Acute radiation risk assessment and mitigation strategies in near future exploration spaceflights

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Acute Radiation Risk Assessment and Mitigation Strategies in Near Future Exploration Spaceflights S. Hu , J.E. Barzilla , E. Semones PII: DOI: Reference:

S2214-5524(19)30124-5 https://doi.org/10.1016/j.lssr.2019.10.006 LSSR 251

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Life Sciences in Space Research

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30 August 2019 24 October 2019 25 October 2019

Please cite this article as: S. Hu , J.E. Barzilla , E. Semones , Acute Radiation Risk Assessment and Mitigation Strategies in Near Future Exploration Spaceflights, Life Sciences in Space Research (2019), doi: https://doi.org/10.1016/j.lssr.2019.10.006

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Acute Radiation Risk Assessment and Mitigation Strategies in Near Future Exploration Spaceflights S. Hu a, J.E. Barzilla b, and E. Semones c a

KBR, Houston, TX, b Leidos, Houston, TX, c NASA Johnson Space Center, Houston TX Abstract

As more exploration spaceflights are planned to travel beyond the protective Earth magnetosphere to deep space destinations, acute health risks due to possible high radiation doses during severe Solar Particle Events (SPEs) are of greater concern to mission planners and management teams. It is expected that some degree of Acute Radiation Syndromes (ARS) symptoms may be observed, but the specific list of health risks that are relevant to exploration missions has been ambiguous and debatable in the past. This mini-review gives a brief summary of the features of radiation exposure if astronauts encounter severe SPEs beyond Low Earth Orbit (LEO), the evidence of ARS radiobiological studies at exposure levels close to recommended limits, and the shortcomings of previous dose projection approaches for ARS risk assessment. Some ARS biomathematical models, particularly those pertinent to the dose ranges that severe SPEs beyond LEO could generate, are reviewed and evaluated, focusing on their capability to predict the incidence of performance incapacitation and time-phased health effects with subsequent medical care recommendations. Using onboard active dosimeter input for estimating organ doses and likely clinical outcomes for SPEs in real time, a new strategy for ARS assessment and mitigation is described to cope with the potential threats of severe SPEs for planned deep space missions. Further studies are needed to expand the current biological response models and to improve their capability to reflect the physiological alteration induced by energetic particles in space. Key words: Solar particle events, Organ dose projection, Acute radiation risk assessment, Biological response models 1.

Introduction

Leaving the protection of Earth’s atmosphere and geomagnetic field, astronauts traveling in deep space are at risk of radiation hazards induced by various high energy particles ubiquitous in our solar system. While the low flux of galactic cosmic rays (GCR) is difficult to shield and may induce stochastic late medical effects that are of post-flight concern, such as cancer and heart disease, intense solar particle events (SPE) can cause Acute Radiation Syndrome (ARS) symptoms that could manifest during missions, i.e., from the first hours to up to 60 days after exposure. Though analysis indicates that, for crew inside a typical interplanetary spacecraft, the ARS symptoms are expected to be mild to moderate even in the worst case SPEs (Townsend et al., 1991), they could compromise the crew’s ability to perform required tasks and thus may adversely impact the success of a mission (Hu et al., 2009). In fact, such an event did occur on August 4, 1972 just four months after the Apollo 16 mission. If the spacecraft had encountered such an event in space, or the astronauts had been exposed to it while on the lunar surface, past analysis indicated that the shielding provided either by the vehicle wall (3-5 g/cm2 aluminum equivalent) or the spacesuits (0.3-0.5 g/cm2) would not be sufficient to prevent the induction of ARS among the crew (Townsend et al., 1991; Hu et al., 2009).

The current International Space Station (ISS) and future exploration vehicles, such as the Orion Multi-Purpose Crew Vehicle (MPCV), are designed with significantly thicker walls (10-20 g/cm2) which substantially reduce exposures. Additionally, the NASA Space Radiation Analysis Group (SRAG) maintains a console position at Mission Control Center – Houston for both nominal and contingency operations. In the case of an SPE contingency, the console operator determines the projected exposure from the event and makes appropriate recommendations for crew, for example, sheltering in locations of the ISS that provide greater shielding. SRAG works with the Flight Control Team (FCT) to mitigate impacts of the SPE on the crew while also minimizing the effect of taking shelter on other crew operations. This practice will be implemented for Orion MPCV, the next generation human exploration spacecraft being developed by NASA. As future manned mission beyond Low Earth Orbit (LEO) such as lunar or Mars missions will more likely experience the effects of more intensive SPEs, it is vital to comprehensively collect knowledge and understanding of the space radiation environment concerning SPEs and biomedical research of ARS, and to provide a thorough and practical plan to manage and mitigate these risks. 2.

