Search

Recent studies reported bisphenol A (BPA) and propyl paraben (PrP) are found in human urine, blood, and breast milk samples as well as in food, packaging, socks, and clothes. This means that the two chemicals co-exist in consumer products, and humans are exposed simultaneously to the mixture chemicals. However, the studies on the mixture effects of the two chemicals on human health are not enough. This study was designed to elucidate the effects of orally administered PrP, BPA, and their mixture effects on the uterotrophic response using ovariectomized rats. In addition, the correlation between the uterotrophic response and tissue concentrations of the two chemicals was studied to investigate whether one chemical has any effect on the absorption, distribution, or excretion of the other chemical. Histopathology, hematology, and plasma biochemistry analysis were also performed to evaluate the chemicals’ toxicological effects in the treated rats. Although a significant increase in uterus weight (absolute and relative) was observed in the positive chemical (17β-estradiol) treated group, there were no statistical differences in the uterus weight between the vehicle control and the chemical-treated groups. However, a slight increase in the endometrial glands and a change in the cuboidal to columnar epithelium of the endometrial epithelium were observed in the mixture-treated group. There was no significant toxicity in all treated groups by the hematology and plasma biochemistry analysis results. The results of tissue distribution showed that BPA was mostly detected in the liver while PrP was not detected in most tissues, and the BPA level was higher when the rats were treated with PrP than without PrP, suggesting that PrP may increase the absorption of BPA after oral administration.

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.

Background Titanium dioxide (TiO2) nanoparticles are among the most manufactured nanomaterials in the industry, and are used in food products, toothpastes, cosmetics and paints. Pregnant women as well as their conceptuses may be exposed to TiO2 nanoparticles; however, the potential effects of these nanoparticles during pregnancy are controversial, and their internal distribution has not been investigated. Therefore, in this study, we investigated the potential effects of oral exposure to TiO2 nanoparticles and their distribution during pregnancy. TiO2 nanoparticles were orally administered to pregnant Sprague-Dawley rats (12 females per group) from gestation days (GDs) 6 to 19 at dosage levels of 0, 100, 300 and 1000 mg/kg/day, and then cesarean sections were conducted on GD 20. Results In the maternal and embryo-fetal examinations, there were no marked toxicities in terms of general clinical signs, body weight, food consumption, organ weights, macroscopic findings, cesarean section parameters and fetal morphological examinations. In the distribution analysis, titanium contents were increased in the maternal liver, maternal brain and placenta after exposure to high doses of TiO2 nanoparticles. Conclusion Oral exposure to TiO2 during pregnancy increased the titanium concentrations in the maternal liver, maternal brain and placenta, but these levels did not induce marked toxicities in maternal animals or affect embryo-fetal development. These results could be used to evaluate the human risk assessment of TiO2 nanoparticle oral exposure during pregnancy, and additional comprehensive toxicity studies are deemed necessary considering the possibility of complex exposure scenarios and the various sizes of TiO2 nanoparticles.

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 μg/mL for 24 hr, zinc oxide nanoparticles showed higher toxicity to cornea cells. LC50 of zinc oxide nanoparticles was less than 25 μg/mL but those of other nanoparticles could not be calculated in this test, which means more than 100 μg/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, CeO2, SiO2 and TiO2 nanoparticles.

Unlike the environmental pollutants or industrial chemicals, the chemicals in consumer products may pose higher levels of risks, depending on how the chemicals are used in the products and how humans interact with the products. Recently, endocrine disrupting chemicals in cosmetics, personal care products, cleaners, sunscreens, and vinyl products were analytically quantified and many active chemicals including phthalates, parabens and bisphenols were detected. This indicates a wide range of exposures from common products. In this study, 35 chemicals known to be ingredients of consumer products were selected and screened for the transactivation of estrogen receptors and androgen receptors. From the results of individual chemicals, the activity of binary/ternary mixture prepared from the agonists for the ER transcription activity was measured, and compared to the predicted values obtained by the full logistic model. The measured and the predicted values were found to be very similar. This study may suggest that prediction of mixture activity by proper models would be one of the supportive tools for the risk assessment and sound regulation of chemical mixtures which have potential endocrine disrupting effects in consumer products.

Methylisothiazolinone (MIT) has been used in combination with methylchloroisothiazolinone (CMIT) for cosmetic products such as shampoo, body lotion, and skin care products. The mixture of CMIT/MIT has been found to cause allergic contact dermatitis and is thus no longer permitted for use as a preservative in leave-on cosmetics. However, MIT itself was approved as a stand-alone preservative at a maximum concentration of 100 ppm as the toxicity was derived from CMIT rather than MIT. However, in many countries, allergic skin irritation caused by MIT remains a social concern. In this study, skin irritation was assessed for the presence of MIT, propylene glycol, and their mixture using a 3D human skin model EpiDerm™. Although non-diluted MIT causes serious skin toxicity, skin irritation was not observed at a concentration of 100 ppm, the maximum permissible level for cosmetics and personal care products according to European regulations. Propylene glycol, the most widely used vehicle for MIT, did not cause skin irritation in the 3D skin model. The results are expected to provide information for regulatory policies and guidelines on the use of biocides in consumer products.

