The irradiation of fetuses at the late period of organogenesis has been known to induce a dramatic increase in malformations. The mechanisms involved, however, have remained unclear for a long time. Using the mouse limb bud system, we first found that radiation-induced apoptosis is involved in the malformation, namely, radiation-induced apoptosis in the predigital regions of embryonic limb buds is responsible for digital defects in mice. An examination of embryonic C57BL/6J mice with different p53 (trp53) status enabled us to further find that susceptibility to radiation-induced apoptosis in the predigital regions and digital defects depend on both the p53 status and the radiation dose; p53 wild-type mice appeared to be the most sensitive, while p53 knockout mice were the most resistant. These results indicate that p53-dependent apoptosis mediates radiation-induced digital defects in the later organogenesis period. The existence of a radioadaptive response in embryonic mice, which has not been reported so far, was found by irradiating embryos with either 5 cGy or 30 cGy on embryonic day 11 prior to a challenging irradiation at 3 Gy on embryonic day 12. p53-heterozygous embryos did not show the radioadaptive response, indicating the involvement of p53 in the radioadaptive response in embryogenesis.

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Ionizing radiation induces a wide variety of modifications to purine and pyrimidine residues. The exocyclic methyl group of thymine does not escape oxidative damage. Any 5-hydroperoxymethyluracil produced is spontaneously decomposed to form 5-formyluracil (5-foU) and 5-hydroxymethyluracil. The yield of 5-foU by ionizing radiation is roughly the same as that of 8-oxoguanine. 5-foU is a potential mutagenic damage in vitro and in vivo. Mammalian cells have an activity that removes 5-foU from X-irradiated DNA. Furthermore, the Nth, Nei and MutM proteins of E. coli have DNA glycosylase/AP lyase activities that recognize and remove 5-foU in DNA. The mutation frequency of 5-foU-containing plasmid increases when replicated in E. coli nthneimutMalkA. Single mutations in the nth, nei or mutM gene do not affect the mutation frequency. Therefore, these gene products are likely backup enzymes used to repair 5-foU in DNA. Furthermore, the human hNTH1 enzyme, a homologue of E. coli Nth, is found to have similar DNA glycosylase activity to that of the Nth protein.

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A crucial task in radiotherapy is dose conformation to the prescribed target volume whilst sparing the surounding healthy tissue around as much as possible. One of the best approaches so far is active dose shaping in three dimensions using scanned beams of charged particles, like carbon ions. Besides their inverse dose profile and minimal lateral scattering, carbon ions have the advantage that their RBEs increase towards the end of their range. An active beam-delivery system for intensity-modulated carbon-ion beams has been operational at GSI since December, 1997. In order to ensure dose conformation, inverse treatment planning with respect to the biologically effective dose distribution must be applied. A typical patient irradiation comprises two singly optimized opposing fields. This paper discusses the superposition of biologically effective dose distributions for radiotherapy with ¹²C ions, which is non-trivial due to the nonlinear nature of the dose response of biological systems. Sum rules for the nonlinear addition of singly optimized fields are derived. This method is being used clinically, and has been successfully applied to more than 50 patients.

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A beta-ray survey was carried out on concrete walls of the boundary and buildings after a criticality accident at a factory of JCO Co. Ltd. at Tokai-mura. A remarkable distribution of beta counts was observed on the walls depending on the complex internal and external structures of buildings surrounding a precipitation vessel containing uranium 23 days after the accident. The directional distribution function, based on the beta counts on the walls, was consistent with data concerning the neutron dose rate measured in several directions during the accident, suggesting an anisotropic neutron distribution to the residential area.

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The effectiveness of an Electronic Personal Dosemeter (Siemens EPD) for cosmic-radiation dosimetry at aviation altitudes was examined on eight international flights between March and September, 1998. The EPD values (H_epd) of the dose equivalent from penetrating radiation, H_p(10), were assumed to be almost the same as the electron absorbed doses during those flights. Based on the compositions of cosmic radiation in the atmosphere and the 1977 ICRP recommendation, an empirical equation to conservatively estimate the personal dose equivalent (H_p77) at a depth of 5 cm was derived as H_p77 =3.1×H_epd. The personal dose equivalent (H_p90) based on the 1990 ICRP recommendation was given by H_p90=4.6×H _epd; the conservative feature of H_p90 was confirmed in a comparison with the calculated effective doses by means of the CARI-6 code. It is thus expected that the EPD will be effectively used for radiation protection dosimetry on selected international flights.

