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.

A new perspective of carcinogenesis from protracted high-LET radiation arises from the two-stage clonal expansion model.

When applied to the Colorado Plateau miner population, the two-stage clonal expansion (TSCE) model of radiation carcinogenesis predicts that radiation-induced promotion dominates radiation-induced initiation. Thus, according to the model, at least for alpha-particle radiation from inhaled radon daughters, lung cancer induction over long periods of protracted irradiation appears to be dominated by radiation-induced modification of the proliferation kinetics of already-initiated cells rather than by direct radiation-induced initiation (i.e., mutation) of normal cells. We explore the possible consequences of this result for radiation exposures to space travelers on long missions. Still unknown is the LET dependence of this effect. Speculations of the cause of this phenomenon include the suggestion that modification of cell kinetics is caused by a "bystander" effect, i.e., the traversal of normal cells by alpha particles, followed by the signaling of these cells to nearby initiated cells which then modify their proliferation kinetics.

The role of promotion in carcinogenesis from protracted high-LET exposure.

Recent analysis of epidemiological studies using the two-stage clonal expansion (TSCE) model has shown that radiation-induced promotion dominates radiation-induced initiation for protracted exposures to radon. This strong promotion effect (i.e. enhanced proliferation of already-initiated cells) causes a pronounced 'inverse dose-rate effect', but by a mechanism completely different from those usually discussed in this connection. This rather startling result is discussed along with implications to extended space missions that include a significant amount of high-LET radiation. It is suggested that the effect might be caused by a 'Bystander Effect' by which normal cells in the vicinity of initiated cells are hit by alpha particles and send out signals that modify the cell kinetics of the already-initiated clones.

Somatostatin receptor subtype expression and function in human vascular tissue.

In animal models the somatostatin analog angiopeptin inhibits intimal hyperplasia by acting primarily through somatostatin receptor 2 (SSTR-2). However, the results of clinical trials using angiopeptin have been disappointing. In this study we showed that human blood vessels express high levels of SSTR-1 with significantly lower levels of SSTR-2 and -4. Samples of normal veins and arteries, as well as atherosclerotic arteries, expressed predominantly SSTR-1. In addition, the levels of SSTR-1 varied between individuals, indicating that the vascular disease process may have affected SSTR gene expression. Immunocytochemical studies demonstrated that SSTR-1 was present in endothelial but not vascular smooth muscle cells. No evidence of SSTR-3 or -5 expression was detected in normal or diseased blood vessels. Two endothelial cell preparations, ECV304 and human umbilical vein endothelial cells, were investigated and shown to express only SSTR-1 and -4. Exposure of these cells to 10 nM somatostatin or 10 nM SSTR-1-specific agonist resulted in alterations to the actin cytoskeleton, as characterized by a loss of actin stress fibers coupled with an increase in lamellipodia formation at the plasma membrane. These results suggest that the lack of effectiveness of angiopeptin in humans may be due to the differential expression of SSTR-1 by human endothelial cells.

The extracellular calcium-sensing receptor on human beta-cells negatively modulates insulin secretion.

The presence and functional significance of the extracellular calcium-sensing receptor (CaR) on human pancreatic beta-cells were investigated. Reverse transcriptase-polymerase chain reaction with primers for the extracellular domain of the CaR expressed in human parathyroid-secreting cells identified a product of the expected size in human pancreatic mRNA. Immunocytochemistry using an antibody against the extracellular region of CaR showed extensive immunoreactivity in insulin- and glucagon-containing cells but not in somatostatin-containing cells. In perifusion experiments, elevations in extracellular Ca2+ produced initial transient increases in insulin secretion, followed by a concentration-dependent and prolonged, but reversible, inhibition of secretion. Microfluorometric measurements of intracellular Ca2+ ([Ca2+]i) in isolated human beta-cells demonstrated that elevations in extracellular Ca2+ (0.5-10 mmol/l) caused rapid elevations in [Ca2+]i. Increases in extracellular Ca2+ caused small increases in the cyclic AMP content of whole human islets. These studies demonstrated that human beta-cells express an extracellular CaR and that activation of the receptor inhibits basal and nutrient-stimulated insulin secretion. The transduction mechanism that mediates this inhibitory effect is unknown, but our results suggest that it is unlikely to be through the adenylate cyclase-cyclic AMP pathway or through the phospholipase C-IP3 pathway. This CaR-mediated inhibitory mechanism may be an important autoregulatory mechanism in the control of insulin secretion.

