National Institute Of Radiological Sciences Research Articles

Creation, evolution, and future challenges of ion beam therapy from a medical physicist's viewpoint (Part 3): Chapter 3. Clinical research, Chapter 4. Future challenges, Chapter 5. Discussion, and Conclusion.

Clinical studies of ion beam therapy have been performed at the Lawrence Berkeley Laboratory (LBL), National Institute of Radiological Sciences (NIRS), Gesellschaft für Schwerionenforschung (GSI), and Deutsches Krebsforschungszentrum (DKFZ), in addition to the development of equipment, biophysical models, and treatment planning systems. Although cancers, including brain tumors and pancreatic cancer, have been treated with the Bevalac's neon-ion beam at the LBL (where the first clinical research was conducted), insufficient results were obtained owing to the limited availability of neon-ion beams and immaturity of related technologies. However, the 184-Inch Cyclotron's helium-ion beam yielded promising results for chordomas and chondrosarcomas at the base of the skull. Using carbon-ion beams, NIRS has conducted clinical trials for the treatment of common cancers for which radiotherapy is indicated. Because better results than X-ray therapy results have been obtained for lung, liver, pancreas, and prostate cancers, as well as pelvic recurrences of rectal cancer, the Japanese government recently approved the use of public medical insurance for carbon-ion radiotherapy, except for lung cancer. GSI obtained better results than LBL for bone and soft tissue tumors, owing to dose enhancement enabled by scanning irradiation. In addition, DKFZ compared treatment results of proton and carbon-ion radiotherapy for these tumors. This article summarizes a series of articles (Parts 1-3) and describes future issues of immune ion beam therapy and linear energy transfer optimization.

Carbon-ion radiotherapy (CIRT) as treatment of pancreatic cancer at HIT: initial radiation plan analysis of the prospective phase II PACK-study

PurposeTo analyze the dose objectives and constraints applied at the prospective phase II PACK-study at Heidelberg ion therapy center (HIT) for different radiobiological models. MethodsTreatment plans of 14 patients from the PACK-study were analyzed and recomputed in terms of physical, biological dose and dose-averaged linear energy transfer (LETd). Both LEM-I (local effect model 1) and the adapted NIRS-MKM (microdosimetric kinetic model), were used for relative biological effectiveness (RBE)-weighted dose calculations (DBio|HIT and DBio|NIRS). A new constraint to the gastrointestinal (GI) tract was derived from the National Institute of Radiological Science (NIRS) clinical experience and considered for plan reoptimization (DBio|NIRS-const_48Gy and DBio|NIRS-const_50.4Gy). The Lyman-Kutcher-Burman (LKB) model of Normal Tissue Complication Probability (NTCP) for GI toxicity endpoints was computed. Furthermore, the computed LETd distribution was evaluated and correlated with Local Control (LC). ResultsOnly two patients showed a LETd98% in the GTV greater than 44 keV/μm. A HIT-dose constraint to the GI of D2cm3=48.6GyRBEHIT was derived from the NIRS experience, in alternative to the standard at HIT Dmax = 45.6 GyRBEHIT. In comparison with the original DBio|HIT,DBio|NIRS-const_48GyandDBio|NIRS-const_50.4Gy resulted in an increase in the ITV’s D98% of 8.7% and 11.3%. The NTCP calculation resulted in a probability for gastrointestinal bleeding of 4.5%, 12.3% and 13.0%, for DBio|NIRS, DBio|NIRS-const_48Gy and DBio|NIRS-const_50.4Gy, respectively. ConclusionThe results indicate that the current standards applied at HIT for CIRT closely align with the Japanese experience. However, to enhance tumor coverage, a more relaxed constraint on the GI tract may be considered. As the PACK-trial progresses, further analyses of various clinical endpoints are anticipated.

