A stochastic model of radiation-induced bone marrow damage

A stochastic model, based on consensus principles from radiation biology, is used to estimate bone-marrow stem cell pool survival (CFU-S and stroma cells) after irradiation. The dose response model consists of three coupled first order linear differential equations which quantitatively describe time dependent cellular damage, repair, and killing of red bone marrow cells. This system of differential equations is solved analytically through the use of a matrix approach for continuous and fractionated irradiations. The analytic solutions are confirmed through the dynamical solution of the model equations using SIMULINK. Rate coefficients describing the cellular processes of radiation damage and repair, extrapolated to humans from animal data sets and adjusted for neutron-gamma mixed fields, are employed in a SIMULINK analysis of criticality accidents. The results show that, for the time structures which may occur in criticality accidents, cell survival is established mainly by the average dose and dose rate.     

自然循环工况下堆舱抢修人员辐射安全分析

目的 开展对反应堆自然循环工况下抢修人员辐射安全研究,阐述反应堆舱应急抢修人员辐射防护方法,为应急抢修人员辐射防护和抢修时间控制提供理论参考。方法 针对反应堆自然循环工况下抢修人员辐射情况,利用蒙特卡罗方法进行模拟计算,并结合自然循环工况下反应堆舱实验测量的辐射数据进行验证分析。结果 反应堆外照射模拟计算中子剂量率约为140 μSv/h,γ辐射剂量率为48 μSv/h,实验测量计算抢修人员在30 min堆舱内受到的有效剂量为2.2 mSv。结论 自然循环功率下进堆舱抢修,γ辐射对抢修人员危害大,但在不同的位置维修,防护重点又有不同;佩戴呼吸器,30 min轮流抢修的方式,对抢修人员是安全的。     

Relative biological effectiveness of fission neutrons for producing micronuclei in the root-tip cells of onion seedlings after irradiation as dry seeds

The relative biological effectiveness (RBE) of mixed neutron and gamma-ray radiation emitted at a 252Cf source at the Research Institute for Radiation Biology and Medicine, Hiroshima University, compared with 60Co gamma-ray radiation was determined. The tissue-absorbed dose contribution of the accompanying gamma radiation was about 35.7% to the total tissue-absorbed dose from the 252Cf mixed radiation. The 252Cf mixed radiation and 60Co gamma rays produced approximate linear changes in the frequency of micronuclei induced in root-tip cells of Allium cepa L. onion seedlings after irradiation as dry dormant seeds with varying absorbed doses in onion seeds. Therefore, the RBE for radiation-induced micronuclei was calculated as the ratio of the slopes for the 252Cf mixed radiation and the 60Co gamma rays. The deduced RBE value of 252Cf mixed radiation to 60Co gamma rays to induce micronuclei in dry dormant onion seed cells was about 90.5 +/- 3.6 (+/- 1sigma); the RBE of neutrons from the 252Cf mixed radiation was about 150 +/- 6 (+/- 1sigma). Furthermore, the sensitivity ratio of the induction rate of micronuclei in dry dormant seeds to that in seedlings by neutrons from 252Cf mixed radiation was significantly different from that by 60Co gamma rays. From these results, we concluded that the repair efficiency of DNA damage induced by neutrons may be different from that by gamma rays.     

A system for radiological protection of the environment: some initial thoughts and ideas.

Radiological protection has always been based on protection of man. Protection of the environment is often assumed to be implicit in the application of radiological protection generally, but this assumption is increasingly being challenged. It is therefore time to consider the feasibility of developing a complementary system for protecting the environment itself from ionising radiation, which would be both explicit and applicable to a wide range of situations. This paper outlines a possible approach using reference dose models and different types of dose effects.     

On the general validity of linear summation of dose equivalents for mixed radiations

The current definition of dose equivalent for a mixture of radiations used in radiation protection implies some interaction between the radiations. This interaction cannot be derived from the existing biophysical models. A simple concept of interaction is introduced based on the postulate that in the chain of radiation inactivation events, there exists an intermediate stage where different initial lesions, produced by different radiations, become functionally indistinguishable. Hence, they are additive thereafter to produce the same end point observed. It can be shown that the definition of dose equivalent and the definition of average quality factors for mixed radiations can be derived from this concept. Furthermore, this simple concept can be shown to be consistent with many of the published experimental results in radiobiology using mixed radiations. The lesion additivity concept helps to provide both theoretical and experimental support for the otherwise arbitrary definitions of dose equivalent and average quality factor.     

