Chemical characterization of 465 known or suspected carcinogens and their correlation with mutagenic activity in the Salmonella typhimurium system.

Since chemicals exhibiting mutagenic activity pose a potential hazard to their users, there is increasing acceptance of mutagenicity testing as an integral part of a premarketing toxicological evaluation of chemicals. In vitro testing has gained much notoriety as quick and relatively inexpensive means to assess the mutagenic potential of chemicals. However, the innovative use of microsomes to simulate metabolism has not changed the fact that in vitro activation cannot duplicate faithfully the metabolism that occurs in vivo. This shortcoming will express itself by the production of false negatives and possibly false positives during mutagenicity screening. This assertion is also borne out by a reanalysis of the ability of known animal carcinogens to cause mutations in the generally recognized premier in vitro system, the Salmonella-S-9 system. Although previous studies have suggested that a high percentage (greater than 85%) of all carcinogens will be mutagenic in this system, with no indication that false negatives are associated with certain chemical types, these findings are of uncertain practical value due to the limited number of chemical types that were considered. An analysis of 465 compounds with known or suspected carcinogenic activity indicates that about 58% have been adequately tested in Salmonella, that the testing has concentrated on certain chemical types and has neglected others, and that some categories of carcinogens exhibit individual correlations that are unsatisfactorily low by any standard. Poorly detected categories of carcinogens include: azonaphthols; carbamyls and thiocarbamyls; phenyls; benzodioxoles; polychlorinated aromatics, cyclics, and aliphatics; steroids; antimetabolites; and symmetrical hydrazines. Nonstandard procedures are necessary to optimize the testing of chemicals that are bactericidal, that are volatile, or that cross-link DNA. False negatives appear to arise for two reasons: an inability to devise an in vitro activation system that can be reliably used in a standard way; and an inability to detect the entire spectrum of mutational events that can lead to the induction of cancer.