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Exposure of human body to neutrons occurs in radiotherapy using high-energy radiations. This review summarizes knowledges related to biological effects of neutrons, including those obtained in recent projects in Japan and Europe. A study of Japanese atomic bomb survivors with recently revised dosimetry indicated very high relative biological effectiveness (RBE) of 25-80 (as point estimates) regarding cancer risk. Animal studies indicate RBE of 2-100 or even higher regarding cancer induction, which seem to have a peak around ～1 MeV. Evidence suggests that these values depend on the age and sex. Reported RBE regarding the effects on the lens of the eye is in a similar range and sometimes very high. Regarding other tissue reactions, reported RBE values range from 2-10. Experiments at the cellular level have reported RBE of 1-5 regarding cell killing, 2-20 regarding induction of mutations (with a peak at ～1 MeV), and ～1 regarding induction of DNA double strand breaks. A simulation study predicted that the RBE of induction of complex DNA breaks peaks at ～1 MeV with a value of ～17. The complex breaks produced are likely to be far less in amount than simple DNA breaks, leading to a subtle increase in the yield of total DNA breaks; however, these complex damages may be very efficient in inducing mutations and cancer. Thus, the combination of the yield of complex DNA damage and its efficacy in inducing cancer is considered to underlie the high RBE of neutrons regarding cancer risk.

Nuclear fusion technology is expected to create new energy in the future. However, nuclear fusion requires a large amount of tritium as a fuel, leading to concern about the exposure of radiation workers to tritium beta radiation. Furthermore, countermeasures for tritium-polluted water produced in decommissioning of the reactor at Fukushima Daiichi Nuclear Power Station may potentially cause health problems in radiation workers. Although, internal exposure to tritium at a low dose/low dose rate can be assumed, biological effect of tritium exposure is not negligible, because tritiated water (HTO) intake to the body via the mouth/inhalation/skin would lead to homogeneous distribution throughout the whole body. Furthermore, organically-bound tritium (OBT) stays in the body as parts of the molecules that comprise living organisms resulting in long-term exposure, and the chemical form of tritium should be considered. To evaluate the biological effect of tritium, the effect should be compared with that of other radiation types. Many studies have examined the relative biological effectiveness (RBE) of tritium. Hence, we report the RBE, which was obtained with radiation carcinogenesis classified as a stochastic effect, and serves as a reference for cancer risk. We also introduce the outline of the tritium experiment and the principle of a recently developed animal experimental system using transgenic mouse to detect the biological influence of radiation exposure at a low dose/low dose rate.

The oxygen effect was observed as 1912 by Swartz. The ratio of doses administered under hypoxic to oxic conditions needed to achieve the same biological effect is called the oxygen enhancement ratio (OER). For low-LET radiation, such as photon radiation, the OER at high doses has a value of between 2.5 and 3, and the OER has a smaller value of about 2.5 or less at lower doses. The oxygen effect is large and important in the case of low-LET radiations. Radio-chemical reactions are generally believed to be the fundamental mechanisms underlying oxygen effects. Oxygen fixes the damage produced by free radical. In the absence of oxygen, damage produced by the indirect action may be repaired. The OER has been determined for a wide variety of chemical and biologic systems with different endpoints. For high-LET radiation such as heavy-ions, oxygen effect is very small. The oxygen-in-the-track hypothesis proposed to account for this effect, suggests that cells exposed to high-LET radiation exhibit an oxygenated microenvironment around the particle track, even when they are irradiated under anoxic conditions.

PHITS is a general purpose Monte Carlo particle transport simulation code to analyze the transport in three-dimensional phase space and collisions of nearly all particles, including heavy ions, over wide energy range up to 100 GeV/u. Various quantities, such as particle fluence and deposition energies in materials, can be deduced using estimator functions "tally". Recently, a microdosimetric tally function was also developed to apply PHITS to medical physics. Owing to these features, PHITS has been used for medical applications, such as radiation therapy and protection.

