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Abstract:
The Granuloma Pouch Assay (GPA) is an animal model in which mutagenic and carcinogenic effects of a testcompound can be detected in rapidly dividing fibroblasts of a granulation tissue in adult male rats. Growth of this tissue was initiated with a small amount of croton oil at the inside wall of a subcutaneous air pouch on the back of the animals. The test compound can be injected either into the pouch (local) or administered by systemic routes. Alkali labile DNA-lesions, chromosome aberrations, sister chromatid exchanges, point mutations and tumor development in situ were determined. The comparison of mutation frequencies after local and systemic administration of testcompounds, provide an estimation of the pharmacokinetic characteristics and the mutagenic potency of the chemical. The local application route allows the detection of locally active mutagens and of compounds which require activation by P-448 dependent mono-oxygenases. Liver mediated proximate metabolites are detectable when they are transformed into ultimate carcinogens in extrahepatic cells whereas chemicals with a strong organ specific activity are not.