Creation, evolution, and future challenges of ion beam therapy from a medical physicist’s viewpoint (Part 2). Chapter 2. Biophysical model, treatment planning system and image guided radiotherapy

When an ion beam penetrates deeply into the body, its kinetic energy decreases, and its biological effect increases due to the change of the beam quality. To give a uniform biological effect to the target, it is necessary to reduce the absorbed dose with the depth. A bio-physical model estimating the relationship between ion beam quality and biological effect is necessary to determine the relative biological effectiveness (RBE) of the ion beam that changes with depth. For this reason, Lawrence Berkeley Laboratory, National Institute of Radiological Sciences (NIRS) and GSI have each developed their own model at the starting of the ion beam therapy. Also, NIRS developed a new model at the starting of the scanning irradiation. Although the Local Effect Model (LEM) at the GSI and the modified Microdosimetric Kinetic Model (MKM) at the NIRS, the both are currently used, can similarly predict radiation quality-induced changes in surviving fraction of cultured cell, the clinical RBE-weighted doses for the same absorbed dose are different. This is because the LEM uses X-rays as a reference for clinical RBE, whereas the modified MKM uses carbon ion beam as a reference and multiplies it by a clinical factor of 2.41. Therefore, both are converted through the absorbed dose. In PART 2, I will describe the development of such a bio-physical model, as well as the birth and evolution of a treatment planning system and image guided radiotherapy.

No evidence of thyroid consequences in seven nuclear workers at the Tokyo Electric Power Company Fukushima Daiichi Nuclear Power Plant accident: 10-year follow-up results of thyroid status.

Seven emergency nuclear workers, who had internal exposure due to an intake of radionuclides, mainly I-131, during the emergency response operation in March 2011, after the accident at the Tokyo Electric Power Company (TEPCO) Fukushima Daiichi Nuclear Power Plant (FDNPP), visited the National Institute of Radiological Sciences (NIRS) outpatient clinic for medical evaluation. They were followed up after their first visit for 10 years. The estimated committed equivalent doses to the thyroid were distributed between 3.2 to 1.2 × 10Sv. This group thought to be received highest exposure at the accident. None of the workers had symptoms related to abnormal thyroid function. The examinations, including thyroid function tests and ultrasound, detected no abnormalities related to radiation exposure. However, there is a need for continuous monitoring of their thyroid status for longer periods in the future.

Creation, evolution, and future challenges of ion beam therapy from a medical physicist's viewpoint (part 1). Introduction and Chapter 1. accelerator and beam delivery system.

Radiation therapy for cancer using the Bragg peak of an ion beam has been making steady progress after being proposed by Robert Wilson in 1946. At the end of 2020, 12 dedicated treatment devices existed in operation worldwide, and approximately 40,000 patients have been treated with ion beams (mostly carbon ions). To date, ion beam therapy is superior to other treatments for rare cancers in the head and neck as well as bone and soft tissues; however, most recently, evidence submitted in Japan for the 2022 revision of public health insurance shows that ion beam therapy outperforms photon therapy for intractable common cancers such as pancreatic cancer and liver cancer. This may greatly expand its indications. Lawrence Berkeley Laboratory in the United States started research of ion beam therapy, National Institute of Radiological Sciences in Japan built the first dedicated device Heavy Ion Accelerator in Chiba and started systematic clinical research, and GSI in Germany developed the scanning irradiation method and rotating gantry for the first time. This paper presents the history and future challenges of ion beam therapy in three fields: accelerator and beam delivery system, physical/biological model and treatment planning system, and clinical research. This study is divided into three parts describing the achievements and roles of the three laboratories. In Part 1, accelerator and beam delivery system are described.

Special radionuclide production activities – recent developments at QST and throughout Japan

Abstract National Institutes for Quantum Science and Technology (QST), formerly known as the National Institute of Radiological Sciences (NIRS), has been engaged in work on radiopharmaceutical science using cyclotrons since 1974. Eight pioneering researchers founded the basis of this field of research at NIRS, and to the present, many researchers and technicians have accumulated both scientific and technical achievements, as well as inherited the spirit of research. Besides, in recent years, we have developed production systems with AVF-930 cyclotron for various ‘non-standard’ radioisotopes applied in both diagnosis and therapy. Here, we review the past 50 years of our activities on radioisotope and radiopharmaceutical development, as well as more recent activities.

