Nitroso compounds carcinogenicity

BD rat represents a particular strain used to test carcinogenicity of some V/-nitroso compounds. Refs. 7 and 62. 

L4RC Working Group on the Evaluation of Carcinogenic Risk of Chemicals to Humans, Some N-Nitroso Compounds, lARC Monograph No. 17, International Agency for Research on Cancer, Lyon, France, 1978. 

The iV-nitroso compounds are carcinogenic, so the reaction could result in stomach cancer. This mechanism is essentially a hypothetical one, and tests were made to evaluate it. Three tests in particular suggested that the hypothesis was not correct, that is, that there is no clear link between stomach cancer and nitrate in water. 

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCl"). Since many V-nitroso compounds are carcinogens, and because some racemization and cyclodehydration of V-nitroso derivatives of V-alkyl amino acids occur during peptide syntheses, V-nitroso derivatives are of limited value as protective groups. 

In 1976, Ross al. first reported that the powerful carcinogens, N-nitrosodimethylamine (NOMA) and N-nitrosodi-n-propyl-amine (NDPA) were found at parts per million (ppm) concentrations in certain commercial herbicide formulations (1., ). Since then, scientists have learned that carcinogenic N-nitroso compounds can be formed in a wide variety of media of interest to those who manufacture, use, or study pesticide products. Some of these nitrosation-supporting media are listed in Table I. 

Recently nitrosamines have attracted attention because of their marked carcinogenic activity in a wide variety of animal species Q, ). Nitrosamines are likely to be carcinogens in man as well human exposure to these compounds is by ingestion, inhalation, dermal contact and vivo formation from nitrite and amines Nitrite and amines react most rapidly at an acidic pH A variety of factors, however, make nitrosation a potentially important reaction above pH 7 these include the presence of microorganisms, and the possibilities of catalysis by thiocyanate, metals and phenols, and of transnitrosation by other nitroso compounds. 

The class of Il-nitroso compounds (l e , nitrosamines and nitrosamides) is currently considered a unique group that includes members with remarkable carcinogenic properties. Because of their potency and almost ubiquitous presence in... 

N-nitroso compounds, once formed and present in vivo> generally do not revert easily or readily back to precursors. Instead, in vivo> they are metabolized or otherwise converted to alkylating agents as terminal or proximal carcinogens. 

Control of N-nitroso compounds as carcinogenic agents so far has rested on agents that can block their formation. It is the intent of this paper to briefly review some of the studies which have been performed on the use of blocking agents to prevent N-nitroso compound formation and describe some recent observations on the mechanism by which these agents function. 

Safe" secondary amines resulting in non-carcinogenic N-nitroso compounds after nitrosation (German Patent Application No P 3029 318 6)... 

Based on the above data and on other available experimental work showing that nitroso compounds can induce gastric cancer in animals (O and that nitrosation reactions leading to synthesis of carcinogens can take place in the gastric cavity environment (27, 28, 29), we have formulated an etiologic hypothesis for gastric cancer (S) ... 

Egan, H. Preussmann, R. Walker, E.A. Castegnaro, M. Wasserman, A.E. Eds. "Environmental Carcinogens Selected Methods of Analysis Vol. 1 - Analysis of Volatile Nitrosamines in Food." lARC Scientific Publications No. 18. International Agency for Research on Cancer Lyon, 1978. Walker, E.A. Griciute, L. Castegnaro, M. Borzsonyi, M., Eds. "N-Nitroso Compounds Analysis Formation and Occurrence" lARC Scientific Publications No. 31. International Agency for Research on Cancer Lyon, 1980. Hedler, L. Schurr, C. Marquadt, P. J. Am. Oil Chem. Soc. 1979, 681-684. 

This far into a nitrosamine symposium it should hardly be necessary to point out that nitrosamines are technically just one of a group of Ji-nitroso compounds that also includes nitros-amides, nitrosocarbamates, nitrosoureas, etc. Or that nitrosa-table pesticides encompass all the categories just mentioned and more. Or that many diverse pesticides, including herbicides, insecticides, and fungicides have been converted to Ji-nitroso derivatives in the laboratory (a recent review contained a 3-page, probably incomplete, compilation), or that some of the Ji-nitroso compounds thus synthesized were determined to be carcinogenic in test animals or mutagenic in various assays. 

When EPA became aware almost five years ago that N-nitroso contaminants occurred in a number of pesticide products, the Agency immediately acted on the authority of Section 3 of FIFRA to place a moratorium on new registrations of pesticides suspected to contain N-nitroso contaminants at detectable levels (this term is defined and explained later in the text). As has been discussed in other papers of the Symposium, many N-nitroso compounds are animal carcinogens and, consequently, suspected human carcinogens. 

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