Chemical mutagenesis at the thymidine kinase locus in L5178Y mouse lymphoma cells: Results for 31 coded compounds in the national toxicology program

Myhr, B.; Caspary, William J.; Holden, Henry E.

doi:10.1002/em.2850180109

Cited by 111 publications

(36 citation statements)

References 18 publications

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“…Technical deficiencies in the conduct of the in vitro mammalian cell mouse lymphoma assay (no colony sizing) limit the usefulness of the in vitro mammalian data (16). In vitro gross chromosome aberration analysis using Chinese hamster ovary cells found TCE to be negative both with and without exogenous activation (17).…”

Section: Trichloroethylenementioning

confidence: 99%

Mutagenicity of trichloroethylene and its metabolites: implications for the risk assessment of trichloroethylene.

Moore

Harrington‐Brock

2000

Environ Health Perspect

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This article addresses the evidence that trichloroethylene (TCE) or its metabolites might mediate tumor formation via a mutagenic mode of action. We review and draw conclusions from the published mutagenicity and genotoxicity information for TCE and its metabolites, chloral hydrate (CH), dichloroacetic acid (DCA), trichloroacetic acid (TCA), trichloroethanol, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG). The new U.S. Environmental Protection Agency proposed Cancer Risk Assessment Guidelines provide for an assessment of the key events involved in the development of specific tumors. Consistent with this thinking, we provide a new and general strategy for interpreting genotoxicity data that goes beyond a simple determination that the chemical is or is not genotoxic. For TCE, we conclude that the weight of the evidence argues that chemically induced mutation is unlikely to be a key event in the induction of human tumors that might be caused by TCE itself (as the parent compound) and its metabolites, CH, DCA, and TCA. This conclusion derives primarily from the fact that these chemicals require very high doses to be genotoxic. There is not enough information to draw any conclusions for trichloroethanol and the two trichloroethylene conjugates, DCVC and DCVG. There is some evidence that DCVC is a more potent mutagen than CH, DCA, or TCA. Unfortunately, definitive conclusions as to whether TCE will induce tumors in humans via a mutagenic mode of action cannot be drawn from the available information. More research, including the development and use of new techniques, is required before it is possible to make a definitive assessment as to whether chemically induced mutation is a key event in any human tumors resulting from exposure to TCE.

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Section: Trichloroethylenementioning

confidence: 99%

Mutagenicity of trichloroethylene and its metabolites: implications for the risk assessment of trichloroethylene.

Moore

Harrington‐Brock

2000

Environ Health Perspect

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“…Among all the experiments, only one dose in lab B with S9 mix showed a statistically significant response in a pair-wise comparison. The mutagenicity of tetrachloroethane in the MLA has been debated and discrepant results were obtained in two experiments by the NTP; McGregor et al (1988b) reported a positive result in the presence and absence of S9 mix, while Myhr and Caspary (1991) reported negative results under both conditions.…”

Section: -Fluorouracil (5fu): Positive (-S9/ϩs9mentioning

confidence: 99%

“…Therefore, this chemical was judged inconclusive with and without S9 mix. NTP reported that bisphenol A was non-mutagenic in the MLA (Ivett et al, 1989;Myhr and Caspary, 1991). p-t-Butylphenol: negative (-S9/ϩS9: -/-).…”

Section: -Fluorouracil (5fu): Positive (-S9/ϩs9mentioning

confidence: 99%

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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“…With the same substance equivocal results in an in vivo host mediated mutation assay were observed at high dose levels (Food and Drug Research Laboratories, Inc., 1975) and negative results in several Ames tests, a TK+/-mouse lymphoma assay (Myhr and Caspary, 1991), sister chromatid exchange (SCE) tests in Chinese hamster ovary (CHO) cells (Ivett et al, 1989) and human lymphocytes (Murthy et al, 1991), and chromosomal aberration assays with human embryonic lung cells (Food and Drug Research Laboratories, Inc., 1975), human lymphocytes (Murthy et al, 1991) and CHO cells (Ivett et al, 1989). Negative results were also reported in two in vivo micronucleus (Shelby et al, 1993) and chromosomal aberration assays (Food and Drug Research Laboratories, Inc., 1975).…”

Section: Genotoxicity Studiesmentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 9, Revision 5 (FGE.09Rev5): Secondary alicyclic saturated and unsaturated alcohols, ketones and esters containing secondary alicyclic alcohols from chemical group 8 and 30, and an ester of a phenol derivat

2014

EFSA Journal

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None of the substances were considered to have genotoxic potential. The substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that the 21 substances 02.075, 02.135, 02.167, 06.136, 07.059, 07.109, 07.202, 07.203, 07.255, 09.154, 09.355, 09.520, 09.618, 09.619, 09.621, 09.843, 09.870, 09.929, 09.935 Seventeen of the flavouring substances have one or more chiral centres.Fourteen of the flavouring substances belong to structural class I, six belong to structural class II and one to structural class III, according to the decision tree approach presented by Cramer et al., 1978. Fourteen of the flavouring substances have been reported to occur naturally in a wide range of food items.In its evaluation, the Panel as a default used the "Maximised Survey-derived Daily Intake" (MSDI) approach to estimate the per capita intakes of the flavouring substances in Europe. However, when the Panel examined the information provided by the European Flavour Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported to be small. In consequence, the Panel had reservations about the data on use and use levels provided and the intake estimates obtained by the MSDI approach.In the absence of more precise information that would enable the Panel to make a more realistic estimate of the intakes of the flavouring substances, the Panel has decided also to perform an estimate of the daily intakes per person using a "modified Theoretical Added Maximum Daily Intake" (mTAMDI) approach based on the normal use levels reported by Industry. In those cases where the mTAMDI approach indicated that the intake of a flavouring substance might exceed its corresponding threshold of concern, the Panel decided not to carry out a formal safety assessment using the Procedure. In these cases the Panel requires more precise data on use and use levels.According to the default MSDI approach the 14 flavouring substances belonging to structural class I have intakes in Europe ranging from 0.0012 to 830 µg/capita/day, for five of the six substances from structural class II the intakes range from 0.0085 to 530 µg/capita/day, and for the substance from structural class III the intake is 1.2 µg/capita/day, which are all below their respective threshold of concern value for structural class I, II or III of 1800, 540 or 90 µg/person/day, respectively. For one substance .520] from structural class II the MSDI is 770 µg/capita/day, which is above the threshold of concern of 540 µg/person/day, however, an NOAEL provides a sufficient margin of safety and therefore do the total combined intakes of the candidate and suppor...

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Chemical mutagenesis at the thymidine kinase locus in L5178Y mouse lymphoma cells: Results for 31 coded compounds in the national toxicology program

Cited by 111 publications

References 18 publications

Mutagenicity of trichloroethylene and its metabolites: implications for the risk assessment of trichloroethylene.

Mutagenicity of trichloroethylene and its metabolites: implications for the risk assessment of trichloroethylene.

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

Scientific Opinion on Flavouring Group Evaluation 9, Revision 5 (FGE.09Rev5): Secondary alicyclic saturated and unsaturated alcohols, ketones and esters containing secondary alicyclic alcohols from chemical group 8 and 30, and an ester of a phenol derivat

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