Toxicological evidence integration to confirm the biological plausibility of the association between humidifier disinfectant exposure and respiratory diseases using the AEP-AOP framework.

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. Conclusion: 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.

Next generation risk assessment of biocides (PHMG-p and CMIT/MIT)-induced pulmonary fibrosis using adverse outcome pathway-based transcriptome analysis.

Next-generation risk assessment (NGRA) has emerged as a promising alternative to non-animal studies owing to the increasing demand for the risk assessment of inhaled toxicants. In this study, NGRA was used to assess the inhalation risks of two biocides commonly used as humidifier disinfectants: polyhexamethylene guanidine phosphate (PHMG-p) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT). Human bronchial epithelial cell transcriptomic data were processed based on adverse outcome pathways and used to establish transcriptome-based points of departure (tPODs) for each biocide. tPOD values were 0.00500-0.0510 µg/cm2 and 0.0342-0.0544 µg/cm2 for PHMG-p and CMIT/MIT, respectively. tPODs may provide predictive power comparable to that of traditional animal-based PODs (aPODs). The tPOD-based NGRA determined that both PHMG-p and CMIT/MIT present a high inhalation risk. Moreover, the identified PHMG-p posed a higher risk than CMIT/MIT, and children were identified as more susceptible population compared to adults. This finding is consistent with observations from actual exposure events. Our findings suggest that NGRA with transcriptomics offers a reliable approach for risk assessment of specific humidifier disinfectant biocides, while acknowledging the limitations of current models and in vitro systems, particularly regarding uncertainties in pharmacokinetics (PK) and pharmacodynamics (PD).

Evidence integration on health damage for humidifier disinfectant exposure and legal presumption of causation.

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.

Characterizing Subjects Exposed to Humidifier Disinfectants Using Computed-Tomography-Based Latent Traits: A Deep Learning Approach.

Around nine million people have been exposed to toxic humidifier disinfectants (HDs) in Korea. HD exposure may lead to HD-associated lung injuries (HDLI). However, many people who have claimed that they experienced HD exposure were not diagnosed with HDLI but still felt discomfort, possibly due to the unknown effects of HD. Therefore, this study examined HD-exposed subjects with normal-appearing lungs, as well as unexposed subjects, in clusters (subgroups) with distinct characteristics, classified by deep-learning-derived computed-tomography (CT)-based tissue pattern latent traits. Among the major clusters, cluster 0 (C0) and cluster 5 (C5) were dominated by HD-exposed and unexposed subjects, respectively. C0 was characterized by features attributable to lung inflammation or fibrosis in contrast with C5. The computational fluid and particle dynamics (CFPD) analysis suggested that the smaller airway sizes observed in the C0 subjects led to greater airway resistance and particle deposition in the airways. Accordingly, women appeared more vulnerable to HD-associated lung abnormalities than men.

Functional and dynamic mitochondrial damage by chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) mixture in brain endothelial cell lines and rat cerebrovascular endothelium.

The mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT, chloromethylisothiazolinone) and 2-methyl-4-isothiazolin-3-one (MIT, methylisothiazolinone) is a commonly used biocide in consumer products. Despite the health issues related to its usage in cosmetics and humidifier disinfectants (HD), understanding its adverse outcome is still limited. Using in vitro cell lines and ex vivo rat models, we examined the effects of CMIT/MIT on the cellular redox homeostasis and energy metabolism in the brain microvascular endothelium, a highly restrictive interface between the bloodstream and brain. In murine bEND.3 and human hCMEC/D3, CMIT/MIT significantly amplified the mitochondrial-derived oxidative stress causing disruption of the mitochondrial membrane potential and oxidative phosphorylation at a sub-lethal concentration (1 µg/mL) or treatment duration (1 h). In addition, CMIT/MIT significantly increased a dynamic imbalance between mitochondrial fission and fusion, and endogenous pathological stressors significantly potentiated the CMIT/MIT-induced endothelial dysfunction. Notably, in the brain endothelium isolated from intravenously CMIT/MIT-administered rats, we observed significant mitochondrial damage and decreased tight junction protein. Taken together, we report that CMIT/MIT significantly impaired mitochondrial function and dynamics resulting in endothelial barrier dysfunction, giving an insight into the role of mitochondrial damage in CMIT/MIT-associated systemic health effects.

New-Onset and Exacerbation of Lung Diseases after Short-Term Exposures to Humidifier Disinfectant during Hospitalization.

