ToxSci Advance Access originally published online on February 18, 2003
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Toxicological Sciences 72, 158-163 (2003)
Copyright © 2003 by the Society of Toxicology
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Thresholds of Carcinogenicity in the ED01 Study
Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky 40292
ABSTRACT
The results of the articles on the carcinogenicity of 2-acetylaminofluorene (J. H. Farmer et al., 1980, J. Environ. Pathol. Toxicol. 3, 55–68; N. A. Littlefield et al., 1980, J. Environ. Pathol. Toxicol. 3, 17–34) in approximately 25,000 female mice were reanalyzed by the procedure proposed earlier (W. J. Waddell, 2002, Toxicol. Sci. 68, 275–279) using the Rozman scale (K. K. Rozman et al., 1996, Drug Metab. Rev. 28, 29–52). In contrast to some conclusions of the lack of a threshold for carcinogenesis that have been made in the past from this study, this reanalysis showed a clear and consistent threshold for bladder neoplasms at about 10 19.5 molecules/kg/day and for liver neoplasms at about 10 19.1 molecules/kg/day. The slopes of the dose-response curves for bladder neoplasms from 17 months through 33 months were consistently very steep, while those for liver neoplasms increased from a shallow slope at 18 months to a steep slope at 33 months. This is interpreted to indicate that the mechanism of carcinogenesis may be different in the two organs. A linear response for percentage tumors plotted against dose on a logarithmic scale is confirmed by this analysis, which is based on the fundamental principle that chemical potential effects a linear response. Furthermore, this application continues to show a sharp threshold for carcinogenesis. The implications of these observations should be important in the extrapolation of results from animal experiments to human risk assessment.
Key Words: thresholds; carcinogenicity; 2-acetylaminofluorene; 2-AAF; ED01; bladder neoplasms; liver neoplasms.
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