Lessons From the Household Humidifier Disinfectant Tragedy (HHDT) With Focus on the Chemical Poisoning Surveillance System: Review and Recommendation.

BACKGROUND: Lessons learned from the Household Humidifier Disinfectant Tragedy (HHDT) in Korea, which poisoned thousands of citizens over a period of years, necessitated an examination of national poison prevention and surveillance systems. The objectives of this study are to identify essential changes needed in chemical poisoning prevention regulations and surveillance systems for effective poison control by comparing recent trends in international poison control center (PCC) operations, and to delineate the critical elements for establishing a state-of-the-art poison control surveillance system in Korea based on recent advances in PCCs with toxicovigilance. METHODS: A comprehensive review of Korea's regulatory and surveillance systems for chemical health hazards, with a focus on household products under the HHDT, was conducted. A review of toxicovigilance systems in major countries shows that creating an effective national PCC requires key elements: a centralized database of toxic substances and poisoning cases, mandatory or voluntary reporting of poisoning cases, real-time alerts, collaboration among health organizations, and targeted follow-up of poisoned individuals. RESULTS: Significant deficiencies in Korea's legislation, toxicological data management, and poisoning surveillance systems, explained the inadequate response of the Korean government to the HHDT for nearly 17 years until the end of 2011. Based on a review of PCC toxicovigilance systems in major countries, a national framework with five core components is recommended for establishing a modern comprehensive Korea PCC system with toxicovigilance capacity. The core components include establishment of a centralized database of toxic substances information and clinical poisoning cases, implementation of mandatory or permissive reporting of poisoning cases, real-time alert mechanisms, collaborative systems among health-related organizations, and clinical follow-up of poisoned sub-groups. CONCLUSION: A rationale and framework for a state-of-the-art national Korean PCC with toxicovigilance is justified and offered. This proposed system could assist neighboring countries in establishing their own sophisticated, globally integrated PCC networks.

Polyhexamethylene Guanidine Phosphate Enhanced Procoagulant Activity through Oxidative-Stress-Mediated Phosphatidylserine Exposure in Platelets.

Polyhexamethylene guanidine phosphate (PHMG-p) is a common biocidal disinfectant that is widely used in industry and household products. However, PHMG-p was misused as a humidifier disinfectant (HD) in South Korea, which had fatal health effects. Various health problems including cardiovascular diseases were observed in HD-exposed groups. However, the potential underlying mechanism of HD-associated cardiovascular diseases is poorly understood. Here, we examined the procoagulant activity of platelets caused by PHMG-p and clarified the underlying mechanism. PHMG-p enhanced phosphatidylserine (PS) exposure through alteration of phospholipid transporters, scramblase, and flippase. Intracellular calcium elevation, intracellular ATP depletion, and caspase-3 activation appeared to underlie phospholipid transporter dysregulation caused by PHMG-p, which was mediated by oxidative stress and mitochondrial dysfunction. Notably, antioxidant enzyme catalase and calcium chelator EGTA reversed PHMG-p-induced PS exposure and thrombin generation, confirming the contributive role of oxidative stress and intracellular calcium in the procoagulant effects of PHMG-p. These series of events led to procoagulant activation of platelets, which was revealed as enhanced thrombin generation. Collectively, PHMG-p triggered procoagulant activation of platelets, which may promote prothrombotic risks and cardiovascular diseases. These findings improve our understanding of HD-associated cardiovascular diseases.

Exposures to humidifier disinfectant and various health conditions in Korean based on personal exposure assessment data of claimants for compensation.

