4-Week repeated oral dose toxicity study of 1,4-dichlorobutane in rats / 한국실험동물학회지

The present study investigated the potential subacute toxicity of 1,4-dichlorobutane by a 4-week repeated oral dose in Sprague-Dawley rats. The test article was administered once daily by gavage to male rats at dose levels of 0, 100, 300, and 1,000 mg/kg/day for 4 weeks. All rats were sacrificed at the end of the treatment period. During the test period, clinical signs, mortality, body weight, hematology, serum biochemistry, gross findings, and organ weight were examined. At 1,000 mg/kg/day, an increase in the clinical signs and weights of the liver and kidneys was observed in the male rats. Serum biochemical investigations revealed an increase in alanine aminotransferase, alkaline phosphatase, total cholesterol, total bilirubin, phospholipids, blood urea nitrogen, and gamma glutamyl transferase levels. There were no treatment-related adverse effects in the low and middle-dose groups. In the present experimental conditions, the target organs were determined to be liver and kidney. The no-observed-adverse-effect level was considered to be 300 mg/kg/day in rats.

Hepatotoxicity in Rats Treated with Dimethylformamide or Toluene or Both

The effects of toluene in dimethylformamide (DMF)-induced hepatotoxicity were investigated with respect to the induction of cytochrome P-450 (CYP) and the activities of related enzymes. The rats were treated intraperitoneally with the organic solvents in olive oil (Single treatment groups: 450 [D1], 900 [D2], 1,800 [D3] mg DMF, and 346 mg toluene [T] per kg of body weight; Combined treatment groups: D1+T, D2+T, and D3+T) once a day for three days, while the control group received just the olive oil. Each group consisted of 4 rats. The activities of the xenobiotic metabolic enzymes and the hepatic morphology were assessed. The immunoblots indicated that the expression of CYP2E1 was considerably enhanced depending on the dosage of DMF and the CYP2E1 blot densities were significantly increased after treatment with both DMF and toluene, compared to treatment with DMF alone. The activities of glutathione-S-transferase and glutathione peroxidase were either decreased or remained unaltered after treatment with DMF and toluene, whereas the lipid peroxide levels were increased with increasing dosage of DMF and toluene. The liver tissue in the D3 group (1,800 mg/kg of DMF) showed signs of microvacuolation in the central vein region and a large necrotic zone around the central vein, in rats treated with both DMF (1,800 mg/kg) and toluene (D3T). These results suggest that the expression of CYP2E1 is induced by DMF and enhanced by toluene. These changes may have facilitated the accelerated formation of N-methylformamide (NMF) from toluene, and the generated NMF may directly induce liver damage.

Subchronic Inhalation Toxicity Study of n-pentane in Rats

OBJECTIVES: This study was conducted in order to obtain information concerning the health hazards that may result from a 13 week inhalation exposure of n-pentane in Sprague-Dawley rats. METHODS: This study was conducted in accordance with the Organization for Economic Co-operation and Development (OECD) guidelines for the testing of chemicals No. 413 'Subchronic inhalation toxicity: 90-day study (as revised in 2009)'. The rats were divided into 4 groups (10 male and 10 female rats in each group), and were exposed to 0, 340, 1,530, and 6,885 ppm n-pentane in each exposure chamber for 6 hour/day, 5 days/week, for 13 weeks. All of the rats were sacrificed at the end of the treatment period. During the test period, clinical signs, mortality, body weights, food consumption, ophthalmoscopy, locomotion activity, urinalysis, hematology, serum biochemistry, gross findings, organ weights, and histopathology were assessed. RESULTS: During the period of testing, there were no treatment related effects on the clinical findings, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, relative organ weight, and histopathological findings. CONCLUSION: The no-observable-adverse-effect level (NOAEL) of n-pentane is evaluated as being more than 6,885 ppm (20.3 mg/L) in both male and female rats. n-pentane was not a classified specific target organ toxicity in the globally harmonized classification system (GHS).

