• Proceedings of the Korean Society of Toxicology Conference
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• 2003.10b
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• pp.24-25
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• 2003

Genotoxicity plays an important role for the safety evaluation of chemicals. When the carcinogenicity is evident on a chemical, the threshold can be estimated only when genotoxic mechanism does not operate for carcinogenesis otherwise threshold cannot be set. Without genotoxic mechanism- non-genotoxic carcinogen-threshold can be estimated but with genotoxic mechanism-genotoxic- carcinogen-it cannot be estimated.(omitted)

• Toxicological Research
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• v.34 no.4
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• pp.281-290
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• 2018

Exposure to chemical agents is an inevitable consequence of modern society; some of these agents are hazardous to human health. The effects of chemical carcinogens are of great concern in many countries, and international organizations, such as the World Health Organization, have established guidelines for the regulation of these chemicals. Carcinogens are currently categorized into two classes, genotoxic and non-genotoxic carcinogens, which are subject to different regulatory policies. Genotoxic carcinogens are chemicals that exert carcinogenicity via the induction of mutations. Owing to their DNA interaction properties, there is thought to be no safe exposure threshold or dose. Genotoxic carcinogens are regulated under the assumption that they pose a cancer risk for humans, even at very low doses. In contrast, non-genotoxic carcinogens, which induce cancer through mechanisms other than mutations, such as hormonal effects, cytotoxicity, cell proliferation, or epigenetic changes, are thought to have a safe exposure threshold or dose; thus, their use in society is permitted unless the exposure or intake level would exceed the threshold. Genotoxicity assays are an important method to distinguish the two classes of carcinogens. However, some carcinogens have negative results in in vitro bacterial mutation assays, but yield positive results in the in vivo transgenic rodent gene mutation assay. Non-DNA damage, such as spindle poison or topoisomerase inhibition, often leads to positive results in cytogenetic genotoxicity assays such as the chromosome aberration assay or the micronucleus assay. Therefore, mechanistic considerations of tumor induction, based on the results of the genotoxicity assays, are necessary to distinguish genotoxic and non-genotoxic carcinogens. In this review, the concept of threshold of toxicological concern is introduced and the potential risk from multiple exposures to low doses of genotoxic carcinogens is also discussed.

• Environmental Mutagens and Carcinogens
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• v.19 no.2
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• pp.89-94
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• 1999

Cell proliferation and c-Jun expression pattern in liver exposed by nongenotoxic carcinogens phenobarbital (PB) and clofibrate, and genotoxic carcinogen 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) were investigated to see whether differential effects of genotoxic and non-genotoxic carcinogens on the development of neoplastic foci may be related to differential effect on cell proliferation. Male F344 rats were initially given a single intraperitioneal injection of diethylnitrosamine (200 mg/kg body weight), and 2 weeks later, animals were fed diets containing 0.03% IQ or 0.5% CE or 0.05% PB or basal diet as a control for 6 weeks. All rats were subjected to the two-thirds partial hepatectomy (PH) at week 3. Sequential sacrifice of rats was performed until 8 weeks. Cell proliferation was examined by immunohistochemical staining of bromodeoxyuridine and c-Jun expression was determined by northern blotting. The increase of cell proliferation rate after PH was significant in the rats fed 0.05% IQ and continued until 8 weeks, while the increase was not significant in the rats fed phenobarbital and clofibrate compared to that in the rats fed control diet. mRNA level of c-Jun in the liver treated with IQ was about 7 fold higher than that of control and peak at 5 hours after rH. In the liver treated with CE, mRNA level of c-Jun was 3-4 fold higher than that of control and the highest level of mRNA of c-Jun was seen at 24 hours after PH. These results show that differential effects of genotoxic and non-genotoxic carcinogens on the development of neoplastic foci may be related to differential effect on cell proliferation pattern.

• Fibers and Polymers
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• v.3 no.4
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• pp.147-152
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• 2002

Copper (II) salts are used as metallizing agents in the synthesis of new non-genotoxic direct dyes for cotton. Specifically, cotton fabric is dyed with non-genotoxic disazo direct dyes and then treated with copper salts. The complexes are characterized by neutron activation analysis, absorption spectrometry and standard Salmonella mammalian mutagenicity assay, and the after-treated fabrics are evaluated for lightfastness and washfastness. Direct dyes possessing ortho-propoxy and ortho'-hydroxy substituted systems formed the corresponding nonmutagenic 1:2 dye:metal complex and undergo significant improvement in lightfastness following metallization.

