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The exposure to the space radiation environment remains a major limiting factor for human long-duration space missions and permanent presence in space habitats due to its high biological effectiveness and the difficulties to effectively shield the radiation. The next decade in human spaceflight will be characterized by a continuous presence of human beings in Low Earth Orbit (LEO), by their return to the Moon and by longer stays in a Moon orbit on the Lunar Orbital Platform - Gateway (LOP-G). These endeavors are also performed to prepare for a human Mars mission. Also, plans for permanent presence of humans on the Moon are assuming shape. To support and enable these missions, ongoing improvement of radiation dosimetry for accurate and continuous monitoring and the development of shielding approaches including personal shielding equipment are necessary. In a cooperative project, a personal protection vest will be tested during the first Orion mission using female phantoms. This will be the first determination of depth dose distribution beyond LEO. The organ doses which are essential for space radiation risk assessment will be derived from the dose distribution in the phantoms. For protection from high-dose exposure during solar flares, a warning system and a suitable radiation shelter are required. In the last decades, the cancer risk induced by exposure to galactic cosmic rays was in the focus of attention. Numerous animal experiments and mechanistic studies were performed to derive the relative biological effectiveness of heavy ions to induce cancer and to elucidate the mechanisms and patterns specific to heavy ions. E.g., heavy ions activate the Nuclear Factor κB (NF-κB) pathway which is involved in inflammatory responses with very high efficiency [1-3]. Radiation quality factors and dose-rate modifying factors based on these results were integrated into a model to estimate space radiation cancer risk (NASA Space Cancer Risk (NSCR) model) [4]. Now, target organs for degenerative effects induced by galactic cosmic rays, especially the brain, the cardiovascular system and the eye lens, are in the focus of the radiobiological research. A suspected cognitive decline by chronic exposure to galactic cosmic rays has achieved some celebrity as “Space Brain”. The roles of neurons, glia cells including astrocytes, oligodendrocytes and microglia remain to be elucidated – even sex-specific differences in the involvement of microglia have to be considered [5]. Experiments with accelerated heavy ions will help to elucidate the mechanisms of the degenerative effects of space radiation and will set the foundation to develop countermeasures. Here, besides the combination of beams to simulate better the radiation field in space, low dose rate experiments are of high interest. Besides the chronic space radiation exposure, astronauts experience a quite unique combination of possibly health-deteriorating environmental factors such as microgravity, noise, smell, disturbed circadian rhythm, increased carbon dioxide concentrations and decreased sleep quality. The interaction of radiation exposure with these space environmental factors such as microgravity or changes in the atmospheric conditions might influence the cells’ capability to cope with radiation damage. Also, the fluid shift towards the head might modulate radiation effects on the brain and eye. Recently, it was observed that the body temperature of astronauts on ISS is increased. In this context, it has to be considered that in some cancer therapy regimens, hyperthermia is combined with radiotherapy in order to augment the tumor cell killing effect. Finally, it has to be considered that humans are not only composed of their body cells that can be affected by heavy ion hits, but they also carry a microbiome inside and at the surface that quickly colonizes the surroundings, also spacecraft. The knowledge on how the human-microbiome and microbiome-environment interactions change under chronic space radiation exposure is very scarce. In conclusion, health risks by space radiation exposure have to be taken into account for an integrated design concept of space habitats, spacesuits and spacecraft. Despite some promising results on dietary measures (berries, dried plums) modulating the deteriorating effects of space radiation, a “magic pill” that can erase all radiation damage will most probably not be available.

The exposure to the space radiation environment remains a major limiting factor for human long-duration space missions due to its high biological effectiveness and the difficulties to effectively shield the radiation. The next decade in human spaceflight will be characterized by a continuous presence of human beings in Low Earth Orbit (LEO), by their return to the Moon and by longer stays in a Moon orbit on the Lunar Orbital Platform - Gateway (LOP-G). These endeavours are also performed to prepare for a human Mars mission.

