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Chem. Res. Toxicol. 2009, 22, 1492
Letters to the Editor Letter to the Editor Regarding Bailey Article Received June 29, 2009
To the Editor: The authors of the Bailey et al. study are to be complimented on the tremendous effort and time spent on this study (1). Such a study was very much needed to demonstrate that carcinogens, like all other chemicals, have thresholds. This study also provided sufficient low-dose response information to estimate thresholds for the DNA-reactive carcinogen dibenzopyrene. However, the authors could have saved much time and effort in their analysis if they had recognized and simply applied the laws of nature. Dose must be plotted on a logarithmic scale with effect on a linear scale to conform to the laws of chemistry (2). There is no need to try the various statistical “models” to see which provides the closest fit. Figure 1 is a plot of their liver tumor data (from Table 1 in the Bailey et al. article) after subtracting the average of the four quartiles for zero dose incidences; the figure is plotted on the Rozman scale (3), which conforms to the laws of chemistry. In Figure 1, it can be seen that a linear fit for incidence of tumors (indicating the presence of a threshold) is better than an exponential fit; the lowest two doses are plotted separately (as zero dose) because at least one of the quartiles falls within the range of one of the quartiles of the zero dose. Even an exponential fit could be indicative of a
threshold if proper adjustment can be made for the background tumor incidence. The same observation occurs with the stomach tumors (Figure 2), but with stomach tumors, the lowest four doses are considered as zero since the linear fit for the three highest doses gives the best fit. The authors state in this paper that a similar experiment is underway with aflatoxin. If that experiment indicates that trout have the same threshold as rats and humans, trout will be the third species having the same threshold (4). The Bailey et al. (1) experiment further supports the presence of a threshold in carcinogenesis. More research needs to be done on doses of a carcinogen at doses closer to those to which humans are exposed. Perhaps we shall even observe hormesis.
References (1) Bailey, G. S., Reddy, A. P., Pereira, C. B., Harttig, U., Baird, W., Spitsbergen, J. M., Hendricks, J. D., Orner, G. A., Williams, D. E., and Swenberg, J. A. (2009) Nonlinear cancer response at ultralow dose: A 40800-animal ED tumor and biomarker study. Chem. Res. Toxicol. 22, 1264–1276. (2) Waddell, W. J. (2008) Thermodynamic basis for expressing dose logarithmically. Toxicol. Appl. Pharmacol. 228, 156–157. ¨ sterle, D., Deml, E., Viluksela, (3) Rozman, K. K., Kerecsen, L., Viluksela, M. K., O M., Stahl, B. U., Greim, H., and Doull, J. (1996) A toxicologist’s view of cancer risk assessment. Drug Metab. ReV. 28, 29–52. (4) Waddell, W. J. (2006) Critique of dose response in carcinogenesis. Hum. Exp. Toxicol. 25, 413–436.
William J. Waddell,* M.D. Department of Pharmacology and Toxicology University of Louisville 14300 Rose Wycombe Lane Prospect, Kentucky 40059 E-mail:
[email protected] John Doull, Ph.D., M.D. Department of Pharmacology, Toxicology & Therapeutics University of Kansas Medical Center 3901 Rainbow Boulevard Kansas City, Kansas 66160 E-mail:
[email protected] Figure 1
Karl K. Rozman, Ph.D. Department of Pharmacology, Toxicology & Therapeutics University of Kansas Medical Center 3901 Rainbow Boulevard Kansas City, Kansas 66160 E-mail:
[email protected] Joseph F. Borzelleca, Ph.D. Department of Pharmacology and Toxicology Virginia Commonwealth University 8718 September Drive Richmond, Virginia 23229 E-mail:
[email protected] Figure 2
TX900218E 10.1021/tx900218e CCC: $40.75 2009 American Chemical Society Published on Web 08/20/2009
