著者

能美 健彦 清水 雅富 グルーズ ピーター

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.2, pp.159-165, 2004 (Released:2005-12-21)

参考文献数

47

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Altered oxidative metabolism is a property of many tumor cells. Oxidation of dNTP pool as well as DNA is a source of genome instability. We report here that two Y-family DNA polymerases of the archaeon Sulfolobus solfataricus strains P1 and P2 incorporate oxidized dNTPs into nascent DNA in an erroneous manner: the polymerases exclusively incorporate 8-hydroxy-dGTP opposite template A, and incorporate 2-hydroxy-dATP opposite G and T. Extension onto the incorporated analogs is only slightly reduced. Human DNA polymerase η, a member of human Y-family DNA polymerases, incorporates the oxidized dNTPs in a similar erroneous manner. These DNA polymerases are shown to bypass a variety of DNA lesions. Thus, our results suggest the Y-family DNA polymerases promote mutagenesis through the erroneous incorporation of the oxidized dNTPs during DNA synthesis in addition to facilitating translesion DNA synthesis.

著者

小野 宏

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.133-137, 2005-07-31

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The OECD established the Guidelines for Testing of Chemicals in 1981, which is the basis of the mutual acceptance of data (MAD) system among the member countries to prevent unnecessary repetition of toxicity tests, and consequently to reduce the number of animals used. The Guidelines was soon subjected to revision from the viewpoint of animal welfare besides its periodical updating with the state-of-art in the toxicological sciences. Revision of the Test Guidelines is in progress according to the 3Rs principle, reduction, refinement and replacement. The acute toxicity test and the skin and eye irritation/corrosion tests were assumed to be the most problematic ones among the animal tests in animal welfare aspect. Three different test methods have been adopted for the alternative to acute oral toxicity test (Test Guideline (TG) 401), namely, the fixed dose procedure (TG420), acute toxic class method (TG423) and up-and-down procedure (TG425), and the reduction of animals was accomplished. Then the traditional acute oral toxicity test (TG401) has been deleted from the Guidelines. Procedures for irritation/corrosion tests for skin (TG404) and eye (TG405) were reorganized into tier-test system in order to prevent any corrosion or strong irritation to take place. The tier system consists of survey of toxicities of the test chemical, structure-activity relationship, pH, and testing with in vitro methods. Moreover, at the final tier animal testing should proceed by one animal. Three kinds of in vitro corrosivity tests have been adopted in the Guidelines.

著者

林 裕造

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.81-89, 2005 (Released:2005-12-26)

参考文献数

9

被引用文献数

2 2

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A threshold represents the theoretically defined dose, below which no abnormal increase in response is observed. Genotoxic carcinogens are known to have an irreversible effect on the genetic cellular structure. Even in small amounts, genotoxic carcinogens are assumed to have additive effects and therefore to subject individuals exposed to them to an incremental risk of developing cancer.Based on this assumption, the no-threshold concept was introduced exclusively for genotoxic carcinogens and has been adopted in Japan as a basis for the regulatory risk assessment in case of such chemicals. The current regulatory policy adheres to the fundamental principle of food safety i.e. to the precedence of protecting people's health.Dose-response studies recently conducted on various genotoxic agents suggest the existence of a threshold. If confirmed, such findings may provide sufficient scientific evidence to substantiate the adoption of a threshold concept as the principle of the regulatory assessment of the risks of genotoxic carcinogens and their impact on health.It should however be emphasized that the limitations of a threshold approach must be clearly understood and presented to lend credence to the proposition of a paradigm shift from the current regulatory policy: A threshold is not a value that can be determined directly and precisely from dose-response data, but one that can be estimated from analytical data by means of a logically-elaborated mathematical model calculation.Scientific efforts in support of the adoption of a threshold in this context should therefore be focused on the development of appropriate mathematical models, and on the establishment of toxicological concepts that substantiate their application.A realistic first step towards a paradigm shift from the no-threshold concept is to seek general consensus on the introduction of an appropriately estimated“virtually safe dose”, instead of a threshold.

著者

鈴木 孝昌

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.24, no.3, pp.179-184, 2002-11-13

参考文献数

10

被引用文献数

3

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この原稿は,今年の7月に淡路島で開かれたMMS研究会第31回定例会での特別講演をもとに作成したものです.これまで,10年以上にわたり国立医薬品食品衛生研究所変異遺伝部において,環境変異原研究に携わってきましたが,この4月に部を移動になり,環境変異原研究とは今後少し距離を置かざるを得なくなりました.この機会に自分としても一歩離れた立場からこれまで歩んできた道を振り返り,少し大胆に提言をさせていただきたいと考え,「環境変異原研究の光と陰」というタイトルで講演をさせていただきました.講演後の反響もあり,内容に関する問い合わせもいただいたことから,今回環境変異原研究の原稿として,まとめ直させていただきました.これがきっかけとなり,環境変異原研究の方向性に関する議論が盛り上がることを期待します.

