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Review paper 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 Kim1orcid , Jun Woo Kim2orcid , Jong-Hyeon Lee3orcid , Younghee Kim4orcid , Jungyun Lim4orcid , Yong-Wook Baek4orcid , Sunkyoung Shin4orcid , Mina Ha5orcid , Hae-Kwan Cheong6orcid , Kyu Hyuck Chung2orcid , Review Committee for the Epidemiological Correlations between Humidifie Exposure and Disease7orcid
Epidemiol Health 2024;e2024060
DOI: https://doi.org/10.4178/epih.e2024060 [Accepted]
Published online: July 7, 2024
1School of Pharmacy, Korea University, Sejong, Sejong, Korea
2School of Pharmacy, Sungkyunkwan University, Suwon, Korea
3EH R&C Co, Incheon, Korea
4Humidifier Disinfectant Health Center, Environmental Health Research Department, National Institute of Environmental Research, Incheon, Korea
5Department of Preventive Medicine, College of Medicine, Dankook University, Cheonan, Korea
6School of Medicine, Sungkyunkwan University, Suwon, Korea
7, , Korea
Corresponding author:  Kyu Hyuck Chung,
Email: khchung@skku.edu
Received: 20 January 2024   • Revised: 22 May 2024   • Accepted: 24 June 2024
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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 3 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
The integration of each AEP-AOP component for PHMG and CMIT/MIT led to the development of an AEP-AOP model, wherein disinfectants released from humidifiers in aerosol or gaseous form reached target sites, causing respiratory damage through molecular initiating events and key events. The model demonstrated high reliability and relevance to the pathogenesis of respiratory diseases.
CONCLUSIONS
The AEP-AOP model developed in this study provides strong evidence 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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