Urinary Solid Carcinogenesis in Rodents

Numerous substances admiiustered to rats and/or mice lead to formation of urinary solids with consequent cytotoxicity, regenerative proliferation, and ultimately the formation of tmnors. A variety of specific mechanisms have been demonstrated for the formation of these solids (Clayson et al. 1995 Cohen 1998 lARC 1999 RBCWG 1995). 

Most readily understood is the direct formation of crystals and calculi composed of the administered substance or metabolite(s). Thus, dietary administration of melamine (Meek et al. 2003), luacil (Shirai et al. 1989), or sulfosulfuron (Arnold et al. 2001) at extremely high levels leads to the formation of crystals composed predominantly of these substances. If the exposure levels do not produce urinary 

Additionally, it appears that these substances have to be administered for an adequate period of time to lead to a detectable incidence of tumors. Thus, short-term administration, even if there is formation of calculi and extensive proliferation, is inadequate for generating a statistically significant incidence of tumors in a standard 

2-year bioassay (Cohen 1998 Shirai et al. 1989). Upon ceasing administration of the test substance, any crystals or calculi that have formed gradually are dissolved and/or excreted, and the proliferative response ends. The removal of the hyperplastic, rapidly proliferating urothelial cells appears to be primarily by apoptosis. The urothelium returns to a normal morphologic and cell kinetic state within a few weeks after the disappearance of the urinary solid (Shirai et al. 1989). 

Numerous substances such as calcium, magnesium, and phosphate, administered to rats and/or mice, have been demonstrated to lead to formation of urinary solids and are listed in Table 19.1. This table includes not only a large number of natural, essential ingredients in om diet, but also a number of substances that are formed from normal intermediary metabolism, such as carbonate, oxalate, cystine, urate, and uracil, which are present in normal urine. Numerous synthetic chemicals also produce urinary solids when administered at very high doses, including agrichemicals (such as sulfosulfuron and Fosetyl-Al), industrial chemicals (such as melamine), and pharmaceuticals (such as sulfonamides, carbonic anhydrase inhibitors, and HIV protease inhibitors). 

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