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Lee, Handule,Park, Kwangsik Korean Society of ToxicologyKorea Environmental Mu 2019 Toxicological Research Vol.35 No.3
The possibility of eye exposure for workers participating in manufacturing of nanoparticles or consumers using products containing nanoparticles has been reported, but toxicity studies on the eye are scarce. In this study, cytotoxicity of five nanoparticles including silver, ceria, silica, titanium and zinc were tested using Statens Seruminstitut Rabbit Cornea (SIRC) cells. When cells were treated with nanoparticles with concentrations of $1-100{\mu}g/mL$ for 24 hr, zinc oxide nanoparticles showed higher toxicity to cornea cells. $LC_{50}$ of zinc oxide nanoparticles was less than $25{\mu}g/mL$ but those of other nanoparticles could not be calculated in this test, which means more than $100{\mu}g/mL$. Generation of reactive oxygen species was observed, and expression of apoptosis related biomarkers including Bax and Bcl-2 were changed after treatment of zinc oxide nanoparticles, while no other significant toxicity-related changes were observed in cornea cells treated with Ag, $CeO_2$, $SiO_2$ and $TiO_2$ nanoparticles.
Handule Lee,Juyoung Park,Kwangsik Park 환경독성보건학회 2021 환경독성보건학회지 Vol.36 No.2
Previous research studies on the toxicity of polyhexamethylene guanidine (PHMG) as a humidifier disinfectant majorly focused on lung fibrosis. Considering that disinfectants in humidifiers are released in aerosol form, the eyes are directly exposed and highly vulnerable to the detrimental effects of the PHMG. Therefore, in the present study we investigated the adverse effects of PHMG on the eyes; considering fibrosis as a manifestation of PHMG toxicity in the eye, we evaluated fibrosis-related biomarkers in cultured Statens Seruminstitut Rabbit Cornea (SIRC) cells. Cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, fibrosis-related biomarkers were evaluated through polymerase chain reaction (PCR) and immunoblotting, and oxidative stress was evaluated using 2’,7’-dichlorodihydrofluorescein diacetate (H₂DCFDA). Polyhexamethylene guanidine showed cytotoxicity in a time and concentration-dependent manner. Fibrosis related biomarkers including transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP) and hemeoxygenase-1 (HO-1) increased in both gene and protein levels. Oxidative stress also increased in the PHMG-treated cultured cells. The findings of the present study suggest that PHMG could cause toxicity in the eye as manifested by fibrosis.
Lee Handule,Park Juyoung,Park Kwangsik 한국독성학회 2022 Toxicological Research Vol.38 No.1
Before being recalled and banned from the Korean market, humidifier disinfectants (HDs) were added to the humidifier water tank to prevent microbial growth. The known HDs active ingredients included the are oligo(2-(2-ethoxy)ethoxyethyl guanidine (PGH), polyhexamethylene guanidine (PHMG), a mixture of methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT), didecyldimethyl ammonium chloride (DDAC), Sodium dichloroisocyanurate (NaDCC), and alkyldimethylbenzyl ammonium chloride (BAC). Previous epidemiological studies have suggested that PHMG induces fatal lung disease in pregnant, post-partum women, and young children. In an animal study, a mixture of DDAC and BAC exhibited decreased fertility and fecundity; increased time to first litter, longer pregnancy intervals, fewer pups per litter, and fewer pregnancies. In this study, endocrine-disrupting effects of HDs were investigated using estrogen receptor (ER) and androgen receptor (AR) transactivation assay based on OECD Test guidelines. Unexpectedly, unlike the previously reported reproductive toxicity data, in the present study, HDs did not show ER and AR transcriptional activation agonist and/or antagonist effects. However, it is difficult to conclude that HDs has no endocrine disruption effects, and further research on the effects of HDs mixtures, and in vivo tests including Uterotrophic bioassay and Hershberger bioassay would be necessary.
Handule Lee,Kwangsik Park 환경독성보건학회 2019 환경독성보건학회지 Vol.34 No.3
Benzalkonium chloride is a cationic surfactant widely used as a disinfectant, preservative, and sanitizer in many public places as well as domestically. The purpose of this study is to compare the acute toxicity of lethal doses (LDx) and the target organs after intratracheal instillation and oral ingestion by mice, which is a preliminary test prior to the repeated dose toxicity test. When Balb/c mice were treated with a single dose of benzalkonium chloride via oral administration, LD50 was 241.7 ㎎/㎏. However, it was comparatively decreased to 8.5 ㎎/㎏ following intratracheal treatment, which suggests that lung may be the main target of toxicity. Although the histopathology showed inflammatory responses in the lung after intratracheal instillation, it still did not confirm that the inflammatory responses were the key factors inducing death in the treated animal. Acute and fatal mechanisms such as bronchoconstriction or neurotoxicity associated with benzalkonium chloride exposure should be further investigated.