BACKGROUND: Humidifier disinfectants (HDs) were commonly used household chemicals to prevent microbial growth in a humidifier water tank in South Korea. A growing body of evidence has indicated that its airborne exposure can induce severe lung injury. However, there has been low awareness of other health outcomes in HD users. This study aimed to evaluate health conditions appealed by claimants for compensation in relation with an increased exposure to HD. METHODS: From survey data of personal HD exposure assessment of claimants for compensation in Korea, we included a total of 4,179 subjects [cases in each dataset were defined by nine reported health conditions, i.e., pneumonia, asthma, cardiovascular disease, respiratory disease, otorhinolaryngologic disease, brain disease (including cerebrovascular disease), dermatological disease, lung cancer, and all cancers]. HD exposures was considered as the following exposure criteria: exposure duration, exposure proximity, exposure direction, chemical type, cumulative exposure time, indoor air concentration, and cumulative exposure level. Logistic regression models were used to evaluate the associations between HD exposure and health conditions. RESULTS: After adjusting for sociodemographic and health behavioral factors and other chemical exposures (households, environmental, and occupational exposures), an increase in cumulative HD exposure time was significantly associated with risks of all nine diseases (all p-trends < 0.05). An increase in HD exposure duration was associated with asthma, respiratory disease, otorhinolaryngologic disease, dermatological disease, all cancers, and lung cancer (p-trends < 0.05). Indoor HD concentration was associated with only pneumonia (p-trend = 0.015). CONCLUSIONS: Our findings suggest that cumulative exposures to airborne HD might potentially increase the risk of various reported health outcomes.

Effects of psychological symptoms on life adjustment among survivors of humidifier disinfectants.

OBJECTIVES: The humidifier disinfectant catastrophe in South Korea was a social disaster caused by toxic chemical substances. The present study aimed to examine the relationships between psychological symptoms and adaptive life functioning in survivors of humidifier disinfectants. This study examined the differential effects of psychological symptoms on life adjustment between survivors of humidifier disinfectant and the general population. MATERIAL AND METHODS: A total of 452 individuals (228 general and 224 survivor groups) participated in this research. This study utilized the Adult Self-Report, one of the most widely used comprehensive mental health scales for measuring both psychological symptoms (e.g., anxiety/depression) and life adjustment functioning (e.g., interpersonal relationship). For the data analysis, multi-group structural equation modeling analysis was conducted using AMOS 21.0 program. RESULTS: The results of this study indicated that attention problems out of 8 psychological symptoms was the only significant factor related to life adjustment in both general and survivor groups. In addition, there was a significant 2-way interaction effect of group status and somatic complaints on life adjustment. CONCLUSIONS: When the somatic complaint symptom was higher, participants in the survivor group were less likely to adjust in life than the general group. Taken together, the somatic complaints of the survivors more strongly influence the life adjustment than the general population. Finally, the authors discuss practical implications for survivors of humidifier disinfectants for designing suitable intervention strategies.Int J Occup Med Environ Health. 2023;36(5):596-605.

Effects of Psychotherapy on the Problem Behaviors of Humidifier Disinfectant Survivors: The Role of Individual Characteristics and Adaptive Functioning.

This study aimed to examine group differences in the survivors of humidifier damage and the effect of individual psychotherapy on the psychological symptoms of the survivor groups, using the single group pre-post study design. A series of Wilcoxon-Mann-Whitney tests were conducted to investigate the level of psychological problems before and after psychotherapy, as well as the main and interaction effects of demographic characteristics and adaptive functioning on the treatment effects in 69 humidifier disinfectant survivors. The results demonstrated significant differences in problems with socioeconomic status (SES), life functioning, friendships, family relationships, and job adjustment in the survivor groups. Groups with high SES, low life functioning, and poor friend relationships had more problem behaviors than other groups. Problem behaviors related to friendship levels were different before and after psychotherapy. After psychotherapy, individuals with limited social connections exhibited a greater decrease in problem behaviors compared to those with strong friendships. This paper extends the international literature on the long-term consequences of environmental health hazards and the importance of tailored mental health interventions.

Effects of stabilizer magnesium nirate on CMIT/MIT-induced respiratory toxicity.