The Effects of Hazardous Chemical Exposure on Cardiovascular Disease in Chemical Products Manufacturing Workers

The purpose of this study was to understand the mechanism of cardiovascular disease (CVD) caused by exposure to hazardous chemicals. We investigated changes in the symptoms of metabolic syndrome, which is strongly related to CVD, and in levels of other CVD risk factors, with a special emphasis on the roles of catecholamines and oxidative stress. The results revealed that neither body mass index (BMI) nor waist and hip circumferences were associated with exposure to hazardous chemicals. Among metabolic syndrome criteria, only HDL-cholesterol level increased on exposure to hazardous chemicals. Levels of epinephrine (EP) and norepinephrine (NEP) were not influenced by exposure to hazardous chemicals; however, the total antioxidative capacity (TAC) reduced because of increased oxidative stress. Both hazardous chemical exposure level and metabolite excretion were related to EP, NEP, and the oxidative stress index (OSI). Logistic regression analysis with these factors as independent variables and metabolic syndrome criteria as dependent variables revealed that EP was associated with blood pressure, and NEP with metabolic syndrome in the chemical-exposed group. In conclusion, the results suggest that reactive oxygen species generated and oxidative stress due to exposure to hazardous chemicals act as mediators and cause changes in the physiological levels of EP and NEP to increase blood pressure. This ultimately leads to the development of CVD through increase in cholesterol, triglyceride, and blood glucose levels by lipid peroxidation.

Estimation of Internal Motion for Quantitative Improvement of Lung Tumor in Small Animal / 의학물리

The purpose of this study was to estimate internal motion using molecular sieve for quantitative improvement of lung tumor and to localize lung tumor in the small animal PET image by evaluated data. Internal motion has been demonstrated in small animal lung region by molecular sieve contained radioactive substance. Molecular sieve for internal lung motion target was contained approximately 37 kBq Cu-64. The small animal PET images were obtained from Siemens Inveon scanner using external trigger system (BioVet). SD-Rat PET images were obtained at 60 min post injection of FDG 37 MBq/0.2 mL via tail vein for 20 min. Each line of response in the list-mode data was converted to sinogram gated frames (2~16 bin) by trigger signal obtained from BioVet. The sinogram data was reconstructed using OSEM 2D with 4 iterations. PET images were evaluated with count, SNR, FWHM from ROI drawn in the target region for quantitative tumor analysis. The size of molecular sieve motion target was 1.59x2.50 mm. The reference motion target FWHM of vertical and horizontal was 2.91 mm and 1.43 mm, respectively. The vertical FWHM of static, 4 bin and 8 bin was 3.90 mm, 3.74 mm, and 3.16 mm, respectively. The horizontal FWHM of static, 4 bin and 8 bin was 2.21 mm, 2.06 mm, and 1.60 mm, respectively. Count of static, 4 bin, 8 bin, 12 bin and 16 bin was 4.10, 4.83, 5.59, 5.38, and 5.31, respectively. The SNR of static, 4 bin, 8 bin, 12 bin and 16 bin was 4.18, 4.05, 4.22, 3.89, and 3.58, respectively. The FWHM were improved in accordance with gate number increase. The count and SNR were not proportionately improve with gate number, but shown the highest value in specific bin number. We measured the optimal gate number what minimize the SNR loss and gain improved count when imaging lung tumor in small animal. The internal motion estimation provide localized tumor image and will be a useful method for organ motion prediction modeling without external motion monitoring system.

Effect of Nano-sized Carbon Black Particles on Lung and Circulatory System by Inhalation Exposure in Rats

OBJECTIVES: We sought to establish a novel method to generate nano-sized carbon black particles (nano-CBPs) with an average size smaller than 100 nm for examining the inhalation exposure risks of experimental rats. We also tested the effect of nano-CBPs on the pulmonary and circulatory systems. METHODS: We used chemical vapor deposition (CVD) without the addition of any additives to generate nano-CBPs with a particle size (electrical mobility diameter) of less than 100nm to examine the effects of inhalation exposure. Nano-CBPs were applied to a nose-only inhalation chamber system for studying the inhalation toxicity in rats. The effect on the lungs and circulatory system was determined according to the degree of inflammation as quantified by bronchoalveolar lavage fluid (BALF). The functional alteration of the hemostatic and vasomotor activities was measured by plasma coagulation, platelet activity, contraction and relaxation of blood vessels. RESULTS: Nano-CBPs were generated in the range of 83.3-87.9 nm. Rats were exposed for 4 hour/day, 5 days/week for 4 weeks to 4.2 x 10(6), 6.2 x 10(5), and 1.3 x 10(5) particles/cm3. Exposure of nano-CBPs by inhalation resulted in minimal pulmonary inflammation and did not appear to damage the lung tissue. In addition, there was no significant effect on blood functions, such as plasma coagulation and platelet aggregation, or on vasomotor function. CONCLUSION: We successfully generated nano-CBPs in the range of 83.3-87.9 nm at a maximum concentration of 4.2 x 10(6) particles/cm3 in a nose-only inhalation chamber system. This reliable method can be useful to investigate the biological and toxicological effects of inhalation exposure to nano-CBPs on experimental rats.

