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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 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
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Epidemiol Health. 2024;46:e2024060. Published online July 7, 2024
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DOI: https://doi.org/10.4178/epih.e2024060
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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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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.
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Evidence integration on health damage for humidifier disinfectant exposure and legal presumption of causation
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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
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Epidemiol Health. 2023;45:e2023095. Published online October 24, 2023
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DOI: https://doi.org/10.4178/epih.e2023095
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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.
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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.
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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
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Effect modification of consecutive high concentration days on the association between fine particulate matter and mortality: a multi-city study in Korea
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Hyungryul Lim, Sanghyuk Bae, Jonghyuk Choi, Kyung-Hwa Choi, Hyun-Joo Bae, Soontae Kim, Mina Ha, Ho-Jang Kwon
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Epidemiol Health. 2022;44:e2022052. Published online June 9, 2022
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DOI: https://doi.org/10.4178/epih.e2022052
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OBJECTIVES Although there is substantial evidence for the short-term effect of fine particulate matter (PM<sub>2.5</sub>) on daily mortality, few epidemiological studies have explored the effect of prolonged continuous exposure to high concentrations of PM<sub>2.5</sub>. This study investigated how the magnitude of the mortality effect of PM<sub>2.5</sub> exposure is modified by persistent exposure to high PM<sub>2.5</sub> concentrations.
METHODS We analyzed data on the daily mortality count, simulated daily PM<sub>2.5</sub> level, mean daily temperature, and relative humidity level from 7 metropolitan cities from 2006 to 2019. Generalized additive models (GAMs) with quasi-Poisson distribution and random-effects meta-analyses were used to pool city-specific effects. To investigate the effect modification of continuous exposure to prolonged high concentrations, we applied categorical consecutive-day variables to the GAMs as effect modification terms for PM<sub>2.5</sub>.
RESULTS The mortality risk increased by 0.33% (95% confidence interval [CI], 0.16 to 0.50), 0.47% (95% CI, -0.09 to 1.04), and 0.26% (95% CI, -0.08 to 0.60) for all-cause, respiratory, and cardiovascular diseases, respectively, with a 10 μg/m3 increase in PM<sub>2.5</sub> concentration. The risk of all-cause mortality per 10 μg/m3 increase in PM<sub>2.5</sub> on the first and fourth consecutive days significantly increased by 0.63% (95% CI, 0.20 to 1.06) and 0.36% (95% CI, 0.01 to 0.70), respectively.
CONCLUSIONS We found increased risks of all-cause, respiratory, and cardiovascular mortality related to daily PM<sub>2.5</sub> exposure on the day when exposure to high PM<sub>2.5</sub> concentrations began and when exposure persisted for more than 4 days with concentrations of ≥35 μg/m3. Persistently high PM<sub>2.5</sub> exposure had a stronger effect on seniors.
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Summary
Korean summary
한국의 7개 대도시를 배경으로 수행한 본 시계열 연구를 통하여 2006년부터 2019년까지의 기간 동안에 초미세먼지의 단기 노출이 일별 사망률을 증가시키며, 교호작용모형을 통해 일평균 35 μg/m3 이상의 고농도 지속기간이 처음 시작되는 날과 넷째 지속일에 이러한 사망효과가 커짐을 보고하였다. 이러한 고농도 지속기간의 교호작용은 65세 이상 연령군에서 더욱 두드러졌다.
Key Message
With our Korean multi-city study design from 2006 to 2019, the short-term effects of PM2.5 on mortality were greater when the high PM2.5 concentration duration began during the day and lasted for approximately 4 days, and the elderly may be more affected by persistently high PM2.5.
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Evaluation report on the causal association between humidifier disinfectants and lung injury
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Mina Ha, Soon Young Lee, Seung-sik Hwang, Hyesook Park, Seungsoo Sheen, Hae Kwan Cheong, Bo Youl Choi
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Epidemiol Health. 2016;38:e2016037. Published online August 18, 2016
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DOI: https://doi.org/10.4178/epih.e2016037
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23,535
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Abstract
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Abstract
OBJECTIVES As of November 2011, the Korean government recalled and banned humidifier disinfectants (HDs) from the market, because four case-control studies and one retrospective epidemiological study proved the association between HDs and lung injury of unknown cause. The report reviewed the causal role of HDs in lung injury based on scientific evidences.
METHODS A careful examination on the association between the HDs and lung injury was based on the criteria of causality inference by Hill and the US Surgeon General Expert Committee.
RESULTS We found that all the evidences on the causality fulfilled the criteria (strength of association, consistency, specificity, temporality, biologic gradient, plausibility, coherence, experiment, analogy, consideration of alternative explanations, and cessation of exposure), which proved the unknown cause lung injury reported in 2011 was caused by the HDs. In particular, there was no single reported case of lung injury since the ban in selling HDs in November 2011 as well as before the HDs were sold in markets.