Despite a humidifier disinfectant (HD) product containing chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) with approximately 22% magnesium nitrate as a stabilizer, no report on the effects of magnesium nitrate on the respiratory toxicity of CMIT/MIT is available. In this study, Kathon CG and Proclin 200, containing approximately 1.5% CMIT/MIT with different magnesium nitrate concentrations (22.6% and 3%, respectively), were used to compare respiratory effects after intratracheal instillation (ITI) in C57BL/6 mice. C57BL/6 mice were randomized into groups of saline control, magnesium nitrate, Kathon CG, and Proclin 200 with 1.14 mg/kg of CMIT/MIT as the active ingredient, and administration was performed 6 times in a 2-3 day-interval in 2 weeks in all groups. Differential cell count analysis, cytokine analysis, and histological analysis of lung tissue were performed to characterize the injury features. Both Kathon and Proclin 200 induced an increase in inflammatory cell levels in the bronchoalveolar lavage (BAL) fluid, in particular, eosinophils and type 2 T helper cell (Th2)-secreted cytokines. All histopathological changes including granulomatous inflammation, mixed inflammatory cell infiltration, mucous cell hyperplasia, eosinophil infiltration, and pulmonary fibrosis were induced with similar frequency and severity in Kathon CG and Proclin 200 groups. Our results suggested that magnesium nitrate did not affect CMIT/MIT-induced lung injury in the intratracheally instilled model. Further inhalation studies are needed to determine the distribution and toxicity differences of CMIT/MIT in the lungs according to the magnesium nitrate concentration.

Toxic hepatitis after exposure to humidifier disinfectant: A case series report.

Health damage from humidifier disinfectants is an unprecedented environmental health disaster. Humidifier disinfectants were used broadly in Korea from 1994 to 2011. Most studies have focused on respiratory problems because of the exposure route and primary respiratory symptoms. This overlooks the previous research results that humidifier disinfectants could move to extrapulmonary organs and induce toxic effects. Thus, the objective of this study was to examine toxic hepatitis cases developed after inhaling humidifier disinfectant. We focused on the indications of toxic hepatitis in two pediatric cases and one female adult case. All patients were exposed to humidifier disinfectants in a residential space. These disinfectants all contained polyhexamethylene guanidine (PHMG). Rapid increases in blood hepatic enzyme levels were seen. Two patients were discharged after treatment. Death occurred in one patient who was diagnosed with fulminant hepatitis of unknown cause. This human case series study supports prior knowledge that hepatotoxicity can occur by inhaling humidifier disinfectant.

Inhalation toxicity of polyhexamethylene guanidine-phosphate in rats: A 4-week inhalation exposure and 24-week recovery period study.

Humidifier disinfectant (HD) is a causative agent of atypical lung injury reported in 2011 in South Korea, and various diseases caused by HD after exposure cessation have been reported to date. However, there is limited research on most of the reported diseases in terms of their association with HD exposure, and information on the progression of diseases caused by HD exposure is also limited. Therefore, we investigated the effects of HD inhalation on the body in rats. Rats were exposed to 0.15, 0.50, and 1.60 mg/m3 polyhexamethylene guanidine-phosphate (PHMG-p), which is the major component of HDs and most closely related to HD-associated lung injury. We conducted necropsy four times during the recovery period (0, 4, 12, and 24 weeks) and evaluated general systemic toxicities. There were significant changes in the mortality rate, body weight, and food consumption in the PHMG-p-exposed groups. Hematology revealed changes in hemoglobin level, hematocrit, red blood cell, reticulocyte, and white blood cell counts until 12 weeks of the recovery period. PHMG-p induced a delay in prothrombin time until 12 weeks of the recovery period. The aspartate aminotransferase, alanine aminotransferase, total bilirubin, and triglyceride levels were higher in the PHMG-p-exposed groups than in the control group at week 4 of the recovery period, and these parameters normalized after 12 weeks of the recovery period. Histopathological examination in PHMG-p exposed groups revealed several changes in the lungs, including the presence of alveolar macrophages, chronic inflammation, squamous metaplasia, alveolar emphysema, and pulmonary fibrosis. The severity of these symptoms was maintained or exacerbated till 24 weeks. Overall, PHMG-p inhalation can induce irreversible histological changes in the lungs and cause various types of damage throughout the body, even after exposure ends.

