Japan Bioassay Research Center

Kawasaki, Japan

Japan Bioassay Research Center

Kawasaki, Japan

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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 | Year: 2014

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).


Fukushima S.,Japan Bioassay Research Center | Gi M.,Osaka City University | Kakehashi A.,Osaka City University | Wanibuchi H.,Osaka City University | Matsumoto M.,Japan Bioassay Research Center
Mutagenesis | Year: 2016

Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2′-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment. © 2015 The Author.


Tsukamoto T.,Mie University | Toyoda T.,Japan National Institute of Health Sciences | Mizoshita T.,Nagoya City University | Tatematsu M.,Japan Bioassay Research Center
Seminars in Immunopathology | Year: 2013

Helicobacter pylori infection is an important factor for gastric carcinogenesis in human. In carcinogen-treated Mongolian gerbils, H. pylori infection enhances stomach carcinogenesis, while infection alone induced severe hyperplasia called heterotopic proliferative glands. A high-salt diet or early acquisition of the bacteria exacerbates inflammation and carcinogenesis. Oxygen radical scavengers or anti-inflammatory chemicals as well as eradication of H. pylori are effective to prevent carcinogenesis. H. pylori-associated inflammation induces intestinal metaplasia and intestinalization of stomach cancers independently. It is necessary to control cancer development not only in H. pylori-positive cases but also in H. pylori-negative metaplastic gastritis. © 2012 Springer-Verlag Berlin Heidelberg.


Niwa T.,National Cancer Center Research Institute | Toyoda T.,Japan National Institute of Health Sciences | Tsukamoto T.,Aichi University | Mori A.,National Cancer Center Research Institute | And 2 more authors.
Cancer Prevention Research | Year: 2013

Suppression of aberrant DNA methylation is a novel approach to cancer prevention, but, so far, the efficacy of the strategy has not been evaluated in cancers associated with chronic inflammation. Gastric cancers induced by Helicobacter pylori infection are known to involve aberrant DNA methylation and associated with severe chronic inflammation in their early stages. Here, we aimed to clarify whether suppression of aberrant DNA methylation can prevent H. pylori-induced gastric cancers using a Mongolian gerbil model. Administration of a DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), to gerbils (0.125 mg/kg for 50-55 weeks) decreased the incidence of gastric cancers induced by H. pylori infection and N-methyl-N-nitrosourea (MNU) treatment from 55.2% to 23.3% (P < 0.05). In gastric epithelial cells, DNA methylation levels of six CpG islands (HE6, HG2, SB1, SB5, SF12, and SH6) decreased to 46% to 68% (P < 0.05) of gerbils without 5-aza-dC treatment. Also, the global DNA methylation level decreased from 83.0% ± 4.5% to 80.3% ± 4.4% (mean ± SD) by 5-aza-dC treatment (P < 0.05). By 5-aza-dC treatment, Il1b and Nos2 were downregulated (42% and 58% of gerbils without, respectively) but Tnfwas upregulated (187%), suggesting that 5-aza-dC treatment induced dysregulation of inflammatory responses. No obvious adverse effect of 5-aza-dC treatment was observed, besides testicular atrophy. These results showed that 5-aza-dC treatment can prevent H. pylori-induced gastric cancers and suggested that removal of induced DNA methylation and/or suppression of DNA methylation induction can become a target for prevention of chronic inflammation-associated cancers. © 2013 AACR.


Tsukamoto T.,Aichi University | Tatematsu M.,Japan Bioassay Research Center
Current Infectious Disease Reports | Year: 2014

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.


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 | Year: 2014

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.


Fukushima S.,Japan Bioassay Research Center
Asian Pacific Journal of Cancer Prevention | Year: 2010

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.


Kasai T.,Japan Bioassay Research Center | Gotoh K.,Japan Bioassay Research Center | Nishizawa T.,Japan Bioassay Research Center | Sasaki T.,Japan Bioassay Research Center | And 4 more authors.
Nanotoxicology | Year: 2014

Because the primary route of human exposure to multi-walled carbon nanotube (MWCNT) is via inhalation, a new dry MWCNT aerosol generation and exposure system for whole-body inhalation exposure using a cyclone and sieve has been developed. The system was tested for operational performance at 0.2, 1 and 5 mg/m3. Additionally, it was examined whether this system can be employed in animal whole-body inhalation studies by exposing rats to MWCNT aerosol for 6 h at 5 mg/m3. The system could consistently provide aerosols with a similar particle size distribution and configuration at all the target exposure concentrations. Almost all MWCNTs were fibrous, and the presence of many well-dispersed, nano-sized particles was confirmed. Additionally, the animal study revealed that large amounts of MWCNTs were inhaled into the lung, resulting in an inflammatory response, with increased LDH and albumin levels, and granulomatous change. Therefore, the aerosol generation and exposure system appears useful for MWCNT inhalation studies using rats. © 2014 Informa UK, Ltd.


Yamasaki K.,Chemicals Evaluation and Research Institute | Okuda H.,Japan Bioassay Research Center
Toxicology Letters | Year: 2012

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.


Matsumoto M.,Japan Bioassay Research Center | Umeda Y.,Japan Bioassay Research Center | Take M.,Japan Bioassay Research Center | Nishizawa T.,Japan Bioassay Research Center | Fukushima S.,Japan Bioassay Research Center
Inhalation Toxicology | Year: 2013

The subchronic toxicity and carcinogenicity of 1,2-dichloropropane (DCP) in male and female B6D2F1 mice exposed to DCP by inhalation for 13 weeks or for 2 years was investigated. The DCP concentrations used were 50, 100, 200, 300 or 400 ppm (v/v) in the 13-week study, and 32, 80 or 200 ppm (v/v) in the 2-year study. Thirteen weeks inhalation exposure of mice to DCP caused death in the mice exposed to 300 ppm and above, and was found to induce hemolytic anemia and lesions of the liver, forestomach and heart. Two years exposure to DCP significantly increased the combined incidence of bronchiolo-alveolar adenomas and carcinomas in females and marginally increased the incidence of Harderian gland adenomas in males. As non-neoplastic lesion, atrophy and respiratory metaplasia in the olfactory epithelium, and respiratory metaplasia in the submucosal gland of the nasal cavity were increased. Thus, two years inhalation exposure to DCP is carcinogenic in female mice and there is a marginal evidence of carcinogenicity in males. © 2013 Informa Healthcare USA, Inc.

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