Role of urinary physiology and chemistry in bladder carcinogenesis.

Urine is a complex mixture of numerous substances, only some of which are described above. Literally thousands of substances have been identified in normal urine, including a variety of ions, non-ionic substances and macromolecules. Their presence and concentrations are highly variable, dependent on fluid intake and on nutritional, physiological and biochemical influences. Marked diurnal variations exist. Methodologies involved in the collection and analysis of these components can greatly influence the interpretation of the results. The influence of these various parameters in the urine on bladder carcinogenicity can be either direct or indirect. A major difficulty in studying this aspect of urothelial carcinogenesis is that it is essentially impossible to alter only one variable in the urine at a time. Alteration of any one variable results in physiological alteration of several other of the constituents in the urine. In addition, the processes involved in urothelial carcinogenesis frequently involve a complex interaction of multiple variables, such as volume, osmolality, cationic concentration, anionic concentration, quantitative and qualitative differences in protein, and generation of precipitate, crystals or calculi. Thus, it is likely that the actual mechanisms involved in the carcinogenic process with many of these chemicals, particularly those that are non-genotoxic, will involve a complex interaction of several constituents of the urine. Although this poses a formidable obstacle to our understanding in experimental situations as well as in extrapolating to humans, the role of specific factors appears to be discernible and should offer insight into the risk assessment process (Cohen and Ellwein, 1991 a,b and 1992).