• Biomolecules & Therapeutics
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• v.16 no.2
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• pp.77-81
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• 2008

The major aim of the Korean Pharmacogenomic Database (KPD) is to offer to users a "bridging" function, making the search for useful information easier. This database has also been established to collect unique Korean genotype data from other databases and to directly link these data to other major databases that offer more informative data. In this way, searches for information about new drug developments and easier and faster evaluation of the more complex and larger databases are possible. The KPD is located at the National Institute of Toxicological Research homepage (http://www.nitr.go.kr/nitr/contents/m134700/view.do), and offers Korean single-nucleotide polymorphism (SNP) information for 154 genes and haplotype information. It also compares the Korean SNP and haplotype frequencies with those of the other ethnic groups registered in the International HapMap. Through the Pharmacogenomic Information and Education facility, we also provide evaluators and the public with information about the concept of pharmacogenomic information, research trends, and the drug regulations of other countries. Because the drug responses of Koreans are not necessarily the same as those of Chinese or Japanese people, it is expected that the systematic operation of the KPD will allow the definition of racial differences and various genomic biomarkers (haplotypes or SNPs) for use in bridging studies and in the approval of new drugs.

• Journal of Environmental Health Sciences
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• v.45 no.5
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• pp.443-456
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• 2019

Objectives: Children are exposed to various environmental pollutants through contact with children's products. We investigated the KC mark, certification number, and contained substances labeled on children's products through market research and collected the toxicological data on these substances. Methods: The environmentally hazardous substances labeled on children's products (n=6576), including toys (n=2812), personal care products (n=2212), stationary/books (n=1333), and playground equipment (n=219) were examined. For the components that could be identified by CAS number, toxicological data on oral, inhalation, and dermal routes, cancer slope factor, and reference dose were collected. Results: Among the investigated products, KC marks or certification numbers were found for 4557 products (69.3%). Except for cosmetics and cleansers, the material information was labeled on most of the products. The frequency of labeling substance information in toys and stationary/books was low since this information could be omitted if KC certification was obtained. In the target products, 617 substances were identified by CAS number, and polypropylene, acrylonitrile butadiene styrene, and polyester were the most frequently displayed. Chronic toxicity data was found for only 32.4% of individual components, and information on toxicity through the dermal route was also highly limited. Conclusion: Our study suggested that labeling guidelines should be required to identify the environmentally hazardous substances contained in children's products. In addition, the toxicological data on many ingredients in children's products were insufficient. The data gap for toxicity data should be filled for future risk assessment.

• Toxicological Research
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• v.14 no.3
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• pp.315-320
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• 1998

In vitro skin iritation of anti-inflammatory drugs was investigated in terms of the cytotoxicity method to human skin fibroblast cells. Five anti-inflammatory drugs (Diclofenac, Naproxen, Meclofenamic acid, Ibuprofen and Fnoprofen) which are commercially available as oral preparations or injections were tested. The cytotoxicity of 5 chemicals was evaluated by using MTT[tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. NRU (neutral red uptake) assay and Alamar Blue assay after fibroblast cells had been exposed to the chemicals for 24 hours or 489 hours. The $IC_{50}$ values of the chemicals showed the comparative strength of cytotoxicity as following order of Meclofenamic acid>Diclofenac>Fenoprofen>Ibuprofen>Naproxen. The values of $IC_{50}$ determined by Alamar Blue assay were lower than those of MTT and NRU assay. These data suggest Alamar Blue assay can be useful method for assessing in vitro skin irritation potential of anti-inflammatory drugs.

• Genomics & Informatics
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• v.7 no.2
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• pp.97-106
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• 2009

Epigallocatechin gallate (EGCG), a well-known antioxidant molecule, has been reported to cause hepatotoxicity when used in excess. However, the mechanism underlying EGCG-induced hepatotoxicity is still unclear. To better understand the mode of action of EGCG-induced hepatotoxicity, we examined the effect of EGCG on human hepatic gene expression in HepG2 cells using microarrays. Analyses of microarray data revealed more than 1300 differentially expressed genes with a variety of biological processes. Upregulated genes showed a primary involvement with protein-related biological processes, such as protein synthesis, protein modification, and protein trafficking, while downregulated genes demonstrated a strong association with lipid transport. Genes involved in cellular stress responses were highly upregulated by EGCG treatment, in particular genes involved in endoplasmic reticulum (ER) stress, such as GADD153, GADD34, and ATF3. In addition, changes in genes responsible for cholesterol synthesis and lipid transport were also observed, which explains the high accumulation of EGCG-induced lipids. We also identified other regulatory genes that might aid in clarifying the molecular mechanism underlying EGCG-induced hepatotoxicity.

