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Taya S.,Chiang Mai University | Punvittayagul C.,Chiang Mai University | Inboot W.,Chiang Mai University | Fukushima S.,Japan Bioassay Research Center | Wongpoomchai R.,Chiang Mai University
Asian Pacific Journal of Cancer Prevention

Purpose: To study the effect of Cleistocalyx nervosum extract (CE) on diethylnitrosamine (DEN) and phenobarbital (PB) induced oxidative stress in early stages of rat hepatocarcinogenesis. Materials and Methods: Male Wistar rats were divided into 4 groups, with Group 1 as a negative control and Group 2 was a positive control receiving DEN injections once a week and PB in drinking water for 6 weeks. Two weeks before DEN initiation and PB treatment, Groups 3 and 4, were fed with 500 and 1000 mg/kg of CEs, respectively, for 8 weeks. Results: A number of GST-P-positive foci, preneoplastic lesions, in the liver were markedly increased in carcinogen administered rats, but was comparatively decreased in rats treated with 1000 mg/kg of CE. The CE reduced malondialdehyde in serum and in the livers of rats treated with DEN and PB. Moreover, CE significantly increased the activities of glutathione peroxidase and catalase in rat liver. Conclusions: CE appeared to exert its chemopreventive effects by modulating antioxidant status during DEN and PB induced early stages of hepatocarcinogenesis in rats. Source

Konishi Y.,Nara Medical University | Konishi Y.,Oklahoma Medical Research Foundation | Hayashi S.-M.,Gen 9 Inc. | Fukushima S.,Japan Bioassay Research Center
Toxicologic Pathology

The advancement of technology and the growth of international commerce underscore the need for global harmonization of regulatory safety requirements and their assessment pertaining to consumer products such as drugs, medical devices, and food. This need is particularly relevant when safety requirements involve time-intensive and costly animal safety studies. Here we present the current regulatory requirements in Europe, the United States, and Japan for flavoring substances (FSs) used in foods and point out significant differences relevant to the international standardization for safety assessments that in our opinion need to be addressed and overcome. The safety assessments that are carried out for FSs in various countries are influenced by divergent definitions of FS, by the information required and available for regulatory submission, and by different regulatory procedures, including the use of decision tree approaches. The European Food Safety Authority (EFSA), the Expert Panel of the U.S. Flavor and Extract Manufacturers Association (FEMA), and the Joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) are making efforts to improve and harmonize the safety assessment of FSs. The application of in silico methods such as quantitative structure-activity relationships and read-across strategies relying on expert input are useful as a first-step screening of the assessment. Application of the Threshold of Toxicological Concern (TTC) approach permits conclusions that are compatible with the risk assessment approaches currently used by international advisory committees.The Japanese Regulatory Authority, on the other hand, does not yet consider in silico methods but still requires in vivo and in vitro genotoxicity test data as well as repeat-dose 90-day toxicity data in at least one species, to be submitted as the first step in the safety assessment of FSs. With this article, we echo requests that have been made for xenobiotics by the pharmaceutical industry worldwide, extending them to food-related products, especially FSs. We encourage regulatory agencies to adopt globally harmonized safety assessment procedures, regulatory guidelines, and review practices for FSs to foster global trade and to reduce costs and laboratory animal use. © 2013 by The Author(s). Source

Tsukamoto T.,Aichi University | Tatematsu M.,Japan Bioassay Research Center
Current Infectious Disease Reports

Helicobacter pylori infection is one of the most important factors in gastric carcinogenesis in humans. Epidemiological studies have revealed that H. pylori-infected patients develop significantly more gastric cancers than uninfected individuals. In rodent models, H. pylori inoculation causes strong promoting effects in carcinogen-treated animals, whereas the bacterial infection alone causes only hyperplasic, atrophic, and/or metaplastic lesions. In both human and rodent models, eradication of H. pylori helps inhibit gastric carcinogenesis, especially when there is only mild gastric inflammation and no evidence of severe atrophy or intestinal metaplasia. Chemoprevention studies in humans have been reported and have shown the effectiveness of several medications including a cyclooxygenase-2 inhibitor. Candidate chemicals used in rodent models could hopefully be used in humans in the future. © Springer Science+Business Media 2014. Source

Fukushima S.,Japan Bioassay Research Center
Asian Pacific Journal of Cancer Prevention

While it has been generally accepted that genotoxic carcinogens have no dose threshold for their carcinogenic potential, there is increasing evidence that very low doses in fact are incapable of inducing tumours or preneoplastic lesions. Thus not only so-called epigenetic 'non-genotoxic' compounds like phenobarbital and benzene hexachloride, but also unequivocally genotoxic carcinogens like the heterocyclic amines, 2-amino-3,8- dimethyl-imidazo[4,5-f]quinoxaline and amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and the nitrosamines diethylnitrosamine, and dimethylnitrosamine, may exhibit a practical dose threshold below which they do not induce histopathologically assessable lesions. Some form of physiological adaptation may thus be expected to occur in response to low doses of all types of DNA-damaging agents. With 'non-genotoxic' agents there may even be hormesis or paradoxical protection at very low dose. Source

The purpose of this study was to compare endocrine-mediated effects of bisphenol A related compounds, 2,2-bis(4-cyanatophyenyl)propane and 4,4'-cyclohexylidenebisphenol with reference to OECD Test Guideline No. 407. Rats were orally gavaged with 0, 4, 20, and 100. mg/kg/day of 2,2-bis(4-cyanatophyenyl)propane, and 0, 30, 100, and 300. mg/kg/day of 4,4'-cyclohexylidenebisphenol for at least 28 days beginning at 8 weeks of age. Endocrine-mediated effects were not observed in rats given 2,2-bis(4-cyanatophyenyl)propane. Male accessory sex organ weights decreased in the 4,4'-cyclohexylidenebisphenol 300. mg/kg group and serum T4 values increased in all male groups treated with this compound. Our results suggest that endocrine-mediated changes caused by the present bisphenol related compound can be divided into estrogenic or thyroid hormonal effects, and estrogenic effects observed in the repeated-dose study were related to their estrogenic potency confirmed by uterotrophic assay. © 2011 Elsevier Ireland Ltd. Source

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