• Toxicological Research
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• 제26권4호
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• pp.285-291
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• 2010

Recently, reproductive and neurobehavioral effects of bisphenol A (BPA) have been documented, and thus a review was requested for BPA management direction by the government. Therefore, this study was performed to establish a Korean tolerable daily intake (TDI) for BPA. An expert committee, consisting of specialists in fields such as toxicology, medicine, pharmacology, and statistics, was asked to evaluate BPA health based guidance values (HbGVs). Although many toxicological studies were reviewed to select a point of departure (POD) for TDI, rat and mouse reproductive studies by Tyl et al. (2002, 2006), which were performed according to GLP standards and OECD guidelines, were selected. This POD was the lowest value determined from the most sensitive toxicological test. The POD, a NOAEL of 5 mg/kg bw/day, was selected based on its systemic toxicity as critical effects. An uncertainty factor of 100 including interspecies and intraspecies differences was applied to calculate the TDI. According to the evaluation results, a TDI of BPA for Korean was suggested at 0.05 mg/kg bw/day. In addition, the BPA exposure level based on food consumption by the Korean population was estimated as 1.509 ${\mu}g/kg$ bw/day, and the HI was evaluated at 0.03 when the TDI of 0.05 mg/kg bw/day was applied. This HI value of 0.03 indicated that hazardous effects would not be expected from BPA oral exposures. Although highly uncertain, further studies on low dose neurobehavioral effects of BPA should be performed. In addition, it is recommended that the 'as low as reasonably achievable' (ALARA) principle be applied for BPA exposure from food packaging materials in newborn infants and children.

• Molecular & Cellular Toxicology
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• 제2권4호
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• pp.236-243
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• 2006

Microarray analysis of gene expression has become a powerful approach for exploring the biological effects of drugs, particularly at the stage of toxicology and safety assessment. Acetaminophen (APAP) has been known to induce necrosis in liver, but the molecular mechanism involved has not been fully understood. In this study, we investigated gene expression changes of APAP using microarray technology. APAP was orally administered with a single dose of 50 mg/kg or 500 mg/kg into ICR mice and the animals were sacrificed at 6, 24 and 72 h of APAP administration. Serum biochemical markers for liver toxicity were measured to estimate the maximal toxic time and hepatic gene expression was assessed using high-density oligonucleotide microarrays capable of determining the expression profile of >30,000 well-substantiated mouse genes. Significant alterations in gene expression were noted in the liver of APAP-administered mice. The most notable changes in APAP-administered mice were the expression of genes involved in apoptosis, cell cycle, and calcium signaling pathway, cystein metabolism, glutatione metabolism, and MAPK pathway. The majority of the genes upregulated included insulin-like growth factor binding protein 1, heme oxygenase 1, metallothionein 1, S100 calcium binding protein, caspase 4, and P21. The upregulation of apoptosis and cell cycle-related genes were paralleled to response to APAP. Most of the affected gene expressions were returned to control levels after 72 hr. In conclusion, we identified potential hepatotoxicity makers, and these expressions profiling lead to a better understanding of the molecular basis of APAP-induced hapatotoxicity.

• 약학회지
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• 제40권6호
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• pp.705-712
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• 1996

We have previously shown that determination of glucose uptake using ${\alpha}$-methylglucose(${\alpha}$-MG) is very sensitive and rapid parameter for the assessment of loss of cellular fu nction in renal cell line($LLC-PK_1$). The present study was designed to elucidate the mechanism of inhibition of ${\alpha}$-MG uptake and the intracellular site of toxic action of cisplatin(CIS). $LLC-PK_1$ cells were exposed to various concentrations(5 ${\mu}$M-l00 ${\mu}$M) of CIS for 5 hrs or 24 hrs and ${\alpha}$-MG uptake was determined. Mitochondrial function was evaluated by measuring intracellular ATP content and MTT reduction. The activities of marker enzymes for the basolateral membrane(Na$^+$-K$^+$ ATPase) and brush border membrane (alkaline phosphatase: ALP) were also measured. CIS treatment significantly inhibited the ${\alpha}$-MG uptake in a time- and dose-dependent manner above 25 ${\mu}$M for 5 hrs. Intracellular ATP content and MTT reduction were affected by 24 hr-treatment of 50 ${\mu}$M CIS. The activities of Na$^+$-K$^+$ ATPase and ALP were significantly decreased at 10 ${\mu}$M and 5 ${\mu}$M of CIS for 24 hrs, respectively. The incubation with CIS for 5 hrs had no effects on the intracellular ATP content, MTT reduction and the activities of marker enzymes up to 100 ${\mu}$M. These results partly indicate that inhibition of ${\alpha}$-MG uptake by CIS may not be attributed to the disturbance of mitochondrial function or inhibition of the activity of Na$^+$-K$^+$ ATPase and can be resulted from direct effect of CIS on the Na$^+$/glucose cotransporter in brush border membrane. This study shows that additional mechanistic information, indicating the intracellular site of nephrotoxic action, can be gained by coupling the ${\alpha}$-MG uptake and ATP content or the activity of Na$^+$-K$^+$ ATPase.

