Michiaki Kai

Dose and dose-rate effects of ionizing radiation: a discussion in the light of radiological protection

Abstract The biological effects on humans of low-dose and low-dose-rate exposures to ionizing radiation have always been of major interest. The most recent concept as suggested by the International Commission on Radiological Protection (ICRP) is to extrapolate existing epidemiological data at high doses and dose rates down to low doses and low dose rates relevant to radiological protection, using the so-called dose and dose-rate effectiveness factor (DDREF). The present paper summarizes what was presented and discussed by experts from ICRP and Japan at a dedicated workshop on this topic held in May 2015 in Kyoto, Japan. This paper describes the historical development of the DDREF concept in light of emerging scientific evidence on dose and dose-rate effects, summarizes the conclusions recently drawn by a number of international organizations (e.g., BEIR VII, ICRP, SSK, UNSCEAR, and WHO), mentions current scientific efforts to obtain more data on low-dose and low-dose-rate effects at molecular, cellular, animal and human levels, and discusses future options that could be useful to improve and optimize the DDREF concept for the purpose of radiological protection.

DNA Double-Strand Breaks Induced by Very Low X-Ray Doses are Largely due to Bystander Effects

Abstract Ojima, M., Ban, N. and Kai, M. DNA Double-Strand Breaks Induced by Very Low X-Ray Doses are Largely due to Bystander Effects. Radiat. Res. 170, 365–371 (2008). Phosphorylated ATM immunofluorescence staining was used to investigate the dose–response relationship for the number of DNA double-strand breaks (DSBs) induced in primary normal human fibroblasts irradiated with doses from 1.2 to 200 mGy. The induction of DSBs showed a supralinear dose–response relationship. Radiation-induced bystander effects may explain these findings. To test this hypothesis, the number of DSBs in cells treated with lindane, an inhibitor of radiation-induced bystander effects, prior to X irradiation was assessed; a supralinear dose–response relationship was not observed. Moreover, the number of DSBs obtained by subtracting the number of phosphorylated ATM foci in lindane-treated cells from the number of phosphorylated ATM foci in untreated cells was proportional to the dose at low doses (1.2–5 mGy) and was saturated at doses from 10–200 mGy. Thus the increase in the number of DSBs in the range of 1.2–5 mGy was largely due to radiation-induced bystander effects, while at doses >10 mGy, the DSBs may be induced mainly by dose-dependent direct radiation effects and partly by dose-independent radiation-induced bystander effects. The findings in our present study provide direct evidence of the dose–response relationship for radiation-induced bystander effects from broad-beam X rays.

The Embryonic and Fetal Effects in ICR Mice Irradiated in the Various Stages of the Preimplantation Period

Pregnant ICR mice were irradiated with 0.1-2.5 Gy 137Cs gamma rays at a dose rate of 0.2 Gy/min at 2, 48, 72 or 96 h postconception. In the mice irradiated during these stages of preimplantation, embryonic/fetal mortalities, incidence of external gross malformations, fetal body weight and sex ratio were observed at day 18 of gestation. There were significant increases in death in the preimplantation period compared to control levels after exposure to at least 0.25 Gy at 2 and 72 h postconception and 0.5 Gy at 96 h postconception. In contrast, a dose of 1.5 Gy was required at 48 h postconception. The frequency of embryonic death was analyzed using a logistic regression for comparing among stages. These analyses demonstrated that the regression slopes were significantly positive for groups in all stages and increased with decreasing time after conception. Furthermore, the regression analyses suggested that the most sensitive stage for preimplantation death and embryonic death was 2 h postconception, when embryos consisted of one cell. Many types of external gross malformations, such as exencephaly, cleft palate and anophthalmia, were observed even in the mice irradiated with 0.1 Gy at 2, 72 and 96 h postconception. In the same manner as embryonic mortality, the regression analyses suggested that the susceptibility of the mice irradiated at 2, 72 and 96 h postconception during preimplantation to external malformations was higher than that of the mice irradiated at 8 or 11 days of gestation, which is the period of organogenesis, and that the most sensitive stage for external malformations was 2 h postconception. However, no malformations were observed in the mice irradiated at 48 h postconception when the embryos were precompacted with four to eight cells.