Toxicity and target organ distribution of cerium oxide nanoparticles (CeNPs) were investigated via single intravenous injection and single oral administration, respectively. Rats were sacrificed at 24 h after treatment with doses of 30 and 300 mg/kg, and cerium concentrations were measured in liver, kidney, spleen, lung, blood, urine and feces. Results revealed cerium levels in blood and tissues were considerably low in oral treated groups and most cerium was detected in feces, meaning CeNPs would not be absorbed in the gastro-intestinal system. Conversely, high concentrations of cerium were detected in all tissues of rats after intravenous injection. Liver and spleen were main target organs. Cerium levels in liver were 594.9 ± 95.3 μg/g tissue in 30 mg/kg treat group and 3741.7 ± 932.7 μg/g tissue in 300 mg/kg treat group. Cerium levels in spleen reached almost levels of liver. Cerium was also detected, that is relatively low compared to oral administration, in feces of rats treated via intravenous injection, that supports biliary excretion of CeNPs. Urine excretion of CeNPs was not detected in oral treatment and intravenous injection. In accordance with level of cerium distribution, toxicities based on hematology, serum biochemistry and histopathology were observed in rats treated by intravenous injection while no significance was revealed in orally treated groups.

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.

Background Cerium oxide nanoparticles (CeO 2 NPs) are widely used in various commercial applications because of their characteristic properties. CeO 2 NPs can be easily exposed to humans in real life, but the safety assessment of CeO 2 NPs has not been fully investigated. Therefore, in this study, we conducted a combined repeated-dose and reproductive/developmental toxicity screening study to investigate the potential effects on general health hazards, including reproductive/developmental functions, after repeated CeO 2 NPs oral exposure. In addition, tissues from parental animals and their pups were collected to analyze the internal accumulation of cerium. CeO 2 NPs were orally administered to Sprague-Dawley rats at doses of 0, 100, 300 and 1000 mg/kg during their pre-mating, mating, gestation and early lactation periods. Results In the general systemic and reproductive/developmental examinations, no marked toxicities were observed in any of in-life and terminal observation parameters in this study. In the biodistribution analysis, cerium was not detected in either parental or pup tissues (blood, liver, lungs and kidneys). Conclusion Repeated oral exposure of CeO 2 NPs did not induce marked toxicities affecting general systemic and reproductive/developmental functions up to the dose level of 1000 mg/kg and the CeO 2 NPs were not systemically absorbed in parental animals or their pups. This result could be used to risk assessment for human, and additional toxicity studies with CeO 2 NPs will be necessary considering various physicochemical properties and exposure probabilities of this nanoparticles.

Yeo Jin Kim,1,2 Md Mujibur Rahman,1 Sang Min Lee,2 Jung Min Kim,3 Kwangsik Park,4 Joo-Hyon Kang,5 Young Rok Seo1,2 1Institute of Environmental Medicine for Green Chemistry, Dongguk University Biomedi Campus, Ilsandong-gu, Goyang-si, Republic of Korea; 2Department of Life Science, Dongguk University Biomedi Campus, Ilsandong-gu, Goyang-si, Republic of Korea; 3Genoplan Korea, Inc., Seocho-gu, Seoul, Republic of Korea; 4College of Pharmacy, Dongduk Women’s University, Seongbuk-gu, Seoul, Republic of Korea; 5Department of Civil & Environmental Engineering, Dongguk University, Jung-gu, Seoul, Republic of Korea Background: Silver nanoparticles (AgNPs) are widely used in industrial and household applications, arousing concern regarding their safety in humans. The risks posed by stabilizer-coated AgNPs continue to be unclear, and assessing their toxicity is for an understanding of the safety issues involved in their use in various applications. Purpose: We aimed to investigated the long-term toxicity of citrate-coated silver nanoparticles (cAgNPs) in liver tissue using several toxicity tests and transcriptomic analysis at 7 and 28 days after a single intravenous injection into rabbit ear veins (n=4). Materials and methods: The cAgNPs used in this study were in the form of a 20% (w/v) aqueous solution, and their size was 7.9±0.95 nm, measured using transmission electron microscopy. The animal experiments were performed based on the principles of good laboratory practice. Results: Our results showed that the structure and function of liver tissue were disrupted due to a single exposure to cAgNPs. In addition, in vivo comet assay showed unrepaired genotoxicity in liver tissue until 4 weeks after a single injection, suggesting a potential carcinogenic effect of cAgNPs. In our transcriptomic analysis, a total of 244 genes were found to have differential expression at 28 days after a single cAgNP injection. Carefully curated pathway analysis of these genes using Pathway Studio and Ingenuity Pathway Analysis tools revealed major molecular networks responding to cAgNP exposure and indicated a high correlation of the genes with inflammation, hepatotoxicity, and cancer. Molecular validation suggested potential biomarkers for assessing the toxicity of accumulated cAgNPs. Conclusion: Our investigation highlights the risk associated with a single cAgNP exposure with unrepaired damage persisting for at least a month. Keywords: nanotoxicity, liver toxicity, prolonged tissue damage, differentially expressed genes, molecular pathway analysis

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.

