Calcium Terephthalate Research Articles

The induction of bladder stones by terephthalic acid, dimethyl terephthalate, and melamine (2,4,6-triamino- s-triazine) and its relevance to risk assessment

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 of 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.

Chemical urolithiasis 2. Thermodynamic aspects of bladder stone induction by terephthalic acid and dimethyl terephthalate in weanling fischer-344 rats

The induction of calcium terephthalate (CaTPA) calculi in the urinary tract of rats ingesting terephthalic acid (TPA) or dimethyl terephthalate is a result of supersaturation with respect to the stone components. The solubility product of CaTPA was determined in water at 37°C, and its value in urine of exposed weanling Fischer-344 rats was calculated based on the electrolyte concentrations of freshly-collected, microliter urine samples. The value of the solubility product in urine is equal to the minimum concentration product of free Ca 2+ and TPA 2− at which crystallization can occur; hence, the urinary solubility product is a parameter that is useful for risk assessment. Estimates of the TPA concentrations required to induce crystals or stones in normal human urine are presented.