Humidifier Disinfectant Research Articles

Thermal Desorption Technique for Analysis of Aerosolized Methylchloroisothiazolinone/Methylisothiazolinone (CMIT/MIT) in Inhalation Toxicity Testing.

When assessing the inhalation toxicity of diverse inhalable substances, a first step is accurate quantitative analysis. In this study, we developed a method for the quantitative analysis of methylisothiazolinone (MIT) and methylchloroisothiazolinone (CMIT), main components in humidifier disinfectants. A simple thermal desorption (TD) method was used to analyze the CMIT/MIT. Using this method, sample loss during aerosolization was minimized compared with other more complicated pretreatment methods, like solvent absorption and extraction (SV). The results of the TD and SV methods were compared to determine the optimal analytical system for CMIT/MIT analysis. In both methods, the concentration of MIT increased systematically with increasing the CMIT/MIT aerosol concentration (R2>0.98). The MIT contents in the aerosol given by the two analytical methods were somewhat similar (MIT content=1.52% (sample solution), 1.43% (TD) and 1.18% (SV)). In contrast, the measured CMIT content in the aerosol was different depending on the type of pretreatment used. The CMIT content was 2.90% for the TD method, while that for the solvent method recorded 0.75% (CMIT content of the sample solution=4.66%). We confirmed that the sample loss of the CMIT with high reactivity occurred in the complicated sampling and pretreatment steps of the SV method.

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

BackgroundUse 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.MethodsEighty-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.ResultsHDLI 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.ConclusionsHD 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.

Korean consumers\u2019 awareness of the risks of chemicals in daily consumer products

BackgroundRecent tragic accidents due to the use of humidifier disinfectants have caused severe distrust and anxiety over chemicals in consumer products in Korea. Therefore, a survey was conducted to determine consumer opinions about the risk of everyday chemical products used in Korea to assess what information should be provided to consumers via risk communication systems.ResultsAn online survey investigated the awareness of 10,000 Korean people regarding potentially harmful substances in consumer chemical products. Concern about the ingredients of chemical products was greatest for pesticides, air fresheners/deodorants, and cleaning agents. There was comparatively little concern about toiletries and personal care products. Respondents were aware of the presence of harmful substances from information on mass media and consumer/environmental organizations, and they also obtained information from ingredient lists and product packaging. Many participants thought that products made from natural materials and products with eco-friendly labeling did not contain harmful substances. Participants replied that they used potentially harmful products as little as possible to reduce the risk. Half of all respondents said that the manufacturers and retailers of products should take responsibility for reducing harmful substances in consumer products. Most respondents were not aware that they could make information disclosure requests for ingredients information.ConclusionThere are numerous concerns about chemicals in consumer products, but many people still do not know exactly what risks they pose. There is a need to communicate information about the risks of chemicals using the media and methods that people can understand.

Effect of Trust in Domain-Specific Information of Safety, Brand Loyalty, and Perceived Value for Cosmetics on Purchase Intentions in Mobile E-Commerce Context

In 2016, the safety issues of humidifier disinfectants and some other safety incidents in personal cares caused chemical phobia syndrome in the Korean society. This series of events has created a trend for cosmetic consumers to undermine brand confidence and to self-check the safety of commercial cosmetic formulations through mobile apps. The purpose of this study is to examine the influence of trust in domain specific information on the safety rating of cosmetic ingredients on the perceived value and the purchase intention of the cosmetics. The results of structural equation modeling showed that involvement of skin safety (ISS) had a positive effect on trust in domain specific information on safety (TDSI) and brand loyalty (BL). TDSI showed a positive effect on the perceived safety value (PFV) and the perceived social value (PSV), and BL had a positive effect on the PSV. ISS, TDSI, and PSV had a positive effect on the purchase intention (PI) of green-grade cosmetics (GGC). As hypothesized, BL had an adverse effect on PI of GGC. Given the results, utilizing the signal of the domain specific information may be recommended to new entrants to the cosmetic business or manufacturers with relatively weak brand power.

How Business Interests and Government Inaction Led to the Humidifier Disinfectant Disaster in South Korea: Implications for Better Risk Governance.