Recent toxicity studies of zinc oxide nanoparticles by oral administration showed relatively low toxicity, which may be resulted from low bioavailability. So, the intrinsic toxicity of zinc oxide nanoparticles needs to be evaluated in the target organs by intravenous injection for full systemic concentration of the administered dosage. Although the exposure chance of injection route is low compared to oral and/or inhalation route, it is important to see the toxicity with different exposure routes to get better risk management tool. In this study, the effects of zinc oxide nanoparticles on dams and fetuses were investigated in rats after intravenous injection (5, 10, and 20 mg/kg) from gestation day 6 to 20. Two of 20 dams in the 20 mg/kg treatment group died during the treatment period. Hematological examination and serum biochemistry showed dose-dependent toxicity in treated dams. Histopathological analysis of treated dams revealed multifocal mixed cell infiltration and thrombosis in lung, tubular dilation in kidneys, and extramedullary hemopoiesis in liver. Total dead fetuses (post-implantation loss) were increased and the body weight of fetus was decreased in the 20 mg/kg treatment group. Statistical differences in corpora lutea, resorption, placental weight, morphological alterations including external, visceral and skeletal malformations were not observed in treated groups. Based on the data, lowest observed adverse effect level of injection route was suggested to be 5 mg/kg in dams and no observed adverse effect level was suggested to be 10 mg/kg in fetal developmental toxicity.

The GBAR experiment is designed to measure the free fall acceleration of antihydrogen atoms almost at rest. We have developed a time-of-flight (TOF) detector for the measurement of free fall time and annihilation position of antihydrogen atoms as well as for the rejection of cosmic ray muons. A scintillator array as a part of the TOF detector was installed and tested at the GBAR experimental hall. The performance of the TOF detector studied by cosmic ray muons is reported in this paper.

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 EpiOcularTM 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.

Combined repeated-dose toxicity study of citrate-capped silver nanoparticles (7.9 ± 0.95 nm) with reproduction/developmental toxicity was investigated in rats orally treated with 62.5, 125 and 250 mg/kg, once a day for 42 days for males and up to 52 days for females. The test was performed based on the Organization for Economic Cooperation and Development test guideline 422 and Good Laboratory Practice principles. No death was observed in any of the groups. Alopecia, salivation and yellow discolouration of the lung were observed in a few rats but the symptoms were not dose-dependent. Haematology, serum biochemical investigation and histopathological analysis revealed no statistically significant differences between control group and the treated groups. Toxicity endpoints of reproduction/developmental screening test including mating, fertility, implantation, delivery and foetus were measured. There was no evidence of toxicity.

The stability of citrate-capped silver nanoparticles (AgNPs) and the embryonic developmental toxicity were evaluated in the fish test water. Serious aggregation of AgNPs was observed in undiluted fish water (DM-100) in which high concentration of ionic salts exist. However, AgNPs were found to be stable for 7 days in DM-10, prepared by diluting the original fish water (DM-100) with deionized water to 10 %. The normal physiology of zebrafish embryos were evaluated in DM-10 to see if DM-10 can be used as a control vehicle for the embryonic fish toxicity test. As results, DM-10 without AgNPs did not induce any significant adverse effects on embryonic development of zebrafish determined by mortality, hatching, malformations and heart rate. When embryonic toxicity of AgNPs was tested in both DM-10 and in DM-100, AgNPs showed higher toxicity in DM-10 than in DM-100. This means that the big-sized aggregates of AgNPs were low toxic compared to the nano-sized AgNPs. AgNPs induced delayed hatching, decreased heart rate, pericardial edema, and embryo death. Accumulation of AgNPs in the embryo bodies was also observed. Based on this study, citrate-capped AgNPs are not aggregated in DM-10 and it can be used as a control vehicle in the toxicity test of fish embryonic development.

Effects of nanoparticles (NPs) on skin corrosion and irritation using three-dimensional human skin models were investigated based on the test guidelines of Organization for Economic Co-operation and Development (OECD TG431 and TG439). EpiDermTM skin was incubated with NPs including those harboring iron (FeNPs), aluminum oxide (AlNPs), titanium oxide (TNPs), and silver (AgNPs) for a defined time according to the test guidelines. Cell viabilities of EpiDermTM skins were measured by the 3-(4, 5-dimethylthi-azol-2-yl)-2.5-diphenyltetrazolium bromide based method. FeNPs, AlNPs, TNPs, and AgNPs were non-corrosive because the viability was more than 50% after 3 min exposure and more than 15% after 60 min exposure, which are the non-corrosive criteria. All NPs were also non-irritants, based on viability exceeding 50% after 60 min exposure and 42 hr post-incubation. Release of interleukin 1-alpha and histopathological analysis supported the cell viability results. These findings suggest that FeNPs, AlNPs, TNPs, and AgNPs are ‘non-corrosive’ and ‘non-irritant’ to human skin by a globally harmonized classification system.

