From mechanisms to risk estimation--bridging the chasm.

We have a considerable amount of work ahead of us to determine the importance of the wealth of new information emerging in the fields of sub-cellular, cellular and tissue biology in order to improve the estimation of radiation risk at low dose and protracted dose-rate. In this paper, we suggest that there is a need to develop models of the specific health effects of interest (e.g., carcinogenesis in specific tissues), which embody as much of the mechanistic (i.e., biological) information as is deemed necessary. Although it is not realistic to expect that every radiation-induced process should or could be included, we can hope that the major factors that shape the time dependence of evolution of damage can be identified and quantified to the point where reasonable estimations of risk can be made. Regarding carcinogenesis in particular, the structure of the model itself plays a role in determining the relative importance of various processes. We use a specific form of a multi-stage carcinogenic model to illustrate this point. We show in a review of the application of this model to lung cancer incidence and mortality in two exposed populations that for both high- and low-LET radiation, there is evidence of an "inverse dose-rate" or protraction effect. This result could be of some considerable importance, because it would imply that risk from protracted exposure even to low-LET radiation might be greater than from acute exposure, an opinion not currently held in the radiation protection community. This model also allows prediction of the evolution of the risk over the lifetimes of the exposed individuals. One inference is that radiation-induced initiation (i.e., the first cellular carcinogenic event(s) occurring in normal tissue after the passage of the radiation) may not be the driving factor in the risk, but more important may be the effects of the radiation on already-initiated cells in the tissue. Although present throughout the length of the exposure, radiation-induced initiation appears to play a dominating role only very late in life, and only for those individuals who began their exposure early in life. These conclusions are very dependent, of course, on the hypotheses embodied in the initiation-promotion-conversion paradigm of carcinogenesis. We suggest that recently identified processes, such as the "bystander effect", might affect initiation, promotion, and malignant conversion in different ways. Finally, the manner in which the quality of radiation affects these processes must be understood in the context of the mixed high- and low-LET radiations that are found in the space environment. Important directions in critical experiment definition are suggested, including a renewed emphasis on well-designed animal experiments over extended periods of time.     

Possible effects of protracted exposure on the additivity of risks from space radiations.

Conventional radiation risk assessments are presently based on the additivity assumption. This assumption states that risks from individual components of a complex radiation field involving many different types of radiation can be added to yield the total risk of the complex radiation field. If the assumption is not correct, the summations and integrations performed to obtain the presently quoted risk estimates are not appropriate. This problem is particularly important in the area of space radiation risk evaluation because of the many different types of high- and low-LET radiation present in the galactic cosmic ray environment. For both low- and high-LET radiations at low enough dose rates, the present convention is that the addivity assumption holds. Mathematically, the total risk, Rtot is assumed to be Rtot = summation (i) Ri where the summation runs over the different types of radiation present. If the total dose (or fluence) from each component is such that the interaction between biological lesions caused by separate single track traversals is negligible within a given cell, it is presently considered to be reasonable to accept the additivity assumption. However, when the exposure is protracted over many cell doubling times (as will be the case for extended missions to the moon or Mars), the possibility exists that radiation effects that depend on multiple cellular events over a long time period, such as is probably the case in radiation-induced carcinogenesis, may not be additive in the above sense and the exposure interval may have to be included in the evaluation procedure. It is shown, however, that "inverse" dose-rate effects are not expected from intermediate LET radiations arising from the galactic cosmic ray environment due to the "sensitive-window-in-the-cell-cycle" hypothesis.     

Radiation-induced transmissable chromosomal instability in haemopoietic stem cells.