Humidifier sterilizers were regarded as innovative and health-promoting products; they were widespread in South Korea until 2011. However, hospitals reported mysterious deaths, and a legal investigation in April 2016 found that hundreds of people have died due to use of the sterilizing disinfectant. This article takes up that topic, discussing the government's role in dealing with the risk regarding the humidifier disinfectant. We pay particular attention to the unequal nature of the uncertainty produced by the distorted socioeconomic structure. Through in-depth interviews with key informants and an examination of relevant documents from the government, civic groups, and newspapers, we find that the government had increasingly acknowledged the risk, yet their inaction failed to stop the high number of casualties, and they have only recently responded proactively. The uncertainty of the risk was unevenly distributed between companies, the government, experts, and citizens. We argue that the proactive and transparent role of the government with the precautionary principle could fix the unequal structure of knowledge production and preserve public health.

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, trβ, 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.

Inhaled Kathon may induce eosinophilia-mediated disease in the lung.

In 2011, a link between humidifier disinfectants and patients with idiopathic pulmonary fibrosis was identified in Korea, and Kathon was suggested as one of the causative agents. In this study, Kathon induced apoptotic cell death along with membrane damage at 24 h post-exposure. Additionally, on day 14 after a single instillation with Kathon, the total number of pulmonary cells and the levels of TNF-α, IL-5, IL-13, MIP-1α, and MCP-1α clearly increased in the lung of mice. The proportion of natural killer cells and eosinophils were significantly elevated in the spleen and the bloodstream, respectively, and the level of immunoglobulin (Ig) A, but not IgG, IgM, and IgE, dose-dependently increased. Therefore, we suggest that inhaled Kathon may induce eosinophilia-mediated disease in the lung by disrupting homeostasis of pulmonary surfactants. Considering that eosinophilia is closely related to cancer and fibrosis, further studies are needed to understand the relationship between them.

Family-based case-control study of exposure to household humidifier disinfectants and risk of idiopathic interstitial pneumonia.

BackgroundIn Korea, several household humidifier disinfectants (HDs) were clinically confirmed to cause HD-associated lung injury (HDLI). Polyhexamethylene guanidine (PHMG) phosphate is the main ingredient of the HDs found to be associated with lung disease. However, the association of HDs with other interstitial lung disease including idiopathic interstitial pneumonia (IIP) is not clear. We examined the relationship between HD exposure and IIP in a family-based study.MethodsThis case-control study included 244 IIP cases and 244 family controls who lived with the IIP patients. The IIP cases were divided into two groups, HDLI and other IIP, and were matched to family controls based on age and gender. Information on exposure to HDs was obtained from a structured questionnaire and field investigations. Conditional logistic regression was used to estimate odds ratio (ORs) and their corresponding 95% confidence interval (CI), investigating the association of HD-related exposure characteristics with IIP risk.ResultsThe risks of IIP increased two-fold or more in the highest compared with the lowest quartile of several HD use characteristics, including average total use hours per day, cumulative sleep hours, use of HD during sleep, and cumulative exposure level. In analyses separated by HDLI and other IIP, the risks of HDLI were associated with airborne HD concentrations (adjusted OR = 3.01, 95% CI = 1.34–6.76; Q4 versus Q1) and cumulative exposure level (adjusted OR = 3.57, 95% CI = 1.59–8.01; Q4 versus Q1), but this relationship was not significant in the patients with other IIP. In comparison between HDLI and other IIP, the odds ratios of average total use hours, cumulative use hours, and cumulative sleeps hours was higher for other IIP.ConclusionThe use of household HDs is associated not only with HDLI but also with other IIP.

Reproductive and developmental toxicity screening of polyhexamethylene guanidine phosphate by oral gavage in rats

Polyhexamethylene guanidine phosphate (PHMG-P) has effective antimicrobial activity against various microorganisms and has been widely used as a biocide in commercial products. However, its use as a humidifier disinfectant has provoked fatal idiopathic lung disease in South Korea, especially in pregnant or postpartum women and their young children. PHMG-P-related toxicological studies of reproduction and development in experimental animals have not been identified, and thus, we investigated the potential effects of early-stage oral exposure to PHMG-P by assessing its toxicological properties. PHMG-P was repeatedly administered by oral gavage at dose levels of 0, 13, 40 and 120 mg/kg to Sprague-Dawley rats during the pre-mating, mating, gestation and early lactation periods, and then general systemic and reproductive/developmental toxicities were investigated. At 120 mg/kg, PHMG-P-related toxicities including subdued behavior, thin appearance, decreased body weight, decreased food consumption and decreased F1 pup body weight were observed. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of PHMG-P for both general systemic effects and development are considered to be 40 mg/kg/day.