Organ dose projection for SPEs

2.1

SPEs and organ dose modeling

The Sun not only constantly releases warmth and light that are essential to maintain the habitability of Earth, but also discharges energetic particles that are hazardous to human health and instruments in space. For space environment measurements, an SPE is defined as an event where flux of protons with energies ≥10 MeV and ≥100 MeV continuously exceed the 10 cm-2 s1 -1 sr and 1 cm-2 s-1 sr-1 operational threshold, respectively1. Only protons with energies > 10 MeV are of major concern for space radiation protection. In literature, the size of SPEs are usually characterized by the total proton fluence in the > 30 MeV range. During the space era, the most commonly occurring events are those with an omnidirectional fluence in the 105 to 106 cm-2 range. The very large events are three orders of magnitude larger (fluence > 1 × 109 cm-2), which occur only a few times a decade. During such large SPEs, the fluence of protons with high energy can increase thousands of times above the background for a duration of several hours or days, causing concerns of ARS in crew and damage to equipment that are not adequately protected. It has been established that, for thin shielding conditions like normal spacesuits, particles in the 10-30 MeV range contribute most to organ doses, while inside thick shielding vehicles such as ISS and Orion, the largest contributors to organ doses are those in the energy range 100-150 MeV. Therefore the effects to human health of such events depend not only on the fluence, but also on the energy spectrum. As only 24 human beings have ventured beyond the protective magnetosphere of Earth for a maximum of approximately 12 days (Apollo 17), and none encountered a significant SPE during these missions, all previous analyses of ARS due to SPEs are conducted through physical modeling of various organ doses and biological projection of relevant responses. The August 4, 1972 event is regarded as one of most hazardous single SPEs in the space era, and has been analyzed in several publications (Wilson et al., 1976; 1997; Townsend et al., 1991; Hu et al., 2009). The October 19, 1989 event has also been modeled and analyzed in numerous papersand has been selected as a design-standard SPE for evaluating the adequacy of proposed radiation 1

https://www.swpc.noaa.gov/products/goes-proton-flux, accessed on 10/16/2019.

shelters for cislunar missions beyond LEO (Townsend et al., 2018). Table 1 lists the projected organ doses in publications as well as with the recently developed NASA tools, assuming various thicknesses of shielding. These analyses consistently indicate that an average nominal spacecraft thickness like the Apollo command module (5 g/cm2) is not sufficient to reduce radiation doses to a level below ARS thresholds; however, within a shelter of 10 g/cm2 thickness, the dose quantities can be significantly diminished to avoid ARS. For thinner shielding thicknesses (e.g. spacesuits in extra-vehicle activities), it is projected that some ARS symptoms are possible for the crew (Wilson et al., 1997; Townsend et al., 1991; Hu et al., 2009). Table 1. Comparison of modeled organ doses (Gy) of the August 1972 and October 1989 SPEs by different methods a SPEs

Aluminum Thickness (g/cm2)

August 1972b

Townsend et al. (1991)

Hu et al. (2009)

Skin

BFO

Skin

BFO

Skin

EVA (0.3-0.5)d

22.80

1.37

32.15

0.92

28.59 0.92

25.07 1.56

1

15.00

1.18

14.38 0.89

14.71 1.28

5

2.65

0.43

2.41

0.31

2.54

0.44

0.70

0.16

0.61

0.12

0.67

0.16

EVA (0.3-0.5)

22.30

0.78

1

11.20

0.67

5

1.40

0.28

10

0.42

0.13

10 October 1989c

d

2.70 25.99 1.45

ARRBOD

0.31 0.63 0.30

OLTARIS

BFO Skin

BFO

37.11 0.58

18.87 0.64

9.72

0.52

6.95

0.54

1.16

0.31

0.92

0.27

0.44

0.19

0.36

0.16

a

All calculations used computerized anatomical man (CAM) model (Billings and Yucker, 1973) inside aluminum sphere in interplanetary space. The results are reported here without incorporating a relative biological effectiveness (RBE) or quality factor. b

For August 1972 event, all calculation used King’s exponential spectrum (King, 1974).

c

For October 1989 event, Townsend et al. (1991) used data from a NOAA-Space Environmental Laboratory report by Sauer et al. (1990), Hu et al. (2009) used an exponential spectrum, while the other tools used a Band function spectrum. d

For EVA calculations, the thicknesses for Townsend et al. (1991), Hu et al. (2009), ARRBOD, and OLTARIS are 0.5, 0.3, 0.3, and 0.4 g/cm2, respectively.

2.2

Limitations of organ dose projection

This organ dose projection approach is subject to numerous limitations. The prominent one is the reliance of the recorded proton fluence on various instruments deployed in space. It was reported that the satellite data may exhibit saturation if the flux of particles above 60 MeV is too high (Wilson et al., 1997), and the measurement of a same event with different devices showed significant discrepancy in the cumulative spectrum (Jiggens, 2010). The input spectrum for particle transport calculation also introduces large uncertainties to the estimated dose quantities. In the past several functional forms (e.g. exponential, Weibull, Band functions) have been applied to fit the spectra of historical events. With the same satellite measurement but different functional forms to fit the spectrum, the projected dose quantities are substantially different

(Atwell et al., 2011). A recent segmental spectrum fitting technique resolved the limitation of functional fitting algorithm, especially for short time period spectrum (Hu et al., 2016). However, the spectrum accuracy is still subject to the effective energies assigned to the particle detectors, which need verification via a sophisticated procedure of cross-calibration (Rodriguez et al., 2017). The most serious limitation of this approach is that the energetic particles released from the Sun are not always accelerated and transported such that they are well-connected via heliospheric magnetic field lines to instrumentation used to monitor particle flux (Reames, 2017). For example, a large SPE occurred in July 2012 and was not recorded by any detectors proximate to Earth, but by the STEREO-A sensors, as the eruption was directed away from Earth toward 125°W longitude (Baker et al., 2013). For upcoming NASA sponsored exploration spaceflights such as the lunar and Mars missions, a feasible way to ensure radiation exposure monitoring real-time and at the spacecraft location is to use onboard active dosimeters to estimate organ doses directly. Such a strategy has been developed specifically for the Orion MPCV and described in a recent publication (Mertens et al., 2018). The organ dose estimation involves a fitting procedure between the real-time vehicle dosimeter measurements and a precomputed database of dose quantities calculated from the HZETRN radiation transport code (Slaba et al., 2016; Wilson et al., 2016), using historic SPEs information and the actual MPCV vehicle geometry and mass distribution as inputs. Mertens et al. (2018) also described how the estimated organ doses at the crew locations are utilized as inputs to biological response models that predict clinical syndromes associated with ARS and quantify radiation-induced performance decrement. The modeled results will provide important information to guide the crew in case of severe SPEs through ground flight surgeons and the FCT. The organ dose fitting algorithm, as well as the biomathematical ARS models, have been incorporated in a software package, the Acute Radiation Risks Tool (ARRT), which is under development and will be tested operationally on NASA’s uncrewed Exploration Mission 1 (EM-1) and will be fully utilized on NASA’s crewed EM-2. As the organ dose fitting algorithm has been described in detail in a previous paper, this paper will summarize the radiobiology investigation on ARS and biological response ARS models that are pertinent to the near future deep space exploration spaceflights, and will give a brief introduction of the ARRT software. 3.

Overview of ARS

ARS are a group of clinical syndromes developing acutely (within several seconds to three days) after high-dose, whole-body or significant partial-body ionizing radiation (Anno et al., 1989; Guskova et al., 2001). The manifestation of these syndromes reflects the disturbance of physiological processes of various cellular groups damaged by radiation. Hematopoietic cells, skin, epithelium, intestine, and vascular endothelium are among the tissues of the human body most sensitive to ionizing radiation. Most ARS are directly related to these tissues, as well as the coupled regulation and adaptation systems (nervous, endocrine, cardiovascular systems) (Guskova et al., 2001 and references therein). 3.1

Three phases of ARS development

There are generally three phases in the development of ARS: the prodromal phase, the latent phase, and the manifest phase, and the severity and duration of each of these phases are dependent on the radiation type, dose and dose rate. The prodromal phase refers to the first 48 hours after exposure, but may persist up to six days (Alexander et al., 2007). In this phase the victims with significant exposure usually show symptoms such as hematopoietic depression

(pancytopenia including lymphocyte, granulocyte, or platelets reduction), gastrointestinal distress (nausea, anorexia, vomiting, diarrhea, or abdominal cramps), neurological symptoms (fatigability, weakness, headache, impaired cognition, disorientation, ataxia, seizures, or hypotension), and cutaneous symptoms (erythema, loss of sensation/itching, blistering, swelling and oedema, desquamation, or ulcer/necrosis). After that, the latent phase begins in about two to 20 days with a seeming improvement of most syndromes (except cytopenia), with duration correlating inversely with the absorbed dose. The manifest phase can start from day two, or as late as day 20, and may persist up to 60 days since exposed, with signs and symptoms expressed in various organ systems. The hematopoietic syndrome are predominate effects at lower accumulated doses for this phase, and the associated immune suppression (reduced number of granulocyte and platelet in peripheral blood) predisposes the body to infection, sepsis and bleeding. This phase is critical for radiation injury. If patients survive this phase, they are still at risk for intermediate effects such as pneumonitis and late effects (NCRP, 2006; Guskova et al., 2001). 3.2

Terrestrial threshold dose for ARS

The foundation of ARS evidence is the ground-based observations of humans who were exposed to high levels of ionizing radiation, in particular to gamma or x-rays, in a short period of time. ARS appear in various forms and each form has different threshold dose for the possible effects. The threshold dose has been defined as an exposure below which clinically significant effects do not occur (NCRP, 2000), or the dose required to cause a 1% incidence of an observable effect (ICRP, 2007; 2012). For the general population, the threshold whole-body dose for ARS is approximately 0.15 to 0.25 Gy for radiation that is delivered under acute conditions (NCRP, 1989a). This estimate considers people at the ages that are more susceptible to irradiation (children < 12 years and adults > 60 years) (Hall and Giaccia, 2006). For typical healthy adults, the threshold dose of inducing ARS is in the range of 0.5-1 Gy as reported in literature (Anno et al., 1989; Fliedner et al., 2001). As for protracted exposure such as those experienced during SPEs outside of protection of Earth’s magnetic field, some early studies suggest that ARS thresholds are higher if the radiation is delivered at lower dose rates than with a single high-intensity dose (NAS/NRC, 1967; Cronkite et al., 1956). However, recent studies suggest that such dose-rate effects are organ and symptom specific, being more evident in prodromal symptoms such as vomiting but not significant in hematopoietic injury (Kennedy, 2014). For homogeneous irradiation such as gamma or x-rays, many committee reports recommend 0.5 Gy whole-body dose as the threshold level of exposure for ARS induction, regardless of if source is delivered acutely or protractedly (NCRP, 1982; 1989a; 1993; 2000; ICRP, 2000; 2002; 2012; NRC, 2008). 3.3

Common acute responses at low doses As a group of symptoms that are observed clinically after exposure, ARS may not manifest in every aspect at a level close to the thresholds discussed above. It is known that radiation exposure induces physiological responses in many organ systems such as the hematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, nervous, and digestive systems, as well as the urinary tract, skin, and eye. However, the early effects (from the first hours to several weeks after exposure) are mainly manifested in the hematopoietic, cutaneous, gastrointestinal, and neurovascular systems, but with different thresholds (Fliedner et al., 2001; ICRP, 2012).

Hematopoietic syndrome is characterized by a drop in the number of functioning cells in peripheral blood, generally at a dose above 0.5 Gy to bone marrow in ground-based observation. However, the onset and time profile of hematopoietic syndrome are different in specific cell lineages, with lymphocyte depression appearing within hours after exposure. Granulocyte and platelet changes follow one to three weeks later, and erythrocytes decline occurs months later only in the severest cases (Fliedner et al., 2001). Cutaneous syndrome includes erythema, pigmentation, and dry and moist desquamation in the early phase (< four weeks) and atrophy and fibrosis (or necrosis) in the later phase (> six weeks) (NCRP, 1989b). The ED10 (skin dose at which 10% of a population exhibits the effect) has been estimated to be 2 Gy for erythema and 14 Gy for the more serious moist desquamation (Haskin et al., 1997; Strom, 2003). Some reports state gastrointestinal syndrome includes early symptoms like nausea, vomiting, anorexia, and diarrhea, which may occur within hours after exposure, and late symptoms like abdominal cramps and diarrhea, which appear 1-2 weeks after exposure (Anno et al., 1989; 1996). However, later studies suggested the early symptoms of nausea, vomiting, anorexia, and diarrhea stem from effects on the periphery and subsequent stimulation of higher nervous centers or from a response of the central nervous system (CNS) (Fliedner et al., 2001; Hesketh, 2008), therefore they should be considered as neurovascular syndrome, which in addition includes diarrhea, disorientation, ataxia, headaches, hypotension, and fever during the prodromal phase, and neurological and cognitive deficits several weeks later (Fliedner et al., 2001). Ground-based observations indicate that low doses (~ 0.5 Gy) can only trigger some early effects such as nausea, vomiting, fatigue, and weakness. For other symptoms of neurovascular syndrome and gastrointestinal syndrome, much higher doses (> 3~10 Gy) are needed (Anno et al., 1989; Fliedner et al., 2001). 3.4

NASA dose limit for ARS

The current NASA short-term (30 days) permissible exposure limit (PEL) for acute radiation effects is 250 mGy-Eq to the blood forming organs (BFO) (NASA, 2014). Dose in unit of grayequivalent (Gy-Eq) is calculated using RBE values of 1.5-6.0 for particles from protons to heavy ions and neutrons of various energies (NCRP, 2000). These limits, although lower than the ARS threshold defined by terrestrial radiation protection guidelines, are instituted to protect astronauts through extensive reviews of humans and experimental radiobiology data for ARS in a series of committee reports (NAS/NRC, 1967; 1970; NCRP, 1989b; 2000; 2006), and have not changed from the Apollo program to the current ISS program. Based on current understanding of radiobiological characterization in SPE scenarios and physiological alteration in spaceflights, there are at least two considerations behind the conservative dose limit that NASA adopts. First, because the fluence of the particles involved in SPEs vary in energy spectrum from several MeV to ~GeV, the deposited energies (and doses) are inhomogeneous in different organs, with superficial ones such as skin several to tens folds higher than deep organs like BFO (Table 1). From ground-based observations, it is known that ARS recovery can be hindered by changes in immune status, including those resulting from combined skin burns and other trauma (Fliedner et al., 2001). Therefore, compared to the nearly homogeneous whole body exposure in terrestrial radiation accidents, a lower BFO dose of SPE exposure may trigger ARS manifestation if other symptoms occur simultaneously. Second, for prolonged spaceflight, a number of physiologic changes are known to occur. The combined

effects of microgravity, radiation, physical and psychological stressors, altered nutrition, disrupted circadian rhythms, and other factors have impacts on many of the body’s systems, including vision, the musculoskeletal system, and the immune system (Chapes et al., 1994). Some marked alterations in physiology are also reported, such as the redistribution of fluids occur after astronauts enter microgravity, and changes in various hematologic parameters (Crucian et al., 2015; 2017). These physiological changes may make the astronauts more sensitive to the acute effects of radiation. Therefore, a lower ARS threshold of BFO dose for the human space program is warranted given the required crew health status for operational performance and the multiple stressors in space. 3.5

Pertinent acute risks at NASA’s limits

Endeavoring to develop and verify various radiation shielding strategies, NASA is working to limit health risks to the crew by minimizing radiation exposures within the short-term PEL (250 mGy-Eq in BFO) for the worst case scenarios. At this level of exposure, it is expected that only the most sensitive organs may manifest some clinical effects, considering the physiological alteration in spaceflights and unique radiobiological features of space radiation exposure during SPEs. First, it is possible that the microgravity may raise the radiosensitivity of the hematopoietic system as the hematological parameters such as granulocyte, platelets, and erythrocyte blood cell counts as well as lymphocyte function are changed in microgravity (Crucian et al., 2015; Kuntz et al., 2017). Therefore the hematopoietic syndrome should be regarded as a relevant concern, and further studies should investigate the alteration of this system under the various stressors in space. Second, the early effects of neurovascular syndrome such as nausea, vomiting, fatigue, and weakness should be considered, because the CNS dose in a typical SPE is generally greater than the BFO dose as the brain has less shielding by skeleton and superficial tissues. In addition, similar symptoms are associated with other spaceflight factors and have been observed in crew in previous short- and long-duration spaceflights even in LEO. Nausea and vomiting are among those in early space-adaptation symptoms (Heer and Paloski, 2006) and sleep-deprivation induced fatigue occur to some extent due to the disrupted circadian rhythms in space (FlynnEvans et al, 2016). The contribution of these factors to ARS are unknown. Finally, if the radiation level is close to the NASA ARS limit, the average skin dose can be one order of magnitude higher than BFO dose in a typical SPE (Table 1), therefore the cutaneous syndrome should be of relevant concern in worst case scenarios. Past analysis indicates that, due to the varying energies of solar protons and body self-shielding, skin doses during an SPE can vary more than five-fold for different regions of the body (Kim et al., 2006). Furthermore, a recent study demonstrates the incidence for skin rashes on board the ISS is 25-fold higher than terrestrial incidence (Crucian et al., 2016), which is possibly due to microbial or fungal effects. This elevated susceptibility indicates good reason to concern radiation injury to skin in space. In summary, if deep space flights encounter severe SPEs with crew exposure close to or beyond NASA limit under worst case conditions, the impact to the sensitive hematopoietic, neurovascular, and cutaneous systems should be of concern for ARS manifestation during missions, and ground-based research and operational development should focus further investigation to illustrate the mechanism of radiation injury to these organ systems and to develop best countermeasure approaches to cope with the adverse effects. With the ongoing

efforts to enhance spacecraft shielding efficiency and the development of contingency radation shielding plan, it is unlikely that the crew will be exposed to any levels similar to those observed in terrestrial radiation accidents/incidents. 4

Acute response models

Biomathematical modeling of ARS in humans has been explored by many research groups for several decades (Bond et al., 1965; Wichmann and Loeffler 1985; Anno et al., 1991; Fliedner et al., 1996). Such models can be used to analyze experimental/empirical data and to gain insights to illustrate mechanisms of physiological alteration due to radiation exposure. In cases of nuclear warfare or radiological accidents, these models are particularly useful for military, civil, and medical stakeholders to predict the incidence of performance incapacitation and health effects, and make accurate estimations of time-phased casualties, patients streaming, and medical care requirements (Pellmar and Oldson 2012). For future exploration of deep space, groundbased operational FCTs and flight surgeons have similar interests in ARS management to prepare for severe SPEs. Hence various ARS models relevant to NASA limits are currently applied to monitor and mitigate the possible health risks due to SPEs. 4.1

Hematopoietic models

One of the best known approaches to model human hematopoietic syndrome is Smirnova’s models, which have been extensively applied to simulate possible effects in human space exploration (Hu and Cucinotta, 2011; Smirnova, 2009; 2017). Compared to other methods (Steinbach et al., 1980; Wichmann and Loeffler, 1985; Fliedner et al., 1996), this compartmental analysis of hematopoietic system assumes an implicit mechanism of regulating hematopoietic stem cells (HSCs) to proliferate and differentiate after radiation injury, aligning with the findings of cytokine networks working for each cell line, nerve fibers in bone marrow that control cellular flow, and continuous migration of HSCs through the blood to ensure a sufficient number of HSCs in each bone marrow subunit (Fliedner et al., 2002). In fact, these factors work together to allow the heterogeneously distributed bone marrow to act and react as “one organ” for the complicated cell renewal processes in the whole body (Fliedner et al., 2002). With this advantage and the simplified structure of coarse-grained compartments, effects of various radiation conditions can be easily incorporated into the cellular kinetic equations, and a dynamic relationship between the peripheral blood cells and the bone marrow precursor cells after radiation damage can be mathematically established (Smirnova, 2017). With a similar approach, models of all four major hematopoietic cell lines (granulocytes, lymphocytes, erythrocytes, and thrombocytes) are developed with parameters measurable by conventional hematological and radiobiological methods by different groups (Smirnova, 2017; Hu et al., 2016; Oldson et al., 2015). These models are the basis of a biodosimeter tool HemoDose which can estimate absorbed dose using either single or serial granulocyte, lymphocyte, leukocyte, and platelet counts after exposure (Hu et al., 2016), and a clinical scoring system to dynamically classify the severity of hematopoietic injury (Hu, 2016). Further works include using more extensive hematological data from human radiation accident database such as REAC/TS (Ricks et al., 2000) and SEARCH (Friesecke et al., 2000) to optimize and validate these models, and using hematological parameters in space (Crucian et al., 2015; Kuntz et al., 2017) to substitute the baseline counts of the terrestrial models. Importantly, it is unclear if the radiosensitivity parameters of the various cellular compartments for astronauts

are different from the general adult group on the ground. If so, the response patterns of various subsystems may be different from those observed in victims of terrestrial radiation accidents. 4.2

Neurovascular models

Two sets of early neurovascular syndrome, one for nausea and vomiting, the other for fatigue and weakness, have also been applied to simulate the health responses of the August 4, 1972 event (Hu et al., 2009). These models were developed by US military agencies in 1980-90s to facilitate consequence assessment and military planning in a nuclear warfare environment (Matheson et al., 1998). The nausea and vomiting model is based on a hypothesis that radiation causes the release of a neuroactive substance that is responsible for the observed upper gastrointestinal distress symptoms. However, this hypothetical physiological process has not been linked to any known mechanisms or biological pathways, and the model is just an empirical one that describes the dose and dose-rate dependent results consistent with experimental and clinical observations (see Anno et al., 1991; 1996). Nevertheless, this model has been tested with the extensive research on emetic mechanisms, and is effective in predicting the dynamics and severity of this syndrome for complex patterns of radiation exposure (McClellan et al., 1992). The fatigue and weakness model is based on a lymphopoietic model developed by Smirnova (Zukhbaya and Smirnova, 1991), with a hypothesis that lymphocyte damage results in the release of a cytokine that is responsible for the observed fatigue and weakness symptoms (Anno et al., 1996). This is also an empirical model as the parameters are not related to the original rodent model but are estimated to fit the data in clinical and accident studies (Anno et al., 1996). It should be noted that some of the biological assumptions upon which this model is based are inconsistent with the most recent experimental data. The current literature suggests that rather than cytokines being released from damaged lymphocytes, they are released from intact T-cells that persist after acute exposures (Pellmar and Oldson, 2012). Although these two sets of models provide a realistic projection of the symptoms following a variety of radiation exposures, and have been applied for decades by different agencies, they need to get update to reflect recent advances in scientific investigation of this system. Progress in understanding the pathophysiology of radiation injury may allow the biology to be reflected with greater fidelity in the mathematical models. As nausea, vomiting, fatigue, and performance degradation have been observed in astronauts that have ventured into space, studies have been performed to characterize the physiological mechanisms of these symptoms, and some mechanistic models have been developed in the NASA research community (Heer and Paloski, 2006; Flynn-Evans et al., 2016). It will be interesting to investigate if these physiologicallybased models can be utilized to explain the relevant symptoms induced by radiation, and to quantitatively describe the effects of neurovascular responses in a new mechanistic approach. 4.3

Cutaneous models

To our knowledge no cutaneous syndrome model is available for humans, but two mechanistic models on swine skin are recently published (Smirnova et al., 2014; Hu and Cucinotta, 2014). Of the available laboratory species, the swine is regarded as the best animal model for skin study. In terms of structure, histology, and cell kinetics of skin, this animal model bears many characteristics similar to human (Hopewell, 1990).

The biomathematical skin model (Smirnova et al., 2014) applied the same approach for the development of hematopoietic models (Smirnova, 2017). Based on the degree of their maturity and differentiation, the epidermal keratinocytes are separated into three groups, and the dynamics of the skin epidermal epithelium is represented by a system of ordinary differential equations, with cell kinetics and radiosensitivity parameters experimentally determined in swine epidermis. It was demonstrated that the modeling results for the dose- and time-dependent changes in different cell populations are in good agreement with experimental data. In addition, there is a correlation between the dynamics of a moist reaction experimentally observed and the corresponding in-silico dynamics of corneal cells. Using this information, the incidence of the moist reaction and its time-phased severity can be quantitatively determined at various radiation conditions (Smirnova et al., 2014). On the other hand, the multiscale tissue model (Hu and Cucinotta, 2014) considered several cell signaling pathways and some simplified biological processes at different scales in epidermis, from inside individual cells to cell proliferation, and macroscale cell-cell interactions. With experimentally measured histological and cell kinetic parameters of swine skin, the simulated population kinetics and proliferation index results are consistent with observations in unirradiated and acutely irradiated swine experiments. Though useful to test various cell regulation and cell manipulation theories, this approach is too complicated for consequence assessment and clinical symptoms prediction. Therefore, future research of cutaneous syndrome modeling should focus on extrapolating the biomathematical model from swine to human. 4.4

Software tools for ARS modeling

Except for the cutaneous syndrome model, the ARS models discussed above have been incorporated into user-friendly software packages such as RIPD (Radiation Induced Performance Decrement, Matheson, 1998), HENRE (Health Effects from Nuclear and Radiological Environments, Oldson et al., 2015), ARRBOD (Acute Radiation Risks and Bryntrn Organ Doses, Kim et al., 2010), and HemoDose (Hu et al., 2015). In addition to the two sets of neurovascular models (nausea and vomiting, fatigue and weakness), RIPD includes a lethality model based on injury estimation of bone marrow, and a gut injury model that can be used to estimate severity of radiation-induced diarrhea (Pellmar and Oldson, 2012). RIPD uses these four sets of models to describe the time profile and incidence of six sign/symptom categories of ARS: upper gastrointestinal distress, fatigability and weakness, lower gastrointestinal distress, hypotension, infection and bleeding, and fluid loss and electrolyte imbalance, which together determine the task performance (Matheson, 1998). As discussed above, at exposures close to the NASA ARS limits, only few of these categories are relevant to ARS management for spaceflight. HENRE is an extension of RIPD, with additional blast injury criteria models, hematopoietic models, a small intestinal model, and combined injury (radiation + burn/trauma) models (Oldson et al., 2015). ARRBOD includes the neurovascular models (nausea and vomiting, fatigue and weakness) adapted from RIPD, and four sets of hematopoietic models (lymphocyte, granulocyte, leukocyte, and platelets), interlinked with space radiation environment models of historical SPEs, enabling user to simulate possible ARS effects during human space explorations (Kim et al., 2010). HemoDose is a biodosimeter tool to use various blood cell counts after exposure to calculate absorbed doses, with a HemoGrade module linking acute and protracted doses with clinical severity scores of hematopoietic ARS (Hu et al., 2015; Hu, 2016). All these software packages include user specific input of radiation exposure, enabling the user to determine the development and severity of various ARS effects in a typical adult after significant exposure.

5 5.1

ARRT development An Orion MPCV operational tool

To make these models operational for the upcoming lunar and Mars missions, ARRT is under development specifically for the NASA Orion MPCV, an interplanetary spacecraft intended to carry a crew of four astronauts to destinations at or beyond LEO. The on-board radiation dosimetry for this spacecraft will be provided by the Hybrid Electronic Radiation Assessor (HERA), which is a distributed dosimeter system based on the coupling of a solid-state silicon detectors with Timepix chips (Kroupa et al., 2015). For the upcoming uncrewed EM-1 flight, a HERA unit with three spatially separate sensors will be deployed. For EM-2, the first scheduled crewed mission of Orion MPCV, two HERA units with a total of six spatially separate sensors will be deployed for more robust measurements of the intravehicular radiation environment. Algorithms have been developed to utilize these onboard vehicle dosimeter measurements to estimate organ doses at crew locations in real time (Mertens et al., 2018). ARRT is expected to work as a real-time console support tool for the ground-based operational FCTs and flight surgeons, integrating tasks of real-time reading and plotting of HERA data, organ dose calculation at crew locations in case of SPEs, and acute risks assessment with the biomathematical ARS models relevant to human space exploration. 5.2

Two datasets for testing and verification

As meaningful real-time HERA data will not be available until EM-1 and EM-2 start their journeys in space, the development of ARRT has to rely on a historical dataset and a mockup real-time dataset. The historical dataset in ARRT is generated by transport calculation with the SEPEM 2.0 dataset (http://www.sepem.eu/), which is a cross-calibrated uniform dataset using the Geostationary Operational Environmental Satellite (GOES) measured solar proton fluxes since 1974, with an energy range 5-289 MeV. Transport calculations of protons in this energy range through the vehicle are performed, by a numerical solution of the one-dimensional Boltzmann transport equation using the HZETRN2015 code (Slaba et al., 2016; Wilson et al., 2016), with spectra of 15-minute cadence generated as the boundary condition, and material and shielding thicknesses (converted to water, polyethylene, and aluminum equivalent) determined by ray tracing the computer-aided design (CAD) model of the MPCV for EM-2 (with six HERA sensors). The resulting dataset contains dose rates for the six sensors spanning uniformly from 1974 to 2015, with a 15 minute cadence. The mockup real-time dataset used in ARRT is provided by linking maintained databases of International Space Station (ISS) instruments from the NASA Space Radiation Analysis Group (SRAG) (https://srag.jsc.nasa.gov/), i.e., Radiation Assessment Detector (RAD), Intra-Vehicle Tissue Equivalent Proportional Counter (IV-TEPC), and Extra-Vehicle Charged Particle Directional Spectrometer (EV-CPDS), which span from their starting service time to the present, with a one minute cadence. These two datasets are used in ARRT to develop and test the functions of data reading and plotting, organ dose calculation, and acute radiation risks assessment. 5.3

SPEs monitoring and acute responses automation

The original SEPEM dataset includes 266 SPEs (Jiggens et al., 2018), but only 159 of them show significant elevation above the background for the simulated dose rates inside MPCV. For

ISS, only minor elevation can be detected from the noisy background even for big events such as the September 10, 2017 event, because the vehicle mostly travels inside the shielding of Earth’s magnetosphere. For testing during EM-1 or EM-2, it is not guaranteed that a measurable SPE will occur; therefore, a module is implemented to introduce a simple artificial SPE with specific onset, size (factors of the background dose rates), and duration. Thus, both datasets can test the function of triggering organ dose calculations and acute risks modeling with SPEs. For historical cases, the onset of an event is defined as a time point with two consequential dose rates two times above the background, but for a real-time mockup SPE, the threshold is raised to 200 times of the background because a lower threshold would misinterpret the dose-rate elevation when ISS passes the South Atlantic Anomaly region as an SPE. Further work can be done to remove these spikes by defining an exclusion zone in accordance to geographic location or B-L coordinate (Lindstrom and Heckman, 1968). The organ dose estimation from dosimeter measurement is a complicated process and the most time consuming step, each involving spectral matching in a precomputed dose database, scaling factors fitting between the vehicle dosimeter measurement and the precomputed dose quantities of the matched event, and linear scaling of the precomputed organ dose quantities (Mertens et al., 2018). The output of this step provides the input BFO dose rates (including relative biological effects (RBE)) to the acute risks models, generating severity scales and incidence of early neurovascular effects such as nausea, vomiting, fatigue and weakness, as well as blood cell kinetics, hematopoietic injury grades, and performance degradation, all synchronized with the real-time data stream. These results help generate a template of flight note for the ground-based operational FCTs and flight surgeons to guide crew if further actions are needed, such as performing the Radiation Event Cabin Reconfiguration protocol and seeking shelter in the storage bays, and coordinating medical countermeasures for the appropriate symptoms if necessary. A snapshot of ARRT is depicted in Figure 1, and a detailed presentation of the functions of this tool will be provided in a future publication.

Figure 1. A snapshot of ARRT with simulation of the October 19, 1989 event, which uses the SEPEM dataset with a factor of 10. The left top panel provides options for user to choose or modify modeling parameters, and the left bottom shows the SPE status, which can be nominal (green), event completed – crew monitoring (yellow), and event in progress (red). The right plot panel displays plots for HERA readings, flight notes, organ doses, and various ARS risks. 6

Summary and discussion

Since planned human space exploration missions for cislunar and Mars are expected to be long duration beyond the protection of Earth’s magnetosphere and atmosphere, the chances of the spacecraft to encounter severe SPEs are greatly enhanced, and the strategy to manage and mitigate the possible acute radiation risks during missions is now a high priority. According to the state-of-the-art radiation research of acute responses and modeling development in this minireview, at the dose level of the NASA PEL, the hematopoietic syndrome, neurovascular syndrome, and cutaneous syndrome should be of concern for worst case scenarios. A recent effort of ARRT development has translated the relevant models and algorithms into an operational analysis tool for the ground-based operational FCTs and flight surgeons to monitor and model the possible acute risks in real time, which can assist in managing the potential threats of severe SPEs for near future deep space missions. The upcoming EM-1 and EM-2 missions will provide platforms for this tool to run in real-time, although the chance of encountering a severe SPE and to trigger the main part of the code may be low for the spacecraft. It is quite clear the available ARS models are not sophisticated enough to describe all possible acute risks caused by severe SPEs. The heterogeneous deposition of energy by solar energetic particles requires consideration of possible skin damage, and a human cutaneous model should be included as discussed. In addition, the two neurovascular models are simply empirical models without physiological corroboration. The symptoms they describe are the most common signs among all acute responses in terrestrial radiation accidents, and are the major factors to

determine performance degradation. It is possible to revise or update these models by applying the mechanistic approaches that the NASA research community are currently used to model the symptoms (nausea/vomiting) induced by gravity alteration, and the stressors due to disrupted circadian rhythm. Furthermore, there is evidence that demonstrates microgravity alters hematopoietic parameters, making it important to determine if the hematopoietic system is more or less resilient to the challenges of radiation in the spaceflight environment. Though extensive investigations have been conducted in this area for decades, further work, particularly the mechanistic understanding and accurate modeling of the biological processes involved in acute injury, are still necessary for a more robust application to upcoming human space exploration. There are other factors that may limit the usage of ARRT to manage and mitigate ARS in future exploration missions. First, uncertainties in physical dose measurement in space may introduce errors in dose projection and risk assessment, especially for long duration missions in inhospitable environment. Second, timely communication of the spacecraft to the ground is not always guaranteed, and any abruption of data stream will result in malfunction of the tool. Additionally, the dose projection algorithm itself involves quite some uncertainties. For example, the configuration parameters for Orion MPCV were estimated with an intermediary CAD model, but the infrastructure of vehicle keeps on changing along with the development, and will change during flights in future missions. If these parameters are not updated regularly, certain discrepancies will yield in calculation. Furthermore, this algorithm largely relies on HZETRN transport calculation of past recorded SPEs. Studies indicate that existing radiation transport codes only agree with measurements of organ doses within 20% (Durante and Cucinotta, 2011). As all these obstacles may not be easily resolved in near future, other approaches to manage ARS during spaceflights in case of severe SPEs worth pursuing at this stage. One way to estimate organ doses is to use some biological tools such as HemoDose (Hu et al., 2015) with onboard bio-sample devices, and the crew can conduct analysis in flight and get recommendation without consulting ground support (Hu, 2016). Another approach is to determine the response category just based on assessing the damage of an organ system as a function of time (Fliedner et al., 2001), which does not rely at all on the physical or biological estimation of radiation dose. These mature practice for terrestrial radiation emergency management can be of great help in case of severe SPE contingency for future exploration spaceflights. Conflicts of interest None. Acknowledgements We thank Christopher Mertens and Tony Slaba for the development of the organ dose projection algorithm for Orion MPCV. The material and shielding thicknesses files of MPCV were determined by ray tracing the CAD model by Hatem Nounu. The development of ARRT web interface was initiated with efforts from 2018 Summer Intern student Shayan Monadjemi at NASA JSC. We also highly appreciate critical review and many constructive suggestions from S. Robin Elgart. This work was supported by KBR Human Health and Performance Contract (HHPC) NNJ15HK11B. We are very thankful to our anonymous referee for a number of critical comments and valuable advice that allowed us to improve the paper.

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