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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
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Journal DOI :
The Korean Society of Toxicology
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Volume & Issues
Volume 17, Issue 4 - Dec 2001
Volume 17, Issue 3 - Oct 2001
Volume 17 - Jul 2001
Volume 17, Issue 2 - Jun 2001
Volume 17, Issue 1 - Mar 2001
Selecting the target year
Genotoxicity in B6C3F1 Mice Following 0.5 ppm Ozone Inhalation
Kim, Min-Young ; Son, Jang-Won ; Cho, Myung-Haing ;
Toxicological Research, volume 17, issue 1, 2001, Pages 1~6
To determine whether ozone is genotoxic at environmentally relevant exposure level, B6C3F1 mice were exposed to 0.5 ppm ozone for 12 weeks, 6 hr/day. Chromosomal aberration, supravital micronucleus and hprt mutation assays were performed. The percentage of abnormal cells was significantly increased at 0.5 ppm ozone when compared to unexposed control in chromosome aberration assay. Significant increase in the frequencies of micro nucleated reticulocytes and 6-thioguanine-resistant (
) lymphocytes was also observed in supravital micronucleus assay using peripheral blood and lymphocyte hprt mutation assay, respectively. The results indicate, that under our experimental conditions, 0.5 ppm ozone are genotoxic in exposed B6C3F1 mice.
Gap Junctional Intercellular Communication: A "Biological Rosetta Stone" Concept for Understanding Epigenetic Toxicology
Trosko, James E. ;
Toxicological Research, volume 17, 2001, Pages 1~9
Some would argue that the search for the origin and treatment of this disease will continue over the next quarter century in much the same manner as it has in the recent past, by adding further layers of complexity to a scientific literature that is already complex almost beyond measure. But we anticipate otherwise: those researching the cancer problem will be practicing a dramatically different type of science than we have experienced over the past 25 years. Surely much of this change will be apparent at the technical level. But ultimately, the more fundamental change will be conceptual.
Non-polar Solvents (Toluene and Styrene) Enhance Methanol Skin Absorption
Lim, Cheol-Hong ; Yu, Il-Je ;
Toxicological Research, volume 17, issue 1, 2001, Pages 7~9
The quantitative assessment of the penetration of organic solvents through skin is necessary for the evaluation of health hazards in occupational environments. We investigated the rate of dermal penetration when mixed or single forms of organic solvents were placed into a diffusion cell in vitro or into an experimental animal in vivo. The diffusion rates of methanol. toluene, and styrene were 6.07, 0.129, and 0.046 mg/
/h, respectively. When skin was exposed to the mixed solvent of methanol and toluene, the penetration rate of toluene did not change significantly (0.110 mg/
/h). However, the rate of methanol penetration increased to 43.90 mg/
/h. The penetration rate of methanol also increased significantly to 54.69 mg/
/h by mixing it with styrene. The concentration of methanol in the blood was monitored during the epicutaneous exposure in rats. The blood concentration of methanol was increased by mixing methanol with toluene as seen in the in vitro experiments. These results showed that the penetration rate of organic solvents would be enhanced by mixing them with other solvents.
The Effect of Repeated Application of A Mouthwash to the Mucosa of the Hamster Cheek Pouch
Toxicological Research, volume 17, issue 1, 2001, Pages 11~15
This study was carried out to evaluate the irritant potential of A mouthwash in hamster cheek pouch. The test substances were applied twice daily to right pouches of hamsters for 14 consecutive days. Animals were administered with A mouthwash, Listerine, saline and control solution, respectively. In order to evaluate the irritant potential in mucosa of hamster cheek pouch, we observed clinical signs, mortality, body weight changes and gross and histopathological findings for 14 days. In all groups, there were neither dead animals nor significant changes of body weights. In addition, there were no differences between saline and A mouthwash treated group in gross and histopathological findings. Therefore, these results suggest that there was no irritant potential of A mouthwash in hamster cheek pouch.
Developmental Anomalies of Central Nervous System in Human
Chi, Je G. ;
Toxicological Research, volume 17, 2001, Pages 11~16
The development of the central nervous system is a continuous process during the embryonic and fetal periods. For a better understanding of congenital anomalies of central nervous system, three major events of normal development, i.e., neurulation (3 to 4 weeks), brain vesicle formation (4 to 7 weeks) and mantle formation (over 8 weeks) should be kept in mind. The first category of anomalies is neural tube defect. Neural tube defects encompass all the anomalies arise in completion of neurulation. The second category of central nervous system anomalies is disorders of brain vesicle formation. This is anomaly that applies for "the face predicts the brain". Holoprosencephaly covers a spectrum of anomalies of intracranial and midfacial development which result from incomplete development and septation of midline structures within the forebrain or prosencephalon. The last category of central nervous system malformation is disorders involving the process of mantle formation. In the human, neurons are generated in two bursts, the first from 8 to 10 weeks and next from 12 to 14 weeks. By 16 weeks, most of the neurons have been generated and have started their migration into the cortex. Mechanism of migration disorders are multifactorial. Abnormal migration into the cortex, abnormal neurons, faulty neural growth within the cortex, unstable pial-glial border, degeneration of neurons, neural death by exogenous factors are some of the proposed mechanism. Agyria-pachygyria are characterized by a four-layerd cortex. Polymicrogyria is gyri that are too numerous and too small, and is morphologically heterogeneous. Cortical dysplasia is characterized by the presence Q[ abnormal neurons and glia arranged abnormally in focal areas of the cerebral cortex. Neuroglial malformative lesions associated with medically intractable epilepsy are hamartia or hamartoma, focal cortical dysplasia and microdysgenesis.ysgenesis.
Evaluation of Peri- and Postnatal Toxicity of Gamma-Irradiated Korean Ginseng in Rats
Toxicological Research, volume 17, issue 1, 2001, Pages 17~25
Korean ginseng products have been fumigated with ethylene oxide (EO) for sterilization and prolongation of storage periods. However, there had been controversies indicating that consumption of EO treated foods might cause harmful effects in human. In Korea, the use EO gas for sterilization of food was banned in 1991. Since then, irradiation technique has been developed as an alternative. This study was carried out to evaluate the safety of irradiated ginseng on peri- and postnatal developmental toxicity in rats. Either EO gas fumigated or gamma-irradiated ginseng was administered to pregnant Wistar rats by oral gavage from gestational day 16 to postnatal day 21. The amount of irradiation used in this study was 5, 10 and 30 kGy, respectively. There were no treatment related changes of dams in deaths, clinical signs, and parturition. No treatment related changes in food consumption, body/organ weight and lactation of dams were observed. Also, no F1 fetuses in external abnormality, physical development, reflex/sensory junctions and behavioral development were found. The results of this study showed that gamma-irradiated ginseng, up to 30 kGy, has no adverse effects on the peri- and postnatal development of rats.
Regulatory Aspect of Risk Assessment and Management
Lee, Hyomin ; EunkyungYoon ; Jeeyeun Han ;
Toxicological Research, volume 17, 2001, Pages 17~24
Risk assessment is useful tool making good decisions on the risks of certain hazardous com-pound and suggests safe margin through scientific process using toxicological data, statistical tool, exposure value and relevant variants. The goal of risk management is to protect the public health from hazardous compound based on result of risk assessment having reality. For the suggestion of exact man-aging information, risk assessment must be designed to represent a "plausible estimate" of the exposure to the individuals and to minimize uncertainty. Risk assessment methodology and knowledge are expected to change more rapidly than before and up-to-date methodology should be applied in regulatory aspects through the Agency. For the useful application of risk assessment, the communication between the risk assessor and the risk manager is needed before the initiation of the risk assessment and upon its completion. Generally, the risk assessment itself as a practical tool in the regulatory decision making process would be regarded with social economic impact.ic impact.
Risk Assessment of Dioxin in Japan
Kurokawa, Yuji ;
Toxicological Research, volume 17, 2001, Pages 25~35
In 1990, Tolerable Daily Intake (TDI) of 10 pg TCDD/kg/day for dioxins based on carcinogenicity and reproductive toxicity was determined by WHO/EURO, that resulted in the establishment of TDIs in other countries. In Japan, Ministry of Health and Welfare and Environment Agency, respectively established the TDI of 10 pg TCDD/kg/day and Health Risk Assessment Index of 5 pg TCDD/kg/day in 1996. Accumulation of new scientific data, especially by molecular toxicology since 1990, resulted in the reevaluation of TDI by WHO-ECEH and IPCS in May, 1998. At this meeting, it was stressed that \circled1 toxic effects of dioxin is mediated through Ah-receptor in both animals and humans, \circled2 use of ebody burdeni concept is better than the use of traditional NOAEL/UF approach, \circled3 inclusion of coplanar PCBs in the TDI by the use of new WHO-TEF. LOAELs (0.16~200 ng TCDD/kg/day) obtained from reproductive toxicity and immunotoxicity in rats, and neurobehavioral toxicity and induction of endometriosis in rhesus monkeys are calculated to be the body burden of 10~50 ng TCDD/kg that is 14~37 pg TEQ/kg/day as human daily intake. Finally TDI of 1~4 pg TEQ/kg/day was established by applying the UF of 10. In Japan, reproductive toxicity and immunotoxicity in rats were used to obtain LOAELs (100~200 ng TCDD/kg/day). Finally TDI of 4 pg TEQ/kg/day was established in June 1999 by applying the UF of 10 to human daily intake of 43.6 pg TEQ/kg/day which corresponds to the body burden of 86 ng TCDD/kg.
Embryo and Fetal Developmental Toxicity Study on Gamma-Irradiated Korean Ginseng in Rats
Toxicological Research, volume 17, issue 1, 2001, Pages 27~32
Korean ginseng products have been fumigated with ethylene oxide (EO) for sterilization and prolongation of storage periods. However, there had been controversies indicating that consumption of EO treated foods might cause harmful effects in human. In Korea, the use EO gas for food treatment was banned in 1991. Since then, irradiation technique has been developed as an alternative. This study was carried out to evaluate the safety of irradiated ginseng on embryo and fetal developmental toxicity effects in rats. Either EO gas fumigated or
-irradiated ginseng was administered to pregnant Wistar rats by oral gavage from gestational day 7 to 17. The amount of irradiation used in this study was 5, 10 and 30 kGy, respectively. There were no treatment related changes of dams in deaths, clinical signs, food consumption and body/organ weight. No treatment related changes in implantation ratio, litter size, sex ratio and body/organ weight of fetuses were observed. Also, no F1fetuses with external, visceral, head and skeletal mal-formation were observed. The results of this study showed that
-irradiated ginseng, up to 30 kGy, has no adverse effects on fetal development of rats.
Effect of Toluene Application to the Rat Skin on the Oxygen Free Radical Metabolizing System
Toxicological Research, volume 17, issue 1, 2001, Pages 33~39
To evaluate the skin toxicity oj topical toluene application, toluene (35 mg/
) was sequentially applied to the portion rat skin for five days. The topical toluene application resulted in increased xanthine oxidase activity and CYP content, and significantly decreased superoxide dismutase and glutathione peroxidase activities at five days in rat skin. Especially catalase activity was remarkably decreased in toluene-applied rat skin. And benzylalcohol dehydrogenase activity showed also a significant decrease in toluene-applied skin. On the other hand, histopathological ultrastructural examination revealed disrupted epidermal basement membrane, rared intercellular adhensions and degenerated keratin layer due to topical toluene application. Increased deposit of cerrous perhydroxide resulted from reaction with
was abserved in toluene-treated animals. These results indicate that oxygen free radical may be responsible for ultrastructural changes in skin tissue by toluene application to rat skin.
The Concept of Toxicants Rating in China
Zhau, Jiang-Liang ;
Toxicological Research, volume 17, 2001, Pages 37~39
As the preliminary data collection for further chemical risk assessment. toxicants rating works is now rather extensively implemented in China. It consists of two parts, ie., rating of the hazard level of the exposed toxicant and that of the toxicant's profession. In the first part, the rating are based on six criteria, ie., acute toxicity, incidence of acute poisoning, prevalence of chronic poisoning, consequence of chronic poisoning, carcinogenecity and MAC level. Four hazardous levels are to be classified as extreme, high, medium, mild. In the second part. three determinants as weighted coefficients are taken into account, ie., toxicant's hazard level. exposure time and folds of MAC surpassing. Eventually, the index of classification C by which the work with toxic hazard can be classified is able to be calculated and assessed. Several comments were discussed and new recommendations were demonstrated.
Effects of Hyperbaric Oxygen and
-Tocopherol on Skin Antioxidant Enzymes Defence in Rats
Kim, Jang-Shu ; Kim, Chung-Hui ; Kim, Gon-Sup ; Hah, Dae-Sik ; Park, Sun-Gun ; Kim, Yang-Mi ;
Toxicological Research, volume 17, issue 1, 2001, Pages 41~47
In order to test the effects of hyperbaric oxygen (HBO) and
-tocopherol on full-thickness skin grafts in rats, we peeformed full-thickness skin grafts bilaterally on rats. After surgery, we analyzed the tissue-concentrations of superoxide dismutase (SOD), catalase, and glutathione peroxidase(GPx)/reductase(GPr) on days 0, 2, 4, 7, 10, 14, 21 and 28. The four groups had similar patterns of change in SOD, catalase, GPx and GPr values. SOD increased initially, and was significantly increased at day 7, returning to the preoperative activity level on day 14 (control, HBO, and
-tocopherol treated alone) and 28 (HBO plus
-tocopherol). Catalase had a similar pattern of change as the SOD enzyme activity, except for the surgical control on day 2. Glutathione peroxidase/reductase activity in the four groups had a similar pat-tern of enzyme activity, with a significant increase from preoperative level on day 4, peaking during days 7 to 10, and returning to preoperative level on day 21(surgical control, HBO, and
-tocopherol-treated alone) and 28 (HBO plus
-tocopherol treated group). Hence, the clinical use of HBO and
-tocopherol mixture can be recommended as an adjunctive treatment for free skin grafts in rats. But, the antioxidant used, its dose, and the timing of its administration, as well as, the exposure time and the pressure of HBO, should be the subject of further research.
Assessment of the Risk of Exposure to Chemical Carcinogens
Purchase, Iain F.H. ;
Toxicological Research, volume 17, 2001, Pages 41~45
The methods used for risk assessment from exposure to chemicals are well established. in most cases where toxicity other than carcinogenesis is being considered, the standard method relies on establishing the No Observed Adverse Effect Level (NOAEL) in the most sensitive animal toxicity study and using an appropriate safety factor (SF) to determine the exposure which would be associated with an acceptable risk. For carcinogens a different approach is used because it has been argued there is no threshold of effect. Thus mathematical equations are used to extrapolate from the high doses used in ani-mal experiments. These methods have been strongly criticised in recent years on several grounds. The most cogent criticisms are a) the equations are not based on a thorough understanding of the mechanisms of carcinogenesis and b) the outcome of a risk assessment based on such models varies more as a consequence of changes to the assumptions and equation used than it does from the data derived from carcinogenicity experiments. Other criticisms include the absence of any measure of the variance on the risk assessment and the selection of default values that are very conservative. Recent advances in the application of risk assessment emphasise that measures of both the exposure and the hazard should be considered as a distribution of values. The outcome of such a risk assessment provides an estimate of the distribution of the risks.
