Introduction

Astronauts on long duration deep space missions require reliable radiation protection to protect them from the exposure to high charge and energy (HZE) particles, neutrons and other densely ionizing radiation [ 1 ]. The opportunity to launch a spacecraft on a minimum-energy transfer orbit from Earth to Mars occurs about every 25-26 months, when there is an elliptical orbit where the periapsis is at Earth’s distance from the Sun and the apoapsis is at Mars’ distance from the Sun. This so called Hohmann transfer orbit determines a fixed time of around 9 months to travel from Earth to Mars. However, it is possible to travel to Mars faster but then a higher energy consumption is required. A rather new suggested type of transfer from Earth to Mars is to end in a ballistic capture, which was first used by the Japanese spacecraft Hiten in 1991 as a method to get to the Moon. This results in a substantial savings in capture Δv from that of a classical Hohmann transfer orbit under certain conditions. This is accomplished by first becoming captured at Mars, very distant from the planet, and then from there following a ballistic capture transfer to a desired altitude within a ballistic capture set. Using ballistic capture is predicted to be safer than using a classical Hohmann transfer orbit, as there is no time critical insertion burn, launchable at almost any time (rather than having to wait for a narrow window of opportunity), and more fuel efficient than a normal short time transfer. A human mission to Mars will therefore vary from 6 to 9 months each way, depending on the mission design [ 2 ], and the crew will be exposed to densely ionizing radiation for a significant period of time. This may cause different health risks which are discussed in previously published papers [ 2 , 3 ]. The exposure to cosmic rays can considerably increase the risk of e.g. cancer, cardiovascular diseases, and damages of the central nervous system (CNS). If exposed to sudden high levels of ionizing radiation, from e.g. a large solar particle event (SPE), the astronauts can even get acute radiation syndrome (ARS). The measurements performed on the Mars Science Laboratory (MSL) robotic space probe mission to Mars during 2012-13 [ 4 ] showed that the dose equivalent rate from GCR in deep space was 1.84 ± 0.30 mSv/day, which means that even with an optimized mission planning and realistic passive shielding, the astronauts would get 0.7 ± 0.1 Sv [ 4 ]. The dose equivalent rate from GCR is lower on the surface of Mars mainly due to the shielding from the planet, but still 0.70 ± 0.17 mSv/day. Measures to protect the astronauts must therefore be developed before humans will be able to safely travel to Mars and stay there. Since, it has been shown, see e.g. [ 5 - 7 ], that passive shielding might not be enough to reduce the radiation risks for long term deep space missions, there is a need for other counter measures, e.g. medical counter measures such as radio-protectors and radio-mitigators. A number of radiation effect modulators, which might be used on future deep space missions, have already been developed and tested by different groups, see e.g. [ 7 ] and references cited therein. However, in this paper we will concentrate on adaptive response and the use of vitamin C as a promising non-toxic, cost-effective, easily available radiation mitigator.

Discussion

Adaptive Response in Space Research

The health effects of sparsely ionizing low dose radiation have been studied for decades [ 8 - 12 ].

Adaptive response is a form of cellular response that can be induced by low doses of radiation followed by a higher challenging dose of radiation. For example, it has been shown that adaptive responses, including DNA repair and antioxidation reactions can be induced following exposures to low doses of sparsely ionizing radiations such as X- and γ-rays. As stated by Feinendegen et al. the decrease of damage from endogenous sources by adaptive protection at low doses can be equal to, or larger than, the induction of radiogenic damage [ 13 ]. Therefore, the empirical linear no-threshold (LNT) model for estimation of the stochastic health effects of low doses of ionizing radiation might not be valid and reevaluation might be needed [ 14 ]. In the beginning of the 2000, a revised model for estimation of the reduction of the radiation risks due to adaptive response in a long duration deep space mission was presented [ 15 , 16 ]. This has been followed by several publications presenting adaptive and bystander effects that might protect human cells against DNA damage caused by a subsequent exposure to energetic ion exposure, see e.g. [ 17 - 19 ]. A recent publication confirms the key role of biological protection of astronauts [ 20 ], an issue discussed in detail in some new publications [ 21 - 23 ]. The consistency of our previous work [ 24 , 25 ] and others [ 26 , 27 ] was noted by Cortese et al. who published this report. There is a strong evidence of a wide range of adaptive responses among different individuals, suggesting that medical selection of the astronaut candidates based on in vitro screening of the adaptive responses might decrease the radiation induced health risks in deep space [ 25 - 27 ]. A key factor is the effect of the space radiation on the organism’s integrated protection systems (e.g., DNA repair and immune system response) against biomolecular damage induced by ionizing radiation. A model has been suggested for the screening and selection of astronauts based on their level of radioadaptation in ground-based in vitro tests [ 28 ].

