Misrejoining of double-strand breaks after X irradiation: relating moderate to very high doses by a Markov model.

Misrejoining of double-strand breaks (DSBs) detected with pulsed-field gel electrophoresis (PFGE) after X irradiation of human cells at very high doses (80-160 Gy) is related to dose-response relationships for chromosome aberrations at moderate doses (1-5 Gy) by the Sax-Markov binary eurejoining/misrejoining (SMBE) model. The SMBE model applies Sax's breakage-and-reunion hypothesis to a subset of DSBs active in binary misrejoining and in binary eurejoining (accidental restitution). The model is numerically consistent with both data on chromosome aberrations and the data obtained by PFGE if proximity effects (restrictions on the range of interactions of DSB free ends) are present. Proximity effects are modeled by partitioning the cell's nucleus into approximately 400 interaction sites, with two active DSB free ends capable of rejoining only if they were produced within the same site. Neglecting one-track action, the SMBE model predicts a quadratic-linear dose-response relationship for DSB misrejoining after exposure to low-LET radiation; i.e., there is a quadratic response at moderate doses which becomes linear as the dose becomes large, rather than vice versa. The linear region results because at very high doses almost all of the active DSB free ends misrejoin rather than eurejoin.