Effect of multiple-dose irradiation on repair capacity in plateau phase C3H 10T1/2 cells

Using plateau phase C3H 10T1/2 cells, we studied the effect of multiple-dose irradiation on the repair capacity of cells after further irradiation. Cells were irradiated with repeated doses of 2.5 Gy delivered two fractions per day at 6 to 7 hours interval. The cell survival after exposure to 1 to 9 fractions was lower above 5 fractions as compared to that predicted by calculating from single dose survival curve by assuming that cells retain their capacity to repair radiation damage after each fraction. Repair kinetics experiments showed that cells were less able to repair potentially lethal damage after test dose following multiple dose irradiations. There was, however, no difference in the ability to repair sublethal damage and potentially lethal damage sensitive to anisotonic treatment in preirradiated and untreated cells. Thus, it would appear that an enhancement of the lethal expression of potentially lethal damage of three types of damage may, at least in part, contribute to the difference between the cell survival curve after multiple fractions and that predicted by calculation.     

Radiobiological evaluation of the radiation dose as used in high-precision radiotherapy: effect of prolonged delivery time and applicability of the linear-quadratic model

Since the dose delivery pattern in high-precision radiotherapy is different from that in conventional radiation, radiobiological assessment of the physical dose used in stereotactic irradiation and intensity-modulated radiotherapy has become necessary. In these treatments, the daily dose is usually given intermittently over a time longer than that used in conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. This phenomenon is almost universarily observed in vitro. In in vivo tumors, however, this decrease in effect can be counterbalanced by rapid reoxygenation, which has been demonstrated in a laboratory study. Studies on reoxygenation in human tumors are warranted to better evaluate the influence of prolonged radiation delivery. Another issue related to radiosurgery and hypofractionated stereotactic radiotherapy is the mathematical model for dose evaluation and conversion. Many clinicians use the linear-quadratic (LQ) model and biologically effective dose (BED) to estimate the effects of various radiation schedules, but it has been suggested that the LQ model is not applicable to high doses per fraction. Recent experimental studies verified the inadequacy of the LQ model in converting hypofractionated doses into single doses. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when it is used for tumor responses in vivo, since it does not take reoxygenation into account. For normal tissue responses, improved models have been proposed, but, for in vivo tumor responses, the currently available models are not satisfactory, and better ones should be proposed in future studies.     

放射性皮肤损伤临床诊断与治疗

本文结合国内外文献、新制定的国家职业卫生标准及笔者的临床经验等解析了外照射急性及慢性放射性皮肤损伤的发病特点、临床表现、诊断标准和治疗原则，为放射性皮肤损伤的及时处理及规范化诊治提供依据。急性放射性皮肤损伤依据受照剂量的大小及临床表现分为Ⅰ、Ⅱ、Ⅲ、Ⅳ度，这四种程度急性放射性皮肤损伤临床经过既表现了损伤的量效关系，也体现了严重放射损伤的明显阶段性，早期通过皮肤损伤程度进行剂量估算有助于快速准确诊断、早期预测病变严重程度和决定治疗策略。慢性放射性皮肤损伤一方面是职业原因长期接触低剂量辐射所致，另一方面是急性放射性皮肤损伤迁延形成，分度为Ⅰ、Ⅱ、Ⅲ度，仅为皮肤损伤程度分类，与所受辐射没有严格的量效关系，急性和慢性放射性皮肤损伤的治疗根据损伤程度治疗有所不同，局部保守治疗以及应用修复手段的外科治疗，并且都考虑了全身治疗对创面愈合的促进作用。     

WORTMANNIN对细胞辐射反应性的影响

目的 了解磷脂酰肌醇-3激酶(Phosphatidylinositol-3Kinase,PI-3K)的特异性抑制剂WORTMAN-NIN(WT)对细胞辐射反应性的影响。方法 将处于对数生长期的LP3细胞经不同浓度WT作用1h,进行⁶⁰Coγ射线照射,继续进行克隆培养,制作剂量存活曲线。应用180°脉冲场琼脂糖凝胶电泳,检测受20Gyγ射线照射后细胞DNA双链断裂及其修复。继续用迁移率变化分析(Eloctrophoretic Mobility Shift Assay,EMSA)观察转录因子NF-kB的相应变化。结果 发现WT可以增加SP3细胞的辐射敏感性,最佳增敏浓度在20μmol/L以上;明显增敏效应时间在6h以内;DNA凝胶电泳实验显示,随着受照后时间的延长,受50μmol/LWT作用的细胞DN进入凝胶的量均高于单纯受照射组;转录因子NF-kB的结合活性在受照后6h内都经历了一个由低升高,然后降低的过程,大概在照后3h是这个变化的峰值。结论 提示存在PI-3K介导的辐射增敏信号途径。电离辐射可能通过激活NF-kB,进而促使一些与DNA损伤修复和细胞其它防御机制有关的基因活动,以减轻辐射损伤。WT有可能是通过阻滞这一过程的早期阶段而发生辐射增敏效应。     