(1) Background: Humidifier disinfectant (HD) is a biocidal chemical to keep the water tank inside a humidifier clean. Thousands of Koreans have experienced HD-related lung injuries. Of them, 6.9% were exposed to HD in hospitals. (2) Methods: This study investigated changes of diseases in patients (or caregivers) who experienced HD exposures during hospitalization and also investigated characteristics of hospital exposure using data from all HD-related lung injury enrollment in Korea. (3) Results: Of a total of 162 subjects, 139 subjects were hospitalized for non-lung diseases, and 23 people were hospitalized for lung diseases at the time of hospitalization. During hospital exposure, 99 (71.2%) of those hospitalized with non-lung disease experienced a new-onset of lung disease, and 15 (65.2%) of those hospitalized with lung diseases experienced exacerbation of their existing lung diseases. When we compared their exposure characteristics, those exposed in hospitals (vs. non-hospital, mostly home) were exposed for shorter periods, at closer distances, at higher HD indoor concentrations, constantly all day, and directly in the facial direction. (4) Conclusion: In conclusion, HD exposures in hospital with a high intensity even for a short term were associated with new-onset or exacerbation of lung diseases. Our findings suggest that acute exposures to HD can cause lung diseases.

Assessment of agonistic and antagonistic properties of humidifier disinfectants to the estrogenic and androgenic receptors by transactivation assay.

Before being recalled and banned from the Korean market, humidifier disinfectants (HDs) were added to the humidifier water tank to prevent microbial growth. The known HDs active ingredients included the are oligo(2-(2-ethoxy)ethoxyethyl guanidine (PGH), polyhexamethylene guanidine (PHMG), a mixture of methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT), didecyldimethyl ammonium chloride (DDAC), Sodium dichloroisocyanurate (NaDCC), and alkyldimethylbenzyl ammonium chloride (BAC). Previous epidemiological studies have suggested that PHMG induces fatal lung disease in pregnant, post-partum women, and young children. In an animal study, a mixture of DDAC and BAC exhibited decreased fertility and fecundity; increased time to first litter, longer pregnancy intervals, fewer pups per litter, and fewer pregnancies. In this study, endocrine-disrupting effects of HDs were investigated using estrogen receptor (ER) and androgen receptor (AR) transactivation assay based on OECD Test guidelines. Unexpectedly, unlike the previously reported reproductive toxicity data, in the present study, HDs did not show ER and AR transcriptional activation agonist and/or antagonist effects. However, it is difficult to conclude that HDs has no endocrine disruption effects, and further research on the effects of HDs mixtures, and in vivo tests including Uterotrophic bioassay and Hershberger bioassay would be necessary.

Misclassification and characterization of exposure to humidifier disinfectants using a questionnaire.

BACKGROUND: Lung disease caused by exposure to chemical substances such as polyhexamethylene guanidine (PHMG) used in humidifier disinfectants (HDs) has been identified in Korea. Several researchers reported that exposure classification using a questionnaire might not correlate with the clinical severity classes determined through clinical diagnosis. It was asserted that the lack of correlation was due to misclassification in the exposure assessment due to recall bias. We identified the cause of uncertainty to recognize the limitations of differences between exposure assessment and clinical outcomes assumed to be true value. Therefore, it was intended to check the availability of survey using questionnaires and required to reduce misclassification error/bias in exposure assessment. METHODS: HDs exposure assessment was conducted as a face-to-face interview, using a questionnaire. A total of 5245 applicants participated in the exposure assessment survey. The questionnaire included information on sociodemographic and exposure characteristics such as the period, frequency, and daily usage amount of HDs. Based on clinical diagnosis, a 4 × 4 cross-tabulation of exposure and clinical classification was constructed. When the values of the exposure rating minus the clinical class were ≥ 2 and ≤ - 2, we assigned the cases to the overestimation and underestimation groups, respectively. RESULTS: The sex ratio was similar in the overestimation and underestimation groups. In terms of age, in the overestimation group, 90 subjects (24.7%) were under the age of 10, followed by 52 subjects (14.2%) in their 50s. In the underestimation group, 195 subjects (56.7%) were under the age of 10, followed by 80 subjects (23.3%) in their 30s. The overestimation group may have already recovered and responded excessively due to psychological anxiety or to receive compensation. However, relatively high mortality rates and surrogate responses observed among those under 10 years of age may have resulted in inaccurate exposure in the underestimation group. CONCLUSIONS: HDs exposure assessment using a questionnaire might not correlate with adverse health effects due to recall bias and various other causes such as recovery of injury and psychological anxiety. This study revealed exposure misclassification and characteristics affected by HDs and proposed a questionnaire-based exposure assessment methodology to overcome the limitations of past exposure assessment.

