• Toxicological Research
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• v.31 no.2
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• pp.137-149
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• 2015

Human hepatocytes, with complete hepatic metabolizing enzymes, transporters and cofactors, represent the gold standard for in vitro evaluation of drug metabolism, drug-drug interactions, and hepatotoxicity. Successful cryopreservation of human hepatocytes enables this experimental system to be used routinely. The use of human hepatocytes to evaluate two major adverse drug properties: drug-drug interactions and hepatotoxicity, are summarized in this review. The application of human hepatocytes in metabolism-based drug-drug interaction includes metabolite profiling, pathway identification, P450 inhibition, P450 induction, and uptake and efflux transporter inhibition. The application of human hepatocytes in toxicity evaluation includes in vitro hepatotoxicity and metabolism-based drug toxicity determination. A novel system, the Integrated Discrete Multiple Organ Co-culture (IdMOC) which allows the evaluation of nonhepatic toxicity in the presence of hepatic metabolism, is described.

• Environmental Analysis Health and Toxicology
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• v.30
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• pp.7.1-7.7
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• 2015

Objectives The widely promising applications of graphene nanomaterials raise considerable concerns regarding their environmental and human health risk assessment. The aim of the current study was to evaluate the toxicity profiling of graphene family nanano-materials (GFNs) in alternative in vitro and in vivo toxicity testing models. Methods The GFNs used in this study are graphene nanoplatelets ([GNPs]-pristine, carboxylate [COOH] and amide [$NH_2$]) and graphene oxides (single layer [SLGO] and few layers [FLGO]). The human bronchial epithelial cells (Beas2B cells) as in vitro system and the nematode Caenorhabditis elegans as in vivo system were used to profile the toxicity response of GFNs. Cytotoxicity assays, colony formation assay for cellular toxicity and reproduction potentiality in C. elegans were used as end points to evaluate the GFNs' toxicity. Results In general, GNPs exhibited higher toxicity than GOs in Beas2B cells, and among the GNPs the order of toxicity was pristine > $NH_2$ > COOH. Although the order of toxicity of the GNPs was maintained in C. elegans reproductive toxicity, but GOs were found to be more toxic in the worms than GNPs. In both systems, SLGO exhibited profoundly greater dose dependency than FLGO. The possible reason of their differential toxicity lay in their distinctive physicochemical characteristics and agglomeration behavior in the exposure media. Conclusions The present study revealed that the toxicity of GFNs is dependent on the graphene nanomaterial's physical forms, surface functionalizations, number of layers, dose, time of exposure and obviously, on the alternative model systems used for toxicity assessment.

• Proceedings of the Korean Institute of Resources Recycling Conference
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• 2001.05b
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• pp.109-112
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• 2001

A case study of foodwaste treatment was conducted to compare the impacts of four scenarios: incineration, incineration after biogasification, biogasification followed by composting, and composting. Potential contributions to climate change, acidification, consumption of landfill and human toxicity were assessed. Characterization of human toxicity caused by metals and PCDD/DF was performed by three multimedia fate models. Scenarios with a biogasification process showed lower impact on climate change and human toxicity. The ranking of four scenarios on human toxicity varied depending on the characterization models applied. The steady state models placed high priority on emission of heavy metals to farmland, whereas the dynamic model estimated the emission of PCDD/DF from the incineration process as more significant.

• Biomolecules & Therapeutics
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• v.2 no.1
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• pp.77-81
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• 1994

The acute toxicity of recombinant human epidermal growth factor, DWP-401 was evaluated in ICR mice of both sexes. Six groups of mice were administered orally or subcutaneously with 0, 0.125, 0.25, 0.5, 1 and 2 mg/kg of DWP-401. Abnormal clinical signs related to the compound were not observed, and no deaths occurred. Gross findings of necropsy revealed no evidence of specific toxicity related to DWP-401. LD$_{50}$ values for both male and female mice were evaluated to be over 2 mg/kg, which is approximately 2, 000 fold of presumed clinical dose.e.

• Journal of Environmental Health Sciences
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• v.38 no.1
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• pp.1-7
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• 2012

Carbon nanotubes (CNTs) stand at the frontier of nanotechnology and are destined to stimulate the next industrial revolution. Rapid increase in their production and use in the technology industry have led to concerns over the effects of CNT on human health and the environment. The prominent use of CNTs in biomedical applications also increases the possibility of human exposure, while properties such as their high aspect ratio (fiber-like shape) and large surface area raise safety concerns for human health if exposure does occur. It is crucial to develop viable alternatives to in vivo tests in order to evaluate the toxicity of engineered CNTs and develop validated experimental models capable of identifying CNTs' toxic effects and predicting their level of toxicity in the human respiratory system. Human lung epithelial cells serve as a barrier at the interface between the surrounding air and lung tissues in response to exogenous particles such as air-pollutants, including CNTs. Monolayer culture of the key individual cell types has provided abundant fundamental information on the response of these cells to external perturbations. However, such systems are limited by the absence of cell-cell interactions and their dynamic nature, which are both present in vivo. In this review, we suggested two viable alternatives to in vivo tests to evaluate the health risk of human exposure to CNTs.