가습기살균제 피해의 행정구제의 문제점과 개선방안

Objectives: The purpose of this study is to identify the causes of the retardation of administrative relief under the Special Act on Remedy for Damages Caused by Humidifier Disinfectant and to suggest the systematic refurbishment of this act for the quick and fair of relief of damages. Methods: This...

Metabolomic study on bleomycin and polyhexamethylene guanidine phosphate-induced pulmonary fibrosis mice models.

Polyhexamethylene guanidine phosphate (PHMG) has been used as a disinfectant and biocide, and was known to be harmless and non-toxic. However, in 2011, PHMG used as a humidifier disinfectant was reported to be associated with lung diseases, such as, fibrosis in the toxicant studies on pulmonary fibrosis by PHMG. However, no metabolomics study has been performed in PHMG-induced mouse models of pulmonary fibrosis. We performed a metabolomic study to understand the biochemical events that occur in bleomycin (BLM)- and PHMG-induced mouse models of pulmonary fibrosis using gas chromatography-mass spectrometry (GC-MS), LC-tandem MS, and GC-tandem MS. The levels of 61 metabolites of 30 amino acids, 13 organic acids, 12 fatty acids, 5 polyamines, and oxidized glutathione were determined in the pulmonary tissues of mice with BLM- and PHMG-induced pulmonary fibrosis and in normal controls. Principal component analysis and partial least squares discriminant analysis used to compare level of these 61 metabolites in pulmonary tissues. Levels of metabolites were significantly different in the BLM and PHMG groups as compared with the control group. In particular, the BLM- and PHMG-induced pulmonary fibrosis models showed elevated collagen synthesis and oxidative stress and metabolic disturbance of TCA related organic acids including fumaric acid by NADPH oxidase. In addition, polyamine metabolism showed severe alteration in the PHMG group than that of the BLM group. This result suggests PHMG will be able to induce pulmonary fibrosis by arginine metabolism and NADPH oxidase signaling.

Humidifier disinfectant and use characteristics associated with lung injury in Korea.

Since around the year 2000, hundreds of people in Korea have developed humidifier disinfectant-associated lung injury (HDLI). We collected all HD exposure-related information from the field investigations into the locations in which the 1199 registered patients had used HD. Among the people who registered, 38% (1st round=214, 2nd=73, 3rd=166) were confirmed as HDLI patients. Children aged under eight years old made up the highest proportion of HDLI cases (N=279, 62%), followed by pregnant women (N=31, 7%). One hundred thirty-three (29%) of the confirmed HDLI patients died. Fifty-seven percent of HDLI patients (N=259) developed HDLI after <1year of HD use. The number of HDLI patients who used only the Oxy Saksak HD brand was found to be 176 (39%), followed by the brands Cefu (N=27, 6%) and Aekyung (N=22, 5%). HD products containing only polyhexamethylene guanidine phosphate (PHMG-P) were the most frequently used among HDLI patients (N=234, 52%), followed by oligo (2-(2-ethoxy)ethoxyethyl) guanidinium (PGH) (N=27, 6%) and a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) (N=26, 6%). The average PHMG-P inhalation level estimated from the patient group classified as suffering lung injury definitely associated with HD use was 145.1μg/m3 (N=91, SD=395.1μg/m3 ), higher than levels estimated from both the probable and possible HDLI patient groups. In conclusion, HD exposure-related variables, including type of HD brand and estimated inhalation HD level, were associated with the risk of HDLI.

