Implications of apoptosis for toxicity, carcinogenicity, and risk assessment: Fumonisin B-1 as an example

The rates of cell proliferation and cell loss in conjunction with the diffe rentiation status of a tissue are among the many factors contributing to ca rcinogenesis. Nongenotoxic (non-DNA reactive) chemicals may affect this bal ance by increasing proliferation through direct mitogenesis or through a re generative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C37F(1) mic e, the mycotoxin fumonisin B-1 caused renal carcinomas in male rats and liv er cancer in female mice. In an earlier study in male ED-IS rats, fumonisin B-1 caused hepatic toxicity and hepatocellular carcinomas. An early effect of fumonisin B-1 exposure in these target organs is apoptosis. However, th ere is also some evidence of oncotic necrosis following fumonisin B-1 admin istration, especially in the liver. Induction of apoptosis may be a consequ ence of ceramide synthase inhibition and disruption of sphingolipid metabol ism by fumonisin B-1. Fumonisin B-1 is not genotoxic in bacterial mutagenes is screens or in the rat liver unscheduled DNA-synthesis assay, Fumonisin B -1 may be the first example of an apparently nongenotoxic (non-DNA reactive ) agent producing tumors through a mode of action involving apoptotic necro sis, atrophy, and consequent regeneration.