著者

西尾 恵里子 森田 士郎 豊川 徹 富田 純史

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.2, pp.81-88, 2004 (Released:2005-12-21)

参考文献数

13

被引用文献数

5 5

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The Ames Salmonella/microsome assay (Ames test) is a convenient method for screening mutagens in our diet including those in drinking water. In this study, we assayed the mutagenicity levels of tap water in Kitakyushu-city and of humic acid solutions treated with chlorine. The amount of chlorine added was calculated to maintain the residual chlorine level constant at 20°C as in city office tap water. The samples were concentrated with adsorbent (CSP800) and the mutagenic activity was assayed with Salmonella typhimurium TA100 and TA98 strains with or without S9 mix. The tap water was analyzed for volatile organic compounds and some factors in conventional water quality monitoring every two months from March 1998 to January 2000. The tap water samples tested showed mutagenicity on strain TA100 without S9 mix. The mutagenicity of the samples tended to be higher from winter to spring than that from summer to fall.Chlorine-treated humic acid solutions were used as a model to examine the effect of the concentrations of humic acid and chlorine, and the temperature on the mutagenicity. The descending order of sensitivity to mutagenicity was TA100 without S9 mix, TA98 without S9 mix, and TA100 with S9 mix; no mutagenicity was observed for TA98 with S9 mix. Mutagenicity seemed to increase with increasing concentrations of humic acid and chlorine, and with lowering the water temperature. The observed seasonal variation of mutagenicity of the tap water may be partly explained by the rainfall and the water temperature during the rainy season, from summer to fall, because the organic substances of river water decreased and the water temperature increased over that season.

著者

小野 宏

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.133-137, 2005 (Released:2005-12-26)

参考文献数

5

---

The OECD established the Guidelines for Testing of Chemicals in 1981, which is the basis of the mutual acceptance of data (MAD) system among the member countries to prevent unnecessary repetition of toxicity tests, and consequently to reduce the number of animals used. The Guidelines was soon subjected to revision from the viewpoint of animal welfare besides its periodical updating with the state-of-art in the toxicological sciences. Revision of the Test Guidelines is in progress according to the 3Rs principle, reduction, refinement and replacement. The acute toxicity test and the skin and eye irritation/corrosion tests were assumed to be the most problematic ones among the animal tests in animal welfare aspect. Three different test methods have been adopted for the alternative to acute oral toxicity test (Test Guideline (TG) 401), namely, the fixed dose procedure (TG420), acute toxic class method (TG423) and up-and-down procedure (TG425), and the reduction of animals was accomplished. Then the traditional acute oral toxicity test (TG401) has been deleted from the Guidelines. Procedures for irritation/corrosion tests for skin (TG404) and eye (TG405) were reorganized into tier-test system in order to prevent any corrosion or strong irritation to take place. The tier system consists of survey of toxicities of the test chemical, structure-activity relationship, pH, and testing with in vitro methods. Moreover, at the final tier animal testing should proceed by one animal. Three kinds of in vitro corrosivity tests have been adopted in the Guidelines.

著者

林 真 長尾 美奈子 祖父尼 俊雄 森田 健 能美 健彦 本間 正充 宇野 芳文 葛西 宏 佐々木 有 太田 敏博 田中 憲穂 中嶋 圓 布柴 達夫

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.3, pp.275-283, 2004-12-20

被引用文献数

1

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食品関連物質の遺伝毒性の評価,解釈をするための戦略を構築するため,日本環境変異原学会に臨時委員会を設立し,厚生労働科学研究費補助金食品安全性確保研究事業「既存添加物等における遺伝毒性評価のための戦略構築に関する研究」の研究班と共同し,定例の検討会議を毎月開催し,統一的な考えについて検討を続けている.本戦略を構築するためのモデルとして,コウジ酸を選択し,評価に必要と考えられる試験を実施し,その結果の評価,解釈を国際的議論のもとに標準化可能なものとするため,海外から指導的立場にある研究者をコンサルタントとして招聘し,議論,提言を受けた.本臨時委員会の活動は3年計画で進められており,現在は約1年半が経過したところである.ここでは,本委員会の設置意図を中心に活動の中間報告を行う.

著者

浅野間 光治 荒木 春美 大澤 浩一 中井 康晴 林 宏行 若田 明裕 森田 健

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.25, no.1, pp.45-59, 2003 (Released:2005-08-19)

被引用文献数

2

著者

鈴木 孝昌

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.25, no.2, pp.119-125, 2003 (Released:2005-08-19)