A Study of Micronucleus Induction with Methyl Formate and 2-Methylbutane in Bone Marrow Cells of Male ICR Mice

OBJECTIVES: We investigated the genotoxicity of two chemicals, methyl formate and 2-methylbutane, using male ICR mice bone marrow cells for the screening of micronucleus induction. Although these two chemicals have already been tested numerous times, a micronucleus test has not been conducted and the amounts used have recently been increased. METHODS: 7 week male ICR mice were tested at dosages of 250, 500, and 1,000 mg/kg for methyl formate and 500, 1,000, and 2,000 mg/kg for 2-methlybutane, respectively. After 24 hours of oral administration with the two chemicals, the mice were sacrificed and their bone marrow cells were prepared for smearing slides. RESULTS: As a result of counting the micronucleated polychromatic erythrocyte (MNPCE) of 2,000 polychromatic erythrocytes, all treated groups expressed no statistically significant increase of MNPCE compared to the negative control group. There were no clinical signs related with the oral exposure of these two chemicals. CONCLUSION: It was concluded that the two chemicals did not induce micronucleus in the bone marrow cells of ICR mice, and there was no direct proportion with dosage. These results indicate that the two chemicals have no mutagenic potential under each study condition.

Development of a High Resolution SPECT Detector with Depth-encoding Capability for Multi-energy Imaging: Monte Carlo Simulation / 의학물리

The aim of this work was to establish the methodology for event positioning by measuring depth of interaction (DOI) information and to evaluate the system sensitivity and spatial resolution of the new detector for I-125 and Tc-99m imaging. For this purpose, a Monte Carlo simulation tool, DETECT2000 and GATE were used to model the energy deposition and light distribution in the detector and to validate this approach. Our proposed detector module consists of a monolithic CsI(Tl) crystal with dimensions of 50.0x50.0x3.0 mm3. The results of simulation demonstrated that the resolution is less than 1.5 mm for both I-125 and Tc-99m. The main advantage of the proposed detector module is that by using 3 mm thick CsI(Tl) with maximum-likelihood position-estimation (MLPE) method, high resolution I-125 imaging and high sensitivity Tc-99m imaging are possible. In this paper, we proved that our new detector to be a reliable design as a detector for a multi-energy SPECT.

Coded Aperture Gamma Camera for Thyroid Imaging: Monte Carlo Simulation / 의학물리

A coded aperture camera has been developed to improve the signal-to-noise ratio (SNR) while keeping the spatial resolution of a pinhole gamma camera. The purpose of this study was to optimize a coded aperture camera and to evaluate its possibility for thyroid imaging by Monte Carlo simulation. A clinical gamma camera, a pinhole collimator with 1.0 mm hole diameter, and a 79x79 modified uniformly redundant array (MURA) mask were designed using GATE (Geant4 Application for Tomographic Emission). The penetration ratio, spatial resolution, integral uniformity and signal-to-noise ratio (SNR) were simulated and evaluated as a function of the mask thickness. The spatial resolution of the coded aperture camera was consistent with the various mask thickness, SNR showed a maximum value at 1.2 mm mask thickness and integral uniformity was improved by increasing mask thickness. Compare to the pinhole gamma camera, the coded aperture camera showed improved SNR by a factor of 30 while keeping almost the same spatial resolution. In this simulation study, the results indicated that high spatial resolution and ultra-high SNR of the thyroid imaging are feasible using a coded aperture camera.

Optimization of Parallel-Hole Collimator for Small Gamma Camera Based on Pixellated Crystal Array / 의학물리

The purpose of this study is to optimize a parallel-hole collimator for small gamma camera having the pixellated crystal array and evaluate the effect of crystal-collimator misalignment on the image quality using a simulation tool GATE (Geant4 Application for Tomographic Emission). The spatial resolution and sensitivity were measured for the various size of hexagonal-hole and matched square-hole collimators with a Tc-99m point source and the uniformity of flood image was estimated as a function of the angle between crystal array and collimator by misalignment. The results showed that the spatial resolution and sensitivity were greatly improved by using the matched collimator and the uniformity was reduced by crystal-collimator misalignment.