• Toxicological Research
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• v.34 no.4
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• pp.311-324
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• 2018

Arsenic is one of the most toxic environmental toxicants. More than 150 million people worldwide are exposed to arsenic through ground water contamination. It is an exclusive human carcinogen. Although the hallmarks of arsenic toxicity are skin lesions and skin cancers, arsenic can also induce cancers in the lung, liver, kidney, urinary bladder, and other internal organs. Arsenic is a non-mutagenic compound but can induce significant cytogenetic damage as measured by chromosomal aberrations, sister chromatid exchanges, and micronuclei formation in human systems. These genotoxic end points are extensively used to predict genotoxic potentials of different environmental chemicals, drugs, pesticides, and insecticides. These cytogenetic end points are also used for evaluating cancer risk. Here, by critically reviewing and analyzing the existing literature, we conclude that inorganic arsenic is a genotoxic carcinogen.

• Environmental Analysis Health and Toxicology
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• v.23 no.1
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• pp.23-32
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• 2008

In the present study, ROS detection of L5178Y cells that were treated with twenty test compounds in order to find out hydrogen peroxide ($H_2O_2$) induction for genotoxicity and carcinogenic toxicity. Twenty test compounds were consist of four classes, such as genotoxic carcinogens, genotoxic noncarcinogens, nongenotoxic carcinogens, and nongenotoxic noncarcinogens. Genotoxic carcinogens are 1,2-dibromoethane, glycidol, melphalan, diethylstilbestrol and urethane. Genotoxic noncarcinogens are 8-hydroxyquinoline, emodin, acetonitrile and diallylphthalate, L-ascorbic acid. Nongenotoxic carcinogens are methyl carbamate, O-nitrotoluene, 1,4-dioxane, tetrachloroethylene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. And nongenotoxic noncarcinogens are D-mannitol, 1,2-dichlorobenzene, caprolactam, bisphenol A and chlorpheniramine maleate.

• Toxicological Research
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• v.34 no.4
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• pp.291-296
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• 2018

Chemical carcinogenesis is a multistep process. Genotoxic carcinogens, which are DNA-reactive, induce DNA adduct formation and genetic alterations in target cells, thereby generating mutated cells (initiation). Subsequently, preneoplastic lesions appear through clonal proliferation of the mutated cells and transform into tumors (promotion and progression). Many factors may influence these processes in a dose-dependent manner. Therefore, quantitative analysis plays an important role in studies on the carcinogenic threshold of genotoxic carcinogens. Herein, we present data on the relationship between key carcinogenic events and their deriving point of departure (PoD). Their PoDs were also compared to those of the carcinogenesis pathway. In an experiment, the liver of rats exposed to 2-amino-3,8-dimethylimidazo-(4,5-f)quinoxaline (MeIQx) was examined to determine the formation of MeIQx-DNA adducts, generation of mutations at LacI transgene, and induction of preneoplastic glutathione S-transferase placental form (GST-P)-positive foci and tumors (benign and malignant). The PoDs of the above key events in the carcinogenicity of MeIQx were increased as the carcinogenesis advanced; however, these PoDs were lower than those of tumor induction. Thus, the order of key events during tumor induction in the liver was as follows: formation of DNA adducts ${\ll}$ Mutations ${\ll}$ GST-positive foci (preneoplasia) ${\ll}$ Tumor (adenoma and carcinoma). We also obtained similar data on the genotoxic and carcinogenic PoDs of other hepatocarcinogens, such as 2-amino-3,8-dimethylimidazo(4,5-f)quinoline. These results contribute to elucidating the existence of a genotoxic and carcinogenic threshold.

