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ABSTRACTChloromethylisothiazolinone (CMIT), a humidifier disinfectant, is known to be toxic to the respiratory system. While the toxic effect of CMIT on the lungs has been widely investigated, its effect on the skin is well unknown. In this study, we examined stress granule (SG) formation to investigate the cytotoxic effects of CMIT on human keratinocytes. We assessed the viability of the cells following CMIT exposure and performed immunofluorescence microscopy and immunoblot analyses to determine SG formation and downstream pathways. The IC50 values in human keratinocyte HaCaT cells after CMIT exposure for 1 and 24 h were 11 and 8 μg/mL, respectively, showing no significant difference. As determined using immunofluorescence microscopy, SG formation was effectively induced after CMIT exposure. Moreover, the phosphorylation of eukaryotic initiation factor-2α (eIF2α), a translation initiation factor, and protein kinase R-like endoplasmic reticulum (ER) kinase, which plays a role in the ER stress-mediated eIF2α phosphorylation, was confirmed by CMIT exposure. These results suggest that exposure to CMIT can have detrimental effects on the skin, even briefly, by inducing SG formation through ER stress in keratinocytes.

Chloromethylisothiazolinone (CMIT), a humidifier disinfectant, is known to be toxic to the respiratory system. While the toxic effect of CMIT on the lungs has been widely investigated, its effect on the skin is well unknown. In this study, we examined stress granule (SG) formation to investigate the cytotoxic effects of CMIT on human keratinocytes. We assessed the viability of the cells following CMIT exposure and performed immunofluorescence microscopy and immunoblot analyses to determine SG formation and downstream pathways. The IC50 values in human keratinocyte HaCaT cells after CMIT exposure for 1 and 24 h were 11 and 8 μg/mL, respectively, showing no significant difference. As determined using immunofluorescence microscopy, SG formation was effectively induced after CMIT exposure. Moreover, the phosphorylation of eukaryotic initiation factor-2α (eIF2α), a translation initiation factor, and protein kinase R-like endoplasmic reticulum (ER) kinase, which plays a role in the ER stress-mediated eIF2α phosphorylation, was confirmed by CMIT exposure. These results suggest that exposure to CMIT can have detrimental effects on the skin, even briefly, by inducing SG formation through ER stress in keratinocytes. [ABSTRACT FROM AUTHOR]

A variety of isothiazolinone-containing small molecules have been registered and used as chemical additives in many household products. However, their biodistribution and potential harmful effects on human health, especially respiratory effects, were not yet identified in sufficient detail. The purpose of this study was to investigate whether a biocide comprising a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) could reach the lungs and induce lung injury when exposure occurs by two administration routes involving the respiratory tract: intratracheal and intranasal instillation. To investigate the biodistribution of CMIT/MIT, we quantified the uptake of 14C-labeled CMIT/MIT in experimental animals for up to seven days after intratracheal and intranasal instillation. In the toxicity study, lung injury was assessed in mice using total inflammatory cell count in bronchoalveolar lavage fluid (BALF) and lung histopathology. The results of the biodistribution study indicated that CMIT/MIT were rapidly distributed throughout the respiratory tract. Using quantitative whole-body autoradiogram analysis, we confirmed that following intranasal exposure, CMIT/MIT reached the lungs via the respiratory tract (nose–trachea–lung). After 5 min post intratracheal and intranasal instillation, the amount of radiotracer ([14C]CMIT/MIT) in the lungs was 2720 ng g−1 and 752 ng g−1 tissue, respectively, and lung damage was observed. A higher amount of the radiotracer resulted in higher toxicity. Both intratracheal and intranasal instillation of CMIT/MIT increased inflammatory cell counts in the BALF and induced injuries in the alveoli. The frequency and the severity scores of injuries caused by intratracheal instillation were approximately-four to five times higher than those induced by intranasal instillation. Therefore, we concluded that CMIT/MIT could reach the lungs following nasal and intratracheal exposure and cause lung injuries, and the extent of injury was dependent on the exposure dose.

