Tissue responses to low protracted doses of high LET radiations or photons: early and late damage relevant to radio-protective countermeasures.

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for gamma-radiation. When total doses of 96 or 247 cGy of neutrons or gamma rays were given as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and gamma-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. After high single doses of neutrons or gamma rays, a significant age- and radiation-related deficiency in host defense mechanisms was detected by a shorter mean survival time following challenge with transplantable leukemia cells. Comparison of dose-response curves for life shortening after irradiation with fission-spectrum neutrons or high energy silicon particles indicated high initial slopes for both radiation qualities at low doses, but for higher doses of silicon, the effect per Gy decreased to a value similar to that for gamma rays. The two component life-shortening curve for silicon particles has implications for the potential efficacy of radioprotectants. Recent studies on protection against early and late effects by aminothiols, prostaglandins, and other compounds are discussed.     

Cancer risk above 1 Gy and the impact for space radiation protection

Analyses of the epidemiological data on the Japanese A-bomb survivors, who were exposed to γ-rays and neutrons, provide most current information on the dose–response of radiation-induced cancer. Since the dose span of main interest is usually between 0 and 1 Gy, for radiation protection purposes, the analysis of the A-bomb survivors is often focused on this range. However, estimates of cancer risk for doses larger than 1 Gy are becoming more important for long-term manned space missions. Therefore in this work, emphasis is placed on doses larger than 1 Gy with respect to radiation-induced solid cancer and leukemia mortality. The present analysis of the A-bomb survivors data was extended by including two extra high-dose categories and applying organ-averaged dose instead of the colon-weighted dose. In addition, since there are some recent indications for a high neutron dose contribution, the data were fitted separately for three different values for the relative biological effectiveness (RBE) of the neutrons (10, 35 and 100) and a variable RBE as a function of dose. The data were fitted using a linear and a linear-exponential dose–response relationship using a dose and dose-rate effectiveness factor (DDREF) of both one and two. The work presented here implies that the use of organ-averaged dose, a dose-dependent neutron RBE and the bending-over of the dose–response relationship for radiation-induced cancer could result in a reduction of radiation risk by around 50% above 1 Gy. This could impact radiation risk estimates for space crews on long-term mission above 500 days who might be exposed to doses above 1 Gy. The consequence of using a DDREF of one instead of two increases cancer risk by about 40% and would therefore balance the risk decrease described above.     

Cataractogenic potential of ionizing radiations in animal models that simulate man.

Aspects of experiments on radiation-induced lenticular opacification during the life spans of two animal models, the New Zealand white rabbit and the rhesus monkey, are compared and contrasted with published results from a life span study of another animal model, the beagle dog, and the most recent data from the ongoing study of the survivors from radiation exposure at Hiroshima and Nagasaki. An important connection among the three animal studies is that all the measurements of cataract indices were made by one of the authors (A.C.L.), so variation form personal subjectivity was reduced to a minimum. The primary objective of the rabbit experiments (radiations involved: 56Fe, 40Ar and 20Ne ions and 60Co gamma photons) is an evaluation of hazards to astronauts from galactic particulate radiations. An analogous evaluation of hazards from solar flares during space flight is being made with monkeys exposed to 32, 55, 138 and 400 MeV protons. Conclusions are drawn about the proper use of animal models to simulate radiation responses in man and the levels of radiation-induced lenticular opacification that pose risks to man in space.     

Relationships between neutron fluxes and rain flows

Registration of secondary cosmic ray neutrons is a convenient tool for investigation of primary cosmic ray variations and meteorological effects as well. At present a large network of neutron monitors exists, providing the studies of cosmic ray variations related to the interplanetary conditions and geomagnetic activity. At the same time cosmic ray variations may be caused by some atmospheric processes. In this connection, using the data from standard and lead-free neutron monitors, and gamma and muon detectors, we studied relations between rain flows and neutron, gamma and ionization component behavior. To explain observable results the calculations of neutron and gamma absorption and albedo neutron spectra have been performed on the basis of universal software package FLUKA-2006. In this study we used hourly data on the neutron flux, corrected for barometric pressure and data from local meteorological stations. It was shown that secondary neutron radiation, recorded by lead-free NM, and gamma radiation as well are strongly effected by meteorological factors. The neutron component behavior depends on the moisture content in the soil, and above its surface.     

Induction of genomic instability after an acute whole-body exposure of mice to Fe ions

The purpose of this study was to evaluate dose–response relationships for the in vivo induction of micronuclei (MN) as a measure of both initial radiation damage and the induction of genomic instability. These measurements were made in mouse blood erythrocytes as a function of radiation dose, radiation quality, time after irradiation, and the genetic background of exposed individuals. Blood samples were collected from two strains of mouse (CBA/CaJ and C57BL/6J) at different times up to 3 months following a whole-body exposure to various doses of 1 GeV/amu ⁵⁶Fe ions (0, 0.1, 0.5 and 1.0 Gy, at the dose rate of a 1 Gy/min) or ¹³⁷Cs gamma rays (0, 0.5, 1.0 and 3.0 Gy, at the dose rate of 0.72 Gy/min). Blood-smear slides were stained with acridine orange (AO). The frequencies of MN were measured in mature normochromatic-erythrocytes (MN-NCEs) and in immature polychromatic-erythrocytes (MN-PCEs). Effects of both types of radiation on erythropoiesis were also evaluated. As a measure of cell progression delay, a dose-dependent decrease in numbers of PCEs was observed at day 2 post-exposure in both strains, regardless of radiation quality. Subsequently, the levels of PCEs increased in all exposed mice, reaching control levels (or higher) by day 7 post-exposure. Further, at day 2 after the exposure, there was no increase in the frequency of MN-PCEs in CBA/CaJ mice exposed to ⁵⁶Fe ions while the frequency of MN-PCEs elevated as a function of dose in the C57BL/6J mice. At day 4, there was no dose related increase in MN-NCEs in either strain of mouse exposed to ¹³⁷Cs gamma rays. Additionally, at the early sacrifice times (days 2 and 4), ⁵⁶Fe ions were slightly more effective (per unit dose) in inducing MN-NCEs than ¹³⁷Cs gamma rays in CBA/CaJ mice. However, there was no increase in the frequency of MN-NCEs at late times after an acute exposure to either type of radiation. In contrast, both types of radiation induced increased MN-PCEs frequencies in irradiated CBA/CaJ mice, but not C57BL/6J mice, at late times post-exposure. This finding indicates the potential induction of genomic instability in hematopoietic cells of CBA/CaJ mice by both types of radiation. The finding also demonstrates the influence of genetic background on radiation-induced genomic instability in vivo.     

Animal studies of life shortening and cancer risk from space radiation.

The U.S. Air Force study of the delayed effects of single, total body exposures to simulated space radiation in rhesus monkeys is now in its 21st year. Observations on 301 irradiated and 57 age-matched control animals indicate that life expectancy loss from exposure to protons in the energy range encountered in the Van Allen belts and solar proton events can be expressed as a logarithmic function of the dose. The primary causes of life shortening are cancer and endometriosis (an abnormal proliferation of the lining of the uterus in females). Life shortening estimates permit comparison of the risk associated with space radiation exposures to be compared with that of other occupational and environmental hazards, thereby facilitating risk/benefit decisions in the planning and operational phases of manned space missions. Calculations of the relative risk of fatal cancers in the irradiated subjects reveal that the total body surface dose required to double the risk of death from cancer over a 20-year post exposure period varies with the linear energy transfer (LET) of the radiation. The ability to determine the integrated dose and LET spectrum in space radiation exposures of humans is, therefore, critical to the assessment of lifetime cancer risk.     

New approaches to biochemical radioprotection: antioxidants and DNA repair enhancement.

Chemical repair may be provided by radioprotective compounds present during exposure to ionizing radiation. Considering DNA as the most sensitive target it is feasible to biochemically improve protection by enhancing DNA repair mechanisms. Protection of DNA by reducing the amount of damage (by radical scavenging and chemical repair) followed by enhanced repair of DNA will provide much improved protection and recovery. Furthermore, in cases of prolonged exposure, such as is possible in prolonged space missions, or of unexpected variations in the intensity of radiation, as is possible when encountering solar flares, it is important to provide long-acting protection, and this may be provided by antioxidants and well functioning DNA repair systems. It has also become important to provide protection from the potentially damaging action of long-lived clastogenic factors which have been found in plasma of exposed persons from Hiroshima & Nagasaki, radiation accidents, radiotherapy patients and recently in "liquidators"--persons involved in salvage operations at the Chernobyl reactor. The clastogenic factor, which causes chromatid breaks in non-exposed plasma, might account for late effects and is posing a potential carcinogenic hazard. The enzyme superoxide dismutase (SOD) has been shown to eliminate the breakage factor from cultured plasma of exposed persons. Several compounds have been shown to enhance DNA repair: WR-2721, nicotinamide, glutathione monoester (Riklis et al., unpublished) and others. The right combination of such compounds may prove effective in providing protection from a wide range of radiation exposures over a long period of time.     

Countermeasures for space radiation induced adverse biologic effects

Radiation exposure in space is expected to increase the risk of cancer and other adverse biological effects in astronauts. The types of space radiation of particular concern for astronaut health are protons and heavy ions known as high atomic number and high energy (HZE) particles. Recent studies have indicated that carcinogenesis induced by protons and HZE particles may be modifiable. We have been evaluating the effects of proton and HZE particle radiation in cultured human cells and animals for nearly a decade. Our results indicate that exposure to proton and HZE particle radiation increases oxidative stress, cytotoxicity, cataract development and malignant transformation in in vivo and/or in vitro experimental systems. We have also shown that these adverse biological effects can be prevented, at least partially, by treatment with antioxidants and some dietary supplements that are readily available and have favorable safety profiles. Some of the antioxidants and dietary supplements are effective in preventing radiation induced malignant transformation in vitro even when applied several days after the radiation exposure. Our recent progress is reviewed and discussed in the context of the relevant literature.     

Thermonuclear flashes on magnetized neutron stars as a model for gamma-ray bursts

We propose, as a model for gamma ray bursts, that the energy released by a thermonuclear runaway at the surface of a slowly accreting, magnetized neutron star, is converted into gamma ray photons by small scale magnetic field reconnection. Most of the energy flux is transported up to the atmosphere by Alfvén waves, driven by oscillatory magnetoconvection. The electric field created by reconnection accelerates electrons to very high energies. The excitation of Landau levels by collisions is followed by gamma ray synchrotron emission. The time scales, energies, and luminosities involved agree with the observations.     

Modeling gamma radiation from millisecond pulsars

We present spectral and directional properties of gamma radiation obtained by numerical modeling of two millisecond pulsars, PSR J0218+4232 and PSR J0437-4715. The general relativistic space charge limited flow model of Muslimov and Harding [Toward the quasi-steady state electrodynamics of a neutron star. Astrophys. J. 485, 735–746, 1997] in its version of an unscreened accelerating electric field was used. The results give both general ideas and constraints on the specific character of magnetospheric activity in each of these two pulsars.     

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.     

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.     

Spaceflight-relevant types of ionizing radiation and cortical bone: Potential LET effect?

Extended exposure to microgravity conditions results in significant bone loss. Coupled with radiation exposure, this phenomenon may place astronauts at a greater risk for mission-critical fractures. In a previous study, we identified a profound and prolonged loss of trabecular bone (29–39%) in mice following exposure to an acute, 2 Gy dose of radiation simulating both solar and cosmic sources. However, because skeletal strength depends on trabecular and cortical bone, accurate assessment of strength requires analysis of both bone compartments. The objective of the present study was to examine various properties of cortical bone in mice following exposure to multiple types of spaceflight-relevant radiation. Nine-week old, female C57BL/6 mice were sacrificed 110 days after exposure to a single, whole body, 2 Gy dose of gamma, proton, carbon, or iron radiation. Femora were evaluated with biomechanical testing, microcomputed tomography, quantitative histomorphometry, percent mineral content, and micro-hardness analysis. Compared to non-irradiated controls, there were significant differences compared to carbon or iron radiation for only fracture force, medullary area and mineral content. A greater differential effect based on linear energy transfer (LET) level may be present: high-LET (carbon or iron) particle irradiation was associated with a decline in structural properties (maximum force, fracture force, medullary area, and cortical porosity) and mineral composition compared to low-LET radiation (gamma and proton). Bone loss following irradiation appears to be largely specific to trabecular bone and may indicate unique biological microenvironments and microdosimetry conditions. However, the limited time points examined and non-haversian skeletal structure of the mice employed highlight the need for further investigation.     

RBE for non-stochastic effects.