UDS and SCE in lymphocytes of persons occupationally exposed to low levels of ionizing radiation

Unscheduled DNA synthesis induced by in vitro UV irradiation was investigated in lymphocytes of persons occupationally exposed to low doses of ionizing radiation (maximum registered radiation dose: 98 mrad/month). For radiation exposures greater than 14 mrad/month above background level, increased rates of UDS after in vitro UV irradiation of lymphocytes were found. The bromodeoxyuridine differential chromatid labeling technique was applied to the examination of spontaneous and Mitomycin C (MMC)-induced sister chromatid exchanges (SCE) in the same population. No statistically significant difference could be determined in spontaneously occurring SCEs, while MMC induced SCEs were significantly reduced in persons exposed to radiation doses greater than 14 mrad/month, thus indicating increased repair capability for DNA lesions inflicted by a second insult after protracted low-dose irradiation.     

Superposition dose calculation in lung for 10MV photons

Currently available radiotherapy treatment planning systems employ scatter function models such as ETAR and Batho dSAR for dose calculation. Errors using these models for high energy photon irradiation occur in and beyond lung tissue for small fields. For larger fields, central axis dose is correctly predicted but penumbral broadening in lung is underestimated. The major source of error is the assumption that lateral electronic equilibrium is always established. A superposition algorithm has been developed for 10MV photons which calculates the dose by convolving the TERMA (Total Energy Released per unit MAss by primary photons) with a dose spread array formed using the EGS4 Monte Carlo code. TERMA and dose spread arrays are both generated using a 10 component photon energy spectrum. Dose in inhomogeneous media is calculated using dose spread arrays generated for different density media and by scaling dose spread arrays according to density variations. This method ensures that electronic disequilibrium is modelled in situations where it exists. Superposition results in a lung phantom for a 5 x 5 cm field agree with EGS4 Monte Carlo results to within 2% for p = 0.20 gcm-3 and p = 0.30 gcm-3 lung. Profiles generated by superposition for a 10 x 10 cm field at mid-lung and compared with film measurements show that penumbral broadening in low density material is also correctly predicted.     

Method of calculating the equivalent tumor dose as a function as to irradiated tumor tissue volume

Based on the assumption that tumor tissue consists of normal and radiation-resistant, that the survival of both types of tumor cells may be described by LQ functions and that the count of radiation-resistant cells is in proportion to that of tumor cells, the author has developed a method for calculating the equivalent tumor dose as a function as to irradiated tumor tissue volume for the fixed value of a single dose in the session of radiation. The developed formalism may be used to test the hypothesis that the count of clonogenic and radiation-resistant cells is in proportion to the baseline number of the cells in the tumor tissue.     

Optimized enzymatic dual functions of PaPrx protein by proton irradiation

We investigated the effects of proton irradiation on the function and structure of the Pseudomonas aeruginosa peroxiredoxin (PaPrx). Polyacrylamide gel demonstrated that PaPrx proteins exposed to proton irradiation at several doses exhibited simultaneous formation of high molecular weight (HMW) complexes and fragmentation. Size-exclusion chromatography (SEC) analysis revealed that the number of fragments and very low molecular weight (LMW) structures increased as the proton irradiation dose increased. The peroxidase activity of irradiated PaPrx was preserved, and its chaperone activity was significantly increased by increasing the proton irradiation dose. The chaperone activity increased about 3–4 fold after 2.5 kGy proton irradiation, compared with that of non-irradiated PaPrx, and increased to almost the maximum activity after 10 kGy proton irradiation. We previously obtained functional switching in PaPrx proteins, by using gamma rays and electron beams as radiation sources, and found that the proteins exhibited increased chaperone activity but decreased peroxidase activity. Interestingly, in this study we newly found that proton irradiation could enhance both peroxidase and chaperone activities. Therefore, we can suggest proton irradiation as a novel protocol for conserved 2-Cys protein engineering.     

Models of interaction between metabolic genes and environmental exposure in cancer susceptibility.

