Carcinogens/mutagens activation

Introduce bulky groups in the vicinity of the epoxide to hinder the ring opening and hence decrease the carcinogenic/mutagenic activity. 

Mutagenicity. The AJ-nitrosamines, in general, induce mutations in standard bacterial-tester strains (117). As with carcinogenicity, enzymatic activation, typically with Hver microsomal preparations, is required. Certain substituted A/-nitrosamine derivatives (12) induce mutations without microsomal activation (31,33,34). Because the a-acetoxy derivatives can hydroly2e to the corresponding a-hydroxy compounds, this is consistent with the hypothesis that enzymatic oxidation leads to the formation of such unstable a-hydroxy intermediates (13) (118). However, for simple /V-nitrosamines, no systematic relationship has been found between carcinogenicity and mutagenicity (117,119—123). 

Sodium chlorite is not Hsted by the USEPA or any regulatory authority as a carcinogen. Studies conducted ia mice and rats did not show an increase in tumors in animals exposed to sodium chlorite in thek drinking water. Sodium chlorite has been found to have mutagenic activity in some in vitro test systems such as the Ames Salmonella reverse mutation assay without the presence of metaboHc activators. The significance of these test results in regard to human health is not clear because of the oxidizing effects of the chlorite ion (149). 

NCI. 1968. Evaluation of carcinogenic, teratogenic and mutagenic activities of selected pesticides and industrial chemicals. Volume I Carcinogenic study. Prepared by Bionetics Research Labs, Inc., Bethesda, MD National Cancer Institute. NCI-DCCP-CG-1973-1-1. 

In summary, preliminary results from two animal models (rabbit and mouse) indicate that poly(N-palmitoylhydroxyproline ester) elicits a very mild, local tissue response that compares favorably with the responses observed for established biomaterials such as medical grade stainless steel or poly(lactic acid)/poly(glycolic acid) implants. At this point, additional assays need to be performed to evaluate possible allergic responses, as well as systemic toxic effects, carcinogenic, teratogenic, or mutagenic activity, and adaptive responses. 

Enslein, K. An overview of structure-activity relationships as an alternative to testing in animals for carcinogenicity, mutagenicity, dermal and eye irritation, and acute oral toxicity. Toxicol Industrial Health 1988 4 479-98. 

A Russian expert system, PASS (prediction of activity spectra for substances) [84], uses substructural descriptors called multilevel neighborhoods of atoms [85] to predict over 900 different pharmacological activities from molecular structure. These activities include a number of toxicity end points such as carcinogenicity, mutagenicity, teratogenicity, and embryotoxicity. The accuracy of prediction has been shown [86] to range from about 85% to over 90%. One-off predictions can be obtained free of charge on the PASS website [84]. 

We demonstrated that the mutagenic activity from the reaction of nitrite and Sanma was carcinogenic (48). It is quite relevant that this product induced glandular stomach cancer in rats. Since the formation of the mutagen can be blocked by vitamin C, it would seem that the formation of glandular stomach cancer can also be so Inhibited. 

We had found earlier that similar pickling of beans, as eaten in high-risk Latin America, or of borscht, as consumed in Eastern Europe, led to mutagenic activity, and thus presumably carcinogenic activity (57)... 

The carcinogenic activity of chemical substances is important as well. They are present in pesticides of different classes OCPs (DDT, aldrine, heptachlor, methoxychlor), thiocarbamates (thiram, zineb, ziram), carbamides (monuron) [3], etc. Even if the official description of a given pesticide does not denote its carcinogenic (mutagenic, teratogenic, embryotoxic, etc.) activity, this merely means that this particular pesticide was not studied sufficiently. 

Simmon VF, Rosenkranz HS, Zeiger E. et al. 1979. Mutagenic activity of chemical carcinogens and related compounds in the intraperitoneal host- mediated assay. J Nat Cancer Inst 62 911-918. 

Khudoley W, Mizgireuv I, Pliss GB. 1987. The study of mutagenic activity of carcinogens and other chemical agents with Salmonella typhimurium assays Testing of 126 compounds. Arch Geschwulstforsch 57 453-462. 

Carbolines are formed in model systems heated for several minutes to several hours in the temperature range 100 to about 225° C. Some of the carbolines are known to display mutagenic activity, however, they are usually weak carcinogens (Friedman and Cuq, 1988 Bartoszek, 2002). 

Substitution in 98/8/EC is maintained indirectly though the application of comparative risk assessment, which is mandated in Article 10 of the directive. In order to include active substances in Annex I, lA or IB, several requirements have to be fulfilled. For example, active substances cannot be incorporated in the list if they are carcinogenic, mutagenic, toxic for reproduction, sensitising or bioaccumulative. 

Imaoka S, Yoneda Y, Matsuda T et al. 1997. Mutagenic activation of minary bladder carcinogens by CYP4B1 and the presence of CYP4B1 in bladder mucosa. Biochemical Pharmacology 54(6) 677-683. 

Dose-response assessment evaluates potential risks to humans at particular exposure levels. The approach to dose-response assessment for a particular agent is based on the conclusion reached as to its potential mode(s) of action for each tumor type. If the mode of action for known carcinogens is anticipated to be a DNA-reactive and direct mutagenic activity, such substances are assessed with a linear approach. Other modes of action may be modeled with either linear or nonhnear approaches after a rigorous analysis of available data. 

National Cancer Institute Evaluation of Carcinogenic, Teratogenic, and Mutagenic Activities of Selected Pesticides and Industrial Chemicals, Vol I. Carcinogenic Study, 1968... 

Vogel, E., Blijleven, W.G.H., Kortselius, M.J.H. and Zijlstra, J.A. (1981) Mutagenic activity of 17 coded compounds in the sex-linked recessive lethal test in Drosophila melanogaster, in Progress in Mutation Research, Volume 1 Evaluation of Short-Term Tests Carcinogens (eds F.J. de Serres and J. Ashby), Elsevier, Amsterdam. 

Rinkus SJ, Legator MS. 1979. Chemical characterization of 465 known or suspected carcinogens and their correlation with mutagenic activity in the Salmonella typhimurium system. Cancer Res 39 3289-3318. 

Natarajan AT, Tates AD, Van Buul PP, Mei-jers M, and De Vogel N. (1976) Cytogenetic effects of mutagens/carcinogens after activation in a microsomal system in vitro 1. Induction of chromosome aberrations and sister chromatid exchanges by diethylnitrosamine... 

A review of the literature on experiments to assess possible chronic effects, especially mutagenic activity and carcinogenicity, of the irritant and vesicant agents reveals that these effects have not been studied systematically by current standards and techniques. 

---