Andersen and Conolly (1998) describe a mechanistic cancer model fit to U-shaped dose-response data of Pitot et al. (1987) on enzymatically altered hepatocellular foci in rats initiated with an acute exposure to diethylnitrosamine (DEN) and promoted by subsequent chronic exposure to 2,3,7,8-tetrachlorobibenzo-p-dioxin (TCDD). Their model is "pharmacodynamic" in that it integrates pharmacokinetic submodels for liver-compartment-specific saturation kinetics of TCDD-receptor interactions into an overall MVK-type 2-stage stochastic framework, with TCDD modeled both as a promoter and anti-promoter. The assumption of Michalis-Menten-Hill saturation kinetics for TCDD provides great flexibility in modeling the nonlinearity evident in the focal occurrence data, but it is interesting to note that in other respects the Andersen-Conolly model is structurally and functionally similar to the generalized "cytodynamic 2-stage" (CD2) model I have previously described (Bogen, 1987) and applied to radon-associated alpha radiation modeled as a cytotoxic initiator (Bogen, 1987,1988).
A U-shaped dose-response relation may be predicted by the Andersen-Conolly model essentially as a consequence of its assumption of two parallel MVK-type 2-stage stochastic processes either or both of which may give rise to malignant cells (M). In the Andersen-Conolly model, one pathway is hypothesized to involve "Type A" cells for which TCDD is presumed to act as an anti-promoter (i.e., net suppresser of premalignant Type A clones), even at relatively low TCDD doses, by virtue of Type-A-cell sensitivity to TCDD-induced net cell loss via supression or reversal or "negative selection" of net proliferation. The other pathway involves "Type B" cells presumed not to be susceptible to TCDD-induced mito-inhibition, and TCDD is presumed to act as a promoter (i.e., net proliferater) of premalignant Type B clones. A U-shaped dose-response in total occurrence of (Type A + Type B) premalignant foci is predicted to occur within a low-dose range in which suppression of Type B foci outweighs promotion of Type A foci.
The 2-parallel-pathway structure of the Andersen-Conolly model is essentially the same as that of the CD2 model, which incorporates an S P M pathway involving exposed stem (S) and corresponding premalignant (P) cells, together with an R Q M pathway involving virtually unexposed stem (R) and corresponding premalignant (Q) cells (cf. Bogen, 1988; Fig. 1). In discussing the generalized CD2 model, it was pointed out that a distinction between these two pathways based on differential susceptibility would yield the same model behavior as the distinction used for alpha radiation based on differential exposure (Bogen, 1987). In the case of alpha radiation, such a distinction is reasonably based on differential exposure of bronchial regions (e.g., surface epithelium vs. deep basal cells and/or submucosal-gland ducts) due to limited alpha track length. Andersen and Conolly (1998) assumed that in the case of TCDD, the distinction is based on genetically controlled susceptibility to TCDD-induced growth suppression. However, a distinction based on dose-dependent differential TCDD concentrations (and hence, effective exposures) within liver subregions may also play a contributing, and possibly major, role in explaining a U-shaped dose-response for TCDD's impact on focal or tumor occurrence, in view of the variation in localized hepatocellular effects induced by TCDD discussed by Andersen and Conolly (1998). The alternative (differential-exposure vs. differential-susceptibility) hypotheses could be tested experimentally by examining whether a shift in Type A vs. B genotype occurs as a function of TCDD dose as expected under the differential-susceptibility hypothesis.
The similar Andersen-Conolly and CD2 model structures lent themselves to similar comparisons to predictions by analogous 2-stage stochastic models incorporating a dose-response for net proliferation within premalignant clones that was constrained to be a monotonically increasing function of TCDD exposure (Moolgavkar et al., 1993; Portier et al. 1996) and radon exposure (Moolgavkar et al., 1993; Luebeck et al., 1996), respectively. The Andersen-Conolly model application explains a U-shaped dose-response pattern solely by differential effects of TCDD on cell proliferation. In contrast, the CD2 model application to radon highlights the possibility that U-shaped dose-response patterns may be expected for many classic genotoxic agents (e.g., high LET ionizing radiations, clastogenic chemicals, etc.) that are also relatively effective at killing cellsparticularly when induced cytotoxicity (i) has an approximately linear dose-response (i.e., with no apparent threshold and little or no "shoulder"), and (ii) is nonhomogeneously imposed (by virtue of differential exposure) or elicited (by virtue of differential susceptibility) within target tissue. The CD2 model may also predict a similar U-shaped dose-response for focal or tumor occurrence for agents that induce a U- or quasi-U-shaped dose-response (i.e., a "hypersensitivity" pattern) for cell killing, e.g., as has been observed for acute X-ray or hydrogen peroxide exposures (Joiner et al., 1996).
CD2 model applications to radon have relied so far on indirect epidemiological evidence (Bogen, 1997,1998), whereas Andersen and Conolly (1998) fit their model directly to data on enzymatically altered foci within DEN-initiated liver. To further test the CD2 model in relation to radon, it would be interesting to examine the effect on such foci within DEN-initiated target tissue exposed chronically to radon-derived alpha radiation. A study currently underway in my laboratory at Lawrence Livermore National Laboratory may shed some light on this question.
Downs and Frankowski (1998) describe a flexible dose-response function involving a linear ratio modeling competing saturable activation and repair processes, which can predict a U-shaped dose-response under certain parameter constraints. That the two specifically posited classes of saturable process are biologically plausible representations of phenomena relevant to carcinogenesis in vivo remains to be established. For example, low-dose saturation (as opposed to induction) of eukaryotic DNA-repair processes has never been demonstrated. It also must be remembered that certain classes of damage, such as that yielding chemical- or radiation-induced stable chromosome translocations (e.g., those often associated with human tumors), are fundamentally irreparable in the sense of being subject to predictable (and often rather substantial) rates of inevitable misrepair.
Andersen, M. E., and Conolly, R. B. 1998. Mechanistic modeling of rodent liver tumor promotion at low levels of exposure: An example related to dose-response relationships for 2,3,7,8-tetrachlorodibenzo-p-dioxin. BELLE Newsletter, this issue.
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Bogen, K.T. 1998. Mechanistic model predicts a U-shaped relation of radon exposure to lung cancer risk reflected in combined occupational and U.S. residential data. BELLE Newletter, this issue.
Downs, T., and Frankowski, R. 1998. A cancer risk model with adaptive repair. BELLE Newletter, this issue.
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Portier, C. J., Sherman, C. D., Kohn, M., Edler, L., Kopp-Schneider, A., Maronpot, R.M., and Lucier, G. 1996. Modeling the number and size of hepatic focal lesions following exposure to 2,3,7,8-TCDD. Toxicol. Appl. Pharmacol. 138, 20-30.