Toxicity of humidifier disinfectant polyhexamethylene guanidine hydrochloride by two-week whole body-inhalation exposure in rats.

The use of polyhexamethylene guanidine hydrochloride (PHMG·HCl) as a humidifier disinfectant caused an outbreak of pulmonary disease, leading to the deaths of pregnant women and children in South Korea. However, limited information is available on the inhalation toxicity of PHMG·HCl. Therefore, this study aimed to characterize the subacute inhalation toxicity of PHMG·HCl by whole-body exposure in rats. F344 rats were exposed to 0 mg/m3, 1 mg/m3, 5 mg/m3, or 25 mg/m3 of PHMG·HCl for 6 h/day, 5 days/week for two weeks via whole-body inhalation. Emaciation and rale were observed in rats in the 25 mg/m3 PHMG·HCl group. Significant changes in body weight, hematology, serum chemistry and organ weight were observed in all PHMG·HCl-exposed groups. Gross lesions showed ballooning or red focus in the lungs of rats in the PHMG·HCl-exposed groups. In histopathological examination, most of histological lesions (including degeneration, atrophy, ulcer, inflammatory cell infiltration, inflammation, and fibrosis in nasal cavity, larynx, trachea, and lungs) indicated tissue damage by PHMG·HCl in all PHMG·HCl-exposed groups. Additionally, atrophy of the spleen, thymus, and reproductive organs; immaturity of the testes; and cell debris in the epididymides were affected by the reduction in body weight in PHMG·HCl-exposed groups. In conclusion, two-week repeated whole-body inhalation exposure of rats to PHMG·HCl reveled toxic effects on the respiratory system and secondary effects on other organs. The results of this study indicate that the no observable adverse effect level (NOAEL) for PHMG·HCl is below 1 mg/m3.

Mitochondria disease due to humidifier disinfectants: diagnostic criteria and its evidences.

Humidifier disinfectant damages caused by the misuse of humidifier disinfects, such as polyhexamethylene guanidine (PHMG), resulted in chemical disasters in South Korea in 2011. About four million people were exposed to humidifier disinfectants (HDs) in the 17 years between 1994 and 2011. Although fatal lung damage was initially reported, investigations into the victims' injuries revealed that the damage was not limited to the lungs, but that systemic damage was also confirmed. Considering the spread of HD from the lungs to the whole body, the toxic effects of PHMG from reactive oxygen species (ROS), NOTCH signaling pathways, and mitochondrial dysfunction resulted in endothelial damage in the lungs, blood vessels, liver, kidneys, bone marrow, nerves, and muscles. The main toxic mechanisms involved in HD damage may be the NOTCH pathway and mitochondrial damage. There are many case reports which include neurologic disorders (ADHD, depression, posttraumatic stress disorder), muscular disorder (exercise intolerance, myalgia), energy metabolism disorder (chronic fatigue syndrome), and immunologic disorder (rheumatoid arthritis) in HDs victims. These case reports involve multi-system involvement in HDs victims. Further well-designed study is needed to clarify whether mitochondrial dysfunction is associated with multi-organs involvement in HDs victims.

Integration of transcriptomics, proteomics and metabolomics identifies biomarkers for pulmonary injury by polyhexamethylene guanidine phosphate (PHMG-p), a humidifier disinfectant, in rats.

Polyhexamethylene guanidine phosphate (PHMG-p) was used as a humidifier disinfectant in Korea. PHMG induced severe pulmonary fibrosis in Koreans. The objective of this study was to elucidate mechanism of pulmonary toxicity caused by PHMG-p in rats using multi-omics analysis. Wistar rats were intratracheally instilled with PHMG-p by single (1.5 mg/kg) administration or 4-week (0.1 mg/kg, 2 times/week) repeated administration. Histopathologic examination was performed with hematoxylin and eosin staining. Alveolar macrophage aggregation and granulomatous inflammation were observed in rats treated with single dose of PHMG-p. Pulmonary fibrosis, chronic inflammation, bronchiol-alveolar fibrosis, and metaplasia of squamous cell were observed in repeated dose group. Next generation sequencing (NGS) was performed for transcriptome profiling after mRNA isolation from bronchiol-alveoli. Bronchiol-alveoli proteomic profiling was performed using an Orbitrap Q-exactive mass spectrometer. Serum and urinary metabolites were determined using 1H-NMR. Among 418 differentially expressed genes (DEGs) and 67 differentially expressed proteins (DEPs), changes of 16 mRNA levels were significantly correlated with changes of their protein levels in both single and repeated dose groups. Remarkable biological processes represented by both DEGs and DEPs were defense response, inflammatory response, response to stress, and immune response. Arginase 1 (Arg1) and lipocalin 2 (Lcn2) were identified to be major regulators for PHMG-p-induced pulmonary toxicity based on merged analysis using DEGs and DEPs. In metabolomics study, 52 metabolites (VIP > 0.5) were determined in serum and urine of single and repeated-dose groups. Glutamate and choline were selected as major metabolites. They were found to be major factors affecting inflammatory response in association with DEGs and DEPs. Arg1 and Lcn2 were suggested to be major gene and protein related to pulmonary damage by PHMG-p while serum or urinary glutamate and choline were endogenous metabolites related to pulmonary damage by PHMG-p.