Polymorphic metabolic genes that confer enhanced genetic susceptibility to the carcinogenic effects of certain environmental carcinogens act according to a type 2 interaction between genetic and environmental risk factors. This type of interaction, for which the gene has no effect on disease outcome by itself but only modifies the risk associated with exposure, must be treated differently from other types of gene-environment interaction. We present a method to analyze different dose effects often seen in studies involving these genes. We define a low exposure-gene effect, when a greater degree of gene environment interaction appears at lower doses of exposure (the interaction follows an inverse dose function), and a converse high exposure-gene effect, when the interaction increases as a function of dose. Using a standard logistic regression model, we define a new term, alpha, that can be determined asa function of exposure dose in order to analyze epidemiological studies for the type of exposure-gene effect. These models are illustrated by the use of hypothetical case-control data as well as examples from the literature.     

True three-dimensional dose computations for megavoltage x-ray therapy: a role for the superposition principle.

The objective of radiation therapy is to concentrate a prescribed radiation dose accurately within a target volume in the patient. Major advances in imaging technology have greatly improved our ability to plan radiation treatments in three dimensions (3D) and to verify the treatment geometrically, but there is a concomitant need to improve dosimetric accuracy. It has been recommended that radiation doses should be computed with an accuracy of 3% within the target volume and in radiosensitive normal tissues. We review the rationale behind this recommendation, and describe a new generation of 3D dose algorithms which are capable of achieving this goal. A true 3D dose calculation tracks primary and scattered radiations in 3D space while accounting for tissue inhomogeneities. In the past, dose distributions have been computed in a 2D transverse slice with the assumption that the anatomy of the patient dose not change abruptly in nearby slices. We demonstrate the importance of computing 3D scatter contributions to dose from photons and electrons correctly, and show the magnitude of dose errors caused by using traditional 2D methods. The Monte Carlo technique is the most general and rigorous approach since individual primary and secondary particle tracks are simulated. However, this approach is too time-consuming for clinical treatment planning. We review an approach that is based on the superposition principle and achieves a reasonable compromise between the speed of computation and accuracy in dose. In this approach, dose deposition is separated into two steps. Firstly, the attenuation of incident photons interacting in the absorber is computed to determine the total energy released in the material (TERMA). This quantity is treated as an impulse at each irradiated point. Secondly, the transport of energy by scattered photons and electrons is described by a point dose spread kernel. The dose distribution is the superposition of the kernels, weighted by the magnitude of the TERMA impulse for all interaction sites. In this review, we demonstrate the capabilities of the superposition method, particularly for situations of charged particle disequilibrium, and we report on the progress made by several research groups in adapting this method to clinical treatment planning. In the future, the superposition method will have a significant role in dose optimization for conformal irradiation techniques because of its close correspondence to image reconstruction by filtered back-projection.     

Toward improved ionizing radiation safety standards

Ionizing radiation safety standards developed by the International Commission on Radiological Protection (ICRP) during the past 50-plus years have provided guidance for effective protection of workers and the public from the potentially harmful effects of exposure to ionizing radiation, including cancer. Earlier standards were based primarily on radiation dose rate to organs of the body. More recent recommendations have calculated cancer risk as a function of cumulative dose using a linear no-threshold cancer risk model based on the acute high dose rate exposures received by the Japanese atomic bomb survivors. The underlying assumption in these current recommendations is that risk of radiation-induced cancer is proportional to cumulative dose without threshold. In conflict with this position are the studies of protracted exposures from internally-deposited radionuclides in people and laboratory animals that have demonstrated that cancer induction risk is a function of average dose rate for protracted exposures to ionizing radiation. At lower average dose rates, cancer latency can exceed natural lifespan leading to a virtual threshold. This forum statement proposes that the conflict of these two cancer risk models is explained by the fact that the increased risk of cancer observed in the atomic bomb survivor studies was primarily the result of acute high dose rate promotion of ongoing biological processes that lead to cancer rather than cancer induction. In addition, ionizing radiation-induced cancer is not the result of a simple stochastic event in a single living cell but rather a complex deterministic systemic effect in living tissues. It is recommended that the ICRP consider revising its position in light of this important distinction between cancer promotion and cancer induction.     