Environmental risk factors are recognized as threats to public health. Stress granules (SGs) are non-membranous assemblies of mRNAs and proteins expressed in response to various stressors to promote cell survival. In this study, SG formation was examined to confirm the effects of polyhexamethylene guanidine phosphate (PHMG), chloromethylisothiazolinone (CMIT), and particulate matter (PM10) in airway epithelial cells, A549, HPAEpiC, and BEAS-2B cells. SGs were not observed after CMIT, PHMG, and PM10 treatments, as determined by immunofluorescence microscopy. Moreover, there was no change in the phosphorylation of the translation initiation factor eIF2αfollowing treatment with PHMG, CMIT, and PM10. Taken together, our findings might help determine the biological hazards of these materials.

5-Chloro-2-methyl-4-isothiazolin-3-one (CMIT) and 2-methyl-4-isothiazolin-3-one (MIT) used as preservatives in various products, including humidifier disinfectants, presents substantial health hazards. This research delves into the toxicological assessments of CMIT/MIT in the respiratory system using animal models. Through the synthesis of radiolabeled [14C]CMIT and [14C]MIT, we investigated the biological uptake and in vivo behaviors of CMIT/MIT in the respiratory tissues following intratracheal exposure. Quantitative whole-body autoradiography (QWBA) revealed significant persistence of CMIT/MIT in lung tissue. In addition, radio high-performance liquid chromatography (radio-HPLC) with tandem mass spectrometry (LC-MS/MS) was employed for metabolite profiling and identification. Notably, around 28% of the radiolabel was retained in tissue after the extraction step, suggesting covalent binding of CMIT/MIT and their metabolites with pulmonary biomolecules. This observation demonstrates the propensity of the electrophilic isothiazolinone ring in CMIT/MIT to undergo chemical interactions with biothiols in proteins and enzymes, fostering irreversible alterations of biomolecules. Such accumulations of transformations could result in direct toxicity at both cellular and organ levels. Additionally, the detection of metabolites, including a MIT dimer conjugated with glutathione (GSH), as analyzed by mass spectrometry indicates the possible reduction of cellular GSH levels and subsequent oxidative stress. This investigation offers an in-depth insight into the toxic mechanisms of CMIT/MIT, underlying their capability to engage in complex formations with biomacromolecules and induce pronounced respiratory toxicity. These results highlight the imperative for stringent safety assessments of these chemicals, advocating for improved public health and safety measures in the use of chemicals. [Display omitted] • The radiolabeled CMIT and MIT were synthesized using radioactive carbon (14C). • The SUV of CMIT/MIT in lung was determined to be 6.01 after 0.083 h post exposure. • In the analysis of metabolites, the parent structures of CMIT/MIT were not observed. • Some metabolites were found to be conjugated with glutathione. • Approximately 28% of the radiolabel was bound to pulmonary biomolecules. [ABSTRACT FROM AUTHOR]

Environmental risk factors are recognized as threats to public health. Stress granules (SGs) are non-membranous assemblies of mRNAs and proteins expressed in response to various stressors to promote cell survival. In this study, SG formation was examined to confirm the effects of polyhexamethylene guanidine phosphate (PHMG), chloromethylisothiazolinone (CMIT), and particulate matter (PM10) in airway epithelial cells, A549, HPAEpiC, and BEAS-2B cells. SGs were not observed after CMIT, PHMG, and PM10 treatments, as determined by immunofluorescence microscopy. Moreover, there was no change in the phosphorylation of the translation initiation factor eIF2αfollowing treatment with PHMG, CMIT, and PM10. Taken together, our findings might help determine the biological hazards of these materials. [ABSTRACT FROM AUTHOR]