Effects of Ionizing Radiation and Long-Term Storage on Hydrated vs. Dried Cell Samples of Extremophilic Microorganisms.

A main factor hampering life in space is represented by high atomic number nuclei and energy (HZE) ions that constitute about 1% of the galactic cosmic rays. In the frame of the “STARLIFE” project, we accessed the Heavy Ion Medical Accelerator (HIMAC) facility of the National Institute of Radiological Sciences (NIRS) in Chiba, Japan. By means of this facility, the extremophilic species Haloterrigena hispanica and Parageobacillus thermantarcticus were irradiated with high LET ions (i.e., Fe, Ar, and He ions) at doses corresponding to long permanence in the space environment. The survivability of HZE-treated cells depended upon either the storage time and the hydration state during irradiation; indeed, dry samples were shown to be more resistant than hydrated ones. With particular regard to spores of the species P. thermantarcticus, they were the most resistant to irradiation in a water medium: an analysis of the changes in their biochemical fingerprinting during irradiation showed that, below the survivability threshold, the spores undergo to a germination-like process, while for higher doses, inactivation takes place as a consequence of the concomitant release of the core’s content and a loss of integrity of the main cellular components. Overall, the results reported here suggest that the selected extremophilic microorganisms could serve as biological model for space simulation and/or real space condition exposure, since they showed good resistance to ionizing radiation exposure and were able to resume cellular growth after long-term storage.

Proton radiation hardness of x-ray SOI pixel sensors with pinned depleted diode structure

X-ray silicon-on-insulator (SOI) pixel sensors, “XRPIX,” are being developed for the next-generation x-ray astronomical satellite, “FORCE.” The XRPIX is fabricated with the SOI technology, which makes it possible to integrate a high-resistivity Si sensor and a low-resistivity Si complementary metal oxide semiconductor (CMOS) circuit. The CMOS circuit in each pixel is equipped with a trigger function, allowing us to read out outputs only from the pixels with x-ray signals at the timing of x-ray detection. This function thus realizes high throughput and high time resolution, which enables to employ anti-coincidence technique for background rejection. A new series of XRPIX named XRPIX6E developed with a pinned depleted diode (PDD) structure improves spectral performance by suppressing the interference between the sensor and circuit layers. When semiconductor x-ray sensors are used in space, their spectral performance is generally degraded owing to the radiation damage caused by high-energy protons. Therefore, before using an XRPIX in space, it is necessary to evaluate the extent of degradation of its spectral performance by radiation damage. Thus, we performed a proton irradiation experiment for XRPIX6E for the first time at Heavy Ion Medical Accelerator in Chiba in the National Institute of Radiological Sciences. We irradiated XRPIX6E with high-energy protons with a total dose of up to 40 krad, equivalent to 400 years of irradiation in orbit. The 40-krad irradiation degraded the energy resolution of XRPIX6E by 25 ± 3 % , yielding an energy resolution of 260.1 ± 5.6 eV at the full-width half maximum for 5.9 keV X-rays. However, the value satisfies the requirement for FORCE, 300 eV at 6 keV, even after the irradiation. It was also found that the PDD XRPIX has enhanced radiation hardness compared to previous XRPIX devices. In addition, we investigated the degradation of the energy resolution; it was shown that the degradation would be due to increasing energy-independent components, e.g., readout noise.

Ion therapy guideline (Version 2020)

Ion therapy guideline (Version 2020)

Carbon Ion Dose Constraints in the Head and Neck and Skull Base: Review of MedAustron Institutional Protocols.