Adaptation of cell renewal systems under continuous irradiation

There are adaptive changes in the proliferative characteristics of renewal tissues under the stress of continuous low-dose-rate irradiation which indicate that cell and tissue kinetics will have a considerable effect on the radiation response. Factors that determine the adaptation response involve cellular radiosensitivity, i.e. cell cycle effects, which determine the rate of cell sterilization and death, and compensatory cell proliferation and the capacity for regeneration, i.e. changes in the patterns of cell population kinetics, which determine the rate of cell birth. In rapidly dividing cell renewal systems, there is an effective elimination of damaged cells, with almost complete repair of cellular nonlethal damage. In slowly dividing renewal tissues, there is some repair or elimination of cellular radiation damage and the pattern of cell proliferation during regeneration is relatively little disturbed by prior continuous irradiation. Experimental data on intestinal epithelium, immunohematopoietic tissues, seminiferous epithelium and regenerating liver are presented. Discussion includes differences in adaptation to continuous low-dose-rate irradiation involving intracellular and extracellular control mechanisms which regulate cellular proliferation and differentiation and, thereby, control cell population levels and physiological function.     

2010—2013年上海市金山区放射工作人员外照射个人剂量监测结果分析

目的了解和掌握金山区2010—2013年放射工作人员外照射个人剂量情况。方法采用热释光剂量测量方法,对金山区2010—2013年接受外照射个人剂量监测的放射工作人员进行监测。结果金山区2010—2013年共监测放射工作人员1 159人次,4年总体剂量当量为0.882人/Sv,人均年有效剂量为0.761m Sv/a,年剂量低于2m Sv者占总监测人次数的95.43%,4年内无一人年剂量超过20m Sv。在不同工种放射工作人员中,从事X射线工业探伤和X射线诊断的人员的集体剂量当量和人均年有效剂量分别为0.538人/Sv、0.290人/Sv和0.813m Sv/a、0.751m Sv/a,二者是集体剂量的主要贡献者。结论近4年来,金山区放射工作人员外照射个人剂量总体处于比较低的水平,均远低于国家标准规定的年剂量限值,同时应进一步加强对工业探伤企业的监管。     

Diminished or inversed dose-rate effect on clonogenic ability in Ku-deficient rodent cells

The biological effects of ionizing radiation, especially those of sparsely ionizing radiations like X-ray and γ-ray, are generally reduced as the dose rate is reduced. This phenomenon is known as ‘the dose-rate effect’. The dose-rate effect is considered to be due to the repair of DNA damage during irradiation but the precise mechanisms for the dose-rate effect remain to be clarified. Ku70, Ku86 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are thought to comprise the sensor for DNA double-strand break (DSB) repair through non-homologous end joining (NHEJ). In this study, we measured the clonogenic ability of Ku70-, Ku86- or DNA-PKcs-deficient rodent cells, in parallel with respective control cells, in response to high dose-rate (HDR) and low dose-rate (LDR) γ-ray radiation (~0.9 and ~1 mGy/min, respectively). Control cells and murine embryonic fibroblasts (MEF) from a severe combined immunodeficiency (scid) mouse, which is DNA-PKcs-deficient, showed higher cell survival after LDR irradiation than after HDR irradiation at the same dose. On the other hand, MEF from Ku70^−/− mice exhibited lower clonogenic cell survival after LDR irradiation than after HDR irradiation. XR-V15B and xrs-5 cells, which are Ku86-deficient, exhibited mostly identical clonogenic cell survival after LDR and HDR irradiation. Thus, the dose-rate effect in terms of clonogenic cell survival is diminished or even inversed in Ku-deficient rodent cells. These observations indicate the involvement of Ku in the dose-rate effect.     

Power and sample size evaluation for the McNemar test with application to matched case-control studies.

Various expressions have appeared for sample size calculation based on the power function of McNemar's test for paired or matched proportions, especially with reference to a matched case-control study. These differ principally with respect to the expression for the variance of the statistic under the alternative hypothesis. In addition to the conditional power function, I identify and compare four distinct unconditional expressions. I show that the unconditional calculation of Schlesselman for the matched case-control study can be expressed as a first-order unconditional calculation as described by Miettinen. Corrections to Schlesselman's unconditional expression presented by Fleiss and Levin and by Dupont, which use different models to describe exposure association among matched cases and controls, are also equivalent to a first-order unconditional calculation. I present a simplification of these corrections that directly provides the underlying table of cell probabilities, from which one can perform any of the alternative sample size calculations. Also, I compare the four unconditional sample size expressions relative to the exact power function. The conclusion is that Miettinen's first-order expression tends to underestimate sample size, while his second-order expression is usually fairly accurate, though possibly slightly anti-conservative. A multinomial-based expression presented by Connor, among others, is also fairly accurate and is usually slightly conservative. Finally, a local unconditional expression of Mitra, among others, tends to be excessively conservative.