ABSTRACT
The L5178Y/tk+/- (-)3.7.2C mouse lymphoma assay (MLA) which detects mutations affecting the heterozygous thymidine kinase (tk) locus is capable of responding to chemicals acting as clastogens as well as point mutagens. Improvements in the assay to enhance detection of this spectrum of genetic events are summarized, and criteria for evaluating the data are defined. Using these criteria, the Phase III Work Group reviewed and evaluated literature containing MLA results published from 1976 through 1993. The data base included 602 chemicals of which 343 were evaluated as positive, 44 negative, 18 equivocal, 54 apparently inappropriate for evaluation in this test system with the published protocols, and 142 that were inadequately tested, and thus a definitive call could not be made. The overall performance of the assay is summarized by chemical class, and the outcome of testing 260 chemicals in the MLA is compared with Gene-Tox and National Toxicology Program evaluations of rodent carcinogenesis bioassay results for the same chemicals. Based on the Work Group's evaluation of published MLA data for chemicals that were considered adequately tested, it is concluded that for most chemicals the L5178Y/tk+/- mouse lymphoma assay is eminently well suited for genotoxicity testing and for predicting the potential for carcinogenicity.
Subject(s)
Chromosome Aberrations , Leukemia L5178/genetics , Mutation , Thymidine Kinase/genetics , Animals , Mice , Reference Standards , Tumor Cells, Cultured , United States , United States Environmental Protection AgencyABSTRACT
3 ketone solvents (methyl ethyl ketone (MEK), methyl isobutyl ketone (MiBK), and isophorone) were tested for potential genotoxicity. The assays of MEK and MiBK included the Salmonella/microsome (Ames) assay, L5178Y/TK+/- mouse lymphoma (ML) assay, BALB/3T3 cell transformation (CT) assay, unscheduled DNA synthesis (UDS) assay, and micronucleus (MN) assay. Only the ML, UDS, and MN assays were conducted on samples of isophorone. No genotoxicity was found for MEK or isophorone. The presence of a marginal response only at the highest, cytotoxic concentration tested in the ML assay, the lack of reproducibility in the CT assay, and clearly negative results in the Ames assay, UDS and MN assays, suggest that MiBK is unlikely to be genotoxic in mammalian systems.
Subject(s)
Butanones/pharmacology , Cyclohexanes/pharmacology , Cyclohexanones/pharmacology , Ketones/pharmacology , Methyl n-Butyl Ketone/pharmacology , Mutagens/pharmacology , Animals , Cell Transformation, Neoplastic , Cells, Cultured , DNA Replication/drug effects , Female , Liver/drug effects , Liver/metabolism , Lymphoma/pathology , Male , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Mutagenicity Tests/methods , Salmonella typhimurium/drug effects , SolventsABSTRACT
The mutagenicity of 4 coffee flavor ingredients (chlorogenic acid, caffeic acid, pyrazine, and trigonelline) was evaluated in the Salmonella plate incorporation assay and mouse lymphoma L5178Y TK +/- assay. Two of the compounds, pyrazine and trigonelline, were negative in both assays. The other two compounds, caffeic acid and chlorogenic acid, were positive in the mouse lymphoma assay but negative in the Salmonella assay.
Subject(s)
Alkaloids/pharmacology , Caffeic Acids/pharmacology , Chlorogenic Acid/pharmacology , Cinnamates/pharmacology , Coffee/analysis , Pyrazines/pharmacology , Salmonella typhimurium/drug effects , Tumor Cells, Cultured/drug effects , Animals , Biotransformation , Chemical Phenomena , Chemistry , Cricetinae , Leukemia L5178/pathology , Male , Mesocricetus , Mice , Mutagenicity Tests/methods , Rats , Rats, Inbred F344ABSTRACT
A total of 27 dyes and related chemicals were tested for mutagenicity in both the Salmonella typhimurium plate-incorporation and FMN-modified assays as well as the mouse lymphoma TK+/- assay. Half of the compounds tested were monoazo dyes (14); the remainder consisted of disazo (3), aminotriphenylmethane derivatives (4), and other miscellaneous (6) color compounds. The results obtained in this study are compared with data from dyes of the same batch tested in other laboratories in the Salmonella plate-incorporation assay and in both in vitro and in vivo/in vitro UDS assays. Agreement of results from the various assays that could be compared (excluding results that were equivocal or indeterminate) ranged from 80 to 91%. Sufficient data were available to provide an overall index of in vitro activity for 15 chemicals; of these, 14 compounds could be compared to and agreed with reports of their carcinogenic potential in the literature.