BackgroundDose constraints are of paramount importance for the outcome of any radiotherapy treatment. In this article, we report dose-volume constraints as well as currently used fractionation schedules for carbon ion radiotherapy as applied in MedAustron (Wiener Neustadt, Austria).Materials and MethodsFor fractionation schedules, both German and Japanese regimes were used. From the clinical experience of National Institute of Radiological Sciences (Chiba, Japan) and Heidelberg Ion Therapy (Heidelberg, Germany; formerly GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany) and the work by colleagues in Centro Nazionale Adroterapia Oncologica (Pavia, Italy) recalculating the dose from the microdosimetric kinetic model to the local effect model, we have set the dose constraints for critical organs of the head and neck area. Where no clinical data was available, an educated guess was made, based on data available from photon and proton series.ResultsWe report the constraints for the optic nerve and chiasm, brainstem, spinal cord, cochlea, brain parenchyma, salivary gland, eye and adnexa, and mandibular/maxillary bone; constraints are grouped based on a fractionation scheme (German versus Japanese) and the risk of toxicity (safe, low to middle, and middle to high).ConclusionWe think validation of dose constraints should present a relevant part of the activity of any carbon ion radiotherapy facility, and we anticipate future multicentric, joint evaluations.

Protective Effects of Amino Acids on Plasmid DNA Damage Induced by Therapeutic Carbon Ions.

Radioprotectors with few side effects are useful for carbon-ion therapy, which directly induces clustering damage in DNA. With the aim of finding the most effective radioprotector, we investigated the effects of selected amino acids which might have chemical DNA-repair functions against therapeutic carbon ions. In the current study, we employed five amino acids: tryptophan (Trp), cysteine (Cys), methionine (Met), valine (Val) and alanine (Ala). Samples of supercoiled pBR322 plasmid DNA with a 17 mM amino acid were prepared in TE buffer (10 mM Tris, 1 mM ethylenediaminetetraacetic acid, pH 7.5). Phosphate buffered saline (PBS) was also used in assays of the 0.17 mM amino acid. The samples were irradiated with carbon-ion beams (290 MeV/u) on 6 cm spread-out Bragg peak at the National Institute of Radiological Sciences and Heavy Ion Medical Accelerator in Chiba, Japan. Breaks in the DNA were detected as changes in the plasmids and quantified by subsequent electrophoresis on agarose gels. DNA damage yields and protection factors for each amino acid were calculated as ratios relative to reagent-free controls. Trp and Cys showed radioprotective effects against plasmid DNA damage induced by carbon-ion beam, both in PBS and TE buffer, comparable to those of Met. The double-strand break (DSB) yields and protective effects of Trp were comparable to those of Cys. The yields of both single-strand breaks and DSBs correlated with the scavenging capacity of hydroxyl radicals (rate constant for scavenging hydroxyl radicals multiplied by the amino acid concentration) in bulk solution. These data indicate that the radioprotective effects of amino acids against plasmid DNA damage induced by carbon ions could be explained primarily by the scavenging capacity of hydroxyl radicals. These findings suggest that some amino acids, such as Trp, Cys and Met, have good potential as radioprotectors for preventing DNA damage in normal tissues in carbon-ion therapy.

Technical Note: validation of a material assignment method for a retrospective study of carbon-ion radiotherapy using Monte Carlo simulation.

We propose a two-step method to converse human tissue materials from patient computed tomography (CT) images, which is required in dose reconstructions for a retrospective study of carbon-ion radiotherapy (CIRT) using Monte Carlo (MC) simulation. The first step was to assign the standard tissues of the International Commission on Radiological Protection reference phantoms according to the CT-number. The second step was to determine the mass density of each material based on the relationship between CT-number and stopping power ratio (Hounsfield unit [HU]-SPR) registered in treatment planning system (TPS). Direct implementation of the well-calibrated HU-SPR curve allows the reproduction of previous clinical treatments recorded in TPS without uncertainty due to a mismatch of the CT scanner or scanning conditions, whereas MC simulation with realistic human tissue materials can fulfill the out-of-field dose, which was missing in the record. To validate our proposed method, depth-dose distributions in the homogenous and heterogeneous phantoms irradiated by a 400 MeV/u carbon beam with an 8 cm spread-out Bragg peak (SOBP) were computed by the MC simulation in combination with the proposed methods and compared with those of TPS. Good agreement of the depth-dose distributions between the TPS and MC simulation (within a 1% discrepancy in range) was obtained for different materials. In contrast, fluence distributions of secondary particles revealed the necessity of MC simulation using realistic human tissue. The proposed material assignment method will be used for a retrospective study using previous clinical data of CIRT at the National Institute of Radiological Sciences (NIRS).

