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T Sofuni

Publications and source records attributed to T Sofuni.

At least 145 records · Page 8Linked to original sources
PubMed1991

Toxicology testing requirements and the U.S.-Japan collaborative study on in vitro tests for chromosomal aberrations.

As part of the U.S.-Japan Agreement on Cooperation in Research and Development in Science and Technology, Japanese and American scientists met in North Carolina to exchange information on toxicology testing requirements and guidelines in the two countries and to review progress in a collaborative study on detection of chemically induced chromosomal aberrations in cultured mammalian cells.

Animals↗
PubMed1991

A fact database for toxicological data at the National Institute of Hygienic Sciences, Japan.

The computerized fact database for the toxicity data of chemicals was constructed at the National Institute of Hygienic Sciences, Tokyo, Japan (biological database, BL-DB). The BL-DB stores data on mutagenicity, teratogenicity, carcinogenicity, and other toxicological tests of chemicals that appeared in the scientific literature. The BL-DB includes information about chemical identification, test system, results of the assays, and a bibliography. The system consists of five modules: data collection, data maintenance, data search, data downloading, and backup. ADABAS is used as a core database management system. Many kinds of test data are stored with the same formats; therefore, users can retrieve data of different toxicological data by the same manner. A user of the BL-DB can use about 50 kinds of commands to interact with the system, and the majority of fields are defined as search fields, thereby facilitating retrieval of target data through many ways. Currently, there are mainly data for the mutagenicity, especially on the Salmonella/microsome assay and the rodent micronucleus assay. These data can be retrieved and used for structure-activity relationship studies.

Abnormalities, Drug-Induced↗
PubMed1991

The expert system for toxicity prediction of chemicals based on structure-activity relationship.

The prediction systems of chemical toxicity has been developed by means of structure-activity relationship based on the computerized fact database (BL-DB). Numbers and ratio of elements, side chains, bonding, position, and microenvironment of side chains were used as structural factors of the chemical for the prediction. Such information was obtained from the BL-DB database by Wiswesser line-formula chemical notation. In the present study, the Salmonella/microsome assay was chosen as indicative of the target toxicity of chemicals. A set of chemicals specified with mutagenicity data was retrieved, and necessary information was extracted and transferred to the working file. Rules of the relations between characteristics of chemical structure and the assay result are extracted as parameters for rules by experts on the rearranged data set. These were analyzed statistically by the discriminant analysis and the prediction with the rules were evaluated by the elimination method. Eight kinds of rules to predict Salmonella/microsome assay were constructed, and currently results of the assay on aliphatic and heterocyclic compounds can be predicted as accurately as +90%.

Algorithms↗
PubMed1991

Quantitative evaluation on the genotoxic potency of chemicals.

Two in vitro tests with different genetic end points, gene mutation and chromosomal damage, and an in vivo test, preferably the micronucleus test in mice, were recommended as a battery system for the primary assessment of genotoxic effects of chemicals. From our comparative studies on the mutagenic potency of chemicals, it was pointed out that results should be evaluated quantitatively rather than qualitatively, since the potency varies extensively, at range of 10(7) fold, among different chemicals, and the in vitro genotoxins relatively weak tend to be negative in in vivo mutagenicity tests as well as in carcinogenicity tests in rodents. New Salmonella tester strains, called YG-series, were established, which showed a high nitroreductase or acetyltransferase activity and specifically sensitive to nitroarens or aromatic anmines in the reverse mutation assays (Ames test). These strains could detect a small amount of mutagenic aromatic amines containing in the urine of cigarette smokers. A new technique in the micronucleus test using peripheral blood erythrocytes was introduced. A cumurative genotoxic effect of benzene, for an example, was detected in the peripheral blood even several weeks after treatment every week by gavage. A cyto-flowmetric analysis can be also applied to monitoring of such effects.

Animals↗
PubMed1990

Mutagenicity of 3-tert-butyl-4-hydroxyanisole (BHA) and its metabolites in short-term tests in vitro.

