Reproductive and developmental toxicity screening of polyhexamethylene guanidine phosphate by oral gavage in rats.

Polyhexamethylene guanidine phosphate (PHMG-P) has effective antimicrobial activity against various microorganisms and has been widely used as a biocide in commercial products. However, its use as a humidifier disinfectant has provoked fatal idiopathic lung disease in South Korea, especially in pregnant or postpartum women and their young children. PHMG-P-related toxicological studies of reproduction and development in experimental animals have not been identified, and thus, we investigated the potential effects of early-stage oral exposure to PHMG-P by assessing its toxicological properties. PHMG-P was repeatedly administered by oral gavage at dose levels of 0, 13, 40 and 120 mg/kg to Sprague-Dawley rats during the pre-mating, mating, gestation and early lactation periods, and then general systemic and reproductive/developmental toxicities were investigated. At 120 mg/kg, PHMG-P-related toxicities including subdued behavior, thin appearance, decreased body weight, decreased food consumption and decreased F1 pup body weight were observed. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of PHMG-P for both general systemic effects and development are considered to be 40 mg/kg/day.

Toxicogenomic analysis of the pulmonary toxic effects of hexanal in F344 rat.

Hexanal is a major component of indoor air pollutants and is a kind of aldehydes; it has adverse effects on human health. We performed an in vivo inhalation study and transcriptomic analysis to determine the mode of toxic actions in response to hexanal. Fischer 344 rats of both sexes were exposed by inhalation to hexanal aerosol for 4 h day-1 , 5 days week-1 for 4 weeks at 0, 600, 1000, and 1500 ppm. Throughout our microarray-based genome-wide expression analysis, we identified 56 differentially expressed genes in three doses of hexanal; among these genes, 11 genes showed dose-dependent expression patterns (10 downregulated and 1 upregulated, 1.5-fold, p < 0.05). Through a comparative toxicogenomics database (CTD) analysis of 11 genes, we determined that five genes (CCL12, DDIT4, KLF2, CEBPD, and ADH6) are linked to diverse disease categories such as cancer, respiratory tract disease, and immune system disease. These diseases were previously known for being induced by volatile organic compounds (VOCs). Our data demonstrated that the hexanal-induced dose-dependent altered genes could be valuable quantitative biomarkers to predict hexanal exposure and to perform relative risk assessments, including pulmonary toxicity. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 382-396, 2017.

MicroRNA response of inhalation exposure to hexanal in lung tissues from Fischer 344 rats.

In previous studies, we have investigated the relationships between environmental chemicals and health risk based on omics analysis and identified significant biomarkers. Our current findings indicate that hexanal may be an important toxicant of the pulmonary system in epigenetic insights. MicroRNA (miRNA) is an important indicator of biomedical risk assessment and target identification. Hexanal is highly detectable in the exhaled breath of patients with chronic obstructive pulmonary disease (COPD) and chronic inflammatory lung disease. In this study, we aimed to identify hexanal-characterized miRNA-mRNA correlations involved in lung toxicity. Microarray analysis identified 56 miRNAs that commonly changed their expression more than 1.3-fold in three doses (600, 1000, and 1500 ppm) within hexanal-exposed Fischer 344 rats by inhalation, and 226 genes were predicted to be target genes of miRNAs through TargetScan analysis. By integrating analyses of miRNA and mRNA expression profiles, we identified one anti-correlated target gene (Chga; chromogranin A; parathyroid secretory protein 1). Comparative toxicogenomics database (CTD) analysis of this gene showed that Chga is involved with several disease categories such as cancer, respiratory tract disease, nervous system disease, and cardiovascular disease. Further research is necessary to elucidate the mechanisms of hexanal-responsive toxicologic pathways at the molecular level. This study concludes that our integrated approach to miRNA and mRNA enables us to identify molecular events in disease development induced by hexanal in an in vivo rat model. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1909-1921, 2016.

A cluster of lung injury associated with home humidifier use: clinical, radiological and pathological description of a new syndrome.