The carbon ion (C-ion) beams provide unique advantageous biological and physical properties in radiotherapy (RT) for malignant tumors. C-ion beams have a high relative biological effectiveness (RBE) resulting from the high linear energy transfer (LET). In terms of their physical characteristics, C-ion beams exhibit a spread-out Bragg peak (SOBP) and make for a better dose distribution of the target volume by specified beam modulations. Between June 1994 and August 2005, a total of 2,371 patients with malignant tumors were registered in phase I/II dose-escalation studies and clinical phase II trials using C-ion beams generated at Heavy Ion Medical Accelerator in Chiba (HIMAC). In the initial dose-escalation studies, grade 3 or more late rectal complications had developed in some patients. However, the adverse effects were resolved because of the use of appropriate dose levels and modification of the radiation technique. C-ion beams can carry out hypofractionated radiotherapy with a large fraction dose and reduce the overall treatment times compared with conventional radiotherapy. They can also achieve better local tumor control even for radio-resistant tumors such as malignant melanoma, hepatocellular carcinoma and bone and soft tissue sarcomas with minimal morbidity to the normal surrounding tissues.

Heavy ion therapy using the energetic (12)C beam is successfully under way at HIMAC, Japan. The method is more advantageous than traditional radiation therapy in dose concentration owing to the Bragg peak and high relative biological effectiveness. A research study using the (11)C beam for heavy ion therapy in the future has been carried out in order to develop the capability of monitoring the dose distribution. Our group has examined the total energy absorption spectrum of the (11)C beam in a plastic scintillator. We could clearly observe the total absorption peak of (11)C in the energy spectrum and, in addition, we found a broad bump structure was associated with the peak. The bump area occupies 37% of the total spectrum and it probably affects the dose calculation for an accurate treatment planning. We elucidated the mechanism that leads to the structure of the total energy absorption spectra given by (11)C and (12)C in a block of plastic scintillator. This paper describes the method in detail and gives experimental analysis results which deal with the bump structure. We could explain the bump structure using the energy spectra caused by the fragmentation reactions.

Heavy particle (ion) beams are characterized by high relative biological effectiveness and improved dose distribution. To establish heavy ion therapy for prostate cancer, three trials have been conducted. For 247 patients with T1b-T3 cancer, carbon ion beam was irradiated 20 times/5 weeks with or without endocrine therapy. Overall and cause-specific survivals were excellent and local control was achieved in all patients except one. Grade 3 late morbidity of rectum and/or bladder/urethra was developed in 7 cases who received higher dose. Thus, total dose was decreased to 66 GyE and the radiation field was coned down during the treatment. In conclusion, carbon ion therapy is expected to exert excellent effect in the treatment of localized and locally advanced prostate cancer.

Purpose: To present the initial experience with proton beam therapy at the new Proton Medical Research Center (PMRC) of the University of Tsukuba., Materials and Methods: The new facility has a synchrotron with maximum energy of 250MeV and two rotational gantries. We treated 105 patients with 120 lesions with proton beams in the first year, beginning in September 2001. The most common lesion treated was primary liver cancer (40 lesions) followed by lung cancer, head and neck cancers, and prostate cancer. Concurrent X-ray radiotherapy was given for 38 of the 120 lesions., Results: The median follow-up period was 11 months (range, 1-19 months). Of the 105 patients, 97% had Grade 0-2 RTOG/EORTC acute morbidities, while the remaining 3% had Grade 3. Tumor response after irradiation was CR for 35% of the lesions, PR for 25%, SD for 22%, PD for 9%, and not evaluated for 9%., Conclusion: The proton beam therapy conducted at the new facility of the University of Tsukuba was safe and effective.

Even in the modern era of advanced external radiotherapy, brachytherapy is an important and useful modality of radiotherapy. In North America and Europe, it has been noted that the proportion of prostate cancer patients treated by HDR or LDR interstitial brachytherapy is rapidly increasing, as it offers several practical and theoretical advantages over external radiotherapy. HDR treatment with 192Ir remote afterloader provides an optimized dose distribution controlled by an accurate dwell time and position of 192Ir source. LDR brachytherapy is a simple, minimally invasive, and outpatient based procedure that avoids hospitalization and allows the patient an early recovery and rapid return to normal activities. It has produced good 10-year outcome with relatively low morbidity. Although in Japan this treatment was behind North America and Europe, the 125I-seed source was approved by the Japanese FDA and a rule for patient discharge was developed recently. The first case was treated in September 2003 and this treatment is expected to become an important option for early prostate cancer. Several areas of brachytherapy including treatment planning, choice of radionuclide, treatment procedure, and treatment outcome are discussed in this paper.