Application of lung substitute material as ripple filter for multi-ion therapy with helium-, carbon-, oxygen-, and neon-ion beams

A development project for hypo-fractionated multi-ion therapy has been initiated at the National Institute of Radiological Sciences in Japan. In the treatment, helium, carbon, oxygen, and neon ions will be used as primary beams with pencil beam scanning. A ripple filter (RiFi), consisting of a thin plastic or aluminum plate with a fine periodic ridge and groove structure, has been used to broaden the Bragg peak of heavy-ion beams in the beam direction. To sufficiently broaden the Bragg peak of helium-, carbon-, oxygen-, and neon-ion beams with suppressed lateral scattering and surface dose inhomogeneity, in this study, we tested a plate made of a lung substitute material, Gammex LN300, as the RiFi. The planar integrated dose distribution of a 183.5 MeV u−1 neon-ion beam was measured behind a 3 cm thick LN300 plate in water. The Bragg peak of the pristine beam was broadened following the normal distribution with the standard deviation σ value of 1.29 mm, while the range of the beam was reduced by 8.8 mm by the plate. To verify the LN300 performance as the RiFi in multi-ion therapy, we measured the pencil beam data of helium-, carbon-, oxygen- and neon-ion beams penetrating the 3 cm thick LN300 plate. The data were then modeled and used in a treatment planning system to achieve a uniform 10% survival of human undifferentiated carcinoma cells within a cuboid target by the beam for each of the different ion species. The measured survival fractions were reasonably reproduced by the planned ones for all the ion species. No surface dose inhomogeneity was observed for any ion species even when the plate was placed close to the phantom surface. The plate made of lung substitute material, Gammex LN300, is applicable as the RiFi in multi-ion therapy with helium-, carbon-, oxygen- and neon-ion beams.

Charged Particle Therapy Technologies Originated in Japan

A charged particle therapy was proposed by Robert R. Wilson in 1946 and a clinical study of proton radiotherapy had been started at Lawrence Berkeley National Laboratory in 1954. Clinical studies have been promoted mainly in the United States and Europe. However, in Japan as well, the University of Tsukuba (KEK Campus) and the National Institute of Radiological Sciences (NIRS) started proton radiotherapy around 1980, and NIRS started carbon-ion radiotherapy in 1994. Following pioneering clinical studies, now in Japan, many proton and carbon-ion radiotherapy facilities are in operation, and some vendors are supplying equipment. Among them, charged particle therapy technologies originating in Japan have been developed, such as a respiratory-gated irradiation technology, a spot scanning irradiation technology, and a clinical dose design for ion radiotherapy. I look back on them and discuss the future direction of research and development of the charged particle therapy.

A validated Geant4 model of a whole-body PET scanner with four-layer DOI detectors

The purpose of this work is to develop a validated Geant4 simulation model of a whole-body prototype PET scanner constructed from the four-layer depth-of-interaction detectors developed at the National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Japan. The simulation model emulates the behaviour of the unique depth of interaction sensing capability of the scanner without needing to directly simulate optical photon transport in the scintillator and photodetector modules. The model was validated by evaluating and comparing performance metrics from the NEMA NU 2-2012 protocol on both the simulated and physical scanner, including spatial resolution, sensitivity, scatter fraction, noise equivalent count rates and image quality. The results show that the average sensitivities of the scanner in the field-of-view were 5.9 cps kBq−1 and 6.0 cps kBq−1 for experiment and simulation, respectively. The average spatial resolutions measured for point sources placed at several radial offsets were 5.2± 0.7 mm and 5.0± 0.8 mm FWHM for experiment and simulation, respectively. The peak NECR was 22.9 kcps at 7.4 kBq ml−1 for the experiment, while the NECR obtained via simulation was 23.3 kcps at the same activity. The scatter fractions were 44% and 41.3% for the experiment and simulation, respectively. Contrast recovery estimates performed in different regions of a simulated image quality phantom matched the experimental results with an average error of -8.7% and +3.4% for hot and cold lesions, respectively. The results demonstrate that the developed Geant4 model reliably reproduces the key NEMA NU 2-2012 performance metrics evaluated on the prototype PET scanner. A simplified version of the model is included as an advanced example in Geant4 version 10.5.