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The stability of glow peaks in ⁶LiF:Mg,Ti (TLD-600) exposed to a high-energy Fe-ion beam was examined in comparison to ¹³⁷Cs γ-ray irradiation under changing annealing conditions. The peak areas induced by the Fe ions were much smaller than those by γ-rays. The sizes and positions of peaks 3-5 in Fe-ion irradiated samples were hardly changed after post-annealing at 100°C×30 min, regardless of the pre-annealing conditions (fast quenching or subsequent pre-annealing at 100°C×2h). Whereas, the peaks in γ-ray irradiated samples were notably affected by post-annealing; the peak positions and peak-area sizes changed in different ways depending on the pre-annealing conditions. The effects of post-annealing on peak 6 were identical for Fe ions and γ-rays. These facts suggest that peaks 3-5 in TLD-600 comprised both stable and unstable luminescent centers, and that the latter part would be easily depleted in highly dense ionization.

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A therapy-dedicated cyclotron was installed in the National Cancer Center Hospital East (NCCHE) at Kashiwa in 1997. Prior to the start of clinical use, we investigated the biological effectiveness of therapeutic proton beams for cell lethality. The proton beams accelerated up to 235 MeV were horizontally extracted from the cyclotron, and scattered by a bar-ridge filter to produce a Spread-Out-Bragg-Peak (SOBP) of 10-cm width. The biological systems used here were mouse intestinal crypt cells and three in vitro cell lines, including SCC61 human squamous cell carcinoma, NB1RGB human fibroblasts and V79 Chinese hamster cells. The dose responses after irradiation at either the entrance plateau or the middle portion of SOBP were compared with those after linac 6 MV X-ray irradiation. The fit of a linear quadratic model to survival curves showed that proton irradiation increased the α value of SCC61 and the β value of V79 cells with a least change for α/β ratio of NB1RGB cells. The isoeffect dose that reduces either cell survivals to 10% or mouse jejunum crypts to 10 per circumference was termed D₁₀. The relative biological effectiveness (RBE) of protons obtained by comparing the D₁₀ values between protons and X-rays ranged from 0.9 to 1.2. The depth distribution of cell lethality was measured by replating V79 cells after irradiation from a "cell stack chamber" that received a single dose of 7 Gy at the middle position of SOBP. The thus-obtained cell survivals at various depths coincided well with the estimated survivals, but tended to decrease at the distal end of SOBP . We conclude that an RBE of 1.1 would be appropriate for 235 MeV proton beams at the NCCHE.

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This study demonstrates that cells adapted to ionizing radiation developed reduced initial DNA damage when compared to non-adapted cells. The results were obtained by subjecting in vitro irradiated whole blood from 10 healthy volunteers (including 2 A-bomb survivors carrying 1.5-2 Gy in vivo exposure) in an unstimulated condition (G₀) using the comet as+say. The intensity of DNA damage was assessed by computing the `tail moment'. Adaptive response (AR) was noticed in only donor 3, as indicated by reduced tail moment when the blood samples received priming+challenging doses over a 4 h interval. The priming dose was either 0.01 Gy ¹³⁷Cs γ-rays or 0.0025 Gy ²⁵²Cf neutrons. The delivered challenging dose was either 1 Gy ⁶⁰Co g-rays or 0.25 Gy ²⁵²Cf neutrons. The irradiation was conducted using the HIRRAC facility. A prior exposure to 0.0025 Gy ²⁵²Cf neutrons nullified the excess tail moment caused by 0.25 Gy neutrons given during a 4 h gap. In a similar way, 0.01 Gy ¹³⁷Cs γ-rays offered a cross-adaptive response to the neutron challenging dose. The tail moment of A-bomb survivors after in vitro irradiation was less than that of the age-matched control and, at the same time, was not influenced by the priming dose. An altered subset and the immunological status of blood after A-bomb exposure were cited as possible factors. Because AR can affect the outcome of RBE, its individual variability only emphasizes the need to have individual biodosimetry for better risk assessment, especially in planning for a long space voyage.

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