Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.

Two hydroxypyridinone-containing actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are being developed for the treatment of internal actinide contamination by chelation therapy. Dose-response efficacy profiles in mice were established for the removal of intravenously injected 238 Pu and 241 Am after parenteral and oral treatment with these chelators. In both cases, presumed efficacious doses promoted substantially greater actinide elimination rates than the currently approved agent, diethylenetriamine-pentaacetic acid, considering two different interspecies scaling methods for the conversion of human doses to equivalent rodent dose levels. In addition, genotoxicity of both ligands was assessed using the Salmonella/Escherichia coli /microsome plate incorporation test and the Chinese hamster ovary cell chromosome aberration assay, showing that neither ligand is genotoxic, in the presence and absence of metabolic activation. Finally, maximum tolerated dose studies were performed in rats for seven consecutive daily oral administrations with the chelators, confirming the safety of the presumed efficacious doses for 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). The results of these studies add to the growing body of evidence that both decorporation agents have remarkable decorporation efficacy properties and promising safety toxicology profiles. These results are necessary components of the regulatory approval process and will help determine the optimal human dosing regimens for the treatment of internal radionuclide contamination.

Radiation exposure from a number of terrestrial sources is associated with an increased risk for atherosclerosis. Recently, concern over whether exposure to cosmic radiation might pose a similar risk for astronauts has increased. To address this question, we examined the effect of 2 to 5 Gy iron ions ( 56 Fe), a particularly damaging component of cosmic radiation, targeted to specific arterial sites in male apolipoprotein E-deficient (apoE −/− ) mice. Radiation accelerated the development of atherosclerosis in irradiated portions of the aorta independent of any systemic effects on plasma lipid profiles or circulating leukocytes. Further, radiation exposure resulted in a more rapid progression of advanced aortic root lesions, characterized by larger necrotic cores associated with greater numbers of apoptotic macrophages and reduced lesional collagen compared to sham-treated mice. Intima media thickening of the carotid arteries was also exacerbated. Exposure to 56 Fe ions can therefore accelerate the development of atherosclerotic lesions and promote their progression to an advanced stage characterized by compositional changes indicative of increased thrombogenicity and instability. We conclude that the potential consequences of radiation exposure for astronauts on prolonged deep-space missions are a major concern. Knowledge gained from further studies with animal models should lead to a better understanding of the pathophysiological effects of accelerated ion radiation to better estimate atherogenic risk and develop appropriate countermeasures to mitigate its damaging effects.

Chang, P. Y., Bakke, J., Orduna, J., Lin, S. and Rupa, D. Proton-Induced Genetic Damage in lacZ Transgenic Mice. Radiat. Res. 164, 481–486 (2005). The plasmid-based lacZ transgenic mouse model system was used to evaluate the mutagenic and genotoxic potential of 250 MeV/nucleon proton radiation by evaluating the frequency of micronucleated polychromatic reticulocytes in peripheral blood and bone marrow and the mutant frequencies of the lacZ reporter transgene in spleen and brain, respectively. Doses of 0.1–2 Gy produced dose- and time-dependent changes in the frequency of micronucleated polychromatic reticulocytes within 48 h, with peak induction up to sixfold above control levels. The frequency of micronucleated polychromatic reticulocytes returned to control levels within 1 week after exposure. With doses of 4 Gy, the elevation in the frequency of micronucleated polychromatic reticulocytes was delayed up to 1 week after exposure, but complete recovery to control levels was observed at 16 weeks postirradiation. Significant increase in mutant frequencies in brain tissue was observed at 8 week after proton exposure at doses as low of 0.1 Gy. Mutant frequencies in spleen increased up to twofold above spontaneous mutant frequencies at 8 weeks after exposure to 0.5–1 Gy. These effects appeared saturated at doses >1 Gy for both tissues, possibly due to elimination of damaged cells from the tissue systems. These in vivo results highlight the importance of considering tissue specificity, dose and temporal dependence when assessing radiation effects.

The combined effects of heavy-ion radiation and hyperthermia on the survival of CHO-SCI cells and its temperature-sensitive (ts) mutant tsH1 cells were studied using accelerated neon ions followed by mild heating at 41.5°C. The sequence of application of heat and high-LET radiation is significant to cell-killing effects. Heat applied to cells prior to irradiation with neon plateau ions (LET = 32 keV/μm) was less effective than heat applied immediately after irradiation. The ability of cells to synthesize new proteins plays a key role in this sequence-dependent thermal sensitization. When protein synthesis was shut down in tsH1 cells, the thermal enhancement of cell killing by high-LET radiation was the same regardless of the sequence. The thermal enhancement of radiation-induced cell killing was LET-dependent for the SC1 cells, but this was not clearly demonstrated in the tsH1 cells. Furthermore, the RBE of heated SC1 cells varied with LET and reached a maximum of >3 at 80 keV/μm. In the absence of protein synthesis, the maximum RBE value was reduced to 2.6. These results suggest that the accumulation of cellular damage caused by exposure to densely ionizing particles with increasing LETs can be potentiated with active protein synthesis during postirradiation heat treatment.

The cell-cycle-dependent capacity of synchronized G 1 -phase human T-1 cells to repair damage from either 425 MeV/u Bragg peak neon ions or 225 kVp X rays has been compared. The dose-survival response to each radiation was measured at early (1.5 h), mid (3.0 h), and late (4.5 h) times after mitotic selection. In addition the age response was characterized by irradiating cell populations at seven ages between 1.5 and 6.0 h after mitosis with single doses of either radiation. Repair of potentially lethal damage (PLDR) was evaluated in both the dose-survival and age-response experiments by holding irradiated cultures at 37°C for 6 h in PBS or PBS containing 60 μM of the DNA polymerase inhibitor 1-β-D-arabinofuranosyladenine (β-araA) before trypsinization and plating. Delayed plating showed significant PLDR at all ages irradiated with X rays, with up to 10-fold increases of survival depending on the dose and the cell age at irradiation. There was negligible PLDR after neon-ion exposures to early and mid G 1 -phase cells; only late G 1 -phase cells repaired neon damage. The β-araA treatment after X rays reduced the shoulder of the survival curves at all G 1 ages studied, and in early and mid G 1 reduced survival below the immediately plated control. β-araA similarly reduced repair of PLD where it was measurable after neon ions. Differences between low- and high-LET radiation damage and repair are discussed.

Unsynchronized exponentially growing V79 monolayer cultures were exposed to high-energy accelerated heavy-ion beams ( ${}^{12}{\rm C},{}^{20}{\rm Ne},{}^{40}{\rm Ar}$ ) at various positions in their unmodified Bragg ionization curves. High-LET particle beams proved to be much more effective in causing a ${\rm G}_{2}+{\rm M}$ block, measured by the method of flow microfluorometry, than low-LET radiation. The number of cells arrested in ${\rm G}_{2}+{\rm M}$ increased linearly with dose up to at least 75% of the maximum effect. In this domain, the RBE values were LET-dependent with a maximum ( ${\rm RBE}_{50}=8.3$ ) at about 100 keV/μm. In contrast to γ and X rays, heavy ions with high LET did not affect cell traverse through the G 1 and S phase. Though the RBE values for ${\rm G}_{2}+{\rm M}$ block are much higher than the RBEs for survival, there was a linear relationship between accumulation of cells in ${\rm G}_{2}+{\rm M}$ and cell killing.