• Archives of Pharmacal Research
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• 제21권4호
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• pp.370-373
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• 1998

Ten substituted phenacyl derivatives of 4-hydroxypiperidine were synthesized and studied for their effects on the mean arterial blood pressure (MABP) in normotensive anaesthetized rats and smooth muscles contractions of isolated rabbit jejunum. Two derivatives caused fall in blood pressure at the dose of 10-20 mg/kg and one rise in blood pressure at the dose of 20 mg/kg. Two compounds exhibited biphasic response (hypotensive followed by hypertensive) and one gave triphasic response at 10 mg/kg dose. Rest of four derivatives were found devoid of any effect on mean arterial blood pressure up to the dose of 30 mg/kg. All the derivatives except two caused relaxant effect on the spontaneous contraction of rabbit jejunum at the dose range of 0.1 -2 mg/kg.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.301-301
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• 1994

〔$^3$H〕Ouabain binding parameters(K$\_$D/ and B$\_$max/,) in homogenates prepared fpom control rat ventricular strip and Langendorff preparations which were not previously exposed to ouabain were compared to those in homogenates from ventricular strip and Langendorff preparations that had been first exposed to a complete ouabain dose-response curve(10$\^$-7/M to 10$\^$-4/ M). In rat ventricular strips and Langendorff perfused rat heart preparations, cumulative dose-response cruves of ouabain revealed biphasic positive inotropic effects, a "low-dose" and a "high-dose" effect with ED$\_$50/ values of 0.5${\mu}$M and 35${\mu}$M ouabain, respectively- The "low-dose" effect in rat ventricular strips disappeared or was diminished significantly when the ouabain dose-response curve wag repeated after the washout of the effects of the first curve, whereas the maximal "high-dose" effect was identical in both exposures to oubain. However, there was no change in the "low-dose" effects in both sets of the Langendorff perfused hearts. The contractile activity of the pre-exposed strips did not indicate the presence of residual ouabain since their basal contractile force was decreased 10% compared to initial control. 〔$^3$H〕Ouabain binding parameters, K$\_$D/ and B$\_$max/, were not changed comparing homogenate of control ventricular strips with that of strips pre-exposed to ouabain. These results suggest that digitalis receptor desensitization in the rat ventricular strip may due to the change of post-receptor events induced by ouabain binding to a high affinity site(${\alpha}$$_2$ isoform).

• Toxicological Research
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• 제20권2호
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• pp.89-100
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• 2004

The comet assay (also called the single-cell gel electrophoresis assay) has been widely used for detecting DNA damage and repair in individual cells. Since the conventional methods of evaluating comet assay data using frequency statistics are unsatisfactory we developed a new quantitative measure of DNA damage/repair that is based on all information residing in the dose/time-response curves of a comet experiment. Blood samples were taken from 25 breast cancer patients before undergoing radiotherapy. The comet assay was performed under alkaline conditions using isolated lymphocytes. Tail DNA, tail length, tail moment and tail inertia of the comet were measured for each patient at four doses of $\gamma$-rays (0, 2, 4 and 8 Gy) and at four time points after irradiation (0, 10, 20 and 30 min) using 100 cells each. The resulting three-dimensional dose-time response surface was modeled by multiple regression, and the second derivative, termed 2D, on dose and time was determined. A software module was programmed in SAS/AF to compute 2D values. We applied the new method successfully to data obtained from cancer patients to be assessed for their radiation sensitivity. We computed the 2D values for the four damage measures, i.e., tail moment, tail length, tail DNA and tail inertia, and examined the pairwise correlation coefficients of 2D both on the log scale and the unlogged scale. 2D values based on tail moment and tail DNA showed a high correlation and, therefore, these two damage measures can be used interchangeably as far as DNA repair is concerned. 2D values based on tail inertia have a correlation profile different from the other 2D values which may reflect different facets of DNA damage/repair. Using the dose-time response surface, other statistical models, e.g., the proportional hazards model, become applicable for data analysis. The 2D approach can be applied to all DNA repair measures, Le., tail moment, tail length, tail DNA and tail inertia, and appears to be superior to conventional evaluation methods as it integrates all data of the dose/time-response curves of a comet assay.