표준입도 분산조건에서 나노입자의 THP-1 세포에 대한 독성영향
이한들(Handule Lee),박주영(Juyoung Park),박광식(Kwangsik Park) 대한약학회 2017 약학회지 Vol.61 No.2
Effect of nanoparticles on cellular toxicity can be influenced by size and/or size distribution of the tested nanoparticles. Therefore, it is necessary to fulfill the requirement of standardized dispersion when toxicity potencies of different types of nanoparticles are compared. In this study, probe-sonicator calibration for delivered acoustic power was performed according to the NANoREG protocol for standardized size-distribution of test nanoparticles including silica nanoparticles (SiNP), ceria nanopaaticles (CeNP), titania nanoparticles (TiNP), silver nanoparticles (AgNP) and zinc nanoparticles(ZnNP). Based on the protocol, the increase of water temperature by sonication power was monitored and Pac value was obtained. When the time of 8 minutes and 25% amplitude calculated from the Pac value was applied to the sonication of silica nanoparticles, size distribution reached to the effective level, 210 nm < size < 270 nm, Polydispersity index(PDI) < 0.46. The same acoustic power used in the dispersion of silica nanoparticles was applied to the other test nanoparticles, and cytotoxicity test was performed by MTS assay in cultured THP-1 cells treated with nanoparticles for 24 hrs. As results, Lethal Concentration 50% (LC50) of silver nanoparticles was 78.44 ppm, which was most toxic among the test nanoparticles. The toxicity compared by the LC50 seemed to be AgNP > SiNP > TiNP > ZnNP > CeNP.
Juyoung Park,Handule Lee,Kwangsik Park 환경독성보건학회 2019 환경독성보건학회지 Vol.34 No.2
Disinfectants including polyhexamethylene guanidine phosphate (PHMG) and mixtures of chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) have been widely used in Korea to prevent microbial growth in the humidifier water, which triggered an outbreak of serious respiratory diseases. In addition to the respiratory syndrome, disease-related symptoms including liver toxicity, asthma, and skin allergies were also found after extensive survey of people exposed to the humidifier disinfectants (HDs). In this study, eye irritation tests were performed based on the Organization for economic co-operation and development (OECD) test guidelines 492 using EpiOcular™ which is a tissue model of reconstructed human cornea-like epithelium. As results, the raw materials of PHMG (26% as active ingredient) and CMIT/MIT (1.5% as active ingredient) were classified under UN globally harmonized system of classification and labeling of chemical (GHS) category 1 or category 2. However, aqueous dilutions of raw materials such as market products of HDs that contain 0.13% of PHMG and 0.03% of CMIT/MIT or further dilutions of the market products for humidifier that contain 0.0013% of PHMG and 0.0003% of CMIT/MIT were classified under any category, which suggested absence of eye irritation at the test concentration.
Juyoung Park,Handule Lee,Kwangsik Park 환경독성보건학회 2021 환경독성보건학회지 Vol.36 No.3
Some chemicals commonly used in personal care products, household items, food vessels, cosmetics, and other consumer products are potentially harmful, and several reviews of epidemiological studies have suggested the associations between the chemical exposure from consumer products, and respiratory diseases, skin sensitization, and reproductive problems. Therefore, risk assessment is essential for management of consumer products safety. Necessarily, the estimation of human exposure is an essential step in risk assessment, and the absorption rate of those chemicals via the gastrointestinal tract, respiratory tract, and skin are very critical in determining the internal dose of the exposed chemicals. In this study, parallel artificial membrane permeability assays (PAMPA) for the gastrointestinal tract and skin were performed to evaluate the permeability of parabens (4-hydroxybenzoic acid, methyl-, propyl-, and butyl paraben), bisphenols (bisphenol A, bisphenol F, and bisphenol S), isothiazolinones (methyl-, chloromethyl-, benz-, octyl-, and dichlorooctyl isothiazolinone), and phthalates [diethyl-, dibutyl-, Di-isononyl-, and bis(2-ethylhexyl) phthalate]. Lipid solubility of test chemicals indicated by log P values was shown as the most critical factor and showed a positive association with the permeability of parabens, bisphenols, and isothiazolinones in PAMPA assay. However, phthalate showed a reverse-association between lipophilicity and permeability. The permeability of all the tested chemicals was higher in the gastrointestinal tract membrane than in the skin membrane. The pH in donor solution did not show significant effects on the permeability in all the chemicals, except the chemicals with a free hydrophilic moiety in their chemical structures.