Molecular dosimetry of chemical mutagens. Relationship between DNA adduct formation and genetic changes analyzed at the molecular level.

This is a review of the work carried out by 16 collaborating institutes within a project which was part of the European Programme: Science and Technology for Environmental Protection (STEP). The purpose of the project was to investigate the relationship between the exposure to genotoxic chemicals and the induction of DNA damage and genetic effects as determined in in vitro and in vivo assays under laboratory conditions. Two types of investigation were performed: (i) determination of the relationship between the extent of exposure to a genotoxic chemical and the frequency of DNA adducts formed in the test organism and (ii) identification of those DNA adducts which are responsible for the biological effects of genotoxic chemicals. The research was carried out with a series of alkylating agents which all induce similar types of DNA damage but for which the proportions of the different types of adducts vary. The frequency of this type of DNA damage was also modulated by base excision repair processes. In addition, a number of genotoxic agents which cause DNA damage recognized by nucleotide excision repair were investigated. The consequences of DNA adduct formation, i.e., the induction of gene mutations, were analyzed at the DNA sequence level, generating mutational spectra. These investigations of the mutational specificities of carcinogens contributed to our understanding of the molecular mechanisms which are involved in cancer induction by genotoxins.