• Nuclear Engineering and Technology
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• 제38권3호
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• pp.285-292
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• 2006

Thermoresistant (TR) clones of radiation-induced fibrosarcoma (RIF) cells have been reported to show an adaptive response to 1cGy of low dose radiation, and HSP25 and inducible HSP70 are involved in this process. In this study, to further elucidate the mechanism by which HSP25 and inducible HSP70 regulate the adaptive response, HSP25 or inducible HSP70 overexpressed RIF cells were irradiated with 1cGy and the cell cycle was analyzed. HSP25 or inducible HSP70 overexpressed cells together with TR cells showed increased G1 phase after 1cGy irradiation, while RIF cells did not. $[^3H]-Thymidine$ and BrdU incorporation also indicated that both HSP25 and inducible HSP70 are involved in G1 arrest after 1cGy irradiation. Molecular analysis revealed upregulation of p27Cip/Kip protein in HSP25 and inducible HSP70 overexpressed cells, and cotransfection of p27Cip/Kip antisense abolished the induction of the adaptive response and 1cGy-mediated G1 arrest. The above results indicate that induction of an adaptive response by HSP25 and inducible HSP70 is mediated by upregulation of p27Cip/Kip protein, resulting in low dose radiation-induced G1 arrest.

• Radiation Oncology Journal
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• 제15권1호
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• pp.65-69
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• 1997

목적 : 전리함의 크기로 인한 공간 분해능의 문제로 나타나는 전리함 반응함수를 제거하여 실제 선량분포를 얻고자 하였다. 대상 및 방법 : 내경 5mm, 6.4mm 등 2개의 서로 다른 크기를 갖는 전리함들과 다이오드, 필름의 반응함수를 구하고, 동일한 방사선 조사면$(10\times20cm^2)$의 선량분포 프로파일을 측정하여, 각각 deconvolution 기법으로 보정한 후, 보절된 격과가 일치하는지 비교하였다. 결과 : 원통형 전리함의 반응함수와 선량분포를 측정하였고, 측정한 선량분포에서 반응 함수의 효과를 deconvolution방법으로 제거하여 실제 선량분포를 찾아내었다. 사용한 에너지는 최대 광자선 에너지 4MV, 6MV, 15MV였으며, 전 에너지 영역에 걸쳐 보정 된 결과가 일치하는 방향으로 변화하였으며, 분해능 증가 효과가 있었다. 결론 : deconvolution 방법으로 전리함 반응 함수의 효과를 제거했을 때, 여러 측정기를 이용하여 측정한 선량 프로파일의 결과가 일치하는 경향을 볼 수 있어서 deconvolution 방법을 통해 얻은 선량 프로파일을 임상적으로 응용할 수 있음을 알았다.

• 한국식품위생안전성학회지
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• 제15권3호
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• pp.267-270
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• 2000

본 연구에서는 유해한 화학물질인 vinyl chloride에 대한 건강 위해성 평가의 주요한 단계인 용량-반응 평가(dose-response assessment)를 수행함에 있어서 실험동물을 대상으로 한 발암성 자료를 사용하여 인체 위해도(risk)를 예측하고자 하였다. 용량 반응 평가에서는 고농도의 독성 자료로 부터 인체에 노출되는 수준인 저농도로 외삽을 위하여 computer software를 사용하지 않고 직접 다양한 통계 모델링을 사용하여 위해도를 산출하였다 이는 추후 국내 화학물질의 위해도 평가시 광범위하게 활용될수 있는 기초자료를 제공할 것이다.