Preparation of Alzheimers Animal Model and Brain Dysfunction Induced by Continuous
-Amyloid Protein Infusion
Akio Itoh ; Kiyofumi Yamada ; Kim, Hyoung-Chun ; Toshitaka Nabeshima ;
Toxicological Research, volume 17, 2001, Pages 47~57
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, and its pathology is characterized by the presence of numerous numbers of senile plaques and neurofibrillary tangles. Several genetic and transgenic studies have indicated that excess amount of
-amyloid protein (A
) is produced by mutations of
TEX>$\beta$-amyloid precursor protein and causes learning impairment. Moreover,
has a toxic effect on cultured nerve cells. To prepare AD model animals, we have examined continuous (2 weeks) infusion of
into the cerebral ventricle of rats. Continuous infusion of
induces learning impairment in water maze and passive avoidance tasks, and decreases choline acetyltransferase activity in the frontal cortex and hippocampus. Immunohistochemical analysis revealed diffuse depositions of
in the cerebral cortex and hippocampus around the ventricle. Furthermore, the nicotine-evoked release of acetylcholine and dopamine in the frontal cortex/hippocampus and striatum, respectively, is decreased in the
-infused group. Perfusion of nicotine (50
) reduced the amplitude of electrically evoked population spikes in the CA1 pyramidal cells of the control group, but not in those of the
-infused group, suggesting the impairment of nicotinic signaling in the
-infused group. In fact, Kd, but not Bmax, values for ［
］ cytisine binding in the hippocampus significantly increased in the
-infused rats. suggesting the decrease in affinity of nicotinic acetylcholine receptors. Long-term potentiation (LTP) induced by tetanic stimulations in CA1 pyramidal cells, which is thought to be an essential mechanism underlying learning and memory, was readily observed in the control group, whereas it was impaired in the
-infused group. Taken together, these results suggest that
infusion impairs the signal transduction mechanisms via nicotinic acetylcholine receptors. This dysfunction may be responsible, at least in part, for the impairment of LTP induction and may lead to learning and memory impairment. We also found the reduction of glutathione- and Mn-superoxide dismutase-like immunoreactivity in the brains of
-infused rats. Administration of antioxidants or nootropics alleviated learning and memory impairment induced by
infusion. We believe that investigation of currently available transgenic and non-transgenic animal models for AD will help to clarify the pathogenic mechanisms and allow assessment of new therapeutic strategies.
Safety Evaluation of Genetically Modified Organisms (GMO) for a 90-day Exposure in Rats
Toxicological Research, volume 17, issue 1, 2001, Pages 49~57
We performed to evaluate the safety of GMOs for a long term exposure in Sprague-Dawley (SD) rats. In this study, groups often or fifteen SD rats were fed one of the following four diets for 90 days: (1) AIN-76A rodent diet only; (2) AIN-76A rodent diet containing 5% genetically modified soybean from USA; (3) AIN-76A rodent diet containing 5% genetically non-modified soybean from USA; (4) AIN-76A rodent diet containing 5% genetically non-modified soybean from Korea. The effects of AIN-76A rodent diet containing genetically modified soybean on body weights, food uptake, water consumption, hematology, serum bio-chemistry, urinalysis, organ weights, gross findings and histopathological findings were not significantly different, compared with others. Taken together, these results suggested that genetically modified soybean did not induce any toxic effects in rats treated for 90 days.
Comparison of Skin Response Between New Zealand White Rabbit and Hartley Guinea Pig to Glycolic Acid
Toxicological Research, volume 17, issue 1, 2001, Pages 59~63
In this study, we compared skin response between Hartley guinea pig and New Zealand white rabbit. New Zealand white rabbit was treated by a glycolic acid (0, 8, 24, 40, 56 mg/
) and UVB (0, 0.4, 3.0 J/
) for 14 days. Skin irritation by glycolic acid and UVB were increased in dose and time-dependent manners, and the combination treatment of UVB increased glycolic acid-induced skin irritation. Comparison the skin irritation index between guinea pig and rabbit showed that guinea pig was much more sensitive to glycolic acid and UVB. This study indicated that selection of reliable species of animal could be considered in chemical-induced skin irritation study.
Transcription Profiles of Human Cells in Response to Sodium Arsenite Exposure
Lee, Te-Chang ; Konan Peck ; Yih, Ling-Huei ;
Toxicological Research, volume 17, 2001, Pages 59~69
Arsenic exposure is associated with several human diseases, including cancers, atherosclerosis, hypertension, and cerebrovascular diseases. In cultured cells, arsenite, an inorganic arsenic com-pound, was demonstrated to interfere with many physiological functions, such as enhancement of oxidative stress, delay of cell cycle progression, and induction of structural and numerical changes of chromosomes. The objective of this study is to investigate the effects of arsenic exposure on gene expression profiles by colorimetric cDNA microarray technique. HFW (normal human diploid skin fibroblasts), CL3 (human lung adenocarcinoma cell line), and HaCaT (immortalized human keratinocyte cell line) were treated with 5
sodium arsenite for 6 or 16 h, respectively. By a dual-color detection system, the expression profile of arsenite-treated cultures was compared to that of control cultures. Several genes expressed differentially were identified on the microarray membranes. For example, MDM2, SWI/SNF, ubiquitin specific protease 4, MAP3K11, RecQ protein-like 5, and Ribosomal protein Ll0a were consistently induced in all three cell types by arsenite, whereas prohibitin, cyclin D1, nucleolar protein 1, PCNA, Nm23, and immediate early protein (ETR101) were apparently inhibited. The present results suggest that arsenite insults altered the expression of several genes participating in cellular responses to DNA damage, stress, transcription, and cell cycle arrest.
Modification of Estrogenic Effect of Nonylphenol Combined with DEHP in Yeast-based Bioassay
Toxicological Research, volume 17, issue 1, 2001, Pages 65~71
The key targets of endocrine disruptors are nuclear hormone receptors, which bind to steroid hormones and regulate their gene transcription. A yeast-based steroid hormone receptor gene trascription assay was previously developed for the evaluation of chemicals with endocrine modulating activity. The yeast transformants used in this assay contain the human estrogen receptor along with the appropriate steroid response elements upstream of the
-galactosidase reporter gene. We tried to evaluate several natural and synthetic steroids of their potential to interact directly with the steroid receptor. Some putative endocrine disruptors, including nonylphenol, are weakly estrogenic. But the combined treatment oj these chemicals with di-(2-ethylhexyl)phthalate (DEHP) significantly increased the
-galactosidase activity in the yeast transformant. These results suggest that we also have to consider the synergistic effects of endocrine disruptors. In this study, we showed that yeast-based bioassay is a valuable tool for screening potential endocrine disruptors and quantitative determination of estrogenicity. And the possibility that the estrogen receptor binds multiple environmental chemicals adds another level of complexity to the interaction between the endocrine disruptors and the human hormone system.
Animal Models for Aging and Neurodegenerative Diseases: Brain Cell Apoptosis in the Dog and its Possible Mechanisms
Nakayama, Hiroyuki ; Kajikawa, Satoru ; Doi, Kunio ;
Toxicological Research, volume 17, 2001, Pages 71~77
The brain of the aged dog possesses senile plaques and amyloid angiopathy, which characterize Alzheimer's disease brains. We have defined the dementia condition of aged dogs and examined which mechanism(s) is responsible for the condition. A series of studies revealed that the dementia condition in aged dogs is significantly related to the number of apoptotic brain cells including both neurons and glial cells, but not to the number of senile plaques. On the other hand, 5-azacytidine (5AzC) is a cytidine analogue, and is thought to induce kinds of cell differentiation possibly through hypomethylation of genomic DNA. We have revealed neuronal apoptosis induced in 5AzC-treated fetal mice and PC12 cells. The ribosomal protein L4 (rpL4) gene is expressed prior to the apoptosis in the PC12 cell system. Therefore, the involvement of the rpL4 gene expression in age-related brain cell apoptosis in dogs may contribute to the investigation of Alzheimer's dementia.
Seizure-related Encephalopathy in Rats Intoxicated with Diisopropylfluorophosphate
Kim, Yun-Bae ; Hur, Gyeung-Haeng ;
Toxicological Research, volume 17, issue 2, 2001, Pages 73~82
The incidence and distribution of necrotic and apoptotic neural cells, and activated astrocytes in the brain of rats intoxicated intra peritoneally with diisopropylfluorophosphate were investigated. Pyridostigmine bromide (0.1 mg/kg) and atropine methylnitrate (20 mg/kg) were pretreated intramuscularly 30 min and 10 min, respectively, prior to diisopropylfluorophosphate (4-10 mg/kg) administration. Diisopropylfluorophosphate induced severe limbic seizures, early necrotic and delayed apoptotic brain injuries, and rapid astrocytic responses. The necrosis, which was closely related to seizure intensity, was observed as early as 1 hr after intoxication predominently in hippocampal pyramidal cells, cerebellar Purkinje cells and neurons in pyriform/entorhinal cortices, showing malacia of neurophils. In contrast, apoptosis started to appear 12 hr after intoxication in neurons in thalamus, amygdala and neocortex, and ephendymal cells surrounding the 4th ventricle. Since marked apoptosis was induced in rats exhibiting relatively-low seizure intensity, the degree of necrosis and apoptosis was shifted to each type of injury according to the seizure intensity. Activated astrocytes, observed within 1 hr along the limbic system, were suggested to affect the neural injury patterns by producing high level of nitric oxide. However, the distribution of activated astrocytes was not in parallel with those of necrotic or apoptotic injuries, implying that the astrocytic responses resulted from seizure activity rather than neural injuries. Furthermore, astrocytes in malacic tissues disappeared during the severe limbic seizures. Therefore, it would be one of the cautionary notes on the expression of glial fibrillary acidic protein in astrocytes as a biochemical marker of brain injuries following acute exposure to organophosphates.
Effect of Dosage Level of Carcinogen and Clonorchis sinensis Infestation on Cholangiocellular Carcinoma Induction in Hamsters
Yoon, Byung-Il ; Joo, Kyung-Whan ; Lee, Joon-Sang ; Lee, Jae-Hyun ; Kim, Dae-Yong ;
Toxicological Research, volume 17, 2001, Pages 79~82
The infection of liver flukes, Clonorchis sinensis (CS) and Opisthorchis viverrini (OV), has been known as a risk factor to induce cholangiocellular carcinoma (CCC) in human living in the endemic area, providing promoting effect on the liver initiated by chemical carcinogens. The present study evaluated the relationship between the dosage level of dimethylnitrosamine (DMN) and the infection load of CS in the neoplastic development by histopathological examination of the treated hamsters. To evaluate the effects of DMN, different doses of DMN ranging from 0 to 25 ppm were administered to hamsters with 20 CS metacercariea. For the risk assessment of the infection load, 0, 5, 15, 50 CS metacercariae were respectively infected with 12 ppm DMN. The mortality was closely related to the infection load rather than the concentration of DMN. The infection of CS clearly promoted the induction of CCC even at dose level of 6 ppm DMN. Only five metacercariae were enough to promote CCC induction at the concentration of 12 ppm DMN.
Historical Control Data for Developmental Toxicity Study in Sprague-Dawley Rats
Toxicological Research, volume 17, issue 2, 2001, Pages 83~90
The background control data were compiled from rat developmental toxicity studies con-ducted at Toxicology Research Center, KRICT during the 1993-1999 period. These data were assembled in order to provide background in formation for the maternal and fetal data collected in 13 developmental toxicity studies using Sprague-Dawley rats. A total of 325 mated females were used in these studies during the seven-year period and overall pregnancy rate of these females was 93.8%. The present background control data included body weights, food consumption, hematological values, and organ weights of pregnant females, caesarean section data, and fetal examination data. These data can be used not only as a historical database for the meaningful interpretation of data from reproductive and developmental toxicity studies, but also as a contribution to biological characterization oj Sprague-Dawley rats.
Free Radical Toxicology and Cancer Chemoprevention
Lin, Jen-Kun ;
Toxicological Research, volume 17, 2001, Pages 83~88
Most reactive oxygen species (ROS) are free radicals and implicated in the development of a number of disease processes including artherosclerosis, neurodegenerative disorders, aging and cancer. ROS are byproducts of a number of in vivo metabolic processes and are formed deliberately as part of nor-mal inflammatory response. On the other hand, ROS are generated either as by products of oxygen reduction during xenobiotic metabolism or are liberated as the result of the futile redox cycling of the chemical agents including several chemical carcinogens. A better understanding of the mechanisms of free radical toxicity may yield valuable clue to risks associated with chemical exposures that leading to the development of chronic diseases including cancer. The molecular biology of ROS-mediated alterations in gene expression, signal transduction and carcinognesis is one of the important subjects in free radical toxicology. Epidemiological studies suggest that high intake of vegetables and fruits are associated with the low incidence of human cancer. Many phytopolyphenols such as tea polyphenols, curcumin, resveratrol, apigenin, genistein and other flavonoids have been shown to be cancer chemopreventive agents. Most of these compounds are strong antioxidant and ROS scavengers in vitro and effective inducers of antioxidant enzymes such as superoxide dismutatse, catalase and glutathione peroxidase in vivo. Several cellular transducers namely receptor tyrosine kinase, protein kinase C, MAPK, PI3K, c-jun, c-fos, c-myc, NFkB, IkB kinase, iNOS, COX-2, Bcl-2, Bax, etc have been shown to be actively modulated by phyto-polyphenols. Recent development in free radical toxicology have provided strong basis for understanding the action mechanisms of cancer chemoprevention.
Cyclooxygenase-2 as a Molecular Target for Cancer Chemopreventive Agents
Surh, Young-Joon ;
Toxicological Research, volume 17, 2001, Pages 89~96
Recently, considerable attention has been focused on the role of cyclooxygenase-2 (COX-2) in the carcinogenesis as well as in inflammation. Improperly overexpressed COX-2 has been observed in many types of human cancers and transformed cells in culture. Thus, it is conceivable that targeted inhibition of abnormally or improperly up-regulated COX-2 provides one of the most effective and promising strategies for cancer prevention. A ubiquitous eukaryotic transcription factor, NF-kB is considered to be involved in regulation of COX-2 expression. Furthermore, extracellular-regulated protein kinase and p38 mitogen-activated protein (MAP) kinase appear to be key elements of the intracellular signaling cascades involved in NF-kB activation in response to a wide array of external stimuli. Certain chemopreventive phytochemicals suppress activation of NF-kB by blocking one or more of the MAP kinases, which may contribute to their inhibitory effects on COX-2 induction. One of the plausible mechanisms by which chemopreventive phytochemicals inhibit NF-kB activation involves suppression of degradation of the inhibitory unit I kB, which hampers subsequent translocation of p65, the functionally active subunit of NF-kB.
