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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh088
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received December 29, 2003; accepted January 23, 2004
© 2004 Society of Toxicology

Carcinogenicity

Correlation of Tumors with DNA Adducts from Methyl Eugenol and Tamoxifen in Rats

William J. Waddell 1*, Neil H. Crooks 2, and Paul L. Carmichael 2

1 Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky, USA
2 Biological Chemistry, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, London, SW72AZ, UK

* To whom correspondence should be addressed. E-mail: bwaddell{at}louisville.edu.


  Abstract

Data on percent tumors in male rats after administration of methyl eugenol, obtained from the National Toxicology Program (NTP TR 491), or tamoxifen (Greaves et al., 1993) were plotted on a linear scale for percent tumors against the dose on a logarithmic scale (Waddell, 2002). Data on 32P-postlabelled DNA adducts were plotted on the same graphs for each of these two compounds in order to correlate adduct formation and tumor incidence with dose. The resulting graph for methyl eugenol showed a linear response for both adduct formation and tumor incidence. The threshold dose of administered methyl eugenol for adduct formation (zero adducts) was 1019.3 molecules of methyl eugenol/kg/day, which compared with a threshold of 1020.1 molecules of methyl eugenol/kg/day for tumor formation; however, 30 adducts/108 nucleotides was the threshold for tumor formation. The dose of tamoxifen for adduct formation fit an exponential plot slightly better than a linear plot, but reached minimal values close to the threshold of 1018.7 molecules of tamoxifen/kg/day for tumor formation. These data confirm that tumor formation coincides with adduct formation and that both have thresholds, or at least reach minimal values, above levels to which humans are exposed. Although the threshold dose for tumor formation from tamoxifen is only about 10x above the dose received by women at risk for breast cancer, this should be an adequate safety margin (Waddell, 2003d). The safety factor for methyl eugenol is several orders of magnitude; therefore, there should be no cause for concern for humans at current levels of exposure.

Key Words: methyl eugenol, tamoxifen, carcinogenesis, thresholds, DNA adducts, 32P-postlabelling .


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