Effect of endothelial and adventitial injury on somatostatin receptor expression.

BACKGROUND: The somatostatin analog, angiopeptin, inhibits intimal hyperplasia formation; although the specific somatostatin receptor (SSTR) subtypes transducing this effect are unknown. The purpose of this study was to determine the expression of SSTR subtypes in rat iliac arteries after balloon catheter endothelial injury and perivascular dissection. METHODS: Male rats received balloon endothelial injury to their left common and external iliac arteries with or without circumferential arterial dissection. The right arteries served as controls. At 1 and 2 months after intimal injury, animals were killed and their iliac arteries harvested and studied for SSTR expression by using immunocytochemical and molecular techniques. Quantitative polymerase chain reaction was used to determine the level of SSTR expression. RESULTS: Normal rat iliac arteries expressed only SSTR2 and 3. After balloon endothelial injury, there was significant upregulation of SSTR2 messenger RNA at 1 and 2 months after injury as compared with controls (1 month, 1.8 +/- 0.3 vs 0.4 +/- 0.1 zmol, P < .001; 2 months, 2.7 +/- 0.5 vs 1.1 +/- 0.2 zmol, P < .001). The addition of adventitial dissection to endothelial injury also showed a significant increase in SSTR2 expression (1 month, 2.4 +/- 0.4 vs 0.8 +/- 0.2, P < .05; 2 months, 1.3 +/- 0.3 vs 0.7 +/- 0.3, P < .05), but not significantly greater than that seen after balloon endothelial injury alone. Immunocyto-chemical studies also demonstrated an increase in SSTR2 immunoreactivity on the luminal surface of the endothelial cells in the balloon catheter-injured arteries. CONCLUSIONS: These findings show that SSTR2 is the primary SSTR that is upregulated after injury and likely mediates the effects of somatostatin analogs on intimal hyperplasia.

Cosmic ray hits in the central nervous system at solar maximum.

It has been suggested that a manned mission to Mars be launched at solar maximum rather than at solar minimum to minimize the radiation exposure to galactic cosmic rays. It is true that the number of hits from highly ionizing particles to critical regions in the brain will be less at solar maximum, and it is of interest to estimate how much less. We present here calculations for several sites within the brain from iron ions (z = 26) and from particles with charge, z, greater than or equal to 15. The same shielding configurations and sites in the brain used in an earlier paper for solar minimum are employed so that direct comparison of results between the two solar activity conditions can be made. A simple pressure-vessel wall and an equipment room onboard a spacecraft are chosen as shielding examples. In the equipment room, typical results for the thalamus are that the probability of any particles with 7 greater than or equal to 15 and from 2.3 percent to 1.3 percent for iron ions. The extra shielding provided in the equipment room makes little difference in these numbers. We conclude that this decrease in hit frequency (less than a factor of two) does not provide a compelling reason to avoid solar minimum for a manned mission to Mars. This conclusion could be revised, however, if a very small number of hits is found to cause critical malfunction within the brain.

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.

Expression of the calcium-sensing receptor on human antral gastrin cells in culture.

The presence of the extracellular calcium-sensing receptor on human antral gastrin cells was investigated. Reverse transcription PCR using mRNA isolated from gastrin cell- enriched cell cultures identified a product with a sequence identical to part of the human parathyroid-secreting cell calcium-sensing receptor. Immunocytochemistry with an antibody to the extracellular region of the receptor immunostained all gastrin cells (but not mucin or somatostatin cells), and detected appropriate-sized bands in Western blots of whole cell lysates. Increasing extracellular calcium levels from 0.5 to 9 mM stimulated gastrin release in a concentration-dependent manner, with maximal release obtained at 7.2 mM. A known agonist of the calcium receptor, spermine also stimulated gastrin release. Microfluorimetry of identified gastrin cells demonstrated that increasing extracellular calcium resulted in an initial rapid rise in intracellular calcium followed by a plateau level that returned to basal levels immediately after removal of the elevated calcium. The traces were consistent with activation of a receptor-mediated mechanism rather than a concentration-dependent influx of calcium. In conclusion, these data indicate that G cells express the calcium-sensing receptor, and that activation of the receptor may explain the acid rebound phenomenon associated with calcium-containing antacid preparations.

