Preneoplastic lesions in rodent kidney induced spontaneously or by non-genotoxic agents: predictive nature and comparison to lesions induced by genotoxic carcinogens

Abstract

The current literature on non-genotoxic renal carcinogens and the associated neoplastic and preneoplastic lesions has been reviewed in order to determine their occurrence and predictive nature with regard to tumor formation. In addition the mechanisms involved in the genesis of renal tumors are discussed. A more generalized classification of preneoplastic and neoplastic renal lesions was introduced, based on studies conducted with genotoxic and non-genotoxic renal carcinogens. Reports on preneoplastic lesions were found in the literature for control animals as well as animals treated with non-genotoxic carcinogens. Due to the paucity of data regarding preneoplastic lesions in control animals and animals treated with non-genotoxic carcinogens, new data were also generated by rereading kidney slides of control animals of a randomly selected NTP study and kidney slides of male rats treated with the highest dose of ochratoxin A, one of the most potent non-genotoxic renal carcinogens known. The control slides and the slides from the ochratoxin A study indicated that the cytologic and morphologic types of preneoplastic lesions characteristically observed in bioassays using genotoxic carcinogens are also present in control animals and animals treated with non-genotoxic carcinogens. The incidence of preneoplastic lesions was low in control animals and higher in animals treated with non-genotoxic carcinogens. The diverse classifications used in the literature did not allow a direct comparison of lesions and corresponding incidences with those of the newly generated data. However, three major tendencies were observed: (a) whenever a high incidence of preneoplastic lesions was reported, renal neoplasms were also found, (b) the larger the size and the further a lesion had progressed, the higher was the probability of tumor formation, and (c) not all preneoplastic lesions are irreversible, but reversibility seemed to decrease with increasing lesion size and progression. It must be emphasized that the data available for these conclusions are limited. This is not due to the lack of adequate numbers of bioassays with non-genotoxic carcinogens, but rather to the lack of consistent reporting of data. A generalized and more widely used classification which incorporates early lesions would certainly improve the current data base on renal lesions and provide future improvements in the predictive nature of these lesions.