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- 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
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Ha Ryong Kim1
, Jun Woo Kim2
, Jong-Hyeon Lee3
, Younghee Kim4
, Jungyun Lim4
, Yong-Wook Baek4
, Sunkyoung Shin4
, Mina Ha5
, Hae-Kwan Cheong6
, Kyu Hyuck Chung2,7
, Review Committee for the Epidemiological Correlations between Humidifier Disinfectants Exposure and Health Effects -
Epidemiol Health 2024;46e2024060-0
DOI: https://doi.org/10.4178/epih.e2024060
Published online: July 7, 2024
2Sungkyunkwan University, School of Pharmacy, Suwon, Korea
3EH R&C Co., Incheon, Korea
4Humidifier Disinfectant Health Center, Environmental Health Research Department, National Institute of Environmental Research, Incheon, Korea
5Dankook University College of Medicine, Cheonan, Korea
6Sungkyunkwan University, School of Medicine, Suwon, Korea
7Kyungsung University College of Pharmacy, Busan, Korea
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Corresponding author:
Kyu Hyuck Chung,
Email: khchung@skku.edu
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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.
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