The Anti-Fibrotic Effects of CG-745, an HDAC Inhibitor, in Bleomycin and PHMG-Induced Mouse Models.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with poor prognosis and progression to lung fibrosis related to genetic factors as well as environmental factors. In fact, it was discovered that in South Korea many people who used humidifier disinfectants containing polyhexamethylene guanidine (PHMG), died of lung fibrosis. Currently two anti-fibrotic drugs, pirfenidone and nintedanib, have been approved by the FDA, but unfortunately, do not cure the disease. Since the histone deacetylase (HDAC) activity is associated with progression to chronic diseases and with fibrotic phenomena in the kidney, heart and lung tissues, we investigated the anti-fibrotic effects of CG-745, an HDAC inhibitor. After lung fibrosis was induced in two animal models by bleomycin and PHMG instillation, the regulation of fibrosis and epithelial mesenchymal transition (EMT)-related markers was assessed. CG-745 exhibited potent prevention of collagen production, inflammatory cell accumulation, and cytokines release in both models. Additionally, N-cadherin and vimentin expression were lowered significantly by the treatment of CG-745. The anti-fibrotic effects of CG-745 proven by the EMT regulation may suggest a potential therapeutic effect of CG-745 on lung fibrosis.

Akt and Notch pathways mediate polyhexamethylene guanidine phosphate-induced epithelial-mesenchymal transition via ZEB2

Polyhexamethylene guanidine phosphate (PHMG-p), an antimicrobial additive, was used as a humidifier disinfectant in Korea and caused severe lung injuries, including lung fibrosis, in hundreds of victims. As PHMG-p-induced lung fibrosis is different from that induced by known fibrogenic agents such as bleomycin, it is important to understand the molecular mechanisms underlying this effect. A recent study showed that epithelial-mesenchymal transition (EMT) could play key roles in PHMG-p-induced pulmonary fibrosis. Therefore, we aimed to characterize the molecular mechanisms associated with PHMG-p-induced EMT.We observed EMT, macrophage infiltration, and fibrosis in mouse lung tissues after intratracheal instillation of PHMG-p. Furthermore, PHMG-p-induced EMT was observed in A549 cells by the evaluation of cell morphology and quantitation of mRNA and protein expression. The use of EMT inhibitors revealed that PHMG-p induced EMT through the activation of Akt and Notch signaling. Moreover, the transcription factor ZEB2 was observed in PHMG-p-treated A549 cells and mouse lungs. The results indicated that upstream regulators, including Akt and Notch 1, acted as intracellular effectors that triggered ZEB2 expression after exposure to PHMG-p. Attenuation of PHMG-p-induced EMT following inhibition or silencing of Akt and Notch signaling or ZEB2 implied that PHMG-p-induced EMT was a result of Akt, Notch, and ZEB2 activation.Our findings showed that PHMG-p induced EMT through Akt/Notch signaling pathways and that ZEB2 played an important role in PHMG-p-induced lung toxicity. This study will help to understand the mechanisms of action of PHMG-p associated with lung fibrogenesis.

Eye irritation tests of polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) using a tissue model of reconstructed human cornea-like epithelium.

Disinfectants including polyhexamethylene guanidine phosphate (PHMG) and mixtures of chloromethylisothiazolinone/ methylisothiazolinone (CMIT/MIT) have been widely used in Korea to prevent microbial growth in the humidifier water, which triggered an outbreak of serious respiratory diseases. In addition to the respiratory syndrome, disease-related symptoms including liver toxicity, asthma, and skin allergies were also found after extensive survey of people exposed to the humidifier disinfectants (HDs). In this study, eye irritation tests were performed based on the Organization for economic co-operation and development (OECD) test guidelines 492 using EpiOcularTM which is a tissue model of reconstructed human cornea-like epithelium. As results, the raw materials of PHMG (26% as active ingredient) and CMIT/MIT (1.5% as active ingredient) were classified under UN globally harmonized system of classification and labeling of chemical (GHS) category 1 or category 2. However, aqueous dilutions of raw materials such as market products of HDs that contain 0.13% of PHMG and 0.03% of CMIT/MIT or further dilutions of the market products for humidifier that contain 0.0013% of PHMG and 0.0003% of CMIT/MIT were classified under any category, which suggested absence of eye irritation at the test concentration.