Persistence of DNA Double-Strand Breaks in Normal Human Cells Induced by Radiation-Induced Bystander Effect

Abstract Our previous study suggested that the DNA double-strand breaks (DSBs) induced by very low X-ray doses are largely due to bystander effects. The aim of this study was to verify whether DSBs created by radiation-induced bystander effects are likely to be repaired. We examined the generation of DSBs in cells by enumeration of phosphorylated ataxia telangiectasia mutated (ATM) foci, which are correlated with DSB repair, in normal human fibroblast cells (MRC-5) after X irradiation at doses ranging from 1 to 1000 mGy. At 24 h after irradiation, 100% (1.2 mGy), 58% (20 mGy), 12% (200 mGy) and 8.5% (1000 mGy) of the initial number of phosphorylated ATM foci were detected. The number of phosphorylated ATM foci in MRC-5 cells treated with lindane, an inhibitor of radiation-induced bystander effects, prior to X irradiation was assessed; phosphorylated ATM foci were not observed at 5 h (20 mGy) or 24 h (200 mGy) postirradiation. We also counted the number of phosphorylated ATM foci in MRC-5 cells cocultured with MRC-5 cells irradiated with 20 mGy. After 48 h of coculture, 81% of the initial numbers of phosphorylated ATM foci remained. These findings suggest that DSBs induced by the radiation-induced bystander effect persist for long periods, whereas DSBs induced by direct radiation effects are repaired relatively quickly.

WAZA-ARI: computational dosimetry system for X-ray CT examinations. I. Radiation transport calculation for organ and tissue doses evaluation using JM phantom.

A web system of WAZA-ARI is being developed to assess radiation dose to a patient in a computed tomography examination. WAZA-ARI uses one of organ dose data sets corresponding to the options selected by a user to describe examination conditions. The organ dose data have been derived by the Particle and Heavy Ion Transport code system, combined with Japanese male (JM) phantom. The configuration of JM phantom is adjusted to the averaged JM adult. In addition, a new phantom is introduced by removing arms from JM phantom to take into account for dose calculations in torso examinations. Some of the organ doses by JM phantom without arms are compared with results obtained by using a MIRD-type phantom, which was applied in some previous dosimetry systems.

WAZA-ARI: computational dosimetry system for X-ray CT examinations II: Development of web-based system

A web-based dose computation system, WAZA-ARI, is being developed for patients undergoing X-ray CT examinations. The system is implemented in Java on a Linux server running Apache Tomcat. Users choose scanning options and input parameters via a web browser over the Internet. Dose coefficients, which were calculated in a Japanese adult male phantom (JM phantom) are called upon user request and are summed over the scan range specified by the user to estimate a normalised dose. Tissue doses are finally computed based on the radiographic exposure (mA s) and the pitch factor. While dose coefficients are currently available only for limited CT scanner models, the system has achieved a high degree of flexibility and scalability without the use of commercial software.

Development of a web-based CT dose calculator: WAZA-ARI

A web-based computed tomography (CT) dose calculation system (WAZA-ARI) is being developed based on the modern techniques for the radiation transport simulation and for software implementation. Dose coefficients were calculated in a voxel-type Japanese adult male phantom (JM phantom), using the Particle and Heavy Ion Transport code System. In the Monte Carlo simulation, the phantom was irradiated with a 5-mm-thick, fan-shaped photon beam rotating in a plane normal to the body axis. The dose coefficients were integrated into the system, which runs as Java servlets within Apache Tomcat. Output of WAZA-ARI for GE LightSpeed 16 was compared with the dose values calculated similarly using MIRD and ICRP Adult Male phantoms. There are some differences due to the phantom configuration, demonstrating the significance of the dose calculation with appropriate phantoms. While the dose coefficients are currently available only for limited CT scanner models and scanning options, WAZA-ARI will be a useful tool in clinical practice when development is finalised.

Estimation of the number of CT procedures based on a nationwide survey in Japan.