The biological activity of particles is largely dependent on their size in biological systems. Dispersion in the aqueous phase has been both a critical impediment to and a prerequisite for particle studies. Carbon black has been used as a surrogate to investigate the biological effects of carbonaceous particles. Here, biocompatible methods were established to disperse carbon black into ultrafine and fine particles which are generally distinguished by the small size of 100 nm. Carbon black with a distinct particle size, N330 and N990 were suspended in blood plasma, cell culture media, Krebs-Ringer's solution (KR), or physiological salt solution (PSS). Large clumps were observed in all dispersion preparations; however, sonication improved dispersion - averaged particle sizes for N330 and N990 were 85.0 ± 42.9 and 112.4 ± 67.9 nm, respectively, in plasma; the corresponding sizes in culture media were 84.8 ± 38.4 and 164.1 ± 77.8 nm. However, sonication was not enough to disperse N330 less than 100 nm in either KR or PSS. Application of Tween 80 along with sonication reduced the size of N330 to less than 100 nm, and dispersed N990 larger than 100 nm (73.6 ± 28.8 and 80.1 ± 30.0 nm for N330 and 349.5 ± 161.8 and 399.8 ± 181.1 nm for N990 in KR and PSS, respectively). In contrast, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) exhibited little effect. Electron microscopy confirmed the typical aciniform structure of the carbon arrays; however, zeta potential measurement failed to explain the dispersibility of carbon black. The methods established in this study could disperse carbon black into ultrafine and fine particles, and may serve as a useful model for the study of particle toxicity, particularly size-related effects.

Purpose: Toxicity caused by acetaminophen and its toxic mechanisms in the liver have been widely studied, including effects involving metabolism and oxidative stress. However, its adverse effects on heart have not been sufficiently investigated. This study evaluated the cardiac influence and molecular events occurring within the myocardium in rats treated with a dose of acetaminophen large enough to induce conventional liver damage. Materials and Methods: Male rats were orally administered a single dose of acetaminophen at 1,000 mg/kg-body weight, and subsequently examined for conventional toxicological parameters and for gene expression alterations to both the heart and liver 24 hours after administration. Results: Following treatment, serum biochemical parameters including aspartate aminotransferase and alanine aminotransferase were elevated. Histopathological alterations of necrosis were observed in the liver, but not in the heart. However, alterations in gene expression were observed in both the liver and heart 24 hours after dosing. Transcriptional profiling revealed that acetaminophen changed the expression of genes implicated in oxidative stress, inflammatory processes, and apoptosis in the heart as well as in the liver. The numbers of up-regulated and down-regulated genes in the heart were 271 and 81, respectively, based on a two-fold criterion. Conclusion: The induced expression of genes implicated in oxidative stress and inflammatory processes in the myo cardium reflects molecular levels of injury caused by acetaminophen (APAP), which could not be identified by conventional histopathology.

Epidemiologists have tried to establish an association between human health and exposure to particulate matter (PM). In addition, many researchers have investigated the adverse effects of PM as a trigger of cardiovascular and pulmonary diseases. It is known that a number of environmental contaminants are attached to PM and the toxicity of PM may depend on the sources. We investigated the effects of PM collected in a residential area of Seoul on the immunotoxic responses including cytokine production in BAL fluid and in blood after a single intratracheal instillation in mice with the characterization of physico-chemical properties of PM 2.5 samples. As results, pro-inflammatory cytokines (IL-1, TNF-α, and IL-6), Th0-type cytokine (IL-2), and Th1-type cytokines (IL-12 and IFN-γ) were increased by a dose-dependent manner. Cell infiltration in the alveolar area and phagocytosis by macrophage was observed until day 28 after instillation. The expressions of oxidative stress-related genes (HSP 1a, HSP 8, and SOD) and tissue damage-related genes (MMP-15, -19, and Slpi) were time-dependently increased. PM 2.5 also induced an increase of T cell distribution in lymphocyte and decreased the CD4+/CD8+ ratio. Based on the results, we suggest that PM 2.5 collected in a residential area of Seoul may induce Th1 type-inflammatory responses with oxidative stress and trigger adverse effects in human health.

