NSF Award
9707991
Hahnfeldt 9707991 When a cell population is subjected to toxic or transforming doses of chemical or radiation agents, the net population effect depends not only on the total dose but also on the time course of dose delivery, i.e. one has dose-rate effects. Dose-rate effects are not only very important in themselves but give insight into the underlying biochemical mechanisms and kinetics of damage formation. For ionizing radiation, DNA repair usually leads to direct dose-rate effects, i.e. less damage if a given dose is prolonged. But, for dynamic cell populations, inverse dose-rate effects, with more damage for prolonged irradiation, also occur. The inverse dose-rate effects are due to the first part of a prolonged dose delivery preferentially killing the more sensitive cells in a diverse cell population, and biological processes then driving the preferentially spared, more resistant cells into more sensitive states, where the remainder of the dose can act upon them more effectively. Such resensitization is often due to redistribution of the cell population attendant on movement through the cell cycle. The investigator studies dose-rate effects for induced damage to a heterogeneous, dynamic population, by combining standard models for cell population dynamics with standard models for cell damage. Various population dynamics models are be used, having the common feature that there is a well-defined asymptotic growth rate and an asymptotically stable population structure. Recent resensitization theorems on the killing of cycling cells are extended to theorems on cell populations having additional diversity. Biologically important examples under investigation include: (a) populations consisting of more than one age-structured subpopulation, (b) maturity-structured populations (with cell cycle synchrony loss ascribed to variable age progression over time), and (c) populations subjected to environmental stochasticity. Quantitative models, developed in p reliminary studies, of the inverse dose-rate effect for in vitro transformation, an indicator of cellular mutagenesis are generalized. Adverse effects of radiation (or chemicals) in the environment often occur at low dose rates over long periods of time. For practical reasons, laboratory studies of the parameters that govern the adverse effects normally use much shorter time periods and much higher dose rates. To bridge this gap, modeling of dose-rate effects is needed. One dose-rate effect is observable for populations, e.g. of cells, that possess any sort of susceptibility variation over time to toxic insults. Under these conditions, prolonging the delivery of a fixed total dose e.g., by halving the intensity (or concentration) and doubling the exposure time will not have neutral effect but will instead change the efficacy of that fixed total exposure. This is because more of the population members, as they undergo their sensitivity variations naturally over time, will now have the opportunity to display their more susceptible states in time to be affected by the exposure. This pattern is different from that anticipated in most laboratory studies. Over a wide range of conditions, the difference can in fact make a given dose more damaging when delivered over a prolonged period rather than rapidly, but for some other conditions, the opposite result can be expected. Mathematical theorems are developed to elucidate these dependencies. Important implications of this investigation include the prediction of cellular mutagenesis and transformation frequencies due to ambient, long-duration stress conditions.