In some recently published papers [ 28 , 29 ], it is stated that instead of selecting the most radioresistant individuals, we should choose those who show the highest levels of adaptive response. The essential point of radioadaption is to improve the radiation stability through a variety of processes including synthesis of DNA repair enzymes, increasing the concentration of oxidants and other substances that together form radioresistance.

Thus, we noted a number of considerations related to the data provided by Cortese et al, [ 20 ]. The following considerations summarize the key points of our proposed biological model:

1. There are individual differences in radioadaptation. These differences vary from a limited effect to significant radioadaptation. Some individuals may even exhibit a form of synergism and the development of more adverse biological effects.
2. Candidates for deep space missions could be screened for a variety of physiological and psychological conditions including radioadaptation.
3. The ability for radioadaptation of each candidate could be quantified by in vitro testing (e.g., exposing blood samples to a low adapting dose of ionizing radiation followed by a high challenging dose) with the associated measurement of biological damage (e.g., chromosome aberrations, DNA damage, and oxidative stress).
4. The level of radioadaptation of each candidate could be evaluated and, if possible, quantified.
5. Candidates with a high level of radioadaptation should be considered for crew assignments for a deep space mission.
6. When being in space, the selected astronauts will receive conditioning doses of ionizing radiation during exposure to the ambient, chronic GCR.
7. Following the lower conditioning doses rates of ionizing radiation, that promotes the induction of an adaptive response, the astronauts might better tolerate sudden high doses from solar particle events (SPEs). Exposure to strong SPEs can lead to very large doses of energetic particles even behind the spacecraft shielding.
8. Selection of candidates with a high level of radioadaptation, due to e.g. an increased ability to adaptive response, could reduce their risks for severe radiation illness. However, the phenomena must be studied in much more details before any conclusion can be made.

Other considerations are less well quantified and will be more difficult to determine. First, Earth based studies do not fully simulate the effects of microgravity. With no preferred direction in space, bodily processes depending upon earth gravity will function differently in space. The prolonged effects of microgravity and the GCR and SPE, as well as their possible combinatory effect on the human organism are uncertain. However, astronauts with high levels of radioadaptation will have better chances of functioning in a deep space environment.

Second, the elevated radiation fields from GCR and their inclusion of HZE particles are difficult to simulate on earth. Exposing blood samples short time periods to high dose rates of a single heavy ion type (e.g., ⁵⁶Fe nuclei) does not accurately simulate the risks astronauts are exposed to when they are exposed to lower dose rates of mixed ions over longer time periods, as in the GCR radiation environment.

Third, established biological effects (e.g., the oxygen, bystander, and dose fractionation effects) may be altered as the deep space mission duration proceeds. It should be noted that more extravehicular activities (EVAs) are expected in future space missions and EVAs may expose astronauts to high-energy space radiation while breathing 100% oxygen [ 30 ]. Therefore, exposure to space radiation while breathing 100% oxygen may cause oxidative stress and neuroinflammation [ 30 ]. Regarding non-targeted effects, some evidence shows that there are in vivo space radiation-induced non-targeted effects [ 31 , 32 ] which can be observed as late as 20 months after the exposure [ 33 ]. Although reasonable judgments regarding these effects during space missions can be inferred, actual operational data must verify this expectation.

