USE OF CELL-PROLIFERATION DATA IN MODELING URINARY-BLADDER CARCINOGENESIS

A multistage, probabilistic, biologically based model of carcinogenesi s has been developed involving qualitative and quantitative aspects of the process. A chemical can affect the risk of cancer by directly dam aging DNA and/or increasing the number of cell divisions during which errors in DNA replication can occur. Based on this model, carcinogens are classified as genotoxic versus nongenotoxic; nongenotoxic chemical s are further divided on the basis of whether or not they act through a specific cell receptor. Nongenotoxic compounds, particularly those a cting through a nonreceptor mechanism, are likely to have dose and/or species-specific thresholds. This classification also implies the exis tence of chemicals that will be carcinogenic at high doses in animal m odels, but because of dose and/or mechanistic considerations, will not be carcinogenic to humans at levels of exposure. N-[4-(5-nitro-2-fury l)-2-thiazolyl] formamide (FANFT) and 2-acetylaminofluorene (AAF) are classical genotoxic bladder carcinogens that also cause proliferative effects at higher doses. Although there is an apparent no-effect level for the urinary bladder carcinogenicity of these two compounds at low doses, in reality, DNA adducts form at these low levels, and it is li kely that there is a cancer effect (no threshold), but it is below the level of detection of the bioassay. These conclusions are based on st udies involving multiple doses and time points in rodents, including r esults from the ED(01). Pellets implanted directly into the rodent bla dder lumen or calculi formed in the urine as a result of an administer ed chemical cause abrasion of the urothelium, and a marked increase in cell proliferation and cell number, and ultimately tumors. A threshol d is readily definable based on physiologic, chemical, and pharmacokin etic considerations. Sodium saccharin also produces bladder cancer at high doses in rats, particularly males, if it is administered beginnin g at birth or earlier. The mechanism appears to be related to the form ation of a silicate precipitate and/or crystals formed in the rat urin e, which act as abrasives or cytotoxic materials, leading to increased cell proliferation and ultimately tumors. Numerous other sodium salts have similar effects. This effect is not observed in the mouse, hamst er, or monkey, and epidemiological evidence suggests that it does not occur in humans. Thus, for sodium saccharin, even in the susceptible s pecies, the rat, there appears to be a dose threshold, and extrapolati on to humans appears inappropriate based on mechanistic considerations .