INTRODUCTION As a prerequisite for developing appropriate countermeasures to mitigate acute effects and late radiation risks for the astronaut and thereby enabling long-term human space flight, the cellular radiation response to densely ionizing radiation needs to be better understood. The biological effectiveness of accelerated heavy ions with high linear energy transfer (LET) for effecting DNA damage response pathways as a gateway to cell death or survival is of major concern for space missions. As body tissues differ in their radiation sensitivity, the radiation response of different cell types such as kidney cells, osteoblasts, fibroblasts, lens epithelial cells and of eyes lenses in culture was analyzed. One Sentence Summary: The strong activation of pro-inflammatory signaling in human cells after heavy ion exposure might be a suitable target for countermeasure development.

Radiation has emerged as the most critical issue to be resolved for long-term missions both orbital and interplanetary. Astronauts are constantly exposed to galactic cosmic radiation (GCR) of various energies at a low dose rate. Primarily late tissue sequels like genetic alterations, cancer and non-cancer effects, i.e. cataracts and degenerative diseases of e.g. the central nervous system or the cardiovascular system, are the potential risks. Cataracts were observed to occur earlier and more often in astronauts exposed to higher proportions of galactic ions (Cucinotta et al., 2001). Predictions of cancer risk and acceptable radiation exposure in space are subject to many uncertainties including the relative biological effectiveness (RBE) of space radiation especially heavy ions, dose-rate effects and possible interaction with microgravity and other spaceflight environmental factors. The initial cellular response to radiation exposure paves the way to late sequelae and starts with damage to the DNA which complexity depends on the linear energy transfer (LET) of the radiation. Repair of such complex DNA damage is more challenging and requires more time than the repair of simple DNA double strand breaks (DSB) which can be visualized by immunofluorescence staining of the phosphorylated histone 2AX (γH2AX) and might explain the observed prolonged cell cycle arrests induced by high-LET in comparison to low-LET irradiation. Unrepaired or mis-repaired DNA DSB are proposed to be responsible for cell death, mutations, chromosomal aberrations and oncogenic cell transformation. Cell killing and mutation induction are most efficient in an LET range of 90-200 keV/µm. Also the activation of transcription factors such as Nuclear Factor κB (NF-κB) and gene expression shaping the cellular radiation response depend on the LET with a peak RBE between 90 and 300 keV/µm. Such LET-RBE relationships were observed for cataract and cancer induction by heavy ions in laboratory animals, with varying maximal efficiencies. Furthermore, there is always the added risk of acute exposure to high proton fluxes during a solar particle event (SPE), which can threaten immediate survival of the astronauts in case of insufficient shielding by eliciting the acute radiation syndrome. Its symptoms depend on absorbed total radiation dose, type of radiation, the dose distribution in the body and the individual radiation sensitivity. After the prodromal stage with nausea and vomiting and a subsequent symptom-free phase, depending on dose, the hematopoietic syndrome with suppression of the acquired immune system and thrombocytopenia (0.7-4 Sv), the gastrointestinal tract syndrome (5-12 Sv) or the central nervous system syndrome (> 20 Sv) develop and they are accompanied by exacerbated innate immune responses. Exposure to large SPE has to be avoided by warning systems and stay inside a radiation shelter during the event. Treatment options encompass e.g. the administration of colony-stimulating factors (CSF), growth factors and blood transfusions to overcome the hematopoietic syndrome and the administration of antibiotics against secondary infections. A concerted action of ground-based studies and space experiments is required to improve the radiobiological basis of space radiation risk assessment and countermeasure development. Reference: Cucinotta FA, Manuel FK, Jones J, Iszard G, Murrey J, Djojonegro B and Wear M (2001) Space Radiation and Cataracts in Astronauts. Rad Res 156, 460-466

