Dose-Dependent Transmissibility of Chromosome Aberrations in Human Lymphocytes at First Mitosis. II. Biological Effectiveness of Heavy Charged Particles Versus Gamma Rays.

Chromosome aberrations (CAs) are large scale structural rearrangements to the genome that have been used as a proxy endpoint of mutagenic and carcinogenic potential. And yet, many types of CAs are incapable of causing either of these effects simply because they are lethal. Using 24-color multi-fluor combinatorial painting (mFISH), we examined CAs in normal human lymphocytes exposed to graded doses of 1 GeV/nucleon accelerated 56Fe ions and 662 keV 137Cs gamma rays. As expected, the high-linear energy transfer (LET) heavy ions were considerably more potent per unit dose at producing total yields of CAs compared to low-LET gamma rays. As also anticipated, the frequency distribution of aberrations per cell exposed to 56Fe ions was significantly overdispersed compared to the Poisson distribution, containing excess numbers of cells devoid of aberrations. We used the zero-inflated negative binomial (ZINB) distribution to model these data. Based on objective cytogenetic criteria that are subject to caveats we discuss, each cell was individually evaluated in terms of likely survival (i.e., its ability to transmit to daughter cell progeny). For 56Fe ion irradiations, the frequency of surviving cells harboring complex aberrations represented a significant portion of aberration-bearing cells, while for gamma irradiation no survivable cells containing complex aberrations were observed. When the dose responses for the two radiation types were compared, and the analysis was limited to surviving cells that contained aberrations, we were surprised to find the high-LET 56Fe ions only marginally more potent than the low-LET gamma rays for doses less than 1 Gy. In fact, based on dose-response modeling, they were predicted to be less effective than gamma rays at somewhat higher doses. The major implication of these findings is that measures of relative biological effectiveness that fail to account for coincident lethality will tend to overstate the impact of transmissible chromosomal damage from high-LET particle exposure.