Animal experiments regarding a possible carcinogenic effect of phenacetin on the resting and proliferating urothelium stimulated by cyclophosphamide.

The present animal experiments were undertaken to clarify whether phenacetin (ph) exerts a complete solitary carcinogenic effect on the resting and rapidly proliferating urothelium of the lower urinary tract of the rat. Cyclophosphamide was repeatedly administered i.p. to stimulate proliferative activity of the urothelium in particular of the bladder. Phenacetin was either fed continuously or administered repeatedly by gavage at the time when cyclophosphamide-induced stimulation of proliferative activity was highest. After 16 months approximately one half of the surviving rats developed uni- and bilateral hyperplasias of the lining epithelium of the renal papilla which were characterised by an endophytic growth pattern and a urothelial differentiation. They were always associated with healed or-rarely-fresh micronecroses of the subjacent papillary tissue. The urothelial hyperplasia of the renal papilla cannot be considered as true preneoplastic, but rather as reactive proliferative lesion in the sense of a reparative hyperregeneration in response to the observed toxic micronecroses. The present experiments did not provide evidence for a solitary carcinogenic effect of ph in the entire lower urinary tract. It seems most likely that a metabolite of ph only plays a role as cocarcinogen with initiation-stimulating and/or initiation-promoting activity in multifactorial multistage carcinogenesis acting together with other causative factors. Thus, the assumption that ph represents a complete solitary carcinogen for the urothelium in man has to be reassessed. Prospective epidemiological investigations should not only consider the consumption of ph-containing analgesics alone, but also the entire occupational and non-occupational environment with its potential carcinogenic and cocarcinogenic hazards.