Epidemiology and Health

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.

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

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1 Web of Science
1 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

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

COVID-19: Original Article

Estimation of the number of working population at high-risk of COVID-19 infection in Korea: Juyeon Lee, Myounghee Kim; Epidemiol Health. 2020;42:e2020051. Published online July 9, 2020; DOI: https://doi.org/10.4178/epih.e2020051

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417 Download
20 Web of Science
15 Crossref

Abstract Summary PDF Supplementary Material

Abstract

OBJECTIVES
We aimed to identify occupational groups at high-risk of coronavirus disease 2019 (COVID-19) infection in Korea, to estimate the number of such workers, and to examine the prevalence of protective resources by employment status.

METHODS

Based on the sixth Standard Occupational Classification codes, 2015 census data were linked with data from the fifth Korean Working Conditions Survey, which measured how frequently workers directly come into contact with people other than fellow employees in the workplace.

RESULTS

A total of 30 occupational groups, including 7 occupations from the healthcare and welfare sectors and 23 from other sectors, were classified as high-risk occupational groups involving frequent contact with people other than fellow employees in the workplace (more than half of the working hours). Approximately 1.4 million (women, 79.1%) and 10.7 million workers (46.3%) are employed in high-risk occupations. Occupations with a larger proportion of women are more likely to be at a high-risk of infection and are paid less. For wage-earners in high-risk occupations, protective resources to deal with COVID-19 (e.g., trade unions and health and safety committees) are less prevalent among temporary or daily workers than among those with permanent employment.

CONCLUSIONS

Given the large number of Koreans employed in high-risk occupations and inequalities within the working population, the workplace needs to be the key locus for governmental actions to control COVID-19, and special consideration for vulnerable workers is warranted.

Summary

Korean summary
코로나바이러스감염증-19 (코로나19) 유행 상황에서 감염 고위험 직업군 종사자는 보건의료복지 업종에서 총 140만 명, 그 외 업종에서 총 1,073만 명으로 추정된다. 고위험 사업장에 대해 정부가 안전보건 관리·감독·규제 및 지원 체계를 수립하고, 방역대책의 중심에 노동자의 안전과 건강 보호를 두는 관점의 전환이 필요하다. 우선 당장 역학조사 과정에서 직업관련 요소를 자세히 확인하고, 직업관련 감염에 대한 모니터링과 그에 걸맞는 대책을 마련해야 한다.

Citations

Citations to this article as recorded by

Managing the unknown or the art of preventing SARS-CoV-2 infection in workplaces in a context of evolving science, precarious employment, and communication barriers. A qualitative situational analysis in Quebec and Ontario
Daniel Côté, Ellen MacEachen, Ai-Thuy Huynh, Amelia León, Marie Laberge, Samantha Meyer, Shannon Majowicz, Joyceline Amoako, Yamin Jahangir, Jessica Dubé
Frontiers in Public Health.2024;[Epub] CrossRef
Mobility and Thermal Comfort Assessment of Personal Protective Equipment for Female Healthcare Workers: Impact of Protective Levels and Body Mass Index
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Fashion & Textile Research Journal.2024; 26(1): 123. CrossRef
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Journal of Caring Sciences.2023; 12(2): 123. CrossRef
National and regional trends in the prevalence of type 2 diabetes and associated risk factors among Korean adults, 2009–2021
Jiyeon Oh, Soeun Kim, Myeongcheol Lee, Sang Youl Rhee, Min Seo Kim, Ju-Young Shin, Hyunjung Lim, Seung Won Lee, Masoud Rahmati, Sunyoung Kim, Dong Keon Yon
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