Brainstem NTCP and Dose Constraints for Carbon Ion RT—Application and Translation From Japanese to European RBE-Weighted Dose

Background and PurposeThe Italian National Center of Oncological Hadrontherapy (CNAO) has applied dose constraints for carbon ion RT (CIRT) as defined by Japan’s National Institute of Radiological Sciences (NIRS). However, these institutions use different models to predict the relative biological effectiveness (RBE). CNAO applies the Local Effect Model I (LEM I), which in most clinical situations predicts higher RBE than NIRS’s Microdosimetric Kinetic Model (MKM). Equal constraints therefore become more restrictive at CNAO. Tolerance doses for the brainstem have not been validated for LEM I-weighted dose (D LEM I). However, brainstem constraints and a Normal Tissue Complication Probability (NTCP) model were recently reported for MKM-weighted dose (D MKM), showing that a constraint relaxation to D MKM|0.7 cm3 <30 Gy (RBE) and D MKM|0.1 cm3 <40 Gy (RBE) was feasible. The aim of this work was to evaluate the brainstem NTCP associated with CNAO’s current clinical practice and to propose new brainstem constraints for LEM I-optimized CIRT at CNAO.Material and MethodsWe reproduced the absorbed dose of 30 representative patient treatment plans from CNAO. Subsequently, we calculated both D LEM I and D MKM, and the relationship between D MKM and D LEM I for various brainstem dose metrics was analyzed. Furthermore, the NTCP model developed for D MKM was applied to estimate the NTCPs of the delivered plans.ResultsThe translation of CNAO treatment plans to D MKM confirmed that the former CNAO constraints were conservative compared with D MKM constraints. Estimated NTCPs were 0% for all but one case, in which the NTCP was 2%. The relationship D MKM/D LEM I could be described by a quadratic regression model which revealed that the validated D MKM constraints corresponded to D LEM I|0.7 cm3 <41 Gy (RBE) (95% CI, 38–44 Gy (RBE)) and D LEM I|0.1 cm3 <49 Gy (RBE) (95% CI, 46–52 Gy (RBE)).ConclusionOur study demonstrates that RBE-weighted dose translation is of crucial importance in order to exchange experience and thus harmonize CIRT treatments globally. To mitigate uncertainties involved, we propose to use the lower bound of the 95% CI of the translation estimates, i.e., D LEM I|0.7 cm3 <38 Gy (RBE) and D LEM I|0.1 cm3 <46 Gy (RBE) as brainstem dose constraints for 16 fraction CIRT treatments optimized with LEM I.

Advancement of microdosimetric kinetic model in heavy-ion radiotherapy

To date, more than 11,000 cancer patients have been treated with therapeutic carbon-ion beams at the National Institute of Radiological Sciences (NIRS). In the treatment planning system, the biological effectiveness of the therapeutic carbon-ion beams has been predicted based on the microdosimetric kinetic (MK) model. The MK model has a variety of applications. For instance, it can be used to predict the biological effectiveness of therapeutic carbon-ion beams under protracted irradiations as well as under hypoxic conditions. Recently, we have updated the MK model to a stochastic microdosimetric kinetic (SMK) model for a new research project about hypo-fractionated multi-ion radiotherapy, referred to as a “Quantum Scalpel”. This report overviews advancement of the MK model in heavy-ion radiotherapy.

