Pathological markers for non-genotoxic agent-associated carcinogenesis

A variety of positive or negative enzyme altered foci have been proposed as preneoplastic marker lesions in the rat liver. Frozen sections are required in some cases. We have compared the suitability of various histochemically or immunohistochemically demonstrated markers and concluded that immunohistochemically-stained glutathione S-transferase placental form (GST-P) positive foci are particularly useful for practical application in risk assessment. Advantages include ease of quantitative foci analysis on a number of samples since acetone or formalin-fixed paraffin blocks can be used and clear contrast of foci against the surrounding liver tissue facilitates recognition. We have established a liver medium-term bioassay model of 8 weeks' duration using diethylnitrosamine as an initiator and GST-P positive foci as the endpoint lesions. At present, 58 non-genotoxic chemicals for which carcinogenicity data are available have been examined and many carcinogenic agents, mostly liver carcinogens, have been satisfactorily detected as having carcinogenic potential. Exceptional examples are two peroxisome proliferators, clofibrate and DEHP. For these chemical, several peroxisomal enzymes such as catalase and enoyl CoA hydratase have been tested as markers.