Integrated evidence supports a causal association between PHMG-P exposure and pneumonitis.

Types of household humidifier disinfectant and associated risk of lung injury (HDLI) in South Korea

BackgroundThis study describes 17 families with 38 lung injury patients (14 males, 24 females; 22 preschool-age children less than six years of age and 16 individuals of 13–50 years) who used disinfectant added to humidifiers in the home.MethodsClinical examination and humidifier disinfectant-use histories were taken, and a thorough home investigation was performed to assess exposure to humidifier disinfectant.ResultsNine of the patients (three pregnant females, six preschool-age children) died soon after they first developed lung damage. Six (16%) were pregnant females and 22 (58%) were preschool-aged children younger than six years. The patients used humidifier disinfectant products containing either polyhexamethylene guanidine phosphate (PHMG, n = 36) or oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH, n = 2). Twenty-six patients (68%) used the brand "Oxy"®, which contains PHMG. Of the ten patients with fatal lung injury, nine were found to have used PHMG.ConclusionsOur findings suggest that the use of humidifier disinfectant products containing either PGH or PHMG can cause lung injury, especially in preschool-age children younger than six years and pregnant women.

BackgroundIn South Korea, a cluster of acute lung disease patients included lung injury disease suspected of being caused by the use of humidifier disinfectants. We examined the relationship between humidifier disinfectant exposure and clinically diagnosed humidifier disinfectant-associated lung injury (HDLI) in a family-based study.MethodsThis case-control study included 169 clinically confirmed HDLI cases and 303 family controls who lived with the HDLI patients. A range of information on exposure to humidifier disinfectants was obtained using a structured questionnaire and field investigations. Odds ratios (ORs) and confidence intervals (CIs) were estimated using unconditional logistic regression models that were adjusted for age, sex, presence of a factory within 1 km of residence, and the number of household chemical products used.ResultsHDLI risk increased approximately two-fold or more among the highest quartile compared with the lowest quartile in terms of the hours sleeping in a room with an operating humidifier treated with disinfectant (adjusted OR = 2.0, 95 % CI = 1.1-3.7), average hours of disinfectant-treated humidifier use per day (adjusted OR = 2.1, 95 % CI = 1.0-4.5), airborne disinfectant intensity (adjusted OR = 2.6, 95% CI = 1.2-5.3), and cumulative disinfectant inhalation level (adjusted OR = 2.0, 95% CI = 1.0-4.1). HDLI risk increased as the distance of the bed from humidifier gets shorter; compared with longer distance (> 1 m), the odds ratio was 2.7 for 0.5 to 1 m (95 % CI = 1.5-5.1) and 13.2 for <0.5 m (95 % CI = 2.4-73.0).ConclusionsThe use of household humidifier disinfectants was associated with HDLI risk in a dose-response manner.

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

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

In South Korea, many cases of humidifier disinfectant-associated lung injury (HDLI) have been reported among people who used humidifier products containing humidifier disinfectant (HD). The objective of this study is to characterize exposure to HD among a total of 221 HDLI patients who used HD. Information and data on the HDs used were collected through a structured questionnaire and home environmental investigations. The conditions of these 221 HDLI patients were clinically confirmed to be caused by the use of HD. Children aged under 5 years old made up the highest proportion of HDLI cases (n=125, 56.6 %), followed by pregnant women (n=35, 15.8%). Forty-three percent (n=95) of the victims died. There were three cases of fetuses and 35 pregnant women among the victims. The number of HDLI patients who used only the Oxy Saksak brand of HD was found to be 85 (38.5%), followed by the HD brands Cefu (n=24, 10.9%), Lottemart Wiselect (n=9, 4.1%) and Aekyung (n=3). Patients who exclusively used HD brands containing polyhexamethylene guanidine phosphate (PHMG) (n=13, 55.7%) as an active ingredient made up the largest share, followed by those who exclusively used HD containing only oligo(2-(2-ethoxy) ethoxyethyl guanidinium (PGH) (n=24, 10.9%) and by those who only used a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) (n=3, 1.4%). HD products containing PHMG were found to be the most commonly used among the confirmed HDLI patients. Three exposed fetuses who never used HD after birth developed lung injuries, indicating a probability of exposure to HD during gestation. All HDLI patients responded that they used HD while sleeping and for longer than 10 hours per day. In conclusion, the development of HDLI was clinically found to be associated with the use of several HD products containing PHMG, PGH and CMIT/MIT.

Association of respiratory diseases with humidifier disinfectants exposure and its latency: A study of health damage reporter cohort in South Korea.

