Genotoxic chemicals

In summary, genotoxicity studies of endosulfan have provided evidence that this compound is mutagenic and clastogenic, and that it induces effects on cell cycle kinetics in two different mammalian species. However, some of these data may be suspect because some formulations of endosulfan have contained epichlorohydrin, a known genotoxic chemical, as a stabilizer (Hoechst 1990). It should be noted that humans may also be exposed to epichlorohydrin along with endosulfan. 

Hazard characterization is a quantitative or semi-quantitative evaluation of the nature, severity, and duration of adverse health effects associated with biological, physical, or chemical agents that may be present in food. The characterization depends on the nature of the toxic effect or hazard. Eor some hazards such as genotoxic chemicals, there may be no threshold for the effect and therefore estimates are made of the possible magnitude of the risk at human exposure level (dose-response extrapolation). 

Another indicator of cell injury induced by genotoxic chemicals is the stabilization of p53 protein in cells. p53 is phosphorylated in response to DNA damage and strand break by the ATM and ATR pathways. Several investigators have utilized antibodies to p53 to examine increased levels of protein following chemical treatment of cells.8 9... 

NOC constitute a large category of genotoxic chemical carcinogens occurring in human diet and are known to induce cancer in experimental animals. Nitrosamines are generally found in foods since they are more stable than nitrosamides. Some NOC precursors do not act directly but must be converted to other nitrosation species. 

Carcinogenicity, usually but not exclusively for non-genotoxic chemicals, the most common reason... 

Renwick considered that in relation to carcinogenicity for non-genotoxic chemicals and teratogenicity, the application of an extra factor for nature of toxicity is difficult to justify scientifically. He concluded that if a safety factor for nature of toxicity is to be used then logically it should be apphed to the NOAEL for the toxicity, which resulted in its use. For example, in relation to teratogenicity, a factor for nature of toxicity should be applied to the NOAEL for teratogenicity and not for maternal toxicity or some other endpoint. For carcinogenicity, the extra factor should be applied only to the NOAEL for the detection of tumors in those studies where this effect was the rationale for the use of an extra factor. In relation to a steep dose-response, it was concluded that this, in reality, concerns the precision of the NOAEL and therefore relates to the adequacy of the database rather than nature of toxicity. 

Dimethyl sulfate is a potent genotoxic chemical and can directly alkylate DNA both in vivo and in vitro The 2003 ACGIH threshold limit value-time-weighted average (TLV-TWA) for dimethyl sulfate is 0.1 ppm... 

Witt, K.L., Livanos, E Kissling, G.E., Torous, D.K., Caspary, W Tice, R.R. and Recio, L. (2008) Comparison of flow cytometry- and microscopy-based methods for measuring micronucleated reticulocyte frequencies in rodents treated with nongenotoxic and genotoxic chemicals. Mutation Research, 649, 101-113. 

Ohno, K., Ishihata, K., Tanaka-Azuma, Y. and Yamada, T. (2008) A genotoxicity test system based on p53R2 gene expression in human cells Assessment ofits reactivity to various classes of genotoxic chemicals. Mutation Research, doi 10.1016/ j.mrgentox.2008.07.002. 

Elmore, E. Fitzgerald, M.P. (1990) Evalnation of the biolnminescence assays as screens for genotoxic chemicals. Prog. din. biol. Res., 340D, 379-387 FAOAVHO (1981) Toxicological Evaluation of Certain Food Additives (WHO Food Add. Ser. 

If current in vitro STTs are expected to replace long-term rodent studies for the identification of chemical carcinogens, that expectation should be abandoned. STTs do, however, continue to offer an economical, rapid, and dependable means to detect genotoxic chemicals. (Termant et al. 1987,... 

Ehling, U.H., Averbeck, D., Cerutti, P.A., Friedman, J., Griem, H., Kolbye, A.C. Jr., and Mendelsohn, M.L, (1983). Review of the evidence for the presence or absence of thresholds in the induction of genetic effects by genotoxic chemicals, International Commission for Protection Against Environmental Mutagens and Carcinogens, ICPEMC Publication No. 10., Mutat. Res. 123,281. 

Several assays in mammals permit a determination of the incidence of micronuclei 393 of these, the only one sufficiently developed to be a standard assay is the in vivo mammalian bone marrow polychromatic-erythrocyte assay.155 Micronuclei are formed from chromosomes or chromosomal fragments that are not incorporated into daughter nuclei at the time of cell division. Ihus, this very rapid test serves as an in vivo somatic cell screening test for finding genotoxic chemicals that might break chromosomes or cause nondisjunction in germ cells. It has been applied to more than 150 chemicals.158... 

Useful for prioritizing genotoxic chemicals for further development... 

Structural similarity of the substance to known carcinogens or genotoxic chemicals should be discussed, if appropriate... 

Birrell L, Cahill P, Hughes C, Tate M, Walmsley RM (2010) GADD45a-GFP GreenScreen HC assay results for the ECVAM recommended lists of genotoxic and non-genotoxic chemicals for assessment of new genotoxicity tests. Mutat Res 695 87-95... 

Pereira MA, Chang LW, McMillan L, et al. 1982. Battery of short-term tests in laboratory animals to corroborate the detection of human population exposures to genotoxic chemicals [Abstract]. Environ Mutagen 4 317. 

Kirkland, D., Aardema, M., Muller, L., and Makoto, H. (2006). Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens II. Further analysis of mammalian cell results, relative predictivity and tumour profiles. Mutat Res 608, 29—12. Kirkland, D., Kasper, R, Muller, L., Corvi, R., and Speit, G. (2008). Recommended lists of genotoxic and non-genotoxic chemicals for assessment of the performance of new or improved genotoxicity tests A follow-up to an ECVAM workshop. Mutat Res 653, 99-108. 

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