Two-stage model of radon-induced malignant lung tumors in rats: effects of cell killing.

A two-stage stochastic model of carcinogenesis is used to analyze lung tumor incidence in 3750 rats exposed to varying regimens of radon carried on a constant-concentration uranium ore dust aerosol. New to this analysis is the parameterization of the model such that cell killing by the alpha particles could be included. The model contains parameters characterizing the rate of the first mutation, the net proliferation rate of initiated cells, the ratio of the rates of cell loss (cell killing plus differentiation) and cell division, and the lag time between the appearance of the first malignant cell and the tumor. Data analysis was by standard maximum likelihood estimation techniques. Results indicate that the rate of the first mutation is dependent on radon and consistent with in vitro rates measured experimentally, and that the rate of the second mutation is not dependent on radon. An initial sharp rise in the net proliferation rate of initiated cell was found with increasing exposure rate (denoted model I), which leads to an unrealistically high cell-killing coefficient. A second model (model II) was studied, in which the initial rise was attributed to promotion via a step function, implying that it is due not to radon but to the uranium ore dust. This model resulted in values for the cell-killing coefficient consistent with those found for in vitro cells. An "inverse dose-rate" effect is seen, i.e. an increase in the lifetime probability of tumor with a decrease in exposure rate. This is attributed in large part to promotion of intermediate lesions. Since model II is preferable on biological grounds (it yields a plausible cell-killing coefficient), such as uranium ore dust. This analysis presents evidence that a two-stage model describes the data adequately and generates hypotheses regarding the mechanism of radon-induced carcinogenesis.

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.

Risk cross sections and their application to risk estimation in the galactic cosmic-ray environment.

Radiation risk cross sections (i.e. risks per particle fluence) are discussed in the context of estimating the risk of radiation-induced cancer on long-term space flights from the galactic cosmic radiation outside the confines of the earth's magnetic field. Such quantities are useful for handling effects not seen after low-LET radiation. Since appropriate cross-section functions for cancer induction for each particle species are not yet available, the conventional quality factor is used as an approximation to obtain numerical results for risks of excess cancer mortality. Risks are obtained for seven of the most radiosensitive organs as determined by the ICRP [stomach, colon, lung, bone marrow (BFO), bladder, esophagus and breast], beneath 10 g/cm2 aluminum shielding at solar minimum. Spectra are obtained for excess relative risk for each cancer per LET interval by calculating the average fluence-LET spectrum for the organ and converting to risk by multiplying by a factor proportional to R gamma L Q(L) before integrating over L, the unrestricted LET. Here R gamma is the risk coefficient for low-LET radiation (excess relative mortality per Sv) for the particular organ in question. The total risks of excess cancer mortality obtained are 1.3 and 1.1% to female and male crew, respectively, for a 1-year exposure at solar minimum. Uncertainties in these values are estimated to range between factors of 4 and 15 and are dominated by the biological uncertainties in the risk coefficients for low-LET radiation and in the LET (or energy) dependence of the risk cross sections (as approximated by the quality factor). The direct substitution of appropriate risk cross sections will eventually circumvent entirely the need to calculate, measure or use absorbed dose, equivalent dose and quality factor for such a high-energy charged-particle environment.

Proinsulin mRNA and peptide are present in beta-cells of diabetic BB rats.

