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: 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: 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: 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: High breast cancer incidence and dense breast prevalence among women in forties are specific to Asian. This study examined the natural history of breast cancer among Korean women. Materials and Methods: We applied a three-state Markov model (i.e., healthy, preclinical, and clinical state) to fit the natural history of breast cancer to data in the Korean National Cancer Screening Program. Breast cancer was ascertained by linkage to the Korean Central Cancer Registry. Disease-progression rates (i.e., transition rates between three states), mean sojourn time (MST) and mammographic sensitivity were estimated across 10-year age groups and levels of breast density determined by the Breast Imaging, Reporting and Data System. Results: Overall prevalence of dense breast was 53.9%. Transition rate from healthy to preclinical state, indicating the preclinical incidence of breast cancer, was higher among women in forties (0.0019; 95% confidence interval [CI], 0.0017 to 0.0021) and fifties (0.0020; 95% CI, 0.0017 to 0.0022), than women in sixties (0.0014; 95% CI, 0.0012 to 0.0017). The MSTs, in which the tumor is asymptomatic but detectable by screening, were also fastest among younger age groups, estimated as 1.98 years (95% CI, 1.67 to 2.33), 2.49 years (95% CI, 1.92 to 3.22), and 3.07 years (95% CI, 2.11 to 4.46) for women in forties, fifties, and sixties, respectively. Having dense breasts increased the likelihood of the preclinical cancer risk (1.96 to 2.35 times) and decreased the duration of MST (1.53 to 2.02 times). Conclusion This study estimated Korean-specific natural history parameters of breast cancer that would be utilized for establishing optimal screening strategies in countries with higher dense breast prevalence.

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.

Purpose: We provide evidence for the reclassification of the BRCA1:c.5017_5019del variant by presenting the clinicopathological characteristics, clinical outcomes, and family history of breast or ovarian cancer in 17 patients with this variant. Methods: This study included breast or ovarian cancer patients tested for BRCA1/2 genes between January 2008 and June 2020 at 10 medical centers in Korea. We retrospectively reviewed 17 probands from 15 families who had the BRCA1:c.5017_5019del variant according to the electronic medical records. Results: We present 10 breast cancer patients and 7 ovarian cancer patients from 15 families identified as having BRCA1:c.5017_5019del and a total of 19 cases of breast cancer and 14 cases of ovarian cancer in these families. The ratio of breast-to-ovarian cancer was 1.3:1. Breast cancer patients with this variant showed a rich family history of breast or ovarian cancer, 8 patients (80.0%). The mean age at diagnosis was 45.4 years and 6 patients (60.0%) were categorized into hormone-receptor–negative breast cancer. Also, the ovarian cancer patients with this variant showed strong family histories of breast and/or ovarian cancer in 4 patients (57.1%). Conclusion We presented clinical evidence for the reclassification of BRCA1:c.5017_5019del as a likely pathogenic variant (LPV). Reclassification as LPV could result in the prophylactic treatment and medical surveillance of probands, family testing recommendations, and appropriate genetic counseling of their families.

Objective: This study sought to examine changes in trends for quality indicators of the population-based Korean National Cancer Screening Program (KNCSP) for cervical cancer from years 2005 to 2013. Methods: Our study data were derived from the KNCSP database. Cervical cancer diagnosis information was ascertained through linkage with the Korean National Cancer Registry and the KNCSP database. Performance measures for cervical cancer screening were estimated, including participation rate, positive rate, crude detection rate (CDR), interval cancer rate (ICR), positive predictive value (PPV), sensitivity, and specificity. Joinpoint analysis was applied to calculate annual percentage changes (APCs) in all indicators according to sociodemographic factors. Results: A significant increasing trend was noted in participation rates (APC=13.4%; 95% confidence interval [CI]=10.5, 16.4). PPV and specificity increased from years 2005 to 2009 and remained stable till 2013. An increasing trend was discovered in CDRs for cervical cancer in situ (APC=3.9%; 95% CI=1.0, 6.9), whereas a decreasing trend was observed in ICRs for invasive cervical cancer (APC=−2.5%; 95% CI=−4.5, −0.5). Medical Aid recipients and women older than 70 years showed the lowest participation rates, but higher CDRs and ICRs, compared to other groups. In general, most of the quality indicators for cervical cancer screening improved from 2005 to 2009 and remained stable to 2013. Conclusion The KNCSP for cervical cancer in Korea has improved in terms of participation rate and accuracy of the screening test. These results may be attributed to the National Quality Improvement Program for KNCSP.

Objective: We aimed to determine the differences in stage at diagnosis of cervical cancer among Korean women according to screening history. Methods: Using linkage data from the Korean Central Cancer Registry and Korean National Cancer Screening Program (KNCSP), we included 18,388 women older than 30 years who were newly diagnosed with cervical cancer between 2013 and 2014 and examined their screening history. Between individuals, age group and socioeconomic status were matched to control for potential confounders. Results: Significantly more cases of carcinoma in situ (CIS) were diagnosed in the ever-screened (71.77%) group than in the never-screened group (54.78%), while localized, regional, distant, and unknown stage were more frequent in the never-screened group. Women in the ever-screened group were most likely to be diagnosed with CIS than with invasive cervical cancer (adjusted odds ratio [aOR]=2.40; 95% confidence interval [CI]=2.18–2.65). The aOR for being diagnosed with CIS was highest among women who were screened 3 times or more (aOR=5.10; 95% CI=4.03–6.45). The ORs were highest for women screened within 24 months of diagnosis and tended to decrease with an increasing time since last screening (p-trend <0.01). Conclusion The KNCSP for cervical cancer was found to be positively associated with diagnosis of cervical cancers at earlier stages among women aged 30 years or older. The benefit of screening according to time was highest for women screened within 24 months of diagnosis.