• Genomics & Informatics
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• v.7 no.3
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• pp.163-167
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• 2009

Since its first release in 2007, the National Institute of Food and Drug Safety Evaluation (NIFDS) has provided pharmacogenomic and comparative information specific to Koreans to allow regulatory reviewers and researchers to adapt their working practices to pharmacogenomics. The highlights of this year's additions include "Drug Information", "Gene Information" and "Pharmacogenomic information in the drug labels" sections. These new additions provide information on 737 genes, 719 drugs and pharmacogenomic data of the labels or relabels of 253 approved drugs as of November 2008. The latest version of the Korean Pharmacogenomic Database (KPD, release 2.0) has expanded significantly since its previous release. More SNP and haplotype information has been added to the database with the latest version of the KPD containing approximately four times as many SNPs and haplotypes than the previous version (719 vs. 152, and 30 vs. 7 respectively). Through the "SNP" and "Haplotype" sections, the KPD provides unique Korean SNP and haplotype information as well as comparative information of other populations (Japanese, Chinese, European, African) to offer a range of pharmacogenomic data that can help reviewers and the public understand pharmacogenomic information. The quality and quantity of information in the KPD has also been improved considerably. This data can be found at: http://www.nitr.go.kr/nitr/contents/m134700/view.do/.

• Journal of Environmental Health Sciences
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• v.47 no.6
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• pp.505-512
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• 2021

Background: The occurrence of environmental disease is known to be associated with chronic exposure to toxic chemicals, including waterborne contaminants, air/indoor pollutants, asbestos, ingredients in humidifier disinfectants, etc. Objectives: In this study, we reviewed toxicological studies related to environmental disease as defined by the Environmental Health Act in Korea and toxic chemicals. We also suggested a direction for future toxicological research necessary for the prevention and management of environmental disease. Methods: Trends in previous studies related to environmental disease were investigated through PubMed and Web of Science. A detailed review was provided on toxicological studies related to the humidifier disinfectants. We identified adverse outcome pathways (AOPs) that can be linked to the induction of environmental diseases, and proposed a chemical screening system that uses AOP, chemical toxicity big data, and deep learning models to select chemicals that induce environmental disease. Results: Research on chemical toxicity is increasing every year, but there is a limitation to revealing a clear causal relationship between exposure to chemicals and the occurrence of environmental disease. It is necessary to develop various exposure- and effect-biomarkers related to disease occurrence and to conduct toxicokinetic studies. A novel chemical screening system that uses AOP and chemical toxicity big data could be useful for selecting chemicals that cause environmental diseases. Conclusions: From a toxicological point of view, developing AOP related to environmental diseases and a deep learning-based chemical screening system will contribute to the prevention of environmental diseases in advance.

• Toxicological Research
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• v.12 no.2
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• pp.143-154
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• 1996

This paper reviews the toxicological role of median lethal dose ($LD_50$) based on animal and human data. Animal oral $LD_50$ values of eighty seven chemicals were collected and comparatively evaluated with human minimum toxic dose ($TD_50$). In general, animal $LD_50$ values were much higher than human $TD_50$. The ratios between $LD_50$ and TDlo were ranged from 0.01 and over 1000, suggesting safety factor of up to 1000 between humans and animals in the case of acute toxicity data. However, about 40% of chemicals investigated were within the ratio of 10. Although the cases (N=20) were small, $LD_50$ values of guinea pig were closer to human TDlo than those of other animal species. In interanimal species (rat, mouse, rabbit, dog), the ratios of $LD_50$ values were between 0.1 and 5 (up to 50-fold difference). When the data are analyzed by chemical strut-ares, human $TD_50$ values were very close to rat oral $LD_50$ values. These data suggest that rat oral $LD_50$ value might be a useful parameter predicting human TDlo and one animal species could be sufficient for acute toxicity test.