Previous studies have demonstrated that islets isolated from newly diabetic BB rat pancreata retain the ability to release insulin in culture, although in vivo the insulin response to stimulation is absent. The purpose of this study was to determine whether the beta-cells in these newly diabetic animals were releasing stored insulin or whether they were still capable of insulin biosynthesis, since secretory defects may reflect abnormalities in insulin synthetic capacity. Insulin gene transcription was examined using in situ hybridization to detect preproinsulin mRNA (ppImRNA) at the level of the single cell since this technique provides a valid semiquantitative index of insulin biosynthesis. In situ hybridization with digoxigenin-labeled rat insulin probes resulted in strong labeling of beta-cells in normal Wistar rat pancreata; other islet and acinar cells were negative. Double labeling of sections with an antibody to insulin confirmed that the labeled cells were beta-cells only. The intensity of the staining was variable between different islets within the same section, and sometimes within an islet. Nondiabetic and diabetic BB islets were also positive for ppImRNA not only in normal islets but also in islets affected by insulitis. Islets that contained very few beta-cells also contained ppImRNA. A consistent finding was that the intensity of the hybridization signal in many islets from the diabetic BB rats was stronger than in controls, suggesting that there is more ppImRNA in these islets. beta-Cells that were positive for ppImRNA but negative for insulin peptide were also observed; these were in islets that were affected by insulitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluence-based relative biological effectiveness for charged particle carcinogenesis in mouse Harderian gland.

Neoplasia in the rodent Harderian gland has been used to determine the carcinogenic potential of irradiation by HZE particles. Ions from protons to lanthanum at energies up to 670 MeV/a have been used to irradiate mice, and prevalence of Harderian gland tumors has been measured 16 months after irradiation. The RBE for tumor induction has been expressed as the RBEmax, which is the ratio of the initial slopes of the dose vs prevalence curve. The RBEmax has been found to be approximately 30 for ions with LET values in excess of 100 keV/micrometer. Analysis on the basis of fluence as a substitute for dose has shown that on a per particle basis all of the ions with LET values in excess of 100 keV/micrometer have equal effectiveness. An analysis of the probabilities of ion traversals of the nucleus has shown that for these high stopping powers that a single hit is effective in producing neoplastic transformation.

Single track effects, Biostack and risk assessment.

The scientific career of Prof. Bucker has spanned a very exciting period in the fledgling science of Space Radiation Biology. The capability for placing biological objects in space was developed, and the methods for properly packaging, retrieving and analyzing them were worked out. Meaningful results on the effects of radiation were obtained for the first time. In fact, many of the successful techniques and methodologies for handling biological samples were developed in Prof. Bucker's laboratories, as attested by the extensive Biostack program. He was the first to suggest and successfully carry out experiments in space directly aimed at measuring effects of single tracks of high-energy heavy galactic cosmic rays by specifically identifying whether or not the object had been hit by a heavy particle track. Because the "hit" frequencies of heavy galactic cosmic rays to cell nuclei in the bodies of space travelers will be low, it is expected that any effects to humans on the cellular level will be dominated by single-track cell traversals. This includes the most important generally recognized late effect of space radiation exposure: radiation-induced cancer. This paper addresses the single-track nature of the space radiation environment, and points out the importance of single "hits" in the evaluation of radiation risk for long-term missions occurring outside the earth's magnetic field. A short review is made of biological objects found to show increased effects when "hit" by a single heavy charged-particle in space. A brief discussion is given of the most provocative results from the bacterial spore Bacillus subtilis: experimental evidence that tracks can affect biological systems at much larger distances from the trajectory than previously suspected, and that the resultant inactivation cross section in space calculated for this system is very large. When taken at face value, the implication of these results, when compared to those from experiments performed at ground-based accelerators with beams at low energies in the same LET range, is that high-energy particles can exert their influence a surprising distance from their trajectory and the inactivation cross sections are some 20 times larger than expected. Clearly, beams from high-energy heavy-ion accelerators should be used to confirm these results. For those end points that can also be caused by low-LET beams such as high-energy protons, it is important to measure their action cross sections as well. The ratio of the cross sections for a high-LET beam to that of a low-LET beam is an interesting experimental ratio and, we suggest, of more intrinsic interest than the RBE (Relative Biological Effectiveness). It is a measure of the "biological" importance of one particle type relative to another particle type. This ratio will be introduced and given the name RPPE (Relative Per Particle Effectiveness). Values of RPPE have appeared in the literature and will be discussed. A rather well-known value of this quantity (13,520) has been suggested for the RPPE of high-energy iron ions to high-energy protons. This value was suggested by Letaw et al. Nature 330, 709-710 (1987)] we will call it the Letaw limit. It will be discussed in terms of the importance of the heavy-ion component vs light-ion component of the galactic cosmic rays. It is also pointed out, however, that there may be unique effects from single tracks of heavy ions that do not occur from light-ion tracks. For such effects, the concepts of both RBE and RPPE lose their meaning.