• Molecular & Cellular Toxicology
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• 제3권3호
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• pp.177-184
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• 2007

As a possible feasibility of the extrapolation between in vivo and in vitro systems, we investigated the global gene expression from both mouse liver and mouse hepatic cell line treated with hepatotoxic chemical, acetaminophen (APAP), and compared between in vivo and in vitro genomic profiles. For in vivo study, mice were orally treated with APAP and sacrificed at 6 and 24 h. For in vitro study, APAP were administered to a mouse hepatic cell line, BNL CL.2 and sampling was carried out at 6 and 24 h. Hepatotoxicity was assessed by analyzing hepatic enzymes and histopathological examination (in vivo) or lactate dehydrogenase (LDH) assay and morphological examination (in vitro). Global gene expression was assessed using microarray. In high dose APAPtreated group, there was centrilobular necrosis (in vivo) and cellular toxicity with the elevation of LDH (in vitro) at 24 h. Statistical analysis of global gene expression identified that there were similar numbers of altered genes found between in vivo and in vitro at each time points. Pathway analysis identified glutathione metabolism pathway as common pathways for hepatotoxicty caused by APAP. Our results suggest it may be feasible to develop toxicogenomics biomarkers or profiles by comparing in vivo and in vitro genomic profiles specific to this hepatotoxic chemical for application to prediction of liver toxicity.

• 한국임상수의학회지
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• 제9권2호
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• pp.373-390
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• 1992

To assay the fertilizing capacity of domestic animal spermatozoa by hamster test, semen were collected from 13 boars(Duroc. Landrace and Yorkshire) which had been proved to be fertile in the past. then, were preserved in BWW medium or in raw state at 18$^{\circ}C$ or at room temperature. The preserved semen were given each different treatment according to the experimental design and coincubated with zona-free hamster ova for 5 hours. The ova were stained by lacmoid and examined under phase contrast microscope to investigate the rates of ova bound with sperm(sperm binding). ova penetrated by sperm(penetration) and formation of a male pronucleus(pronucleus formation) and also numbers of both bound and penetrated sperm per ovum. Between BWW and TBM medium for boar sperm. no difference in the results of hamster test was obtained. The boar spermatozoa in BWW medium, BWW with caffeine, BWW with heparin, and BWW with both caffeine and heparin showed no difference in the results of hamster test. The boar spermatozoa in BWW medium containing both calcium and RSA showed considerably higher rates of sperm binding, penetration and pronucleus formation as well as higher numbers of both bound and penetrated sperm than those not containing calcium with or without BSA( p<0.01) and also the same results higher than that containing calcium without BSA( p< 0.05). The boar spermatozoa irradiated by X-ray(70 KVP, 20mA) for 3 seconds. then, maintained at 18$^{\circ}C$ for 18 hours showed considerably lower rate of sperm binding than all the other groups including the control and X-ray groups irradiated by smaller dose or maintained for shorter period(p<0.01), and also showed lower number of bound sperm than the other groups(p<0.01, p<0.05). All the control groups of both raw and diluted sperm in BWM medium showed higher rates of sperm binding, penetration and pronucleus formation as well as higher number of penetrated sperm than all the X-ray groups irradiated for 3 seconds(70KVP, 20mA) and maintained for either 3 or 18 hours (p<0.01, p<0.05). At the same time the control groups of diluted sperm showed considerably higher rates of sperm penetration and pronucleus formation than the control group of raw sperm( p<0.01). These results indicates that fertile boar sperm showed considerably lower rates In the results of hamster test, when incubated in the medium without calcium and irradiated by X-ray than when incubated in the medium with calcium and not irradiated by X-ray, respectively, to prove consequently that hamster test would be of great value in assaying the fertilizing capacity of boar spermatozoa.