• Environmental Engineering Research
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• v.11 no.5
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• pp.277-284
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• 2006

The genetic toxicity of environmental pollutants, namely, nonylphenol (NP), bisphenol A (BPA) and chloropyriphos (CP) was investigated in aquatic sentinel species, freshwater crustacean, Daphnia magna, and larva of aquatic midge, Chironomus tentans, using Comet assay. Physiological effect of such pollutants was also investigated by studying the specimens' rates of reproduction, growth and survival. Acute toxicity results showed that, as expected, Daphnia was more sensitive than Chironomus to chemical exposure. The order of acute toxicity was CP > NP > BPA in D. magna and NP > CP > BPA in C. tentans. BPA may exert a genotoxic effect on D. magna and C. tentans, given that DNA strand breaks increased in both species exposed to this compound, whereas NP- and CP-induced DNA damage occurred only in C. tentans. In vivo genotoxic data obtained in aquatic sentinel species could provide valuable information for freshwater quality monitoring. The experiments with NP-exposed D. magna showed that the pollutant has long-term effects on reproduction, whereas no short-term effect on DNA integrity was found, being an example of a false-negative result from the biomarkers perspective. This result could be interpreted that other mechanism than genetic alteration might be involved in NP-induced reproduction failure in D. magna. False-positive results from the genotoxic biomarker obtained in BPA-exposed D. magna and in NP-exposed C. tentans make it difficult to use DNA integrity as an early warning biomarker. However, as the mere presence of genotoxic compounds, which are potentially carcinogenic, is of high concern to human and ecosystem health, it could also be important to rapidly and effectively detect genotoxic compounds in the aquatic system in ways that do not necessarily accompany a higher level of alteration. Considering the potential of D. magna and C. tentans as bioindicator species, and the importance of genotoxic biomarkers in ecotoxicity monitoring, DNA damage in these species could provide useful information for environmental risk assessment.

• Environmental Analysis Health and Toxicology
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• v.30
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• pp.14.1-14.7
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• 2015

Objectives Cigarette smoking is associated with carcinogenesis owing to the mutagenic and genotoxic effects of cigarette smoke. The aim of this study was to evaluate the mutagenic and genotoxic effects of Korean cigarettes using in vitro assays. Methods We selected 2 types of cigarettes (TL and TW) as benchmark Korean cigarettes for this study, because they represent the greatest level of nicotine and tar contents among Korean cigarettes. Mutagenic potency was expressed as the number of revertants per ${\mu}g$ of cigarette smoke condensate (CSC) total particulate matter whereas genotoxic potency was expressed as a concentration-dependent induction factor. The CSC was prepared by the International Organization for Standardization 3308 smoking method. CHO-K1 cells were used in vitro micronucleus (MNvit) and comet assays. Two strains of Salmonella typhimurium (Salmonella enterica subsp. enterica ; TA98 and TA1537) were employed in Ames tests. Results All CSCs showed mutagenicity in the TA98 and TA1537 strains. In addition, DNA damage and micronuclei formation were observed in the comet and MNvit assays owing to CSC exposure. The CSC from the 3R4F Kentucky reference (3R4F) cigarette produced the most severe mutagenic and genotoxic potencies, followed by the CSC from the TL cigarette, whereas the CSC from the TW cigarette produced the least severe mutagenic and genotoxic potencies. Conclusions The results of this study suggest that the mutagenic and genotoxic potencies of the TL and TW cigarettes were weaker than those of the 3R4F cigarette. Further study on standardized concepts of toxic equivalents for cigarettes needs to be conducted for more extensive use of in vitro tests.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.4993-4998
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• 2012

Vanillic acid, a vegetable phenolic compound, is a strong antioxidant. The aim of the present study was to determine its effects on mitomycin C-induced DNA damage in human blood lymphocyte cultures in vitro, both alone and in combination with mitomycin C (MMC). The cytokinesis block micronucleus test and alkaline comet assay were used to determine genotoxic damage and anti-genotoxic effects of vanillic acid at the DNA and chromosome levels. MMC induced genotoxicity at a dose of $0.25{\mu}g/ml$. Vanillic acid ($1{\mu}g/ml$) significantly reduced both the rates of DNA damaged cells and the frequency of micronucleated cells. A high dose of vanillic acid ($2{\mu}g/ml$) itself had genotoxic effects on DNA. In addition, both test systems showed similar results when tested with the negative control, consisting of dimethyl sulfoxide (DMSO) in combination with vanillic acid ($1{\mu}g/ml$)+MMC. In conclusion, vanillic acid could prevent oxidative damage to DNA and chromosomes when used at an appropriately low dose.