CONCLUSIONS Although only a few epidemiological studies in Korea have evaluated the association between lung injury and the use of HDs, those studies contributed to proving the strong association between the use of the HDs and lung injury, based on scientific evidence.
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Summary
Korean summary
본 논문에서는 Hill의 기준과 US Surgeon General 전문위원회에서 제시하는 기준에 근거하여 가습기살균제와 폐손상과의 인과성을 검토하였다. 검토결과, 11개 조건(관련성의 강도, 일관성, 특이성, 시간적 선후관계, 생물학적 용량-반응 관계, 개연성, 기존 지식과의 일치성, 실험, 유사성, 다른 가능한 해석에 대한 고려 및 노출의 중단) 을 모두 충족함을 확인하므로 써, 2011년 발생한 원인미상 폐손상의 원인이 가습기살균제 노출로 인한 것임을 알 수 있었다. 무엇보다도 가습기살균제 시판 전에는 원인미상 폐손상이 보고된 바가 없었고, 2011년 11월 가습기살균제 판매중지 이후 폐손상이 한 건도 발생하지 않은 것은 원인미상의 폐손상이 가습기살균제로 인한 것임을 강력하게 지지하는 것으로 판단된다.
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Citations
Citations to this article as recorded by
- New-Onset and Exacerbation of Lung Diseases after Short-Term Exposures to Humidifier Disinfectant during Hospitalization
Seula Lee, Kyunghee Han, Jeonggyo Yoon, Eun-Kyung Jo, Wonho Yang, Yoon-Hyeong Choi Toxics.2022; 10(7): 371. CrossRef - Characterizing Subjects Exposed to Humidifier Disinfectants Using Computed-Tomography-Based Latent Traits: A Deep Learning Approach
Frank Li, Jiwoong Choi, Xuan Zhang, Prathish K. Rajaraman, Chang-Hyun Lee, Hongseok Ko, Kum-Ju Chae, Eun-Kee Park, Alejandro P. Comellas, Eric A. Hoffman, Ching-Long Lin International Journal of Environmental Research and Public Health.2022; 19(19): 11894. CrossRef - Physical analysis reveals distinct responses of human bronchial epithelial cells to guanidine and isothiazolinone biocides
Tae Yoon Kwon, Jaeseong Jeong, Eunyoung Park, Youngbin Cho, Dongyoung Lim, Ung Hyun Ko, Jennifer H. Shin, Jinhee Choi Toxicology and Applied Pharmacology.2021; 424: 115589. CrossRef - Need for individual-based evaluation to determine the association between humidifier disinfectants and health injuries
Hyeong-Cheol Kim, Hyunil Kim, Eun-Chan Mun, Yesung Lee, Soyoung Park Annals of Occupational and Environmental Medicine.2021;[Epub] CrossRef - Strength of Association. Report 1. Graduations of Relative Risk
А. Котеров, A. Koterov, Л. Ушенкова, L. Ushenkova, Э. Зубенкова, E. Zubenkova, А. Вайнсон, A. Vaynson, М. Калинина, M. Kalinina, А. Бирюков, A. Biryukov Medical Radiology and radiation safety.2019; : 5. CrossRef - Causal inference in environmental epidemiology
Sanghyuk Bae, Hwan-Cheol Kim, Byeongjin Ye, Won-Jun Choi, Young-Seoub Hong, Mina Ha Environmental Health and Toxicology.2017; 32: e2017015. CrossRef
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Hebei Spirit oil spill exposure and acute neuropsychiatric effects on residents participating in clean-up work.
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Jin Hee Eum, Hae Kwan Cheong, Mina Ha, Ho Jang Kwon, Eun Hee Ha, Yun Chul Hong, Ye Yong Choi, Woo Chul Jeong, Jong Il Hur, Seungmin Lee, Eun Jung Kim, Eun Hee Lee, So Young Lee Ahn, Jong Hun Kim
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Korean J Epidemiol. 2008;30(2):239-251. Published online December 31, 2008
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DOI: https://doi.org/10.4178/kje.2008.30.2.239
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Abstract
OBJECTIVES Hebei Spirit oil spill accident has brought about the worst coastal oil contamination in Korean history.
Following the accident, residents and volunteers, number exceeding a million from nationwide, were exposed to chemicals from the crude oil itself and dispersants, including volatility organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs), and heavy metals through the clean-up works over months. This study was undertaken to investigate the effect of clean-up work on the peripheral nerve function and psychologic status of the residents after a prolonged exposure to clean-up work after the oil spill exposure.