• Toxicological Research
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• v.29 no.4
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• pp.221-227
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• 2013

Embryonic stem (ES) cells have potential for use in evaluation of developmental toxicity because they are generated in large numbers and differentiate into three germ layers following formation of embryoid bodies (EBs). In earlier study, embryonic stem cell test (EST) was established for assessment of the embryotoxic potential of compounds. Using EBs indicating the onset of differentiation of mouse ES cells, many toxicologists have refined the developmental toxicity of a variety of compounds. However, due to some limitation of the EST method resulting from species-specific differences between humans and mouse, it is an incomplete approach. In this regard, we examined the effects of several developmental toxic chemicals on formation of EBs using human ES cells. Although human ES cells are fastidious in culture and differentiation, we concluded that the relevancy of our experimental method is more accurate than that of EST using mouse ES cells. These types of studies could extend our understanding of how human ES cells could be used for monitoring developmental toxicity and its relevance in relation to its differentiation progress. In addition, this concept will be used as a model system for screening for developmental toxicity of various chemicals. This article might update new information about the usage of embryonic stem cells in the context of their possible ability in the toxicological fields.

• Biomolecules & Therapeutics
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• v.2 no.2
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• pp.161-172
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• 1994

This study was conducted to examine DA-3002, a biosynthetic human growth hormone, for its acute and subacute toxicities in mice and rats. The drug was administered subcutaneously and orally at a dose level of 1.0, 3.0, 8.9, 26.7 or 80.0 lU/kg once for single dose toxicity and given subcutaneously at a dose level of 0.34, 1.7 or 8.4 lU/kg daily for 13 weeks to investigate repeated dose toxicity. In the acute toxicity study, doses up to 80 lU/kg had no adverse effect on the behavior or body weight gain. Pathological examinations revealed no abnormal changes which could be attributed to toxic effect of DA-3002. In the subacute toxicity study, the growth hormone was tolerated well in broth mice and rats. No drug related deaths occurred and all animals appeared to be normal throughout the dosing period. Increases in body weight gain, food utilisation and absolute organ weights were observed in the rats in the high dose group. Mild changes in the blood chemical parameters were also seen in the treated groups. Histopathologically, however, no abnormal changes were observed in any organ. The changes noted during the treatment periods presumably represent exaggerated pharmacological effects of the growth hormone, and no observed adverse effect level (NOAEL) was considered to be more than 8.4 lu/kg/day.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2004.05a
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• pp.60-60
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• 2004

• Biomolecules & Therapeutics
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• v.6 no.2
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• pp.182-190
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• 1998

DA-3585 is a recombinant human erythropoietin produced by Dong-A pharmaceutical Co. Ltd. using recombinant DNA technique. Recently, recombinant human erythropoietin (rHu-EPO) has been used to treat various types of anemia. In this study, we examined acute and subacute toxicity of DA-3585 in rats. DA-3585 was intravenously administered to rats at dose levels of 0, 6,250, 12,500 and 25,000 lU/kg for single dose toxicity study and at dose levels of 0,100,500 and 2,500IU/kg daily for 4 week-repeated dose toxicity study. In the single dose toxicity study, there were no death, clinical signs and changes in body weight gain related to the treatment. Necropsy revealed no evidence of toxicity related to DA-3585, In the repeated dose toxicity study, all the rats survived throughout the study. There were no treatment-related changes in clinical signs, food and water intake, and body weight. Hematological examination showed increases in the number of erythrocytes, hemoglobin concentration, hematocrit value and mean corpuscular volume, and decrease in the number of platelet in 500 and 2,500 lU/kg dosed groups. Extramedullary hematopoiesis in the spleen and erythroid hyperplasia in the bone marrow were noted as treatment-related histological changes. Toxicologically significant changes were not observed in blood biochemistry, urinalysis, organ weights and in any other examinations. The treatment-related changes observed in this study were hematological or histological changes associated with pharmacological effects of DA-3585. On the basis of the results of this study, LD5n value of DA-3585 was above 25,000 lU/kg and the no-observed-adverse-effect-level was estimated to be 100 lU/kg.

• Journal of Food Hygiene and Safety
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• v.9 no.1
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• pp.31-36
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• 1994

The acute toxicity of recombinant human epidermal growth factor, DWP-401 was evaluated in SD rats. Male and female rats aging 6 weeks were administered orally or subcutaneously with 0, 0.125, 0.25, 0.5, 1 and 2 mg/kg of DWP-401. No deaths and no toxic symptoms related to the DWP-401 were observed. The body weights of treated animals were not significantly different from the controls. The results of necropsy revealed no abnormal gross findings of the organs in treated animals. LD50 values of DWP-401 for male and female rats were estimated to be over 2 mg/kg, which is approximately 2, 000 times of expected clinical dose.