The mutagenicity of 3-tert-butyl-4-hydroxyanisole (BHA) and its metabolites was investigated in the reverse mutation assay using S. typhimurium strains and the chromosomal aberration test in vitro using a Chinese hamster fibroblast cell line, CHL. BHA, tert-butylhydroquinone (BHQ), tert-butylquinone (BQ) and BHA dimer (diBHA) did not show any mutagenic potential with and without S9 mix in the reverse mutation assay. In addition to the above 4 chemicals, 3-tert-butyl-4,5-dihydroxyanisole (BHA-OH), 3-tert-butylanisole-4,5-quinone (BHA-o-Q), and tert-butylquinone oxide (BQO) were tested in the chromosomal aberration test. BHA, BHQ and BQ induced chromosomal aberrations only in the presence of S9 mix, while BHA-OH, BHA-o-Q and BQO induced chromosomal aberrations only without S9 mix. DiBHA, however, showed no clastogenic potential with and without S9 mix. The present findings suggest that BHA-OH, BHA-o-Q or BQO may contribute to the clastogenicity of BHA in the presence of S9 mix.

Animals↗
PubMed1990

A comparison of chromosome aberration induction by 25 compounds tested by two Chinese hamster cell (CHL and CHO) systems in culture.

Twenty-five chemicals were tested for the induction of chromosomal aberrations in 2 cultured mammalian cell systems, Chinese hamster lung cells (CHL) and Chinese hamster ovary cells (CHO). This study was carried out to provide a data set that would permit an assessment of the extent to which the 2 systems agree in the results produced. Results presented for the 2 systems in this paper are not based on the same criteria but rather on the criteria standardly used in each of the systems. In tests conducted in the absence of S9 mix, 7 chemicals gave positive results in both systems and 12 were negative in both. In tests with S9 mix, 5 were positive in both systems and 9 were negative in both. When the overall results including tests both with and without S9 mix were considered, the 2 systems agreed on 15 results, 11 positives and 4 negatives. A review of the test conditions and data suggests that disagreements in test results were more often due to differences in the protocols used in these 2 systems than to a difference in the sensitivities of the 2 cell lines.

Animals↗
PubMed1990

The micronucleus assay with mouse peripheral blood reticulocytes using acridine orange-coated slides.

Ultra-vital staining with acridine orange (AO) is introduced into the micronucleus assay with mouse peripheral blood cells. Peripheral blood was stained vitally by dropping whole blood on an AO-coated slide and covering the sample with a coverslip. With this method, reticulocytes are identified easily by their red fluorescing reticulum structure. The distinction between young and mature erythrocytes was clearer and less subjective than the distinction between polychromatic and normochromatic erythrocytes by Giemsa staining or by conventional AO fluorescent staining. Although the induction of micronucleated peripheral reticulocytes (MNRETs) was delayed by about 12 h compared to that of micronucleated polychromatic erythrocytes (MNPCEs) in the bone marrow, the frequencies of MNRETs and MNPCEs were almost identical at each optimal sampling time. It is concluded that bone marrow cells can be replaced by peripheral blood as material for the micronucleus assay.

Acridine Orange↗
PubMed1989

A procedure for data analysis of the rodent micronucleus test involving a historical control.

No standard procedure of data analysis for rodent micronucleus tests involving historical controls has been established. In the present paper, under the presumption that the distribution of the historical control is stable and reliable, a procedure with three statistical steps is proposed to analyze the frequency of micronucleated polychromatic erythrocytes (MNPCEs). In the first step, the frequencies of MNPCEs in negative and positive control groups of a current experiment of the micronucleus test are compared with the distribution of historical negative and positive controls to examine the technical validity of the current experiment. In the second step, the frequency of MNPCEs in each treatment group is compared with the distribution of the historical negative control. In the third step, the dose-response relation is tested with the Cochran-Armitage trend test. A Monte Carlo stimulation study shows that the power of this procedure is acceptable and also this procedure is robust. An application of this procedure on real data reveals that it is effective in detecting clastogenic chemicals when the probability of a type I error is nearly .01.

Animals↗
PubMed1989

Mutagenicity of ptaquiloside, the carcinogen in bracken, and its related illudane-type sesquiterpenes. II. Chromosomal aberration tests with cultured mammalian cells.