METHODS We performed a study on the residents of Jango-do Island, Chungnam, on 5 and 12 January 2008, six to eight weeks after the accident. A questionnaire on general characteristics, Korean Beck Depression Inventory (K-BDI), color vision test (Lanthony desaturated D-15 test), and vibration perception threshold test were done. Among 210 residents with 30 years or older, 63 (30%) finished questionnaires and completed at least one among K-BDI, color vision test, or vibration perception threshold test.
Descriptive statistics was done on the residents.
RESULTS The residents participated in clean-up work for average 20 days, max 30 days, during 6 weeks following the accident. Average work hours were 7.4 hours per day, max 10 hours. On K-BDI, 21 (33.3%) had a severe depressive state.
Mean color confusion index was 1.29 in the right and 1.20 in the left. Mean vibration perception threshold was 3.69 VU (right) and 3.55 VU (left), respectively.
DISCUSSIONS AND CONCLUSIONS: Compared to literature report, the residents had higher depression scale. Color vision threshold was not higher compared to general population near an industrial complex. Vibration perception threshold was significantly higher than the residents of similar age living near an abandoned mine in southern coastal area only in the age group of forties. These suggests there is some evidence of neuropsychiatric effect related to oil cleaning work and a mid- and long-term study of the oil exposure health effects with continuous monitoring should be done for the exposed residents in the affected area.
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Citations
Citations to this article as recorded by
- Cancer Incidence Trend in the Hebei Spirit Oil Spill Area, from 1999 to 2014: An Ecological Study
Kyung-Hwa Choi, Myung-Sook Park, Mina Ha, Jong-Il Hur, Hae-Kwan Cheong International Journal of Environmental Research and Public Health.2018; 15(5): 1006. CrossRef - Inquiring into activist publics in chronic environmental issues: use of the mutual-gains approach for breaking a deadlock
Soojin Kim, Jeong-Nam Kim, Laishan Tam, Gwang Tae Kim Journal of Public Affairs.2015; 15(4): 404. CrossRef - Community mental health status six months after the Sewol ferry disaster in Ansan, Korea
Hee Jung Yang, Hae Kwan Cheong, Bo Youl Choi, Min-Ho Shin, Hyeon Woo Yim, Dong-Hyun Kim, Gawon Kim, Soon Young Lee Epidemiology and Health.2015; 37: e2015046. CrossRef - Disaster management from the perspective of governance: case study of the Hebei Spirit oil spill
Joon‐Young Hur Disaster Prevention and Management: An International Journal.2012; 21(3): 288. CrossRef - Psychological Health in Residents Participating in Clean-up Works of Hebei Spirit Oil Spill
Minkyo Song, Yun-Chul Hong, Hae-Kwan Cheong, Mina Ha, Hojang Kwon, Eun-Hee Ha, Yeyong Choi, Woo-Chul Jeong, Jongil Hur, Seung-Min Lee, Eun-Jung Kim Journal of Preventive Medicine and Public Health.2009; 42(2): 82. CrossRef
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Glutathione S-transferase(GST) M1 and T1 Genetic Polymorphism in Benign Breast Disorders of Korean Women.
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Sue Kyung Park, Mina Ha, Sook Un Kim, Daehee Kang, Keun Young Yoo
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Korean J Epidemiol. 2000;22(1):52-58.
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PURPOSE A hospital-based case-control study was conducted to evaluate the role of glutathione-S-transferase(GST)M1 and GSTT1 genetic polymorphism for developing benign breast disorders(fibrocystic diseases and fibroadenoma) in Korea.
MATERIALS AND METHODS: Histologically confirmed incident cases of benign breast disorder(n=56) were selected from inpatients at the Department of General Surgery, Seoul National University Hospital since 1994. Women with free of self-reporting past history of any malignancies were regarded as controls who were selected from the inpatients at the same department at three hospitals during 1994 to 1998(n=180). Information on life-styles including reproductive factors were obtained by direct interview using questionnaire. Age and menopausal status were matched and 51 cases and 102 controls were finally selected. Odds ratio and 95% confidence interval were estimated by multiple logistic regression after adjusting for age, education, body mass index, smoking history, drinking history, menstrual regularity, age at menarch, age at first pregnancy, frequency of fullterm pregnancy, breast feeding history, duration of breast feeding, and family history of breast cancer.RESULTS GSTM1-null type showed no significance related to the risk of benign breast disorder(adjusted OR=0.8, 95% CI=0.38-1.83) and GSTT1-null type was also not significant(adjusted OR=1.4, 95% CI=0.63-3.29). Increasing tendency of disease risk by the number of GSTs null type was not observed (ptrend>0.1) after adjusting for all other variables.DISCUSSIONS Further investigation with larger sample size should be needed to provide more concrete information on the role of GST genetic polymorphism in benign breast cancer and a lots of studies relation in normal level of GST genetic polymorphism in general population should be performed.
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