OBJECTIVES: Exposure to humidifier disinfectants has been linked to respiratory diseases, including interstitial lung disease, asthma, and pneumonia. Consequently, numerous toxicological studies have explored respiratory damage as both a necessary and sufficient condition for these diseases. We systematically reviewed and integrated evidence from toxicological studies by applying the evidence integration method established in previous research to confirm the biological plausibility of the association between exposure and disease. METHODS: We conducted a literature search focusing on polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT), the primary ingredients in humidifier disinfectants. We selected relevant studies based on their quality and the population, exposure, comparator, outcome (PECO) statements. These studies were categorized into three lines of evidence: hazard information, animal studies, and mechanistic studies. Based on a systematic review, we integrated the evidence to develop an aggregate exposure pathway–adverse outcome pathway (AEP-AOP) model for respiratory damage. The reliability and relevance of our findings were assessed by comparing them with the hypothesized pathogenic mechanisms of respiratory diseases. RESULTS: By integrating toxicological evidence for each component of the AEP-AOP framework for PHMG and CMIT/MIT, we developed an AEP-AOP model that elucidates how disinfectants released from humidifiers expose target sites, triggering molecular initiating events and key events that ultimately lead to respiratory damage. This model exhibits high reliability and relevance to the pathogenesis of respiratory diseases. CONCLUSIONS The AEP-AOP model developed in this study provides strong evidence, based on evidence-based toxicology, that exposure to humidifier disinfectants causes respiratory diseases. This model demonstrates the pathways leading to respiratory damage, a hallmark of these conditions.

Purpose: To investigate the prevalence of copper, zinc, and vitamin D deficiencies in surgical intensive care unit (SICU) patients and the associations between those deficiencies and clinical outcomes. Methods: We conducted a retrospective study of 210 patients admitted to the SICU of Asan Medical Center between June 2020 and June 2022. Micronutrient levels were measured within 7 days of SICU admission. Primary outcomes were the mortality rate, length of SICU stay, hospital stay duration, and mechanical ventilation duration. Results: Copper deficiency was found in 35% (68/193), zinc deficiency in 52% (100/193), and severe vitamin D deficiency in 46% (82/179) of patients. Copper-deficient patients showed a significantly higher mortality rate (25.0% vs. 12.8%, P=0.044), longer hospital stays (57.8±47.0 vs. 45.2±36.6 days, P=0.041), and extended mechanical ventilation duration (26.9±23.3 vs. 18.8±15.7 days, P=0.012). Zinc deficiency was associated with higher C-reactive protein levels (16.2±9.5 vs. 11.5±8.8 mg/dL, P=0.001) and lower prealbumin levels (6.5±2.8 vs. 9.9±5.6 mg/dL, P<0.001). Severe vitamin D deficiency (<10 ng/mL) was not significantly associated with mortality or other clinical outcomes (mortality:<10 ng/mL vs. ≥10 ng/mL, 13% vs. 18%, P=0.583). Conclusion Micronutrient deficiencies are prevalent in SICU patients. Copper deficiency significantly correlated with poor clinical outcomes, and zinc deficiency showed a strong association with inflammatory markers. Early assessment and supplementation of micronutrients could be beneficial for critically ill surgical patients.