Dermal and Ocular Irritation Studies of Some Phthalates in Rabbits
Toxicological Research, volume 17, issue 2, 2001, Pages 91~96
Phthalates are widely used as plasticizers to impart softness and flexibility to normally rigid polyvinylchloride products. However, there are not much studies jar dermal and ocular irritation toxicity of phthalates. So we investigated the skin or eye irritation effect of some phthalates which was not reported. The primary skin irritation of diethyl phthalate (DEP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP), dipropyl phthalate (DPP) and dipropyl phthalate (DPrP) was studied. The ocular irritation of dibutyl phthalate(DBP), DIDP, DINP, DPP and DPrP was also studied. DEP, DIDP, DINP, DPP, and DPrP were found to be non-irritating to the skin of the test animals. DBP, DIDP, DINP and DPP were found to be non-irritating to the eye of the rabbits. DPrP caused the slight irritations to the eye in 1 or 2 days after treatment but irritation of the animals was soon recovered.
Effects of Gamma-Irradiated Korean Ginseng on Fertility and General Reproductive Toxicity in Rats
Toxicological Research, volume 17, issue 2, 2001, Pages 97~106
Korean ginseng products have been fumigated with ethylene oxide (EO) for sterilization and prolongation of storage periods. However, there had been controversies indicating that the consumption of food treated with EO might cause harmful effects in human. Since, in Korea the use of EO gas for food treatment was banned in 1991. Since then, irradiation technique has been developed as an alternative. This study was carried out to investigate the effects of irradiated ginseng on fertility, and reproductive and developmental toxicity. Either EO gas fumigated or gamma-irradiated ginseng was administered to male rats by oral gavage for 63 days during the premating period. Female rats were administered from 14 days before mating to day 20 of gestation or to day 21 of lactation. The exposure amount of irradiation used was 5, 10 and 30 kGy, respectively. There were no treatment related changes of darns in clinical signs, and parturition. No treatment related changes in food consumption, body/organ weights, male/female reproductive and fertility performances were observed. F1 fetuses showed no external abnormality. Reflex/sensory junctions, physical/behavioral development, and reproductive performance of F1 rats were not adversary affected. The results of this study show that gamma-irradiated ginseng, up to 30 kGy, has no adverse effects on the fertility, reproduction and development in Wistar rats.
Biochemical Characterization of Serine Proteases with Fibrinolytic Activity from Tenodera sinensis (Praying Mantis)
Kim, Yeong-Shik ; Hahn, Bum-Soo ; Cho, So-Yean ; Chang, Il-Moo ;
Toxicological Research, volume 17, 2001, Pages 97~104
Three types of proteases (MEF-1, MEF-2 and MEF-3) were purified from the egg cases of Ten-odera sinensis using ammonium sulfate fractionation, gel filtration on Bio-Gel P-60 and affinity chromatography on DEAE Affi-Gel blue gel. The proteases were assessed homogeneous by SDS-polyacrylamide gel electrophoresis and have molecular weight of 31,500, 32,900 and 35,600 Da, respectively. The N-terminal regions of the primary structure were compared and they were found to be different each other. MEFs readily digested the
- and B
-chains of fibrinogen and more slowly the
-chain. The action of the enzymes resulted in extensive hydrolysis of fibrinogen and fibrin, releasing a variety of fibrinopeptides. MEF-1 was inactivated by Cu
and inhibited by PMSF and chymostatin. MEF-2 was inhibited by PMSF, TLCK. soybean trypsin inhibitor. MEF-3 was only inhibited by PMSF and chymostatin. Antiplasmin was not sensitive to MEF-1 but antithrombin III inhibited the enzymatic activity qf MEF-1. MEF-2 specifically bound to anti plasmin Among the chromogenic protease substrates, the most sensitive one to the hydrolysis of MEFs was benzoyl-Phe-Val-Arg-p-nitroanilide with maximal activity at pH 7.0 and 3
. MEF-1 preferentially cleaved the oxidized B-chain of insulin between Leu15 and Tyr16. In contrast, MEF-2 specifically cleaved the peptide bond between Arg23 and Gly24. D-dimer concentrations increased on incubation of cross-linked fibrin with MEF-1, indicating the enzyme has a strong fibrinolytic activity.ity.
Novel Macrolide Actin-inhibitors Isolated from Sea Sponges
Karaki, Hideaki ; Ozaki, Hiroshi ;
Toxicological Research, volume 17, 2001, Pages 105~108
Several marine toxins with macrolide structure have been found to act on actin. One of these toxins is mycalolide B isolated from the genus Mycale. This compound belongs to macrolide antibiotics and consists of tris-oxazole with strong cytotoxic activity (
: 10-50 nM for growth of L1210 murine leukemia cells). This compound was found to be an actin-depolymerizing agent with the mode of action distinct from that of the known actin inhibitor, cytochalasin D. Tolytoxin, a macrolide isolated from cyano-bacteria with similar chemical structure to mycalolide B, seems to have similar effect. Another macrolide compound, aplyronine A, showed the effects similar to those of mycalolide B. Although bistheonellide A, a dimeric macrolide, did not show a severing effect, it de polymerized F-actin and sequestered G-actin by forming 1 : 2 complex with G-actins. Swinholide A has a structure and effects similar to those of bistheonel-lide A. In conclusion, mycalolide B, tolytoxin, aplyronine A, bistheonellide A and swinholide A are the members of "actin de polymerizing macrolide" the mechanism of which is different from that of cytochalasin D.halasin D.
Four-week Repeated Oral Dose Toxicity Study of A New Hepatotherapeutic Agent GODEX (HEPADIF-S) in Rats
Toxicological Research, volume 17, issue 2, 2001, Pages 107~114
This study was designed to evaluate a repeated oral dose toxicity of a new hepatotherapeutic agent GODEX in Sprague-Dawley rats. Male and female rats were orally administered with dosages of 500, 100, 20, and 0 /kg/day of GODEX daily for 4 weeks, respectively. There were no dose-related changes in clinical signs, body weight changes, food and water consumption, opthalmoscopy, organ weights, urine analysis, biochemical examination, and hematological findings of all animals treated with GODEX. Gross and histopathological findings revealed no evidence of specific toxicity related to GODEX. These indicate that GODEX may have no side effects and its oral maximum tolerated dose value may be over 500 mg/kg in rats.
Antitumor Toxic Protein Abrin and Abrus Agglutinin
Liu, Chao-Lin ; Lin, Jung-Yaw ;
Toxicological Research, volume 17, 2001, Pages 109~115
Abrus agglutinin was purified from the kernels of Abrus precatorius by Sepharose 4B affinity column chromatography followed by Sephadex G-100 gel filtration column chromatography. About 1.25 g of abrus agglutinin was obtained from 1 kg of the kernels. The LD
of abrus agglutinin is 5 mg/kg of body weight, which is less toxic than that of abrin, 20
/kg body weight. The amino acid sequence of abrus agglutinin was determined by protein sequencing techniques and deduced from the nucleotide sequence of a cDNA clone encoding full length of abrus agglutinin. There are 258 residues, 2 residues and 267 residues in the A-chain, the linker peptide and the B-chain of abrus agglutinin, respectively. Abrus agglutinin had high homology to abrin-a (77.8%). The 13 amino acid residues involved in catalytic function, which are highly conserved among abrin and ricin, were also conserved within abrus agglutinin. The protein synthesis inhibitory activity of abrus agglutinin (
/ = 3.5 nM) was weaker than that of abrin-a (0.05 nM). By molecular modeling followed by site-directed mutagenesis showed that Pro199 of abrus agglutinin A-chain located in amphipathic helix H and corresponding to Asn200 of abrin A-chain, can induce bending of helix H. This bending would presumably affect the binding of abrus agglutinin A-chain to its target sequence GpApGpAp, in the tetraloop structure of 285 r-RNA subunit and this could be one of major factors contributing to the relatively weak protein synthesis inhibitory activity and toxicity of abrus agglutinin.n.
Effects of Di(n-butyl) Phthalate on the Developing Immune System of Fetal and Neonatal SD Rats
Toxicological Research, volume 17, issue 2, 2001, Pages 115~121
Some of endocrine disruptors with sexual hormone-like effects have been increasingly reported to be immunotoxic in many species in recent several years. Phthalate esters have possible effects on the endocrine system. Prenatal exposure to di(n-butyl) phthalate (DBP) has been reported to impair the androgen-dependent development of the male reproductive tract in rat. Therefore, the immunomodulatory effect of DBP was investigated in the developing immune system of fetal and neonatal Sprague-Dawley rats. Timed-bred pregnant SD rats were given to the doses of 0, 250, 500, and 750 mg DBP/kg
body weight /day by gavage once a day from gestational day (GD) 5 to 18. On GD19 or GD22/postnatal day one (PD1), the dams were euthanized, and the changes in organ weights and thymus phenotypes were examined for their offsprings. At 750 mg DBP/kg
b.w./day in maternal exposure group, GD19 fetuses showed decreases in body weight. The spleen/body weight ratios were reduced in GD 19 fetuses from the dams exposed to 500 and 750 mg DBP/kg
b.w./day. There were no significant changes in thymus and spleen cellularities though these cellularities showed a tendency to decrease in a dose dependent way. In the DBP-exsposed GD22/PD1 offsprings, the body weights, the relative organ weights and the cellularities did not exhibit alteration. Additionally, the percentages of CD3
, and CD4
) and CD3
, and CD4
) thymocyte subsets were not changed in any DBP-treated group. The proliferative responses of splenic T cells to Con A and B cells to LPS were decreased in all DBP-exposed GD22/PD1 offsprings.
Mechanisms of Russell's Viper Venom Toxicity on Renal Function; Reversal by Antivenom
Chaiyabutr, Narongsak ; Napathorn, Sophon ; Sitprija, Visith ;
Toxicological Research, volume 17, 2001, Pages 117~125
Envenoming by Russells viper causes a broad spectrum of renal impairment. Renal failure is an important complication in patients bitten by Russells viper. Experimental work in animals and in vitro has elucidated pathophysiological mechanisms that contribute to life threatening complications and have suggested possibilities for therapeutic intervention. The evidence in experimental animals regarding mechanisms of venom action in relation to changes in either extrarenal or intrarenal factors is presented. The cardiovascular system and renal hemodynamics are affected by venom. Reductions of renal function including renal hemodynamics are associated directly with changes in general circulation during envenomation. Possible endogenous mechanisms for releasing the hormone inducing renal vasoconstriction after envenomation are evident. Hormonal factor such as the catecholamine, prostaglandin and renin angiotensin systems induce these changes. Direct nephrotoxicity of venom action is studied in the isolated per-fused kidney. Characteristic polarization of the cell membrane, changes of mitochondrial activity and Na-K ATPase in renal tubular cells are observed. Changes in renal function and the cardiovascular system are observed of ter envenomation and are reversed by the administration of Russells viper antivenom (purified equine immunoglobulin,
fragment). The neutralizing effects are more efficient when the intravenous injection of antivenom is given within 30 min after the envenomation.
The Cytotoxic Effects of Paraquat and Bentazon Compensatory Effects of 3-Methylcholanthrene on Kindney of the Rat
Toxicological Research, volume 17, issue 2, 2001, Pages 123~129
This study were carried out to investigate cytotoxicity of paraquat and bentazon that is scattering to farm products were essensial for human diet and compensatory effects of 3-methylcholanthrene (3-MC) in vitro and in vivo. In vitro, The 5.0
cell/ml of NIH 3T3 fibroblast in each well of 24 multidish were cultured. After 24 hours, the cells were treated with solution of paraquat and bentazon (1, 25, 50, 100 pM respectively). After the NIH 3T3 fibroblast of all groups were cultured in same condition for 48 hours, Sulfohordamin B Protein (SRB) assay were performed to evaluate the cytotoxicity of cell organelles. Paraquat and bentazon
M respectively. In vivo, Sprague Dawley male rats divided into paraquat and bentazon only administered group and simultaneous application group of paraquat and bentazon and 3-MC. At 30 min. and 1, 3, 6, 12, 24, 48 and 96 hrs. interval after each treatment, the animals were sacrificed by decapitation and kidney were immediately removed, immersed in fixatives, and processed with routine method for light microscopic study. Paraffin sections were stained with H-E, PAM, and PAS. Under the light microscope, atrophic change of renal corpuscles were frequently observed from 3 hrs after paraquat and bentazon treatment. The increase of the mesangium was apparent from 12 hrs later after paraquat and bentazon treatment. Necrotic changes of the epithelium and loss of brush border of proximal tubules were most severe at 48 hrs after paraquat and bentazon treatment, respectively. In contrast there were no evidences of the toxic effects on renal tissues at 48hrs in paraquat and bentazon plus 3-MC treated groups.
Phenotyping of Flavin-Containing Monooxygenase (FMO) Activity and Factors Affecting FMO Activity in Korean
Jeon, Sun-Ho ; Park, Chang-Shin ; Cha, Young-Nam ; Chung, Woon-Gye ;
Toxicological Research, volume 17, 2001, Pages 127~133
Together with cytochrome P450 (CYP), flavin-containing monooxygenase (FMO) present in liver microsomes oxidizes various endogenous and exogenous chemicals. In an effort to determine the human FMO activity, we have developed two non-invasive urine analysis methods using caffeine (CA) and ranitidine (RA) as the probe compounds. As the production of theobromine (TB) and ranitidine N-oxide (RANO) from CA and RA is catalyzed primarily by the hepatic FMO, we have assigned the urinary molar ratios of TB/CA and RA/RANO as the in vivo FMO activity. In 200 age-matched Korean volunteers, the obtained TB/CA ratio ranged from 0.4 to 15.2 (38-fold difference) and the RA/RANO ratio from 5.7 to 27.2 (4.8-fold). The FMO activity of 20's, determined by caffeine metabolism, was the highest (2.5
l.9) and those of 30's, 40's, 50's, 60's and 70's were 40%, 50%, 24%, 39% and 36% of the 20's, respectively. Intake of grapefruit juice, known to contain flavonoids, inhibited the in vivo FMO (TB/CA) activity by 79%. Addition of the flavonoids like naringin, quercitrin and kaempferol, present in grapefruit juice, to the in vitro microso-mal FMO assay, thiobenzamide S-oxidation, produced 75%, 70% and 60% inhibition, respectively. Obtained Ki values of quercitrin, kaempferol and naringin on the in vitro FMO activity were 6.2, 12.0 and 13.9
, respectively. This suggested that the dose of drug should need to be adjusted to suit the individual FMO activities when the drugs metabolized by FMO are given to patients. As the intake of grapefruit juice has been identified to inhibit the FMO as well as CYP3A4 and lA2 activities, patients taking drugs metabolized by these enzymes should not drink grapefruit juice as the carrier.
