14300 Rose Wycombe Lane, Prospect, KY 40059, Fax: 5022286779
E-mail: bwaddell{at}louisville.edu.
To the Editor:
Calculations showing that dose thresholds should exist for chemical carcinogens have been presented by this author in a series of publications (e.g., Waddell, 2002, 2003a
d
). Subsequently, many investigators have challenged these calculations as flawed (e.g., Andersen et al., 2003
; Crump and Clewell, 2003
; Haseman, 2003
; Lutz, 2003
); one has described them as "interesting" (Bolt et al., 2004
), and others have been pointed out as supportive (e.g., Bruning and Bolt, 2000
; Hoshi et al., 2004
; Rozman 2003
; Tsuda et al, 2003
; Williams et al., 2000
). In my opinion, this is too important an issue in both toxicology and society simply to ignore. Therefore, I am proposing that an experiment be undertaken that might settle the question. This letter is an open solicitation for ideas on the design of such an experiment, and possibly for a sponsor, or sponsors, of that experiment. It would be desirable if all interested parties could agree on the design prior to initiation of the experiment.
The basic question in an animal experiment, as I see it, is whether or not doses of a chemical carcinogen below what is calculated to be a threshold produce any more tumors than are produced in control animals receiving no carcinogen. As a beginning for the experimental design, I would propose the following. The minimum number of groups would be two; however, the number of animals required in each group would be large. One group would receive a dose of the chemical carcinogen below the threshold calculated by the procedure, and the other would not receive that chemical. The size of the groups must satisfy statisticians to be of sufficient size to reasonably detect a difference between the two groups.
For specifics, I would suggest that methyl eugenol be used as the test compound. I recommend this compound for at least two reasons. Methyl eugenol is widely consumed in foods and is consequently of practical interest to humans (see Waddell, 2002). Furthermore, the carcinogenicity of methyl eugenol has been investigated extensively and its doseresponse has been characterized (NTP, 2000
). If only one dose is used, I would suggest 1019 molecules/kg/day of methyl eugenol to male F344 rats and examine them for hepatocellular carcinomas as in the NTP protocol. This dose is about one order of magnitude below the calculated threshold and about three orders of magnitude above the estimated consumption by pesto eaters (see Waddell, 2002
).
If funds are available for additional groups, then groups could be added for additional doses between 1019 and 1020 molecules/kg/day (the approximate calculated threshold) and additional doses between 1019 and the amounts consumed by humans (see Waddell, 2002). Additionally, the livers could be analyzed for adducts to determine correlations.
Although some authors apparently do not yet recognize that a threshold is absolutely essential to the concept of hormesis, the proposed experiment might also be useful in testing for hormesis. For example, if a strain of animal is used that has a high incidence of background tumors, and if the doses proposed above reduce the incidence of background tumors, it would support the concept of hormesis for carcinogenesis.
Any comments are welcome.
REFERENCES
Andersen, M. E., Conolly, R. B., and Gaylor, D. W. (2003). Letter to the Editor. Toxicol. Sci. 74, 486487.
Bolt, H. M., Foth, H., Hengstler, J. G., and Degen, G. H. (2004). Carcinogenicity categorization of chemicalsNew aspects to be considered in a European perspective. Toxicol. Lett. 151, 2941.[CrossRef][ISI][Medline]
Bruning, T., and Bolt, H. M. (2000). Renal toxicity and carcinogenicity of trichlorethylene: Key results, mechanisms, and controversies. Crit. Rev. Toxicol. 30, 253285.[ISI][Medline]
Crump, K. S., and Clewell, H. J. (2003). Letter to the Editor. Toxicol. Sci. 74, 485.
Haseman, J. K. (2003). An alternative perspective: A critical evaluation of the Waddell threshold extrapolation model in chemical carcinogenesis. Toxicol. Pathol. 31, 468470.[CrossRef][ISI][Medline]
Hoshi, M., Morimura, K., Wanibuchi, H., Wei, M., Okoshi, E., Ushijima, T., Takaoka, K., and Fukushima, S. (2004). No-observed effect levels for carcinogenicity and for in vivo mutagenicity of a genotoxic carcinogen. Toxicol. Sci. 81, 273279.
Lutz, W. K. (2003). Letter to the Editor. Toxicol. Sci. 75, 223.
NTP TR 491 (2000). Toxicology and carcinogenesis studies of methyleugenol in F344/N rats and B6C3F1 mice. National Toxicology Program TR 491 Available online at http://ntp-server.niehs.nih.gov/.
Rozman, K.K. (2003). Letter to the Editor. Toxicol. Sci. 75, 224225.
Tsuda, H., Fukushima, S., Wanibuchi, H., Morimura, K., Nakae, D., Imaida, K., Tatematsu, M., Hirose, M., Wakabayashi, K., and Moore, M.A. (2003). Value of GST-P positive preneoplastic hepatic foci in dose-response studies of hepatocarcinogenesis: Evidence for practical thresholds with both genotoxic and nongenotoxic carcinogens. A review of recent work. Toxicol. Pathol. 31, 8086.[CrossRef][ISI][Medline]
Waddell, W. J. (2002). Thresholds of carcinogenicity of flavors. Toxicol. Sci. 68, 275279.
Waddell, W. J. (2003a). Threshold of carcinogenicity of nitrosodiethylamine for esophageal tumors in rats. Food Chem. Toxicol. 41, 739741.[CrossRef][ISI][Medline]
Waddell, W. J. (2003b). Thresholds of Carcinogenicity in the ED01 study. Toxicol. Sci. 72, 158163.
Waddell, W. J. (2003c). Thresholds in chemical carcinogenesis: What are animal experiments telling us. Toxicol. Pathol. 31, 260262.[CrossRef][ISI][Medline]
Waddell, W. J. (2003d). Comparison of human exposures to selected chemicals with thresholds from NTP carcinogenicity studies in rodents. Hum. Exp. Toxicol. 22, 501506.[CrossRef][ISI][Medline]
Williams, G. M., Iatropoulos, M. J., and Jeffrey, A. M. (2000). Mechanistic basis for nonlinearities and thresholds in rat liver carcinogenesis by the DNA-reactive carcinogens 2-acetylaminofluorene and diethylnitrosamine. Toxicol. Pathol. 28, 388395.[ISI][Medline]
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