Furthermore, a 2016 NASA report [ 34 ] stress the importance of better understanding adaptive response and its possible application in deep space missions. The NASA report also confirms that it would be realistic to expect that cells will be exposed to multiple hits of protons before being traversed by an HZE particle (e.g. ⁵⁶Fe ions).

It is well known that a pre-exposure to low dose radiation of sparsely ionizing radiation, e.g. photons, can stimulate the defense mechanisms such as increasing antioxidant levels reducing the endogenous DNA damage, increasing DNA repair capacity, and increasing apoptosis of damaged cells [ 13 ]. It should be noted that Ramadan et al. have previously shown that a low dose of protons can prevent the biological responses to a subsequent challenge dose of heavy ions (0.1 Gy of protons 24 hours prior to 0.5 Gy of ⁵⁶Fe) [ 35 ]. Moreover, Buonanno have shown that exposure of normal human fibroblasts to 20 cGy of 0.05 or 1-GeV protons protects the irradiated cells against chromosomal damage induced by a subsequent exposure to 50 cGy from 1 GeV/u iron ions [ 36 ]. Zhou et al. [ 37 ] have reported that calculations performed by Curtis and Letaw [ 38 ] indicate that the nucleus of a cell in a space traveler shielded by 0.4 g/ cm² of aluminum (which is however an unrealistic thin shield) would be hit by 400 protons and about 0.4 HZE particles during a 3-year Mars mission [ 38 , 39 ]. Thus most astronauts’ cells would be hit by a proton(s) before being hit by an HZE particle.

Cells which are first exposed to multiple hits of protons from the GCR, prior to being traversed by an HZE particle, might be influenced by adaptive response and to some extent protected against future exposures. It has therefore been suggested that before any deep-space manned mission, the adaptive response of all candidates should be measured by ground-based routine cytogenetic tests [ 7 , 14 , 20 , 21 ]. If the theory presented in refs [ 7 , 14 ] is correct, the constant exposure to elevated levels of space radiation from the GCR would serve as adapting “dose” and hence decrease their radiation susceptibility to potential high levels of exposure, i.e. from large SPEs.

Radioadaptation of Microorganisms in Space

The challenging issue of bacterial growth under microgravity conditions in space experiments and its associated physiological responses, which range from modified cell morphology and growth dynamics to a putative increased tolerance to antibiotics, have been addressed recently [ 40 ]. Aunins et al. [ 40 ] note that E. coli grown aboard the ISS showed resistance against increasing concentrations of the antibiotic gentamicin compared to identical ground controls (experiments conducted on Earth). They especially note that E. coli adapted to grow at higher antibiotic concentrations in space showed consistent changes in expression of 63 genes in response to an increase in drug concentration. The authors concluded that the increased resistance against antibiotics in microgravity can be due to both diminished transport processes and a resultant antibiotic cross-resistance response conferred by an overlapping effect of stress response genes. Although the paper authored by Aunins et al. [ 40 ] addresses a challenging issue, they are omitting the possibility that the space radiation might have induced adaptation phenomena in the bacteria and that this might have caused the observed bacterial resistance against antibiotics. Substantial evidence shows induction of radiation-induced adaptive response in bacteria. It has been shown that bacteria can become more resistant to antibiotics after receiving a mild physical stressor (e.g. pre-exposure to ionizing electromagnetic [ 41 ] or non-ionizing electromagnetic radiation [ 42 ]. Given these observations, any low-level initial stress (e.g. exposure to chronic galactic space radiation or acute solar particle events) can alter the bacterial resistance to antibiotics. Some evidence shows that this type of adaptive response may be life-threatening in space. However, this issue cannot be well understood before additional data becomes available. During long-term space missions, the combined effect of space radiation (GCR and SPE) and microgravity might also affect the susceptibility of bacteria to antibiotics. Moreover, factors such as immunosuppression, increased bacterial virulence, and presence of particles in suspension are involved in increased risk of infection in space [ 43 ]. It has been reported that even in the absence of immune dysregulation, factors such as increased microbial virulence during spaceflight [ 44 ], can increase the risk of infectious disease in space crew [ 45 ].

Radioprotectors vs Radiation Mitigators

Oxidative damage induced by prolonged exposure to ionizing radiation during space flights has been reported by some researchers [ 46 ]. Astronauts’ visual systems, particularly the central and peripheral photoreceptors of the retina, are among the organs most affected by cosmic radiation [ 47 ]. In space research, studies on mitigators have mostly been focused on developing drugs to reduce carcinogenesis of whole body exposures [ 48 ]. In vivo protection against detrimental effects of radiation by chemicals dates back to more than 60 years ago. After September 11^th terrorist attacks, 2001, new funding became available for development of medical countermeasures for major threats such as radiological, nuclear, biological, and chemical hazards. Therefore, in U.S. and many other countries studies on biological effects of radiation that furthered the development of prophylactic and therapeutic agents were supported [ 49 ].

In 2008, a diet supplemented with the antioxidants plus coenzyme Q10 was evaluated for its ability to prevent carcinogenesis in rodents exposed to different forms of space radiation (protons and HZE particles). This study showed that dietary supplements could be effective in the prevention of malignancies and other neoplastic lesions induced by exposure to space radiation [ 50 ].

As long-term exposure to GCR and SPE may increase the risks for cataract, cancers, and cardiovascular diseases [ 51 - 55 ], antioxidants with considerable effectiveness and low toxicity, have been also introduced to protect against relatively low levels of radiation [ 56 ]. Even dietary supplementation with dried plum has been reported to prevent the radiation induced skeletal effects such as bone loss either in space or on Earth [ 57 ]. Moreover, treatment with soybean-derived Bowman-Birk inhibitor (BBI), BBI concentrate (BBIC) or antioxidants has been shown to prevent, at least to some extent, the adverse biological effects of space radiation [ 58 ]. D-selenomethionine is also introduced as a potential countermeasure against the detrimental effects of space radiation [ 59 ]. Melanins, biomolecules which are capable of shielding ionizing radiation, can also be used for interplanetary manned space missions [ 60 ].

In contrast to treatments of low-levels of ionizing radiation exposures, pharmacological countermeasures should be used for treatments of life-threatening, high level radiation exposures, as e.g. occur when exposed to large SPEs. Although large SPEs are rare, during a large event the fluence of protons with energies greater than 30 MeV can be more than 10¹⁰ cm^-2 in several hours or days [ 61 ]. Therefore, if crew and equipment are not adequately protected, these events can lead to deposition of large ionizing radiation doses. Despite advances in technology, it is still difficult to predict the occurrence of these large events and giving enough time of warning before the onset of large SPEs seems to be unrealistic [ 61 ]. Due to unpredictable SPEs, astronauts face the risk of blood cell death which causes disruption of the immune system as well as increased susceptibility to different infections [ 62 ]. Although that SPEs which produce doses > 1 Gy are rare, the likelihood for doses that can induce prodromal risks is considerable [ 63 ]. There are reports which estimate that the astronauts’ effective doses can be as high as several Sv during solar flare events. “Ancedotal reports” suggest that Amifostine may have been carried by US astronauts on their trips to the moon (Hall, 2012 [ 64 ]), to be used in case of a solar flare event when astronauts could be exposed to an estimated effective dose of several Sv [ 65 ]. Moreover, in some reports the probability of short-term SPEs during the round trip to and from Mars is estimated to be as high as 20% [ 66 ]. There is also an additional ~20% probability of short-term solar particle events (SPEs) during a 12-18 months round trip to Mars, which could conceivably impart a relatively high acute dose of predominantly protons and light ions within an hour or less, which significantly complicates the mission planning [ 1 , 67 , 68 ].

