Mammalian cell gene mutation assays working group report

Aaron, C.S.; Bölcsföldi, George; Glatt, Hansruedi; Moore, Martha M.; Nishi, Yoshisuke; Stankowski, Leon F.; Theiss, Jeffrey C.; Thompson, Elizabeth I.

doi:10.1016/0165-1161(94)90038-8

Cited by 58 publications

(21 citation statements)

References 2 publications

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“…The standard MLA protocol requires only pulse treatment and a treatment time extended over two cell cycles is generally not needed for mammalian cell gene mutation assays (Aaron et al, 1994). Our present study, however, implied that some chemicals may need long-term continuous treatment to exhibit their mutagenicity in the MLA.…”

Section: Protocol Issuesmentioning

confidence: 38%

Evaluation of the mouse lymphoma tk assay (microwell method) as an alternative to the in vitro chromosomal aberration test

et al. 1999

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In order to evaluate the utility of the mouse lymphoma assay (MLA) for detecting in vitro clastogens and spindle poisons and to compare it with the in vitro chromosomal aberration test (CA), we conducted an international collaborative study of the MLA that included 45 Japanese laboratories and seven overseas laboratories under the cooperation of the Ministry of Health and Welfare of Japan and the Japanese Pharmaceutical Manufacturer's Association. We examined 40 chemicals; 33 were reportedly positive in the CA but negative in the bacterial reverse mutation assay, six were negative in both assays and one was positive in both. We assayed mutations of the thymidine kinase (TK) locus (tk) of L5178Y tk ϩ/-mouse lymphoma cells using the microwell method. According to our standard protocol, cells were exposed to the chemical for 3 h, cultured for 2 days and TK-deficient mutants were expressed in 96-well plates under trifluorothymidine. Each chemical was coded and tested by two or three laboratories. Among the 34 CA-positive chemicals, positive MLA results were obtained for 20 and negative results were obtained for nine. The remaining five chemicals were inconclusive or equivocal because of discrepant inter-laboratory results or reproduced discrepant results, respectively. Among the six CA-negative chemicals, one was negative in the MLA, two were positive and three were inconclusive. Thus, the MLA could detect only 59% (20/34) of CA-positive chemicals. We concluded that the MLA was not as sensitive as the CA. Some MLA-negative chemicals evoked positive responses in the CA only after long continuous treatment. These might also be genotoxic in the MLA with long continuous treatment. Improvement of the MLA protocol, including alteration of the duration of the treatment, might render the MLA as sensitive as the CA. IntroductionThe genotoxicity tests that have been developed and validated over the years differ in the biological system used (prokaryotic,

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Section: Protocol Issuesmentioning

confidence: 38%

Evaluation of the mouse lymphoma tk assay (microwell method) as an alternative to the in vitro chromosomal aberration test

et al. 1999

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“…These negative results provide important corroboration of a lack of gene mutation activity in the earlier negative CHO/HGPRT study. They also indicate a lack of induction of effects such as large deletions in DNA that may be detected in the autosomal tk locus assay (Aaron et al, 1994).…”

Section: Glyphosate and Glyphosate Saltsmentioning

confidence: 99%

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Kier

Kirkland²

2013

Critical Reviews in Toxicology

120

102

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An earlier review of the toxicity of glyphosate and the original Roundupä-branded formulation concluded that neither glyphosate nor the formulation poses a risk for the production of heritable/somatic mutations in humans. The present review of subsequent genotoxicity publications and regulatory studies of glyphosate and glyphosate-based formulations (GBFs) incorporates all of the findings into a weight of evidence for genotoxicity. An overwhelming preponderance of negative results in well-conducted bacterial reversion and in vivo mammalian micronucleus and chromosomal aberration assays indicates that glyphosate and typical GBFs are not genotoxic in these core assays. Negative results for in vitro gene mutation and a majority of negative results for chromosomal effect assays in mammalian cells add to the weight of evidence that glyphosate is not typically genotoxic for these endpoints in mammalian systems. Mixed results were observed for micronucleus assays of GBFs in nonmammalian systems. Reports of positive results for DNA damage endpoints indicate that glyphosate and GBFs tend to elicit DNA damage effects at high or toxic dose levels, but the data suggest that this is due to cytotoxicity rather than DNA interaction with GBF activity perhaps associated with the surfactants present in many GBFs. Glyphosate and typical GBFs do not appear to present significant genotoxic risk under normal conditions of human or environmental exposures.

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“…Mutagenicity assays can be done in several systems, While the bacterial systems (e.g., 15) are easier and faster, assays employing mammalian cells have the theoretical advantage that the DNA and its packaging and processing in mammalian cells is different than that in bacteria and, thus, is a more relevant test system (16). One mammalian cell assay uses the CHO ovary cell line (1 7) as a test cell.…”

Section: The Chinese Hamster Ovary (Cho) Assaymentioning

confidence: 99%

“…In contrast, the complete carcinogen EMS gave consistently positive results with the maximal dose of 500 pg/mL, yielding 494k139 (mean i standard deviation) colonies per lo6 surviving cells over 13 separate experiments. Similarly, treatment with 5 pg/rnL BaP, with the addition of activating enzymes (S9), yielded 232h104 colonies per lo6 surviving cells over 16 experiments, but yielded only background levels of colonies without S9 treatment.…”

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confidence: 99%