Mutagenic responses

Benzyl chloride induced a positive mutagenic response ia the Ames Assay ia strain TA 100 with and without rat Hver S-9 metaboHc activation. 

One important point of controversy in risk extrapolation is the existence of the threshold level for carcinogenic and mutagenic response to a pollutant. Some argue that an organism is able to cope with low doses of a substance through metabolic processes or repair mechanisms, so that harmful effects do not appear until a certain minimum threshold, or "safe dose", is surpassed. Others contend that a carcinogenic substance must be considered potentially harmful at any dose, and that even a single molecule may initiate a tumor at the cellular level. This is the so-called "one-hit" hypothesis. 

Mutagenic responses were produced in Escherichia coli and certain strains of Salmonella typhimurium bacteria by 2,3,7,8-TCDD, but not by octa-CDD (Vos 1978). Further, chromosomal aberrations were induced in at least one species of higher plant and mammal (Ramel 1978). It must be concluded at this time that 2,3,7,8-TCDD is mutagenic or has mutagenic potential. 

Haukaas, S.A., Hoisater, P.A. and Kalland, T. (1982). In vitro and in vivo effects of diethylstilbestrol and estramustine phosphate (Estracyte) on the mutagen responsiveness of human peripheral blood lymphocytes. Prostate 3 405-414. 

Driscoll KE, Carter JM, Howard BW, Hassenbein DG, Pepelko W, Baggs RB, Oberdorster G (1996) Pulmonary inflammatory, chemokine, and mutagenic responses in rats after subchronic inhalation of carbon black. Toxicology and Applied Pharmacology 136 372-380. 

The observed mutagenic responses to AFB reflect the overall effects of activation and detoxification systems on the in vitro metabolism of AFB. It appeared that the effect of high casein levels fed to trout was that a greater amount of activated AFB was produced and/or that less could be detoxified by these fish than by those fed lower casein diets. If lowered cytochrome P-450 content and AE activities in fish fed the high casein diets represented a decrease in the activation of AFB, then these effects were overcome by the observed decreases in GTr activity and/or increases in AFB conversion to AFL relative to those of trout fed lower casein diets. Alternately, the results could be explained by dietary effects upon some unknown OAFB metabolizing enzyme system in trout, upon free GSH levels in hepatic tissue, or that the levels of the cytochrome P-450 involved in AFB activation were not reflected by the observed total cytochrome P-450 levels. 

Dichlorophenol with or without metabolic activation did not induce an increase in mutagenic response in the Chinese hamster ovary HGPRT forward mutation assay (Litton Bionetics 1986a). This compound was also inactive in the Balb/3T3 in vitro transformation assay (Litton Bionetics 1985). 

Figure 4. Toxic and mutagenic response of diploid human lymphoblast line MIT-2 to aflatoxin B,. Open symbols afatoxin + phenobarbital-induced rat liver postmitochondrial supernatant (PMS) closed symbols effect of treatment with either aflatoxin or FMS alone.

King, C. M., L. J. Romano, and D. Schuetzle, Eds., Carcinogenic and Mutagenic Responses to Aromatic Amines and Nitroarenes, Elsevier, New York, 1988. 

Mutation Mutagenic responses mutations/locus/ gamete mutations/locus/ survivor... 

In assessing the potential for a chemical to produce heritable mutations in humans, it is necessary to examine the weight of evidence obtained from in vitro tests for mutations in microorganisms and cultured mammalian cells, from in vivo tests of mutations in animals, and from in vitro and in vivo tests for chromosome aberrations in mammalian cells. The strongest evidence would come from the demonstration that a chemical causes mutations or chromosome aberrations in human cells. As no studies were located that tested isophorone in cultured human cells or examined the cells of people with known exposure, this evidence is lacking. Of the five experiments that tested whether isophorone caused mutations or chromosome aberration in cultured mammalian cells, only two were positive a weak mutagenic response in mouse lymphoma cells and a positive test for sister... 

Chen, C.C., Speck, W.T. Rosenkranz, H.S. (1975) Mutagenicity testing with Salmonella typhimurium strains. II. The effect of unusual phenotypes on the mutagenic response. Mutat. Res., 28,31-35... 

Provost, G.S., Mirsalis, J.C., Rogers, B.J. Short, J.M. (1996) Mutagenic response to benzene andtris(2,3-dibromopropyl)phosphate in the lambda lad transgenic mouse mutation assay a standardized approach to in vivo mutation analysis. Environ, mol. Mutag., 28, 342-347... 

Hsie, A.W., O Neill, J.P., Machanoff, R., Schenley, R.L. Brimer, PA. (1981) Screening for mutagenic response of four coded chemicals by the CHO/HGPRT system. In de Serres, F.J. Ashby, J., eds. Evaluation of Short-Term Tests for Carcinogens. Report of the International Collaborative Program (Progress in Mutation Research, Vol. 1). Amsterdam, Elsevier, pp.602-607... 

McGregor, D.B., Riach, C., Cattanach, P, Edwards, I., Shepherd, W. Caspary, W.J. (1996) Mutagenic responses of L5178Y mouse lymphoma cells at the tk and hprt loci. Toxicol. In Vitro, 10,643-647... 

Routine controls were included to check for the presence of histidine and other growth-stimulating substances or possible effects in the sample. First, 0.5 mL of each DMSO concentrate was plated out in the absence of histidine in the top agar and then compared with the normal spontaneous background level. Second, as an internal control, a fixed amount of test mutagen (nitrofurazone) was dissolved in 0.50 mL of each concentrate and tested for possible differences in the mutagenic response. 

With the exception of indolylacetonitrile and dichloroacetonitrile, the compounds identified in the XAD-2/ethyl ether extracts of the chlorinated amino acids have also been identified by Glaze et al. (14), and Trehy and Bieber (15) have shown that dichloroacetonitrile can be produced by chlorination of certain amino acids. Of the compounds identified by GC-MS, only dichloroacetonitrile is a known mutagen (8). However, as in extracts of drinking water, dichloroacetonitrile is unlikely to account for a significant proportion of the activity observed in the extract of chlorinated methionine at the level detected. With the exception of chlorohydroxybenzyl cyanide, for which no authentic standard is available, all the compounds identified were tested for mutagenic activity, and no mutagenic response was obtained. 

Lee, et al. (7 1) carried out long-term (up to 12 months) feeding experiments of browned egg albumin with rats. Several changes were found, but no mutagenic response was observed. 

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