Reduced Diffusing Capacity in Humidifier Disinfectant-Associated Asthma Versus Typical Asthma: A Retrospective Case Control Study.

BACKGROUND: Humidifier disinfectant-related lung injury (HDLI) is a severe form of toxic inhalational pulmonary parenchymal damage found in residents of South Korea previously exposed to specific guanidine-based compounds present in humidifier disinfectants (HD). HD-associated asthma (HDA), which is similar to irritant-induced asthma, has been recognized in victims with asthma-like symptoms and is probably caused by airway injury. In this study, diffusing capacity of the lung for carbon monoxide (DLCO) in individuals with HDA was compared to that in individuals with pre-existing asthma without HD exposure. METHODS: We retrospectively compared data, including DLCO values, of 70 patients with HDA with that of 79 patients having pre-existing asthma without any known exposure to HD (controls). Multiple linear regression analysis and logistic regression analysis were performed to confirm the association between HD exposure and DLCO after controlling for confounding factors. The correlation between DLCO and several indicators related to HD exposure was evaluated in patients with HDA. RESULT: The mean DLCO was significantly lower in the HDA group than in the control group (81.9% vs. 88.6%; P = 0.021). The mean DLCO of asthma patients with definite HD exposure was significantly lower than that of asthma patients with lesser exposure (P for trend = 0.002). In multivariable regression models, DLCO in the HDA group decreased by 5.8%, and patients with HDA were 2.1-fold more likely to have a lower DLCO than the controls. Pathway analysis showed that exposure to HD directly affected DLCO values and indirectly affected its measurement through a decrease in the forced vital capacity (FVC). Correlation analysis indicated a significant inverse correlation between DLCO% and cumulative HD exposure time. CONCLUSION: DLCO was lower in patients with HDA than in asthma patients without HD exposure, and decreased FVC partially mediated this effect. Therefore, monitoring the DLCO may be useful for early diagnosis of HDA in patients with asthma symptoms and history of HD exposure.

Multi-layer relationships between psychological symptoms and life adaptation among humidifier disinfectant survivors.

In April 2011, the Korea Centers for Disease Control and Prevention (CDC) announced the results of an epidemiological investigation that an unknown cause of lung disease that occurred throughout Korea was caused by humidifier disinfectants. The unprecedented social catastrophe caused by humidifier disinfectants, a household chemical, has so far reported 1,784 deaths and 5,984 survivors in South Korea. This study was designed to investigate the multi-layer relationships between psychological symptoms and adaptive functioning in survivors of the Humidifier disinfectants in South Korea caused by chemical toxic substances. Specifically, this study aimed to explore how psychological symptoms affect actual interpersonal relationships and job adjustment with two variable sets, six internalizing and externalizing subscales, and three adaptation subscales. A total of 224 survivors recruited from a program to support humidifier disinfectant survivors by the government participated in this study. This research was approved by the Institutional Review Board of one of the Universities in South Korea. The age range of the participants was 18-73 years (M = 42.23, SD = 10.90), 37.1% (n = 83) were male, and 62.9% (n = 141) were female. The participants responded to the Adult Self-Report (ASR) of the Achenbach System of Empirically Based Assessment (ASEBA). A Canonical Correlation Analysis (CCA) generated three unique patterns in the relationships between psychological symptoms and adaptive functions. Humidifier disinfectant survivors in the first pattern were more vulnerable to psychological symptoms and showed maladaptive functioning in life. Survivors in the second pattern showed intrusive behaviors and appeared to be adaptive in relationships with friends. Finally, survivors in the third pattern showed aggressive behaviors and reported poor partner relationships while showing good relationships with friends. The practical implications of the interventions are also discussed.

