PPARγ and combined agonists have been shown to produce urothelial tumors in rats and a suggestion of urothelial changes in the monkey (and possibly the dog). These effects are either due to a direct effect on PPARc in the urothelium or a pharmacologically based indirect mechanism involving fluid changes in the animal leading to alterations in urine composition. Such urine compositional changes produce urinary solids which are cytotoxic to the urothelium, resulting in regenerative proliferation and, ultimately, tumors. This is expected to be greater in male than in female rats, and greater in rats than in mice. It is much less likely to occur in primates, including humans. An indirect pharmacologic mode of action produced by PPAR agonists is not unique for the urothelium. Such an indirect effect has also been seen with PPARa agonists in production of rat pancreatic acinar cell tumors and, to some extent, rat testicular Leydig cell neoplasms. These neoplasms also do not appear to be relevant to humans (Klaunig et al., 2003). A variety of other indirect mechanisms have been identified with other classes of chemicals operating through other modes of action. A direct effect on urothelial PPARc receptors as the cause of the carcinogenic response is highly unlikely for a variety of reasons, most notably the fact that the biologic effect of these agonists on the urothelium is to inhibit proliferation rather than to increase the rate of proliferation expected for a carcinogen. The direct and indirect hypotheses are readily testable. However, based on theoretical and practical considerations, the indirect mode of action at the present time appears more likely. These agents have been in the clinic for more than 10 years, and although no individual patient has been treated that long with any one of these agents, we are nearing a time when a signal would be expected to be detectable if these agents are bladder carcinogens in humans. Such a signal has not been reported, despite some relatively careful evaluations of human populations. Also, clinical trials have not revealed any evidence of urinary calculus formation or urothelial toxicity by PPARc or combined agonists. Even if calculi were to occur, they do not pose a significant carcinogenic risk in humans.
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