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

Abstract

Data on percent tumors in male rats after administration of methyl eugenol, obtained from the National Toxicology Program, or tamoxifen were plotted on a linear scale for percent tumors against the dose on a logarithmic scale. 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 10^19.3 molecules of methyl eugenol/kg/day, which compared with a threshold of 10^20.1 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 10^18.7 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 10× above the dose received by women at risk for breast cancer, this should be an adequate safety margin. 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.