Epidemiology and Health

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

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Abstract Summary PDF Supplementary Material: 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

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Abstract Summary PDF Supplementary 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

Special Article

Evidence integration on health damage for humidifier disinfectant exposure and legal presumption of causation: Mina Ha, Taehyun Park, Jong-Hyun Lee, Younghee Kim, Jungyun Lim, Yong-Wook Baek, Sol Yu, Hyen-Mi Chung, Kyu Hyuck Chung, Hae-Kwan Cheong, Review Committee for the Epidemiological Correlations between Humidifier Disinfectants Exposure and Health Effects; Epidemiol Health. 2023;45:e2023095. Published online October 24, 2023; DOI: https://doi.org/10.4178/epih.e2023095

16,092 View
204 Download
6 Web of Science
6 Crossref

Abstract Summary PDF Supplementary Material

Abstract

OBJECTIVES
Inhalation exposure to humidifier disinfectants has resulted to various types of health damages in Korea. To determine the epidemiological correlation necessary for presuming the legal causation, we aimed to develop a method to synthesize the entire evidence.

METHODS

Epidemiological and toxicological studies are systematically reviewed. Target health problems are selected by criteria such as frequent complaints of claimants. Relevant epidemiologic studies are reviewed and the risk of bias and confidence level of the total evidence are evaluated. Toxicological literature reviews are conducted on three lines of evidence including hazard information, animal studies, and mechanistic studies, considering the source-to-exposure-to-outcome continuum. The confidence level of the body of evidence is then translated into the toxicological evidence levels for the causality between humidifier disinfectant exposure and health effects. Finally, the levels of epidemiological and toxicological evidence are synthesized.

RESULTS

Under the Special Act revised in 2020, if the history of exposure and the disease occurred/worsened after exposure were approved, and the epidemiological correlation between the exposure and disease was verified, the legal causation is presumed unless the company proves the evidence against it. The epidemiological correlation can be verified through epidemiological investigations, health monitoring, cohort investigations and/or toxicological studies. It is not simply as statistical association as understood in judicial precedents, but a general causation established by the evidence as a whole, i.e., through weight-of-the-evidence approach.

CONCLUSIONS

The weight-of-the-evidence approach differs from the conclusive single study approach and this systematic evidence integration can be used in presumption of causation.

Summary

Korean summary
저자들은 가습기살균제 노출로 인한 건강피해의 법적 인과관계 추정요건인 역학적 상관관계를 확인하기 위한 과정으로서 체계적 문헌고찰과 역학과 독성학의 전체 과학적 근거를 체계적으로 종합하는 방법을 제시하였다. 이것은 법적 증거 방법에서 개별 연구가 가지는 제한점이나 불확실성을 이유로 배척하지 않고, 전체 증거의 부분으로서 종합적으로 접근하는 것을 통해 사실 관계에 도달하는 방법이다. 이 전체증거접근법은 향후 인과관계 추정에서 전범(model)이 될 수 있다.

Key Message
We establish a systematic method for integrating a body of scientific evidence of epidemiology and toxicology to verify the epidemiological correlation, which is essential for presuming legal causation of health damages due to exposure to humidifier disinfectants. In terms of a legal proof, this method does not exclude individual studies due to their limitations or uncertainty but integrates them as part of a body of evidence to arrive at a conclusion that better reflects the truth of the evidence. This weight-of-the-evidence approach can be a model for future causal inference.

Citations

Citations to this article as recorded by

CMIT/MIT produces mitochondrial ROS via inhibiting mitochondrial complex I and II
Donghyun Kim, Yusun Shin, Jong-In Park, Taecheol Kwak, Hangoo Kang, Haewon Kim, Youngmee Lee, Wondong Kim, Yong Joo Park, Ha Ryong Kim, Kyu Hyuck Chung, Ok-Nam Bae
Free Radical Biology and Medicine.2026; 244: 505. CrossRef
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
Prenatal and Childhood Exposure to Humidifier Disinfectants and Attention-Deficit/Hyperactivity Disorder (ADHD): Insights from a Retrospective Cohort Design
Hyowon Choi, Hunju Lee, Yeon-Soon Ahn
Toxics.2025; 13(2): 78. 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
A systematic review and BMD modeling approach to develop an AOP for humidifier disinfectant-induced pulmonary fibrosis and cell death
Donghyun Kim, Yusun Shin, Jong-In Park, Donghyeon Lim, Hyunjoon Choi, Seongwon Choi, Yong-Wook Baek, Jungyun Lim, Younghee Kim, Ha Ryong Kim, Kyu Hyuck Chung, Ok-Nam Bae
Chemosphere.2024; 364: 143010. CrossRef
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
Epidemiology and Health.2024; 46: e2024060. CrossRef

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