URINARY-BLADDER HYPERPLASIA IN THE RAT - NONSPECIFIC PATHOGENETIC CONSIDERATIONS USING A BETA-LACTAM ANTIBIOTIC

Eight of the known chemical substances associated with neoplasia in ma n are known to target the urinary bladder urothelium. Preneoplastic ch anges have been identified following exposure to each of these chemica ls, and they have also been seen to occur in many species of lab anima ls. The most important such change is preneoplastic hyperplasia. Adapt ive hyperplasia is the first form of hyperplasia to appear. It can be seen both in untreated controls and dosed animals. The distinguishing features are that in treated groups it does not progress with dose or time, and the process is reversible. Reparative hyperplasia involves d isruption of homeostasis. Its severity increases with dose and time. I t is not seen in controls but it is still reversible during the recove ry segment after exposure to a toxic substance. When reparative hyperp lasia continues beyond a certain threshold of time and dose, it progre sses to preneoplastic hyperplasia, which further progresses with conti nued stimulation to frank neoplasia. The synthetic beta-lactam penem a ntibiotic FCE 22891 and its metabolite FCE 22101 caused adaptive uroth elial hyperplasia of the urinary bladder only in rats and in no other species. Based on the pharmacokinetic profile of FCE 22891 and FCE 221 01, it can be deduced that the morphologic finding of adaptive urothel ial hyperplasia is caused by reduction of intravesicular urine pH. Thi s effect has no relevance to therapeutic use in humans. Further, it is important to distinguish adaptive and reparative hyperplasia in precl inical toxicity studies.