OBJECTIVES: Exposure to humidifier disinfectants has been linked to respiratory diseases, including interstitial lung disease, asthma, and pneumonia. Consequently, numerous toxicological studies have explored respiratory damage as both a necessary and sufficient condition for these diseases. We systematically reviewed and integrated evidence from toxicological studies by applying the evidence integration method established in previous research to confirm the biological plausibility of the association between exposure and disease. METHODS: We conducted a literature search focusing on polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT), the primary ingredients in humidifier disinfectants. We selected relevant studies based on their quality and the population, exposure, comparator, outcome (PECO) statements. These studies were categorized into three lines of evidence: hazard information, animal studies, and mechanistic studies. Based on a systematic review, we integrated the evidence to develop an aggregate exposure pathway–adverse outcome pathway (AEP-AOP) model for respiratory damage. The reliability and relevance of our findings were assessed by comparing them with the hypothesized pathogenic mechanisms of respiratory diseases. RESULTS: By integrating toxicological evidence for each component of the AEP-AOP framework for PHMG and CMIT/MIT, we developed an AEP-AOP model that elucidates how disinfectants released from humidifiers expose target sites, triggering molecular initiating events and key events that ultimately lead to respiratory damage. This model exhibits high reliability and relevance to the pathogenesis of respiratory diseases. CONCLUSIONS The AEP-AOP model developed in this study provides strong evidence, based on evidence-based toxicology, that exposure to humidifier disinfectants causes respiratory diseases. This model demonstrates the pathways leading to respiratory damage, a hallmark of these conditions.

Purpose: To investigate the prevalence of copper, zinc, and vitamin D deficiencies in surgical intensive care unit (SICU) patients and the associations between those deficiencies and clinical outcomes. Methods: We conducted a retrospective study of 210 patients admitted to the SICU of Asan Medical Center between June 2020 and June 2022. Micronutrient levels were measured within 7 days of SICU admission. Primary outcomes were the mortality rate, length of SICU stay, hospital stay duration, and mechanical ventilation duration. Results: Copper deficiency was found in 35% (68/193), zinc deficiency in 52% (100/193), and severe vitamin D deficiency in 46% (82/179) of patients. Copper-deficient patients showed a significantly higher mortality rate (25.0% vs. 12.8%, P=0.044), longer hospital stays (57.8±47.0 vs. 45.2±36.6 days, P=0.041), and extended mechanical ventilation duration (26.9±23.3 vs. 18.8±15.7 days, P=0.012). Zinc deficiency was associated with higher C-reactive protein levels (16.2±9.5 vs. 11.5±8.8 mg/dL, P=0.001) and lower prealbumin levels (6.5±2.8 vs. 9.9±5.6 mg/dL, P<0.001). Severe vitamin D deficiency (<10 ng/mL) was not significantly associated with mortality or other clinical outcomes (mortality:<10 ng/mL vs. ≥10 ng/mL, 13% vs. 18%, P=0.583). Conclusion Micronutrient deficiencies are prevalent in SICU patients. Copper deficiency significantly correlated with poor clinical outcomes, and zinc deficiency showed a strong association with inflammatory markers. Early assessment and supplementation of micronutrients could be beneficial for critically ill surgical patients.

Purpose: To investigate the prevalence of copper, zinc, and vitamin D deficiencies in surgical intensive care unit (SICU) patients and the associations between those deficiencies and clinical outcomes. Methods: We conducted a retrospective study of 210 patients admitted to the SICU of Asan Medical Center between June 2020 and June 2022. Micronutrient levels were measured within 7 days of SICU admission. Primary outcomes were the mortality rate, length of SICU stay, hospital stay duration, and mechanical ventilation duration. Results: Copper deficiency was found in 35% (68/193), zinc deficiency in 52% (100/193), and severe vitamin D deficiency in 46% (82/179) of patients. Copper-deficient patients showed a significantly higher mortality rate (25.0% vs. 12.8%, P=0.044), longer hospital stays (57.8±47.0 vs. 45.2±36.6 days, P=0.041), and extended mechanical ventilation duration (26.9±23.3 vs. 18.8±15.7 days, P=0.012). Zinc deficiency was associated with higher C-reactive protein levels (16.2±9.5 vs. 11.5±8.8 mg/dL, P=0.001) and lower prealbumin levels (6.5±2.8 vs. 9.9±5.6 mg/dL, P<0.001). Severe vitamin D deficiency (<10 ng/mL) was not significantly associated with mortality or other clinical outcomes (mortality:<10 ng/mL vs. ≥10 ng/mL, 13% vs. 18%, P=0.583). Conclusion Micronutrient deficiencies are prevalent in SICU patients. Copper deficiency significantly correlated with poor clinical outcomes, and zinc deficiency showed a strong association with inflammatory markers. Early assessment and supplementation of micronutrients could be beneficial for critically ill surgical patients.