In 2007, a nationwide survey was conducted to determine the frequency of CT procedures in Japan in order to compare the current use of CT among developed countries. The frequency of adult and pediatric CT scans was estimated using a model based on the results of the survey. Survey questionnaires were sent to 2,266 CT facilities: 1,068 government hospitals and 1,198 other hospitals and non-hospital medical centers. The questionnaire requested information including the number of beds, outpatients per day, type of CT scanner, various body regions scanned, and the number of scans performed. The results of the study indicate that the number of CT procedures was closely correlated with the number of hospital beds. The authors estimate that approximately 20.5 million procedures were performed in 2005 and 21.2 million in 2006. The number of pediatric CT procedures was calculated by multiplying the total number of CT procedures by the estimated fraction of pediatric (0–15 y) CT procedures. Annual pediatric CT procedures were estimated to have been approximately 580,000 in 2005 and 600,000 in 2006. The present study indicates that the number of procedures per thousand of population, 166 for total CT and 32–34 for pediatric CT, is lower in Japan than in the U.S.

Some lessons on radiological protection learnt from the accident at the Fukushima Dai-ichi nuclear power plant

The accident at the Fukushima Dai-ichi nuclear power plant released a large quantity of radioactive iodine and caesium into the environment. In terms of radiological protection, the evacuation and food restrictions that were adopted in a timely manner by the authorities effectively reduced the dose received by people living in the affected area. Since late March, the transition from an emergency to an existing exposure situation has been in progress. In selecting the reference exposure levels in some areas under an existing exposure situation, the authorities tried to follow the situation-based approach recommended by the ICRP. However, a mixture of emergency and post-emergency approaches confused the people living in the contaminated areas because the reactor conditions continued to be not completely stable. In deriving the criteria in an existing exposure situation, the regulatory authority selected 20 mSv y(-1). The mothers in the affected area believed that a dose of 20 mSv y(-1) was unacceptably high for children since 1 mSv y(-1) is the dose limit for the public under normal conditions. Internet information accelerated concern about the internal exposure to children and the related health effects. From some experiences after the accident the following lessons could be learned. The selection of reference doses in existing exposure situations after an accident must be openly communicated with the public using a risk-informed approach. The detriment-adjusted nominal risk coefficient was misused for calculating the hypothetical number of cancer deaths by some non-radiation experts. It would not be possible to resolve this problem unless the ICRP addressed an alternative risk assessment to convey the meaning and associated uncertainty of the risk to an exposed population. A situation-based approach in addition to a risk-informed approach needs to be disseminated properly in order to select the level of protection that would be the best possible under the prevailing circumstances. A dialogue between radiation and other risk experts such as those dealing with chemical exposures is now needed.

Cytogenetic analysis of radiation-induced leukemia in Trp53-deficient C3H/He mice

Abstract Ban, N., Yoshida, K., Aizawa, S., Wada, S. and Kai, M. Cytogenetic Analysis of Radiation-Induced Leukemia in Trp53-Deficient C3H/He Mice. Radiat. Res. 158, 69–77 (2002). C3H/He mice develop acute myeloid leukemia (AML) after whole-body irradiation, but the strain becomes highly susceptible to stem cell leukemia (SCL) when a null mutation is introduced into the Trp53 gene. To examine the etiology of SCL and the influence of chromosomal instability on leukemogenesis, 12 SCLs and two AMLs arising from Trp53-deficient C3H/He mice were investigated cytogenetically. Each SCL demonstrated cell-to-cell variation in the number and structural integrity of their chromosomes, indicating chromosomal instability. Typical deletion of chromosome 2 was observed in the two AML cases, while most SCL cells did not display this aberration. Deletions and rearrangements of chromosome 11 were noticeable in SCLs from Trp53 heterozygotes but not in AMLs. Analysis of loss of heterozygosity revealed that aberrations involving chromosome 11 in SCLs resulted in loss of the wild-type Trp53 allele. These results suggest that loss of Trp53 function triggers the tumorigenic process leading toward SCL through the induction of chromosomal instability, and that SCL and AML are distinct varieties of leukemia.