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Comparison of the Dependence of the TD50 on Maximum Tolerated Dose for Mutagens and Nonmutagens

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  • Gay Goodrnan
  • Richard Wilson

Abstract

The relationship between the minimum TD50(i‐e., the TD50 measured at the most sensitive site)and the maximum dose administered (maxD)in rodent carcinogenicity bioassays was investigated separately for mice and rats. The relationship between log(l/D)and log(l/maxD)was analyzed as a function of(1)mutagenicity and (2)the statistical significance cutoff for selecting the minimum TD50 values. For rat bioassays, the variance of l o g (l)is larger and the correlation of log(l/TD,)with log(l/maxD)is weaker for mutagens than for nonmutagens, suggesting that the rela‐tionship between minimum TD50 and MTD is, in general, stronger for nonmutagens than for mutagens. The difference in correlation does not depend on the TD50 statistical significance cutoff, but the difference in variance is not significant for the most stringently selected dataset. For mouse bioassays, no significant mutagen/nonmutagen differences in log(lRD5)variance are found. A significantly weaker correlation of log(l/TD50)with log(l/maxD)for mutagens in comparison to nonmutagens occurs only for the dataset with minimum TD50 chosen at the least stringent level, suggesting that this difference may be due to chance variation. We also looked for changes in correlation and regression parameters as a function of mutagenic potency in Salmonella; the variance of l o g (l)and its correlation with log(l/maxD)are not found to vary in a consistent manner. Taken as a whole, our results indicate that (1)mutagenicity is a determinant of the TD, dmaxD relationship in rats and (2)any effect that mutagenicity may exert on the TD,dmaxD relationship in mice is unimportant. A pseudo‐single‐dose model, equivalent to that analyzed by Bernstein et al. (Fundurn. Appl. Toxicol. 5, 79‐86, 1985), was imposed upon the experimental data in order to determine the extent to which the resultant artificial datasets reproduce the mutagen/nonmutagen differences in sample variance. We discovered that this model does not approximatethe actual distribution of log(l/TD50)vs. log(l/maxD)closely enough to be useful for examining artifacts in the relationship between these two variables.

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  • Gay Goodrnan & Richard Wilson, 1992. "Comparison of the Dependence of the TD50 on Maximum Tolerated Dose for Mutagens and Nonmutagens," Risk Analysis, John Wiley & Sons, vol. 12(4), pages 525-533, December.
    • Handle: RePEc:wly:riskan:v:12:y:1992:i:4:p:525-533
    DOI: 10.1111/j.1539-6924.1992.tb00709.x
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    References listed on IDEAS

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    1. David W. Gaylor & James J. Chen, 1986. "Relative Potency of Chemical Carcinogens in Rodents," Risk Analysis, John Wiley & Sons, vol. 6(3), pages 283-290, September.
    2. Alexander Shlyakhter & Gay Goodman & Richard Wilson, 1992. "Monte Carlo Simulation of Rodent Carcinogenicity Bioassays," Risk Analysis, John Wiley & Sons, vol. 12(1), pages 73-82, March.
    3. Christopher J. Portier & David G. Hoel, 1987. "Issues Concerning the Estimation of the TD50," Risk Analysis, John Wiley & Sons, vol. 7(4), pages 437-447, December.
    4. Lauren Zeise & Richard Wilson & Edmund Crouch, 1984. "Use of Acute Toxicity to Estimate Carcinogenic Risk," Risk Analysis, John Wiley & Sons, vol. 4(3), pages 187-199, September.
    5. Lauren Zeise & Edmund A. C. Crouch & Richard Wilson, 1985. "Reply to Comments: On the Relationship of Toxicity and Carcinogenicity," Risk Analysis, John Wiley & Sons, vol. 5(4), pages 265-270, December.
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    1. D. Krewski & D .W. Gaylor & A. P. Soms & M. Szyszkowicz, 1993. "An Overview of the Report: Correlation Between Carcinogenic Potency and the Maximum Tolerated Dose: Implications for Risk Assessment," Risk Analysis, John Wiley & Sons, vol. 13(4), pages 383-398, August.

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