Gene mutation assays genotoxicity testing

The genotoxic potency of ethyl chloride appears to be low. It was negative in in vivo micronucleus tests, but it has produced both positive and negative results in bacterial gene mutation assays. ... 

In general, genotoxicity standard assays (e.g., bacterial reverse mutation assay [Ames test], in vitro chromosomal aberration assay, mouse lymphoma gene mutation assay, and rodent micronucleus assay) may not be suitable assays because the test cells do not contain the appropriate receptors to transport the product (i.e.,not a relevant species) or because the biopharmaceutical... 

Twenty-seven out of 44 FDA-approved biopharmaceuticals have been tested in a battery of genotoxicity assays. Eighty-five different assays performed yielded negative results. The most commonly performed assays were the Ames test, the chromosomal aberration assay in human lymphocytes, the mouse lymphoma gene mutation assay, and the mammalian in vivo erythrocyte micronucleus test. Examples of the range of biopharmaceutical products tested include, domase alfa (deoxyribonuclease I-DNAse), trastuzumab (mAb to human epidermal growth factor receptor 2), alteplase (tissue plasminogen activator), infliximab (mAb to the human tumor necrosis factor a). 

Moore MM, Honma M, Clements J, et al. (2002) Mouse lymphoma thymidine kinase gene mutation assay followup International Workshop on Genotoxicity Test Procedures, New Orleans, Louisiana, April 2000. Environmental and Molecular Mutagenesis 40(4) 292-299. 

J., Omori, T., Ouldelhkim, M. C., Pant, K., Preston, R., Riach, C., San, R., Stankowski, L. R, Jr., Thakur, A., Wakuri, S., and Yoshimura, I. (2003). Mouse lymphoma thymidine kinase gene mutation assay International Workshop on Genotoxicity Tests Workgroup report—Plymouth, UK 2002. Mutat Res 540, 127-140. 

Species. In vivo genotoxicity assays mainly use rodents (rats and mice), because they are small (standard animal facilities and low amount of test article needed) and because abundant toxicologic and metabolic data are available on these species. Most assays are also theoretically applicable to noiu odent animals, but limited data have been reported in the literature. Most of the assays are applicable to wild-type and readily available animal strains. It should nevertheless be noted that a few models require specific strains (e.g., some gene mutation assays). 

In Ames and micronucleus tests of urine from human volunteers administered the compound arbutin at doses of 420 mg, no mutagenic or genotoxic activity was observed (Siegers et al. 1997). No mutagenicity of arbutin was observed in a gene mutation assay at a concentration of 0.01 M, whereas the compound hydroquinone caused an increase in mutation frequency at a concentration of 0.01 M (Mueller and Kasper 1996). 

No genotoxic activity of European mistletoe was observed in a variety of assays, including a bacterial mutation assay, mammalian cell gene mutation assay, in vitro cytogenetic assay, cell transformation assay, and the Ames test (Mengs 1998 Mengs et al. 1997). 

Cerium sulfide pigments also show no genotoxic or carcinogenicity effects. Bacterial and in vitro gene mutation assays (OECD 471 476) fail to show mutagenic activity. In vitro chromosomal aberration tests (OECD 473) show no clastogenic activity. Additionally, sub-chronic toxicity (28 day, OECD 407) studies show no significant adverse effects (dose of 150 mg/kg/day), unlike cadmium and some other pig-ments . ... 

Genotoxic Effects. No studies were located regarding the genotoxic effects of hexachloroethane in humans after inhalation, oral, or dermal exposure. In vitro studies of hexachloroethane using microbial, fungal, and rodent cell assays are summarized in Table 2-4. Tests of prokaryotic cell systems failed to detect gene mutation (Haworth et al. 1983 Roldan-Arjona et al. 1991 Simmon and Kauhanen 1978 ... 

ICH guidelines specifically require three genotoxicity assays for all devices (see Table 6.2). The assays should preferably evaluate DNA effects, gene mutations and chromosomal aberrations, and two of the assays should preferably use mammalian cells. Guidance for providing tests for selection to meet these needs are the OECD guidelines, which include 8 in vitro and 7 in vivo assays. 

DIPE has been tested for genotoxic activity in bacterial mutation assays, a yeast assay for mitotic gene conversion, and in tests using rat liver and Chinese hamster ovary cells with structural chromosome damaging the end point. Negative responses were observed in the bacterial and yeast assays. 

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