This study evaluates the behavioral characteristics of components (methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT)) contained in disinfectant solutions when they convert to liquid aerosols. The analytical method for MIT and CMIT quantitation was established and optimized using sorbent tube/thermal desorber-gas chromatography-mass spectrometry system; their behavioral characteristics are discussed using the quantitative results of these aerosols under different liquid aerosol generation conditions. MIT and CMIT showed different behavioral characteristics depending on the aerosol mass concentration and sampling time (sampling volume). When the disinfectant solution was initially aerosolized, MIT and CMIT were primarily collected on glass filter (MIT = 91.8 ± 10.6% and CMIT = 90.6 ± 5.18%), although when the generation and filter sampling volumes of the aerosols increased to 30 L, the relative proportions collected on the filter decreased (MIT = 79.0 ± 12.0% and CMIT = 39.7 ± 8.35%). Although MIT and CMIT had relatively high vapor pressure, in liquid aerosolized state, they primarily accumulated on the filter and exhibited particulate behavior. Their relative proportions in the aerosol were different from those in disinfectant solution. In the aerosol with mass concentration of ≤5 mg m−3, the relative proportion deviations of MIT and CMIT were large; when the mass concentration of the aerosol increased, their relative proportions constantly converged at a lower level than those in the disinfectant solution. Hence, it can be concluded that the behavioral characteristics and relative proportions need to be considered to perform the quantitative analysis of the liquid aerosols and evaluate various toxic effects using the quantitative data.

The inhalation of humidifier disinfectants (HDs) is linked to HD-associated lung injury (HDLI). Polyhexamethylene guanidine (PHMG) is significantly involved in HDLI, but the correlation between chloromethylisothiazolinone (CMIT) and HDLI remains ambiguous. Additionally, the differences in the molecular responses to PHMG and CMIT are poorly understood. In this study, RNA sequencing (RNA-seq) data showed that the expression levels of metallothionein-1 (MT1) isoforms, including MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X, were increased in human pulmonary alveolar epithelial cells (HPAEpiCs) that were treated with PHMG but not in those treated with CMIT. Moreover, upregulation of MT1B, MT1F, MT1G, and MT1H was observed only in PHMG-treated HPAEpiCs. The protein expression level of metal regulatory transcription factor 1 (MTF1), which binds to the promoters of MT1 isoforms, was increased in PHMG-treated HPAEpiCs but not in CMIT-treated HPAEpiCs. However, the expression of early growth response 1 (EGR1) and nuclear receptor superfamily 3, group C, member 1 (NR3C1), other transcriptional regulators involved in MT1 isomers, were increased regardless of treatment with PHMG or CMIT. These results suggest that MTF1 is an essential transcription factor for the induction of MT1B, MT1F, MT1G, and MT1H by PHMG but not by CMIT.

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.

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 <1 year 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 145.1 μg/m3 (N = 91, SD = 395.1 μg/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. [ABSTRACT FROM AUTHOR]

Currently available toxicity data on humidifier disinfectants are primarily limited to polyhexamethylene guanidine phosphate-induced lung fibrosis. We, therefore, investigated whether the sterilizer component Kathon, which is a mixture of chloromethylisothiazolinone and methylisothiazolinone, induces fibrotic lung injury following direct lung exposure in an animal model. Mice were intratracheally instilled with either the vehicle or Kathon. Differential cell counts, cytokine analysis, and histological analysis of lung tissue were then performed to characterize the injury features, and we investigated whether Kathon altered fibrosis-related gene expression in lung tissues via RNA-Seq and bioinformatics. Cell counting showed that Kathon exposure increased the proportion of macrophages, eosinophils, and neutrophils. Moreover, T helper 2 (Th2) cytokine levels in the bronchoalveolar lavage were significantly increased in the Kathon groups. Histopathological analysis revealed increased perivascular/alveolar inflammation, eosinophilic cells, mucous cell hyperplasia, and pulmonary fibrosis following Kathon exposure. Additionally, Kathon exposure modulated the expression of genes related to fibrotic inflammation, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, extracellular signal regulated kinase (ERK)1 and ERK2 cascade, extracellular matrix (ECM)-receptor interaction pathway, transforming growth factor beta receptor signaling pathway, cellular response to tumor necrosis factor, and collagen fibril organization. Our results suggest that Kathon exposure is associated with fibrotic lung injury via a Th2-dependent pathway and is thus a possible risk factor for fibrosis.

