The potential for radiogenic neoplasia from charged-particle irradiation has been estimated using the Harderian gland of the mouse as a test system. Particles ranging in Z from Z = 1 (proton) to Z = 41 (niobium), in energy from 228 to 670A MeV, and in LET from 0.4 to 464 keV/microns were produced at the Lawrence Berkeley Laboratory BEVALAC. Expression of the tumorigenic potential of the initiated cells was enhanced by hormones from isogeneic grafts of pituitaries. The goal of the studies was to estimate the initial slope of the relationship between increased tumor prevalence at 16 months after irradiation and the dose received. Initial slopes were measured with good precision for 60Co gamma rays and the Bragg plateau beams of 228A MeV 4He ions, 600A MeV 56Fe ions, and 350A MeV 56Fe ions. The ratio of the initial slope for these ions to that of 60Co gamma rays give an estimate of the maximum RBE for radiogenic neoplasia. These values were 2.3 for the 4He ions, 40 for 600A MeV 56Fe, and 20 for 350A MeV 56Fe. In the studies reported here the prevalence of tumors as the result of pituitary isografts was not enhanced after irradiation with 56Fe ions. It remains to be seen how effective pituitary isografts are for enhancement of radiogenic neoplasia from other ions at different LET values. A risk analysis was undertaken using particle fluence rather than dose as the independent variable. This analysis provides a value for a "cross section" expressed in microns 2. This parameter expresses as the increase in proportion of mice with one or more Harderian gland tumors per unit increase in particle fluence. The plot of the cross section (risk coefficient) as a function of LET is monotonic, with no clear evidence of a maximum value of the risk coefficient for even the highest LET particle used.

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This report presents data for survival of mouse intestinal crypt cells, mouse testes weight loss as an indicator of survival of spermatogonial stem cells, and survival of rat 9L spheroid cells after irradiation in the plateau region of unmodified particle beams ranging in mass from 4He to 139La. The LET values range from 1.6 to 953 keV/microns. These studies examine the RBE-LET relationship for two normal tissues and for an in vitro tissue model, multicellular spheroids. When the RBE values are plotted as a function of LET, the resulting curve is characterized by a region in which RBE increases with LET, a peak RBE at an LET value of 100 keV/microns, and a region of decreasing RBE at LETs greater than 100 keV/microns. Inactivation cross sections (sigma) for these three biological systems have been calculated from the exponential terminal slope of the dose-response relationship for each ion. For this determination the dose is expressed as particle fluence and the parameter sigma indicates effect per particle. A plot of sigma versus LET shows that the curve for testes weight loss is shifted to the left, indicating greater radiosensitivity at lower LETs than for crypt cell and spheroid cell survival. The curves for cross section versus LET for all three model systems show similar characteristics with a relatively linear portion below 100 keV/microns and a region of lessened slope in the LET range above 100 keV/microns for testes and spheroids. The data indicate that the effectiveness per particle increases as a function of LET and, to a limited extent, Z, at LET values greater than 100 keV/microns. Previously published results for spread Bragg peaks are also summarized, and they suggest that RBE is dependent on both the LET and the Z of the particle.

The purpose of this investigation was to 1) evaluate the relative accuracy of the Sokoloff and Patlak tracer kinetic models in estimating glucose metabolic rate (GMR) in the presence and absence of insulin; 2) evaluate the effect of nutritional state on the lumped constant (LC); and 3) compare the kinetics of 2-fluoro-2-deoxy-d-[14C]glucose (FDG) and 2-deoxy-d-[3H]glucose (DG) membrane transport and phosphorylation. The experimental preparation was the isolated, red blood cell-albumin-perfused rabbit heart. Our results showed that both tracer kinetic models provided GMR estimates that correlated well with the Fick method (for FDG, R = 0.84 and 0.91 for the Sokoloff and Patlak models, respectively); nutritional state did not affect the LC; and FDG and DG have different transport and/or phosphorylation parameters. We also observed that 1) the addition of a fourth compartment to the Sokoloff model reduced the mean squared error between measured and modeled data by a factor of 7.4; 2) a longer time (21.8 min) was required to obtain a linear phase of the Patlak plot than is allowed in clinical studies; and 3) accurate GMR estimates were obtained only by using different LCs reflecting insulin’s presence or absence. Our results indicate potential sources of error in the use of FDG and positron emission tomography to quantify GMR in patients.

The lenses of mice exposed to 600 MeV/amu iron ions were evaluated by slit-lamp biomicroscopy and cytopathological analyses. The doses ranged from 0.05 to 1.6 Gy, and the lenses were assessed at several intervals postirradiation. Cataract, the development of which is dependent on both time and dose, is significantly more advanced in all of the exposed mice when compared to the unirradiated controls. The great difference between the severity of the cataracts caused by 0.05 Gy (the lowest dose used) and those that developed spontaneously in the control animals is an indication that 0.05 Gy may far exceed the threshold dose for the production of cataracts by accelerated iron ions. Cytopathologically, a similar dose dependence was observed for a number of end points including micronucleation, interphase death, and meridional row disorganization. In addition the exposure to the 56Fe ions produced a long-term effect on the mitotic population and a pronounced "focal" loss of epithelial cytoarchitecture. The microscopic changes support the view that the mechanism of heavy-ion-induced cataractogenesis is the same as that for cataracts caused by low-LET radiation.