Terephthalic acid (TPA),
dimethyl terephthalate (DMT), and
melamine (MA) induced
calculi and transitional cell
hyperplasia in urinary bladders of rats. A high incidence of
calculi was induced in weanling rats, but the incidence was much lower in adult rats ingesting the same dietary concentration of the chemical. The dose-response curves for the induction of
urolithiasis in weanling rats were extremely steep, consistent with the fact that the formation
calculi can occur in urine that is supersaturated, but not in urine that is undersaturated with respect to the stone components. In the cases of TPA and DMT, stones were composed primarily of
calcium terephthalate (CaTPA). By determining the solubility of CaTPA, the concentration of TPA that would be required to achieve urinary saturation was calculated, and a conservative estimate of the amount of TPA or DMT that would have to be absorbed in order to induce
calculi was derived. TPA and MA induced
bladder tumors in rats in chronic feeding studies. However, it is likely that these
tumors were secondary to the development of
calculi. TPA and MA are apparently nongenotoxic, and they do not appear to be metabolized. Increased cell replication in the urothelium of the bladder caused by chronic physical injury was probably a major factor in the mechanism of induction of
bladder tumors by
bladder stones.
Bladder neoplasms occurred primarily in the high dose groups, and they were usually, although not invariably, associated with stones. The possibility that stones were passed or were lost during processing of tissues for histopathologic examination could explain the absence of
calculi from some of the neoplastic bladders. The formation of
bladder calculi is an example of a threshold effect. Although there is strong evidence linking
bladder stones with the induction of
tumors, the existence of thresholds in chemical
carcinogenesis continues to be controversial. A decision by the U.S. Environmental Protection Agency concerning the levels of MA allowed to occur in the food chain indicates that data regarding thresholds, even in the case of
urolithiasis, are not being utilized in the risk assessment process.