Induction of Apoptosis by Baicalein in Human Leukemia HL-60 Cells
Kim, Jang-Ho ; Park, Sun-Young ; Shin, Kwang-Sig ; Yoo, Byung-Sun ;
Toxicological Research, volume 17, issue 2, 2001, Pages 131~137
Baicalein, a major flavonoid of extract from Scutellaria baicalensis Georgi, has been shown to exhibit antioxidant and anti proliferative effects. In the present study, we investigate the effects of baicalein on viability and induction of apoptosis in human promyelocytic leukemia HL-60 cells. Baicalein was found to induce apoptosis of HL-60 cells in a concentration-dependent and time-dependent manner. When HL-60 cells were exposed to 100
baicalein for 6h, the viability was decreased remarkably to 27% of control, whereas DNA fragmentation was significantly increased to 64%. Nucleosomal fragmentation of baicalein treated HL-60 cells, a hallmark of apoptosis, was further identified by agarose gel electrophoresis (DNA ladder). Flow cytometric analysis showed that apoptotic cells were increased to 66.6% after treatment with 100
baicalein for 6 h. Baicalein-induced apoptosis of HL-60 cells was reduced by 1h pretreatment with inhibitor of caspases, z-Asp-
-DCB. At 3 and 10
-DCB, DNA fragmentation of HL-60 cells induced by baicalein (50
) was 36.8 and 17.1 %, respectively, whereas, that of HL-60 cells treated by baicalein (50
) without pretreatment with inhibitor of caspases was 62.7%. These data suggest that baicalein induces apoptosis in human leukemia HL-60 cells, and that caspase enzymes might be involved in baicalein-induced apoptosis.
The Effects of Multi-minerals on Susceptibility to Lead Toxicity in Rats
Lu, Jing ; Zhang, Jun ; Zhang, Lili ; Cui, Tao ; Xie, Guangyun ; He, Xiwen ;
Toxicological Research, volume 17, 2001, Pages 135~138
Female Wistar rats were randomly divided into 5 groups: Control, received distilled water; Low lead, received 0.5 g/ιlead (as acetate) in drinking water; High lead, received 2.0 g/ιlead; Low lead + Minerals, received 0.5 g/ιlead in drinking water and received minerals (Ca
, 25 mg/kg/day; Fe
, 0.47 mg/ kg/day; Zn
, 0.33 mg/kg/day; Se, 0.83
/kg/day) by gavage; High lead + Minerals, received 2.0 g/ιlead and received the same minerals. Animals exposure to lead was from 10 days before mating till postnatal day 21; and the minerals was administered from the first day of pregnancy and during lactation. No statistical difference was found either in body weights or in blood lead levels between the pups received minerals and those only exposed to lead at the same dose. The developmental and behavioral teratological effects of lead on pups, such as time-lag of eye opening, pinna detachment, fur developing, incisor eruption, ear unfolding, and surface righting were observed in this study; and the minerals decreased the toxicity of lead either in low or in high lead exposure pups. The numbers of step-down were significantly increased in lead exposed animals, and the effect of intervention by the minerals was appeared only in the pups exposed to low lead. The ChAT activity and levels of glutamate and aspartate in hippocampus decreased in treated animals compared to control animals, no effect of intervention by the minerals was found. The results of this study indicate that the applied multi-minerals can alter the outcome of develop-mental lead poisoning in rats.s.s.s.
Effect of 17
-Estradiol on Sexual Behavior and Reproductivity of Male Medaka (Oryzias latipes)
Toxicological Research, volume 17, issue 2, 2001, Pages 139~142
Sexual behavior and reproductivity of male fIsh were studied as an in vivo screening method of endocrine disruptors. Male medaka (Oryzias latipes) were exposed to 17
-estradiol at nominal concentrations of 2 and 20
/l for 14 days. After exposure of the chemical, sexual behavior between male medaka and normal female which were injected with prostaglandin
just before the test, was analysed by using video camera for one hour. Normal control male showed courtship dancing such as following, guarding, dancing and crossing while 17
-estradiol treated male did not show any type oj courtship dancing. Furthermore, fecundity and fertility were significantly decreased in the treated group. It was suggested that analysis of sexual behavior could be a useful endpoint for the screening of the endocrine disruptors.
Metabolism of Safrole, a Betel Quid Component, and its Role in the Development of Oral Cancer in Taiwan
Liu, Tsung-Yun ; Chen, Chiu-Lan ; Chung, Yu-Ting ; Chi, Chin-Wen ;
Toxicological Research, volume 17, 2001, Pages 139~144
Chewing betel quid is associated with an increased risk of oral cancer. The betel quid chewed in Taiwan includes the inflorescence of Piper betle, which contains high concentrations of safrole (15 mg/fresh weight). Piper betle leaf is also used in betel quid; however, the concentration of safrole in betel leaf has not been documented. Chewing betel quid may contribute to safrole exposure in man (420 mm in saliva). Using
P-postlabeling method, we have recently demonstrated the presence of stable safrole-like DNA adducts in human oral tissues following betel quid chewing. Safrole is a rodent hepatocar-cinogen, and the real nature of safrole-DNA adducts in human tissues beside oral has not been elucidated. In this paper, we tested the safrole DNA adducts forming potential in human hepatic and oral derived cells by the
-postlabeling technique. The results suggest that oral cancer derived cell OC-2 alone is not able to form safrole-DNA adduct. However, safrole DNA adducts can be detected following I'-hydroxysafrole, a proximate safrole metabolite, treatment. In addition, pretreament of cytochrome P450 inducers also enhanced the formation of previously undetectable safrole DNA adducts. This finding couples with our previous results suggest that oral may serve as a target tissue for safrole, and safrole may be involved in oral carcinogenesis.
Comparison of Eye Irritation Potency with Skin Irritation and Cytotoxicity Potency of Anti-wrinkle Agents
Toxicological Research, volume 17, issue 2, 2001, Pages 143~149
In the present study, we examined eye irritation oj six anti-wrinkle agents (ascorbic acid, glycolic acid, all trans-retinoic acid, ginseng extract, retinol, EB). We also compared eye irritation with skin irritation and cytotoxicity in HaCaT cells by these agents. The highest eye irritation was found in glycolic acid, but all trans-retinoic acid showed the highest skin irritation. The rank of eye irritation was not correlated with the cytotoxicity of agents. This result shows that eye irritation potency by these agents were not correlated with skin irritation potency, and cytotoxicity in HaCaT cells.
Interethnic Variations of CYP2C19 Genetic Polymorphism
Tassaneeyakul, Wongwiwat ; Tassaneeyakul, Wichittra ;
Toxicological Research, volume 17, 2001, Pages 145~155
Cytochrome P4502C19 (CYP2C19) is one of human polymorphic xenobiotic-metabolizing enzymes. The enzyme has been reported to catalyze more than 70 substrates, involving more than 100 reactions. These include several classes of therapeutic agents (e.g. anti-microbial. cardiovascular, psycho-active, etc.), sex hormones and insecticides. Associations of the CYP2C19 genotype/phenotype with individual differences in drug efficacy (e.g. diazepam, omeprazole, proguanil) and toxicity (e.g. mephenytoin, barbiturates) have been documented by many investigators. At least 11 allelic variants of CYP2C19 gene were reported to date. Most of the mutant alleles found in the poor metabolizer (PM) led to the production of truncated and/or inactive proteins. Except for the exon 6, single-nucleotide mutations were reported in all nine exons of the gene. Genetic polymorphism of CYP2C19 shows marked interethnic variation with the population frequencies of PM phenotype ranging from 1∼2% up to more than 50%. The prevalence of CYP2C19 PM tends to be higher in Asian and certain Pacific Islanders than other race or ethnic specificity. Genotyping results of CYP2C19 also revealed that there are different proportions of individual mutant alleles among ethnic populations. This may, in part, explains the interethnic difference in the metabolism of certain drugs (i.e. diazepam), though they were from the same CYP2C19 phenotype. Recently, our research group has studied the genotype and phenotype of CYP2C19 and found that the PM frequency (7∼8%) in Thais is lower than other Asian populations. Molecular and clinical impacts of this finding warrant to further investigation.
Therapeutic Effect of HM 10411 on Neutropenia Caused by Anticancer Agents in Mice
Toxicological Research, volume 17, issue 2, 2001, Pages 151~157
Neutropenia is a major dose-limiting side effect of cancer chemotherapy. The therapeutic effect of HM 10411 was examined on neutropenia caused by anticancer agents. Neutropenia in normal ICR mice was induced by a single combined intraperitoneal injection of 130 mg/kg of cyclophosphamide (CPA). 4.5 mg/kg of doxorubicin (DXR). and 1 mg/kg of vincristine (VCR) on day O. Neutropenia in tumor-bearing mice was made by a single intraperitoneal injection of 200 mg/kg of cyclophosphamide (CPA) into BALB/c mice bearing Colon 26 adenocarcinoma at 7 day after tumor implantation. HM 10411 or filgrastim (100
/kg/day) was subcutaneously administered for 5 consecutive days starting 1 day after injection of anticancer agents in order to stimulate neutrophil production. Injection of HM 10411 accelerated the recovery from these anticancer drug-induced neutropenia. In normal and tumor-bearing mice. neutrophil production efficacy of HM 10411 was similar than that of filgrastim. These results suggest that HM 10411 could be useful in the clinical treatment for neutropenia induced by anticancer agents.
High Efficiency Retroviral Vectors with Improved Safety
Yu, Seung-Shin ; Kim, Jong-Mook ; Kim, Sunyoung ;
Toxicological Research, volume 17, 2001, Pages 157~166
Almost all currently available retroviral vectors based on murine leukemia virus (MLV) contain one or more viral coding sequences. Because these sequences are also present in the packaging genome, it has been suggested that homologous recombination may occur between the same nucleotide sequence in the packaging genome and the vector, resulting in the production of replication competent retrovirus (RCR). Up until now, it has been difficult to completely remove viral coding sequences since some were thought to be involved in the optimum function of the retroviral vector. For example, the gag coding sequence present in almost all available retroviral vectors has been believed to be necessary for efficient viral packaging, while the pol coding sequence present in the highly efficient vector MFG has been thought to be involved in achieving the high levels of gene expression. However, we have now developed a series of retroviral vectors that are absent of any retroviral coding sequences but produce even higher levels of gene expression without compromising viral titer. In these vectors, the intron and exon sequences from heterologous cellular or viral genes are present. When compared to the well known MLV-based vectors, some of these newly developed vectors have been shown to produce significantly higher levels of gene expression for a longer period. In an experimental system that can maximize the production of RCR, our newly constructed vectors produced an absence of RCR. These vectors should prove to be safer than other currently available retroviral vectors containing one or more viral coding sequences.
Anti-emetic Effect of Ondaron in Ferrets
Toxicological Research, volume 17, issue 2, 2001, Pages 159~161
The anti-emetic effect of a 5-HT
receptor antagonist, Ondaron, was compared with that of the approved ondansetron agent, Zofran
in the ferrets. Emesis was induced by single intraperitoneal injection of cisplatin 10 mg/kg, and Ondaron or Zofran
was injected intraperitoneally in a dose of 1.0 mg/kg, respectively. Ondaron and Zofran
effectively antagonised the emetic response for 4 hours after injection. They significantly reduced the number of vomiting and retching, and prolonged the latency to the first episode. The anti-emetic effect of Ondaron was almost the equal to that of Zofran
. These results suggest that Ondaron is an effective anti-emetic agent against cisplatin-induced emesis, and its anti-emetic potency is similar to that of 5-
receptor abtagonist, Zofran
Case Report of Asbestosis
Lee, Yong-Hwan ; Chang, Hee-Kyung ; Kiyoshi Sakai ; Naomi Hisanaga ; Chung, Yong-Hyun ; Han, Jeong-Hee ; Yu, Il-Je ;
Toxicological Research, volume 17, issue 3, 2001, Pages 163~165
A patient,58 years of age, with suspected 0/l pneumoconiosis since 1993, complained of a dry cough and exertioning dyspnea for 6 months. He had worked in an asbestos company for more than 20 years from 1974. He was subsequently diagnosed with an interstitial lung disease during an annual special health check-up for asbestos workers. h chest X-ray showed an interstitial lung disease and high-resolution computed tomography (HRCT) showed a round opaque asbestosis with chronic hypersensitivity pneumonitis. A pulmonary function test indicated that the patient had a mild restrictive lung disease with FEV1 1.67 litters and 82% FEVl/FVC. The bronchoalveloar larvage fluid included many asbestos bodies, indicating previous exposure to asbestos. Transmission electron microscopy (TEM) using an energy dispersive X-ray analyzer (EDX) revealed many asbestos bodies consisting of mainly crocidolite fibers (6,071
fibers/g of dry lung). The patient had an unusually high asbestos content of 6,112
asbestos fibers/9 of dry lung.
Evaluation of Irritating Potential of Newly Developed Toothpaste in the Hamster Oral Mucous Membrane
Kim, Bae-Hwan ; Kim, Jin-Woo ; Chang, Ih-Seop ; Sim, Young-Chul ; Lee, Yong-Soon ;
Toxicological Research, volume 17, issue 3, 2001, Pages 167~171
Oral mucous membrane test using Syrian hamsters was performed to evaluate the reliability as a model system for the assessment of the potentially irritating substances intended for the mucous membranes, and to determine the irritating potential of a new emulsion-type formulated toothpaste. After test substances were implanted into the cheek pouches of hamsters with diluents (20 mg/kg) under pento-barbital sodium anesthesia, we made the comparison in irritation between emulsion-type and dispersion-type of triclosan (TCS) formulations in the range of 0.2% to 0.3%. The emulsion-type formulations using non-ionic surfactant showed less mucosal lesion than other commercial toothpastes with 0.3% TCS, or dispersion-type ones. However, no significant difference in irritation was detected between 0.2% and 0.3% TCS. We report that this hamster cheek pouch method could be a reliable approach for the evaluation slight difference in the irritating potentials of cosmetics and hygiene products intended for the lips or other mucous membranes, and this method showed that the new emulsion-type formulation significantly lowered the TCS-induced toxicity, compared with other commercial toothpastes.
Safety Assessment of Foods Produced Using Recombinant DNA Techniques
Toyoda, Masatake ;
Toxicological Research, volume 17, 2001, Pages 167~171
The introduction of genetically modified crops has raised concerns regarding safety issues over the insertion of foreign genes into plant genomes using recombinant DNA technology. Since 1991 in Japan, 29 foods and 6 food additives have been evaluated, based on the "Guideline for Safety Assessment", before these foods were marketed. The MHW, however, decided that safety assessment of such foods and food additives should be legally imposed. because soon such foods and food additives are expected to circulate globally and a new system for assessing safety of such foods and food additives at a pre-market stage is necessary, in order to avoid the distribution of any genetically modified foods that have had no safety assessment. The MHW published relevant announcements to amend existing regulations on 1 May 2000. "Standards for safety assessment of seed plant" is established based on a concept of substantial equivalence, and applicable to the products which are regarded as equivalent to the existing products used as foods and food additives. The characterization of the food products entails consideration of the molecular characterization. phenotypic and compositional characteristics, key nutrients and toxicants, and toxicity and allergenicity of the introduced proteins, and if there are indications of unintended effects of the modification, whether further safety testing (animal studies etc.) is needed should be considered. Safety and wholesomeness studies with whole foods should be care fully designed in order to avoid nutritional imbalances causing artifacts and uninterpretable results as was the case of Dr. Pusztaiis report. A case study of genetically modified soybeans (glyphosate-tolerant soybeans) on the immune system of rats and mice is shown. Chemical compositions were also compared with those of the non-GM soybeans. The studies failed to detect any differences in immuno-toxic activity.muno-toxic activity.