Health Effects Associated With Humidifier Disinfectant Use: A Systematic Review for Exploration.

BACKGROUND: It has been 10 years since the outbreak of lung disease caused by humidifier disinfectants in Korea, but the health effects have not yet been summarized. Therefore, this study aims to systematically examine the health effects of humidifier disinfectants that have been discovered so far. METHODS: All literature with humidifier disinfectants and their representative components as the main words were collected based on the web, including PubMed, Research Information Sharing Service, and government publication reports. A total of 902 studies were searched, of which 196 were selected. They were divided into four groups: published human studies (group 1), published animal and cytotoxicology studies (group 2), technical reports (group 3), and gray literature (group 4). RESULTS: Out of the 196 studies, 97 (49.5%) were published in peer-reviewed journals as original research. Group 1 consisted of 49 articles (50.5%), while group 2 consisted of 48 articles (49.5%). Overall, respiratory diseases such as humidifier disinfectant associated lung injury, interstitial lung disease, and asthma have a clear correlation, but other effects such as liver, heart, thymus, thyroid, fetal growth, metabolic abnormalities, and eyes are observed in toxicological experimental studies, but have not yet been identified in epidemiologic studies. CONCLUSION: The current level of evidence does not completely rule out the effects of humidifier disinfectants on extrapulmonary disease. Based on the toxicological evidence so far, it is required to monitor the population of humidifier disinfectant exposure continuously to see if similar damage occurs.

Review of Inhalation Health Risks Involving Chloromethylisothiazolinone (CMIT) and Methylisothiazolinone (MIT) Used as Disinfectants in Household Humidifiers.

The association between lung injury and exposure to humidifier disinfectant (HD) containing a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) has been controversial in South Korea. This study conducts a literature review in order to evaluate the likelihood of CMIT/MIT reaching the lower part of the respiratory tract and causing lung injury. A literature review focused on the inhalation risk of HD containing a mixture of CMIT and MIT. The major contents included the physicochemical properties of CMIT and MIT contained in HDs and methodological reviews on substance analysis, toxicity tests and clinical cases. HD products marketed in South Korea have been reported to contain approximately 1-2% CMIT and 0.2-0.6% MIT along with magnesium nitrate (20-25%), magnesium chloride (0.2-1.0%), and water (70-75%). The types of CMIT and MIT dispersed into the air and deposited in the respiratory tract are assumed to be either gaseous substances or nanoparticles mixed with magnesium salts. The result of the literature review including clinical cases of lung injury among CMIT/MIT HD product users, demonstrated that these chemicals likely reach the lower respiratory tract and accordingly cause lung injury. A number of humidifier disinfectant-associated lung injury cases with clinical evidence should be prioritized in risk assessment of HD containing CMIT and MIT, even though there might be insufficient evidence in all related areas, including inhalation exposure assessment studies, animal testing, and epidemiological studies.

Analysis of lung cancer-related genetic changes in long-term and low-dose polyhexamethylene guanidine phosphate (PHMG-p) treated human pulmonary alveolar epithelial cells.

