Cover Image

PAPERBACK
$49.00



View/Hide Left Panel

their HERP (Human Exposure/Rodent Potency) index as the fraction of the TD50 accounted for by human exposure, Ames et al. (1987) implicitly assume a linear dose-response relationship below the TD50. Wartenburg and Gallo (1990) have objected to the latter application of the TD 50 on the grounds that many dose-response relationships are highly nonlinear. In practice, however, linear extrapolation from the TD 50 will often approximate q1* in experiments employing only two or three doses because of the limited opportunity to observe curvature (Krewski, 1990). Although the HERP index appears to be based on the tacit assumption of a linear dose-response, Gold & Ames (1990) and Gold et al. (1992) emphasize that the index is intended for priority ranking rather than quantitative risk assessment.

5.3. Preliminary Estimate of Risk

The fact that q1* is highly correlated with the MDT suggests that preliminary estimates of cancer risk may be based on the MTD. Gaylor (1989) exploited this correlation to estimate the 10-6 RSD. Estimates of the RSD were obtained by the linear interpolation procedure given by Gaylor & Kodell (1980), as modified by Farmer et al. (1982), for 38 chemical carcinogens tested by oral administration in the U.S. National Toxicology Program. Estimates of the RSD were compared with the MTD for up to 69 tumor sites in both rats and mice, for a total of 138 cases. The ratio of the MTD to the RSD varied over a 184-fold range, which is considerably larger than the 32-fold range suggested by Bernstein et al. (1985) for the range of TD50 values relative to the MTD. The overall geometric mean of the ratio MDT/RSD was 3.8 × 105; only 3 of the 138 ratios were more than a factor of 10 from the mean. This suggests that a preliminary estimate of the RSD may be obtained by dividing the MTD by 380,000.

As in predicting the TD50 from the MDT (section 4.1), linear regression analysis may also be used to predict low dose slopes from the MDT. This may be illustrated using the 191 rodent carcinogens considered previously. The results of regressing the logarithms of the linearized upper bounds on low dose slope based on either the LMS model or MFX are given in Table 4. The estimated slope of the linear regression model is approximately -1 for both the LMS and MFX methods. The



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 139
APPENDIX F 139 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. their HERP (Human Exposure/Rodent Potency) index as the fraction of the TD50 accounted for by human exposure, Ames et al. (1987) implicitly assume a linear dose-response relationship below the TD50. Wartenburg and Gallo (1990) have objected to the latter application of the TD50 on the grounds that many dose-response relationships are highly nonlinear. In practice, however, linear extrapolation from the TD50 will often approximate q1* in experiments employing only two or three doses because of the limited opportunity to observe curvature (Krewski, 1990). Although the HERP index appears to be based on the tacit assumption of a linear dose-response, Gold & Ames (1990) and Gold et al. (1992) emphasize that the index is intended for priority ranking rather than quantitative risk assessment. 5.3. Preliminary Estimate of Risk The fact that q1* is highly correlated with the MDT suggests that preliminary estimates of cancer risk may be based on the MTD. Gaylor (1989) exploited this correlation to estimate the 10-6 RSD. Estimates of the RSD were obtained by the linear interpolation procedure given by Gaylor & Kodell (1980), as modified by Farmer et al. (1982), for 38 chemical carcinogens tested by oral administration in the U.S. National Toxicology Program. Estimates of the RSD were compared with the MTD for up to 69 tumor sites in both rats and mice, for a total of 138 cases. The ratio of the MTD to the RSD varied over a 184-fold range, which is considerably larger than the 32-fold range suggested by Bernstein et al. (1985) for the range of TD50 values relative to the MTD. The overall geometric mean of the ratio MDT/RSD was 3.8 × 105; only 3 of the 138 ratios were more than a factor of 10 from the mean. This suggests that a preliminary estimate of the RSD may be obtained by dividing the MTD by 380,000. As in predicting the TD50 from the MDT (section 4.1), linear regression analysis may also be used to predict low dose slopes from the MDT. This may be illustrated using the 191 rodent carcinogens considered previously. The results of regressing the logarithms of the linearized upper bounds on low dose slope based on either the LMS model or MFX are given in Table 4. The estimated slope of the linear regression model is approximately -1 for both the LMS and MFX methods. The