Evaluation of Irritating Potential of Newly Developed Toothphaste in the Hamster Oral Mucous Membrane
Kim, Bae Hwan ; Kim, Jin U ; Jang, Lee Seop ; Sim, Yeong Cheol ; Lee, Yong Sun ;
Toxicological Research, volume 17, issue 3, 2001, Pages 167~167
The Protective Effects of the Extract of Saururus chinesis against Cadmium Induced Cytotoxicity(II)
Toxicological Research, volume 17, issue 3, 2001, Pages 173~180
This study was conducted to investigate the antitoxic component in ethanol extract of Saururus chinesis (S. chinesis). The results were as follows: Generally, detoxication effects by s. chinesis extract increased in proportion to the extract concentration. non 8
/g dosage of S. chinesis extract was administered, it showed the highest antitoxic effects in metallothionein induction. After the extract treatment, body weights generally increased In proportion to the extract concentrations. from the above results, S. chinesis extract Increased Metallothionein concentration and decreased the toxicity of cadmium In rats. In vitro the antitoxic activity of ethanol extract of S. chinesis on NIH3T3 fibroblasts was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) and SRB (sulforhodamine B protein) assays. The light microscopic study was carried out to observe morphological changes of the treeated cells.
mg/ml Concentrations of S. chinesis extract was shown significant antitoxic activity. The number of NIH 3T3 fibroblasts were increased and tend to regenerate. These result suggest that S. chinesis extract retains a potential antitoxic activity.
Toxicities in Gene Therapy
Nam, Myeong-Jin ;
Toxicological Research, volume 17, 2001, Pages 173~183
Although there are still many technical difficulties to be overcome, recent advances in the molecular and cellular biology of gene transfer have made it likely that gene therapy will soon start to play an increasing role in clinical practice. However. safety issues are raised from vector system. It is not clear whether it is safe to incorporate genes into nuclear DNA. Little is known about the antigenicity of gene product which the immune system is encountering. In this review, some safety-related topics are introduced and discussed.
Vitellogenin mRNA Induction in Male Carp Treated with Bisphenol A
Toxicological Research, volume 17, issue 3, 2001, Pages 181~186
The estrogenic potency of bisphenol A using reverse trancriptase-PCR response of liver vitellogenin mRNA in male carp was studied. For this, six combination of primers which were synthesized on the basis of cDNA consensus region of various species, were evaluated and one pair of primers was selected as the best to show 286 bp size-transcript. By using the selected primers, vitellogenin mRNA induction in carp treated with bisphenol A was measured and the chemical showed dose-and time-dependent Induction response. From this result, it was concluded that RT-PCR technique wing the selected primers in this study can be wed to monitor the estrogenic effects exerted In carp living in Korean freshwater.
Safety Assessment of Genetically Modified Foods and Food Additives in Korea
Kim, Chang-Min ;
Toxicological Research, volume 17, 2001, Pages 185~188
Genetically modified foods and food additives are derived from organisms that have been inserted foreign genetic materials by recombinant DNA techniques to improve the quality or any other pur-poses. The problems such as toxicity, allergenicity and antibiotics resistance in the safety of genetically modified foods are usually concerned. In Korea, the safety of foods is ensured by the Food Sanitation Act. Although there is no specific provision regarding the genetically modified foods in it, any foods that might cause negative effect(s) on public health or human life are prohibited to sell in the market. In order to systematically evaluate safety of genetically modified foods, the Korea Food and Drug Administration (KFDA) promulgated "Guidelines regarding review of safety assessment data for genetically modified foods and food additives (KFDA Notification 1999-46)". The objectives of these guidelines are to ensure safety of genetically modified foods and food additives. In order to evaluate the safety of genetically modified foods. KFDA operates a special expert committee composed by experts from government, universities, research institutes. and consumer's unions. Recently. manufacturers and consumers are interested in the issues on safety and labeling of genetically modified foods, because of increment of imported genetically modified crops and processed foods. Since government and consumers unions have different viewpoints, their positions regarding the issue are different each other. Therefore, the regulation of labeling on genetically modified foods is prepared and should be enforced at July 2000 in Korea. in Korea.
Bile Duct Obstruction Stimulates Lipid Peroxidation and Liver Fibrosis (Cirrhosis) in Rat
Toxicological Research, volume 17, issue 3, 2001, Pages 187~194
The oxidative stress causes the cell damage and death and thereby, stimulates membrane lipid peroxidation. In this study, the correlation between the lipid peroxidation product and the parameter of liver fibrosis (cirrhosis) was investigated in cholestasis induced rats. The Sprague-Dawley rats were divided into 3 groups (sham: sham operation, BDL/S-I and BDL/S-II : bile duct ligation/scission) and were observed for 2 or 4 weeks. After observation period, the organs were weighed and the ratio of organ weight/body weight was calculated. Sera and liver tissue were used for the measurement of malondealdehyde (MDA), parameter of clinical biochemistry, total collagen content and the staining. The ratio of organ weight/body weight in BDL/S-I and BDL/S-II was significantly increased compared to sham operated group. Serological parameters (Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and Total bilirubin) in BDL/S-I and BDL/S-II group were significantly higher than those in sham operated group. Concentration of MDA in BDL/S-I (261%) and BDL/S-II(790%) was significantly increased compared to MDA in sham operated group. And the content of hydroxyproline (hyp) in BDL/S-I and BDL/S-II group was significantly increased 2~4 times than in sham operated group. The good correlations between hyp in liver tissue and MDA in sera of sham operated group and all operated group were found (r=0.825). The significantly higher value of MDA, hyp and serological parameters in BDL/S-I and BDL/S-II group suggests the stimulation of lipid peroxidation and chronic liver damage. Especially the activation of lipid peroxidation and the stimulation of liver fibrosis was stronger in BDL/S-II group than in BDL/S-I group. The stronger fibrosis, portal-portal septum formation, the more massive bile duct proliferation in portal triads and stroma, and hepatocytes swelling were observed in liver tissue of and BDL/S-II group compared to BDL/S-I group. Conclusively, a good correlation between MDA as a lipid peroxidation marker and hyp as a liver fibrotic parameter could be connected with the process of liver fibrosis. Moreover, cholestasis condition may cause jaundice, activation of lipid peroxidation, and collagen accumulation in liver. Additionally, optimal observation period of bile duct obstruction for the screening of antioxidant and antifibrotic effect in rats would be four weeks.
International Harmonization of Accreditation of Toxicologists
Satoh, Tetsuo ;
Toxicological Research, volume 17, 2001, Pages 189~191
In the past, IUTOX engaged in dialogue with various international toxicology organizations to address this important issue. IUTOX Executive Committee engaged in activities that support accreditation and/or registration of toxicologists around the world. As a result of discussions held during the IUTOX-sponsored workshop at the 2000 Annual Meeting of the SOT in Philadelphia, it was decided to create an international forum, the "International Assembly for the Recognition of Toxicologists"(IART). The mission of IART was defined as threefold: 1) to establish a forum for development of criteria for recognizing qualified experts in toxicology; 2) to assist "recognizing organizations" in establishing these criteria; and 3) to promote identification and training needs to enhance expertise in toxicology. The membership of IART is open to all organizations (e.g., registries, boards, academies, etc.) whose purpose is the recognition of expertise in toxicology.rtise in toxicology.
Current Situation of the International Recognition of Toxicologists -Update of the Japanese Society of Toxicology-
Horii, Ikuo ;
Toxicological Research, volume 17, 2001, Pages 193~196
Issuance of certification and licensing for toxicologists authorized by the Japanese Society of Thxicology (JST) became effective on July 24, 1997. The certification system consists of examination, eligibility requirements for the applicants, authorization/license by the board of trustees of JST, and the re-certification of previously authorized qualification. In the last 2-3 years, about 30-40% of candidates for the examination have succeeded. The Committee has estimated that the level of the examination would be sufficient to determine qualified toxicologists. This updated status and a detailed explanation are to be presented at the workshop. In global terms, the JST special committee agrees that "harmonization of certification/registration procedure for qualified toxicologists means to ensure/set the minimum requirement for the global authorization of qualified toxicologists". The following items in global authorization are ad-dressed for further discussion: (1) What's the benefit\ulcorner (2) Toxicological safety assessment standards, and (3) the JST position for authorization.orization.
Review Newly Adopted OECD Acute Oral Toxicity Test Guideline 420
Toxicological Research, volume 17, issue 3, 2001, Pages 195~201
The OECD acute toxicity guideline has been revised recently to protect animal welfare. The GLP authority of the Ministry of Environment, the National Institute for Environmental Research, recommended GLP laboratories in Korea to ufo the revised acute toxicity guideline. This study was carried out to optimize newly adopted OECD test guideline 420 (TG 420). Bisphenol A was selected for test chemical. Following TG420, Bisphenol A was classified as class 5/unclassified group. The revised TG 420 was very effective test in minimizing animal number and classifying chemicals. The method, however had short-coming in evaluation of test results statistically because the test had no control group, and the test should be stopped when animals were dead at the lowest dose or alive at the highest dose. TG 420 required at Least 20 animals to complete the test, but it could result in producing unused animals that need to sacrifice.
Significance of a Highly Specific and Sensitive Enzyme Linked Immunosorbent Assay on Evaluation of Environmental Toxicant-Mediated Allergic Responses
Kim, Hyoung-Ah ; Yong Heo ;
Toxicological Research, volume 17, 2001, Pages 197~199
Enhancement of antigen-specific IgE is a hallmark of allergic hyperresponsiveness, therefore it is necessary to adopt or develop a highly sensitive and specific assay for determination of allergen-specific IgE levels in vivo. In this presentation, we introduce an ELISA (enzyme linked immunosorbent assay) system developed to measure the levels of chicken egg ovalbumin (OVA)-specific IgE in serum. The ELISA method uses a commercially available purified rat anti-mouse IgE as a capture Ab and biotinylated OVA as a detection reagent. Avidin-peroxidase with its substrate is used for color development resulting in optical density measurement at 405 nm. The ELISA system produces a highly sensitive dose-response relation-ship between optical density levels and the dilution titer of the OVA-IgE standard serum but no cross-reaction with unrelated IgE or IgG. It is believed that the system is an Efficient tool to delineate an adjuvant effect of environmental pollutants on development of asthmatic and atopic responses.
Establishment of Immunotoxicology Evaluation Procedures for Pharmaceuticals
Nakamura, Kazuichi ;
Toxicological Research, volume 17, 2001, Pages 201~203
The Japan Pharmaceutical Manufacturers Association. with the cooperation of the Japan Association of Contract Laboratories for Safety Evaluation. launched a collaborative study with 38 companies aimed at elucidating the correlation between histopathological/hematological findings and immune function. Seven substances were individually administered to Crj : CD (SD)IGS rats for 14 or 28 days. Their immunotoxicity was assessed by histopathology. hematology. plaque-forming cell assay. enzyme-linked immunosorbent assay of serum antibody to sheep red blood cells. and flow cytometry. Appropriate procedures for immunotoxicology evaluation of pharmaceuticals were considered.
Pre-validation of the OECD Enhanced Test Guideline 407 Protocol on Screening and Testing for Endocrine Disrupters
Toxicological Research, volume 17, issue 3, 2001, Pages 203~213
We investigated the toxic effects of propylthiouracil (PTU) In Sprague-Dawley (SD) rats to develop and validate an enhanced Protocol for Test Guideline 407 as OECD Project. Twenty male and female SD rats,7 weeks old, were treated with PTU in corn oil at levels of 0, 0.1, 1 and 10 mg/kg/day for 4 weeks orally. Clinical observation, body weight changes, food uptake, water consumption, urinalysis, estrus cycle and sperm analysis, serum chemist교, autopsy findings and histopathological findings were evaluated in this study. No clinical signs and mortality were observed in the study. The body weights and food uptakes in the group treated with 10 mg/kg/day were reduced from 3 weeks after the initiation of the treatment. The levels of 3,5,3'-triiodothyronine (T3) and thyroxine (T4, 3,5,3',5'-tetraiodothyrosine) were also significantly decreased in the group treated with 10 mg/kg/day. Also, the relative and absolute organ weights of thymuses were decreased. Thyroid glands of rats in the group treated with PTU 10 mg/kg/day were bigger than those of rats in the control group. In the histopathological examination, diffuse hyperplasia and hypertrophy of thyroid follicular cells were observed in all treatment groups, leading to the reduction of lumen size and papillary enfolding of lining epithelium. The degree of lesion was increased in a dose-dependent manner. The results suggested that PTU would cause toxicity in thyroid gland and decrease the levels of T3 and T4 in SD rats. However there were no effects on the other organ including testis and uterus especially in spermatogenesis and estrus cycle. On the basis of the results, enhanced protocol for Test Guideline (TG) 407 may be sensitive and reliable to detect endocrine-active substances like PTU.
Looking Inside the Cell for Mechanisms of Immunotoxicity: Experimental Design and Approaches Aimed Toward Elucidation of 2,3,7,8-Tetrachlor- dibenzo-p-dioxin-mediated B Cell Dysfunction
Norbert E. Kaminski ; Kang, Jong-Soon ;
Toxicological Research, volume 17, 2001, Pages 205~210
One of the major focuses and perhaps the greatest challenges during the past decade in the discipline of immunotoxicology has been the elucidation of the molecular mechanisms responsible for immunotoxicity by specific agents. Much is currently understood about the basic underlying intracellular processes that control leukocyte effector function. This fundamental information in cell biology can now be applied toward developing systematic approaches, through the application of cell and molecular biology techniques, to identify the intracellular targets and processes disrupted by immunotoxicants. The objective of this paper is two fold. First to discuss fundamental principles of experimental design aimed at elucidation of cellular mechanisms in immunotoxicology; and second to discuss the application of molecular biology techniques in characterizing the mechanism of TCDD-induced B cell dysfunction as a working example.
Immunotoxicology Evaluation of New Drugs
Ahn, Chang-Ho ; Kenneth L. Hastings ;
Toxicological Research, volume 17, 2001, Pages 211~216
Drugs can have various adverse effects on the immune system including unintended immun-osuppression, induction of both drug-specific immune responses (including drug allergies) and non-specific immunostimulation (including autoimmune reactions), and direct activation of effector mechanisms (such as histamine release). As a practical matter, the Center for Drug Evaluation (CDER) relies on standard non-clinical toxicology studies to detect unintended immunosuppression. Specific assays using guinea pigs and mice are available to identify drugs that can induce immune-mediated dermal hypersensitivity reactions. Respiratory and systemic hypersensitivity and autoimmune reactions are more difficult to model in non-clinical studies. Unintended nonspecific immunstimulation can be detected in animal studies. CDER is currently developing specific guidance for evaluating potential drug immunotoxicity.