参考文献数

15

被引用文献数

1 1

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The transgenic mouse mutation assay was developed as a striking new tool for mutation research in 1990. This assay enables the detection of mutations in a transgene in multiple organs including germinal tissues and thus reveals organ-specific genotoxicity of the mutagen. Following its introduction in MutaMouse and Big Blue mouse systems, modification of the methodology, mainly the introduction of the positive selection system and development of other transgenic animal models including rat, improved and assured the relevance of the assay. Accumulation of experimental data suggests the transgenic mouse mutation assay can be used as a standard in vivo test for mutagenesis.We have developed a multi-endpoint test, by combining the peripheral blood micronucleus assay with the transgenic mouse mutation assay. This test allows simultaneous detection of clastogenecity and mutagenecity in vivo. Since these two endpoints indicate different characteristics of the mutagen, data from many chemicals suggest the importance of detecting both endpoints. With this approach, the transgenic assay could detect the mutagenecity of diethylnitrosamine, which failed to be detected in micronucleus assay.Another important advantage of this assay is its suitability for sequence analysis. Sequencing of the transgene enables to draw mutagen-specific mutation spectrum, a molecular signature of the mutagen, and is very useful to deduce the mechanism of mutagenesis. In this regard, we have intensively used a positively selectable target gene ‘cII’. This gene is relatively short (300 bp) which made the sequencing process easier and less time consuming and enables us to generate data on mutagenesis of several mutagens. We hope the database will be useful for molecular epidemiology in future.A quantitative comparison of carcinogenic and mutagenic potency of chemicals revealed a good correlation with transgenic mutation assay and therefore suggesting a usefulness of this assay for the quantitative risk assessment.

著者

森田 健 石光 進 森川 馨

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.47-56, 2005 (Released:2005-12-26)

参考文献数

20

被引用文献数

2 2

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Global new perspectives on genotoxicity, i.e., threshold and germ cell mutagenicity, are summarized. On the aspect of threshold, proposal of a flow scheme toward risk assessment and standard setting for chemical carcinogens from European Academy, guideline on the limits of genotoxic impurities in pharmaceutical from the European Medicines Agency, and the concept of thresholds of toxicological concern (TTC) are introduced. On germ cell mutagenicity, health hazard classification criteria by a system of Globally Harmonized System of Classification and Labeling of Chemicals (GHS) and examples of classification by EU or Germany MAK Commission are also explained. These give major impacts to genotoxicity evaluation, risk assessment and hazard classification of chemicals.

著者

森田 健 石光 進 森川 馨

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.47-56, 2005-07-31

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Global new perspectives on genotoxicity, i.e., threshold and germ cell mutagenicity, are summarized. On the aspect of threshold, proposal of a flow scheme toward risk assessment and standard setting for chemical carcinogens from European Academy, guideline on the limits of genotoxic impurities in pharmaceutical from the European Medicines Agency, and the concept of thresholds of toxicological concern (TTC) are introduced. On germ cell mutagenicity, health hazard classification criteria by a system of Globally Harmonized System of Classification and Labeling of Chemicals (GHS) and examples of classification by EU or Germany MAK Commission are also explained. These give major impacts to genotoxicity evaluation, risk assessment and hazard classification of chemicals.

著者

羽倉 昌志 鈴木 聡 佐藤 哲男

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.25, no.2, pp.135-146, 2003 (Released:2005-08-19)

参考文献数

57

被引用文献数

3 4

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Because of the recent advances in the acquisition of human materials for research in addition to the value in the evaluation of the mutagenicity in humans, the use of human S9 fractions in the Ames test is starting to attract attention. However, until recently, available data on the mutagenicity with human S9 fractions has been limited. We have thus accumulated a large and extensive body of data on the Ames test with human S9 fractions during the last 5 years. In this report, these data are reviewed, and the utility of the human S9 fractions in mutagenicity testing systems is discussed.

著者

長尾 美奈子 日本環境変異原学会臨時委員会

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.2, pp.193-198, 2004 (Released:2005-12-21)

参考文献数

15

被引用文献数

2 2

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Kojic acid (KA) , belonging to existing food additives for which compositions or usages are not clarified, had been used for prevention of enzymatic browning. In 1995, the food sanitation law was largely revised to harmonize with JECFA, OECD and FDA. Under the new law, reevaluation of existing food additives was required. In 1998, it was found that KA induced tumors in the thyroid and liver of mice. KA also showed genotoxicities; gene mutations in S. typhimurium, chromosome aberrations in CHO-K1 and CHL/IU cells in vitro, and micronuclei in the liver of mice and hematopoietic cells in rats. Although it has not been clarified whether liver or thyroid tumors were induced by genotoxic effects of KA or not, use of KA as a food additive was banned in 2003, based on the fact that KA was not used in any country at that time. The ad hoc committee which was set-up for a three-year task from 2003-2005 considered that KA was an appropriate model compound to re-evaluate the strategies presently used to detect genotoxicity in vitro and in vivo, and to re-evaluate the regulatory rules (use of genotoxic carcinogens as food additives should be totally avoided; genotoxic non-carcinogens in rodents can be used as food additives). First of all, we confirmed the genotoxicity of KA; we demonstrated that genotoxicity in S. typhimurium was due to KA itself, but not due to contaminants, KA induced TK mutations, micronuclei and DNA damage (Comet) in human lymphoblastoid cells, TK6 and WTK-1. These results support the finding that KA is genotoxic in vivo, although it is not clear yet whether KA induces tumors by its genotoxicity or not. Speculating that liver tumors induced by KA were due to its genotoxicity, human risks to KA to which humans are exposed by taking fermented food products was calculated to be 2×10-7 by the linearized multistage model.