Monte Carlo Simulation Codes for Nuclear Medicine Imaging / 핵의학분자영상

Monte Carlo simulation methods are especially useful in studying a variety of problems difficult to calculate by experimental or analytical approaches. Nowadays, they are extensively applied to simulate nuclear medicine instrumentations such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) for assisting system design and optimizing imaging and processing protocols. The goal of this paper is to address the practical issues, a potential user of Monte Carlo simulations for nuclear medicine can encounter, to help them to choose a code. This review introduces the different types of Monte Carlo codes currently available for nuclear medicine, comments main features and properties for a code to be proper for a given purpose, and discusses current research trends in Monte Carlo codes.

A Computer Simulation for Small Animal Iodine-125 SPECT Development / 대한핵의학회잡지

PURPOSE: Since I-125 emits low energy (27-35 keV) radiation, thinner crystal and collimator could be employed and, hence, it is favorable to obtain high quality images. The purpose of this study was to derive the optimized parameters of I-125 SPECT using a new simulation tool, GATE (Geant4 Application for Tomographic Emission). MATERIALS AND METHODS: To validate the simulation method, gamma camera developed by Weisenberger et al. was modeled. NaI (Tl) plate crystal was used and its thickness was determined by calculating detection efficiency. Spatial resolution and sensitivity curves were estimated by changing variable parameters for parallel-hole and pinhole collimator. Performances of I-125 SPECT equipped with the optimal collimator were also estimated. RESULTS: In the validation study, simulations were found to agree well with experimental measurements in spatial resolution (4%) and sensitivity (3%). In order to acquire 98% gamma ray detection efficiency, NaI (Tl) thickness was determined to be 1 mm. Hole diameter (mm), length (mm) and shape were chosen to be 0.2: 5: square and 0.5: 10: hexagonal for high resolution (HR) and general purpose (GP) parallel-hole collimator, respectively. Hole diameter, channel height and acceptance angle of pinhole (PH) collimator were determined to be 0.25 mm, 0.1 mm and 90 degree. The spatial resolutions of reconstructed image of the I-125 SPECT employing HR: GP: PH were 1.2: 1.7: 0.8 mm. The sensitivities of HR: GP: PH were 39.7: 71.9: 5.5 cps/MBq. CONCLUSION: The optimal crystal and collimator parameters for I-125 imaging were derived by simulation using GATE. The results indicate that excellent resolution and sensitivity imaging is feasible using I-125 SPECT.

Development of a Small Animal Positron Emission Tomography Using Dual-Layer Phoswich Detector and Position Sensitive Photomultiplier Tube: Preliminary Results / 대한핵의학회잡지

PURPOSE: The purpose of this study was to develop a small animal PET using dual layer phoswich detector to minimize parallax error that degrades spatial resolution at the outer part of field-of-view (FOV). MATERIALS AND METHODS: A simulation tool GATE (Geant4 Application for Tomographic Emission) was used to derive optimal parameters of small PET, and PET was developed employing the parameters. Lutetium Oxyorthosilicate (LSO) and Lutetium-Yttrium Aluminate-Perovskite (LuYAP) was used to construct dual layer phoswitch crystal. 8 X 8 arrays of LSO and LuYAP pixels, 2 mm X 2 mm X 8 mm in size, were coupled to a 64-channel position sensitive photomultiplier tube. The system consisted of 16 detector modules arranged to one ring configuration (ring inner diameter 10 cm, FOV of 8 cm). The data from phoswich detector modules were fed into an ADC board in the data acquisition and preprocessing PC via sockets, decoder block, FPGA board, and bus board. These were linked to the master PC that stored the events data on hard disk. RESULTS: In a preliminary test of the system, reconstructed images were obtained by using a pair of detectors and sensitivity and spatial resolution were measured. Spatial resolution was 2.3 mm FWHM and sensitivity was 10.9 cps/micro Ci at the center of FOV. CONCLUSION: The radioactivity distribution patterns were accurately represented in sinograms and images obtained by PET with a pair of detectors. These preliminary results indicate that it is promising to develop a high performance small animal PET.

Nuclear Medicine Imaging Instrumentations for Molecular Imaging / 대한핵의학회잡지

Small animal models are extensively utilized in the study of biomedical sciences. Current animal experiments and analysis are largely restricted to in vitro measurements and need to sacrifice animals to perform tissue or molecular analysis. This prevents researchers from observing in vivo the natural evolution of the process under study. Imaging techniques can provide repeatedly in vivo anatomic and molecular information noninvasively. Small animal imaging systems have been developed to assess biological process in experimental animals and increasingly employed in the field of molecular imaging studies. This review outlines the current developments in nuclear medicine imaging instrumentations including fused multi-modality imaging systems for small animal imaging.