Apoptotic Signaling Pathway by Cadmium in Hepalclc7 cells
Toxicological Research, volume 17, issue 3, 2001, Pages 215~223
Cadmium is an ubiquitous toxic metal and chronic exposure to cadmium results in the accumulation of cadmium in the liver and kidneys. In contrast, acute exposure leads to damage mainly in the liver. Apoptosis induced by cadmium has been shown in many tissues in vivo and in cultured cells in vitro. However, the molecular mechanism of cadmium-induced apoptosis is not clear in hepatocyte. To investigate the induction of apoptosis in the hepatocyte, we used mouse hepatoma cell line, Hepalclc7 cells, and analysed the molecules that involved in cadmium-induced apoptosis. Cadmium induced the genomic DNA fragmentation, PARP cleavage, and activation of caspase-3 like protease. Caspase-9 cysteine protease was activated in a time-dependent manner but caspase-8 cysteine protease was not significantly activated in cadmium-treated Hepalclc7 cells. Cadmium also induced mitochondrial dysfunction including cytochrome c release from mitochondria, change oj mitochondrial membrane potential tranition, and tranlocation of Bax Protein into mitochondria. These results strong1y indicated that the signal Pathway of apoptotic death in cadmium-treated Hepalclc7 cells is modulated by caspase cascade via mitochondria.
Mechanism of T-cell Specific Immunosuppression Induced by Prodigiosin
Kim, Hwan-Mook ; Park, Se-Hyung ; Jeon, Young-Jin ; Lee, Sang-Han ; Kim, Hyung-Chin ; Yang, Kyu-Hwan ; Han, Sang-Bae ;
Toxicological Research, volume 17, 2001, Pages 217~218
In a series of our screening for immunomodulating substances, we isolated prodigiosin from the culture broth qf Serratia marcescens B-1231. This compound inhibited the T cell-mediated immune responses such as concanavalin A-induced proliferation, mixed lymphocyte response, local graft versus host reaction and T-dependent antibody response at nontoxic concentrations. However. prodigiosin did not effect B cell-mediated immune functions such as lipopolysaccharide-induced proliferation and -activated polyclonal antibody production at the same concentrations. Prodigiosin did not cause death in vitro to lymphocytes at effective concentrations (＜100 nM) and also did not show toxicity in vivo to lymphoid organs at effective dos-ages (10 and 30 mg/kg). The pharmacological potencies were comparable to the activities of well-known T-cell specific immunosuppressants such as cyclosporin A. In our continuing study, mechanism of action of PDG is investigated with respect to the effect of PDG on IL-2/IL-2R pathway and transcription factor.
An Examination of Variation in Risk Assessment Practices in Relation to Assessors' Goals: American and International Practices
Park, Lorenz R. mberg ;
Toxicological Research, volume 17, 2001, Pages 219~225
The basic structure for assessment of potential health risks from environmental chemicals is widely agreed upon, but many of the details of risk assessment procedures differ among practitioners. Government regulatory agencies typically have guidelines or standard procedures for their risk assessments, established to ensure consistency and comparability, to set standards for adequacy, and to embody underlying tenets. In setting and updating such guidelines, each agency takes into account not only the prevailing thinking about appropriate procedures, but also its own goals and responsibilities and the precedents it has set for itself in past analyses. This results in variations in methods, and consequently in characterization of risks, among regulatory assessments, even when they are based on the same data. As a result, adopting existing assessments from a variety of regulatory bodies needs to be done with caution. This paper examines some of the variants in risk assessment approaches among American federal regulatory agencies and relates them to the variations in regulatory responsibilities of those groups. Comparisons to international practices are also drawn. The impact on development of world-wide risk standards is discussed.
Effects of Korean Red Ginseng Water Extract on Bisphenol A-induced Developmental Toxicity in Rats
Toxicological Research, volume 17, issue 3, 2001, Pages 225~234
The present study was conducted to investigate the effects of Korean red ginseng water extract (KRGWE) on developmental toxicity caused by the environmental estrogen bisphenol A (BPA) in Sprague-Dawley rats. fifty males successfully mated were randomly assigned to five experimental groups, 1.e., group I (vehicle control), group II (BPA 1000mg/kg), group III (KRGWE 400mg/kg), group IV (BPA 1000mg/kg & KRGWE 200mg/kg), and group V (BPA 1000mg/kg & KRGWE 400mg/kg). The test articles were administered by gavage to mated females from gestational days (GD) 1 through 20 (sperm vaginal lavage=day O). All females were subjected to caesarean section on GD 21 and their fetuses were examined for external, visceral, and skeletal abnormalities. In the group II, significant maternal toxic effects including suppressed body weight, decreased body weight gain during pregnancy, and reduced food consumption were observed in pregnant rats. The minimal developmental toxicity including fetal ossification delay was also found in fetuses. In addition, a tendency for increased pregnancy failure, increased pre-and postimplantation loss, and decreased fetal body weight was observed. However, no fetal morpho-logical abnormalities were seen in surviving fetuses at a dose level of 1000mg BPA/kg. On the other hand, the maternal toxicity and developmental toxicity found in the groups IV and V were comparable to those of the group II. There were no adverse signs of either maternal toxicity or developmental toxicity in the group III. These results showed that administration of BPA at a dose level of 1000mg/kg to pregnant rats resulted in significant maternal toxicity and minimal developmental toxicity, and that no protective effects on BPA-induced maternal toxicity and developmental toxicity were found by concomitant gavage dosing of KRGWE.
Improving International Access to the IARC Monographs Database with Linkage to other Sources of Information
Rice, Jerry M. ; Waters, Michael D. ; Wright, R.Glenn ;
Toxicological Research, volume 17, 2001, Pages 227~236
The IARC Monographs Programme on the Evaluation of Carcinogenic Risks to Humans has reviewed, summarized and evaluated 869 environmental agents and exposures as oj June 2000. This large collection includes all relevant published epidemiological data on cancer in exposed humans and results of bioassays for carcinogenicity in experimental animals. Since 1986. cancer data have been systematically supplemented by summaries of other toxicological data that are relevant to assessments of carcinogenic hazard. These include summaries qf genetic and related effects of chemicals. which have been prepared as Genetic Activity Profiles (GAP) by the U.S. EPA in collaboration with IARC. As the Mono-graphs have proved increasingly valuable and influential worldwide. they have evolved into an encyclopedia on environmental carcinogenic risks to humans. However. the Monographs have historically been prepared only as printed books with limited distribution. and the Monographs Programme has needed to adjust to expectations oj wider availability. Since 1998 the evaluations and summaries have been globally accessible by Internet from IARC (http://www.iarc.fr) and the GAP profiles by Internet from EPA (http://www.epa.gov/gapdb/). with the two web sites linked. Improved EPN/ARC GAP database and software. GAP2000. now link GAP profiles directly to the appropriate IARC web pages for summaries of evaluations of a given compound and its overall IARC classification. During the year 2000. by means of optical character recognition (OCR) technology the entire series of IARC Monographs is being converted to an electronic version. The first edition is now available commercially in CD-ROM format and will soon become available on-line at
Mutagenicity Tests on CJ-50005 (Hepatitis A Vaccine)
Toxicological Research, volume 17, issue 3, 2001, Pages 235~239
CJ-50005 is an inactivated whole virus vaccine derived from hepatitis A virus (HM175) grown in human MRC-5 diploid fibroblasts cell culture. In order to evaluate the mutagenic potential of CJ-50005, : 3 sets of mutagenicity tests were performed. In the reverse mutation test wing Salmonella typhimurium TA1535, TA1 537, TA98, TA100 and TA102, CJ-50005 did not increase the number of revertants at any concentration tested in this study (2.8, 1.4, 0.7, 0.35 and 0.175
/plate). CJ-50005, at concentration of 2.8, 1.4 and 0.7
/ml, did not increase the number of cells having structural or numerical chromosome aberration in cytogenic test using Chinese Hamster Lung cells. In mouse micronucleus test, no significant increase in the occurrence of micronucleated polychromatic erythrocytes was observed in ICR male and female mice intraperitoneally administered with CJ-50005 at the doses of 25, 12.5 and 6.25
/kg. These results indicate that CJ-50005 has no mutagenic potential in these in vitro and in vivo system.
The Formation of Information Network on Chemical Safety with Toxicological Data in China
Yao, Peipei ;
Toxicological Research, volume 17, 2001, Pages 237~239
China is an Asia country with population more than 1,200 millions. According to the national registration, the number Q[ chemicals commonly used in China reaches 80,000, and the number of chemicals produced in China is more than 30,000, about 10% of which has been evaluated for safety and has the toxicological data. Most of the chemicals still need safety evaluation and a part of chemicals need a renewed evaluation. At present. the information techniques and telecommunication network are develop-ing widely and intensively. It is used not only in different institutions and enterprises, but also in many governmental sectors in my country. Here is the introduction of the situation of information network on chemical safety with toxicological data and the work done by different institutions and governmental sectors in China.
Induction of Apoptosis in the Testes of SD Rats After Exposure to 2-Bromopropane
Kim, Young-Hee ; Cho, Sung-Whan ; Ha, Chang-Su ; Kang, Boo-Hyon ;
Toxicological Research, volume 17, issue 4, 2001, Pages 241~248
Exposure to 2-Bromopropane has been known to cause degeneration of male germ cells. However the mechanism underlying this process is poorly understood. The objective of this study was to determine whether or not the exposure of male Sprague-Dawley rats to 2-BP induces apoptosis in male germ cells. Male rats(N=3 or 4 in each group) were orally administered either with the corn oil vehicle (10 ml/kg body weight) or with 2-BP (3,500 mg/kg) once a day for 3 days. The presence of apoptosis was determined by TUNEL detection in situ and by an increase in DNA fragmentation. A low spontaneous incidence of apoptosis was observed in vehicle control animals, especially in pre-meiotic germ cells of stages I-VI and stages XII-XIV the seminiferous tubules. In 2-BP exposure rats, the incidence of apoptosis markedly increased at 4 h, reached a peak at 8 h (about 7-fold over control), and then decreased rapidly to control level by 48 h after the last administration. Although apoptosis induced by 2-BP occurred in all stages of germ cells, it was most pronounced in spermatogonia and early spermatocytes in stages I-VI and stages XII-XIV. Taken together, our results suggest that apoptosis is involved in the toxicity of testicular germ cells resulting in oligospermia or azoospermia after exposure to 2-BP.
Future of Toxicology and Role of Asian Chemical Safety Network
Kaminuma, Tsuguchika ;
Toxicological Research, volume 17, 2001, Pages 241~249
Toxicology is under challenge from several new trends in science and technology, namely computer, the Internet, genome projects, genomic technologies, and combinatorial chemistry. These new trends will drastically change research style of toxicology. In addition to conventional uni cellular tests and animal tests using rodents, computer simulation, DNA chips (microarrays), in vivo tests using simple model organisms such as nematodesor flies become important routine screening tests. How to arrange these tests in tiers will become a new problem. Endocrine disruptors hypothesis is a good example for this kind of futuristic approach. Computer, particularly the Internet, is also enabling toxicologists and regulatory experts to collaborate more closely. The IPCS (International Program for Chemical Safety) which is ajoint project of WHO, ILO and UNEP, is a well-known international collaborative research for chemical risk assessments. The GINC project of IPCS is an effort to utilize the Internet for such collaborations. Some efforts were also made to establish regional collaboration network in East Asia under this project.
Free Radical Involvement in the DNA Damaging Activity of Fumonisin Bl
Lee, Wan-Hee ; Lee, Kil-Soo ;
Toxicological Research, volume 17, issue 4, 2001, Pages 249~253
Fumonisin B1, a mycotoxin, is thought to induce esophageal cancer in humans and apoptosis in animal cells by inhibiting ceramide synthase. Dumonisin Bl may also generate reactive oxygen species directly or indirectly, leading to DNA damage and lipid peroxidation. In this study, a DNA fragmentation assay, dichlorofluorescein (DCF) analysis, and single cell gel electrophoresis (SCGE) were used to investigate the involvement of cellular free radicals, specifically hydrogen peroxide, in the DNA damaging activity of fumonisin B1. From an in vitro DNA fragmentation assay, E. coli DNA, damage by fumonisin Bl was increased by the addition of superxide dismutase (SOD) and decreased by catalase. SCGE and DCF analysis in vivo showed that the nuclear DNA damage and intracellular free radicals in cultured rat hepatocytes treated with fumonisin B1 were increased with the concentration of fumonisin Bl . DNA damage and free radical generation were inhibited by the addition of catalase. Fumonisin Bl , in the presence of SOD, produces hydrogen peroxide causing oxidative DNA damage and protein malfunction, leading to genotoxicity and cytotoxicity of the toxin.
Role of PI3-kinase and MAP Kinases in the ARE-mediated Glutathione S-Transferase Induction by Phytochemicals: Comparison with the Oxidative Stress Caused by Decreased Glutathione
Kim, Sang-Geon ; Kang, Keon-Wook ;
Toxicological Research, volume 17, 2001, Pages 251~256
The expression of phase II detoxifying enzymes is affected by a variety of compounds and the induction of the enzymes plays an essential role in chemoprevention. A variety of phytochemicals such as sulfur-containing chemoprotective agents (SCC) may trigger cellular signals and activate phase II gene expression through ARE activation. see induces glutathione S-transferases. Studies were conducted to investigate the role of mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3-kinase) in the induction of GST (e.g. rGSTA2) by sec. We also studied the MAP kinase pathway responsible for the GST expression by see and compared that with the pathway activated by oxidative stress as a result of sulfur amino acids deprivation (SAAD). see inhibited phosphorylation of ERK1/2 although the effect of see on JNK and p38 MAP kinase was minimal. Wortmannin and LY294002. PI3-kinase inhibitors. abolished the increases in rGSTA2 mRNA and protein levels by SCC. Deprivation of cystine and methionine caused oxidative stress in H4IIE cells. as evidenced by a decrease in the reduced glutathione and an increase in prooxidant production. Electrophoretic mobility shift assay revealed that the ARE complex consisting of Nrf-1/2 and Maf proteins was activated 12~48 h. The rGSTA2 mRNA and protein levels were increased by SAAD. Activation of ARE and induction of rGSTA2 were both completely inhibited by PI3-kinase inhibitors. Inhibition of p38 MAP kinase by SB203580 prevented the ARE-mediated rGSTA2 induction. The results of this study showed that PI3-kinase might play an essential role in the ARE-mediated rGSTA2 induction by see or SAAD and that the dual MAP kinase pathways were responsible for the enzyme induction.