The past, present, and future of humidifier disinfectant-associated interstitial lung diseases in children.

Exposure to environmental factors can cause interstitial lung diseases (ILDs); however, such types of ILDs are rare. From 2007 to 2011, an ILD epidemic occurred in South Korea owing to inhalational exposure to toxic chemicals in humidifier disinfectants (HDs). HD-associated ILDs (HD-ILDs) are characterized by rapidly progressing respiratory failure with pulmonary fibrosis and a high mortality rate of 43.8%-58.0%. Although 18.1%-31.1% of the general population used HDs, only a small proportion of HD users were diagnosed with HD-ILDs. This finding suggests that investigation of the pathophysiologies underlying HD-ILDs is needed in addition to the identification of susceptibility to HD-ILDs. Further, there have been several concerns regarding the diverse health effects of exposure to toxic chemicals in HDs, including those that have not been identified, and long-term prognoses in terms of pulmonary function and residual pulmonary lesions observed on follow-up chest images. In this review, we summarize the clinical features, pathologic findings, and changes in radiologic findings over time in patients with HD-ILDs and the results of previous experimental research on the mechanisms underlying the effects of toxic chemicals in HDs. Studies are currently underway to identify the pathophysiologies of HD-ILDs and possible health effects of exposure to HDs along with the development of targeted therapeutic strategies. The experience of identification of HD-ILDs has encouraged stricter control of safe chemicals in everyday life.

Early-life exposure to humidifier disinfectant determines the prognosis of lung function in children.

BACKGROUND: Use of humidifier disinfectants (HD) at home leads to chemical airborne exposure, causing HD associated lung injury (HDLI) with high mortality. However, the lung function in children diagnosed with HDLI is not well studied. We investigated the effect of HD exposure on lung function, prognosis, and exposure characteristics associated with the lung function phenotype in children. METHODS: Eighty-one children diagnosed with HDLI in a nationwide cohort were tested for spirometry and diffusing capacity of the lung for carbon monoxide (DLco) from July 2013 and followed up with at five time points over 2 years. The results were compared with 122 children without HD exposure as controls. Home investigation and questionnaire analysis were conducted to assess HD inhalation exposure. RESULTS: HDLI survivor's mean percent of predicted forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and corrected DLco were significantly lower compared with the control group. On longitudinal assessment, FVC was within the normal range, but flattened, and spirometry showed a predominantly restrictive pattern. Corrected DLco did not normalize above 80% despite increasing age. The persistently low phenotype of lung function was associated with initial exposure age, especially less than 12 months of age. Higher density HD exposure during sleep and close distance between the bed and the humidifier were significantly associated with persistently low corrected DLco. CONCLUSIONS: HD exposure affects prolonged decrement in lung function, especially DLco, particularly among children who are exposed within the first year of life. These results suggested that early-life HD exposure determines long-term prognosis of lung function in children.

Immunohistochemical characterization of oxidative stress in the lungs of rats exposed to the humidifier disinfectant polyhexamethylene guanidine hydrochloride.

Polyhexamethylene guanidine hydrochloride (PHMG-HCl), an antimicrobial additive in humidifier disinfectants, was associated with the pulmonary disease outbreak in South Korea. However, PHMG-mediated oxidative stress has only been studied in vitro. Here, we evaluated PHMG-induced oxidative stress in the lungs of rats exposed to PHMG-HCl. Male F344 rats were exposed to different concentrations of PHMG-HCl for 13-weeks via whole-body inhalation. Histopathological examination of the exposed rats showed the presence of lung lesions, including alveolar/interstitial fibrosis with inflammatory cell infiltration, bronchioalveolar hyperplasia, bronchiolar/alveolar squamous metaplasia, bronchial/bronchiolar epithelial detachment, and alveolar hemorrhage. Immunohistochemical analysis showed that 4-hydroxynonenal (4-HNE) was expressed in the bronchiolar epithelium, mainly in Clara cells and macrophages of the fibrotic tissue. The number of 4-HNE-positive cells increased significantly in a dose-dependent manner. This is the first in vivo study to report PHMG-induced oxidative stress. Our study provides clues to elucidate the mechanisms underlying PHMG-induced damage in patients affected by humidifier disinfectants.

