ABSTRACT
The determination of the maximum tolerated dose has been the subject of debate for many years; the development and consequences of the use and subsequent interpretation of data obtained using high doses in rodent carcinogenicity assays. This chapter examines the specifics of five examples of nongenotoxic rodent carcinogenesis: urinary bladder, renal tumors, forestomach, endocrine organs, and receptor-mediated tumors. In the early 1970s it was shown that exposure of male rats to high doses of sodium saccharin for 2 years resulted in urinary bladder tumors. In addition to the species-specific nature of this response, it is important to emphasize for our current discussion that the cytotoxic response is dependent on exposure to high levels of the chemicals. As with most secondary mechanisms, there is a threshold below which the cytotoxic response is not seen and thus no tumors are produced in the kidney. Tumors in endocrine organs account for approximately 70% of all positive findings in rat carcinogenicity studies.