• 한국식품위생안전성학회지
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• 제14권4호
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• pp.319-326
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• 1999

최근 국내에서는 Escherichia coli O157:H7, Listeria monocytogenes등의 미생물에 대한 건강위해성이 강조되면서 미생물 위해성평가에 대한 필요성이 제기되고 있고, U.S.FPA, U.S.DA, FAO/WHO를 비롯한 국제기구 및 외국 유관기관들에서도 미생물 위해성평가 방법을 식품관리에 활용하고자 방법론 연구에 주력하고 있다. 미생물 위험성은 화학물질과 달리 인체건강에 대한 영향이 즉각적이고, 심각하게 나타나 정량적인 위해성평가가 용이하지 않고 유해화학물질과는 다른 평가방법이 요구된다. 식품중 미생물의 위해성평가는 크게 4단계로 구분되는데, 미생물관련질환 추세파악 및 미생물 관련질병에 관한 역학조사 등을 활용하는 위험성확인 단계와 실제 식품원료, 식품가공, 수송, 포장단계 중 식품의 물리적, 화학적 조건에 따른 미생물 변화를 고려하여 식품중 미생물에 대한 노출을 정량화하는 노출평가 단계, 미생물의 용량에 따른 질병발생에 근거하여 용량-반응관계를 규명하는 용량-반응평가 단계, 규명된 모델을 활용하여 모든 평가결과를 통합함으로 위해 도치 예측과 불확실성 분석 등을 수행하는 위해도결정단계로 구성되어 있다. 미생물 용량-반응평가는 크게 비역치(Nonthreshold)와 역치(Threshold) 평가 방법론으로 구분되는데, 비역치 평가방법론은 단일 병원균이 감염을 일으킬 수 있다는 것과 감염을 일으킬 수 있는 확률이 독립적이라는 가정을 전제로 하고, 역치평가방법론은 미생물이 감염을 일으키기 위해서 각기 개별 역치가 존재하는데 어느 정도의 미생물수가 모여 서로 작용해야 독성유발물질을 만들어 낸다는 가정을 전제로 한다. 현재 받아들여지고 있는 비역치 모델로는 Exponential, Beta-poisson, Gompertz, Gamma-weibull 모델 등이 있으며, 역치모델로는 Log-normal, Log-logistic모델 등이 있다. 본 연구에서는 인체 volunteer자료를 활용하여 용량-반응자료를 입력하고 용량-반응자료를 토대로 적합한 수학적 모델을 찾아내어, 선별한 모델의 적합도 검정을 실시하는 방법론 연구를 실시하였으며, 노출평가 자료와 용량-반응평가 결과를 연계하여 위해도를 결정하는 과정에 대해 연구하였다 이 밖에도 모델(Food MicroModel)을 이용하여 식품의 염도, 수분활성도, 온도, pH등의 조건에 따른 미생물의 성장률, 사멸률 등 변화를 예측할 수 있는 방법론 연구를 통해 식품의 최적 보관 조건등을 찾아내는 방법을 습득하였다. 미생물 위해성평가는 외국에서도 아직 초기 연구단계에 있으며 현재로서 사후조사자료인 역학자료보다 건강한 성인남자를 대상으로 한 volunteer 자료를 우선적으로 활용하고 있으나 노약자나 민감그룹에 대한 실험은 현실적으로 불가능하여 동물실험을 이용한 평가방법을 연구중에 있다. 추후 연구방향으로는 국내 volunteer들을 대상으로 한 미생물별 용량-반응결과를 토대로 population sensitivity를 비교할 수 있는 기초자료를 확보함으로써 미생물에 대한 인구집단의 반응 민감성 차이를 비교하고 시료채취 후 즉각적인 실험실적 분석이 가능토록하여 정확한 인체노출평가를 수행함으로써 미생물 위해성평가방법론을 식품미생물관리에 적용하는 것이다.

• Toxicological Research
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• 제6권2호
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• pp.205-213
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• 1990

