Thresholds of carcinogenicity in the ED01 study.
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.
Waddell
William J
WJ
Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky 40292, USA. bwaddell@louisville.edu
D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008113:Liver Neoplasms / Q000139:chemically induced; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced
D002273:Carcinogens; D015073:2-Acetylaminofluorene