Early life exposure of a biocide, CMIT/MIT causes metabolic toxicity via the O-GlcNAc transferase pathway in the nematode C. elegans

Unusual cases of fatal lung injury, later determined to be a result of exposure to chemicals used as humidifier disinfectants, were reported among Korean children from 2006 to 2011. This resulted in considerable study of the pulmonary toxicity of humidifier disinfectant chemicals to establish the causal relationship between exposure and lung disease. However, the systemic toxicity of the former and health effects other than lung disease are not fully understood. Here, we investigated the effect of 5-chloro-2-methyl-4-isothiazoline-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT), among the humidifier disinfectants used in the accidents, on the development of metabolic toxicity in the model organism, Caenorhabditis elegans using an exposure scenario comparison. We screened the potential of CMIT/MIT to induce metabolic toxicity using C. elegans oga-1(ok1207) and ogt-1(ok1474) mutants. We also performed a pathway analysis based on C. elegans transcription factor RNAi library screening to identify the underlying toxicity mechanisms. Finally, to understand the critical window of exposure for metabolic toxicity, responses to exposure during different periods in the life cycles of the worms were compared. We determined that CMIT/MIT could induce metabolic toxicity through O-linked N-acetylglucosamine transferase and early life seems to be the critical window for exposure for metabolic toxicity for this substance. The O-linked N-acetylglucosamine transferase pathway is conserved from worms to humans; our results thus insinuate that early-life exposure to CMIT/MIT could cause metabolic health problems during adult life in humans. We therefore suggest that a systemic toxicity approach should be considered to comprehensively understand the adverse health effects of humidifier disinfectant misuse.

Guanidine-based disinfectants, polyhexamethylene guanidine-phosphate (PHMG-P), polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) induced epithelial-mesenchymal transition in A549 alveolar epithelial cells

sObjective: The major active ingredient of humidifier disinfectant, polyhexamethylene guanidine-phosphate (PHMG-P), caused hundreds of deaths with pulmonary fibrosis. However, structurally similar guanidine-based disinfectants are still in use in various fields. Moreover, as they are precursors of excellent antimicrobial compounds, new chemicals with guanidine-based structures have been synthesized and introduced. In this study, we evaluated pulmonary fibrotic responses induced by PHMG-P, polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) and their toxicity mechanisms in type II alveolar epithelial A549 cells.Materials and methods: Cellular damage was compared by using the cytotoxicity test (WST-1 assay) and plasma membrane toxicity tests (Lactate dehydrogenase leakage detection assay and plasma membrane staining). As a measure of fibrotic response, induction of the epithelial-mesenchymal transition (EMT) was evaluated by measuring E-cadherin and α-smooth muscle actin (α-SMA) protein expression (epithelial and mesenchymal marker, respectively).Results: All tested compounds showed membrane damage; PHMG-P and PGH induced the highest and lowest damage, respectively. Moreover, they induced EMT when the test chemicals were treated with similar cytotoxic concentrations.Conclusions: Our study indicates that three guanidine-based disinfectants are potential fibrosis-inducing chemicals that induce EMT through cellular damage. Therefore, use of guanidine-based polymers should be strictly regulated by considering their potential adverse effects on the lungs.

가습기살균제 사용에 따른 피해 신청자들의 특성 및 노출평가 오류 영향요인 분석

Objectives: The lung injuries by exposure to the humidifier disinfectants (HDs) were reported in 2011, Korea. For the HD victims, environmental exposure level and clinical diagnosis were conducted to determine the levels of damage by HDs. Methods: The exposure assessment to the HDs from 1st to 4th q...

First case of acute respiratory distress syndrome and alimentary tract hemorrhage following mass ingestion of methylisothiazolinone

The frequency of methylisothiazolinone (MIT)-related health concerns regarding allergic contact dermatitis with a spongiotic reaction pattern and restrictive lung function indicating peripheral airway dysfunction caused by the use of humidifier disinfectant is increasingly rising. There is a limited number of evidences supporting the environmentally acute and mass exposure to MIT resulting in acute respiratory distress syndrome (ARDS). Here, we report the first case of ARDS and alimentary tract hemorrhage following mass ingestion of methylisothiazolinone.