In microgravity, astronauts were constantly exposed to space radiation containing various kinds of radiation with a low-dose rate during long-term stays in space. It is very difficult to define the relative biological effectiveness (RBE) of space radiation under microgravity. In order to understand correct the RBE of space radiation, therefore, utilization of Centrifuge Facility is desired as a control experiment at orbit for removing other factors such as microgravity except space radiation. Here, we summarized the importance of Centrifuge Facility in the study of biological effect of space radiation.

For interpretation of results from future biological experiments in the International Space Station (ISS), radiation doses received by the biological samples must be accurately determined. This paper demonstrates that small integrating detectors, such as thermoluminescent dosemeters (TLDs) and glasses, can be used in a simple way for evaluation of biological doses from space radiation. Statistical errors (type-A uncertainty) of this method would be satisfactorily small relative to those generally observed in biological responses. Permissible levels of systematic errors (type-B uncertainty) should depend on both dosimetry purpose (most-probable or conventional evaluation) and reproducibility of the biological responses. It is expected that this method will be suitably applied to future experiments in the ISS where any instruments have to be small-scale, light-weight, physico-chemically stable and simple in handling.

The paper summarized issues, current status and the recent topics in biological research of space radiation. Researches to estimate a risk associated with space radiation exposure during a long-term manned space flight, such as in the International Space Station, is emphasized because of the large uncertainty of biological effects and a complexity of the radiation environment in space. The Issues addressed are; 1) biological effects and end points in low dose radiation, 2) biological effects under low dose rate and long-term radiation exposure, 3) modification of biological responses to radiation under space environments, 4) various aspects of biological end points vs. cellular and molecular mechanisms, 5) estimation of human risk associated with radiation exposure in space flight, 6) regulations for radiation exposure limits for space workers. The paper also summarized and introduced recent progress in space related radiation researches with various biological systems.

A preliminary experiment was made for a 137Cs gamma-ray irradiation system, which was designed for the simulation-irradiation of gamma-rays when studying the biological effects of internal exposure. The dose rate of the system decreased according to the inverse square of the distance from the source. In simulation-irradiation, the difference was less than 2% in the integral absorbed dose between the measurement and the calculation. Consequently, it became evident that the present simulation fulfilled its function satisfactorily.

This study was performed to determine the biological effect of carbon beams on 13 human tumor cells, in comparison with 200 KVp X-rays. Carbon beams were generated by the Riken Ring Cyclotron. The RBE (relative biological effectiveness) values were distributed from 1.46 to 2.20 for LET of 20 ke V/micron, and 2.29-3.54 for 80 keV/micron. The RBEs were increased in all cell lines as the LET of carbon beams was increased from 20 to 80 keV/micron. There was no significant difference in radiosensitivity between cells from adenocarcinoma and those from squamous cell carcinoma. The relationship between the radiosensitivity of cells to X-rays and RBE was analyzed, but no significant correlation was suggested. Several survival curves of 20-40 keV/micron carbon beam irradiation showed the initial shoulders and the recovery ratios between two split doses were determined. Recovery was observed for LET of 20 keV/micron but not for that of 40 keV/micron. Furthermore, recovery ratios were 1.0-1.8, smaller than those for X-rays (1.5-2.4).

The need of radiation therapy in cancer treatment is increasing, however, the dose of radiation is limited by its late effects on normal tissues. Hyperfractionated radiotherapy was applied to patients with various kinds of carcinomas in the 1980s, expecting to improve tumor control rates. Some reports showed that the total radiation dose could be increased without increasing late radiation damage by using hyperfractionated radiotherapy. We calculated the early and late biologically effective doses (BED) for conventional and hyperfractionated radiotherapy to predict the early and late radiation damage based on the linear-quadratic model (L-Q model). Setting the values of the alpha/beta ratio and t1/2 (half time repair) in the L-Q model is still controversial, and few reports deal with t1/2. Assuming t1/2 = 0.5 hour, the total radiation dose can be up to 71 Gy by hyperfractionated schedule (1.2Gy/fr. 2 times/day) without increasing the late BED of conventional schedule (2Gy/day, total 60Gy). However, the late BED should be increased in tissues with a larger t1/2 value, even if applying the same hyperfractionated schedule. Thus, it is not recommended to apply the same hyperfractionated protocol to all organs.