BACKGROUND: Lung injury elicited by respiratory exposure to humidifier disinfectants (HDs) is known as HD-associated lung injury (HDLI). Current elucidation of the molecular mechanisms related to HDLI is mostly restricted to fibrotic and inflammatory lung diseases. In our previous report, we found that lung tumors were caused by intratracheal instillation of polyhexamethylene guanidine phosphate (PHMG-p) in a rat model. However, the lung cancer-related genetic changes concomitant with the development of these lung tumors have not yet been fully defined. We aimed to discover the effect of long-term exposure of PHMG-p on normal human lung alveolar cells. METHODS: We investigated whether PHMG-p could increase distorted homeostasis of oncogenes and tumor-suppressor genes, with long-term and low-dose treatment, in human pulmonary alveolar epithelial cells (HPAEpiCs). Total RNA sequencing was performed with cells continuously treated with PHMG-p and harvested after 35 days. RESULTS: After PHMG-p treatment, genes with transcriptional expression changes of more than 2.0-fold or less than 0.5-fold were identified. Within 10 days of exposure, 2 protein-coding and 5 non-coding genes were selected, whereas in the group treated for 27-35 days, 24 protein-coding and 5 non-coding genes were identified. Furthermore, in the long-term treatment group, 11 of the 15 upregulated genes and 9 of the 14 downregulated genes were reported as oncogenes and tumor suppressor genes in lung cancer, respectively. We also found that 10 genes of the selected 24 protein-coding genes were clinically significant in lung adenocarcinoma patients. CONCLUSIONS: Our findings demonstrate that long-term exposure of human pulmonary normal alveolar cells to low-dose PHMG-p caused genetic changes, mainly in lung cancer-associated genes, in a time-dependent manner.

Exploring Socio-Demographic Factors Affecting Psychological Symptoms in Humidifier Disinfectant Survivors.

This study aimed to compare the psychological symptoms of humidifier disinfectant survivors to the general population and explore socio-demographic factors influencing survivors' psychological symptoms. A one-way Multivariate Analysis of Covariance (MANCOVA) and a series of two-way MANCOVA were conducted with a sample of 228 humidifier disinfectant survivors and 228 controls. The results demonstrated that the survivor group displayed higher anxious/depressed symptoms, withdrawn symptoms, somatic complaints, thought problems, attention problems, aggressive behavior and rule-breaking behavior than the general group. Moreover, among the socio-demographic factors, the two-way interaction effects of group × family economic status and group × number of friends were found to be statistically significant. The limitations and implications of this study are discussed.

Need for individual-based evaluation to determine the association between humidifier disinfectants and health injuries.

BACKGROUND: Injuries caused by humidifier disinfectants (HDs) can no longer be grouped under the concept of HD lung injury. Focusing on individual cases, we were able to evaluate the relevance not only of diseases for which epidemiological correlation is recognized but also all diseases and symptoms that the victims complain of. METHODS: In-depth interviews and reassessment of 113 HD-exposed patients who had not been acknowledged as victims by the government were conducted, and their medical records were reviewed. Based on these processes, an assessment questionnaire for the injuries related to HDs was completed and the involvement of HDs was assessed either as "strong association," "association," or "no association." RESULTS: In this study, of the 113 patients included who claimed damages, 78 (69.0%) had HD-related injuries. Among the cases of 22 patients who applied for injury acknowledgment due to upper respiratory inflammation that was not included among the acknowledged diseases, 17 (77.3%) were judged to be HD-related injuries (strong association vs. association: 10 [45.5%] vs. 7 [31.8%]). When the cases of 12 rhinitis patients were reassessed, 9 were HD-related injuries (strong association vs. association: 4 [33.3%] vs. 5 [41.7%]). When the cases of 18 asthma patients unacknowledged as a victim were reassessed, 17 (94.4%) were humidifier-related injuries (strong association vs. association: 12 [66.6%] vs. 5 [27.8%]). Among 4 interstitial lung disease patients unacknowledged as a victim, 2 (50.0%) were HD-related injuries. CONCLUSIONS: HD-related health injuries should be assessed through both individual interviews and detailed chart reviews for more accurate injury acknowledgment. In the future, efforts should go beyond existing methods based on the adherence to acknowledgment criteria to directly listen to the victims.

Characteristics of the Molecular Weight of Polyhexamethylene Guanidine (PHMG) Used as a Household Humidifier Disinfectant.