The adverse effects of silver nanoparticles (AgNPs) to human and environment have not been known well, although AgNPs are now widely applicated to consumer products. In this study, we investigated the inflammatory responses including cytokine production and gene expression in mice after a single intratracheal instillation of AgNPs. As results, pro-inflammatory cytokines (IL-1, TNF-a, and IL-6) and Th0 cytokine (IL-2) were progressively increased by the day 28 after a single instillation. The secretion of Th2 type cytokine was more dominant than that of Th1 type cytokine, and the increase of B cell distribution was also observed. But, histopathological changes in lung were observed only at day 1 after instillation. We identified the changes of gene expression induced by AgNPs in lung tissue using microarray. The 261 genes related to inflammation and tissue damages including Saa3, Krt 13, Lor, Krtdap, and Lcn 2 were up-regulated by over 2 fold, while 103 genes including H2-Ea, Chka, BC030476, Heg1 and Hbb-b1 were down-regulated. Based on the data, it is suggested that AgNPs may induce Th2 type dominant inflammatory responses and tissue damage in the lung of mice.

Bioavailability, tissue distribution, blood concentration, and excretion of citrate-coated silver nanoparticles (AgNPs; size, 7.9 ± 0.95 nm by TEM diameter) were investigated. Male SD rats were treated by a single oral or intravenous administration of either 1 or 10 mg/kg AgNPs. Silver concentration of blood was determined at 10 min, and at 1, 2, 4, 8, 24, 48, and 96 h after treatment. Silver in the liver, lungs, and kidneys was also measured at 24 and 96 h after treatment. Excretion of silver nanoparticles via feces and urine was determined at 24 h after treatment. After oral administration, most AgNPs were found in feces, and their blood concentration was very low. This suggests that absorption through the gastrointestinal tract was not good. However, a high level of silver in the blood was detected after tail vein injection. When rats were injected with 1 mg/kg AgNPs, the silver concentration of blood was significantly elevated at 10 min after injection; the level subsequently decreased. In the rats treated with 10 mg/kg AgNPs, the elevated level did not decrease, but was maintained during the experimental period. On the basis of the values of AUC(oral)/AUC(iv), the bioavailability of orally administered AgNPs was 1.2% in the group treated with 1 mg/kg AgNPs and 4.2% in the group treated with 10 mg/kg AgNPs. AgNPs accumulated in the liver, lungs, and kidneys; the accumulated AgNPs were released into the blood stream. AgNP levels in the urine were extremely low compared to the levels in the feces. When rats were injected with AgNPs, these particles were also detected in feces at 24 h after treatment, which suggests bile secretion of AgNPs.

Concentrations of ambient air particles such as total suspended particulates (TSP), particulate matter (PM)₁?, and PM 2.5 , were monitored simultaneously from May to June, 2007, at four locations at Alashan and Beijing in China, and Seoul and Gosan in South Korea. These monitoring sites are in the pathway of Asian dust (AD) storms traveling from China to the Korean peninsula. An AD event was observed in the Korean peninsula on May 25-26. During the sampling period, the average concentrations of TSP and PM10 were each higher than 150 ㎍/㎥ in Alashan and Beijing, but not in Seoul and Gosan. The concentration of TSP in Alashan (where the dust storm originated) on the day of the AD event reached 1824.7 ㎍/㎥, this being the highest concentration of air particles observed during the sampling period. The level was decreased to 15% of this (274.7 ㎍/㎥) in Seoul and to 8.7% (159. 0 ㎍/㎥) in Gosan when the AD was observed two days later in Korea. Gosan, a representative background site in East Asia, displayed the lowest concentration of particles, with this maximal TSP concentration of 159 ㎍/㎥. Inorganic element contents in the air particles were also measured, and the concentrations in the four different regions compared. Concentrations of anthropogenically-enriched heavy metals in PM10 and PM2.5, such as lead, arsenic, cadmium, and mercury, were higher in the metropolitan cities of Beijing and Seoul compared to non-industrialized regions of Alashan and Gosan. However, the concentrations of inorganic soil elements including iron, magnesium, aluminum sodium, and manganese, were higher in Alashan compared to those in other sampling sites.

Citrate-stabilized silver nanoplates (AgNPs) were prepared via a seed-mediated method without surfactants, such as cetyltrimethylammonium bromide (CTAB), in a short amount of time (15 min). Silver seeds with 3–4 nm in diameter were added to a growth solution containing AgNO3, trisodium citrate (TSC) and L-ascorbic acid (AA). The size of the AgNPs depended on the concentration of the silver seed and TSC. The physical properties of the AgNPs were analyzed by transmission electron microscopy (TEM) and by an ultraviolet-visible (UV-vis) spectrophotometer. In addition, we tested the nanotoxicity of AgNPs prepared in TSC solution to the spleen of a rat, and found that AgNPs induced inflammation and white spots on the surface of the spleen.