Heritable radiation-induced genetic alterations have long been assumed to be "fixed" within the first cell division. However, there is a growing body of evidence that a considerable fraction of cells surviving radiation exposure appear normal, but a variety of mutational changes arise in their progeny due to a transmissible genomic instability. In our investigations of G-banded metaphases, non-clonal cytogenetic aberrations, predominantly chromatid-type aberrations, have been observed in the clonal descendants of murine and human haemopoietic stem cells surviving low doses (approximately l track per cell) of alpha-particle irradiations. The data are consistent with a transmissible genetic instability induced in a stem cell resulting in a diversity of chromosomal aberrations in its clonal progeny many cell divisions later. Recent studies have demonstrated that the instability phenotype persists in vivo and that the expression of chromosomal instability has a strong dependence on the genetic characteristics of the irradiated cell. At the time when cytogenetic aberrations are detected, an increased incidence of hprt mutations and apoptotic cells have been observed in the clonal descendants of (alpha-irradiated murine haemopoietic stem cells. Thus, delayed chromosomal abnormalities, delayed cell death by apoptosis and late-arising specific gene mutations may reflect diverse consequences of radiation-induced genomic instability. The relationship, if any, between these effects is not established. Current studies suggest that expression of these delayed heritable effects is determined by the type of radiation exposure, type of cell and a variety of genetic factors.     

On the radiosensitivity of man in space.

Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical model of radiation-induced myelopoiesis which includes the effect of microgravity on bone marrow kinetics. It is assumed that cellular radiosensitivity is not modified by the space environment, but repopulation rates of stem and stromal cells are reduced as a function of time in weightlessness. A realistic model of the space radiation environment, including the HZE component, is used to simulate the radiation damage. A dedicated computer code was written and applied to solar particle events and to the mission to Mars. The results suggest that altered myelopoiesis and lymphopoiesis in microgravity might increase human radiosensitivity in space.     

Importance of dose-rate and cell proliferation in the evaluation of biological experimental results.

The nuclei of cells within the bodies of astronauts traveling on extended missions outside the geomagnetosphere will experience single traversals of particles with high LET (e.g., one iron ion per one hundred years, on average) superimposed on a background of tracks with low LET (approximately one proton every two to three days, and one helium ion per month). In addition, some cell populations within the body will be proliferating, thus possibly providing increasing numbers of cells with "initiated" targets for subsequent radiation hits. These temporal characteristics are not generally reproduced in laboratory experimental protocols. Implications of the differences in the temporal patterns of radiation delivery between conventionally designed radiation biology experiments and the pattern to be experienced in space are examined and the importance of dose-rate and cell proliferation are pointed out in the context of radiation risk assessment on long missions in space.     

The space-developed dynamic vertical cutoff rigidity model and its applicability to aircraft radiation dose.

We have developed a dynamic geomagnetic vertical cutoff rigidity model that predicts the energetic charged particle transmission through the magnetosphere. Initially developed for space applications, we demonstrate the applicability of this library of cutoff rigidity models for computing aircraft radiation dose. The world grids of vertical cutoff rigidities were obtained by particle trajectory tracing in a magnetospheric model. This reference set of world grids of vertical cutoff rigidities calculated for satellite altitudes covers all magnetic activity levels from super quiet to extremely disturbed (i.e., Kp indices ranging from 0 to 9+) for every three hours in universal time. We utilize the McIlwain "L" parameter as the basis of the interpolation technique to reduce these initial satellite altitude vertical cutoff rigidities to cutoff rigidity values at aircraft altitudes.     

半空间中机载甚低频双拖曳天线电磁辐射特性

对半空间中机载甚低频双拖曳天线电磁辐射特性进行了研究.基于有限元算法建立了机载甚低频双拖曳天线半空间全波仿真模型,利用边界条件模拟了海面半空间环境,深入分析了海面半空间环境对于机载甚低频双拖曳天线辐射特性的影响,通过调整机载甚低频双拖曳天线长短比,优化了机载甚低频双拖曳天线的输入阻抗、辐射效率等设计参数,该研究结果与美国海空军发展中心公布的数据吻合较好,验证了研究结论的有效性和可信性,对机载甚低频双拖曳天线的设计及应用具有参考意义.      

Effects of exposure to different types of radiation on behaviors mediated by peripheral or central systems.

The effects of exposure to ionizing radiation on behavior may result from effects on peripheral or on central systems. For behavioral endpoints that are mediated by peripheral systems (e.g., radiation-induced conditioned taste aversion or vomiting), the behavioral effects of exposure to heavy particles (56Fe, 600 MeV/n) are qualitatively similar to the effects of exposure to gamma radiation (60Co) and to fission spectrum neutrons. For these endpoints, the only differences between the different types of radiation are in terms of relative behavioral effectiveness. For behavioral endpoints that are mediated by central systems (e.g., amphetamine-induced taste aversion learning), the effects of exposure to 56Fe particles are not seen following exposure to lower LET gamma rays or fission spectrum neutrons. These results indicate that the effects of exposure to heavy particles on behavioral endpoints cannot necessarily be extrapolated from studies using gamma rays, but require the use of heavy particles.     

Cosmic ray hit frequencies in critical sites in the central nervous system.

One outstanding question to be addressed in assessing the risk of exposure to space travelers from galactic cosmic rays (GCR) outside the geomagnetosphere is to ascertain the effects of single heavy-ion hits on cells in critical regions of the central nervous system (CNS). As a first step toward this end, it is important to determine how many "hits" might be received by a neural cell in several critical CNS areas during an extended mission outside the confines of the earth's magnetic field. Critical sites in the CNS: the macula, and an interior brain point (typical of the genu, thalamus, hippocampus and nucleus basalis of Meynert) were chosen for the calculation of hit frequencies from galactic cosmic rays for a mission to Mars during solar minimum (i.e., at maximum cosmic-ray intensity). The shielding at a given position inside the body was obtained using the Computerized Anatomical Man (CAM) model, and a radiation transport code which includes nuclear fragmentation was used to calculate yearly fluences at the point of interest. Since the final Mars spacecraft shielding configuration has not yet been determined, we considered the minimum amount of aluminum required for pressure vessel-wall requirements in the living quarters of a spacecraft, and a typical duty area as a pressure vessel plus necessary equipment. The conclusions are: (1) variation of the position of the "target site" within the head plays only a small role in varying hit frequencies; (2) the average number of hits depends linearly on the cross section of the critical portion of the cell assumed in the calculation; (3) for a three-year mission to Mars at solar minimum (i.e., assuming the 1977 spectrum of galactic cosmic rays), 2% or 13% of the "critical sites" of cells in the CNS would be directly hit at least once by iron ions, depending on whether 60 micrometers2 or 471 micrometers2 is assumed as the critical cross sectional area; and (4) roughly 6 million out of some 43 million hippocampal cells and 55 thousand out of 1.8 million thalamus cell nuclei would be directly hit by iron ions at least once on such a mission for space travelers inside a simple pressure vessel. Also, roughly 20 million out of 43 million hippocampal cells and 230 thousand out of 1.8 million thalamus cell nuclei would be directly hit by one or more particles with z > or = 15 on such a mission.     

Dose protraction studies with low- and high-LET radiations on neoplastic cell transformation in vitro.

A major objective of our heavy-ion research is to understand the potential carcinogenic effects of cosmic rays and the mechanisms of radiation-induced cell transformation. During the past several years, we have studied the relative biological effectiveness of heavy ions with various atomic numbers and linear energy transfer on neoplastic cell transformation and the repair of transformation lesions induced by heavy ions in mammalian cells. All of these studies, however, were done with a high dose rate. For risk assessment, it is extremely important to have data on the low-dose-rate effect of heavy ions. Recently, with confluent cultures of the C3H10T1/2 cell line, we have initiated some studies on the low-dose-rate effect of low- and high-LET radiation on cell transformation. For low-LET photons, there was a decrease in cell killing and cell transformation frequency when cells were irradiated with fractionated doses and at low dose rate. Cultured mammalian cells can repair both subtransformation and potential transformation lesions induced by X rays. The kinetics of potential transformation damage repair is a slow one. No sparing effect, however, was found for high-LET radiation. There was an enhancement of cell transformation for low-dose-rate argon (400 MeV/u; 120 keV/micrometer) and iron particles (600 MeV/u; 200 keV/micrometer). The molecular mechanisms for the enhancement effect is unknown at present.     

Recent results of comparative radiobiological experiments with short and long term expositions of arabidopsis seed embryos

Comparison of experimental data obtained from short (SDEF) and long duration exposure flights (LDEF) recently led to results, which will contribute for the estimation of genetic risk for long and/or repeated stay of man in space. Under orbital conditions biological stress and damage are induced in test subjects by cosmic radiation, especially the high energetic, densely ionizing component of heavy ions. Plant seeds were successful model systems for a biotest in studying the physiological damages and mutagenic effects caused by ionizing radiation in particular stem cells. In this article we present an overview of our space experiments with Arabidopis thaliana seeds. We present first results of investigations on certain damage endpoints (seed germination, plant survival, mutation frequencies), caused by cosmic ionizing radiation in dry dormant plant seeds of Arabidopsis thaliana after different short term (e.g. IML-1 and D-2) and long term (e.g. EURECA and LDEF-1) space exposures. Total dose effects of heavy ions and the other components of the mixed radiation field on damage endpoints and survival after space exposure and gamma-ray preirradiation were obtained. A new method of total dose spectrometry by neutron activation has been applied.     

Radiation protection against early and late effects of ionizing irradiation by the prostaglandin inhibitor indomethacin.

Protective effects of indomethacin, a prototype prostaglandin-inhibiting agent, against early and late sequelae of radiation injury (after X-rays or gamma rays) in mice were investigated. The following tissues or organs were examined: hematopoietic tissue, esophagus, jejunum, colon, lung, hair follicles, and tissues involved in the development of radiation-induced leg contractures. In addition, the effect of indomethacin was tested against radiation-induced carcinogenesis. In all experiments, the radiation was delivered as a single dose. Indomethacin led to significant protection of hematopoietic tissue, by a factor of 1.3. There was also some protection against radiation-induced pneumonitis and against radiation-induced carcinogenesis (protection factor of 1.2). The other tissues tested showed no change in their radioresponse after being treated with indomethacin. Thus, indomethacin can act as a radioprotective agent against both early and late sequelae of radiation, but its effect is dependent on the tissue tested. This protection is smaller than that observed with WR-2721. However, indomethacin combined with WR-2721 produced a radioprotective effect greater than the radioprotection achieved by individual treatments.     

Chromosome aberrations as biomarkers of radiation exposure: modelling basic mechanisms.

The space radiation environment is a mixed field consisting of different particles having different energies, including high charge and energy (HZE) ions. Conventional measurements of absorbed doses may not be sufficient to completely characterise the radiation field and perform reliable estimates of health risks. Biological dosimetry, based on the observation of specific radiation-induced endpoints (typically chromosome aberrations), can be a helpful approach in case of monitored exposure to space radiation or other mixed fields, as well as in case of accidental exposure. Furthermore, various ratios of aberrations (e.g. dicentric chromosomes to centric rings and complex exchanges to simple exchanges) have been suggested as possible fingerprints of radiation quality, although all of them have been subjected to some criticisms. In this context a mechanistic model and a Monte Carlo code for the simulation of chromosome aberration induction were developed. The model, able to provide dose-responses for different aberrations (e.g. dicentrics, rings, fragments, translocations, insertions and other complex exchanges), was further developed to assess the dependence of various ratios of aberrations on radiation quality. The predictions of the model were compared with available data, whose experimental conditions were faithfully reproduced. Particular attention was devoted to the scoring criteria adopted in different laboratories and to possible biases introduced by interphase death and mitotic delay. This latter aspect was investigated by taking into account both metaphase data and data obtained with Premature Chromosome Condensation (PCC).     

On the spatial extent of the proton radiation belt from solar cell output variation of the Akebono satellite

Output current of silicon solar cells of Akebono satellite orbiting in the inner magnetosphere decreased from 13 A in 1989 to about 7 A in 2009, due to accumulated damage by energetic particles. A fair correlation between the monthly decrease rate of solar cell output current and trapped proton flux was found between 1989 and 1992, indicating that trapped energetic protons are responsible for the solar cell degradation. Simple variation from month to month was dominated by a fluctuation with one-year period and the correlation was not discernible after 1993. On the other hand, during orbiting the earth, another kind of decrease of output current emerged at low altitude above the sub-solar point, i.e., in the midst of sunlit condition. The decrease was larger in later years. The fact indicates more prominent temperature effect in the later years because of progress of the degradation. By removing data affected by the orbit condition above, variation from the same month in the previous year shows a clear oscillation due to orbit precession correlated with trapped energetic proton flux up to 1996. The amplitude of the annual variation oscillation tends to be larger than that expected from a degradation model based on energetic proton distribution of the NASA’s AP8 model. The larger oscillation amplitude suggests that the proton radiation belt was more sharply localized than given by the AP8 model throughout the early half of 1990s.     

Tumor suppressor function of Betaig-h3 gene in radiation carcinogenesis.

Interaction between cell and extracellular matrix (ECM) plays a crucial role in tumor invasiveness and metastasis. Using an immortalized human bronchial epithelial (BEP2D) cell model, we showed previously that expression of a list of genes including Betaig-h3 (induced by transforming growth factor-beta), DCC (deleted in colorectal cancer), p21(cipl), c-fos, Heat shock protein (HSP27) and cytokeratin 14 were differentially expressed in several independently generated, radiation-induced tumor cell lines (TL1-TL5) relative to parental BEP2D cells. Our previous data further demonstrated that loss of tumor suppressor gene(s) as a likely mechanism of radiation carcinogenesis. In the present study, we chose Betaig-h3 and DCC that were downregulated in tumorigenic cells for further study. Restored expression of Betaig-h3 gene, not DCC gene, by transfecting cDNA into tumor cells resulted in a significant reduction in tumor growth. While integrin receptor alpha 5 beta 1 was overexpressed in tumor cells, its expression was corrected to the level found in control BEP2D cells after Betaig-h3 transfection. These data suggest that Betaig-h3 gene is involved in tumor progression by regulating integrin alpha 5 beta 1 receptor. Furthermore, exogenous TGF- beta 1 induced expression of Betaig-h3 gene and inhibited the growth of both control and tumorigenic BEP2D cells. Therefore, downregulation of Betaig-h3 gene may results from the decreased expression of upstream mediators such as TGF-beta. The findings provide strong evidence that the Betaig-h3 gene has tumor suppressor function in radiation-induced tumorigenic human bronchial epithelial cells and suggest a potential target for interventional therapy.     

Induction and repair of DNA strand breaks in bovine lens epithelial cells after high LET irradiation.