(1) Background: Household humidifier disinfectant (HD) brands containing polyhexamethylene guanidine (PHMG) have been found to cause the most HD-associated lung injuries (HDLIs) in the Republic of Korea. Nevertheless, no study has attempted to characterize the potential association of the health effects, including HDLI, with the physicochemical properties of PHMG dissolved in different HD brands. This study aimed to characterize the molecular weight (MW) distribution, the number-average molecular weight (Mn), the weight-average molecular weight (Mw), and the structural types of PHMG used in HD products. (2) Methods: Quantitative measurements were made using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The Mn, Mw, and MW distributions were compared among various HD products. (3) Results: The mean Mn and Mw were 542.4 g/mol (range: 403.0-692.2 g/mol) and 560.7 g/mol (range: 424.0-714.70 g/mol), respectively. The degree of PHMG oligomerization ranged from 3 to 7. The MW distribution of PHMG indicated oligomeric compounds regardless of the HD brands. (4) Conclusions: Based on the molecular weight distribution, the average molecular weight of PHMG, and the degree of polymerization, the PHMG collected from HDLI victims could be regarded as an oligomer. PHMG, as used in household humidifiers, should not be exempted from toxic chemical registration as a polymer. Further study is necessary to examine the association of PHMG oligomeric compounds and respiratory health effects, including HDLI.

Association between humidifier disinfectant exposure during infancy and subsequent neuropsychiatric outcomes during childhood: a nation-wide cross-sectional study.

BACKGROUND: The purpose was to determine the association between infant exposure to humidifier disinfectant (HD) with neuropsychiatric problems in pre-school children. METHODS: A total of 2,150 children (age 4-11 months) were enrolled in the Panel Study of Korean Children (PSKC) study. The Korean version of the Child Behavior Checklist (CBCL) was used for assessments of neuropsychiatric problems. 1,113 children who participated in all the first to third PSKC studies and answered a question about HD exposure were finally enrolled. RESULTS: There were 717 (64.5%) children in non-HD group who were not exposed to HD and 396 (35.5%) in HD group with former exposure to HD. Exposure to HD was associated with total neuropsychiatric problems (adjusted odds ratio, aOR = 1.54, 95% CI = 1.15-2.06), being emotionally reactive (aOR = 1.55, 95% CI = 1.00-2.39), having attention problems (aOR = 1.96, 95% CI = 1.10-3.47), having oppositional defiant problems (aOR = 1.70, 95% CI = 1.07-2.71), and having attention deficit/hyperactivity problems (aOR = 11.57, 95% CI = 1.03-2.38). The risks for neuropsychiatric problems were clearly increased in boy, firstborn, and secondary smoker. CONCLUSIONS: Exposure to HD during early childhood had a potential association with subsequent behavioral abnormalities.

Humidifier Disinfectant Consumption and Humidifier Disinfectant-Associated Lung Injury in South Korea: A Nationwide Population-Based Study.

Humidifier disinfectant (HD) is a household biocidal product used in humidifier water tanks to prevent the growth of microorganisms. In 2011, a series of lung injury cases of unknown causes emerged in children and pregnant women who had used HD in Korea. This study investigated changes in the nationwide number of cases of humidifier disinfectant-associated lung injury (HDLI) in concordance with nationwide HD consumption using data covering the entire Korean population. More than 25 kinds of HD products were sold between 1994 and 2011. The number of diagnosed HDLI, assessed by S27.3 (other injuries of lungs) of the Korea National Health Insurance Service (NHIS) data, sharply increased by 2005, subsequently decreased after 2005, and almost disappeared after 2011 in concordance with the annual number of HD sales. The number of self-reported HDLIs, assessed using data from all suspected HDLI cases registered in the Korea Ministry of Environment, changed with the annual number of HD sales, with a delay pattern, potentially induced by the late awareness of lung injury diseases. The present study suggests that changes in the nationwide annual consumption of HD products were consistent with changes in the annual number of HDLI cases in Korea.

