Working paper no. 6 Estimation of genetic risks of exposure to chemical mutagens: relevance of data on spontaneous mutations and of experience with ionizing radiation

Abstract

This paper examines the impact of advances in knowledge on the molecular biology of human Mendelian diseases on the estimation of genetic risks of exposure to ionizing radiation and to chemical mutagens. More specifically, it addresses the question of whether and to what extent naturally occurring Mendelian diseases can be used as a baseline for efforts in this area. Data on the molecular nature and mechanisms of origin of spontaneous mutations underlying naturally occurring Mendelian diseases and on radiation-induced mutations in experimental systems suggest that for ionizing radiation, naturally occurring Mendelian diseases may not constitute an entirely adequate frame of reference and the current risk estimates for this class of diseases are conservative; these estimates however provide a margin of safety in formulating radiation protection guidelines. Currently available data on mechanisms and specificities of action of chemical mutagens, molecular dosimetry, repair of chemically induced adducts in the DNA, adduct-mutation relationships etc., permit the tentative conclusion that naturally occurring Mendelian diseases may provide a better baseline for genetic risk estimation for chemical mutagens than for ionizing radiation. With both ionizing radiation and chemical mutagens, the question of which Mendelian diseases are potentially inducible will become answerable in the near future when more molecular data on human genetic diseases become available. It is therefore essential that risk estimators keep abreast of advances in human genetics and integrate these into their conceptual framework. However, induced Mendelian diseases (especially the dominant ones which are of more immediate concern) are likely to represent a very small fraction of the adverse genetic effects of induced mutations. More attention therefore needs to be devoted to studies on the heterozygous effects of induced mutations.