Biologically Based Dose Response (BB-DR) Models for Dioxin Hepatocarcinogenicity. M. E. Andersen, K. S. Crump Division, ICF Kaiser International, Morrisville, NC 27560
While there is consensus that introduction of BB-DR models will reduce some of the uncertainties in health risk assessments, the utility of these models depends on their fidelity with actual biological processes. None of the previously developed BB-DR models for dioxin, including those used in the US EPA dioxin reassessment, have incorporated homeostatic responses of the organism or the regionally-specific hepatic protein induction known to be caused by dioxin exposure. With many hepatic tumor promoters, there is strong support for a negative selection mechanism of promotion. Here, the promoter provides a mitogenic stimulus; the stimulus is countered by mitosuppressant growth factors elaborated by the tissues; and mutated cells resistant to mitosuppression grow out to foci and eventually to tumors. This talk describes the coupling of a regionally-specific physiologically-based pharmacokinetic (PB-PK) model for protein induction with a negative selection BB-DR model for tumor promotion. The PB-PK model provides dose estimates for regional effects on protein induction and presumably cell growth factors that are then used in the negative selection BB-DR model. The negative selection BB-DR model assumes that there are at least two distinct populations of initiated cells. One of these populations of initiated cells is sensitive to the cytostatic effects of the negative growth factors and its growth is inhibited by dioxin exposure; the other population is insensitive and represent the cells that grow out to foci in the presence of dioxin. Due primarily to the differential mitosuppressant activity of negative growth factors on these two populations of initiated cells, this negative selection BB-DR model does not predict linearity of tumor responses at low doses. This conclusion contrasts to that reached by applications of earlier models that ignored homeostatic, adaptive responses of the liver following dioxin exposures. Obviously, acceptance of a particular model structure will eventually depend on the consistency of the model assumptions with biological evidence, not on the impressiveness of model fits or the overall complexity of the particular model employed. In general, though, it is clear that little attention has been paid to the role of these homeostatic, compensatory processes in determining dose-response behaviors in any area of toxiciology. With hepatic tumor promoters, these compensatory biological processes appear critical in regulating the overall toxicological sequelae of exposure and in forming inferences about the low-dose risks of these compounds