Evidence is reviewed concerning the variation of RBE values of high-LET radiations for non-stochastic effects, generally impairment of tissue integrity and function. The RBE values are dependent on the type of radiation, the type of tissue effect and the dose rate or fractionation schedule. RBE values depend strongly on the effect considered, with high values for late effects in lung, kidney and central nervous system. RBE values generally increase with decreasing dose rate or dose per fraction. Maximum values can be derived by extrapolation on the basis of a radiobiological model. These values are denoted RBEm to distinguish them from RBEM derived for stochastic effects, e.g. carcinogenesis. Values of RBEm are generally in the range of 2 to 10 and are considerably smaller by a factor of 2 to 5 than values of RBEM for various types of stochastic effects. RBE values for effects from actual exposures to mixtures of high-LET and low-LET radiations can be derived by considering the doses received and the tissue at risk. Applications of RBEm values will yield estimates of maximum values of equivalent doses and these should only be applied for planning medical interventions if the contribution from high-LET radiation is small. The selection of Q values for radiation protection is mostly based on RBE--values and the application of Q values in cases where non-stochastic effects are important might therefore result in an overestimate of the risks of exposure.     

Neutron yields from interactions of GCR-like beams in stopping targets.

In order to accurately determine the radiation risk to astronauts from GCR, the nature of the secondary radiation field created by the fragmentation of GCR in shielding and tissue must be understood. Due to the their high penetrabilities, neutrons are an important component of the secondary radiation field, especially for astronauts protected by thick shielding on lunar or Martian bases. Neutron yields from 435A MeV and 272A MeV Nb stopping in Nb and Al targets are presented, along with some preliminary analysis of neutron yields from 155A MeV C stopping in Al. Energy spectra and angular distributions are shown for neutron energies above 20 MeV. The data provides some information about the dependence of the neutron yield on projectile energy and target mass. Comparisons of the data with BUU calculations are also shown.     

Radiation protection standards in space.

Radiation protection standards for the individual exposed to ionizing radiation in his/her daily work have evolved over more than 50 years since the first recommendations on limits by the NCRP and the ICRP. Initial standards were based on the absence of observable harm, notably skin erythema, but have since been modified as other concerns, such as leukemia and genetic effects, became more important. More recently, the general carcinogenic effect of radiation has become the principal concern at low doses. Genetic effects are also of concern in the younger individual. Modern radiation protection practices take both of these risks into account. Quantification of these risks improves as new information emerges. The study of the Japanese survivors of the atomic bombs continues to yield new information and the recent revisions in the dosimetry are about to be completed. The special circumstances of space travel suggest approaches to limits not unlike those for radiation workers on the ground. One approach is to derive a career limit based on the risks of accident faced by many nonradiation workers in a lifetime. The career limit can be apportioned according to the type of mission. The NCRP is considering this and other approaches to the specification of radiation standards in space.     

Mapping the earth's magnetic and gravity fields from space: Current status and future prospects

Orbital potential field measurements are sensitive to regional variations in earth density and magnetization that occur over scales of a few hundred kilometers or greater. Global field models currently available are able to distinguish gravity variations of ±5 milligal over distances of ～1,000 km and magnetic variations of ±6 gamma over distances of ～300 km at the earth's surface. Regional variations in field strength have been detected in orbital measurements that are not apparent in higher resolution, low altitude surveys. NASA is presently studying a spacecraft mission known as GRAVSAT/MAGSAT, which would be the first satellite mission to perform a simultaneous survey of the earth's gravity and magnetic fields at low orbital altitudes. GRAVSAT/MAGSAT has been proposed for launch during the latter nineteen-eighties, and it would measure gravity field strength to an accuracy of 1 milligal and magnetic field strength to an accuracy of 2 gamma (scalar)/5 gamma (vector components) over a distance of roughly 100 km. Even greater improvements in the accuracy and spatial resolution of orbital surveys are anticipated during the nineteen-nineties with the development of potential field gradiometers and a tethered satellite system that can be deployed from the Space Shuttle to altitudes of 120 km above the earth's surface.     

Radiation protection issues in galactic cosmic ray risk assessment.

Radiation protection involves the limitation of exposure to below threshold doses for direct (or deterministic) effects and a knowledge of the risk of stochastic effects after low doses. The principal stochastic risk associated with low dose rate galactic cosmic rays is the increased risk of cancer. Estimates of this risk depend on two factors (a) estimates of cancer risk for low-LET radiation and (b) values of the appropriate radiation weighting factors, WR, for the high-LET radiations of galactic cosmic rays. Both factors are subject to considerable uncertainty. The low-LET cancer risk derived from the late effects of the atomic bombs is vulnerable to a number of uncertainties including especially that from projection in time, and from extrapolation from high to low dose rate. Nevertheless, recent low dose studies of workers and others tend to confirm these estimates. WR, relies on biological effects studied mainly in non-human systems. Additional laboratory studies could reduce the uncertainties in WR and thus produce a more confident estimate of the overall risk of galactic cosmic rays.     

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.