Causal relationship between humidifier disinfectant exposure and Th17-mediated airway inflammation and hyperresponsiveness.

In this study, we investigated whether humidifier disinfectants (HDs) induce asthmatic airway inflammation in an animal model and compared the features of HD-induced inflammatory symptoms with ovalbumin (OVA)-induced allergic asthma. Mice were intratracheally instilled three times with either the control or 0.1, 0.3, or 0.5 mg/kg of polyhexamethylene guanidine phosphate (PHMG-P). To characterize asthmatic features, the following parameters were analyzed: (i) differential cell counts and cytokine expression in the bronchoalveolar lavage fluid (BALF); (ii) presence of mucus-producing goblet cells and pulmonary eosinophilic infiltration in the lungs; (iii) serum immunoglobulin levels; and (iv) airway hyperresponsiveness (AHR). RNA-Seq and bioinformatics tools were used to investigate whether PHMG-P altered asthma-related gene expression in lung tissues. The PHMG-P exposure groups showed higher peribronchial/perivascular inflammation, elevated goblet cell hyperplasia, and inhaled methacholine-induced airway resistance. Additionally, IL-13 and IL-17 in BALF were significantly increased in the PHMG-P exposure groups. However, there were no significant differences in total serum IgE and BALF IL-4 and IL-5 levels in the PHMG-P exposure groups compared to the control group. PHMG-P exposure modulated the expression of genes related to Th17 signaling pathways including the IL-17A, IL-23, and STAT3 signaling pathways, but not the Th2 signaling pathway. Altogether, our results suggest that repeated exposure to low does PHMG-P induces asthma-like symptoms and is thus a possible risk factor for developing asthma. The PHMG-P-induced asthmatic airway inflammation showed a different pattern from that found in typical allergic asthma and may be related to irritant-induced airway inflammation and hyperresponsiveness characterized by Th2-low, Th17-related, IgE-independent, and mixed granulocytic features.

A mixture of chloromethylisothiazolinone and methylisothiazolinone impairs rat vascular smooth muscle by depleting thiols and thereby elevating cytosolic Zn2+ and generating reactive oxygen species.

Chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) are biocidal preservatives and the active ingredients in Kathon CG, which contains ca. 1.5% mixture of CMIT and MIT at a ratio of 3:1 (CMIT/MIT). CMIT/MIT was misused as humidifier disinfectant products, which caused serious health problems in Korea. Here, the vascular effects of CMIT/MIT were investigated to evaluate claims of putative cardiovascular toxicity observed in humidifier disinfectant users. CMIT/MIT did not affect the basal tension of the rat thoracic aorta up to 2.5 µg/mL in myograph experiments. Instead, pretreatment with CMIT/MIT impaired phenylephrine- or 5-hydroxytryptamine-induced vasoconstriction in a range of 0.5-2.5 µg/mL, which was largely irreversible and not recovered by washing out the CMIT/MIT. Similarly, the application of CMIT/MIT to pre-contracted aorta caused a gradual loss of tension. In primary cultured vascular smooth muscle cells (VSMCs), CMIT/MIT caused thiol depletion, which in turn led to cytosolic Zn2+ elevation and reactive oxygen species (ROS) formation. CMIT/MIT-induced shrinkage, detachment, and lysis of VSMCs depending on the concentration and the treatment time. All events induced by CMIT/MIT were prevented by a thiol donor N-acetylcysteine (NAC). Cytolysis could be inhibited by a Zn2+ chelator TPEN and a superoxide scavenger TEMPOL, whereas they did not affect shrinkage and detachment. In accordance with these results, CMIT/MIT-exposed aortas exhibited dissociation and collapse of tissue in histology analysis. Taken together, CMIT/MIT causes functional impairment and tissue damage to blood vessels by depleting thiol and thereby elevating cytosolic Zn2+ and generating ROS. Therefore, exposure to CMIT/MIT in consumer products may be a risk factor for cardiovascular disorders.