoung Shin, Mina Ha, Hae-Kwan Cheong, Kyu Hyuck Chung, Review Committee for the Epidemiological Correlations between Humidifier Disinfectants Exposure and Health Effects
Epidemiol Health. 2024;46:e2024060.   Published online July 7, 2024
DOI: https://doi.org/10.4178/epih.e2024060
  • 11,883 View
  • 164 Download
  • 2 Web of Science
  • 4 Crossref
AbstractAbstract AbstractSummary PDFSupplementary Material
Abstract
OBJECTIVES
Exposure to humidifier disinfectants has been linked to respiratory diseases, including interstitial lung disease, asthma, and pneumonia. Consequently, numerous toxicological studies have explored respiratory damage as both a necessary and sufficient condition for these diseases. We systematically reviewed and integrated evidence from toxicological studies by applying the evidence integration method established in previous research to confirm the biological plausibility of the association between exposure and disease.
METHODS
We conducted a literature search focusing on polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT), the primary ingredients in humidifier disinfectants. We selected relevant studies based on their quality and the population, exposure, comparator, outcome (PECO) statements. These studies were categorized into three lines of evidence: hazard information, animal studies, and mechanistic studies. Based on a systematic review, we integrated the evidence to develop an aggregate exposure pathway–adverse outcome pathway (AEP-AOP) model for respiratory damage. The reliability and relevance of our findings were assessed by comparing them with the hypothesized pathogenic mechanisms of respiratory diseases.
RESULTS
By integrating toxicological evidence for each component of the AEP-AOP framework for PHMG and CMIT/MIT, we developed an AEP-AOP model that elucidates how disinfectants released from humidifiers expose target sites, triggering molecular initiating events and key events that ultimately lead to respiratory damage. This model exhibits high reliability and relevance to the pathogenesis of respiratory diseases.
CONCLUSIONS
The AEP-AOP model developed in this study provides strong evidence, based on evidence-based toxicology, that exposure to humidifier disinfectants causes respiratory diseases. This model demonstrates the pathways leading to respiratory damage, a hallmark of these conditions.
Summary
Korean summary
- PHMG와 CMIT/MIT에 대한 AEP-AOP 프레임워크와 독성학적 근거종합 방법에 의해 가습기살균제의 호흡기계 손상 AEP-AOP 모델을 개발하였다. - 이 모델은 가습기살균제 복합 노출과 호흡기계 질환 간의 인과성을 규명하는 과학적 근거를 제공하며, 향후 다양한 살균제 성분의 호흡기계 건강영향을 예측하는데 활용할 수 있다.
Key Message
• The AEP-AOP model for humidifier disinfectant-induced respiratory damage developed by the AEP-AOP frameworks for PHMG and CMIT/MIT, along with the toxicological evidence integration method. • This model provides a scientific basis for establishing causality between mixed exposure to humidifier disinfectants and respiratory diseases, and can be used in the future to predict the health effects of various disinfectant ingredients.

Citations

Citations to this article as recorded by  
  • Association of respiratory diseases with humidifier disinfectants exposure and its latency: A study of health damage reporter cohort in South Korea
    Jaiyong Kim, Kyoung Sook Jeong, Seungyeon Heo, Youngmee Lee, Taksoo Kim, Hye-Jin Kim, Suejin Kim, Hae-Kwan Cheong, Mina Ha
    Ecotoxicology and Environmental Safety.2026; 309: 119552.     CrossRef
  • Risk of non-cancer respiratory diseases attributed to humidifier disinfectant exposure in Koreans: age-period-cohort and differences-in-difference analyses
    Jaiyong Kim, Kyoung Sook Jeong, Seungyeon Heo, Younghee Kim, Jungyun Lim, Sol Yu, Suejin Kim, Sun-Kyoung Shin, Hae-Kwan Cheong, Mina Ha
    Epidemiology and Health.2025; 47: e2025006.     CrossRef
  • Association between humidifier disinfectant use duration and lung cancer development in Korea
    Sungchan Kang, Jeong-In Hwang, Su Hwan Kim, Hyungryul Lim, Dong-wook Lee, Woojoo Lee, Jong Hun Kim, Sol Yu, Jungyun Lim, Younghee Kim, Kyoung-Nam Kim
    Epidemiology and Health.2025; 47: e2025023.     CrossRef
  • The CMIT/MIT Humidifier Disinfectant Ruling: Environmental Health Implications of the Reversal by the Supreme Court
    Sungkyoon Kim
    Journal of Environmental Health Sciences.2025; 51(6): 345.     CrossRef
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