Microdosimetric study for helium-ion beam using fully 3D silicon microdosimeters

In this study, the survival fraction of pancreatic cancer cells exposed to a spread-out Bragg peak (SOBP) helium-ion beam are estimated using the microdosimetric method with the microdosimetric kinetic (MK) model, by measuring the specific energy with a microdosimeter. To measure the microdosimetric spectra, a 3D mushroom microdosimeter was used by mounting it on silicon-on-insulator (SOI) substrates. At different positions of the Bragg curve of a pristine helium-ion beam of 166 MeV/u, microdosimetric spectra were measured via a scanning beam port in the National Institute of Radiological Sciences. The MK parameters were determined such that the survival fraction (SF) calculated by the MK model predicts the previously reported in vitro data. For a cuboid target of 10×10×6 cm3, a treatment plan that utilised helium-ion beam was designed from the in-house treatment planning software (TPS) to achieve a 10% SF of pancreatic cancer cells throughout the target. The physical doses and microdosimetric spectra were measured for different depths by irradiating the scanning-SOBP helium-ion beam; consequently, the SF at each position of the SOBP was predicted. The predicted SFs from measured physical dose and microdosimetric spectra were in good agreement with the planned SF from TPS.

Estimation of Dose-Rate Effectiveness Factor for Malignant Tumor Mortality: Joint Analysis of Mouse Data Exposed to Chronic and Acute Radiation

Uncertainties due to confounding factors in epidemiological studies have limited our knowledge of the effects of low-dose-rate chronic exposure on human health. Animal experiments, wherein each subject is considered to be nearly identical, can complement the limitations of epidemiological studies. Therefore, we conducted a joint analysis of previously published cancer mortality data in B6C3F1 female mice chronically and acutely irradiated with 137Cs γ rays to estimate the dose-rate effectiveness factor. In the chronically irradiated animal experiment conducted by the Institute for Environmental Sciences, mice received irradiation at dose rates of 0.05, 1.1 or 21 mGy per day for 400 days from 8 weeks of age. For the acutely irradiated animal experiment conducted by the National Institute of Radiological Sciences, mice received irradiation at 35, 105, 240 or 365 days of age with 1.9, 3.8 or 5.9 Gy at a dose rate of 0.98 Gy per min. Because the preliminary analyses suggested that the risk was dependent on the age at exposure, a model was applied that considered risk differences depending on this factor. The model analysis revealed a three-fold, significantly decreased risk per Gy in mice exposed to 21 mGy per day compared to that in acutely irradiated mice. This resulted in a dose-rate effectiveness factor larger than that reported previously.

Cytoplasmic Radiation Induced Radio-Adaptive Response in Human Lung Fibroblast WI-38 Cells.

It has been reported that in cells exposed to low-dose radiation, radio-adaptive responses can be induced which make irradiated cells refractory to subsequent high-dose irradiation. However, whether adaptive responses are possible when only the cytoplasm, not the nucleus, of the cell is exposed to radiation is still unclear. In this study, using the proton microbeam facility at the National Institute of Radiological Sciences (Japan), we found that cytoplasmic irradiation activates radio-adaptive responses in normal human lung fibroblast WI-38 cells. Our results showed that when cells received cytoplasmic irradiation with 500 protons prior to 2 Gy or 6 Gy X-ray broad-beam irradiation, the DNA double-strand break levels were significantly reduced. In contrast, at cytoplasmic irradiation with less than 100 protons, the radio-adaptive response was not detected. Moreover, the time interval between cytoplasmic irradiation and whole-cell X-ray irradiation should be longer than 6 h for the induction of adaptive responses. In addition, cytoplasmic irradiation elevated the level of cellular mitochondrial superoxide, which enhanced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK 1/2) and its mediated nuclear accumulation of nuclear factor (erythroid-derived 2)-like 2 (NRF2). This signaling pathway contributed to cytoplasmic irradiation-induced adaptive response as supported by the observations that treatment with the mitochondrial superoxide scavenger mito-tempol, ERK 1/2 inhibitor U0126 or NRF2 inhibitor ML385 could repress the adaptive response. Overall, we showed that cytoplasmic irradiation induces radio-adaptive responses and that mitochondrial superoxide/ERK 1/2/NRF2 signaling is a mechanism. Our results provide new information on the biological effects induced by cytoplasm-targeted irradiation.