• Toxicological Research
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• v.14 no.3
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• pp.307-313
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• 1998

Dimethyl dimethoxy biphenylate (DDB) is an agent used to treat hepatits. DDB-S (DDB-soluble), a new DDB derivative, was synthsized to increase water solubility of the original DDB. In the present study, the antigenic potential of DDB-S was examined by active systemic anaphylaxis (ASA), passive cutaneous anaphylaxis (PCA) and passive hemagglutination (PHA) tests. The experimental groups consist of a low dosage group, a high dosage group, he group emulsified with Freund's complete adjuvant (FCA, ASA test) or an alum (PCA and PHA tests) and the macromolecule conjugate group emulsified with FCA or an alum. In the ASA test, all experimental groups showed negative responses whereas the positive control group given ovalbumin plus FCA showed severe anaphylactic responses. In the heterologous PCA test using mice and rats, positive responses were not detected in any of the experimental groups. In the PHA test, all experimental groups showed negative responses whereas the positive control group given ovalbumin plus an alum showed 512~2048 PHA titers. These results demonstrated that DDB-S does not have any antigenic potential. These can be utilized as a part of preclinical data for the development of DDB-S as an intravenous injection.

• Environmental Mutagens and Carcinogens
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• v.25 no.1
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• pp.40-46
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• 2005

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) displays high toxicity in animals and has been implicated in human carcinogenesis. Although the mechanism of carcinogenesis by TCDD is unclear, it is considered to be a non-genotoxic compound and tumor promoter. In our experiment, we investigated the effects of TCDD on gene expression in mouse skin carcinogenesis. We used cDNA microarray to detect the differential gene expression in tumors induced in hairless mouse skin by MNNG plus TCDD protocol. We found that erb-2, c-ets2 and p27$^{kip1}$ were significantly up-regulated, but TNFR2, AKT-l, integrin $\beta$l, maspin, IGF-l, c-raf-l, Rb were significantly down-regulated, in tumor region, respectively. We also found that the expression of 53 genes involved in cen cycle, signal transduction, apoptosis, adhesion molecule, angiogenesis, and invasion, were changed two fold more, in tumor surrounding region. These data suggest that TCDD alters the expression of a large array of genes involved in apoptosis, cytokine production and angiogenesis in mouse skin carcinogenesis.

• Toxicological Research
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• v.34 no.2
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• pp.111-125
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• 2018

Solvents can be used in the manufacture of medicinal products provided their residual levels in the final product comply with the acceptable limits based on safety data. At worldwide level, these limits are set by the "Guideline Q3C (R6) on impurities: guideline for residual solvents" issued by the ICH. Diisopropyl ether (DIPE) is a widely used solvent but the possibility of using it in the pharmaceutical manufacture is uncertain because the ICH Q3C guideline includes it in the group of solvents for which "no adequate toxicological data on which to base a Permitted Daily Exposure (PDE) was found". We performed a risk assessment of DIPE based on available toxicological data, after carefully assessing their reliability using the Klimisch score approach. We found sufficiently reliable studies investigating subchronic, developmental, neurological toxicity and carcinogenicity in rats and genotoxicity in vitro. Recent studies also investigated a wide array of toxic effects of gasoline/DIPE mixtures as compared to gasoline alone, thus allowing identifying the effects of DIPE itself. These data allowed a comprehensive toxicological evaluation of DIPE. The main target organs of DIPE toxicity were liver and kidney. DIPE was not teratogen and had no genotoxic effects, either in vitro or in vivo. However, it appeared to increase the number of malignant tumors in rats. Therefore, DIPE could be considered as a non-genotoxic animal carcinogen and a PDE of 0.98 mg/day was calculated based on the lowest No Observed Effect Level (NOEL) value of $356mg/m^3$ (corresponding to 49 mg/kg/day) for maternal toxicity in developmental rat toxicity study. In a worst-case scenario, using an exceedingly high daily dose of 10 g/day, allowed DIPE concentration in pharmaceutical substances would be 98 ppm, which is in the range of concentration limits for ICH Q3C guideline class 2 solvents. This result might be considered for regulatory decisions.