Metal Effects of Urban Air Particulates on Cytokine Production and DNA Damage
Lee, Kwan-Hee ; Hong, Yun-Chul ;
Toxicological Research, volume 17, issue 4, 2001, Pages 255~265
Epidemiologic studies have demonstrated an association between short-term exposure to particulate air pollutants and increased mortality. However the biological mechanism underlying these associations have not been fully established and also the chemical and physical characteristics of the pollutant particles are not well understood. The metal constituents of air pollutant particles and their bioavailability are considered to Play an important role as possible mediators of Particle-induced airway injury and inflammation. Sprague-Dawley rat alveolar macrophage cells (NR8383) were exposed to airborne and acid-leached particulate matter (PM). Titanium oxide and nickel subsulfide were used as negative and positive controls. Particle-induced reactive oxygen species formation in cells was detected using the fluorescent probe 2',7'-dichlorofluorescin diacetate. Expression of TNF-
and IL-6 were measured by enzyme-linked immunosorbent assay, and PM-induced DNA double-strand breaks were determined with
DNA/Hind III marker. Metals associated with air pollutant particles mediated intracellular oxidant production in alveolar macrophages, and the cytotoxicity and proinflammatory cytokine production induced by PM were associated with oxidative stress. The oxidants produced by air pollutant particles also are likely to induce DNA double-strand breaks. Our findings in alveolar macrophage cells exposed to PM and acid-leached PM support the hypothesis that metal components in urban air pollutants and their bioavailabilities might play an Important role in the induction of the adverse health effects.
Anti-dementia Effects of Gouteng-san and Si-Wu-Tang
Watanabe, Hiroshi ;
Toxicological Research, volume 17, 2001, Pages 257~261
Recently, a traditional medicine called Gouteng-san, which consists of eleven herbs, was reported to be effective in treating vascular dementia with a double-blind, placebo-controlled study. Gout-eng-san is also used for patients with vascular dementia in combination with Si-Wu-Tang. The effect of Gouteng-san and Si-Wu-Tang on deficit of learning behavior was investigated using step-down passive avoidance task in mice. Hot-water extract of Gouteng-san (1.5 and 6 g/kg, p.o.) significantly prolonged the step-down latency shortened by scopolamine. The extract of Uncaria hook (150 mg/kg, p.o.), one of the component herb of Gouteng-san, significantly prevented the decrease in the latency after scopolamine. Hot-water extract of Si-Wu-Tang (1.5 and 6 g/kg of dried herbs, p.o.) prevented dose-dependently scopola-mine-induced disruption qf learning behavior. Si-Wu-Tang also prevented the ischemia-induced deficit of learning behavior. Both hot water extract of peony and angelica (1.5 g/kg, p.o.), which are component herbs qf Si-Wu-Tang, prevented the scopolamine-induced learning behavior deficit. Scopolamine (10 uM) suppressed long-term potentiation (LTP) of population spike in the CA1 region of the rat hippocampal slices. Peoniflorin (0.1~ 1uM) extracted from paeony root significantly ameliorated scopolamine-induced inhibition of LTR These results suggest that improvement of deficit of learning behavior by Gouteng-san and Si-Wu-Tang is mediated by direct and/or indirect activation of the cholinergic system in the brain.
Chronic Oral Toxicity and Carcinogenicity Study of Steviol, a Metabolite of Stevioside, in Hamsters
Toskulkao, C. ; Suwannatrai, M. ; Temcharoen, P. ; Chaturat, L. ; Suttajit, M. ; Sahaphong, S. ; Glinsukon, T. ;
Toxicological Research, volume 17, 2001, Pages 263~270
The carcinogenic potential of steviol, a metabolite of/ stevioside (a compound that is used as a sweetener for food and drink), was examined in hamsters of both sexes. Groups of 55 male and 55 female hamsters were given diets containing steviol at 0, 100 and 500 mg/kg diet for 22 months in males and 18 months in females. After 6, 12 and 22 months in males and 18 months in females. hamsters from each group were sacrificed for hematological and biochemical tests. Growth food utilization and consumption, general appearance and mortality were similar in treated and control groups. The mean life span of hamsters given steviol was not significantly different from that of the controls. No treatment-related changes were observed in hematological, urinary and biochemical values at any stage of the study. There was no significantly altered development of neoplastic or non-neoplastic lesions attributable to steviol treatment in any organ or tissue. The highest level oj steviol in the diet which still causes no effects in hamsters was 500 mg/kg diet, under the experimental conditions used.
Reproductive Toxicity Assessment on 2-Bromopropane using Spematogenesis Stage Classification and Sertoli Cell Indices
Toxicological Research, volume 17, issue 4, 2001, Pages 267~272
This study was carried out to assess the reproductive toxicity of 2-bromopropane (S-BP) using spermatogenesis stage classification and Sertoli cell indices (SCI).Vehicle control olive oil and 2-BP doses of 125, 250 and 500 mg/kg of body weight were injected in the interaperitoneum of 12 weeks male Sprague-Dawley rats for 28 days respectively of SCI on germ cells including the spermatogonia of stages II-III, Ⅵ,Ⅹ, XII, ⅩIII, and spermatocytes of stages VIII (preleptotene), Ⅹ (leptotene), XII (leptotene), V and Ⅵ (pachytene), and the round spermatids of stage Ⅵ. Considering the process of maturation depletion in spermatonesis, spermatogonia may be the primary target cells of 2-BP toxicity.
Peroxyl Radical Scavenging Capacity of the Flavonolignan Silybin, Ginkgo Biloba Extract EGb 761, American Green Tea and a Series of Germacranolides
Winston, Gary W. ; Kim, Young Chul ; Dugas, Alton J. ; Castaneda-Acosta, Jose ; Fischer, Nikolaus H. ;
Toxicological Research, volume 17, 2001, Pages 271~280
We report on the applicability oj a method recently developed in our laboratory for measuring the antioxidant potential of isolated chemicals and extracts derived from natural products. Peroxyl radicals generated by thermal homolysis of 2,2'-azobis-amidinopropane (ABAP) oxidize
-methiolbutyric acid (KMBA) to ethylene, which is monitored by gas chromatography. Inhibition of ethylene formation in the presence of antioxidants that compete with KMBA for peroxyl radicals is the basis of the Total Oxyradical Scavenging Capacity Assay (TOSCA; Winston et al., 1998). Antioxidative activities of water-soluble extracts of American green tea, the anti-hepatotoxic flavonolignan from milk thistle (Silybum marianum) silybin, Ginkgo biloba extract EGb 761, and a series of naturally occuring sesquiterpene lactones (all ger-macranolides found in in fungi, liverworts, and plants) were studied. The specific TOSC value per
M silybin was 5.2, which is essentially comparable to that of Trolo
, a water-soluble vitamine E analog. Tea and Ginkgo extracts exhibited potent peroxyl radical scavenging capacity with values, respectively of =1700 and 1000
equivalent per gram dry matter. The known anti-inflammatory activity of some germacranolides prompted study of their antioxidant capacity. None of the lactones exhibited antioxidant capacity toward peroxyl radicals comparable to Trolo
; costunilide, the most lipophilic, had a TOSC value = to glutathione. The potential role of peroxyl radicals in lipidperoxidation, other cellular damage, and var-ious disease states suggest a possible preventive role for silybin, green tea and Ginkgo biloba in oxidative stress caused by these free radical species.ecies.
Single Dose Toxicity Studies of the Bamboo Salt (Jukyum) in rats
Toxicological Research, volume 17, issue 4, 2001, Pages 273~277
Though the bamboo salt, called as "JUKYUM" has been widely used in Korea as panacea, it's toxicity were not screened completely. To investigate the toxicity of bamboo salt, we compared with the toxicity of crude salt and reagent-grade NaCl by performing single dose oral toxicity test in SD rats. Crude salt, natural sun-dried salt (crude salt) production, was purchased from the western seashore of Korean peninsular, and reagent-grade NaCl was purchased from Sigma company. Results of the single dose oral toxicity tests on bamboo salt, crude salt and reagent-grade NaCl to SD rats are as follows,
of bamboo salt was 4174mg/kg (male) and 4074mg/kg (female), that of crude salt was 4871mg/kg (male) and 4898mg/kg (female) and that of reagent-grade NaCl was 4247mg/kg (male) and 4025mg/kg (female), respectively. There were little differences in clinical signs and gross legions among groups. Finding of gross autopsy and necropsy of bamboo salt treated group were similar to other groups.er groups.
Effects of 00 Hz Horizontally Polarized Magnetic Fields on Embryo-fetal Development in SD Rats
Toxicological Research, volume 17, issue 4, 2001, Pages 279~286
Recently, there is an increasing nationwide concern in Korea that exposure to electric and magnetic fields in the home environment may not be safe in humans. To identify possible effects of horizontally polarized magnetic fields (MF) exposure on embryo-fetal development, timed-mated female Sprague-Dawley rats (24/group) received continuous exposure to 60 Hz MF at field strengths of 0 Gauss (sham control), 50mG,833 mG, or 5000 mG. Dams received MF of sham exposures for 22hr/day on gestation days 6 through 20. Experimentally generated MF were monitored continuously througout the study. There was no evidence of maternal toxicity of developmental toxicity in any MF-exposed groups. Mean maternal body weight, organ weights, and gross findings in groups exposed to MF did not differ from those in sham control. No significant differences in fetal deaths, fetal body weight, and placental weight were observed between MF-exposed groups and sham control. External, visceral, and skeletal examination of fetuses demonstrated no significant differences in the incidence of fetal malformations between MF-exposed and sham control groups. In conclusion, exposure of pregnant Sprague-Dawley rats to 60 Hz at MF strengths up to 5000 mG during gestation day 6-20 did not produce any biologically significant effect in either dams of fetuses.
Study on Applying Artichoke Extract to Lessen The Toxicity of Aflatoxin to Chicken
Diep, Le Thi Ngoc ;
Toxicological Research, volume 17, 2001, Pages 281~287
The Artichoke extract at 10% was used to add in drinking water to understand its effect on Aflatoxicosis of chickens. The Artichoke extract at the dose of 6 ml per liter of drinking water was given (experiment group) or not (control group) and to Hybro chickens (150 birds), during the first 49 days of life. Also, the chickens were fed with foodstuff containing 200 ppb or 500 ppb Aflatoxin
. Results showed that, the chickens having Artichoke extract: (1) Had overcome the growth retardation caused by the toxin at concentration of 200 ppb and 500 ppb of Aflatoxin
(an addittonal weight gain of about 200-400 g/bird). (2) The feed conversion was improved (a reduction of 200-400 g of feed per kg of bird living weight). (3) Aflatoxicosis lesions were mild in the chickens, which fed 500 ppb of Aflatoxin
or not found in those having the toxin 200 ppb. The blood examinations at 28th and 49th days of the trial gave the following results: (1) The Artichoke extract had an effect of suppressing the changes of blood cell numbers, hemoglobin amount. packed cell volume. leukocyte formula that were caused by Aflatoxin
. (2) The Artichoke extract had an effect of suppressing the diminution oj sugar, protein levels and the increase of the levels of GOT, GPT, alkaline phosphatase and bilirubin in the blood of intoxicated chickens. There was not or very Jew residue of Aflatoxin
contained in the liver and muscle of chickens intoxicated by Aflatoxin
having Artichoke, that was much lower than the allowed level in animal products.
Acute Oral Toxicity Test in Japanese Quail
Toxicological Research, volume 17, issue 4, 2001, Pages 287~296
The acute oral LD5O toxicity values of isazofos, pyraclofos, diazinon and methomyl were determined for Japanese quail based on OECD guideline. The
of isazofos, pyraclofos and diazinon was 16.26 mg/kg, and 7.11mg/kg body weight In female respectively. And the
of each chemical in male was 21.44, 35.64, 8.28 mg/kg body weight respectively. Diazinon was the most susceptible compounds to Japanese quail in both sexes. The
of methomyl was 21.24 mg/kg body weights in female, and 28.28 mg/kg body weight in male respectively. Diazinon, isazofos and methomyl were more toxic In the female than male. The symptoms of poisoning were similar in quails administrated with each chemicals. The clinical sign in Japanese quail were ataxia, salivation, diarrhea, ruffled feather and convulsion at dead point. There were severe hemorrhage and catarrhal inflammation from duodenum to ileum In all compounds. In Japanese quail treated with organophosphorus and carbamate compounds, brain acetylcholinesterase was inhibited by 88-96. The recovery was not observed after 5 h in sublethal dose.
Induced Mutant Animal Models for Studying the Genetics of Hypertension and Atherosclerosis
Oh, Goo-Taeg ;
Toxicological Research, volume 17, 2001, Pages 289~292
Gene targeting allows precise, predetermined changes to be made in a chosen gene in the mouse genome. To date, targeting has been used most often for generation of animals completely lacking the product of a gene of interest. Models of essential hypertension have been produced by mutated genes relating renin angiotensin system. The most significant contribution to understanding the genetic etiology of essential hypertension is probably the demonstration that discrete alterations in the expression of a variety of different genes can individually cause changes in the blood pressures of mice, even when the mice have all their compensatory mechanisms intact. These effects are readily detected in animals having moderate decreases in gene function due to heterozygosity for gene disruptions or modest increases due to gene duplication. As a species the mouse is highly resistant to atherosclerosis. However. through induced mutations it has been possible to develop lines oj mice that are deficient in apolipoprotein E, a ligand important in lipoprotein clearance, develop atherosclerotic lesions resembling those observed in humans. The atherosclerotic lesions in apoE-deficient mice have been well characterized, and they resemble human lesions in their sites of predilection and progression to the fibroproliferative stage. Other promising models are mice that are deficient in the low-density lipoprotein receptor. Considerable work still remains to be done in dissecting out in a rigorous manner the effects of alterations in single genes on the induction or progression of atherosclerosis and on the control of blood pressures. Perhaps even more exciting is the opportunity now becoming available to breed animals in which the effects oj precise differences in more than one gene can be studied in combination.
CB6F1-Tg rasH2 Mouse Carrying Human Prototype c-Ha-ras Gene As an Alternative Model For Carcinogenicity Testing For Pharmaceuticals
Usui, T. ; Urano, K. ; Suzuki, S. ; Hioki, K. ; Maruyama, Ch. ; Tomisawa, M. ; Ohnishi, Y. ; Suemizu, H. ; Yamamoto, S. ;
Toxicological Research, volume 17, 2001, Pages 293~297
The international pharmaceutical and regulatory communities had been recognizing the limited utility of conventional rodent carcinogenicity study particularly on the second species, mouse, after intense investigation of carcinogenicity data base worldwide, and a new scheme for carcinogenicity testing for pharmaceuticals was proposed at the Expert Working Group on Safety in the International Conference on Harmonization (ICH) in 1996. CB6F 1-Tg rasH2 mouse carrying human prototype c-Ha-ras gene with its own promoter/enhancer is one oj the new carcinogenicity assay model for human cancer risk assessment. Studies have been conducted since 1992 to validate the transgenic (Tg) mice for rapid carcinogenicity test-ing, short term (26 weeks) studies with genotoxic (by Salmonella), non-genotoxic carcinogens, genotoxic non-carcinogens, non-genotoxic non-carcinogens revealed relatively high concordance oj the response of the Tg mouse with classical bioassay across classes of carcinogenic agents. Mechanistic basis for carcinogensis in the model are being elucidated in terms of the role of overexpression and/or point mutation of the transgene. This report review the initial studies of validation of the model and preliminary results of on-going ILSI HESI ACT project will be presented.
