Risk-assessment implications of mechanistic model's prediction of low-dose nonlinearity of liver tumor risk for mice fed fumonisin b(1).
A two-stage, clonal-expansion model of liver tumor risk in mice was developed by Kodell et al. (Food Addit Contam 18:237-253, 2001) based on the hypothesis that fumonisin B(1), a naturally occurring mycotoxin in corn, is not genotoxic, but rather causes cancer through the disruption of sphingolipid metabolism. This disruption is assumed to cause an increase in apoptosis, in response to which cells proliferate to compensate for reduced tissue mass. The resulting differential increase in the number of pre-neoplastic cells at risk of mutation during cell division is assumed to lead to an increase in the incidence of tumors. Two-year liver tumor incidences predicted by the model using data on organ weight, cell proliferation, and sphingolipid metabolism provided a reasonable match to the actual 2-year observed incidences in a study conducted at the National Center for Toxicological Research. The predictions indicated no risk at low doses (even a possible hormetic effect) and high risk at high doses in females, as well as a complete absence of a dose response (or perhaps, a hormetic effect) in males. This paper provides a commentary on the risk-assessment implications of the modeling results, pointing out that the model's low-dose predictions provide scientific support and justification for the U.S. Food and Drug Administration's low-ppm guidance levels in corn products. These guidance levels are significantly higher than would be obtained using linear extrapolation, the method most often used for genotoxic carcinogens and other carcinogens for which low-dose linearity cannot be ruled out.
Kodell
Ralph L
RL
Division of Biometry and Risk Assessment, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas.
Turturro
Angelo
A