ECETOC workshop on the biological significance of DNA adducts: Summary of follow-up from an Expert Panel Meeting

This workshop on the biological significance of DNA adducts included presentations of research results in the following areas: endogenous versus exogenous adduct levels; in vitro dose–response data on adducts and mutagenesis from alkylating agents; methyltransferases and alkyl transferase-like proteins in repair of O6-alkylguanine adducts; mathematical modeling of threshold dose–response in mutagenesis and carcinogenesis; and the use of genomics to characterize the relationships between adducts, gene expression, and downstream adverse effects. Presentations by regulatory scientists and other authorities addressed the role of adduct and mutation data in risk characterization. Consensus statements were developed and included the following: DNA adducts should be considered as biomarkers of exposure, which may play a key role in establishing a mode of action (MOA) for cancer. Adducts themselves should not be considered as equivalent to mutations or later stage events in carcinogenesis. Although it was not possible at this time to agree on a general level of adducts below which there is no adverse biological effect, there are examples of genotoxic mutagens/carcinogens for which thresholds have been demonstrated. Evidence regarding thresholds for mutations should be considered on a case-by-case basis, in light of available MOA and mechanistic data, to build a knowledge base. Participants agreed that guidance on a recommended format for data presentation (especially agreement on units and appropriate statistical analyses) would be beneficial. Finally, for initial cases, provision of a mechanistic explanation to support a hypothesis of a threshold for mutations was essential for the eventual use of this information in risk assessment.