Single Dose Toxicity Studies of C.1-50005 (Hepatitis A virus Vaccine) in Rats and Dogs
Toxicological Research, volume 17, issue 4, 2001, Pages 297~301
The acute toxicity of CJ-50005, an inactivated whole virus vaccine derived from hepatitis A virus (HM175) grown in human MRC-5 diploid fibroblast culture, was tested in Sprague Dawley (SD) rats and beagle dogs. CJ-50005 was orally and intramuscularly administered up to the maximum dose of 81
/kg. as much as 3,000 times of the expected clinical dose, in SD rats and was intramuscularly administered up to 27
/kg, as much as 1,000 times of the expected clinical dose, in beagle dogs. In these experiments, there were no death and clinical changes which were related to CJ-50005 administration. In addition, there were no significant changes between control and treated groups in body weights and autopsy findings. In conclusion, the administration of CJ-50005 over 81
/kg in SD rats and over 27
/kg in beagle dogs was proved to be safe, and it is thought that CJ-50005 may not show any toxicity in its clinical use.
Nrf2 Knockout Mice that Lack Control of Drug Metabolizing and Antioxidant Enzyme Genes - Animals Highly Sensitive to Xenobiotic Toxicity
Enomoto, Akiko ; Itoh, Ken ; Harada, Takanori ; Yamamoto, Masayuki ;
Toxicological Research, volume 17, 2001, Pages 299~304
Xenobiotics and their reactive intermediates bind to cellular macromolecules and/or generate oxidative stress. which provoke deleterious effects on the cell function. Induction of xenobiotic-biotrans-forming enzymes and antioxidant molecules is an important defense mechanism against such insults. A group of genes involved in the defense mechanism. e.g. genes encoding glutathione S-transferases. NAD(P)H: quinone oxidoreductase, UDP-glucuronosyltransferase (UDP-GT) and
-glutamylcysteine synthetase (GGCS). have a common regulatory sequence, Antioxidant or Electrophile Responsive Element (ARE/EpRE). Recently. Nrf2. discovered as a homologue of erythroid transcription factor p45 NF-E2, was shown to bind ARE/EpRE and induce the expression of these defense genes. Mice that lack Nrf2 show low basal levels of expression and/or impaired induction of these genes. which makes the animals highly sensitive to xenobiotic toxicity. Indeed. we show here that nrf2-deficient mice had a higher mortality than did the wild-type mice when exposed to acetaminophen (APAP). Detailed analyses of APAP hepatotoxicity in the nrf2 knockout mice indicate that a large amount of reactive APAP metabolites was generated in the livers due to the impaired basal expression of two detoxifying enzyme genes, UDP-GT (Ugt1a6) and GGCS. while the cytochrome P450 content was unchanged. Thus. the studies using the nrf2 knockout mice clearly demonstrate significance of the expression of Nrf2-regulated enzymes in protection against xenobiotic toxicity.
Difference of Age-Related Sensitivity to Organophosphates
Toxicological Research, volume 17, issue 4, 2001, Pages 303~308
The potential for a given anticholinesterase pesticide to exhibit age-related toxicity is essential information for an accurate and proper risk assessment of that compound. This investigation was designed to study the age-related toxicity of active metabolites of four organophosphates using in vitro detoxification measurement. The blood samples were collected from 1 month and 18 months old rats. The
values of mouse brain recombinant AChE of chlorpyrifos-oxon, diazoxon, malaoxon and paraoxon were 10.35, 112.84, 151.28 and 18.43 nM, respectively. When the plasma of young rats, and
were added, the
values of mouse brain recombinant AChE of chlorpyrfos-oxon, diazoxon, malaoxon and paraoxon were 31.89, 164.25, 139.94 and 16.36 nM, respectively. The
values of mouse brain recombinant AChE of chlorpyrifos-oxon, diazoxon, malaoxon and paraoxon were changed to 136.840, 1244.45, 654.54 and 52.66 nM by A-esterases In adult rats. These results suggest that four organophosphates have a potential toxicity to exhibit age-related sensitivity.
Use of Tumor Necrosis Factor Receptor (TNFR)-Knockout Mice to Probe the Mechanism of Chemically-Induced Asthma
Karol, Meryl H. ; Matheson, Joanna M. ; Lange, Robert W. ; Lemus, Ranulfo ; Luster, Michael I. ;
Toxicological Research, volume 17, 2001, Pages 305~307
Toluene diisocyanate (TDI) is widely used in the manufacture of polyurethanes and is a recognized cause of occupational asthma. Although extensive investigations have been undertaken, the molecular mechanism(s) of the disease is still unclear. We hypothesized that inflammatory cytokines are required during both the sensitization and elicitation phases of the disease and have utilized TNF-R knock-out (KO) mice to address the hypothesis. Black C57 TNFR knock-out mice were exposed to TDI by sc injection and challenged by inhalation of 100 ppb TDI vapor. Control animals included: wild type C57 animals, sham-exposed animals that were challenged with TDI, and animals that were injected with anti-TNF antibodies prior to sensitization and again prior to challenge. Total IgE was increased in the knock-out animals compared with the wild type sensitized and challenged animals whereas TDI-specific IgG antibodies did not differ significantly in KO and wild type animals. There was less inflammation in the nares and trachea in KO animals compared with the wild type animals exposed to TD1 as well as less goblet cell hyperplasia and epithelial damage. Airway reactivity was assessed in animals treated with anti-TNF
antibody and found to be substantially reduced compared with that in sensitized and challenged animals. These results indicate that TNF
plays a role in the immunologic and physiologic responses and in airways inflammation in this animal model and suggests a role for TNF in occupational asthma due to TDI.
Effects of Repeated Exposure to Pb Acetate on Hematopoietic Function, Testis and Kidney in Male Rats
Toxicological Research, volume 17, issue 4, 2001, Pages 309~316
Male Sprague Dawley rats were exposed to 0, 0.04, 0.2, and 0.8% Pb acetate in drinking water for 13 weeks and fed a commercial diet. Dose-related adverse effects observed at the end of the Pb acetate exposure in the drinking water were as follows: decrease in body weight gain, decrease in hemoglobin, hematocrit(HCT), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), increase in serum glucose, decrease in serum testosterone, increase in lead accumulation and
-ALA release in urine, and decrease in
-ALAD activities DNA content and histopathlogy (intranuclear inclusion body in kidney proximal tubule cell). Taken together, repeated exposure of lead acetate induced toxicities in hematopoietic system, especially testis and kidney.
Alkyl Hydroxy Benzoate Preservatives (Parabens) Are Estrogenic Compounds; Their Adverse Effects on Animals and Human
Kang, Kyung-Sun ; Che, Jeong-Hwan ; Park, Jin-Sung ; Lee, Yong-Soon ;
Toxicological Research, volume 17, 2001, Pages 309~312
It has recently been suggested that the release of "endocrine disrupters (EDs)" into the environment has resulted in adverse health effects on wild life populations and humans (Golden et al., 1998; Tyler et al., 1998; Kang et al., 2000). Human sperm counts have declined significantly throughout the world during the past fifty years, and which is a significant public health concern (Carlsen et al., 1992; Carlsen et al.. 1995). In addition, the EDs persisting in the environment are known to disrupt the normal endocrine systems of wildlife (Colborn, 1995; Crewet al., 1995; Folmer et at, 1996; Sumpter, 1995; Tyler, 1998). Some estrogenic chemicals bind to estrogen receptors (Bolger et al.. 1998), interfere with the binding of physiological ligands to steroid hormone-binding proteins (Danjo, 1997; Milligan et al., 1998). and show immunotoxicity (Sakae et al., 1998). (omitted) (omitted)
Hormone-Mimic Chemicals and Their Possible Endocrine Disruption - Development of Testing Methods -
Imai, Kiyoshi ;
Toxicological Research, volume 17, 2001, Pages 313~317
The Ministry of Health and Welfare of Japan has set up six research groups concerning the endocrine disrupting chemicals. One of these projects was "A study on development of testing methodology for health effects due to exposure of environmental endocrine disruptors". In this paper, three topics are described. In OECD collaboration for pre-validation of uterotrophic assay, the most sensitive response to ethnyl estradiol was noted in the ovarectomized rats treated subcutaneously for 7 days. Secondly, it was suggested that changes of the serum
-globulin level may be a sensitive parameter for detecting the estrogenic activities of chemicals. Finally, development of the sexually dimorphic nucleus of preoptic area in the brain oj male rats was inhibited by the treatment with estrogenic chemicals, and their masculine behaviors and reproductive abilities were impaired after sexual maturation. In conclusion, these parameters are considered to be sensitive endpoints for testing estrogenic chemicals.chemicals.
Dermal Penetration Rate and Pharmacokinetics of the Insecticide Methidathion in Sprague-Dawley Rats
Sung, Ha-Jung ; Kim, Jeong-Han ;
Toxicological Research, volume 17, issue 4, 2001, Pages 317~323
The skin penetration rate of methidathion in vitro and pharmacokinetics of methidathion in vivo were studied with male Sprague-Dawley rats by dermal treatment. The in vitro skin penetration rates for Sprague-Dawley rats of methidathion technical (50 mg, 100
) and emulsifable concentrate (EC,40mg, 100
) were determined as 18.4
/h (RSD : 6.5) and 18.5
/h (RSD : 3.2), respectively. Dose-related systemic exposure (AUC) was observed in rats after dermal treatment. The corresponding AUC,
2/ of methidathion in plasma were 1.5
.hr/ml, 6 h, 0.10
/ml, and 16 h, for 116mg/kg doses, 3.2
. hr/ml, 8 h, 0.12
/ml, and 23 h, for 232 mg/kg doses and 10
. hr/ml, 12 h, 0.32
/ml, and 20 h, for 1,160 mg/kg doses respectively. The urinary excretion of methidathion, estimated wing an equation derived from the in vitro skin penetration study was 0.24~0.35% of the absorbed dose. The concentration of methidathion in kidney was higher than that in liver. Dose-dependent absorption and excretion of methidathion without saturation was observed under in vivo experimental condition.n.n.
Endocrine Disruptive Potentials in Surface Water Samples from Taihu Lake, Yangtze Delta
Shen, L. ; Lin, G.F. ; Shen, J.H. ;
Toxicological Research, volume 17, 2001, Pages 319~321
Taihu Lake is a major water source for part of Yangtze Delta, which is one of the most urbanized and economically prosperous areas in China. In last couple of decades, some parts of the lake were highly polluted due to eutrophication. This study analyzed dioxin-like potential and mutagenic potential in surface water samples from Taihu Lake. The samples were prepared by XAD-2 resin procedure. A batch of biological assays, including dioxin-like potential microassay with the rat hepatocyte cell line H411E, and Ames test was employed in the research. Results showed that jour water samples have high content of dioxin-like biological potential, the highest activity TEQ to 2,3,7,8-TCDD was 48 pg/ι in sample 1. The mutagenic effect with reading-frame shifting mechanism was confirmed in 3 of 4 samples. The effective sewage treatment facilities and reliable monitoring surveillance system are urgently needed for this area.
An Approach to Detect Health Risk of Dioxins
Pavittranon, Sumol ; Sinhaseni, Palarp ;
Toxicological Research, volume 17, 2001, Pages 323~327
March 19, 1999, the renovation qf the runway of the Bo-Fai ai1field in Hua Hin, Prachubk-erikhan, Thailand, unearthed chemicals which were left over from the project "anch Hand Operation" held during the Vietnam war era. The chemical mixtures were analyzed by the US EPA, the Department oj Medical Sciences (DMSc), Ministry oj Public Health (MoPH) and the Pollution Control Department (PCD), the Ministry oj Science Technology and Environment (MOSTE) of Thailand, The samples were found to contain several defoliants used in the operation. They were 2,4-D, 2,4,5-T, Dicamba, Cocydelic acid, and Dioxins. Due to the complexity of the issue, the multiplicity of possible health effects, and the socio-economic implications for imports and exports, the Thai Society of Toxicology submitted a proposal to request World Health Organization (WHO), Geneva. The assistance is for the area of chemical safety and called for immediate action to explore the magnitude qf risk involved with Dioxins. In this paper we present our approach to health risk assessment which takes into an account the epidemiological studies of high-risk group exposed to the Ranch Hand operation. Dioxins are endocrine disruption chemicals which public concerns are developed due to presumption that a hazard exists (www.eva.gov/dioxins/html) for which current methodologies are deemed insufficient. The recent concepts of how oxidative stress toxicants may affect health end points and biomarkers of exposure of exposed individuals are discussed. While research activities are undergoing, The Thai Society of Toxicology do not anticipate significant risk to local residents and the environment due to our concurrence with opinion from the international experts invited by the World Health Organization proposed to the local experts at a workshop in Bangkok.n Bangkok.
Similar Pattern of Fourier-Transformed Infrared Spectrum of Bond Shift Shown in Human Cervical Cancer Cells and Rat Splenocytes Exposed to Colchicine and Methomyl
Sindhuphak, Ratana ; Sinhaseni, Palarp ; Suramana, Teerayut ; Issaravanich, Somchai ; Udomprasertkul, Venus ; Dusitsin, Nikorn ;
Toxicological Research, volume 17, 2001, Pages 329~333
Apoptosis is the normal physiological process of cell death essential for the maintenance of homeostasis. The function of nicotinamide adenine dinucleotide (NAD) and adenine diphosphate (ADP) ribosylation (transfer of ADP-ribose to proteins) reactions in modifying apoptosis have recently been of great interest. Recently. CD38. a type 2 transmembrane glycoprotein expressed in hematopoietic and non hematopoietic cell lines. has been reported to possess NAD glycohydrolase activity (Han. 1999) and PC-1 and CD38 NADase regulates T cells by inhibition of phosphodiesterase/pyrophosphatase activity of PC-1 by its association with glycosaminoglycan (Hozada et al., 1999). Sindhuphak et al. (2000) has reported that cervical cancer cells can be differentiated from normal cells by using FTIR (Fourier-Transformed Infrared) technique. which has characterized shifts to be due to the phosphodiester bond in nucleic acid. protein amide I&II. carbohydrate and glycogen bands. Mechanisms how phosphodiester bond shift in cervical cancer cells as compared to control cells remain to be elucidated. Suramana et al. (2000) as well as Lohitnavy and Sinhaseni (1998) have studied methomyl and colchicine effects in rat splenocytes. Lactate Dehydroge-nase Isozymes 3 (LDH3) and LDH4 were observed to increase transiently and subsided in plasma of rats exposed to 6~8 mg/kg methomyl after 48 hours. Phosphodiester bond shift of nucleic acid. detected by FTIR. was also reported (Suramana et al., 2000). We report here, after analysis of bond shift patterns. a similar bond shifts detected by FTIR spectrum observed in human cervical cells and splenocytes of rats exposed orally to 2~8 mg/kg methomyl as well as rats exposed to colchicine 2~6 mg/kg orally.