Analysis of genomic responses in a rat lung model treated with a humidifier sterilizer containing polyhexamethyleneguanidine phosphate

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.

BackgroundLung 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.MethodsWe 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.ResultsAfter 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.ConclusionsOur 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.

We conducted a comprehensive humidifier disinfectant exposure characterization for 374 subjects with lung disease who presumed their disease was related to humidifier disinfectant use (patient group) and for 303 of their family members (family group) for an ongoing epidemiological study. We visited the homes of the registered patients to investigate disinfectant use characteristics. Probability of exposure to disinfectants was determined from the questionnaire and supporting evidence from photographs demonstrating the use of humidifier disinfectant, disinfectant purchase receipts, any residual disinfectant, and the consistency of their statements. Exposure duration was estimated as cumulative disinfectant use hours from the questionnaire. Airborne disinfectant exposure intensity (μg/m(3)) was estimated based on the disinfectant volume (ml) and frequency added to the humidifier per day, disinfectant bulk level (μg/ml), the volume of the room (m(3)) with humidifier disinfectant, and the degree of ventilation. Overall, the distribution patterns of the intensity, duration, and cumulative exposure to humidifier disinfectants for the patient group were higher than those of the family group, especially for pregnant women and patients ≤6 years old. Further study is underway to evaluate the association between the disinfectant exposures estimated here with clinically diagnosed lung disease. Retrospective exposure to household humidifier disinfectant as estimated here can be used to evaluate associations with clinically diagnosed lung disease due to the use of humidifier disinfectant in Korea. The framework, with modifications to account for dispersion and use patterns, can also be potentially adapted to assessment of other household chemical exposures.

Adverse postnatal developmental effects in offspring from humidifier disinfectant biocide inhaled pregnant rats

In South Korea, many cases of humidifier disinfectant-associated lung injury (HDLI) have been reported among people who used humidifier products containing humidifier disinfectant (HD). The objectives of this study are to estimate both airborne HD concentration in the room where HD was used and the amount of humidifier disinfectant absorbed into the respiratory system. Information and data on the HDs were collected using a structured questionnaire and home environmental investigations include the volume of HD (ml) and hours used per day, concentration of disinfectants contained in the HD brand (<TEX>${\mu}g/ml$</TEX>), volume of the room (<TEX>$m^3$</TEX>), assumed ventilation rate (<TEX>$m^3/hr$</TEX>) and breathing rate assumed (<TEX>$m^3/hr$</TEX>). We used children aged under five years old as a sample and estimated both airborne HD concentrations and amount of HD absorbed into the respiratory system. The estimated airborne concentration of HD in the room ranged from 68 to <TEX>$369{\mu}g/m^3$</TEX> for PHMG (polyhexamethylene guanidine phosphate) and from 16 to <TEX>$239{\mu}g/m^3$</TEX> for PGH (oligo (2-(2-ethoxy) ethoxyethyl guanidine). The amount of HD absorbed in the respiratory system per day was estimated to range from 227 to <TEX>$1,225{\mu}g$</TEX> for PHMG and from 53 to <TEX>$794{\mu}g$</TEX> for PGH. In conclusion, a great amount of HD was likely absorbed into respiratory system, likely beyond the level of the capacity of the immune system to remove the HD absorbed.

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

This study was conducted to assess the association between the duration of humidifier disinfectant use and lung cancer development. We analyzed data from 3,605 applicants registered for compensation from the Korean government due to health conditions related to humidifier disinfectant exposure. Among these individuals, 121 were diagnosed with lung cancer at least 4 years after their initial exposure (through December 2021). Hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer incidence were estimated according to the duration of disinfectant use using Cox proportional hazards models. Compared with <5 months of use, the HRs for lung cancer were 1.81 (95% CI, 0.41 to 7.97) for 5-14 months, 2.45 (95% CI, 0.58 to 10.41) for 15-29 months, and 4.61 (95% CI, 1.12 to 18.91) for ≥30 months. Using never smokers with <15 months of use as the reference category, the HRs were 2.97 (95% CI, 1.34 to 6.56) for never smokers with ≥15 months of use, 2.73 (95% CI, 0.94 to 7.95) for current or former smokers with <15 months of use, and 4.74 (95% CI, 1.94 to 11.61) for current or former smokers with ≥15 months of use. Our study provides some of the first robust epidemiological evidence that prolonged humidifier disinfectant use contributes to lung cancer development. Future studies-particularly those including unexposed populations-are needed to confirm these findings.