BACKGROUND: Over a few months in the spring of 2011, a cluster of patients with severe respiratory distress were admitted to our intensive care unit (ICU). Household clustering was also observed. Extensive laboratory investigations failed to detect an infectious cause. METHODS: Clinical, radiological and pathological investigations were conducted and the Korean Center for Disease Control performed epidemiological studies. RESULTS: The case series consisted of 17 patients. Their median age was 35 (range 28-49) years. Six were pregnant at presentation and four had given birth 2 weeks previously. All presented with cough and dyspnoea. In the majority of patients (14/17), multifocal areas of patchy consolidation were identified in the lower lung zones on the initial CT. As the condition progressed, the patchy consolidation disappeared (10/13) and diffuse centrilobular ground-glass opacity nodules started to predominate and persist. Pathological specimens (11/17) showed a bronchiolocentric, temporally homogenous, acute lung injury pattern with sparing of the subpleural and peripheral alveolar areas. Ten patients required mechanical ventilation, eight of whom subsequently received extracorporeal life support. Four of the latter underwent lung transplantation. Five of the six patients in the ICU who did not receive lung transplantation died. An epidemiological investigation revealed that all patients had used humidifier disinfectants in their homes. CONCLUSIONS: This case series report showed that lung injury and respiratory failure can occur as a result of inhaling humidifier disinfectants. This emphasises the need for more stringent safety regulations for potentially toxic inhalants that might be encountered in the home.

Drosophila melanogaster as potential alternative animal model for evaluating acute inhalation toxicity.

Drosophila melanogaster (D. melanogaster) is a promising model biological system. It has a short life cycle and can provide a substantial number of specimens suitable for comprehensive genetic and molecular analyses in a short time. In this study, we investigated the acute inhalation toxicity of methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT) in a D. melanogaster model. During exposure, environmental conditions, mass median aerodynamic and geometric standard diameters were measured. After inhalation exposure, the survival rate, climbing ability, and bang sensitivity were measured on days 1, 2, and 7. Notably, the survival rate of flies decreased in an exposure concentration-dependent manner. Climbing ability and bang sensitivity were also altered in the MIT/CMIT group, compared with the negative control group. Overall, these results provide a reliable D. melanogaster model system for inhalation toxicity study.

Size-resolved culturable airborne bacteria sampled in rice field, sanitary landfill, and waste incineration sites.

Size-resolved bacterial concentrations in atmospheric aerosols sampled by using a six stage viable impactor at rice field, sanitary landfill, and waste incinerator sites were determined. Culture-based and Polymerase Chain Reaction (PCR) methods were used to identify the airborne bacteria. The culturable bacteria concentration in total suspended particles (TSP) was found to be the highest (848 Colony Forming Unit (CFU)/m(3)) at the sanitary landfill sampling site, while the rice field sampling site has the lowest (125 CFU/m(3)). The closed landfill would be the main source of the observed bacteria concentration at the sanitary landfill. The rice field sampling site was fully covered by rice grain with wetted conditions before harvest and had no significant contribution to the airborne bacteria concentration. This might occur because the dry conditions favor suspension of soil particles and this area had limited personnel and vehicle flow. The respirable fraction calculated by particles less than 3.3 mum was highest (26%) at the sanitary landfill sampling site followed by waste incinerator (19%) and rice field (10%), which showed a lower level of respiratory fraction compared to previous literature values. We identified 58 species in 23 genera of culturable bacteria, and the Microbacterium, Staphylococcus, and Micrococcus were the most abundant genera at the sanitary landfill, waste incinerator, and rice field sites, respectively. An antibiotic resistant test for the above bacteria (Micrococcus sp., Microbacterium sp., and Staphylococcus sp.) showed that the Staphylococcus sp. had the strongest resistance to both antibiotics (25.0% resistance for 32 microg ml(-1) of Chloramphenicol and 62.5% resistance for 4 microg ml(-1) of Gentamicin).

Inhalation of carbon black nanoparticles aggravates pulmonary inflammation in mice.

An increasing number of recent studies have focused on the impact of particulate matter on human health. As a model for atmospheric particulate inhalation, we investigated the effects of inhaled carbon black nanoparticles (CBNP) on mice with bleomycin-induced pulmonary fibrosis. The CNBPs were generated by a novel aerosolization process, and the mice were exposed to the aerosol for 4 hours. We found that CBNP inhalation exacerbated lung inflammation, as evidenced by histopathology analysis and by the expression levels of interleukin-6 protein, fibronectin, and interferon-γ mRNAs in lung tissues. Notably, fibronectin mRNA expression showed a statistically significant increase in expression after CBNP exposure. These data suggest that the concentration of CBNPs delivered (calculated to be 12.5 µg/m(3)) can aggravate lung inflammation in mice. Our results also suggest that the inhalation of ultrafine particles like PM 2.5 is an impactful environmental risk factor for humans, particularly in susceptible populations with predisposing lung conditions.