Cancer risk estimation of genotoxic chemicals based on target dose and a multiplicative model

A mechanistic model and associated procedures are proposed for cancer risk assessment of genotoxic chemicals. As previously shown for ionizing radiati on, a linear multiplicative model was found to be compatible with published experimental data for ethylene oxide, acrylamide, and butadiene. The valid ity of this model was anticipated in view of the multiplicative interaction of mutation with inherited and acquired growth-promoting conditions. Concu rrent analysis led to rejection of an additive model (i.e. the model common ly applied for cancer risk assessment). A reanalysis of data for radiogenic cancer in mouse, dog and man shows that the relative risk coefficient is a pproximately the same (0.4 to 0.5 percent per rad) for tumours induced in t he three species. Doses in vivo, defined as the time-integrated concentrations of ultimate mu tagens, expressed in millimol x kg(-1) x h (mMh) are, like radiation doses given in Gy or rad, proportional to frequencies of potentially mutagenic ev ents. The radiation dose equivalents of chemical doses are, calculated by m ultiplying chemical doses tin mMh) with the relative genotoxic potencies ti n rad x mMh(-1)) determined in vitro. In this way the relative cancer incid ence increments in rats and mice exposed to ethylene oxide were shown to be about 0.4 percent per rad-equivalent, in agreement with the data for radio genic cancer. Our analyses suggest that values of the relative risk coefficients for geno toxic chemicals are independent of species and that relative cancer risks d etermined in animal tests apply also to humans. If reliable animal test dat a are not available, cancer risks may be estimated by the relative potency. In both cases exposure dose/target dose relationships, the latter via macr omolecule adducts, should be determined.