3H-thymidine (3HTdR) incorporated into DNA; Dosimetric and radiobiological considerations

Tritium can be selectively incorporated into DNA in vivo by administration of tritiated thymidine (3HTdR), and this labelled precursor is used widely and effectively in investigations on the mechanism of DNA synthesis, in studies on the kinetics of cell proliferation, and for the purpose of selective cell destruction. It is important, of course, to be aware of the threshold for toxicity of the isotope used in this manner. In addition, the unique dosimetric features involved present theoretical and practical problems, the solutions of which will shed light on mechanisms of radiobiology effect. The highly selective irradiation of the nucleus of those cells which incorporated 3HTdR at the time of DNA synthesis constitutes not only partial-body irradiation, but partial-cell irradiation, and homogeneity of exposure can be defined only in terms of subcellular dimensions. The toxicity of 3HTdR and the associated problems have been reviewed extensively. The object of the present paper is to: (a) evaluate from data in the literature and from data to be presented, whether observed effects from intranuclear 3H can be accounted for on the basis of calculated absorbed dose in rads to the cell nucleus, or, alternatively, whether additional factors deriving from the presence of the 3H in the DNA molecule must be invoked. In the latter case the biological effects would not be generally predictable on the basis of absorbed dose; and (b) to discuss the implications of the findings with respect to radiobiology and radiation protection. The conclusion is reached that while data are as yet inadequate for firm evaluation, biological effects of 3HTdR are those predictable on the basis of the average absorbed dose to the nucleus. The applicability of the absorbed dose concept can be evaluated satisfactorily only if adequate comparisons of the effect of incorporated 3HTdR can be made with a suitable standard external radiation such as X-rays, or possibly with the same isotope (3H) distributed essentially randomly in tissue, as is tritiated water. The low dose rate from the incorporated 3H must be taken into account in practically all experiments, as must the possibility of an intrinsic relative biological effectiveness (RBE) of 3H /3-radiation, compared to X- or γ-rays. The possibility of transmutation effects cannot be ignored. In evaluating the effects of intranuclear tritium the following approach will be used: the method of calculating the absorbed dose for the nucleus will be presented first. This is followed by a discussion of three factors required in the evaluation of the relative effectiveness of tritium disintegrations: (1) the intrinsic RBE of 3H /3-rays; (2) possible transmutation effects; and (3) asynchronous chromosome labelling. Dose-effect relationships for 3H incorporated in the nucleus from administered 3HTdR will then be discussed in the following order: (1) cell killing effects in tissue culture; (2) cytogenetic effects in mammalian cells; (3) mitotic delay in tissue culture; (4) cell killing effects in the intact mammal; and (5) genetic effects and carcinogenesis