• Tuberculosis and Respiratory Diseases
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• 제56권2호
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• pp.144-150
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• 2004

연구배경 및 목적 : 기류가역성의 유무와 정도의 평가는 기도질환 환자의 진단 및 치료에 있어서 매우 중요하지만, 기관지확장제 사용 후 기류 가역성을 관찰하기 위한 적절한 폐기능 검사 시간과 폐활량 측정치의 변화에 대한 연구는 매우 적다. 따라서 본 연구는 기관지확장제 사용 후 시간에 따른 폐활량 측정치의 변화를 분석하고자 하였다. 방 법 : 천식 환자 15명을 대상으로 salbutamol $200{\mu}g$을 일 회 흡입 후 15, 30, 45, 60분에 mini-Wright 유량측정기 및 폐활량검사를 이용하여 기관지확장제 반응을 측정하였다. 결 과 : $FEV_1$ 과 FVC의 평균값은 기관지확장제 사용 후 60분에 가장 높게 관찰 되었다. 폐활량 측정치 및 mini-Wright유량측정계의 두 측정치에서 PEF의 평균값은 기관지확장제 사용 후 45분에 가장 높게 관찰되었다. 결 론 : 이상의 결과로서 기류폐색이 의심되는 환자에서 기류가역성을 평가할 때 salbutamol 사용 후 15분 보다는 45분 내지 60분에 PEF 또는 $FEV_1$을 측정하는 것이 기관지확장제 반응을 적절히 평가할 것으로 사료된다.

• The Korean Journal of Pain
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• 제9권1호
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• pp.151-158
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• 1996

Background: Buprenorphine, a new synthetic thebaine derivative, is a partial agonist of the opioid $\mu$-receptor with high receptor affinity, great lipid solubility, and slow rate of opiate receptor association and dissociation. Continuous epidural infusion of opioid can possibly produced undesirable effects, such as respiratory depression, pruritus, etc, in spite of effective postoperative analgesia. Methods: The present study was undertaken to compare the analgesic properties and side effects of continuous epidural infusion of buprenorphine combined with bupivacaine, and morphine combined with bupivacaine in 90 patients following elective gynecologic lower abdominal surgery. At the end of surgery, the initial bolus doses were 3 mg morphine (M group), 0.15 mg buprenorphine (0.15B group), 0.3 mg buprenorphine (0.3B group) combined with 0.25% bupivacaine 10ml, and subsequent continuous infusion doses were 6 mg morphine plus 0.125% bupivacine 100 ml (M group) and 0.6mg buprenorphine plus 0.125% bupivacaine 100 ml (0.15B, 0.3B, group) during 48 hours. The assessment of analgesic efficacy and side effects were made at arrival of recovery room, 1 hr, 4 hr, 8 hr, 24 hr, 36 hr, and 48 hr after the epidural injection. Results: The pain score during 48 hours was significantly higher in the 0.15B group than in the M group and 0.3B group (P<0.05), and the number of patients requiring additional analgesics was significantly higher in the 0.15B group than in the M group and 0.3B group (P<0.05). Signs of respiratory depression were not noted, and the incidence of pruritus, nausea, and vomiting was slightly lower in the 0.15B group and 0.3B group than in the M group, and the incidence of sedation and urinary retention was similar in three group. The subjective rating of satisfaction was better in the 0.3B group than in the M group and 0.15B group (P<0.05). Conclusion: The above results suggest that continuous epidural infusion of buprenorphine combined with low-dose bupivacaine is an advisable method of postoperative analgesia.

• Journal of Astronomy and Space Sciences
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• 제22권4호
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• pp.441-450
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• 2005

유기재료(organic material)는 위성이나 우주비행체의 열을 조절하고 우주환경에 직접 노출되는 것을 차단하기 위하여 가장 흔하게 사용되는 재료 중 하나이다. 본 논문에서는 지상설비를 이용하여 모사한 우주환경에서 유기재료의 물성변화를 관찰하였다. 대표적인 위성용 유기 열조절 재료 중 하나인 2mil ITO(Indium Tin Oxide) coated aluminized KAPTON을 실험 대상으로 선택하였다. 양성자에 의한 단일 우주환경효과를 실험하기 위하여, 한국 원자력의학원의 MC-50 싸이클로트론(cyclotron)을 이용하여 양성자를 조사(irradiation)하였으며, 조사조건은 지구궤도 주변 최고의 양성자 발생기록인 1972년 8월의 최고치 상황을 적용하였다. 조사에너지는 평균 관측에너지인 30MeV으로 고정하였으며, 등가 조사량은 우주노출 시간 1년, 3년, 5년 및 10년을 기준으로 설정하였다. 분석과정은 인장강도를 측정하여 정량적 물성저하를 확인하였고, 전계방출 전자주사현미경 등으로 결정성변화와 노출표면의 손상을 분석하였다.

