Comments on Commentary by D. Billen

Abstract

Billen (1) proposes that the spontaneous to DNA due primarily to the thermodynamic instability arising from storage in the living genome at 37?C can be used to determine a negligible for ionizing radiations. The concept of DNA instability is, I believe, of great relevance to radiobiology, but logically it leads to a rather different conclusion, namely that however small the dose and however low the dose rate there is a finite chance that a biological effect will be caused. The concept of negligible does not belong in the domain of the physicochemical properties of DNA but in the domain of the acceptability of risk, a sociopolitical issue. My argument is as follows. I agree with Billen (1) that about 100 events occur in the genome of the diploid mammalian cell per minute and that cells have evolved efficient repair processes to enable them to cope with this rate of induction. The nature of these sites in double-stranded DNA, the repository of the genetic information, is base loss, base damage, and single-strand breaks, i.e., single-strand damage. While this is being continually produced it must be equally continually being repaired; i.e., there is a dynamic equilibrium between degradation and repair in the living cell. Even at this rate of formation the distances between the transitory lesions are enormous, and so the generation of double-strand due to the coincidence of single-strand sites in opposing strands is indistinguishable from zero. Cells do generate double-strand breaks; however, this is not primarily but rather part of their normal functioning and a controlled process. Radiation induces both singleand double-strand and DNA-protein crosslinks (2). I think, as does Billen, that provided the single-strand is not induced at a rate comparable to the rate of induction of spontaneous single-strand then the continually active repair processes will satisfactorily repair both the radiation-induced and the spontaneous damage. This is then irrelevant to biological effect. However, the double-strand (mainly breaks) and the DNA-protein crosslinks caused by radiation will not necessarily be repaired effectively, and it is these lesions that can constitute relevant damage and lead to biological effects at low dose rates. Thus I would predict that at low dose rates, radiation-induced biological effects would be directly proportional to dose and invariant with dose rate. At dose rates where the ate of induced single-strand was comparable with that ue to spontaneous I would predict a transition to a dependence of effect on dose rate due to the disruption of the dynamic equilibrium between DNA degradation and repair and the consequent build-up of unrepaired of both spontaneous and radiolytic origin. Indeed, such a transition is exactly what is observed for the induction of specific locus mutations in mice when males are irradiated at the spermatogonial stage (to be published elsewhere). At dose rates of 0.015 Gy/min (a singlestrand induction rate of about one-third that due to spontaneous damage) a transition is observed; below this rate mutation frequency is invariant with dose rate, and above this rate it increases sharply with increasing dose rate. Viewed in this way I believe the concept of DNA instability is of considerable value to radiobiology and radiological protection in the following ways: