Limitations in predicting the space radiation health risk for exploration astronauts

Jeffery Chancellor; Rebecca Blue; Keith Cengel; Serena Auñón-Chancellor; Kathleen Rubins; Helmut Katzgraber; Ann Kennedy

doi:10.1038/s41526-018-0043-2

Limitations in predicting the space radiation health risk for exploration astronauts

Chancellor, Jeffery; Blue, Rebecca; Cengel, Keith; Auñón-Chancellor, Serena; Rubins, Kathleen; Katzgraber, Helmut; Kennedy, Ann 2018-04-03 00:00:00 www.nature.com/npjmgrav REVIEW ARTICLE OPEN Limitations in predicting the space radiation health risk for exploration astronauts 1 2 3 4,5 4 Jeffery C. Chancellor , Rebecca S. Blue , Keith A. Cengel , Serena M. Auñón-Chancellor , Kathleen H. Rubins , 1,6,7 3 Helmut G. Katzgraber and Ann R. Kennedy Despite years of research, understanding of the space radiation environment and the risk it poses to long-duration astronauts remains limited. There is a disparity between research results and observed empirical effects seen in human astronaut crews, likely due to the numerous factors that limit terrestrial simulation of the complex space environment and extrapolation of human clinical consequences from varied animal models. Given the intended future of human spaceﬂight, with efforts now to rapidly expand capabilities for human missions to the moon and Mars, there is a pressing need to improve upon the understanding of the space radiation risk, predict likely clinical outcomes of interplanetary radiation exposure, and develop appropriate and effective mitigation strategies for future missions. To achieve this goal, the space radiation and aerospace community must recognize the historical limitations of radiation research and how such limitations could be addressed in future research endeavors. We have sought to highlight the numerous factors that limit understanding of the risk of space radiation for human crews and to identify ways in which these limitations could be addressed for improved understanding and appropriate risk posture regarding future human spaceﬂight. npj Microgravity (2018) 4:8 ; doi:10.1038/s41526-018-0043-2 INTRODUCTION A recent report by Schwadron et al. has identiﬁed further concerns regarding the interplanetary radiation environment. While space radiation research has expanded rapidly in recent The unusually low activity between solar cycles 23 and 24 (1996- years, large uncertainties remain in predicting and extrapolating present) has resulted in the longest period of minimum solar biological responses to radiation exposure in humans. As future activity observed in over 80 years of solar measurements. The lack missions explore outside of low-Earth orbit (LEO) and away from of solar activity has led to a substantial decrease in solar wind the protection of the Earth’s magnetic shielding, the nature of the density and magnetic ﬁeld strengths that typically attenuate the radiation exposures that astronauts encounter will include higher ﬂuence (the ﬂux of particles crossing a given plane) of Galactic radiation exposures than any experienced in historical human Cosmic Ray (GCR) ions during periods of solar minimum. As a spaceﬂight. In 1988, the National Council on Radiation Protection result, Schwadron et al. project that GCR ﬂuences will be and Measurements (NCRP) released Report No. 98: Guidance On substantially higher during the next solar cycles (24–25) leading Radiation Received in Space Activities. In this report, authors to increased background radiation exposure and, subsequently, as recommended that NASA astronauts be limited to career lifetime much as a 20% decrease in the allowable safe days in space radiation exposures that would induce no more than a 3% Risk of (outside of LEO) to stay below the 3% REID limits. Exposure-Induced Death (REID). This was re-emphasized in the The study of human health risks of spaceﬂight (e.g., bone 2015 NCRP Commentary No. 23: Radiation Protection for Space health, behavior, nutrition, etc.) typically involves analogs that Activities: Supplement to Previous Recommendations, which closely represent the space environment. In most cases, theory, concluded that NASA should continue to observe the 3% REID models, and study outcomes can be validated with available career limit for future missions outside of LEO. This limit has been spaceﬂight data or, at a minimum, observation of humans accepted in NASA’s Spaceﬂight Human-System Standard docu- subjected to analog terrestrial stresses. In contrast, space radiation ment, NASA STD-3001 Volume 1 (Revision A). research is limited to the use of analogs or models that for many Despite the adoption of these guidelines and the past 30 years of research, there has been little progress on fully deﬁning or reasons do not accurately represent the operational space radiation environment or the complexity of human physiology. mitigating the space radiation risk to human crew. In fact, the For example, studies on the effects of space radiation generally NCRP’s recent conclusions speciﬁed that their 3% limit may not be use mono-energetic beams and acute, single-ion exposures conservative enough given the incomplete biological data used in (including protons, lithium, carbon, oxygen, silicon, iron, etc.) existing projection models, and that such models may over- estimate the number of allowable “safe days” in space for missions instead of the complex energy spectra and diverse ionic outside of LEO. composition of the space radiation environment. In addition, a 1 2 Department of Physics and Astronomy, Texas A&M University, College Station, TX 77843-4242, USA; Aerospace Medicine and Vestibular Research Laboratory, The Mayo Clinic 3 4 Arizona, Scottsdale, AZ 85054, USA; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; National 5 6 Aeronautics and Space Administration (NASA), Johnson Space Center, Houston 77058, USA; University of Texas Medical Branch, Galveston, TX 77555, USA; 1QB Information Technologies (1QBit), Vancouver, BC V6B 4W4, Canada and Santa Fe Institute, 1399 Hyde Park Road, Santa Fe, NM 87501, USA Correspondence: Jeffery C. Chancellor (jeff@chancellor.space) Received: 19 August 2017 Revised: 20 February 2018 Accepted: 12 March 2018 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA Limitations in predicting the space radiation health risk JC Chancellor et al. projected, cumulative mission dose is often delivered in one-time, or rapid and sequential, doses delivered to experimental animals. 3.5 In most cases, these dose-rates are several orders of magnitude higher than actual space environment exposures. Even the use of animal models introduces error, as studies make use of a variety of Human 2.5 d = 30 cm animal species with differing responses and sensitivity to radiation that may not represent human responses to similar exposures. Pig Further, studies do not challenge multiple organ systems to d = 20 cm 1.5 respond concurrently to the numerous stressors seen in an operational spaceﬂight scenario. Historical epidemiological studies of humans, which are generally used for correlation of animal and Mouse experimental models, include populations such as atomic bomb or 0.5 d = 3 cm nuclear accident survivors exposed to whole-body irradiation at high doses and high dose-rates, limited to scenarios not found in 0 102030 405060 spaceﬂight. These disparities and numerous other environmental Proton Energy (MeV) considerations contribute to the large uncertainties in the Fig. 1 Depth dose, energy, and linear energy transfer characteristics outcomes of space radiobiology studies and the applicability of of protons. The range of proton energies relative to the body such studies for extrapolation and prediction of clinical health diameter (dotted lines) and bone marrow depth (ordinate) for mice, outcomes in future spaceﬂight crews. pigs, and humans for energies up to 60 MeV. Figure reprinted by Here we seek to highlight these factors that contribute to the permission from Conditions for RightsLink Permissions Springer challenge of radiation risk prediction and mitigation for future Customer Service Center GmbH:Springer-Verlag exploration spaceﬂight. Our intent is to provide an understanding of the current state of radiation-speciﬁc literature, efforts towards better deﬁning the space radiation environment, and the difﬁculties in realization of this effort that limit current knowledge. Further, we hope to identify opportunities for future research that could best elucidate a path towards successful deﬁnition and mitigation of the space radiation risk to humans outside of LEO. THE SPACE RADIATION ENVIRONMENT 10 Biological stressors related to space radiation are due to the effects of energy transfer from a charged particle to the human 10 body. The combination of a particle’s charge, mass, and energy determines how quickly it loses energy when interacting with 5–7 matter. For example, given equal initial kinetic energies, an 0 5 10 15 20 25 Charge (Z) electron will penetrate further into aluminum than a heavy charged particle, and an X-ray will, on average, penetrate even Fig. 2 Relative abundance of atomic species, normalized to Z = 1 further. In biological tissue, the absorbed dose that a particular (hydrogen) and up to Z = 26 (iron), in the Galactic Cosmic Ray (GCR) target organ receives from heavy-charged particle radiation spectrum. The GCR spectrum includes every atom in the periodic depends not only on the energy spectrum of the particles but table, with ions up to nickel (Z = 28) contributing to any signiﬁcance. also on the depth and density of the tissue mass that lie between Note the energy of each ion species varies widely, more prominently in the range of 400–600 MeV. This broad disparity in ions and the skin surface and the target organ (for example, see Fig. 1, energies makes it extremely difﬁcult to accurately simulate the GCR which demonstrates the tissue depth ionized hydrogen (proton) environment during ground-based radiobiology experiments. While penetrates as a function of energy). larger ions may provide lower relative contribution to the spectrum The radiation dose to an astronaut, measured in units of Gray makeup they may have a more signiﬁcant biological impact than (Gy,deﬁned as Joules per kilogram (J/kg)), is deposited with a 108 smaller, abundant ions. Data adapted from Saganti et al. 2014 distribution in tissues that results from the speciﬁc energy ﬂuence of the particles. The heavier the charged particle, the greater the rules and mission planners. The vast majority of crew radiation amount of energy deposited per unit path length for that particle. exposures are delivered by the complex radiation environment in This is called linear energy transfer (LET). which they must travel and live. The space weather environment is most commonly categorized into three sources of ionizing radiation, each of which is Galactic Cosmic Rays associated with different energy and prevalence and, thus, GCR ions, originating from outside our solar system, are relativistic different radiation-related risk. First, the GCR spectrum consists nuclei that possess sufﬁcient energies to penetrate any shielding of primarily ionized hydrogen, as well as less frequent heavier- technology used on current mission vehicles. The GCR spectrum charged particles, with relatively high LET, that contribute to the is a complex combination of fast-moving ions derived from most chronic, background radiation exposure for long-duration astro- atomic species found in the periodic table. The GCR spectrum, nauts. Solar Particle Events (SPEs) consist mostly of short-duration from hydrogen (Z, or atomic number, of 1) through iron (Z = 26), is exposures of high-energy protons that emanate from the Sun shown in Fig. 2. This spectrum consists of approximately 87% within regions of solar magnetic instability. Finally, solar wind hydrogen ions (protons), 12% helium ions (α particles), and 1–2% consists of mostly low energy protons and electrons. The heavier nuclei with charges ranging from Z = 3 (lithium) to Z = 28 background dose-rate for solar wind varies with the solar cycle, 10,11 (nickel). Ions heavier than nickel are also present, but they are but is easily shielded by modern spacecraft designs and is rare in occurrence. GCR ions with charge Z ≥ 3 are frequently considered to be of negligible risk. In addition to space environment radiation, some small amounts of radioisotopes are referred to as HZE particles (High nuclear charge Z and energy E). used in manned space missions for instrument calibration and During transit outside of LEO, every cell nucleus within an research; however, these sources are highly controlled by ﬂight astronaut’s body would be traversed by a hydrogen ion or delta npj Microgravity (2018) 8 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; Depth in Tissue (cm) Relative Contribution Per Z=1 Limitations in predicting the space radiation health risk JC Chancellor et al. ray (a recoil electron caused by fragmentation after ion interac- sequelae. These highly energetic SPE exposures delivered to crews tions) every few days, and by a heavier GCR ion (e.g., O, Si, Fe) undertaking interplanetary ﬂight could result in potentially serious 12,13 every few months. Despite their infrequency, the heavy ions symptoms ranging from prodromal responses (nausea, vomiting, contribute a signiﬁcant amount to the GCR dose that astronauts fatigue, weakness) to fatality. In addition, large SPE doses can would incur outside of LEO. The energies of the heavier GCR ions produce degenerative effects associated with cancer, ocular are so penetrating that shielding can only partially reduce the cataracts, respiratory and digestive diseases, and damage to the intravehicular doses. Thicker shielding could provide protection, microvasculature; while these effects are mostly latent and do not but is limited by mass and volume restrictions of exploration necessarily pose an immediate risk to crew health, their overall vehicles and dependent upon the capabilities of spacecraft launch impact upon long-duration crews is an important consideration. systems. The high-LET radiation found in the GCR spectrum can produce Interplanetary radiation environment excessive free radicals that instigate oxidative damage to cell The ﬂuence of GCR particles in interplanetary space ﬂuctuates structures. Chronic exposure to such oxidative stress contributes inversely with the solar cycle, with dose-rates of 50–100 mGy/year to the radiation-induced changes associated with premature at solar maximum to 150–300 mGy/year at solar minimum. The aging, cardiovascular disease, and the formation of cataracts. The ﬂuence and occurrence of SPEs is unpredictable, but dose-rates as large ionization power of GCR ions makes them a potentially 1,8,23 high as 1400–2837 mGy/hour are possible. signiﬁcant contributor to tissue damage and carcinogenesis, As discussed above, even if shielding in spacecraft effectively central nervous system (CNS) degeneration, and deleterious health reduces radiation dose to the crew from SPEs, spallation occurring 14,15 outcomes. In addition, as GCR ions pass through a space as GCR particles collide with shielding materials may lead to vehicle, interaction with the spacecraft hull attenuates the energy 9,13,18,19 biological damage. Aluminum shielding greater than of heavy-charged particles and frequently causes their fragmenta- 2 20–30 g/cm could only reduce the GCR effective dose by no tion into numerous particles of reduced atomic weight, a process 29 more than 25%. An equivalent mass of polyethylene would only 16,17 referred to as spallation. Spallation occurring as GCR particles 30,31 provide about a 35% reduction in GCR dose. While this degree collide with shielding materials can result in ‘cascade showers’ that of shielding has been achieved aboard the International Space produce progeny ions with much higher potential for biological Station (ISS), similar shielding is impractical within exploration 9,13,18,19 destruction than the original particle. This process changes mission design parameters due to the limited lift-mass capabilities the makeup of the intravehicular radiation spectrum, adding to of planned space launch systems. The Apollo crew module is the the complexity of the radiation environment unique to only vehicle to date that has transported humans outside of LEO; spaceﬂight. this vehicle could only effectively shield SPE protons with energies ≤75 MeV. To date, no studies have successfully emulated the Solar Particle Events complexity of energetic elements of the intravehicular radiation spectrum that astronauts are actually exposed to during space During SPEs, magnetic disturbances on the surface of the sun travel or successfully incorporated vehicular design and shielding result in the release of intense bursts of ionizing radiation that are 20–22 parameters in analog testing environments, limiting the under- difﬁcult to forecast in advance. SPE radiation is primarily standing of the true effects of such an environment on the human composed of protons with kinetic energies ranging from 10 MeV body. up to several GeV (determined by the relativistic speed of particles) and is predicted to produce a heterogeneous dose distribution within an exposed astronaut’s body, with a relatively CHALLENGES IN ESTIMATING RADIOBIOLOGICAL EFFECT high superﬁcial (skin) dose and a signiﬁcantly lower dose to Modeling the transfer of energy internal organs. As extravehicular space suits provide relatively low shielding As a charged particle traverses a material (such as spacecraft protection, SPE exposures occurring during extravehicular activ- shielding, biological tissue, etc.), it continuously loses energy in ities would pose signiﬁcant risk to astronauts. However, particle interactions until the particle escapes the medium or has astronauts would still receive potentially signiﬁcant elevations in slowed enough to have strong interactions with orbiting radiation dose even within a shielded spacecraft and remain electrons. This results in a rapid loss of particle energy over a vulnerable, especially on long-duration missions, to both acute very small distance with a corresponding rapid and sharp rise in effects of sudden SPE radiation boluses and to the overall additive LET. The ‘Bragg peak’ (Fig. 3a) describes the rapid transfer of effects of GCR and repetitive SPEs over the course of a mission. kinetic energy from a charged particle before the particle comes While many SPEs show modest energy distributions, there are to rest in a medium. This peak is particularly pronounced for fast- occasional and unpredictable high ﬂuence events; for example, a moving, charged particles, indicating more substantial energy particularly large SPE in October 1989 is predicted to have transfer and, as a result, the potential for greater deleterious delivered dose-rates as high as 1454 mGy/hour to an exposed biological effect from such particles. However, if a particle instead astronaut in a vehicle traveling in interplanetary space (for passes directly through tissue without sufﬁcient energy loss to context, consider that the daily dose for long-duration astronauts provide effective stopping power, the sudden energy loss 23–25 aboard the ISS is approximately 0.282 mGy per day). Similarly, associated with a Bragg peak does not occur and damage is some SPE can deliver particularly high-energy doses: for example, minimal. Space radiation studies to date generally presume a 10–15% of the total ﬂuence of an October 1989 SPE was made up homogeneous distribution of energy loss inclusive of the Bragg 1,23 of protons with energies in excess of 100 MeV. If an astronaut peak for each type of radiation, likely overestimating the relative were exposed to such an event during long-duration spaceﬂight, damage of some exposures. Improved modeling of dose there are potential risks for both acute radiation-induced illnesses deposition and resultant biological sequelae speciﬁc to the space and for signiﬁcant increase in the overall mission dose accumula- environment would advance risk estimation capabilities. tion. It should be noted that these predictions made use of classic The biological effects of space radiation depend on multiple shielding values (5 g/cm ) similar to those of the Apollo command particle- and energy-speciﬁc factors, such as the LET speciﬁcto 2 26 module (average shielding of 6.15 g/cm ). each ion, as well as the dose-rate of exposure. The Relative Energetic SPE events produce protons with energies ≥100 MeV Biological Effectiveness (RBE) of a particular radiation type is the that would penetrate classic spacecraft shielding, potentially numerical expression of the relative amount of damage that a reaching blood-forming organ depths with deleterious clinical ﬁxed dose of that type of radiation will have on biological tissues. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 8 Limitations in predicting the space radiation health risk JC Chancellor et al. quality factor), W , that represents an average of calculated RBEs for a given particle. To identify the relative biological risk of a speciﬁc type and dose of radiation exposure, the physical dose (in Gy) is multiplied by W to obtain the biologically effective dose in units of Sieverts (Sv). This method of estimating dose and relative effect introduces limitations in predicting the true biological risk of exposures, particularly exposures to complex and poorly under- stood radiation environments. Limitations of terrestrial analogs Mechanisms of biological impact. There are numerous limitations of current terrestrial analogs used for studying and predicting space radiation effects on biological tissues. The mechanisms that cause biological damage from space radiation are uniquely different from those associated with terrestrial radiation sources that are frequently used as surrogates in space radiobiology studies. Charged particle radiation, including GCR and SPE, causes primarily direct ionization events, where biological effects are the direct result of interactions between the charged ion and impacted tissue. As charged particles lose energy successively through material interactions, each energy loss event can result in damage to the biological tissue. In contrast, terrestrial analogs often use radiation that causes indirect ionizing events. In indirect ionization, non-charged particles, such as photons, interact with other molecules and cause the release of charged particles, such as free radicals or electrons, that ultimately cause biological damage. Thus, it is difﬁcult to extract a meaningful estimation of the direct ionizing space radiation impact through the use of terrestrial analogs and indirect ionizing radiation. Fig. 3 a The Bragg peak and depth dose characteristics of space Cumulative dose delivery and tissue distribution. Models of the radiation. The Bragg peak and relative dose deposition for ions at space environment outside of LEO have predicted that astronaut energies commonly used in space radiation studies compared to the crews may receive a total body dose of approximately 1–2 mSv/ X-ray and gamma sources used as surrogate radiations for Relative day in interplanetary space and approximately 0.5–1 mSv/day on Biological Effectiveness (RBE) quantiﬁcation. The Bragg peak refers 13,33 the Martian surface. These doses would increase with any SPE to the point where a charged particle promptly loses kinetic energy before coming to rest in a medium. This effect is very pronounced encountered over the course of the mission. for fast moving, charged particles. Shown are 60 MeV Protons Many recent studies have led to ominous conclusions regarding 56 12 (hydrogen, purple), 600 MeV Fe (iron, light blue), 290 MeV C the non-acute effects of GCR radiation on CNS and cardiovascular (carbon, green), 1 GeV Fe (iron, dark blue), X-ray (orange dotted health that are difﬁcult to interpret as real effects likely to occur in line), and Co (cobalt, yellow dotted line). The shaded gray area, humans, but suggest that the protracted, low dose and dose-rate representing the average diameter of a mouse, demonstrates that radiation exposure expected on the longer, exploration missions the Bragg peak, and thus the majority of dose deposition, is outside 34,35 might lead to mission-relevant threats to astronaut health. the mouse body for SPE protons (energies ≥50 MeV) and GCR ions. b These experiments were performed using rodent models exposed The proton and electron range, energy and dose distributions for to single ion, mono-energetic heavy-ion beams, in some cases at the October 1989 solar particle event compared to a dose- total doses that are many times higher than the radiation human equivalent Co exposure. Charged particles (electrons, protons, 36–38 heavy-charged particles) typically deposit more energy towards the crews would experience during interplanetary space travel. end of their range. In contrast, the current standard, Co radiation, Even in studies where lower total doses are used, study methods loses the most energy at the tissue surface. These energy delivered the cumulative mission doses for an entire mission over characteristics demonstrate the poor ﬁdelity of Co as a surrogate 39,40 a very short period of time, typically over a few minutes. These for studying the complex SPE and GCR spectrums. Figure 3 (b) parameters do not allow for critical physiologic components of the reprinted by permission from Conditions for RightsLink Permissions 32 radiobiological response that would be expected under chronic, Springer Customer Service Center GmbH:Springer-Verlag low-dose and low-dose-rate radiation conditions, such as cell regrowth and up-regulation of repair mechanisms. Additionally, Higher RBEs are associated with more damaging radiation for a there is substantial evidence that GCR exposure at the dose-rates given dose. RBE is determined using the effectiveness of cobalt expected in interplanetary space may not induce acute or ( Co) gamma rays as a standard. An RBE = 1 means that the “test” subacute biological responses, while acute exposure to total/ radiation type (for example, heavy ion exposure) is as effective as cumulative dosage easily could. Co radiation at producing a biological effect, and an RBE > 1 Recently, NASA has developed an updated GCR simulator means that the test radiation is more effective than Co radiation capable of providing three to ﬁve consecutive mono-energetic ion at producing a biological effect. However, in some cases this beams, with rapid switching between ion species. The NASA comparative value does not fully represent the energy transfer Space Radiation Laboratory (NSRL) is located at Brookhaven curve of a speciﬁc radiobiological insult (Fig. 3b). National Laboratory in Brookhaven, NY. Currently, NSRL is the only The effect of quantifying factors such as LET, particle identity, U.S. facility with the capapbilites to generate heavy-charged dose-rate, and total dose on RBE remains incompletely under- particles at energies relevent to space radiation studies. While an stood. The RBE can vary for the same particle type, depending on improvement upon previous methods, NASA’s new GCR simulator energy, dose-rate, target organ, and other factors. Different remains limited in its ability to emulate the GCR environment of particle types are assigned a radiation weighting factor (formerly deep space. The simulator lacks the capacity to generate the pions npj Microgravity (2018) 8 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA Limitations in predicting the space radiation health risk JC Chancellor et al. Table 1. LD of various animal models used in space radiobiology studies compared to the human LD dose following radiation exposures Species LD (Gy) Reference Ferret <2 Harding Pigs 2.57 Morris and Jones Dogs 2.62 Morris and Jones Primates 4.61 Morris and Jones Mice 8.16 Morris and Jones Humans 3–4 Hall and Giaccia This broad spectrum in LD values emphasizes the difﬁculty in interpreting results of studies using speciﬁc radiation exposures in Fig. 4 The intravehicular LET of the Space Shuttle. Displayed are the different animal models and translating them into clinical outcomes in integrated LET/day values measured by Badhwar et al. 1998 (purple humans. Note: Table is adapted from the reported results of Harding 109 110 6 dotted line), as well as the LET of ﬁve single-ion exposures 1988, Morris and Jones 1988, and Hall and Glaccia 2012 14 16 47 (290 MeV C (carbon), 600 MeV O (oxygen), 1 GeV Ti (titanium), 56 56 1GeV Fe (iron), and 600 MeV Fe (iron)). As studies generally focus 32,55,56 on a single, mono-energetic radiation exposure, this ﬁgure high- spectrum and dose distribution of an SPE using protons. lights the lack in breadth of energies or radiation ﬁeld complexity Larger animal models, such as pigs or primates, allow for matching used in current radiobiological studies. Data adapted from Badhwar of the anticipated dose distribution for human SPE exposure using et al. 1998 protons with a similar LET spectrum; thus, larger animal models are more likely than smaller species to provide robust estimations (subatomic particles) and neutrons that would follow spallation of human-speciﬁc space radiation effects. However, it remains reactions, though these would make up 15–20% of a true unclear whether the concurrent exposure to low-dose and dose- 39,41,42 intravehicular dose. Sequential beam exposures remain rate GCR radiation can be successfully emulated in small or large ineffective in modeling complex and simultaneous exposures of animal models. Modeling of GCR radiation effects may be the actual GCR environment, and there is signiﬁcant debate similarly altered by variations in animal species; however, without regarding the appropriate order of ion exposures delivered (as dedicated efforts towards expanding understanding of these alteration of exposure sequence can affect the outcomes of an phenomena, prediction of the biological consequences of long- 42,43 experiment). Finally, dose-rate delivered by this simulator will term GCR exposure will remain theoretical at best. remain signiﬁcantly higher than the radiation dose-rate antici- Animal models pose further challenges in the development of 39,41 pated for human crews during spaceﬂight. meaningful and accurate analog research. While animal models As an additional challenge, SPE radiation has a unique dose are used in radiobiology studies as surrogates to obtain data that distribution with respect to whole body irradiation. Research has typically cannot be gained in ethical studies of humans, there are demonstrated that the biological response to space radiation is numerous metabolic, anatomic, and cellular differences between unique due to a non-homogeneous, multi-energetic dose humans and other animal species. Most of the animals used in 44,45 distribution. The majority of the protons in SPEs have energies all U.S. scientiﬁc research are mice and rats, bred speciﬁcally for less than 100 MeV, with Bragg peaks that occur inside the body use in research endeavors. While larger species are likely to and LET of 10–80 keV/μm (Fig. 3b). While these energies might be provide more meaningful correlation to human effects, due to mitigated with effective shielding, an exposed human would be animal protection issues and relative societal value, less than one expected to receive a much higher absorbed dose to skin and quarter of 1% of scientiﬁc studies are performed on non-human 23,32,46,47 subcutaneous tissues than to internal organs. Until primates and less than one half of 1% of studies use dogs and recently, these SPE-speciﬁc toxicity proﬁles and dose distributions cats. Few studies utilize rabbits, guinea pigs, sheep, pigs, or other were poorly understood. As a result, the majority of prior research large mammals. While rodent experiments have contributed has been based largely on simpliﬁed models of radiation signiﬁcantly to our understanding of mechanisms of disease, transport, relying upon simple spherical geometry to estimate including disease caused by radiation, their value in predicting the 48,49 organ dose approximation at average depths. However, with effectiveness of treatment modalities for human application has 60–62 this new evidence of heterogeneous dose distribution, spherical remained controversial. geometry is insufﬁcient for the modeling of radiation delivered Differences between animals and humans are clearly demon- within the space environment. strated by the characteristics of radiation-induced death (RID). The LD deﬁnes the required dose of an agent (e.g., radiation) Animal model sensitivity and dose simulation. For ease of dose necessary to cause fatality in 50% of those exposed. As illustrated speciﬁcation and modeling, mono-energetic protons and GCR ions in Table 1, remarkably different LD values have been reported in the 100–1000 MeV range are often used for in vivo animal for radiation exposure among different species. Currently, the model experiments such that the entire target is contained within genetic and physiologic basis for inter-species and intra-species 50–54 the plateau portion of the depth-dose distribution. In variation in LD is not well understood. Mice have been the most experimental animals that are much smaller than humans, simple extensively developed model for human diseases including scaling of particle energies to match dose distribution dramatically radiation-induced tissue damage. Rodent models have a high alters the LET spectrum for the protons (Fig. 3 and Fig. 4). potential utility in describing the physiologic and genetic basis for Conversely, delivering a simulated SPE or GCR exposure to smaller many aspects of the mammalian radiation response. Even so, it animals without scaling the energies would match their respective should be noted that, in addition to simple physiological LET spectrum but create an heterogeneous dose distribution that differences between mice and larger animals (including signiﬁ- is higher to internal organs than to superﬁcial tissues, the exact cantly higher metabolic rate, shorter lifespan, and lower body inverse of the human SPE dose distribution. For smaller animals mass), the LD for mice is signiﬁcantly higher than that of most (such as rodents), it is not possible to match both the LET other mammalian species, including humans. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 8 Limitations in predicting the space radiation health risk JC Chancellor et al. It has been proposed that the differences between the LD values for humans compared to small mammals, like rodents, are due to different mechanisms involved in RID at these dose levels. For mammals, death at the LD dose is thought to be caused by the hematopoietic syndrome, which includes destruction of precursor cell lines within blood-forming organs. Historically, it was thought that infection and hemorrhage are the major causes of death from hematopoietic syndrome, with one or the other of these factors predominating in different species’ responses to lethal radiation exposure. For example, bacterial infection is the predominate factor leading to RID in mice at doses near their 63–65 respective LD levels. However, recent results from Krigsfeld et al. have indicated that radiation-induced coagulopathy (RIC) and clinical sequelae that mimic disseminated intravascular coagulation (DIC) can result in hemorrhage, microvascular thrombosis, organ damage, and death from multiorgan failure from exposure of large animals (including ferrets and pigs) to doses of radiation at or near 66–70 the species’ LD . RIC-associated hemorrhage occurs well before the expected decline in peripheral platelet counts after irradiation. Rodents do not exhibit signs of hemorrhage or disorders of primary hemostasis at time of necropsy after lethal radiation exposure at doses near the LD dose, while large animals, including humans, do exhibit hemorrhage at death following radiation exposure. These ﬁndings suggest that humans may be at risk for coagulopathy-induced complications after radiation exposure in addition to the classically anticipated (delayed) concerns of infectious sequelae or cell-count decline, effects that may not be modeled by rodent surrogates. Further, RBE values for proton irradiation vary between animal models. In general, RBE values increase with animal size, with mini-pigs demonstrating higher RBEs than ferrets, and ferrets, in turn, exhibiting higher RBEs than mice (Table 2). Numerous studies have focused on RBE values for hematopoietic cells in mice Fig. 5 Comparison of lymphocyte and neutrophil counts following at various time points after the animals have been exposed to proton and X-ray (comparable to gamma radiation) exposures in 45,71 mice, ferrets, and Yucatan mini-pigs. The relative fraction of different doses of proton or gamma radiation. In these rodent lymphocyte (a) and neutrophil (b) counts following a homogeneous models, RBEs do not differ signiﬁcantly from one at any of the proton or X-ray exposure to the bone marrow compartment are time points or doses of radiation evaluated. However, similar shown. Note: calculations indicate that animals received approxi- studies in ferrets and mini-pigs have demonstrated alterations of mately a 2 Gy marrow dose. In both cases, the mouse models RBE value that are dependent upon animal model, type of demonstrated the ability to fully recover within 30 days following radiation, time since exposure, and cell-line evaluated (for proton exposures while the ferret and pig models showed no example, total white blood cell count vs. neutrophils). In one recovery. The ferrets were euthanized at day 13. The RBE values for study, proton-irradiated ferrets examined 48 h after exposure white blood cell counts varied greatly between the mice, ferret and demonstrated RBEs for white blood cells ranging from 1.2–1.6 and pig models. RBE values were greater in ferrets than mice, and considerably greater in pigs compared to either ferrets or mice. This RBEs for neutrophils ranging from 1.9 to 2.1. In Yucatan mini- suggests that model-speciﬁc sensitivity to radiation exposure may pigs evaluated 4 days after exposure, the RBEs for white blood lead to drastically different results in experimental outcome, leading cells was found to be 2.4–4.1 and the RBEs for neutrophils was 56 to difﬁculty in extracting clinical signiﬁcance from animal models 2.2–5.0 (see Table 2, Fig. 5). with dissimilar radiation sensitivity compared to humans. Data from In other experiments, proton exposure in mini-pigs again 44 66,67 Kennedy (mouse and ferret results) and Krigsfeld et al. resulted in signiﬁcantly greater hematopoietic injury and white (Yucatan mini-pig results) blood cell count reduction than comparable gamma exposure 55,56 (Fig. 6). The results of these studies demonstrate that RBE values of different radiation types, calculated for the same endpoints, can vary greatly by animal species and cell line. One contributing factor may be the repair capacity of the blood cell Table 2. The relative biological effectiveness (RBE) for SPE-like protons renewal systems in mice; such capabilities appear to be lacking in compared with standard reference radiations (gamma or electron) in mini-pigs (an animal model with more human-like hematopoietic animal models characteristics), making them more susceptible to radiation- Animal WBC Neutrophil induced declines in cell counts. Given the presumed closer approximation of radiation effects in larger animals to human- Mouse 1 1 speciﬁc consequences, this suggests that space radiation-speciﬁc Ferret 1.16–1.6 1.9–2 RBE values for humans may be considerably higher than those in mice. Mini-Pig 2.4–4.1 2.2–5 These studies demonstrated novel efforts towards an inte- 45,56,71,72 Source: Refs. grated, physiology-based approach for the evaluation of organ The RBE of proton exposure varies greatly for total white blood cells (WBC) system-speciﬁc and species-speciﬁc endpoints. Using a more and speciﬁcally for neutrophils when comparing animal models. Note that comprehensive evaluation of radiation toxicity for multiple doses ferret RBE values were determined 48 h after exposure; mini-pig values and dose-rates in multiple animal models, this effort advanced the were determined 4 days post-irradiation understanding of the impact of genetic heterogeneity and npj Microgravity (2018) 8 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA Limitations in predicting the space radiation health risk JC Chancellor et al. related to signiﬁcant cell damage or death (for example, the spectrum of clinical manifestations that make up Acute Radiation Sickness), or stochastic, where increased exposure is associated with increased risk though no threshold dose is necessary for biological impact (for example, carcinogenesis). Currently, carcinogenesis is the only long-term, stochastic effect that has a clearly deﬁned permissible exposure limit in spaceﬂight. Terrestrial radiation (e.g., occupational or clinical radiotherapy gamma or X- ray exposures) is known to be associated with carcinogenic risk; at this time, there is no deﬁnitive evidence that space radiation causes human cancer, but it is reasonable to assume that it can. The dose-equivalent of radiation received by astronauts currently traveling to the ISS for 6 months is approximately 100 mSv; doses of 100 mSv of terrestrial radiation sources have been associated with an elevated cancer risk in human populations. Fig. 6 Results from Yucatan mini-pigs exposed to simulated Solar NASA’s “Lifetime Surveillance of Astronaut Health” (LSAH) Particle Event (SPE)-like radiation consisting of several different program documents cancer cases in astronauts, among other energies of protons. In this study, Kennedy et al. utilized an health parameters. Previous review of LSAH data suggests that inhomogeneous distribution of protons that resembled a SPE there may be evidence of increased cancer risk in astronauts spectrum, as demonstrated in Fig. 3. Electrons were used as the compared to a control population, though data are inconclusive surrogate radiation for determining the RBE following exposure to a and limited by the very small sample size. SPE-like distribution of protons. Electrons were chosen because a Most evidence for the effects of space-like radiation exposures SPE-like distribution could not be achieved with Co as demon- in humans has been derived from epidemiological studies on the strated in Fig. 3. Note the white blood cell counts in the mini-pig atomic-bomb survivors, radiotherapy patients, and occupationally model recovered to near pre-irradiation levels following exposure to the electron radiation while the white blood cell counts for those exposed workers. These studies have focused on the association exposed to a SPE-like proton spectrum remained suppressed for between ionizing radiation exposure and the long-term develop- 30 days after exposures. These results indicate that the mini-pigs ment of degenerative tissue effects such as heart disease, were not capable of repairing the hematopoietic damage caused by cataracts, immunological changes, cancer, and premature aging the proton radiation exposure as efﬁciently as they could repair the 1,8 for moderate to high doses of low-LET radiation. The ﬁndings electron radiation damage. Data from Kennedy 2014 are further supported by results of laboratory studies using rodent animal models. However, true risks for these diseases from low demonstrated that animal model, physiology, body mass, and dose-rate exposures to GCR and intermittent SPE are much more ﬁdelity of a space radiation analog (in this case, a multi-energy difﬁcult to assess due to long latency periods and the numerous proton spectrum) all contribute to radiation response. Such efforts challenges involved in studying the radiation environment. towards the integration of the numerous factors that contribute to Additionally, the types of radiation exposure produced by atomic radiation-induced effects will be critical to translation of research bombs (high dose and high dose-rate gamma and neutron results and prediction of clinical responses in humans. radiation) are dissimilar to radiation exposures for astronaut crews Finally, studies of the synergistic effects of radiation combined during spaceﬂight. with spaceﬂight environment stressors (e.g., microgravity, envir- The theoretical, calculated RBEs for some space radiation- onmental factors, isolation and emotional stress, etc.) show that induced cancers are quite high, which has led to speculation that such factors in combination impart an increased susceptibility to the risk of cancer development from space radiation exposure is at 71,73,74 infection and delayed wound healing. While spaceﬂight least as high, and perhaps higher, than the risk of cancer 91,92 medical capabilities have been developed for the management of development from exposure to radiation on Earth. However, some acute injuries, such as wound care and infection control, it is there are currently no biophysical models that can accurately unclear whether standard management techniques will be project all acute, subacute, degenerative, and carcinogenic risks effective against the synergistic variables that alter wound healing speciﬁc to the range of particles and energies of ionizing radiation and associated risks speciﬁc to the space environment. Histori- in the space environment. There is little information available cally, there has been limited testing on the efﬁcacy of manage- about dose response and dose-rate modiﬁers for speciﬁc effects or ment techniques, including pharmaceutical interventions, when about the degenerative effects associated with ionizing radiation, radiation exposure is a factor. Similarly, few research protocols and very few biological models describe degenerative processes examining operational medical care have included the additional (e.g., cardiovascular degeneration) caused by ionizing radiation. 75–77 variables of the high-stress and isolated environment, Exposure to the LEO radiation environment has been associated 94–97 infections related to the altered bacterial and chemical exposures with alterations to chromatin structure. However, it is not well 78–81 speciﬁc to space vehicles, or factors related to gravitational understood how such damage relates to impacts on cellular 73,82–84 unloading, and no studies have effectively examined all of function or long-term carcinogenic risk. There is a paucity of these variables simultaneously. It is unclear whether these understanding regarding the interpretation of chromosomal complex interactions can be fully simulated even in large animal damage rates identiﬁed in astronauts and the long-term effects models for appropriate extrapolation of human risk. There is a induced by the space radiation environment, without relying on need to better understand the mechanism of the synergistic terrestrial studies of different radiation sources, doses, dose-rates, effects observed, deﬁne appropriate animal models for analog or complexity for context. For example, NASA’s Human Research research efforts, and determine efﬁcacy of standard treatments Program Evidence Report on the Risk of Radiation Carcinogen- against damage resulting from radiation-combined injury. Dedi- esis, published in 2016, cites numerous studies to provide an cated effort towards these goals will better allow for operationally assessment of risk for chromosomal damage (and, ultimately, relevant and appropriate countermeasures. carcinogenesis). A review of the studies cited in this report highlights the limitations described throughout this manuscript, Translation of space radiobiology research to human health including reliance upon mono-energetic radiation 36,38,40,97,99,100 outcomes. Biological damage from radiation exposure is gen- sources, comparison to or interpretation of results 38,40,99–101 erally classiﬁed as deterministic, dose threshold-based effects in the context of gamma or X-ray exposures, or use of Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 8 Limitations in predicting the space radiation health risk JC Chancellor et al. dose or dose-rates far exceeding those expected during space- 36,38,40,97 ﬂight. Indeed, many of these same factors are cited as limitations to NASA’s primary radiation cancer risk prediction model. In addition, few studies have assessed mutation rates due to LEO radiation at a whole genome level. Whole genome sampling techniques are being employed for other carcinogenic stres- sors. Direct observations of mutation rates, as well as an understanding of the epigenetic changes and cellular damage using in vitro cell culture models, may now be possible due to recent advances in long-term cell culture aboard the ISS (Sharma, Fig. 7 Moderator block geometry concept for the emulation of A. & Wu, J. Personal Communication (2016)). Quantiﬁcation of space radiation spectra. Artist conception of GCR analog detailed in 42 56 Chancellor et al. A primary beam of Fe (iron, left) is selectively observable mutation rates from LEO exposures may better inform degraded with a carefully designed moderator block to produce a future modeling efforts and provide a critical understanding of the desired distribution of energies and ions (represented by the molecular mechanisms behind observed pathologies. However, colorful lines on the right) simulating the intravehicular space even data obtained from the LEO environment is less than ideal, radiation environment. To preferentially enhance fragmentation and as the ISS is heavily shielded and the close proximity of the Earth energy loss, cuts are performed in the moderator block made up of provides signiﬁcant protection from radiation exposure. While different materials (depicted by different shades of gray). Before the improved understanding of the LEO environment may help inform spallation products exit the moderator block, a high-Z material layer risk predictions, there is signiﬁcant work to be done in is added for scattering. Image courtesy of R. Blue characterizing these risks in the radiation environment outside of LEO. initial characterization studies and for statistically signiﬁcant outcomes, true advances are more likely to come from an effort DISCUSSION to utilize larger animals with more human-like physiology for The health risks associated with exposures to space radiation will landmark studies on how speciﬁc outcomes may translate to become more onerous as future manned spaceﬂight missions humans. Finally, while there would be numerous challenges and require extended transit outside of LEO and beyond the ethical considerations involved, studies of non-human primates protection of the Earth’s magnetosphere. The indigenous shield- for ﬁnal validation of risk and mitigation strategies would likely ing provided by the Earth’s magnetic ﬁeld attenuates the major prove highly beneﬁcial for the protection of future human crews. effects of space radiation exposures for current LEO missions; in As described above, NASA’s updated GCR simulator may be the highly mixed-ﬁeld environment of interplanetary space, able to provide some improvements to simulation studies by use 39,41 radiation dose could increase dramatically. Even behind shielding, of rapid-sequential mono-electric beam exposures. Recent secondary particles produced by interactions of primary cosmic developments by Chancellor et al. demonstrate the potential for rays and the atomic molecules of the spacecraft structure can more accurate analog recreation of the GCR radiation environ- deliver a signiﬁcant fraction of the total dose equivalent. Astronaut ment by allowing for continuous generation of ionizing radiation crews could be exposed to multiple SPEs of unpredictable that more closely matches the ion distribution, LET spectrum, and magnitude with doses that could induce clinical illness and dose-rate of GCR (Fig. 7). These recent ﬁndings suggest that the exacerbate biological outcomes from the chronic GCR radiation environment inside spaceﬂight vehicles can be experi- environment. mentally generated by perturbing the intrinsic properties of The limited accumulation of knowledge to date has yet to hydrogen-rich crystalline materials in order to produce speciﬁc provide sufﬁcient data for even an estimation of total risk, nuclear spallation processes when placed in an accelerated mono- let alone predictions of human clinical outcomes or appropriate energetic heavy ion beam. While still limited by dose-rate (as are mitigation strategies before, during, or after exposure. Accurately all terrestrial beam exposures), such an approach could allow for simulating the spectrum of energies, ion species, doses, and dose- improvements to the simulation of the complex mix of nuclei and rates found in the space radiation environment is a non-trivial energies found in the space radiation spectrum. endeavor. For the numerous reasons described above, emulation Potential radiation exposure to astronaut crews occurs on a of the radiation environment, choice of surrogate animal model, timescale that is measured in days to months for SPE and GCR. and delivery of appropriate complexity, rate, and magnitude of Technological, practical, and ﬁnancial considerations make con- dose have all limited the knowledge available for extrapolation of tinuously irradiating animals for more than a few hours exceed- radiation risk within the context of spaceﬂight. These factors have ingly difﬁcult. In addition, because the lifespan of most limited our ability to develop operational and useful medical experimental animals is more than an order of magnitude shorter countermeasures to mitigate the radiation risk of future than the human lifespan, the interpretation of long-term, low exploration-class spaceﬂight. dose-rate exposures using such models would be questionable To improve upon the limitations described, there must be a even given the open opportunity to perform long-duration focused effort to develop novel or new methods of simulating the experiments. As radiation dose-rate can have a major impact on space radiation environment in more realistic analogs. This should modulating the severity of the radiation response, it is critical to include more realistic dose-rate studies that can determine if obtain at least some dose-rate data for radiation experiments presumed or modeled outcomes are being observed at mission investigating clinical outcomes of space radiation exposures. relevant dose-rates and dose. Additionally, heavier utilization of While some radiation effects are either unchanged or mitigated by the animal laboratory on board the ISS with comparison of tissues, decreased dose-rates, data on non-targeted radiation effects (such organ, and blood samples, identifying realistic dose thresholds as genomic instability and adaptive responses) suggest that dose and dose-rates, and comparing these data to ground-based response could be altered at lower dose-rates, with signiﬁcant studies, would greatly improve the current approach to analog differences in quantitative (slope of the dose-toxicity curve) or construction. The use of animal models should be strategic and qualitative (toxicity effects) biological responses. This is especially consistent with species, strain, dose, and dose-rates with an effort true for high-LET radiation exposure under conditions of increased 104–107 towards the highest-ﬁdelity studies possible for human risk oxidative stress promoted by spaceﬂight. In previous extrapolation. While rodent models may be highly useful for studies on SPE-like radiation, dose-rates from 17 cGy/hour up to npj Microgravity (2018) 8 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA Limitations in predicting the space radiation health risk JC Chancellor et al. 50 cGy/minute have been modeled experimentally and statistical that would improve upon our ability to better predict risk and analysis of these data have begun to explore the potential provide realistic strategies and risk posturing for future explora- quantitative or qualitative impact of dose-rate on the toxicity of tion spaceﬂight. Use of improved modeling techniques to emulate multi-energy spectrum. Use of such data to better design dose- the space environment, selection of appropriate biological rate extrapolation experiments would be highly useful for more surrogates for extrapolation of human effects, and careful use of robust, future studies. ﬂown astronaut data could provide much-needed advances in There have been other advances in ﬁelds related to space space radiation research. As humans seek to explore space outside radiation effects, including whole genome sequencing, as well as of the close proximity and protection of LEO, we have the transcriptional, proteomic, and epigenomic studies of cellular responsibility to address the space radiation risk to the extent of response. There is a growing list of genes known to affect terrestrial capabilities in order to provide the best information and radiation sensitivity for many different biological effects of protection possible for our future explorers. radiation (e.g., molecular, chromosomal, signal transduction- associated growth-regulating changes, cell killing, animal tissue ACKNOWLEDGEMENTS and tumor acute and late effects, and animal carcinogenesis). Even H.G.K. acknowledges support from the NSF (Grant No. DMR-1151387). Part of the so, there is a need to correlate observed sequence changes with work of H.G.K. and J.C.C. has been based upon work supported by the Ofﬁce of the corresponding alterations of radiosensitivity. Incorporation of Director of National Intelligence (ODNI), Intelligence Advanced Research Projects these investigational directions opens new opportunities to Activity (IARPA), via Interagency Umbrella Agreement IA1-1198. The views and evaluate space radiation risk on a genomic level, deﬁning risk conclusions contained herein are those of the authors and should not be interpreted and allowing for improved understanding of the pathology of as necessarily representing the ofﬁcial policies or endorsements, either expressed or radiation-induced injury and the potential for intervention in such implied, of the ODNI, IARPA, or the U.S. Government. The U.S. Government is authorized to reproduce and distribute reprints for Governmental purposes processes. notwithstanding any copyright annotation thereon. Finally, there are a number of lessons that may be learned from historical spaceﬂight and the health of early space pioneers, though it has been difﬁcult to extract meaningful conclusions AUTHOR CONTRIBUTIONS from historical data. For example, some sources suggest that there J.C.C. developed the concept of the review. J.C.C., K.A.C., and H.G.K. contributed to the is no statistically signiﬁcant increase in carcinogenesis in Apollo, discussion on space physics. J.C.C., R.S.B., S.M.A., and K.A.C. contributed to the Space Shuttle, or ISS astronaut crews in comparison to the average discussion on operational space radiation. J.C.C., K.A.C., and A.R.K. contributed to the U.S. population; other reviews of data suggest that risk is indeed discussion on dosimetry. J.C.C., R.S.B., S.M.A., K.H.R., and A.R.K. contributed to the 1,14,89,92 increased for astronauts. Given that the broad research discussion on countermeasures. R.S.B., S.M.A., K.A.C., K.H.R., and A.R.K. contributed to base has utilized non-ideal and highly limited analogs for the the discussion on clinical effects of space radiation on humans. J.C.C., R.S.B., S.M.A., K. prediction of risk, the fact that reality has deviated from A.C., K.H.R., and A.R.K. contributed to the discussion on space radiobiology. J.C.C., R.S. theoretical, calculated risk is not entirely surprising. Medicine B., S.M.A., K.A.C., K.H.R., and A.R.K. contributed to the discussion on animal models. R. S.B., K.H.R., and A.R.K. contributed to the discussion on genetics. J.C.C., K.A.C., and H.G. does not advance without clarifying treatment options using K. contributed to the discussion on computational modeling. All authors contributed human subjects. Models and animal data are useful surrogates for equally to the review of the literature, discussion on the interpretation of research space radiation studies but provide limited beneﬁt for the outcomes to spaceﬂight operations, and drafting of the manuscript. interpretation to human outcomes, and studies on humans exposed to occupational radiation and clinical radiotherapy are imperfect proxies. The reliance upon these surrogates continues ADDITIONAL INFORMATION to limit the ability to translate radiation knowledge to spaceﬂight Competing interests: The authors declare no competing interests. scenarios. We now have the beneﬁt of a larger, cumulative astronaut Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims population that has ﬂown in space while exposed to a variety of in published maps and institutional afﬁliations. doses that exceed the identiﬁed thresholds for some degenerative and carcinogenic outcomes. The health of these astronauts, including early indicators of disease, is closely monitored by NASA REFERENCES medical and epidemiological resources with yearly medical 1. National Council on Radiation Protection andMeasurements (NCRP). Guidance examinations and careful records of clinical outcomes. This on Radiation Received in Space Activities. Tech. Rep. 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Risk of Cardiovascular Disease and Other Degenerative © The Author(s) 2018 Tissue Effects From Radiation Exposure and Secondary Spaceﬂight Stressors.TR Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 8 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Microgravity Springer Journals http://www.deepdyve.com/lp/springer-journals/limitations-in-predicting-the-space-radiation-health-risk-for-A4nFLQaOCA

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Publisher: Springer Journals
Copyright: Copyright © 2018 by The Author(s)
Subject: Life Sciences; Life Sciences, general; Classical and Continuum Physics; Biotechnology; Immunology; Space Sciences (including Extraterrestrial Physics, Space Exploration and Astronautics) ; Applied Microbiology
eISSN: 2373-8065
DOI: 10.1038/s41526-018-0043-2
Publisher site: See Article on Publisher Site

Abstract

www.nature.com/npjmgrav REVIEW ARTICLE OPEN Limitations in predicting the space radiation health risk for exploration astronauts 1 2 3 4,5 4 Jeffery C. Chancellor , Rebecca S. Blue , Keith A. Cengel , Serena M. Auñón-Chancellor , Kathleen H. Rubins , 1,6,7 3 Helmut G. Katzgraber and Ann R. Kennedy Despite years of research, understanding of the space radiation environment and the risk it poses to long-duration astronauts remains limited. There is a disparity between research results and observed empirical effects seen in human astronaut crews, likely due to the numerous factors that limit terrestrial simulation of the complex space environment and extrapolation of human clinical consequences from varied animal models. Given the intended future of human spaceﬂight, with efforts now to rapidly expand capabilities for human missions to the moon and Mars, there is a pressing need to improve upon the understanding of the space radiation risk, predict likely clinical outcomes of interplanetary radiation exposure, and develop appropriate and effective mitigation strategies for future missions. To achieve this goal, the space radiation and aerospace community must recognize the historical limitations of radiation research and how such limitations could be addressed in future research endeavors. We have sought to highlight the numerous factors that limit understanding of the risk of space radiation for human crews and to identify ways in which these limitations could be addressed for improved understanding and appropriate risk posture regarding future human spaceﬂight. npj Microgravity (2018) 4:8 ; doi:10.1038/s41526-018-0043-2 INTRODUCTION A recent report by Schwadron et al. has identiﬁed further concerns regarding the interplanetary radiation environment. While space radiation research has expanded rapidly in recent The unusually low activity between solar cycles 23 and 24 (1996- years, large uncertainties remain in predicting and extrapolating present) has resulted in the longest period of minimum solar biological responses to radiation exposure in humans. As future activity observed in over 80 years of solar measurements. The lack missions explore outside of low-Earth orbit (LEO) and away from of solar activity has led to a substantial decrease in solar wind the protection of the Earth’s magnetic shielding, the nature of the density and magnetic ﬁeld strengths that typically attenuate the radiation exposures that astronauts encounter will include higher ﬂuence (the ﬂux of particles crossing a given plane) of Galactic radiation exposures than any experienced in historical human Cosmic Ray (GCR) ions during periods of solar minimum. As a spaceﬂight. In 1988, the National Council on Radiation Protection result, Schwadron et al. project that GCR ﬂuences will be and Measurements (NCRP) released Report No. 98: Guidance On substantially higher during the next solar cycles (24–25) leading Radiation Received in Space Activities. In this report, authors to increased background radiation exposure and, subsequently, as recommended that NASA astronauts be limited to career lifetime much as a 20% decrease in the allowable safe days in space radiation exposures that would induce no more than a 3% Risk of (outside of LEO) to stay below the 3% REID limits. Exposure-Induced Death (REID). This was re-emphasized in the The study of human health risks of spaceﬂight (e.g., bone 2015 NCRP Commentary No. 23: Radiation Protection for Space health, behavior, nutrition, etc.) typically involves analogs that Activities: Supplement to Previous Recommendations, which closely represent the space environment. In most cases, theory, concluded that NASA should continue to observe the 3% REID models, and study outcomes can be validated with available career limit for future missions outside of LEO. This limit has been spaceﬂight data or, at a minimum, observation of humans accepted in NASA’s Spaceﬂight Human-System Standard docu- subjected to analog terrestrial stresses. In contrast, space radiation ment, NASA STD-3001 Volume 1 (Revision A). research is limited to the use of analogs or models that for many Despite the adoption of these guidelines and the past 30 years of research, there has been little progress on fully deﬁning or reasons do not accurately represent the operational space radiation environment or the complexity of human physiology. mitigating the space radiation risk to human crew. In fact, the For example, studies on the effects of space radiation generally NCRP’s recent conclusions speciﬁed that their 3% limit may not be use mono-energetic beams and acute, single-ion exposures conservative enough given the incomplete biological data used in (including protons, lithium, carbon, oxygen, silicon, iron, etc.) existing projection models, and that such models may over- estimate the number of allowable “safe days” in space for missions instead of the complex energy spectra and diverse ionic outside of LEO. composition of the space radiation environment. In addition, a 1 2 Department of Physics and Astronomy, Texas A&M University, College Station, TX 77843-4242, USA; Aerospace Medicine and Vestibular Research Laboratory, The Mayo Clinic 3 4 Arizona, Scottsdale, AZ 85054, USA; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; National 5 6 Aeronautics and Space Administration (NASA), Johnson Space Center, Houston 77058, USA; University of Texas Medical Branch, Galveston, TX 77555, USA; 1QB Information Technologies (1QBit), Vancouver, BC V6B 4W4, Canada and Santa Fe Institute, 1399 Hyde Park Road, Santa Fe, NM 87501, USA Correspondence: Jeffery C. Chancellor (jeff@chancellor.space) Received: 19 August 2017 Revised: 20 February 2018 Accepted: 12 March 2018 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA Limitations in predicting the space radiation health risk JC Chancellor et al. projected, cumulative mission dose is often delivered in one-time, or rapid and sequential, doses delivered to experimental animals. 3.5 In most cases, these dose-rates are several orders of magnitude higher than actual space environment exposures. Even the use of animal models introduces error, as studies make use of a variety of Human 2.5 d = 30 cm animal species with differing responses and sensitivity to radiation that may not represent human responses to similar exposures. Pig Further, studies do not challenge multiple organ systems to d = 20 cm 1.5 respond concurrently to the numerous stressors seen in an operational spaceﬂight scenario. Historical epidemiological studies of humans, which are generally used for correlation of animal and Mouse experimental models, include populations such as atomic bomb or 0.5 d = 3 cm nuclear accident survivors exposed to whole-body irradiation at high doses and high dose-rates, limited to scenarios not found in 0 102030 405060 spaceﬂight. These disparities and numerous other environmental Proton Energy (MeV) considerations contribute to the large uncertainties in the Fig. 1 Depth dose, energy, and linear energy transfer characteristics outcomes of space radiobiology studies and the applicability of of protons. The range of proton energies relative to the body such studies for extrapolation and prediction of clinical health diameter (dotted lines) and bone marrow depth (ordinate) for mice, outcomes in future spaceﬂight crews. pigs, and humans for energies up to 60 MeV. Figure reprinted by Here we seek to highlight these factors that contribute to the permission from Conditions for RightsLink Permissions Springer challenge of radiation risk prediction and mitigation for future Customer Service Center GmbH:Springer-Verlag exploration spaceﬂight. Our intent is to provide an understanding of the current state of radiation-speciﬁc literature, efforts towards better deﬁning the space radiation environment, and the difﬁculties in realization of this effort that limit current knowledge. Further, we hope to identify opportunities for future research that could best elucidate a path towards successful deﬁnition and mitigation of the space radiation risk to humans outside of LEO. THE SPACE RADIATION ENVIRONMENT 10 Biological stressors related to space radiation are due to the effects of energy transfer from a charged particle to the human 10 body. The combination of a particle’s charge, mass, and energy determines how quickly it loses energy when interacting with 5–7 matter. For example, given equal initial kinetic energies, an 0 5 10 15 20 25 Charge (Z) electron will penetrate further into aluminum than a heavy charged particle, and an X-ray will, on average, penetrate even Fig. 2 Relative abundance of atomic species, normalized to Z = 1 further. In biological tissue, the absorbed dose that a particular (hydrogen) and up to Z = 26 (iron), in the Galactic Cosmic Ray (GCR) target organ receives from heavy-charged particle radiation spectrum. The GCR spectrum includes every atom in the periodic depends not only on the energy spectrum of the particles but table, with ions up to nickel (Z = 28) contributing to any signiﬁcance. also on the depth and density of the tissue mass that lie between Note the energy of each ion species varies widely, more prominently in the range of 400–600 MeV. This broad disparity in ions and the skin surface and the target organ (for example, see Fig. 1, energies makes it extremely difﬁcult to accurately simulate the GCR which demonstrates the tissue depth ionized hydrogen (proton) environment during ground-based radiobiology experiments. While penetrates as a function of energy). larger ions may provide lower relative contribution to the spectrum The radiation dose to an astronaut, measured in units of Gray makeup they may have a more signiﬁcant biological impact than (Gy,deﬁned as Joules per kilogram (J/kg)), is deposited with a 108 smaller, abundant ions. Data adapted from Saganti et al. 2014 distribution in tissues that results from the speciﬁc energy ﬂuence of the particles. The heavier the charged particle, the greater the rules and mission planners. The vast majority of crew radiation amount of energy deposited per unit path length for that particle. exposures are delivered by the complex radiation environment in This is called linear energy transfer (LET). which they must travel and live. The space weather environment is most commonly categorized into three sources of ionizing radiation, each of which is Galactic Cosmic Rays associated with different energy and prevalence and, thus, GCR ions, originating from outside our solar system, are relativistic different radiation-related risk. First, the GCR spectrum consists nuclei that possess sufﬁcient energies to penetrate any shielding of primarily ionized hydrogen, as well as less frequent heavier- technology used on current mission vehicles. The GCR spectrum charged particles, with relatively high LET, that contribute to the is a complex combination of fast-moving ions derived from most chronic, background radiation exposure for long-duration astro- atomic species found in the periodic table. The GCR spectrum, nauts. Solar Particle Events (SPEs) consist mostly of short-duration from hydrogen (Z, or atomic number, of 1) through iron (Z = 26), is exposures of high-energy protons that emanate from the Sun shown in Fig. 2. This spectrum consists of approximately 87% within regions of solar magnetic instability. Finally, solar wind hydrogen ions (protons), 12% helium ions (α particles), and 1–2% consists of mostly low energy protons and electrons. The heavier nuclei with charges ranging from Z = 3 (lithium) to Z = 28 background dose-rate for solar wind varies with the solar cycle, 10,11 (nickel). Ions heavier than nickel are also present, but they are but is easily shielded by modern spacecraft designs and is rare in occurrence. GCR ions with charge Z ≥ 3 are frequently considered to be of negligible risk. In addition to space environment radiation, some small amounts of radioisotopes are referred to as HZE particles (High nuclear charge Z and energy E). used in manned space missions for instrument calibration and During transit outside of LEO, every cell nucleus within an research; however, these sources are highly controlled by ﬂight astronaut’s body would be traversed by a hydrogen ion or delta npj Microgravity (2018) 8 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; Depth in Tissue (cm) Relative Contribution Per Z=1 Limitations in predicting the space radiation health risk JC Chancellor et al. ray (a recoil electron caused by fragmentation after ion interac- sequelae. These highly energetic SPE exposures delivered to crews tions) every few days, and by a heavier GCR ion (e.g., O, Si, Fe) undertaking interplanetary ﬂight could result in potentially serious 12,13 every few months. Despite their infrequency, the heavy ions symptoms ranging from prodromal responses (nausea, vomiting, contribute a signiﬁcant amount to the GCR dose that astronauts fatigue, weakness) to fatality. In addition, large SPE doses can would incur outside of LEO. The energies of the heavier GCR ions produce degenerative effects associated with cancer, ocular are so penetrating that shielding can only partially reduce the cataracts, respiratory and digestive diseases, and damage to the intravehicular doses. Thicker shielding could provide protection, microvasculature; while these effects are mostly latent and do not but is limited by mass and volume restrictions of exploration necessarily pose an immediate risk to crew health, their overall vehicles and dependent upon the capabilities of spacecraft launch impact upon long-duration crews is an important consideration. systems. The high-LET radiation found in the GCR spectrum can produce Interplanetary radiation environment excessive free radicals that instigate oxidative damage to cell The ﬂuence of GCR particles in interplanetary space ﬂuctuates structures. Chronic exposure to such oxidative stress contributes inversely with the solar cycle, with dose-rates of 50–100 mGy/year to the radiation-induced changes associated with premature at solar maximum to 150–300 mGy/year at solar minimum. The aging, cardiovascular disease, and the formation of cataracts. The ﬂuence and occurrence of SPEs is unpredictable, but dose-rates as large ionization power of GCR ions makes them a potentially 1,8,23 high as 1400–2837 mGy/hour are possible. signiﬁcant contributor to tissue damage and carcinogenesis, As discussed above, even if shielding in spacecraft effectively central nervous system (CNS) degeneration, and deleterious health reduces radiation dose to the crew from SPEs, spallation occurring 14,15 outcomes. In addition, as GCR ions pass through a space as GCR particles collide with shielding materials may lead to vehicle, interaction with the spacecraft hull attenuates the energy 9,13,18,19 biological damage. Aluminum shielding greater than of heavy-charged particles and frequently causes their fragmenta- 2 20–30 g/cm could only reduce the GCR effective dose by no tion into numerous particles of reduced atomic weight, a process 29 more than 25%. An equivalent mass of polyethylene would only 16,17 referred to as spallation. Spallation occurring as GCR particles 30,31 provide about a 35% reduction in GCR dose. While this degree collide with shielding materials can result in ‘cascade showers’ that of shielding has been achieved aboard the International Space produce progeny ions with much higher potential for biological Station (ISS), similar shielding is impractical within exploration 9,13,18,19 destruction than the original particle. This process changes mission design parameters due to the limited lift-mass capabilities the makeup of the intravehicular radiation spectrum, adding to of planned space launch systems. The Apollo crew module is the the complexity of the radiation environment unique to only vehicle to date that has transported humans outside of LEO; spaceﬂight. this vehicle could only effectively shield SPE protons with energies ≤75 MeV. To date, no studies have successfully emulated the Solar Particle Events complexity of energetic elements of the intravehicular radiation spectrum that astronauts are actually exposed to during space During SPEs, magnetic disturbances on the surface of the sun travel or successfully incorporated vehicular design and shielding result in the release of intense bursts of ionizing radiation that are 20–22 parameters in analog testing environments, limiting the under- difﬁcult to forecast in advance. SPE radiation is primarily standing of the true effects of such an environment on the human composed of protons with kinetic energies ranging from 10 MeV body. up to several GeV (determined by the relativistic speed of particles) and is predicted to produce a heterogeneous dose distribution within an exposed astronaut’s body, with a relatively CHALLENGES IN ESTIMATING RADIOBIOLOGICAL EFFECT high superﬁcial (skin) dose and a signiﬁcantly lower dose to Modeling the transfer of energy internal organs. As extravehicular space suits provide relatively low shielding As a charged particle traverses a material (such as spacecraft protection, SPE exposures occurring during extravehicular activ- shielding, biological tissue, etc.), it continuously loses energy in ities would pose signiﬁcant risk to astronauts. However, particle interactions until the particle escapes the medium or has astronauts would still receive potentially signiﬁcant elevations in slowed enough to have strong interactions with orbiting radiation dose even within a shielded spacecraft and remain electrons. This results in a rapid loss of particle energy over a vulnerable, especially on long-duration missions, to both acute very small distance with a corresponding rapid and sharp rise in effects of sudden SPE radiation boluses and to the overall additive LET. The ‘Bragg peak’ (Fig. 3a) describes the rapid transfer of effects of GCR and repetitive SPEs over the course of a mission. kinetic energy from a charged particle before the particle comes While many SPEs show modest energy distributions, there are to rest in a medium. This peak is particularly pronounced for fast- occasional and unpredictable high ﬂuence events; for example, a moving, charged particles, indicating more substantial energy particularly large SPE in October 1989 is predicted to have transfer and, as a result, the potential for greater deleterious delivered dose-rates as high as 1454 mGy/hour to an exposed biological effect from such particles. However, if a particle instead astronaut in a vehicle traveling in interplanetary space (for passes directly through tissue without sufﬁcient energy loss to context, consider that the daily dose for long-duration astronauts provide effective stopping power, the sudden energy loss 23–25 aboard the ISS is approximately 0.282 mGy per day). Similarly, associated with a Bragg peak does not occur and damage is some SPE can deliver particularly high-energy doses: for example, minimal. Space radiation studies to date generally presume a 10–15% of the total ﬂuence of an October 1989 SPE was made up homogeneous distribution of energy loss inclusive of the Bragg 1,23 of protons with energies in excess of 100 MeV. If an astronaut peak for each type of radiation, likely overestimating the relative were exposed to such an event during long-duration spaceﬂight, damage of some exposures. Improved modeling of dose there are potential risks for both acute radiation-induced illnesses deposition and resultant biological sequelae speciﬁc to the space and for signiﬁcant increase in the overall mission dose accumula- environment would advance risk estimation capabilities. tion. It should be noted that these predictions made use of classic The biological effects of space radiation depend on multiple shielding values (5 g/cm ) similar to those of the Apollo command particle- and energy-speciﬁc factors, such as the LET speciﬁcto 2 26 module (average shielding of 6.15 g/cm ). each ion, as well as the dose-rate of exposure. The Relative Energetic SPE events produce protons with energies ≥100 MeV Biological Effectiveness (RBE) of a particular radiation type is the that would penetrate classic spacecraft shielding, potentially numerical expression of the relative amount of damage that a reaching blood-forming organ depths with deleterious clinical ﬁxed dose of that type of radiation will have on biological tissues. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 8 Limitations in predicting the space radiation health risk JC Chancellor et al. quality factor), W , that represents an average of calculated RBEs for a given particle. To identify the relative biological risk of a speciﬁc type and dose of radiation exposure, the physical dose (in Gy) is multiplied by W to obtain the biologically effective dose in units of Sieverts (Sv). This method of estimating dose and relative effect introduces limitations in predicting the true biological risk of exposures, particularly exposures to complex and poorly under- stood radiation environments. Limitations of terrestrial analogs Mechanisms of biological impact. There are numerous limitations of current terrestrial analogs used for studying and predicting space radiation effects on biological tissues. The mechanisms that cause biological damage from space radiation are uniquely different from those associated with terrestrial radiation sources that are frequently used as surrogates in space radiobiology studies. Charged particle radiation, including GCR and SPE, causes primarily direct ionization events, where biological effects are the direct result of interactions between the charged ion and impacted tissue. As charged particles lose energy successively through material interactions, each energy loss event can result in damage to the biological tissue. In contrast, terrestrial analogs often use radiation that causes indirect ionizing events. In indirect ionization, non-charged particles, such as photons, interact with other molecules and cause the release of charged particles, such as free radicals or electrons, that ultimately cause biological damage. Thus, it is difﬁcult to extract a meaningful estimation of the direct ionizing space radiation impact through the use of terrestrial analogs and indirect ionizing radiation. Fig. 3 a The Bragg peak and depth dose characteristics of space Cumulative dose delivery and tissue distribution. Models of the radiation. The Bragg peak and relative dose deposition for ions at space environment outside of LEO have predicted that astronaut energies commonly used in space radiation studies compared to the crews may receive a total body dose of approximately 1–2 mSv/ X-ray and gamma sources used as surrogate radiations for Relative day in interplanetary space and approximately 0.5–1 mSv/day on Biological Effectiveness (RBE) quantiﬁcation. The Bragg peak refers 13,33 the Martian surface. These doses would increase with any SPE to the point where a charged particle promptly loses kinetic energy before coming to rest in a medium. This effect is very pronounced encountered over the course of the mission. for fast moving, charged particles. Shown are 60 MeV Protons Many recent studies have led to ominous conclusions regarding 56 12 (hydrogen, purple), 600 MeV Fe (iron, light blue), 290 MeV C the non-acute effects of GCR radiation on CNS and cardiovascular (carbon, green), 1 GeV Fe (iron, dark blue), X-ray (orange dotted health that are difﬁcult to interpret as real effects likely to occur in line), and Co (cobalt, yellow dotted line). The shaded gray area, humans, but suggest that the protracted, low dose and dose-rate representing the average diameter of a mouse, demonstrates that radiation exposure expected on the longer, exploration missions the Bragg peak, and thus the majority of dose deposition, is outside 34,35 might lead to mission-relevant threats to astronaut health. the mouse body for SPE protons (energies ≥50 MeV) and GCR ions. b These experiments were performed using rodent models exposed The proton and electron range, energy and dose distributions for to single ion, mono-energetic heavy-ion beams, in some cases at the October 1989 solar particle event compared to a dose- total doses that are many times higher than the radiation human equivalent Co exposure. Charged particles (electrons, protons, 36–38 heavy-charged particles) typically deposit more energy towards the crews would experience during interplanetary space travel. end of their range. In contrast, the current standard, Co radiation, Even in studies where lower total doses are used, study methods loses the most energy at the tissue surface. These energy delivered the cumulative mission doses for an entire mission over characteristics demonstrate the poor ﬁdelity of Co as a surrogate 39,40 a very short period of time, typically over a few minutes. These for studying the complex SPE and GCR spectrums. Figure 3 (b) parameters do not allow for critical physiologic components of the reprinted by permission from Conditions for RightsLink Permissions 32 radiobiological response that would be expected under chronic, Springer Customer Service Center GmbH:Springer-Verlag low-dose and low-dose-rate radiation conditions, such as cell regrowth and up-regulation of repair mechanisms. Additionally, Higher RBEs are associated with more damaging radiation for a there is substantial evidence that GCR exposure at the dose-rates given dose. RBE is determined using the effectiveness of cobalt expected in interplanetary space may not induce acute or ( Co) gamma rays as a standard. An RBE = 1 means that the “test” subacute biological responses, while acute exposure to total/ radiation type (for example, heavy ion exposure) is as effective as cumulative dosage easily could. Co radiation at producing a biological effect, and an RBE > 1 Recently, NASA has developed an updated GCR simulator means that the test radiation is more effective than Co radiation capable of providing three to ﬁve consecutive mono-energetic ion at producing a biological effect. However, in some cases this beams, with rapid switching between ion species. The NASA comparative value does not fully represent the energy transfer Space Radiation Laboratory (NSRL) is located at Brookhaven curve of a speciﬁc radiobiological insult (Fig. 3b). National Laboratory in Brookhaven, NY. Currently, NSRL is the only The effect of quantifying factors such as LET, particle identity, U.S. facility with the capapbilites to generate heavy-charged dose-rate, and total dose on RBE remains incompletely under- particles at energies relevent to space radiation studies. While an stood. The RBE can vary for the same particle type, depending on improvement upon previous methods, NASA’s new GCR simulator energy, dose-rate, target organ, and other factors. Different remains limited in its ability to emulate the GCR environment of particle types are assigned a radiation weighting factor (formerly deep space. The simulator lacks the capacity to generate the pions npj Microgravity (2018) 8 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA Limitations in predicting the space radiation health risk JC Chancellor et al. Table 1. LD of various animal models used in space radiobiology studies compared to the human LD dose following radiation exposures Species LD (Gy) Reference Ferret <2 Harding Pigs 2.57 Morris and Jones Dogs 2.62 Morris and Jones Primates 4.61 Morris and Jones Mice 8.16 Morris and Jones Humans 3–4 Hall and Giaccia This broad spectrum in LD values emphasizes the difﬁculty in interpreting results of studies using speciﬁc radiation exposures in Fig. 4 The intravehicular LET of the Space Shuttle. Displayed are the different animal models and translating them into clinical outcomes in integrated LET/day values measured by Badhwar et al. 1998 (purple humans. Note: Table is adapted from the reported results of Harding 109 110 6 dotted line), as well as the LET of ﬁve single-ion exposures 1988, Morris and Jones 1988, and Hall and Glaccia 2012 14 16 47 (290 MeV C (carbon), 600 MeV O (oxygen), 1 GeV Ti (titanium), 56 56 1GeV Fe (iron), and 600 MeV Fe (iron)). As studies generally focus 32,55,56 on a single, mono-energetic radiation exposure, this ﬁgure high- spectrum and dose distribution of an SPE using protons. lights the lack in breadth of energies or radiation ﬁeld complexity Larger animal models, such as pigs or primates, allow for matching used in current radiobiological studies. Data adapted from Badhwar of the anticipated dose distribution for human SPE exposure using et al. 1998 protons with a similar LET spectrum; thus, larger animal models are more likely than smaller species to provide robust estimations (subatomic particles) and neutrons that would follow spallation of human-speciﬁc space radiation effects. However, it remains reactions, though these would make up 15–20% of a true unclear whether the concurrent exposure to low-dose and dose- 39,41,42 intravehicular dose. Sequential beam exposures remain rate GCR radiation can be successfully emulated in small or large ineffective in modeling complex and simultaneous exposures of animal models. Modeling of GCR radiation effects may be the actual GCR environment, and there is signiﬁcant debate similarly altered by variations in animal species; however, without regarding the appropriate order of ion exposures delivered (as dedicated efforts towards expanding understanding of these alteration of exposure sequence can affect the outcomes of an phenomena, prediction of the biological consequences of long- 42,43 experiment). Finally, dose-rate delivered by this simulator will term GCR exposure will remain theoretical at best. remain signiﬁcantly higher than the radiation dose-rate antici- Animal models pose further challenges in the development of 39,41 pated for human crews during spaceﬂight. meaningful and accurate analog research. While animal models As an additional challenge, SPE radiation has a unique dose are used in radiobiology studies as surrogates to obtain data that distribution with respect to whole body irradiation. Research has typically cannot be gained in ethical studies of humans, there are demonstrated that the biological response to space radiation is numerous metabolic, anatomic, and cellular differences between unique due to a non-homogeneous, multi-energetic dose humans and other animal species. Most of the animals used in 44,45 distribution. The majority of the protons in SPEs have energies all U.S. scientiﬁc research are mice and rats, bred speciﬁcally for less than 100 MeV, with Bragg peaks that occur inside the body use in research endeavors. While larger species are likely to and LET of 10–80 keV/μm (Fig. 3b). While these energies might be provide more meaningful correlation to human effects, due to mitigated with effective shielding, an exposed human would be animal protection issues and relative societal value, less than one expected to receive a much higher absorbed dose to skin and quarter of 1% of scientiﬁc studies are performed on non-human 23,32,46,47 subcutaneous tissues than to internal organs. Until primates and less than one half of 1% of studies use dogs and recently, these SPE-speciﬁc toxicity proﬁles and dose distributions cats. Few studies utilize rabbits, guinea pigs, sheep, pigs, or other were poorly understood. As a result, the majority of prior research large mammals. While rodent experiments have contributed has been based largely on simpliﬁed models of radiation signiﬁcantly to our understanding of mechanisms of disease, transport, relying upon simple spherical geometry to estimate including disease caused by radiation, their value in predicting the 48,49 organ dose approximation at average depths. However, with effectiveness of treatment modalities for human application has 60–62 this new evidence of heterogeneous dose distribution, spherical remained controversial. geometry is insufﬁcient for the modeling of radiation delivered Differences between animals and humans are clearly demon- within the space environment. strated by the characteristics of radiation-induced death (RID). The LD deﬁnes the required dose of an agent (e.g., radiation) Animal model sensitivity and dose simulation. For ease of dose necessary to cause fatality in 50% of those exposed. As illustrated speciﬁcation and modeling, mono-energetic protons and GCR ions in Table 1, remarkably different LD values have been reported in the 100–1000 MeV range are often used for in vivo animal for radiation exposure among different species. Currently, the model experiments such that the entire target is contained within genetic and physiologic basis for inter-species and intra-species 50–54 the plateau portion of the depth-dose distribution. In variation in LD is not well understood. Mice have been the most experimental animals that are much smaller than humans, simple extensively developed model for human diseases including scaling of particle energies to match dose distribution dramatically radiation-induced tissue damage. Rodent models have a high alters the LET spectrum for the protons (Fig. 3 and Fig. 4). potential utility in describing the physiologic and genetic basis for Conversely, delivering a simulated SPE or GCR exposure to smaller many aspects of the mammalian radiation response. Even so, it animals without scaling the energies would match their respective should be noted that, in addition to simple physiological LET spectrum but create an heterogeneous dose distribution that differences between mice and larger animals (including signiﬁ- is higher to internal organs than to superﬁcial tissues, the exact cantly higher metabolic rate, shorter lifespan, and lower body inverse of the human SPE dose distribution. For smaller animals mass), the LD for mice is signiﬁcantly higher than that of most (such as rodents), it is not possible to match both the LET other mammalian species, including humans. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 8 Limitations in predicting the space radiation health risk JC Chancellor et al. It has been proposed that the differences between the LD values for humans compared to small mammals, like rodents, are due to different mechanisms involved in RID at these dose levels. For mammals, death at the LD dose is thought to be caused by the hematopoietic syndrome, which includes destruction of precursor cell lines within blood-forming organs. Historically, it was thought that infection and hemorrhage are the major causes of death from hematopoietic syndrome, with one or the other of these factors predominating in different species’ responses to lethal radiation exposure. For example, bacterial infection is the predominate factor leading to RID in mice at doses near their 63–65 respective LD levels. However, recent results from Krigsfeld et al. have indicated that radiation-induced coagulopathy (RIC) and clinical sequelae that mimic disseminated intravascular coagulation (DIC) can result in hemorrhage, microvascular thrombosis, organ damage, and death from multiorgan failure from exposure of large animals (including ferrets and pigs) to doses of radiation at or near 66–70 the species’ LD . RIC-associated hemorrhage occurs well before the expected decline in peripheral platelet counts after irradiation. Rodents do not exhibit signs of hemorrhage or disorders of primary hemostasis at time of necropsy after lethal radiation exposure at doses near the LD dose, while large animals, including humans, do exhibit hemorrhage at death following radiation exposure. These ﬁndings suggest that humans may be at risk for coagulopathy-induced complications after radiation exposure in addition to the classically anticipated (delayed) concerns of infectious sequelae or cell-count decline, effects that may not be modeled by rodent surrogates. Further, RBE values for proton irradiation vary between animal models. In general, RBE values increase with animal size, with mini-pigs demonstrating higher RBEs than ferrets, and ferrets, in turn, exhibiting higher RBEs than mice (Table 2). Numerous studies have focused on RBE values for hematopoietic cells in mice Fig. 5 Comparison of lymphocyte and neutrophil counts following at various time points after the animals have been exposed to proton and X-ray (comparable to gamma radiation) exposures in 45,71 mice, ferrets, and Yucatan mini-pigs. The relative fraction of different doses of proton or gamma radiation. In these rodent lymphocyte (a) and neutrophil (b) counts following a homogeneous models, RBEs do not differ signiﬁcantly from one at any of the proton or X-ray exposure to the bone marrow compartment are time points or doses of radiation evaluated. However, similar shown. Note: calculations indicate that animals received approxi- studies in ferrets and mini-pigs have demonstrated alterations of mately a 2 Gy marrow dose. In both cases, the mouse models RBE value that are dependent upon animal model, type of demonstrated the ability to fully recover within 30 days following radiation, time since exposure, and cell-line evaluated (for proton exposures while the ferret and pig models showed no example, total white blood cell count vs. neutrophils). In one recovery. The ferrets were euthanized at day 13. The RBE values for study, proton-irradiated ferrets examined 48 h after exposure white blood cell counts varied greatly between the mice, ferret and demonstrated RBEs for white blood cells ranging from 1.2–1.6 and pig models. RBE values were greater in ferrets than mice, and considerably greater in pigs compared to either ferrets or mice. This RBEs for neutrophils ranging from 1.9 to 2.1. In Yucatan mini- suggests that model-speciﬁc sensitivity to radiation exposure may pigs evaluated 4 days after exposure, the RBEs for white blood lead to drastically different results in experimental outcome, leading cells was found to be 2.4–4.1 and the RBEs for neutrophils was 56 to difﬁculty in extracting clinical signiﬁcance from animal models 2.2–5.0 (see Table 2, Fig. 5). with dissimilar radiation sensitivity compared to humans. Data from In other experiments, proton exposure in mini-pigs again 44 66,67 Kennedy (mouse and ferret results) and Krigsfeld et al. resulted in signiﬁcantly greater hematopoietic injury and white (Yucatan mini-pig results) blood cell count reduction than comparable gamma exposure 55,56 (Fig. 6). The results of these studies demonstrate that RBE values of different radiation types, calculated for the same endpoints, can vary greatly by animal species and cell line. One contributing factor may be the repair capacity of the blood cell Table 2. The relative biological effectiveness (RBE) for SPE-like protons renewal systems in mice; such capabilities appear to be lacking in compared with standard reference radiations (gamma or electron) in mini-pigs (an animal model with more human-like hematopoietic animal models characteristics), making them more susceptible to radiation- Animal WBC Neutrophil induced declines in cell counts. Given the presumed closer approximation of radiation effects in larger animals to human- Mouse 1 1 speciﬁc consequences, this suggests that space radiation-speciﬁc Ferret 1.16–1.6 1.9–2 RBE values for humans may be considerably higher than those in mice. Mini-Pig 2.4–4.1 2.2–5 These studies demonstrated novel efforts towards an inte- 45,56,71,72 Source: Refs. grated, physiology-based approach for the evaluation of organ The RBE of proton exposure varies greatly for total white blood cells (WBC) system-speciﬁc and species-speciﬁc endpoints. Using a more and speciﬁcally for neutrophils when comparing animal models. Note that comprehensive evaluation of radiation toxicity for multiple doses ferret RBE values were determined 48 h after exposure; mini-pig values and dose-rates in multiple animal models, this effort advanced the were determined 4 days post-irradiation understanding of the impact of genetic heterogeneity and npj Microgravity (2018) 8 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA Limitations in predicting the space radiation health risk JC Chancellor et al. related to signiﬁcant cell damage or death (for example, the spectrum of clinical manifestations that make up Acute Radiation Sickness), or stochastic, where increased exposure is associated with increased risk though no threshold dose is necessary for biological impact (for example, carcinogenesis). Currently, carcinogenesis is the only long-term, stochastic effect that has a clearly deﬁned permissible exposure limit in spaceﬂight. Terrestrial radiation (e.g., occupational or clinical radiotherapy gamma or X- ray exposures) is known to be associated with carcinogenic risk; at this time, there is no deﬁnitive evidence that space radiation causes human cancer, but it is reasonable to assume that it can. The dose-equivalent of radiation received by astronauts currently traveling to the ISS for 6 months is approximately 100 mSv; doses of 100 mSv of terrestrial radiation sources have been associated with an elevated cancer risk in human populations. Fig. 6 Results from Yucatan mini-pigs exposed to simulated Solar NASA’s “Lifetime Surveillance of Astronaut Health” (LSAH) Particle Event (SPE)-like radiation consisting of several different program documents cancer cases in astronauts, among other energies of protons. In this study, Kennedy et al. utilized an health parameters. Previous review of LSAH data suggests that inhomogeneous distribution of protons that resembled a SPE there may be evidence of increased cancer risk in astronauts spectrum, as demonstrated in Fig. 3. Electrons were used as the compared to a control population, though data are inconclusive surrogate radiation for determining the RBE following exposure to a and limited by the very small sample size. SPE-like distribution of protons. Electrons were chosen because a Most evidence for the effects of space-like radiation exposures SPE-like distribution could not be achieved with Co as demon- in humans has been derived from epidemiological studies on the strated in Fig. 3. Note the white blood cell counts in the mini-pig atomic-bomb survivors, radiotherapy patients, and occupationally model recovered to near pre-irradiation levels following exposure to the electron radiation while the white blood cell counts for those exposed workers. These studies have focused on the association exposed to a SPE-like proton spectrum remained suppressed for between ionizing radiation exposure and the long-term develop- 30 days after exposures. These results indicate that the mini-pigs ment of degenerative tissue effects such as heart disease, were not capable of repairing the hematopoietic damage caused by cataracts, immunological changes, cancer, and premature aging the proton radiation exposure as efﬁciently as they could repair the 1,8 for moderate to high doses of low-LET radiation. The ﬁndings electron radiation damage. Data from Kennedy 2014 are further supported by results of laboratory studies using rodent animal models. However, true risks for these diseases from low demonstrated that animal model, physiology, body mass, and dose-rate exposures to GCR and intermittent SPE are much more ﬁdelity of a space radiation analog (in this case, a multi-energy difﬁcult to assess due to long latency periods and the numerous proton spectrum) all contribute to radiation response. Such efforts challenges involved in studying the radiation environment. towards the integration of the numerous factors that contribute to Additionally, the types of radiation exposure produced by atomic radiation-induced effects will be critical to translation of research bombs (high dose and high dose-rate gamma and neutron results and prediction of clinical responses in humans. radiation) are dissimilar to radiation exposures for astronaut crews Finally, studies of the synergistic effects of radiation combined during spaceﬂight. with spaceﬂight environment stressors (e.g., microgravity, envir- The theoretical, calculated RBEs for some space radiation- onmental factors, isolation and emotional stress, etc.) show that induced cancers are quite high, which has led to speculation that such factors in combination impart an increased susceptibility to the risk of cancer development from space radiation exposure is at 71,73,74 infection and delayed wound healing. While spaceﬂight least as high, and perhaps higher, than the risk of cancer 91,92 medical capabilities have been developed for the management of development from exposure to radiation on Earth. However, some acute injuries, such as wound care and infection control, it is there are currently no biophysical models that can accurately unclear whether standard management techniques will be project all acute, subacute, degenerative, and carcinogenic risks effective against the synergistic variables that alter wound healing speciﬁc to the range of particles and energies of ionizing radiation and associated risks speciﬁc to the space environment. Histori- in the space environment. There is little information available cally, there has been limited testing on the efﬁcacy of manage- about dose response and dose-rate modiﬁers for speciﬁc effects or ment techniques, including pharmaceutical interventions, when about the degenerative effects associated with ionizing radiation, radiation exposure is a factor. Similarly, few research protocols and very few biological models describe degenerative processes examining operational medical care have included the additional (e.g., cardiovascular degeneration) caused by ionizing radiation. 