The chromosomal aberration test using a Chinese hamster lung cell line (CHL) was carried out on ptaquiloside and its related compounds, hypoloside B, hypoloside C, illudin M and illudin S. Ptaquiloside induced chromosomal aberrations at doses as low as 4.5 micrograms/ml (0.0113 mM). The clastogenic effect was pH-dependent. The same activity was observed at a 90-fold higher dose at pH 5.3 in the culture medium compared with the activity at pH 7.4 or pH 8.0. Both hypoloside B and hypoloside C were also clastogenic at almost the same dose level as that of ptaquiloside. Illudin M and illudin S were also potent clastogens and induced aberrations at much lower doses than ptaquiloside. These results suggest that the clastogenic effect is involved in the mechanism of carcinogenic potency of ptaquiloside in animals.

Animals↗
PubMed1989

Micronucleus test with 1-beta-D-arabinofuranosylcytosine administered by intraperitoneal injection and oral gavage.

The effect of route of administration on the outcome of the micronucleus test was evaluated in 2 laboratories by administering the model chemical, 1-beta-D-arabinofuranosylcytosine (Ara-C), by intraperitoneal injection (i.p.) and oral gavage (p.o.) to 2 mouse strains, MS/Ae and CD-1. On the basis of a small-scale acute toxicity study and a pilot experiment for the micronucleus test, a full-scale test was performed with a 24-h sampling time at doses of 12.5, 25, 50, and 100 mg/kg i.p. and 25, 50, 100, and 200 mg/kg p.o. In both strains, MNPCEs were induced at lower dose levels by the i.p. treatment, as determined not only on the basis of mg/kg but also as a ratio of the LD50. When compared with other chemicals tested in this collaborative study, the effective dose levels of this chemical based on the LD50s were exceptionally low by both routes and in both strains, e.g., less than 0.3% of the LD50 by the i.p. treatment. The maximum frequencies of MNPCEs induced were, however, identical (MS/Ae) or even higher (CD-1) by the p.o. treatment.

Administration, Oral↗
PubMed1988

Induction of chromosomal aberrations in active oxygen-generating systems. I. Effects of paraquat in Chinese hamster cells in culture.

A possible role for the superoxide anion radical (O2-) in the clastogenicity of paraquat (PQ) was investigated in cultured Chinese hamster cells. When cells were treated with 0.8 mg/ml of PQ for 3 h followed by 21 h of recovery time, structural chromosome aberrations were induced in about 50% of the metaphases examined. Almost all aberrations were of the chromatid-type and involved exclusively gaps and breaks. The induction of chromosomal aberrations by PQ was enhanced by a 1-h pretreatment with diethyldithiocarbamate, an inhibitor of superoxide dismutase. Diethyl maleate, a glutathione scavenger, also enhanced the induction of chromosomal aberrations, but 3-aminotriazole, an inhibitor of catalase, showed no such effects. Enhanced induction of chromosomal aberrations was also observed when PQ-treated cells were cultured at a high oxygen concentration (80%). The present results suggest that the production of chromosomal aberrations by PQ may be directly or indirectly related to the generation of O2-, but not to the formation of hydrogen peroxide by the dismutation reaction of O2- or of other active oxygen species including the hydroxyl radical and singlet oxygen.

Amitrole↗
PubMed1988

Induction of chromosomal aberrations in active oxygen-generating systems. II. A study with hydrogen peroxide-resistant cells in culture.

Cells hyper-resistant to hydrogen peroxide (H2O2) were obtained from a Chinese hamster cell line (CHL) by repeated treatments with H2O2 at stepwise increasing concentrations. A clonal line (R-8) was approximately 10 times more resistant to H2O2 than the parental cells, and retained its resistance for about 2 months in normal medium. However, with further passages after the completion of the present study, the elevated resistance gradually decreased. Although the concentration of H2O2 required to induce chromosomal aberrations in 50% of treated cells was about 10 times higher in R-8 than in the parental cells, there were no distinct differences between the cells in the induction of chromosomal aberrations by 3 alkylating agents (N-methyl-N'-nitro-N-nitrosoguanidine, N-ethyl-N-nitrosourea and mitomycin C). The catalase activity of R-8 was 10-fold in comparison with the parental cells, but no obvious differences were seen in the activities of superoxide dismutase (SOD), glutathione peroxidase and glutathione reductase. Therefore, the elevated H2O2-resistance seemed to be associated with the enhanced catalase activity. The induction of chromosomal aberrations in two O2- generating systems--xanthine oxidase plus hypoxanthine (XO + HX), and paraquat--was compared between R-8 cells and the ordinary CHL cells. XO + HX produced chromosomal aberrations in the parental cells but not in the R-8, while paraquat induced almost the same level of aberrations in both cell lines. This finding suggests that different active oxygens are responsible for the induction of aberrations in these two O2- generating systems, i.e., H2O2 in XO + HX and O2- in paraquat.

