Issues in Risk Assessment (1993) / Chapter Skim
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APPLICATIONS OF THE TWO-STAGE MODEL TO ANIMAL DATA
APPLICATIONS OF THE TWO-STAGE MODEL TO ANIMAL DATA
Pages 196-211
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From page 196... ...
Please use the print version of this publication as the authoritative version for attribution. malignant cells, measures of the proliferation rates of intermediate cells and the rates of transformation of cells from one-stage to another, and whenever these quantities are dose-related, measures of the response of the parameters to dose.
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From page 197... ...
In the bladder, a linear rate of DNA adduct formation is observed as well, but the tumor rate is consistent with a nonlinear increase in the rate of cell proliferation at high doses and with an effect of dose on rates of transition between cell stages. Saccharin, a nongenotoxic agent, appears to induce bladder cancer as a result of toxicity induced regenerative hyperplasia, and its dose-response model is thus based on an effect on the cell growth rate function and not on transition rates.
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From page 198... ...
Please use the print version of this publication as the authoritative version for attribution. does not exist, assessing both the model's goodness-of-fit and the uncertainty in parameter estimates is important to understand the applicability of the model for calculating risk.
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is: where M is the background tumor rate parameter, S is the exposure dependent transition rate between cell stages, G is the exposure-independent growth rate of intermediate cells, and t is the time (or age) at which risk is evaluated.
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From page 200... ...
Please use the print version of this publication as the authoritative version for attribution. transition rate, using Equation 8.
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From page 201... ...
Please use the print version of this publication as the authoritative version for attribution. lung cancer and B[a]
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From page 202... ...
Please use the print version of this publication as the authoritative version for attribution. where G(0)
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Please use the print version of this publication as the authoritative version for attribution. Equation 14 can be fitted to the bioassay data for chlordane shown in Table 2 by using the log-logistic form of the growth-rate function described above and making a number of assumptions regarding the needed parameter estimates (see Table 3)
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From page 204... ...
. TABLE 4 Estimates of Chlordane's Human Cancer Risk Dose ppm Lifetime Cancer Risk Tumor Promotion Model Linearized Multistage Model 1.6 × 10-5 4.8 × 10-2 1 1.2 × 10-9 4.9 × 10-3 0.1 8.8 × 10-14 4.9 × 10-4 0.01 Source: Thorslund and Charnley, 1988 Even if all those assumptions are correct, the critical assumption regarding how chlordane affects the growth rate of intermediate cells still requires validation.
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From page 205... ...
Please use the print version of this publication as the authoritative version for attribution. All other parameter values used by Thorslund and Charnley were retained (M = 2.8622 × 10-6, t = 78 weeks)
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From page 206... ...
Please use the print version of this publication as the authoritative version for attribution. Thorslund and Charnley model with those from the alternative model at both the experimental doses and the lower doses for which additional risk was estimated.
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From page 207... ...
Table 8 shows virtually the same risks at low doses for the exact models as shown in Table 6 for the approximate models. TABLE 7 Chlordane Data: Fit of Alternative Exact Two-Stage Models Dose, ppm Number Male Mice with Liver Tumors Observed Predicted Expression 18 Expression 17 0 3/33 (9%)
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Please use the print version of this publication as the authoritative version for attribution. graphically in Figures 2 and 3.
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From page 209... ...
Please use the print version of this publication as the authoritative version for attribution.THE TWO-STAGE MODEL OF CARCINOGENESIS FIGURE 2 Comparison of exact and approximate two-stage models applied to chlordane data on male mice.
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From page 210... ...
Please use the print version of this publication as the authoritative version for attribution.THE TWO-STAGE MODEL OF CARCINOGENESIS FIGURE 3 Comparison of exact and approximate two-stage models at low exposures applied to chlordane data on male mice.
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From page 211... ...
Please use the print version of this publication as the authoritative version for attribution. where β1,…,βk are parameters that are unaffected by dose and G(x)
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