Methylisothiazolinone (MI) is one of the most used preservatives in shampoos and also one of the most effective. A preservative mixture known as Kathon™ CG is commercially available. It contains 5-chloro-2-methyl-4-isothiazolin-3-one (CMI) and 2-methyl-4-isothiazolin-3-one (MI) (3:1) and stabilizers. The aim of this study is to evaluate the influence of formulation factors in the quantification and stability of isothiazolinones in shampoos. Two shampoo bases containing Kathon™ CG as a preservative were prepared. Some ingredients that are at risk of interfering with the preservative stability were added to these formulations. The preservative was quantified by HPLC-DAD (High-performance liquid chromatography with a diode-array detector) after preparation of the formulation and after storage at room temperature and at 40 °C. The addition of magnesium silicate proved to be essential for the breakdown of the interaction between the matrix and the analytes in the extraction procedure. The content of CMI/MI decreased right after preparation indicating that immediate interactions between CMI/MI and the ingredients may have occurred after preparation resulting in a decrease in the preservative concentration. Detrimental interactions between the ingredients, regarding the stability of the isothiazolinones were detected immediately after preparation and over time resulting in the reduction of CMI/MI concentration in these cosmetic shampoos.

Chloromethylisothiazolinone (MCI) and methylisothiazolinone (MI) have been widely used as preservatives in cosmetics, household products and industrial products since the late 1970s. First cases of contact allergy to the MCI/MI combination were noted in 1980–1982 in Sweden. Then, a significant increase in the frequency of sensitization to these compounds was observed in many European centers. The increase has been stopped by the introduction of legislation on their maximum concentrations in consumer and industrial products in Europe and in some non-European countries. But approval of the use of MI alone without limits in industrial products (from 2000) and at a maximum concentration of 100 ppm in cosmetics (from 2005) resulted in an unprecedented increase in the number of individuals sensitized to this compound. Allergic contact dermatitis due to MI occurs in both adults and children. It is often manifested by severe symptoms, which may be also induced by airborne exposure. The most important sources of sensitization include cosmetic products and paints. To counteract the increasing problem of contact allergy epidemic to MI, the recommendations have been developed, suggesting the ban on the use of MI in “leave-on” cosmetics and maximum concentration of 15 ppm in “rinse-off” products. These recommendations are likely to be implemented in 2014. Med Pr 2014;65(4):543–554

A total of 221 patients were evaluated to be humidifier disinfectant associated with lung injury (HDLI) through two rounds of programs through April 2015. The humidifier disinfectant (HD) brands most often associated with HDLI were found to be Oxy (n=151, 68 %) and Cefu (n=26, 17 %). Polyhexamethylene guanidine used for disinfectant for four types of HD brands including Oxy was found to be associated with the highest number of HDLI cases (n=188). Further programs are operating to identify various health effects including lung injury which may be associated with the use of HD. Not only national agencies, but also pertinent environmental health societies should cooperate in the necessary investigations so that this tragedy can be properly addressed and future incidents concerning chemicals and chemical-containing products can be prevented.