Magnetite iron nanoparticles have been widely used as contrast agents and in thermal therapy for cancer. However, their adverse effects on human health have not been fully investigated. In this study, iron oxide nanoparticles were prepared using inorganic iron chloride (size: 5.3+/-3.6 nm in phosphate buffered saline, surface charge: 23.14 mV), and their inflammatory responses were investigated. When mice were treated with iron oxide nanoparticles (250 microg/kg, 500 microg/kg, and 1mg/kg) by a single intratracheal instillation, the level of intracellular reduced glutathione (GSH) was decreased in the cells of bronchoalveolar lavage (BAL) fluid. The arrest of cell cycles in G1 phase was observed, but S-phase was significantly decreased. The concentrations of pro-inflammatory cytokines (IL-1, TNF-alpha, and IL-6) were dose-dependently increased at day 1 after instillation in the BAL fluid and in the blood. During the experimental period of 28 days, pro-inflammatory cytokines (IL-1, TNF-alpha, and IL-6), Th0 cytokine (IL-2), Th1 type cytokine (IL-12), Th2 type cytokines (IL-4 and IL-5), TGF-beta, and IgE were also elevated. Expressions of many genes related with inflammation or tissue damage such as heat shock protein, matrix metalloproteinase, tissue inhibitors of metalloproteinases, and serum amyloid A were significantly induced. Formation of microgranuloma, which is one of the indicators for chronic inflammatory response, was observed in the alveolar space. In addition, distribution of B cell and CD8+ T cell in blood lymphocytes was increased at day 28. Based on the result, iron oxide nanoparticles may subchronic induce inflammatory responses via oxidative stress in mice by a single intratracheal instillation.

The appearance of Asian Dust (AD) originating from China and Mongolia during spring each year is a meteorological phenomenon periodically observed in extensive regions of East Asia. According to a previous epidemiological study, AD has adverse effects on both human beings and ecosystems. In this study, we collected total suspension particles (TSP) in the AD period and Non-AD (NAD) period. We extracted organic components from TSP using dichloromethane (DCM), and the polyaromatic hydrocarbons (PAHs) were analyzed. The DCM extracts contained PAHs such as benzo(b)fluoranthene, benzo[g,h,i]perylene, benzo(k)fluoranthene, benzo(a)pyrene, and pyrene. No significant difference was observed in cytotoxicity of the DCM extracts from AD versus NAD when tested on the human bronchial epithelial cells, BEAS-2B. We also examined the toxic mechanisms of AD extracts in cultured BEAS-2B cells and RAW264.7 cells, and in BEAS-2B cells observed increased levels of reactive oxygen species (ROS), decreased glutathione (GSH), and induced caspase-3 activity. Increased expression of oxidative stress-related and inflammation- related genes were also observed in BEAS-2B cells, while nitric oxide (NO) levels were increased in RAW264.7 cells. Taken together, the results suggest that in these cultured cells, AD may induce cytotoxicity through oxidative stress and pro-inflammatory signals.

Platinum nanoparticles (PNPs) are potentially useful for sensing, catalysis, and other applications in the biological and medical sciences. However, toxicity data on the PNPs are very limited. In this study, we prepared PNPs using K(2)PtCl(6), (21 nm in phosphate buffered saline) and tested inflammatory responses in mice after a single intratracheal instillation. The concentrations of pro-inflammatory cytokines (IL-1, TNF-alpha, and IL-6), TH0 cytokine (IL-2), TH1-type cytokine (IL-12), and TH2-type cytokines (IL-4 and IL-5) were increased in broncho-alveolar lavage fluid by PNPs. It was found that the induciton of TH2-type cytokines were higher than TH1-type cytokine on day 28 after instillation. TGF-beta was also significantly increased in broncho-alveolar lavage fluid during the experimental period. IgE level in serum was increased with the increase of B cells distribution. Intracellular level of glutathione (GSH) was diminished by treatment of PNPs. When the distribution of T cell subtype (CD4(+)/CD8(+)) was analyzed, the ratio was decreased. Gene expression of matrix metalloproteinases was found to be significantly increased on day 1. By histopathological examination, cell infiltration of macrophages and neutrophils was observed in lung tissue during the experimental period. Based on these findings, it is suggested that the exposure to PNPs may induce inflammatory responses in mice.

Manganese, an essential trace nutrient in human beings, has been widely used in the steel industry to improve hardness, stiffness, and strength. With the increased applications of manganese compounds, discharge into the environment has rapidly increased and may exert adverse effects on human health. In this study, manganese toxicity was investigated using cultured T98G cells, which are derived from human glioblasts with the ability to differentiate into several different types of neuroglia. Cytotoxicity was shown in manganese-treated groups (100, 200, 400, and 800microM of MnCl(2)), and cell viability was decreased to 58.8% of the control group at 2days after treatment with 800microM of MnCl(2). When cells were treated with manganese for 24h, ROS dose-dependently increased while antioxidant intracellular GSH decreased. With the generation of ROS, the increased activity of caspase-3 was shown, and was followed by chromatin condensation and breakage, which is an indication of the cellular apoptotic process. ROS also triggered pro-inflammatory responses in cultured T98G cells, which were demonstrated by the increased gene expression and protein levels of IL-6 and IL-8.