The regulation of neurotoxicants has usually been based upon setting reference doses by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that theoretically account for interspecies and intraspecies extraploation of experimental results in animals to humans. Recently, we have proposed a four-step alternative procedure which provides quantitative estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect or biomarker and the dose of chemical administered. The second step is to determine the distribution (variability) of individual measurements of biological effects or their biomarkers about the dose response curve. The third step is to define an adverse or abnormal level of a biological effect or biomarker in an untreated population. The fourth and final step is to combine the information from the first three steps to estimate the risk (proportion of individuals exceeding on adverse or abnormal level of a biological effect or biomarker) as a function of dose. The primary purpose of this report is to enhance the certainty of the first step of this procedure by improving our understanding of the relationship between a biomarker and dose of administered chemical. Several factors which need to be considered include: 1) the pharmacokinetics of the parent chemical, 2) the target tissue concentrations of the parent chemical or its bioactivated proximate toxicant, 3) the uptake kinetics of the parent chemical or metabolite into the target cell(s) and/or membrane interactions, and 4) the interaction of the chemical or metabolite with presumed receptor site(s). Because these theoretical factors each contain a saturable step due to definitive amounts of required enzyme, reuptake or receptor site(s), a nonlinear, saturable dose-response curve would be predicted. In order to exemplify this process, effects of the neurotoxicant, methlenedioxymethamphetamine (MDMA), were reviewed and analyzed. Our results and those of others indicate that: 1) peak concentrations of MDMA and metabolites are ochieved in rat brain by 30 min and are negligible by 24 hr, 2) a metabolite of MDMA is probably responsible for its neurotoxic effects, and 3) pretreatment with monoamine uptake blockers prevents MDMA neurotoxicity. When data generated from rats administerde MDMA were plotted as bilolgical effect (decreases in hippocampal serotonin concentrations) versus dose, a saturation curve best described the observed relationship. These results support the hypothesis that at least one saturable step is involved in MDMA neurotoxicity. We conclude that the mathematical relationship between biological effect and dose of MDMA, the first step of our quantitative neurotoxicity risk assessment procedure, should reflect this biological model information generated from the whole of the dose-response curve.

• 한국육종학회지
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• 제40권1호
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• pp.15-21
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• 2008

It was previously pointed out that mutation is the ultimate source of variation. Adequate variation is needed for plant breeding if there is a limitation in natural genetic resources. When the ionizing radiation has been known to cause chromosomal and genomic alternations, it is widely used for inducing mutagenesis. The electron beam as an ionizing radiation is the principal physical mutagens that induces mutation and effectively used in plant breeding. Since dose-response relationships of electron beam in plant species are rarely known, we investigated the seed germination rate and early seedling growth of irradiated seeds of creeping bentgrass (Agrostis palustris Huds., cv Penn-A1) with various electron beam irradiating conditions (1, 1.3, 2 MeV at both 0.03 mA and 0.06 mA with dose of 100 Gy (Gray) and 0.03, 1, 1.3, 2 MeV at 0.03 mA with dose of 200 Gy, respectively) using electron accelerator at Korea Atomic Energy Research Institute. The growth parameters in terms of shoot length, primary root length, and secondary root length showed similar response between 0.06 / 1 (mA / MeV) at 100 Gy and 0.03 / 0.3 (mA / MeV) at 200 Gy. Bentgrass seed germination was mainly affected by the intensity of irradiated dose (Gray). Germination rate was lowered as the irradiated dose increased. On the other hand, early seedling growth was mainly governed not by the dose of radiation but by voltage.

• Nuclear Engineering and Technology
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• 제55권6호
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• pp.1949-1958
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• 2023

The International Commission on Radiological Protection (ICRP) Publication 116 was released to provide a comprehensive dataset of the dose coefficients (DCs) for external exposures produced with the adult reference voxel phantoms of ICRP Publication 110. Although an advanced skeletal dosimetry method for photons and neutrons using fluence-to-dose response functions (DRFs) was introduced in ICRP Publication 116, the ICRP-116 skeletal DCs were calculated by using the simple method conventionally used (i.e., doses to red bone marrow and endosteum approximated by doses to spongiosa and/or medullary cavities). In the present study, the photon and neutron DRFs were used to produce skeletal DCs of the ICRP-110 reference phantoms, which were then compared with the ICRP-116 DCs. For photons, there were significant differences by up to ~2.8 times especially at energies <0.3 MeV. For neutrons, the differences were generally small over the entire energy region (mostly <20%). The general impact of the DRF-based skeletal DCs on the effective dose calculations was negligibly small, supporting the validity of the ICRP-116 effective DCs despite their skeletal DCs derived from the simple method. Meanwhile, we believe that the DRF-based skeletal DCs could be beneficial in better estimates of skeletal doses of individuals for risk assessments.