Mutation and inactivation of cultured mammalian cells exposed to beams of accelerated heavy ions. IV. Biophysical interpretation.

A biophysical analysis is made of the results of recent experiments which used accelerated heavy ions of 20 to 470 keV micron-1 to induce inactivation and mutation (resistance to 6-thioguanine) in cultured V79 Chinese hamster cells and HF19 human diploid fibroblasts. It is shown that the discrete nature of the primary ions must be explicity taken into account before the numbers of induced lethal and mutagenic lesions can be deduced from the observed radiosensitivities. The measured numbers of lesions produced by the radiations of different LET are compared with the relative numbers predicted by various models of radiation action. The observations can be explained on the hypothesis that each lethal lesion is produced by a deposition of small energy (small number of ionizations) in a distance of about 3 nm. Two different lesions appear to be involved, one of which requires greater than or equal to 100 eV and is dominant with low-LET radiations, and the other requires greater than or equal to 300 eV and is dominant at high-LET. Similar conclusions may apply to mutagenic lesions except that the mechanism which dominates at high-LET requires significantly more than 300 eV. More precise assessments of the hypothesis and these numerical values must await detailed track structure calculations of the radiation on the nanometre scale. Alternative models which invoke 'accumulation of sublethal damage' or 'interaction between sublesions', over distances of the order of microns, do not provide a consistent explanation of the observations. This suggests that the frequently observed curvature of low-LET dose-responses is not due to interaction between sublesions but rather to some other mechanism such as a dose-dependent repair process. It is also shown that low velocity, high-LET ions produce an average of appreciably less than one lethal lesion in traversing the nucleus of the above mammalian cells; 90 keV micron-1 helium ions produce about 0.03-0.06 lethal lesions micron-1 of track through the nucleus of the cells of thickness about 7 microns. Some estimates are also made of the size of the nuclear region which is sensitive to the induction of mutation to 6-thioguanine-resistance; it is concluded that this region extends beyond the DNA of the structural gene itself.