[Display omitted] • The biodistribution of CMIT/MIT was assessed using a 14C-labeled radiotracer. • After exposure via the inhalation routes, CMIT/MIT is rapidly distributed to the lungs. • Intratracheal exposure induces greater lung damage than intranasal instillation. • The amount of CMIT/MIT in the lungs is positively associated with the toxicity. A variety of isothiazolinone-containing small molecules have been registered and used as chemical additives in many household products. However, their biodistribution and potential harmful effects on human health, especially respiratory effects, were not yet identified in sufficient detail. The purpose of this study was to investigate whether a biocide comprising a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) could reach the lungs and induce lung injury when exposure occurs by two administration routes involving the respiratory tract: intratracheal and intranasal instillation. To investigate the biodistribution of CMIT/MIT, we quantified the uptake of 14C-labeled CMIT/MIT in experimental animals for up to seven days after intratracheal and intranasal instillation. In the toxicity study, lung injury was assessed in mice using total inflammatory cell count in bronchoalveolar lavage fluid (BALF) and lung histopathology. The results of the biodistribution study indicated that CMIT/MIT were rapidly distributed throughout the respiratory tract. Using quantitative whole-body autoradiogram analysis, we confirmed that following intranasal exposure, CMIT/MIT reached the lungs via the respiratory tract (nose–trachea–lung). After 5 min post intratracheal and intranasal instillation, the amount of radiotracer ([14C]CMIT/MIT) in the lungs was 2720 ng g−1 and 752 ng g−1 tissue, respectively, and lung damage was observed. A higher amount of the radiotracer resulted in higher toxicity. Both intratracheal and intranasal instillation of CMIT/MIT increased inflammatory cell counts in the BALF and induced injuries in the alveoli. The frequency and the severity scores of injuries caused by intratracheal instillation were approximately-four to five times higher than those induced by intranasal instillation. Therefore, we concluded that CMIT/MIT could reach the lungs following nasal and intratracheal exposure and cause lung injuries, and the extent of injury was dependent on the exposure dose. [ABSTRACT FROM AUTHOR]

This study evaluates the behavioral characteristics of components (methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT)) contained in disinfectant solutions when they convert to liquid aerosols. The analytical method for MIT and CMIT quantitation was established and optimized using sorbent tube/thermal desorber-gas chromatography-mass spectrometry system; their behavioral characteristics are discussed using the quantitative results of these aerosols under different liquid aerosol generation conditions. MIT and CMIT showed different behavioral characteristics depending on the aerosol mass concentration and sampling time (sampling volume). When the disinfectant solution was initially aerosolized, MIT and CMIT were primarily collected on glass filter (MIT = 91.8 ± 10.6% and CMIT = 90.6 ± 5.18%), although when the generation and filter sampling volumes of the aerosols increased to 30 L, the relative proportions collected on the filter decreased (MIT = 79.0 ± 12.0% and CMIT = 39.7 ± 8.35%). Although MIT and CMIT had relatively high vapor pressure, in liquid aerosolized state, they primarily accumulated on the filter and exhibited particulate behavior. Their relative proportions in the aerosol were different from those in disinfectant solution. In the aerosol with mass concentration of ≤5 mg m−3, the relative proportion deviations of MIT and CMIT were large; when the mass concentration of the aerosol increased, their relative proportions constantly converged at a lower level than those in the disinfectant solution. Hence, it can be concluded that the behavioral characteristics and relative proportions need to be considered to perform the quantitative analysis of the liquid aerosols and evaluate various toxic effects using the quantitative data. [ABSTRACT FROM AUTHOR]

In 2019, the Dutch Food and Consumer Product Safety Authority performed a market surveillance for toy-slime (23 samples) and putty (16 samples). For 35% of the toy-slimes and 13% of the putties, the migration of boron exceeded the European legal limit of 300 and 1200 mg/kg respectively. In 36% of the toy samples, methylisothiazolinone (MI) and chloromethylisothiazolinone (CMI) were detected in levels up to 25 and 38 mg/kg, respectively, much higher than the European legal limit for aqueous toys intended for children younger than three. 59% of the toys contained other preservatives such as 2-phenoxyethanol, p-hydroxybenzoic acid and parabens. In 2 toy-slimes and 2 putties N-nitrosodiethanolamine (NDELA) was found in amounts up to 2.3 mg/kg. A risk assessment was performed for boron and NDELA. The estimated exposure to boron did not exceed the health based guidance value. The estimated exposure to NDELA from 2 toy-slimes may pose a health risk. For 2 putties the estimated exposure to NDELA was somewhat lower, but health risks could not be excluded. The presence of isothiazolinones may lead to skin sensitisation. It is recommended to extend the legal limit for NDELA, MI and CMI in finger-paint and labelling requirements to other aqueous toys. • Market surveillance data of a Dutch survey on toy-slime and putty. • 33% of the toy-slimes and 23% of the putties exceed the EU limit for boron. • Methodology to calculate the exposure to chemical substances in toy-slime and putty. • Presence of NDELA in these aqueous toys may impose a health risk. • The presence of isothiazolinones may lead to sensitisation. [ABSTRACT FROM AUTHOR]