Animals↗
PubMed1988

A comparative analysis of data on the clastogenicity of 951 chemical substances tested in mammalian cell cultures.

A literature review was conducted using original papers published during 1964-1985 on the in vitro clastogenicity of chemical substances. Results of tests on 951 chemical substances were abstracted from over 240 reports to form the database. The evaluation of these data relied on each author's original conclusion on a positive or negative outcome. Of these 951 substances, 447 (47%) were consistently positive either with or without activation; 417 (44%) were negative in the direct test but not tested with metabolic activation systems; 4 were negative but tested only with activation; and 30 (3%) were clearly negative both with and without activation. The remaining 53 substances gave variable results when tested under different experimental protocols or in different cell types, but were positive in at least one test. Although discrepant results were found associated with some cell types, the addition of metabolic activation systems tended to eliminate such variability. No one cell appeared to be superior in response to all clastogens. For screening purposes, the choice of cell may thus depend more on the general usefulness and reliability of a cell type than on a strong response to a particular chemical. However, the use of a suitable metabolic activation system does appear to be of critical importance. The concentration at which clastogenic effects were detected varied extensively for different test substances, ranging from a minimum of 4.3 X 10(-8) to 6.9 X 10(2) mM. Possible mechanisms of action for substances active at only high levels are discussed, but no satisfactory explanation is available at this time. The relevance of tests conducted at concentrations high enough to alter significantly the osmolarity and other culture conditions is considered, and caution urged in the interpretation of test results obtained under physiologically stressful conditions. The clastogenic potential was compared quantitatively using an index of effective concentration (D20) and one which estimates the number of cells with exchange aberrations expected per mg/ml (TR) for data obtained by using a uniform protocol and cultures of Chinese hamster lung (CHL) cells. Both values were distributed over a wide range, demonstrating the variety of genotoxic potential in chemicals. In general, a substance which was active at only high concentrations produced fewer exchange-type aberrations. In vivo activity, as measured by tumourigenic effect and formation of micronuclei in bone marrow, tended to be greater for substances with a D20 below 10(-2) mg/ml and a TR value over 10(3).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals.

A total of 47 chemical substances including 32 synthetic food additives, seven additives from natural sources, three trihalogenated methanes, two fluoro-compounds for dental use, one insecticide, and two other compounds were subjected to the micronucleus test in mice. Five compounds, i.e. chlorine dioxide, maltol, potassium bromate, sodium chlorite and sodium dehydroacetate, were found to induce micronuclei after a single ip injection. Potassium bromate, sodium chlorite and sodium dehydroacetate were tested further by oral administration, and potassium bromate showed a clearly positive result. Almost all the compounds which were negative with the single treatment were additionally tested by four or five multiple treatments, but none showed any indication of micronucleus induction.

Animals↗
PubMed1987

Cytogenetic studies on 1,1-dichloroethylene and its two isomers in mammalian cells in vitro and in vivo.

Chromosomal aberration and sister-chromatid exchange (SCE) tests in vitro on 1,1-dichloroethylene (1,1-DCE), its two isomers, cis- and trans-1,2-DCE, and two possible metabolites of 1,1-DCE, chloroacetyl chloride and chloroacetic acid, were carried out using a Chinese hamster cell line, CHL. 1,1-DCE induced chromosomal aberrations in the presence of S9 mix prepared from the rat liver, but not in the absence of S9 mix. SCEs were also slightly induced by 1,1-DCE only in the presence of S9 mix. On the other hand, two isomers and two metabolites of 1,1-DCE induced neither chromosomal aberrations nor SCEs with and without S9 mix. 1,1-DCE, however, was negative even at a sublethal dose in the micronucleus test using mouse bone marrow, fetal liver and blood.

Animals↗