Intracavitary irradiation therapy for carcinoma of the uterine cervix used with high or low dose rate irradiation is fractionated in Japan. The optimal treatment dose is determined according to the biological effect on both diseased and healthy tissues. The equations of modified NSD and TDF biological equivalents were recalculated from Arai's clinical data, which were used to examine the optimal time-dose-fractionation relationship for high and low dose rate intracavitary irradiation on squamous cell carcinoma of the cervix uteri. The optimal time-dose-fractionation relationship at point A is expressed as follows: D = NSD N0.26 T0.06 where NSD is 17.75 get for high dose rate and 31.78 get for low dose rate. TDF = K n d1.47 x-0.09 where K is 1.46 for high dose rate and 0.62 for low dose rate. The range of the optimal total dose to point A given by one fraction per week was 30.7 Gy for 4 fractions and 38.3 Gy for 8 fractions in high dose rate irradiation. In the case of low dose rate irradiation, the optimal total dose given by one fraction per week and the dose rate of 75.0 cGy/h was 55.0 Gy for 4 fractions. The maximum dose difference between our result and Arai's was about +/- 10%. The dose modification ratio for high dose rate and low dose rate is 1.79.

Pulsed brachytherapy is starting to be used for patients with various kinds of carcinoma, in the expectation of fair treatment results without increasing the late radiation-induced damage. We calculated the early and late biologically effective dose (BED) of this modality to predict early and late radiation damage based on the linear-quadratic model (L-Q model). The way to set the values of alpha/beta and mu (factor of repair) in the L-Q model remains controversial. The value of alpha/beta has been fixed at 3Gy for the late effect and 10Gy for the early effect in recent studies. In this study, we applied these alpha/beta values to calculate the BED, however, the effects of its alteration ranged from 0.5Gy through 15Gy on BED were also analysed. We assumed mu = 0.5 (T1/2 = 1-2 hours) in this study, but we also tried to examine the effects of its variation. Our results indicate that pulsed brachytherapy is a safe treatment procedure even if the dose-rate ranges from 1Gy/hr through 100Gy/hr, but the fractionation number should be increased when using a very high dose rate. Pulsed brachytherapy should be applied cautiously for tissues with a small mu value, such as the spinal cord, because an extremely high late BED would be expected in such cases.

The inactivation of hematopoiesis and survival of mice have been used in determining the relative biological effectiveness (RBE) of heavy charged particles of carbon 12 generated by Riken ring-cyclotron. Whole bodies of anesthetized mice were exposed to accelerator-generated carbon 12 of 135 MeV/u or X-rays of 200 kVp in graded doses. At about 5 hours after exposure, exogenous spleen colonies (CFU-S), granulocyte-macrophage progenitor cells (GM-CFC) and megakaryocyte progenitor cells (Meg-CFC) were assayed to determine dose relationships, and then D0 doses were determined. The inactivation of blood cells and lethality of mice (LD50/30) were also monitored for 30 days after irradiation. The RBE values of the 135 MeV/u carbon beam in terms of CFU-S were 1.68 for marrow and 1.41 for spleen, for GM-CFC they were 1.56 for marrow and 3.29 for spleen, for Meg-CFC they were 1.25 for marrow and 3.73 for spleen, while they were about 1.0 for erythrocytes, leukocytes and thrombocytes in mice irradiated with 2 Gy. However, the RBE values of the carbon beam were 1.32 for LD50/30.

This study was performed to determine the biological effect of carbon beams on mammalian cells (HeLa, RMUG), in comparison with 200 KVp X-rays. Carbon beams were generated by the Riken Ring Cyclotron. An increase in the relative biological effect (RBE) was observed in both cell lines as the LET of the carbon beam increased between 20 and 80 keV/microns. The RBE depended on the size of the irradiation dose at the higher LET region, and increasing the dose from 0.8 Gy to 3.2 Gy decreased the RBE from 2.9 to 2.7. The survival curves of cells irradiated with 20 keV/microns carbon beams showed an initial shoulder. When RMUG was irradiated at 4 Gy with 200 KVp X-rays, the recovery rate between two split doses (6 hour interval) was 1.7. RMUG irradiated with 20 keV/microns carbon beams (4 Gy) showed a recovery rate of 1.4. Recovery between split dose irradiation was observed with both X-ray and carbon beam irradiation; however, the recovery rate was lower with carbon beams. Cells irradiated with LET higher than 40 keV/microns did not show recovery between split doses.