• Toxicological Research
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• 제22권4호
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• pp.307-313
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• 2006

The development of in vitro assays has been recommended to screening and testing the potential endocrine disruptors (EDs). These assay systems focus only on identifying the estrogenic or antiestrogenic activity of EDs, whereas a few studies have been carried out to screen the thyroid hormone (TH) disruptors. The aim of this study was to evaluate a test system to detect TH disruptors using rat pituitary tumor $GH_3$ cells. The test system is based on the TH-dependent increase in growth rate. As expected, L-3,5,3-triiodothyronine ($(T_3)$ markedly induced a morphological change in $GH_3$ cells from flattened fibroblastic types to rounded or spindle-shaped types. $T_3$ stimulated $GH_3$ cell growth in a dose-dependent manner with the maximum growth-stimulating effect being observed at a concentration $1{\times}10^9M$. In addition, $T_3$ increased the release of growth hormone and prolactin into the medium of the $GH_3$ cells culture. Using this assay system, the TH-disrupting activities of bisphenol A (BPA) and its related compounds were examined. BPA, dimethy/bisphenol A (DMBPA), and TCI-EP significantly enhanced the growth of $GH_3$ cells in the range of $1{\times}10^{-5}M\;to\;1{\times}10^{-6}M$ concentrations. In conclusion, this in vitro assay system might be useful for identifying potential TH disruptors. However, this method will require further evaluation and standardization before it can be used as a broad-based screening tool.

• Toxicological Research
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• 제29권1호
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• pp.21-25
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• 2013

The selective targeting of an integrin ${\alpha}_v{\beta}_3$ receptor using radioligands may enable the assessment of angiogenesis and integrin ${\alpha}_v{\beta}_3$ receptor status in tumors. The aim of this research was to label a peptidomimetic integrin ${\alpha}_v{\beta}_3$ antagonist (PIA) with $^{99m}Tc(CO)_3$ and to test its receptor targeting properties in nude mice bearing receptor-positive tumors. PIA was reacted with tris-succinimidyl aminotriacetate (TSAT) (20 mM) as a PIA per TSAT. The product, PIA-aminodiacetic acid (ADA), was radiolabeled with $[^{99m}Tc(CO)_3(H_2O)_3]^{+1}$, and purified sequentially on a Sep-Pak C-18 cartridge followed by a Sep-Pak QMA anion exchange cartridge. Using gradient C-18 reverse-phase HPLC, the radiochemical purity of $^{99m}Tc(CO)_3$-ADA-PIA (retention time, 10.5 min) was confirmed to be > 95%. Biodistribution analysis was performed in nude mice (n = 5 per time point) bearing receptor-positive M21 human melanoma xenografts. The mice were administered $^{99m}Tc(CO)_3$-ADA-PIA intravenously. The animals were euthanized at 0.33, 1, and 2 hr after injection for the biodistribution study. A separate group of mice were also co-injected with 200 ${\mu}g$ of PIA and euthanized at 1 hr to quantify tumor uptake. $^{99m}Tc(CO)_3$-ADA-PIA was stable in phosphate buffer for 21 hr, but at 3 and 6 hr, 7.9 and 11.5% of the radioactivity was lost as histidine, respectively. In tumor bearing mice, $^{99m}Tc(CO)_3$-ADA-PIA accumulated rapidly in a receptor-positive tumor with a peak uptake at 20 min, and rapid clearance from blood occurring primarily through the hepatobiliary system. At 20 min, the tumor-to-blood ratio was 1.8. At 1 hr, the tumor uptake was 0.47% injected dose (ID)/g, but decreased to 0.12% ID/g when co-injected with an excess amount of PIA, indicating that accumulation was receptor mediated. These results demonstrate successful $^{99m}TC$ labeling of a peptidomimetic integrin antagonist that accumulated in a tumor via receptor-specific binding. However, tumor uptake was very low because of low blood concentrations that likely resulted from rapid uptake of the agent into the hepatobiliary system. This study suggests that for $^{99m}Tc(CO)_3$-ADA-PIA to be useful as a tumor detection agent, it will be necessary to improve receptor binding affinity and increase the hydrophilicity of the product to minimize rapid hepatobiliary uptake.