The inhalation of humidifier disinfectants (HDs) is linked to HD-associated lung injury (HDLI). Polyhexamethylene guanidine (PHMG) is significantly involved in HDLI, but the correlation between chloromethylisothiazolinone (CMIT) and HDLI remains ambiguous. Additionally, the differences in the molecular responses to PHMG and CMIT are poorly understood. In this study, RNA sequencing (RNA-seq) data showed that the expression levels of metallothionein-1 (MT1) isoforms, including MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X, were increased in human pulmonary alveolar epithelial cells (HPAEpiCs) that were treated with PHMG but not in those treated with CMIT. Moreover, upregulation of MT1B, MT1F, MT1G, and MT1H was observed only in PHMG-treated HPAEpiCs. The protein expression level of metal regulatory transcription factor 1 (MTF1), which binds to the promoters of MT1 isoforms, was increased in PHMG-treated HPAEpiCs but not in CMIT-treated HPAEpiCs. However, the expression of early growth response 1 (EGR1) and nuclear receptor superfamily 3, group C, member 1 (NR3C1), other transcriptional regulators involved in MT1 isomers, were increased regardless of treatment with PHMG or CMIT. These results suggest that MTF1 is an essential transcription factor for the induction of MT1B, MT1F, MT1G, and MT1H by PHMG but not by CMIT. [ABSTRACT FROM AUTHOR]

Currently available toxicity data on humidifier disinfectants are primarily limited to polyhexamethylene guanidine phosphate-induced lung fibrosis. We, therefore, investigated whether the sterilizer component Kathon, which is a mixture of chloromethylisothiazolinone and methylisothiazolinone, induces fibrotic lung injury following direct lung exposure in an animal model. Mice were intratracheally instilled with either the vehicle or Kathon. Differential cell counts, cytokine analysis, and histological analysis of lung tissue were then performed to characterize the injury features, and we investigated whether Kathon altered fibrosis-related gene expression in lung tissues via RNA-Seq and bioinformatics. Cell counting showed that Kathon exposure increased the proportion of macrophages, eosinophils, and neutrophils. Moreover, T helper 2 (Th2) cytokine levels in the bronchoalveolar lavage were significantly increased in the Kathon groups. Histopathological analysis revealed increased perivascular/alveolar inflammation, eosinophilic cells, mucous cell hyperplasia, and pulmonary fibrosis following Kathon exposure. Additionally, Kathon exposure modulated the expression of genes related to fibrotic inflammation, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, extracellular signal regulated kinase (ERK)1 and ERK2 cascade, extracellular matrix (ECM)-receptor interaction pathway, transforming growth factor beta receptor signaling pathway, cellular response to tumor necrosis factor, and collagen fibril organization. Our results suggest that Kathon exposure is associated with fibrotic lung injury via a Th2-dependent pathway and is thus a possible risk factor for fibrosis. [ABSTRACT FROM AUTHOR]

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.

A total of 221 patients were evaluated to be humidifier disinfectant associated with lung injury (HDLI) through two rounds of programs through April 2015. The humidifier disinfectant (HD) brands most often associated with HDLI were found to be Oxy (n=151, 68 %) and Cefu (n=26, 17 %). Polyhexamethylene guanidine used for disinfectant for four types of HD brands including Oxy was found to be associated with the highest number of HDLI cases (n=188). Further programs are operating to identify various health effects including lung injury which may be associated with the use of HD. Not only national agencies, but also pertinent environmental health societies should cooperate in the necessary investigations so that this tragedy can be properly addressed and future incidents concerning chemicals and chemical-containing products can be prevented.