OBJECTIVES: Exposure to humidifier disinfectants has been linked to respiratory diseases, including interstitial lung disease, asthma, and pneumonia. Consequently, numerous toxicological studies have explored respiratory damage as both a necessary and sufficient condition for these diseases. We systematically reviewed and integrated evidence from toxicological studies by applying the evidence integration method established in previous research to confirm the biological plausibility of the association between exposure and disease. METHODS: We conducted a literature search focusing on polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT), the primary ingredients in humidifier disinfectants. We selected relevant studies based on their quality and the population, exposure, comparator, outcome (PECO) statements. These studies were categorized into three lines of evidence: hazard information, animal studies, and mechanistic studies. Based on a systematic review, we integrated the evidence to develop an aggregate exposure pathway–adverse outcome pathway (AEP-AOP) model for respiratory damage. The reliability and relevance of our findings were assessed by comparing them with the hypothesized pathogenic mechanisms of respiratory diseases. RESULTS: By integrating toxicological evidence for each component of the AEP-AOP framework for PHMG and CMIT/MIT, we developed an AEP-AOP model that elucidates how disinfectants released from humidifiers expose target sites, triggering molecular initiating events and key events that ultimately lead to respiratory damage. This model exhibits high reliability and relevance to the pathogenesis of respiratory diseases. CONCLUSIONS The AEP-AOP model developed in this study provides strong evidence, based on evidence-based toxicology, that exposure to humidifier disinfectants causes respiratory diseases. This model demonstrates the pathways leading to respiratory damage, a hallmark of these conditions.

Purpose: To investigate the prevalence of copper, zinc, and vitamin D deficiencies in surgical intensive care unit (SICU) patients and the associations between those deficiencies and clinical outcomes. Methods: We conducted a retrospective study of 210 patients admitted to the SICU of Asan Medical Center between June 2020 and June 2022. Micronutrient levels were measured within 7 days of SICU admission. Primary outcomes were the mortality rate, length of SICU stay, hospital stay duration, and mechanical ventilation duration. Results: Copper deficiency was found in 35% (68/193), zinc deficiency in 52% (100/193), and severe vitamin D deficiency in 46% (82/179) of patients. Copper-deficient patients showed a significantly higher mortality rate (25.0% vs. 12.8%, P=0.044), longer hospital stays (57.8±47.0 vs. 45.2±36.6 days, P=0.041), and extended mechanical ventilation duration (26.9±23.3 vs. 18.8±15.7 days, P=0.012). Zinc deficiency was associated with higher C-reactive protein levels (16.2±9.5 vs. 11.5±8.8 mg/dL, P=0.001) and lower prealbumin levels (6.5±2.8 vs. 9.9±5.6 mg/dL, P<0.001). Severe vitamin D deficiency (<10 ng/mL) was not significantly associated with mortality or other clinical outcomes (mortality:<10 ng/mL vs. ≥10 ng/mL, 13% vs. 18%, P=0.583). Conclusion Micronutrient deficiencies are prevalent in SICU patients. Copper deficiency significantly correlated with poor clinical outcomes, and zinc deficiency showed a strong association with inflammatory markers. Early assessment and supplementation of micronutrients could be beneficial for critically ill surgical patients.