Single-track effects and new directions in GCR risk assessment.

Light flashes in the eye as recorded by astronauts on missions outside the geomagnetosphere are presumably caused by single particle traversals of galactic cosmic rays traversing the retina. Although these flashes are not considered to have deleterious short- or long-term effects on vision, they are testimony that the body can detect single particle traversals. The frequencies of the flashes implicate ions in the charge range of 6 to 8 (i.e., carbon and/or oxygen ions). Other particles with higher charge and causing more ionization are present at lower frequencies. The possibility of the importance of such single-track effects in radiation carcinogenesis and other late effects suggest that a risk assessment system based on particle fluence rather than absorbed dose might be useful for assessing risk on long-term space missions. Such a system based on the concept of a risk cross section is described. Human cancer risk cross sections obtained from recently compiled A-bomb survival data are presented, and problems involving the determination of the LET-dependence of such cross sections are discussed.

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.

Tumorigenic potential of high-Z, high-LET charged-particle radiations.

The potential for radiogenic neoplasia from charged-particle irradiation has been estimated using the Harderian gland of the mouse as a test system. Particles ranging in Z from Z = 1 (proton) to Z = 41 (niobium), in energy from 228 to 670A MeV, and in LET from 0.4 to 464 keV/microns were produced at the Lawrence Berkeley Laboratory BEVALAC. Expression of the tumorigenic potential of the initiated cells was enhanced by hormones from isogeneic grafts of pituitaries. The goal of the studies was to estimate the initial slope of the relationship between increased tumor prevalence at 16 months after irradiation and the dose received. Initial slopes were measured with good precision for 60Co gamma rays and the Bragg plateau beams of 228A MeV 4He ions, 600A MeV 56Fe ions, and 350A MeV 56Fe ions. The ratio of the initial slope for these ions to that of 60Co gamma rays give an estimate of the maximum RBE for radiogenic neoplasia. These values were 2.3 for the 4He ions, 40 for 600A MeV 56Fe, and 20 for 350A MeV 56Fe. In the studies reported here the prevalence of tumors as the result of pituitary isografts was not enhanced after irradiation with 56Fe ions. It remains to be seen how effective pituitary isografts are for enhancement of radiogenic neoplasia from other ions at different LET values. A risk analysis was undertaken using particle fluence rather than dose as the independent variable. This analysis provides a value for a "cross section" expressed in microns 2. This parameter expresses as the increase in proportion of mice with one or more Harderian gland tumors per unit increase in particle fluence. The plot of the cross section (risk coefficient) as a function of LET is monotonic, with no clear evidence of a maximum value of the risk coefficient for even the highest LET particle used.

Risk from relativistic heavy ions on manned space missions.

The risk from exposure to radiation posed to space travelers outside the magnetic shielding provided by the geomagnetosphere will come from two sources: the slowly varying but low intensity high-energy galactic cosmic rays and the more intense predominantly low-energy protons from large solar particle events associated with magnetic disturbances originating sporadically on or within the solar surface during the active period of the 11-year solar cycle. The energy spectra of the protons in solar particle events are quite soft, with large numbers of low-energy protons and a rather steep decrease of the energy spectra with increasing energy. This allows for the possibility to provide, within the space vehicle or habitat, a well-shielded area sometimes called a "storm shelter" or "safe haven" where the travelers could gather during the largest particle events. Intensity risetimes on the order of half an hour or more and overall event durations of 1 to 2 days would make actively seeking a well-shielded shelter for the duration a distinct possibility. The high-energy and penetrating nature and relative constancy of the galactic cosmic rays, on the other hand, do not allow the use of highly shielded areas as a means of protection against them. The first question to answer becomes: what is the risk to human health from the galactic cosmic rays? We need to have a good idea of the answer to this question before we can address the problem of how to best protect human health or, indeed, whether any specific measures need to be taken.