Exposure to humidifier disinfectants induces developmental effects and disrupts thyroid endocrine systems in zebrafish larvae.

Humidifier disinfectants have been widely used in Korea to prevent the growth of microorganisms in humidifier water. However, their use has been banned since 2011 after epidemiological studies reported humidifier disinfectant induced lung injury. In the present study, the developmental effects of exposure to two humidifier disinfectants (Oxy® and Wiselect) and their main component, polyhexamethylene guanidine (PHMG)-phosphate, were investigated in zebrafish embryos/larvae for seven days. The effects on triiodothyronine (T3) and thyroxine (T4) hormones, reactive oxygen species (ROS) generation, antioxidant enzyme activities, and changes in expression of the genes related to the hypothalamus-pituitary-thyroid (HPT) axis and oxidative stress were also investigated. Zebrafish embryos exposed to the highest concentration (amounts recommended for use by the manufacturers) of all tested humidifier disinfectants showed an increase in embryo coagulation, leading to death without hatching. Exposure to Oxy® and Wiselect resulted in significantly decreased body length, increased ROS generation and antioxidant enzyme activities, decreased T4, and up-regulated genes related to the HPT axis (trh, trß, and tpo) and oxidative damage (sod2 and gpx1b). The humidifier disinfectants and PHMG-phosphate could induce oxidative stress and disrupt thyroid hormone systems in zebrafish, leading to developmental retardation when used at sub-lethal concentrations. Potential effects of long-term exposure to humidifier disinfectants and mixture effects of several major components deserve further investigation.

Association of high-level humidifier disinfectant exposure with lung injury in preschool children.

BACKGROUND: Children aged ≤6years reportedly account for 52% of victims of humidifier disinfectant-associated lung injuries. OBJECTIVES: To evaluate the association of humidifier disinfectants with lung injury risk among children aged ≤6years. METHODS: Patients with humidifier disinfectant-associated lung injuries (n=214) who were clinically evaluated to have a definite (n=108), probable (n=49), or possible (n=57) association with humidifier disinfectants as well as control patients (n=123) with lung injury deemed unlikely to be associated with humidifier disinfectant use were evaluated to determine factors associated with increased risk of humidifier disinfectant-associated lung injury using unconditional multiple logistic regression analysis. RESULTS: For estimated airborne humidifier disinfectant concentrations, risk of humidifier disinfectant-associated lung injury increased ≥two-fold in a dose-dependent manner in the highest quartile (Q4, 135-1443µg/m3) compared with that in the lowest quartile (Q1, ≤33µg/m3). Registered patients using more than two humidifier disinfectant brands were at an increased risk of humidifier disinfectant-associated lung injury (adjusted OR, 2.2; 95% confidence interval, 1.3-3.8) compared with those using only one brand. With respect to the duration of humidifier disinfectant use, risk of humidifier disinfectant-associated lung injury increased ≥two-fold in the lowest quartile (≤5months) compared with that in the highest quartile (≥14months; adjusted OR 0.3; 95% confidence interval, 0.2-0.6). CONCLUSIONS: Younger children are more vulnerable to HDLI when exposed to HD chemicals within short period in early life.

Inhalation Lung Injury Associated with Humidifier Disinfectants in Adults.

We recently established a novel disease entity presented as progressive respiratory failure associated with the inhalation of humidifier disinfectants. In April 2011, we encountered a series of peripartum patients with complaints of respiratory distress of unknown etiology, which was an uncommon phenomenon. Accordingly, we created a multidisciplinary team comprising intensivists, radiologists, pathologists, epidemiologists, and the Korea Centers for Disease Control and Prevention (KCDC). Further, we defined the disease entity and performed a case-control study, epidemiologic investigation, and animal study to determine the etiology. The study findings indicated that the lung injury outbreak was related to the inhalation of humidifier disinfectants and showed that household chemical inhalation can cause severe respiratory failure. Following the withdrawal of humidifier disinfectants from the Korean market in 2012, no such cases were reported. This tragic event is a warning that appropriate safety regulations and monitoring for potential toxic household chemicals are critical to protect public health.