The lens epithelium is the initiation site for the development of radiation induced cataracts. Radiation in the cortex and nucleus interacts with proteins, while in the epithelium, experimental results reveal mutagenic and cytotoxic effects. It is suggested that incorrectly repaired DNA damage may be lethal in terms of cellular reproduction and also may initiate the development of mutations or transformations in surviving cells. The occurrence of such genetically modified cells may lead to lens opacification. For a quantitative risk estimation for astronauts and space travelers it is necessary to know the relative biological effectiveness (RBE), because the spacial and temporal distribution of initial physical damage induced by cosmic radiation differ significantly from that of X-rays. RBEs for the induction of DNA strand breaks and the efficiency of repair of these breaks were measured in cultured diploid bovine lens epithelial cells exposed to different LET irradiation to either 300 kV X-rays or to heavy ions at the UNILAC accelerator at GSI. Accelerated ions from Z=8 (O) to Z=92 (U) were used. Strand breaks were measured by hydroxyapatite chromatography of alkaline unwound DNA (overall strand breaks). Results showed that DNA damage occurs as a function of dose, of kinetic energy and of LET. For particles having the same LET the severity of the DNA damage increases with dose. For a given particle dose, as the LET rises, the numbers of DNA strand breaks increase to a maximum and then reach a plateau or decrease. Repair kinetics depend on the fluence (irradiation dose). At any LET value, repair is much slower after heavy ion exposure than after X-irradiation. For ions with an LET of less than 10,000 keV micrometers-1 more than 90 percent of the strand breaks induced are repaired within 24 hours. At higher particle fluences, especially for low energetic particles with a very high local density of energy deposition within the particle track, a higher proportion of non-rejoined breaks is found, even after prolonged periods of incubation. At the highest LET value (16,300 keV micrometers-1) no significant repair is observed. These LET-dependencies are consistent with the current mechanistic model for radiation induced cataractogenesis which postulates that genomic damage to the surviving fraction of epithelial cells is responsible for lens opacification.     

深空星间链路信道建模及硬件模拟器研制

针对深空通信信道距离长、信噪比低、链路损耗巨大等特点,提出了太阳闪烁与多径效应影响下的深空星间链路信道理论模型。在此基础上,构建了一个基于硬件现场可编程门阵列和控制计算机的深空星间链路信道模拟器,有效模拟了深空星间通信的多径衰落、传播路径损耗和信道延迟,规避了投入高、风险高、耗时长的实地通信实验。实测结果表明,该深空星间链路模拟器输出的载噪比及误比特率波形与理论结果吻合,可用于实验室条件下对深空星间链路的实时模拟复现。     

Chromosomal changes in cultured human epithelial cells transformed by low- and high-LET radiation.

For a better assessment of radiation risk in space, an understanding of the responses of human cells, especially the epithelial cells, to low- and high-LET radiation is essential. In our laboratory, we have successfully developed techniques to study the neoplastic transformation of two human epithelial cell systems by ionizing radiation. These cell systems are human mammary epithelial cells (H184B5) and human epidermal keratinocytes (HEK). Both cell lines are immortal, anchorage dependent for growth, and nontumorigenic in athymic nude mice. Neoplastic transformation was achieved by irradiating cells successively. Our results showed that radiogenic cell transformation is a multistep process and that a single exposure of ionizing radiation can cause only one step of transformation. It requires, therefore, multihits to make human epithelial cells fully tumorigenic. Using a simple karyotyping method, we did chromosome analysis with cells cloned at various stages of transformation. We found no consistent large terminal deletion of chromosomes in radiation-induced transformants. Some changes of total number of chromosomes, however, were observed in the transformed cells. These transformants provide an unique opportunity for further genetic studies at a molecular level.     

Role of chromosome instability in long term effect of manned-space missions.

Astronauts are exposed to heavy ions during space missions and heavy ion induced-chromosome damages have been observed in their lymphocytes. This raises the problem of the consequence of longer space flights. Recent studies show that some alterations can appear many cell generations after the initial radiation exposure as a delayed genomic instability. This delayed instability is characterized by the accumulation of cell alterations leading to cell transformation, delayed cell death and mutations. Chromosome instability was shown in vitro in different model systems (Sabatier et al., 1992; Marder and Morgan, 1993, Kadhim et al., 1994 and Holmberg et al., 1993, 1995). All types of radiation used induce a chromosome instability, however, heavy ions cause the most damage. The period of chromosome instability followed by the formation of clones with unbalanced karyotypes seems to be shared by cancer cells. The shortening of telomere sequences leading to the formation of telomere fusions is an important factor in the appearance of this chromosome instability.