Subject(s)
Coloring Agents/pharmacology , Salmonella typhimurium/drug effects , Tumor Cells, Cultured/drug effects , Animals , Cricetinae , Leukemia L5178/enzymology , Leukemia L5178/genetics , Male , Mesocricetus , Mice , Mutagenicity Tests , Neoplasm Proteins/genetics , Rats , Rats, Inbred F344 , Thymidine Kinase/genetics , Tumor Cells, Cultured/enzymologyABSTRACT
To aid in the selection of chemical candidates for in vivo tests, the mutagenicity of 5 thiazole compounds was evaluated in the Salmonella plate incorporation assay and mouse lymphoma L5178Y TK+/- assay. Two of the compounds, 2-thiazolamine and 3-methyl-5-isothiazolamine, were positive in both assays; and one, thiazole, was negative. With the other 2 compounds the results were nonconcordant: 5-phenyl-2,4-thiazolediamine was negative in the Salmonella assay but positive in the mouse lymphoma assay, and C.I. Basic Red 29 was positive in the Salmonella assay while the response in the mouse lymphoma assay was considered equivocal.
Subject(s)
Mutation/drug effects , Thiazoles/toxicity , Animals , Biotransformation , Cell Survival/drug effects , Cells, Cultured , Lymphoma/enzymology , Mice , Microsomes, Liver/metabolism , Mutagenicity Tests , Salmonella typhimurium/drug effects , Thymidine Kinase/geneticsABSTRACT
Di-(2-ethylhexyl)phthalate (DEHP) and its two major metabolites, mono-(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol (EH), were tested for genetic activity in both the Salmonella/mammalian microsome mutagenicity (Ames) assay and the L5178Y TK+/- mouse lymphoma cell mutagenicity assay. All chemicals were tested in both the presence and absence of Aroclor-induced liver microsomes prepared from male Sprague-Dawley rats. Dose levels for both assays were selected from preliminary toxicity studies for each chemical. Neither DEHP, MEHP, nor EH exhibited any significant mutagenic activity in strains TA-98, TA-100, TA-1535, TA-1537, and TA-1538 in the Ames test or when tested in the L5178Y TK+/- mouse lymphoma cell mutagenicity assay.
Subject(s)
Diethylhexyl Phthalate/toxicity , Hexanols/toxicity , Leukemia L5178/genetics , Leukemia, Experimental/genetics , Mutagens , Mutation , Phthalic Acids/toxicity , Animals , Biotransformation , Diethylhexyl Phthalate/analogs & derivatives , Mice , Microsomes, Liver/metabolism , Mutagenicity Tests , Plasticizers , Salmonella typhimurium/drug effects , Structure-Activity RelationshipABSTRACT
Commercially produced oil furnace carbon black (Chemical Abstract Service Registry No. 1333-86-4) has been evaluated by five different assay for genetic activity. These were the Ames Salmonella typhimurium reverse mutation test, sister chromatid exchange test in CHO cells, mouse lymphoma test, cell transformation assay in C3H/10T1/2 cells, and assay for genetic effects in Drosophila melanogaster. Limited cellular toxicity was exhibited but no significant genetic activity was noted.
Subject(s)
Air Pollutants, Occupational/toxicity , Air Pollutants/toxicity , Carbon/toxicity , Mutagens , Animals , Cells, Cultured , Clone Cells/drug effects , Cricetinae , Female , Lymphoma/physiopathology , Male , Mutagenicity Tests , Neoplasms, Experimental/physiopathology , Salmonella typhimurium/genetics , Sister Chromatid Exchange/drug effects , Y Chromosome/drug effectsABSTRACT
A quantitative microbial assay was used to study the stability of known mutagenic and carcinogenic compounds in cell culture medium. Ten direct-acting carcinogens, when incubated in culture medium with 15% fetal bovine serum at pH 7.2-7.4 and 37 degrees C, became inactive at varying rates. Biologic half-lives of the test compounds ranged from 8 minutes to 67 hours. In contrast, six procarcinogens showed no significant inactivation after 3 weeks' incubation. The biologic half-lives of each compound were presented, and the significance of these findings as they relate to cell culture carcinogenesis and mutagenesis assays was discussed.