75–77 variables of the high-stress and isolated environment, Exposure to the LEO radiation environment has been associated 94–97 infections related to the altered bacterial and chemical exposures with alterations to chromatin structure. However, it is not well 78–81 speciﬁc to space vehicles, or factors related to gravitational understood how such damage relates to impacts on cellular 73,82–84 unloading, and no studies have effectively examined all of function or long-term carcinogenic risk. There is a paucity of these variables simultaneously. It is unclear whether these understanding regarding the interpretation of chromosomal complex interactions can be fully simulated even in large animal damage rates identiﬁed in astronauts and the long-term effects models for appropriate extrapolation of human risk. There is a induced by the space radiation environment, without relying on need to better understand the mechanism of the synergistic terrestrial studies of different radiation sources, doses, dose-rates, effects observed, deﬁne appropriate animal models for analog or complexity for context. For example, NASA’s Human Research research efforts, and determine efﬁcacy of standard treatments Program Evidence Report on the Risk of Radiation Carcinogen- against damage resulting from radiation-combined injury. Dedi- esis, published in 2016, cites numerous studies to provide an cated effort towards these goals will better allow for operationally assessment of risk for chromosomal damage (and, ultimately, relevant and appropriate countermeasures. carcinogenesis). A review of the studies cited in this report highlights the limitations described throughout this manuscript, Translation of space radiobiology research to human health including reliance upon mono-energetic radiation 36,38,40,97,99,100 outcomes. Biological damage from radiation exposure is gen- sources, comparison to or interpretation of results 38,40,99–101 erally classiﬁed as deterministic, dose threshold-based effects in the context of gamma or X-ray exposures, or use of Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 8 Limitations in predicting the space radiation health risk JC Chancellor et al. dose or dose-rates far exceeding those expected during space- 36,38,40,97 ﬂight. Indeed, many of these same factors are cited as limitations to NASA’s primary radiation cancer risk prediction model. In addition, few studies have assessed mutation rates due to LEO radiation at a whole genome level. Whole genome sampling techniques are being employed for other carcinogenic stres- sors. Direct observations of mutation rates, as well as an understanding of the epigenetic changes and cellular damage using in vitro cell culture models, may now be possible due to recent advances in long-term cell culture aboard the ISS (Sharma, Fig. 7 Moderator block geometry concept for the emulation of A. & Wu, J. Personal Communication (2016)). Quantiﬁcation of space radiation spectra. Artist conception of GCR analog detailed in 42 56 Chancellor et al. A primary beam of Fe (iron, left) is selectively observable mutation rates from LEO exposures may better inform degraded with a carefully designed moderator block to produce a future modeling efforts and provide a critical understanding of the desired distribution of energies and ions (represented by the molecular mechanisms behind observed pathologies. However, colorful lines on the right) simulating the intravehicular space even data obtained from the LEO environment is less than ideal, radiation environment. To preferentially enhance fragmentation and as the ISS is heavily shielded and the close proximity of the Earth energy loss, cuts are performed in the moderator block made up of provides signiﬁcant protection from radiation exposure. While different materials (depicted by different shades of gray). Before the improved understanding of the LEO environment may help inform spallation products exit the moderator block, a high-Z material layer risk predictions, there is signiﬁcant work to be done in is added for scattering. Image courtesy of R. Blue characterizing these risks in the radiation environment outside of LEO. initial characterization studies and for statistically signiﬁcant outcomes, true advances are more likely to come from an effort DISCUSSION to utilize larger animals with more human-like physiology for The health risks associated with exposures to space radiation will landmark studies on how speciﬁc outcomes may translate to become more onerous as future manned spaceﬂight missions humans. Finally, while there would be numerous challenges and require extended transit outside of LEO and beyond the ethical considerations involved, studies of non-human primates protection of the Earth’s magnetosphere. The indigenous shield- for ﬁnal validation of risk and mitigation strategies would likely ing provided by the Earth’s magnetic ﬁeld attenuates the major prove highly beneﬁcial for the protection of future human crews. effects of space radiation exposures for current LEO missions; in As described above, NASA’s updated GCR simulator may be the highly mixed-ﬁeld environment of interplanetary space, able to provide some improvements to simulation studies by use 39,41 radiation dose could increase dramatically. Even behind shielding, of rapid-sequential mono-electric beam exposures. Recent secondary particles produced by interactions of primary cosmic developments by Chancellor et al. demonstrate the potential for rays and the atomic molecules of the spacecraft structure can more accurate analog recreation of the GCR radiation environ- deliver a signiﬁcant fraction of the total dose equivalent. Astronaut ment by allowing for continuous generation of ionizing radiation crews could be exposed to multiple SPEs of unpredictable that more closely matches the ion distribution, LET spectrum, and magnitude with doses that could induce clinical illness and dose-rate of GCR (Fig. 7). These recent ﬁndings suggest that the exacerbate biological outcomes from the chronic GCR radiation environment inside spaceﬂight vehicles can be experi- environment. mentally generated by perturbing the intrinsic properties of The limited accumulation of knowledge to date has yet to hydrogen-rich crystalline materials in order to produce speciﬁc provide sufﬁcient data for even an estimation of total risk, nuclear spallation processes when placed in an accelerated mono- let alone predictions of human clinical outcomes or appropriate energetic heavy ion beam. While still limited by dose-rate (as are mitigation strategies before, during, or after exposure. Accurately all terrestrial beam exposures), such an approach could allow for simulating the spectrum of energies, ion species, doses, and dose- improvements to the simulation of the complex mix of nuclei and rates found in the space radiation environment is a non-trivial energies found in the space radiation spectrum. endeavor. For the numerous reasons described above, emulation Potential radiation exposure to astronaut crews occurs on a of the radiation environment, choice of surrogate animal model, timescale that is measured in days to months for SPE and GCR. and delivery of appropriate complexity, rate, and magnitude of Technological, practical, and ﬁnancial considerations make con- dose have all limited the knowledge available for extrapolation of tinuously irradiating animals for more than a few hours exceed- radiation risk within the context of spaceﬂight. These factors have ingly difﬁcult. In addition, because the lifespan of most limited our ability to develop operational and useful medical experimental animals is more than an order of magnitude shorter countermeasures to mitigate the radiation risk of future than the human lifespan, the interpretation of long-term, low exploration-class spaceﬂight. dose-rate exposures using such models would be questionable To improve upon the limitations described, there must be a even given the open opportunity to perform long-duration focused effort to develop novel or new methods of simulating the experiments. As radiation dose-rate can have a major impact on space radiation environment in more realistic analogs. This should modulating the severity of the radiation response, it is critical to include more realistic dose-rate studies that can determine if obtain at least some dose-rate data for radiation experiments presumed or modeled outcomes are being observed at mission investigating clinical outcomes of space radiation exposures. relevant dose-rates and dose. Additionally, heavier utilization of While some radiation effects are either unchanged or mitigated by the animal laboratory on board the ISS with comparison of tissues, decreased dose-rates, data on non-targeted radiation effects (such organ, and blood samples, identifying realistic dose thresholds as genomic instability and adaptive responses) suggest that dose and dose-rates, and comparing these data to ground-based response could be altered at lower dose-rates, with signiﬁcant studies, would greatly improve the current approach to analog differences in quantitative (slope of the dose-toxicity curve) or construction. The use of animal models should be strategic and qualitative (toxicity effects) biological responses. This is especially consistent with species, strain, dose, and dose-rates with an effort true for high-LET radiation exposure under conditions of increased 104–107 towards the highest-ﬁdelity studies possible for human risk oxidative stress promoted by spaceﬂight. In previous extrapolation. While rodent models may be highly useful for studies on SPE-like radiation, dose-rates from 17 cGy/hour up to npj Microgravity (2018) 8 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA Limitations in predicting the space radiation health risk JC Chancellor et al. 50 cGy/minute have been modeled experimentally and statistical that would improve upon our ability to better predict risk and analysis of these data have begun to explore the potential provide realistic strategies and risk posturing for future explora- quantitative or qualitative impact of dose-rate on the toxicity of tion spaceﬂight. Use of improved modeling techniques to emulate multi-energy spectrum. Use of such data to better design dose- the space environment, selection of appropriate biological rate extrapolation experiments would be highly useful for more surrogates for extrapolation of human effects, and careful use of robust, future studies. ﬂown astronaut data could provide much-needed advances in There have been other advances in ﬁelds related to space space radiation research. As humans seek to explore space outside radiation effects, including whole genome sequencing, as well as of the close proximity and protection of LEO, we have the transcriptional, proteomic, and epigenomic studies of cellular responsibility to address the space radiation risk to the extent of response. There is a growing list of genes known to affect terrestrial capabilities in order to provide the best information and radiation sensitivity for many different biological effects of protection possible for our future explorers. radiation (e.g., molecular, chromosomal, signal transduction- associated growth-regulating changes, cell killing, animal tissue ACKNOWLEDGEMENTS and tumor acute and late effects, and animal carcinogenesis). Even H.G.K. acknowledges support from the NSF (Grant No. DMR-1151387). Part of the so, there is a need to correlate observed sequence changes with work of H.G.K. and J.C.C. has been based upon work supported by the Ofﬁce of the corresponding alterations of radiosensitivity. Incorporation of Director of National Intelligence (ODNI), Intelligence Advanced Research Projects these investigational directions opens new opportunities to Activity (IARPA), via Interagency Umbrella Agreement IA1-1198. The views and evaluate space radiation risk on a genomic level, deﬁning risk conclusions contained herein are those of the authors and should not be interpreted and allowing for improved understanding of the pathology of as necessarily representing the ofﬁcial policies or endorsements, either expressed or radiation-induced injury and the potential for intervention in such implied, of the ODNI, IARPA, or the U.S. Government. The U.S. Government is authorized to reproduce and distribute reprints for Governmental purposes processes. notwithstanding any copyright annotation thereon. Finally, there are a number of lessons that may be learned from historical spaceﬂight and the health of early space pioneers, though it has been difﬁcult to extract meaningful conclusions AUTHOR CONTRIBUTIONS from historical data. For example, some sources suggest that there J.C.C. developed the concept of the review. J.C.C., K.A.C., and H.G.K. contributed to the is no statistically signiﬁcant increase in carcinogenesis in Apollo, discussion on space physics. J.C.C., R.S.B., S.M.A., and K.A.C. contributed to the Space Shuttle, or ISS astronaut crews in comparison to the average discussion on operational space radiation. J.C.C., K.A.C., and A.R.K. contributed to the U.S. population; other reviews of data suggest that risk is indeed discussion on dosimetry. J.C.C., R.S.B., S.M.A., K.H.R., and A.R.K. contributed to the 1,14,89,92 increased for astronauts. Given that the broad research discussion on countermeasures. R.S.B., S.M.A., K.A.C., K.H.R., and A.R.K. contributed to base has utilized non-ideal and highly limited analogs for the the discussion on clinical effects of space radiation on humans. J.C.C., R.S.B., S.M.A., K. prediction of risk, the fact that reality has deviated from A.C., K.H.R., and A.R.K. contributed to the discussion on space radiobiology. J.C.C., R.S. theoretical, calculated risk is not entirely surprising. Medicine B., S.M.A., K.A.C., K.H.R., and A.R.K. contributed to the discussion on animal models. R. S.B., K.H.R., and A.R.K. contributed to the discussion on genetics. J.C.C., K.A.C., and H.G. does not advance without clarifying treatment options using K. contributed to the discussion on computational modeling. All authors contributed human subjects. Models and animal data are useful surrogates for equally to the review of the literature, discussion on the interpretation of research space radiation studies but provide limited beneﬁt for the outcomes to spaceﬂight operations, and drafting of the manuscript. interpretation to human outcomes, and studies on humans exposed to occupational radiation and clinical radiotherapy are imperfect proxies. The reliance upon these surrogates continues ADDITIONAL INFORMATION to limit the ability to translate radiation knowledge to spaceﬂight Competing interests: The authors declare no competing interests. scenarios. We now have the beneﬁt of a larger, cumulative astronaut Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims population that has ﬂown in space while exposed to a variety of in published maps and institutional afﬁliations. doses that exceed the identiﬁed thresholds for some degenerative and carcinogenic outcomes. The health of these astronauts, including early indicators of disease, is closely monitored by NASA REFERENCES medical and epidemiological resources with yearly medical 1. National Council on Radiation Protection andMeasurements (NCRP). Guidance examinations and careful records of clinical outcomes. This on Radiation Received in Space Activities. Tech. Rep. 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Review of NASA’s Longitudinal Attribution 4.0 International License, which permits use, sharing, Study of Astronaut Health. (National Academies Press, U.S. Institute of Medicine, adaptation, distribution and reproduction in any medium or format, as long as you give Washington, 2004). OCLC: ocm55201397. appropriate credit to the original author(s) and the source, provide a link to the Creative 90. Blakely, E. A. & Chang, P. Y. A review of ground-based heavy-ion radiobiology Commons license, and indicate if changes were made. The images or other third party relevant to space radiation risk assessment. Part II: cardiovascular and immu- material in this article are included in the article’s Creative Commons license, unless nological effects. Adv. Space Res. 40, 461–469 (2007). indicated otherwise in a credit line to the material. If material is not included in the 91. Kennedy, A. & Wan, X. Countermeasures for space radiation induced adverse article’s Creative Commons license and your intended use is not permitted by statutory biological effects. Adv. Space Res. 48, 1460–1479 (2011). regulation or exceeds the permitted use, you will need to obtain permission directly 92. Cucinotta, F. A. & Cacao, E. Non-targeted effects models predict signiﬁcantly from the copyright holder. To view a copy of this license, visit http://creativecommons. higher mars mission cancer risk than targeted effects models. Sci. Rep. 7, org/licenses/by/4.0/. 1832–1843 (2017). 93. Huff, J. & Cucinotta, F. Risk of Cardiovascular Disease and Other Degenerative © The Author(s) 2018 Tissue Effects From Radiation Exposure and Secondary Spaceﬂight Stressors.TR Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 8

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Limitations in predicting the space radiation health risk for exploration astronauts

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