As the use of carbon fullerene increases in the chemical industry, the concern over its biological and toxicological effects is also increasing. In this study, the suspension of carbon fullerene (C60) in phosphate buffered saline was prepared and toxicity was investigated using cultured RAW 264.7 and in intraperitoneally injected mice, respectively. The average size of carbon fullerene in the suspension was 53.7 ± 26.5 nm when determined by particle size analyzer. Cell viability was significantly decreased by the exposure of carbon fullerene (0.25~2.00 μg/ml) for 96 hrs in the cultured RAW 264.7 cells. Intracellular reduced glutathione (GSH) level was also decreased compared to the level of the non-treated control group during the exposure period, while the level of nitric oxide was increased. When mice were intraperitoneally injected with carbon fullerene, serum cytokine levels of IL-1 and IL-6 were increased with the increased expression of inflammatory genes in peritoneal macrophage and T cell distribution in blood lymphocytes.The results suggested inflammatory responses were induced by carbon fullerene.

Cerium oxide nanoparticles have a high thermodynamic affinity for oxygen and sulfur, which makes them useful in applications such as catalysts, solar cells, and gas sensors. In this study, we investigated the effects of intratracheal instillation of cerium oxide nanoparticles on the inflammatory responses in mice. The number of neutrophils in bronchoaveolar lavage (BAL) fluids was significantly elevated on day 1 after instillation. Inflammatory cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF)-α, and IL-6, were also increased in BAL fluid and the cytokine increase initiated the differentiation of naive T cells, followed by the induction of Th1-type cytokines [IL-12 and interferon (IFN)-γ] and Th2-type cytokines (IL-4, IL-5, and IL-10). The secretion of Th1-type cytokines was more dominant than that of Th2-type cytokines. The inflammatory responses were maintained for 28 days by a positive feedback stimulation of IFN-γ and IL-10. In the lung, the expression of inflammatory genes was increased in a time-dependent manner, and granuloma formation appeared on day 14 after instillation. This suggests that intratracheal instillation of cerium oxide nanoparticles causes a delayed-type hypersensitivity reaction and lung fibrosis in mice.

Recent publications showed that metal nanoparticles which are made from TiO2, CeO2, Al2O3, CuCl2, AgNO3 and ZnO2 induced oxidative stress and pro-inflammatory effects in cultured cells and the responses seemed to be common toxic pathway of metal nanoparticles to the ultimate toxicity in animals as well as cellular level. In this study, we compared the gene expression induced by two different types of metal oxide nanoparticles, titanium dioxide nanoparticles (TNP) and cerium dioxide nanoparticles (CNP) using microarray analysis. About 50 genes including interleukin 6, interleukin 1, platelet-derived growth factor β, and leukemia inhibitory factor were induced in cultured BEAS-2B cells treated with TNP 40 ppm. When we compared the induction levels of genes in TNP-treated cells to those in CNP-treated cells, the induction levels were very correlated in various gene categories (r = 0.645). This may suggest a possible common toxic mechanism of metal oxide nanoparticles.

Cytotoxicity induced by silver nanoparticles (AgNPs) and the role that oxidative stress plays in this process were demonstrated in human hepatoma cells. Toxicity induced by silver (Ag(+)) ions was studied in parallel using AgNO(3) as the Ag(+) ion source. Using cation exchange treatment, we confirmed that the AgNP solution contained a negligible amount of free Ag(+) ions. Metal-responsive metallothionein 1b (MT1b) mRNA expression was not induced in AgNP-treated cells, while it was induced in AgNO(3)-treated cells. These results indicate that AgNP-treated cells have limited exposure to Ag(+) ions, despite the potential release of Ag(+) ions from AgNPs in cell culture. AgNPs agglomerated in the cytoplasm and nuclei of treated cells, and induced intracellular oxidative stress. AgNPs exhibited cytotoxicity with a potency comparable to that of Ag(+) ions in in vitro cytotoxicity assays. However, the toxicity of AgNPs was prevented by use of the antioxidant N-acetylcysteine, and AgNP-induced DNA damage was also prevented by N-acetylcysteine. AgNO(3) treatment induced oxidative stress-related glutathione peroxidase 1 (GPx1) and catalase expression to a greater extent than AgNP exposure, but treatment with AgNO(3) and AgNPs induced comparable superoxide dismutase 1 (SOD1) expression levels. Our findings suggest that AgNP cytotoxicity is primarily the result of oxidative stress and is independent of the toxicity of Ag(+) ions.

Cerium oxide nanoparticles (size: 30 nm) were prepared by the supercritical synthesis method, Acute oral toxicity and tissue distribution of the nanoparticles were evaluated by a single administration in rats. Oral administration of the nanoparticles to the rats did not lead to death when the animals were treated by a dose of 5 g/kg (high dose) as well as 100 mg/kg (low dose). Abnormal clinical signs, changes in serum biochemistry and hematology were not observed in high-dose treated group compared to the vehicle control group. Lesions in liver, lung and kidney were not observed in high-dose treated group by histopathological examination. Tissue distribution analysis in liver, kidney, spleen, lung, testis and brain was performed on day 1, day 7 and day 14 after treatment. The average values of the accumulated cerium oxide nanoparticles were elevated in all tissues but statistical significance was only shown in lung. Low levels of tissue distributions after a single oral administration seem to be the low bioavailability of the nanoparticles.

