The multiplicative model for cancer risk assessment: applicability to acrylamide

According to a multiplicative model for prediction of cancer risk for genot oxic agents the incremental cancer risk is, for low-intermediate exposures, proportional to target doses of the genotoxic substance and to the backgro und risk in control groups. This model has been applied to evaluate cancer tests of acrylamide in rodents. Because of its reactivity toward DNA, glyci damide is assumed to be the causative genotoxic metabolite of acrylamide. E valuation of experimental data according to the multiplicative model shows that mice, compared with rats, are of the order of 10 times more sensitive per administered dose of acrylamide, The US EPA procedure would, however, g enerally predict rats to be about twice as sensitive as mice to carcinogeni c chemicals, because their estimates are based on scaling of the dose per s quare meter body surface area, as a surrogate for metabolic differences bet ween the species. The comparison of rats and mice with respect to observed cancer incidence is at a key position in the evaluation of the usefulness o f risk models for extrapolation between species, In the present study mice and rats were compared, with respect to in vivo doses of acrylamide and the metabolite glycidamide, after exposure to acrylamide. The relative in vivo doses were inferred from levels of hemoglobin adducts. The adduct levels f rom glycidamide were, per administered dose of acrylamide, similar to3-10 t imes higher in mice than in rats. In combination with the above mentioned h igher sensitivity of mice than rats in canter tests of acrylamide this is c ompatible with the concept that glycidamide is the key genotoxic factor in acrylamide exposure. Furthermore, it is shown that the multiplicative, i.e. relative, risk model and measurements of the dose of the genotoxic factor give good prediction of the observed risk from acrylamide in cancer tests w ith rats and mice.