Abstract B80: Possibilities for individualization of radiogenic cancer risk

Abstract

Abstract B80 One of the major long-term effects of ionizing radiation (IR) on humans is the increase of risk of cancer development. An important practical task is the assessment of population and individual risks for persons subject to protracted low-dose irradiation. Successive model for individualized prognostication has to be capable of combining available extensive epidemiological information on radiation induced solid cancer and leukemia risks with individual measurements determining the risks. In this report we present a new approach to modeling spontaneous and radiation carcinogenesis, a distinguishing feature of which consists in the fact that the modeling scheme proposed remains within the scope of the mutation theory, though it includes parameters measurable for a specific individual. Biological background of the approach to carcinogenesis modeling is based on the consideration of carcinogenesis as the dynamic trade-off between two antagonistic forces or processes, promoting or hindering carcinogenesis at its different stages (initiation, promotion, conversion). Processes promoting the cell malignization are represented by mutations or adverse epigenetic events. Antagonistic processes preventing the neoplastic transformation of the cell and forthcoming its fixation in next cell generations are represented by barrier mechanisms. The intercellular barrier mechanisms (e.g., antioxidant defense, repair, apoptosis) represent the complex of cell responses to similar, negative for the cell and/or the whole organism, events. Detrimental phenotypic changes in cells are caused by an insufficiency of interacting barrier mechanisms. Disorders in the barrier mechanism functioning occur as a result of one or more mutations, and there exists a conceptual possibility to measure the efficiency of each barrier functioning in sensitive cells of a certain individual. One advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and measures characterizing fractions of cells with breaking barriers. Another advantage is in the application to the case of protracted low-dose IR, when barrier mechanisms for repair of genetic damages or elimination of cells carrying unrepaired damages play a special role. The report provides the substantiation for inclusion of specific cellular barrier mechanisms into the model describing radiation-induced carcinogenesis. Respective properties of candidate barrier systems such as apoptosis, repair system, antioxidant defense, growth arrest, telomerase etc. are reviewed and conclusion about their inclusion into the minimal model is made. The theoretical formalism of the model structure is presented as a synthesis of ideas for multistage and multiple pathway mechanistic models of carcinogenesis and leukemia and population models of aging, cancer morbidity, and mortality. Discussed, also, are the schemes for measuring the parameters introduced, methods for individual risk estimation, relation to the IR-induced genomic instability, and further generalization of the model. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B80.