Titanium dioxide nanoparticles (TNP) are nanomaterials which have various applications including photocatalysts, cosmetics, and pharmaceuticals because of their high stability, anticorrosiveness, and photocatalytic properties. Induction of cytokines and potential chronic inflammation were investigated in mice treated with TNP (5 mg/kg, 20 mg/kg, and 50 mg/kg) by a single intratracheal instillation. Pro-inflammatory cytokines such as IL-1, TNF-a, and IL-6 were significantly induced in a dose-dependent manner at day 1 after instillation. The levels of Th1-type cytokines (IL-12 and IFN-gamma) and Th2-type cytokines (IL4, IL-5 and IL-10) were also elevated dose-dependently at day 1 and the inflammatory responses were sustained until the remainder of experimental period for 14 days. By the induction of Th2-type cytokines, the increased B cell distributions both in spleen and in blood, and increased IgE production in BAL fluid and serum were observed. In lung tissue, increase of inflammatory proteins (MIP and MCP) and granuloma formation were observed. Furthermore, the expressions of genes related with antigen presentation (H2-T23, H2-T17, H2-K1, and H2-Eb1) and genes related with the induction of chemotaxis of immune cells (Ccl7, Ccl3, Cxcl1, Ccl4, Ccl2) were markedly increased using microarray analysis. From these data, it could be suggested that TNP possibly cause chronic inflammatory diseases through Th2-mediated pathway in mice.

The increased application of engineered carbon nanotubes (CNTs) has also raised the level of public concern regarding possible toxicities caused by exposure to these nanostructures. In this study, pulmonary and systemic immune responses induced by intratracheal instillation of multi-walled carbon nanotubes (MWCNTs) were investigated in mice. Total numbers of immune cells in bronchoalveolar lavage (BAL) fluid were significantly increased in treated groups (5, 20, and 50mg/kg doses of MWCNTs) and the distribution of neutrophils was elevated at day 1 after instillation. Pro-inflammatory cytokines (IL-1, TNF-alpha, IL-6, IL-4, IL-5, IL-10, IL-12, and IFN-gamma) were also increased in a dose-dependent manner, both in BAL fluid and in blood. Most of the cytokines showed the highest levels at day 1 after instillation and then decreased. Th2-type cytokines (IL-4, IL-5, and IL-10) were elevated in the treated group to levels higher than those of the Th1-type cytokines (IL-12 and IFN-gamma). Furthermore, distributions of B cells in spleen and blood were significantly increased at day 1 after instillation, indicating that Th2-type cytokines had activated B cells, causing them to proliferate. Along with the additional numbers of B cells, granuloma formation in the lung tissue and IgE production were also observed, with an intensity dependent on the dose of MWCNTs instilled. Based on these observations, it is suggested that MWCNTs may induce allergic responses in mice through B cell activation and production of IgE.

This paper presents a new open stub structure of Kuroda low-pass filter using DGS(Defected Ground Structure). The open stub having 130ohm is made with equivalent new structure using DGS. This method enable to the fabrication of Kuroda low-pass filter by extending width of the line. In case of FR4(er

As the applications of industrial nanoparticles are being developed, the concerns on the environmental health are increasing. Cytotoxicities of titanium dioxide nanoparticles of different concentrations (5, 10, 20 and 40 microg/ml) were evaluated in this study using a cultured human bronchial epithelial cell line, BEAS-2B. Exposure of the cultured cells to nanoparticles led to cell death, reactive oxygen species (ROS) increase, reduced glutathione (GSH) decrease, and the induction of oxidative stress-related genes such as heme oxygenase-1, thioredoxin reductase, glutathione-S-transferase, catalase, and a hypoxia inducible gene. The ROS increase by titanium dioxide nanoparticles triggered the activation of cytosolic caspase-3 and chromatin condensation, which means that titanium dioxide nanoparticles exert cytotoxicity by an apoptotic process. Furthermore, the expressions of inflammation-related genes such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), TNF-a, and C-X-C motif ligand 2 (CXCL2) were also elevated. The induction of IL-8 by titanium dioxide nanoparticles was inhibited by the pre-treatment with SB203580 and PD98059, which means that the IL-8 was induced through p38 mitogen-activated protein kinase (MAPK) pathway and/or extracellular signal (ERK) pathway. Uptake of the nanoparticles into the cultured cells was observed and titanium dioxide nanoparticles seemed to penetrate into the cytoplasm and locate in the peri-region of the nucleus as aggregated particles, which may induce direct interactions between the particles and cellular molecules, to cause adverse biological responses.