The broad, long-term objective of the proposed research is to determine which, if any, of a selected sample of themical carcinogens that have been classified as nongenotoxic are in reality genotoxic. Some chemical carcinogens have been classified as nongenotoxic only on the basis of their nonmutagenicity in certain strains in the Ames Salmonella/mammalian microsome reverse-mutation test. Furthermore, a fraction of these so- called nongenotoxic carcinogens has been classified as """"""""cryptic mutagens"""""""", which Rosenkranz and Klopman (1990) have defined as """"""""...agents, which although nonmutagenic [used by the authors as nonmutagenic in the Ames test], contain structural moieties that have a high probability of being associated with mutagenicity in Salmonella..."""""""".
The specific aim of the proposed research is to determine which, if any, of the 19 """"""""cryptic mutagens"""""""" identified by Rosenkranz and Klopman (1990) are mutagenic in another short-term test for genotoxicity in Salmonella-- a forward-mutation test for arabinose resistance (Ara test). The hypothesis being tested is that 11 or most of these 19 """"""""cryptic mutagens"""""""" will be mutagenic in the Ara test. This hypothesis is based: (i) theoretically on the knowledge that as a forward-mutation test the Ara test should detect almost all kinds of intracistronic mutations, including base-pair substitutions, additions and deletions, and other more complex alterations; and (ii) experimentally on the fact that the Ara test has been shown to detect not only essentially the same mutagens detected by the Ames test, but also some chemicals not mutagenic in the Ames test (Dorado and Pueyo, 1988). The 19 """"""""cryptic"""""""" mutagens will be assayed in the Ara test according to published methods in strain BA9 in the absence and presence of S9 mix using the plate-incorporation procedure. Any chemicals giving a negative or equivocal response with the plate-incorporation procedure will be tested with the pre-incubation and liquid procedures. No one has specifically approached the question posed in this proposal: Will the hidden mutageniticity of """"""""cryptic mutagens"""""""" be revealed by the Ara test? The proposed experiments also will contribute to our understanding of the mechanisms of chemical carcinogenicity, because if some of the cryptic mutagens are mutagenic in the Ara test, the estimated fraction of carcinogens that is nongenotoxic will decline.
