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Transgenic mouse mutation assays, such as MutaMouse (lacZ, CD2F1) and Big Blue (lacI, B6C3F1), afford the opportunity to evaluate the mutagenic potential of chemicals in any target organ in vivo. This paper discusses published data collected from the analysis of the skin, stomach and lung DNA after topical, oral and inhalation exposure, respectively. These data indicate that both MutaMouse and Big Blue should play an important part in the evaluation of genotoxicity in vivo, particularly where the endpoint or target tissue available in the more conventional tests is inappropriate. It is concluded that there is a distinct role for this type of assay in genetic toxicology testing. For substances applied to the skin or dosed orally or by inhalation and which are unlikely to reach either the bone marrow or the liver, then data derived from these assays may be more relevant to an assessment of possible risk to man than the currently used unscheduled DNA synthesis in liver and cytogenetics assays in bone marrow or peripheral blood.

A streamlined bacterial mutagenicity assay, the MINISCREEN, was developed to enable the rapid screening of a large number of chemical compounds on a purely qualitative basis. Experiments with a series of known carcinogens/mutagens and non-carcinogens/mutagens showed a good correlation with conventional bacterial mutagenicity assays (Ames tests), and the subsequent testing of over 300 candidate agricultural chemicals and over 100 industrial chemicals has proven its value as a screening method.

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Two hydrocarbon solvents (heptane and Special Boiling Point Spirit 100/140) and eight oxygenated solvents [methyl ethyl ketone, methyl isobutyl ketone, diacetone alcohol, di-isobutyl ketone, isopropyl ether, hexylene glycol, secondary butyl alcohol and ME 6K (pentoxone)] have been tested for genotoxic activity. The solvents were tested in bacterial mutation assays, a yeast assay for mitotic gene conversion and in cultured mammalian cells (either rat liver or Chinese hamster ovary) for structural chromosome damage. All of the solvents gave a negative response in the bacterial mutation assays and the yeast mitotic gene conversion assay. In the rat liver chromosome assay, diacetone alcohol evoked a weak positive response, the remaining solvents gave a negative response.

A modified bacterial mutagenicity assay based on the Ames Salmonella/mammalian microsome test has been developed for application in the genotoxicity testing of mineral oils. The assay uses washed microsomes from rat liver in place of S9 fraction in order to increase the sensitivity of detection of genotoxicity. The modified assay was used to test a series of oils for which skin carcinogenicity bioassay data in mice were available. Oils were tested as emulsions in water using Tween 80 as a dispersant. A mutagenicity index for each oil was obtained using non-linear regression analysis of data from the dose-response curve. The results showed an empirical correlation between increasing mutagenicity index, carcinogenicity and the polycyclic aromatic hydrocarbon content of the oils. The washed-microsome assay was also compared with modified Ames assays developed by Blackburn et al. (Cell Biol. Toxicol., 1, 40, 1984; Cell Biol. Toxicol., 2, 63, 1986) which employed increased levels of S9 (rat and hamster liver) to test dimethyl sulphoxide extracts of oils. The washed-microsome assay can be used for the testing of whole oils rather than extracts which are necessary for the modified Ames assay. It is recognised that the determinants of carcinogenic activity in vivo include promoting activity which such assays are unable to detect. Nevertheless, such modified bacterial assays may be a useful prescreen since genotoxicity is recognised as a key initial step in carcinogenesis.

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