As exposure to large SPEs can be fatal, the toxicity risk associated with using radioprotective agents would be justified. Although some recent studies have focused on traditional or new radioprotectors [ 69 ], evidence shows that radiation mitigators could play a more important role during space missions. Currently, amifostine (WR-2721) is the only FDA-approved broad spectrum radioprotector in clinical application [ 70 - 73 ]. Although the mechanism behind the cytoprotective of amifostine is still not fully known, it is believed that free-radical scavenging, DNA repair and induction of cellular hypoxia are involved in its radioprotective properties [ 74 ]. It has recently been shown that decreasing the oxygen pressure in tissues can be involved in the radioprotective effects of amifostine [ 75 ]. Current findings support the efficacy of treatment with amifostine at high-doses (910 mg m^-2) 30 minutes before exposure to ionizing radiation [ 76 ]. Moreover, it has long been known that vitamin C can play an important role as a radioprotector in radiation accidents or medical exposures [ 77 ]. The observed significant radioprotective effect of vitamin C suggests that this antioxidant agent is a potential non-toxic, low-cost, easily available radiation mitigator which can be used at lethal doses of ionizing radiation (e.g. during and after SPEs) [ 78 ].

It has previously been shown that vitamin C can decrease radiation-induced chromosomal damage in rodents but it was reported that it cannot reduce mortality [ 79 ]. Mortazavi et al. in 2014 [ 80 ] and Sato et al. in 2015 [ 81 ] reported that administration of vitamin C can be effective even after exposure to sparsely ionizing radiation. However, even if the radiation environment is very different in space, with highly densely ionizing particles, it is worth studying vitamin C as a possible non-toxic, low-cost, easily available radiation mitigator in space missions. Vitamin C could be used up to 24 hours after exposure to high levels of ionizing radiation in cases such as the occurrence of SPE. The fact that the vitamin C can successfully be taken so long time after the exposure will allow the astronauts to both estimate their radiation exposure before choosing any therapeutic intervention, and consult expert physicians/scientists on Earth to make sure about the dosage of vitamin C and possible other therapeutic agents, as illustrated in Figure 1. It is well known that the space radiation has a negative effect on the eyes of the astronauts [ 82 ], and that cataracts are developed if a threshold dose is exceeded. The recent observation that vitamin C intake can decrease the risks of getting cataracts is therefore important. Researchers have also observed an inverse association between serum ascorbate and nuclear and posterior subcapsular cataract [ 83 ].

Figure 1. Vitamin C can be used up to 24 hours after exposure to high levels of ionizing radiation (e.g. doses caused by large and solar energetic particles (SPE) [ 7 , 22 ]).

Enhancing the Immune System by Hormetic Responses

Dysregulation of the immune system during spaceflight has been well documented [ 84 , 85 ]. Disrupted immune system, especially in conjunction with relatively high levels of ionizing radiation and limited clinical care can significantly increase the health risks during manned deep space missions, such as a journey to Mars [ 85 ]. Both short and long duration spaceflights can be associated with consistent peripheral phenotype changes and altered cytokine production. However, mission duration may affect the functional immune dysregulation [ 84 ]. Developing methods which can improve the immune system of astronauts during long-term missions is therefore very important.

Conclusion

A journey to Mars would require an extended period of time in deep space, in addition to a possible longer stopover on Mars. This will expose the astronauts to high doses of densely ionization particles. Today, no single countermeasure exists which can reduce the crew exposure/risks to below existing accepted risk limits during the transit periods from Earth to Mars. Even if the dose rate on Mars is lower than in deep space, the astronauts would be exposed to around 40 % of the dose rate in deep space without proper shielding. Developing different countermeasures to reduce the radiation health risks is therefore very important. In addition to passive and active shielding, in vitro pre-flight screening of the candidates to evaluate their level of radioadaptation, due to e.g. adaptive responses, could reduce the radiation induced health risks. Different medical countermeasures will most likely also be needed. In addition to traditional radioprotectors, radiation mitigators might play an important role in future space missions. Intake of vitamin C has been documented to decrease radiation-induced chromosomal damage in rodents and reduce the risks of getting cataracts, etc. Studies shows also that intake of vitamin C, up to 24 hours after the exposure to high levels of ionizing radiation, can be used for reducing the radiation induced health effects. Vitamin C is therefore a potential non-toxic and cheap radiation mitigator which could be used by astronauts on future long-term deep space missions.

Authors’ Contribution:

Sihver S. and Mortazavi S.M.J. developed the theory and made substantial contributions to the design of the work. All authors discussed the results and contributed to the final manuscript.

Conflict of Interest

None

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