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TABLE 4 Regression of Upper Bounds on Low Dose Slopes on the Maximum Tolerated Dosea

Regression Parameter

Extrapolation Method

Multistage Model

Model-Free Extrapolation

Intercept ± SE

0.01 ± 0.05

0.11 ± 0.04

Slope ± SE

-1.05 ± 0.03

-1.07 ± 0.02

Correlation

0.944

0.961

Root Mean Square (s)

0.462

0.386

Factor 102s 95% Prediction Intervalb

8.4

5.9

aBased on simple linear regression of log slope on log MDT.

bUpper limit is 102s x MDT; lower limit is 10-2s x MDT.

approximate 95% prediction intervals for the low dose slope encompass a range of about 8 × 8 = 64-fold about the MDT with the LMS model, and a range of about 36-fold for MFX. Given an upper bound on the low dose slope ß, the corresponding 10-6 RSD is simply 10-6/ß.

6. Interspecies Extrapolation

Since mammalian species share many common physiological characteristics it is expected that they may respond in a somewhat similar manner to toxic substances. While many differences exist between species (Oser, 1981), allometric relationships among physiological parameters have suggested different metrics for quantitative interspecies extrapolation: heat loss, for example, appears to be proportional to the surface area of mammals, whereas metabolism is related to body weight to the 3/4 power (Schmidt-Nielsen, 1984). Such considerations have led to suggestions that allometric equations of the form



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APPENDIX F 140 original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution. approximate 95% prediction intervals for the low dose slope encompass a range of about 8 × 8 = 64-fold about the MDT with the LMS model, and a range of about 36-fold for MFX. Given an upper bound on the low dose slope β, the corresponding 10-6 RSD is simply 10-6/β. TABLE 4 Regression of Upper Bounds on Low Dose Slopes on the Maximum Tolerated Dosea Regression Parameter Extrapolation Method Multistage Model Model-Free Extrapolation Intercept ± SE 0.01 ± 0.05 0.11 ± 0.04 Slope ± SE -1.05 ± 0.03 -1.07 ± 0.02 Correlation 0.944 0.961 Root Mean Square (σ) 0.462 0.386 102σ 95% Intervalb Factor Prediction 8.4 5.9 aBased on simple linear regression of log slope on log MDT. bUpper limit is 102σ x MDT; lower limit is 10-2σ x MDT. 6. INTERSPECIES EXTRAPOLATION Since mammalian species share many common physiological characteristics it is expected that they may respond in a somewhat similar manner to toxic substances. While many differences exist between species (Oser, 1981), allometric relationships among physiological parameters have suggested different metrics for quantitative interspecies extrapolation: heat loss, for example, appears to be proportional to the surface area of mammals, whereas metabolism is related to body weight to the 3/4 power (Schmidt- Nielsen, 1984). Such considerations have led to suggestions that allometric equations of the form