Purpose: To investigate the prevalence of copper, zinc, and vitamin D deficiencies in surgical intensive care unit (SICU) patients and the associations between those deficiencies and clinical outcomes. Methods: We conducted a retrospective study of 210 patients admitted to the SICU of Asan Medical Center between June 2020 and June 2022. Micronutrient levels were measured within 7 days of SICU admission. Primary outcomes were the mortality rate, length of SICU stay, hospital stay duration, and mechanical ventilation duration. Results: Copper deficiency was found in 35% (68/193), zinc deficiency in 52% (100/193), and severe vitamin D deficiency in 46% (82/179) of patients. Copper-deficient patients showed a significantly higher mortality rate (25.0% vs. 12.8%, P=0.044), longer hospital stays (57.8±47.0 vs. 45.2±36.6 days, P=0.041), and extended mechanical ventilation duration (26.9±23.3 vs. 18.8±15.7 days, P=0.012). Zinc deficiency was associated with higher C-reactive protein levels (16.2±9.5 vs. 11.5±8.8 mg/dL, P=0.001) and lower prealbumin levels (6.5±2.8 vs. 9.9±5.6 mg/dL, P<0.001). Severe vitamin D deficiency (<10 ng/mL) was not significantly associated with mortality or other clinical outcomes (mortality:<10 ng/mL vs. ≥10 ng/mL, 13% vs. 18%, P=0.583). Conclusion Micronutrient deficiencies are prevalent in SICU patients. Copper deficiency significantly correlated with poor clinical outcomes, and zinc deficiency showed a strong association with inflammatory markers. Early assessment and supplementation of micronutrients could be beneficial for critically ill surgical patients.

OBJECTIVES: Exposure to humidifier disinfectants has been linked to respiratory diseases, including interstitial lung disease, asthma, and pneumonia. Consequently, numerous toxicological studies have explored respiratory damage as both a necessary and sufficient condition for these diseases. We systematically reviewed and integrated evidence from toxicological studies by applying the evidence integration method established in previous research to confirm the biological plausibility of the association between exposure and disease. METHODS: We conducted a literature search focusing on polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT), the primary ingredients in humidifier disinfectants. We selected relevant studies based on their quality and the population, exposure, comparator, outcome (PECO) statements. These studies were categorized into three lines of evidence: hazard information, animal studies, and mechanistic studies. Based on a systematic review, we integrated the evidence to develop an aggregate exposure pathway–adverse outcome pathway (AEP-AOP) model for respiratory damage. The reliability and relevance of our findings were assessed by comparing them with the hypothesized pathogenic mechanisms of respiratory diseases. RESULTS: By integrating toxicological evidence for each component of the AEP-AOP framework for PHMG and CMIT/MIT, we developed an AEP-AOP model that elucidates how disinfectants released from humidifiers expose target sites, triggering molecular initiating events and key events that ultimately lead to respiratory damage. This model exhibits high reliability and relevance to the pathogenesis of respiratory diseases. CONCLUSIONS The AEP-AOP model developed in this study provides strong evidence, based on evidence-based toxicology, that exposure to humidifier disinfectants causes respiratory diseases. This model demonstrates the pathways leading to respiratory damage, a hallmark of these conditions.

OBJECTIVES: Inhalation exposure to humidifier disinfectants has resulted to various types of health damages in Korea. To determine the epidemiological correlation necessary for presuming the legal causation, we aimed to develop a method to synthesize the entire evidence. METHODS: Epidemiological and toxicological studies are systematically reviewed. Target health problems are selected by criteria such as frequent complaints of claimants. Relevant epidemiologic studies are reviewed and the risk of bias and confidence level of the total evidence are evaluated. Toxicological literature reviews are conducted on three lines of evidence including hazard information, animal studies, and mechanistic studies, considering the source-to-exposure-to-outcome continuum. The confidence level of the body of evidence is then translated into the toxicological evidence levels for the causality between humidifier disinfectant exposure and health effects. Finally, the levels of epidemiological and toxicological evidence are synthesized. RESULTS: Under the Special Act revised in 2020, if the history of exposure and the disease occurred/worsened after exposure were approved, and the epidemiological correlation between the exposure and disease was verified, the legal causation is presumed unless the company proves the evidence against it. The epidemiological correlation can be verified through epidemiological investigations, health monitoring, cohort investigations and/or toxicological studies. It is not simply as statistical association as understood in judicial precedents, but a general causation established by the evidence as a whole, i.e., through weight-of-the-evidence approach. CONCLUSIONS The weight-of-the-evidence approach differs from the conclusive single study approach and this systematic evidence integration can be used in presumption of causation.