CC2-001-UMAN: Quantitative Associations Between DNA Adduct Levels and Mutations: a Tool for Human Risk Assessment

Description

Specific DNA adducts have been shown to cause gene mutations and carcinogenesis but despite extensive work the biological significance of DNA adduct levels in human populations is largely unknown, in part because all human tissues contain DNA adducts of varying mutagenic potential from endogenous and exogenous exposures. Large inter-individual variability in adduct levels has been demonstrated and depends upon a number of different factors which will vary depending upon the agent concerned. In addition, the risk, if any, associated with a specific adduct level will depend on other cell and tissue specific factors including cell proliferation and the induction of cell death. The interactions between all these factors tend to be poorly characterised even in animal models but especially in human tissues.

To obtain further information of direct relevance to risk assessment, the objectives of the present study are to determine the quantitative associations between specific DNA adducts, gene mutations and cell death in (i) DNA repair proficient and DNA repair deficient cell lines and (ii) in target and non-target tissues in DNA repair proficient and DNA repair deficient animals. The levels of adducts associated with no detectable mutational affect will also be determined. By comparing the quantitative associations between in vitro and in vivo studies, the presence of other tissue specific factors will be revealed, which will help to determine the relevance, if any, of specific DNA adduct levels in human tissues. This study will then determine the levels of DNA adducts associated with the induction of gene mutations in both cells and target/non-target tissues. Though gene mutations may not necessarily be associated with tumour risk, determination of adduct levels with no observable mutational effect will be of relevance to risk assessment.