Astronauten auf Weltraummissionen, vor allem auf Langzeit-Missionen zu Mond oder Mars, haben ein höheres Risiko für Späteffekte der Strahlenexposition wie Krebs oder subkapsuläre corticale Augenlinsentrübungen. Dies ist auf eine höhere Dosis und eine unterschiedliche zelluläre Energiedeposition der Komponenten der galaktischen kosmischen Strahlung mit hohem linearen Energietransfer (LET) im Vergleich mit der Niedrig-LET-Strahlung auf der Erde zurückzuführen. Die Augenlinse wird als ein strahlungsempfindliches Organ betrachtet. Der strahlungsinduzierte Katarakt tritt mit einer Schwellenenergiedosis von 0,5 Gy dünn ionisierender Strahlung auf. Für die terrestrische Strahlenexposition von der Internationalen Strahlenschutzkommission (ICRP, 2011) wurde der Grenzwert auf jährlich 20 mSv festgelegt. Astronauten sind viel höheren Dosen ausgesetzt: durchschnittlich 150 mSv pro Jahr auf der Internationalen Raumstation (ISS) und 1,2 bis 1,4 mSv pro Tag auf Apollo- und Skylab-Missionen (Cucinotta et al., 2001).

Introduction: As a prerequisite for developing appropriate countermeasures to mitigate acute effects and late radiation risks for the astronaut and thereby enabling long-term human space flight, the cellular radiation response to densely ionizing radiation needs to be better understood. The biological effectiveness of accelerated heavy ions (which constitute the biologically most important radiation type in space) with high linear energy transfer (LET) for effecting DNA damage response pathways as a gateway to cell death or survival is of major concern not only for space missions but also for new regimes of tumor radiotherapy.

Bevor wir die lange Reise zum Mars antreten, müssen wir die kleinsten Wege, die Signalwege in den Körperzellen, die durch Weltraumstrahlung moduliert werden, verstehen. Diese frühen Ereignisse können den Weg für spätere Erkrankungen wie Krebs oder Katarakt bereiten. Die Schwerionenkomponente der Weltraumstrahlung zeichnet sich durch einen mittleren bis hohen linearen Energietransfer (LET) und eine hohe biologische Wirksamkeit aus. Die DNA-Schadensantwort als Schalter zwischen Zelltod oder –überleben steht im Zentrum der Strahlenantwort. Der Nuclear Factor κB (NF-κB) Signalweg kann Teil der Reaktion auf durch ionisierende Strahlung induzierten zellulären Antwort sein und steuert Immun-, Entzündungs- und Überlebensreaktionen.

Space is a special workplace not only because of microgravity and the dependency on life support systems, but also owing to a constant considerable exposure to a natural radiation source, the cosmic radiation. Galactic cosmic rays (GCR) and solar cosmic radiation (SCR) are the primary sources of the radiation field in space. Whereas the GCR component comprises all particles from protons to heavy ions with energies up to 10¹¹ GeV, the SCR component ejected in Solar Energetic Particle events (SPE) consists mostly of protons, with a small percentage of heavy ions with energies up to several GeV. In low Earth orbit, the exposure to GCR is ~ 100-250 x higher compared to sea level. This factor rises to ~ 770 x for travel in the interplanetary space according to recent measurements on a journey to Mars. On a six month mission to the International Space Station (ISS), astronauts accumulate radiation doses exceeding the terrestrial occupational annual limit of 20 mSv by far. Astronauts experience a chronic whole body exposure with single energetic particles (electrons, protons, α-particles and heavy ions) of GCR. Contrary to other workplaces, the exposure on ISS or in future, on exploratory missions, continues after end of the working hours. The main concerns resulting from this exposure are increased risks of cancer, cataract, neurodegenerative effects and infertility. The effective dose as a pre-requisite for the radiation risk assessment was determined from organ doses measured within a human antrophomorphic phantom (MATROSKHA) which was exposed four times on the ISS. The ratio of organ to skin dose determined in these experiments allows estimation of the effective dose based on personal dosimeters of the astronauts. In interplanetary missions, in addition to the chronic, in average low dose GCR exposure at low dose rate, an acute whole body exposure to a high radiation dose at a high dose rate can occur during a SPE with the risk of acute radiation sickness. While shielding (e.g. in a radiation shelter) is effective against SPE protons and high dose exposures can be prevented by alerts based on active dose monitoring and sun activity data from satellites, the chronic GCR exposure cannot be shielded completely during space travel. Currently, radiation protection for astronauts is based on risk management including reduction of exposure (limiting mission duration, shielding of sleeping quarters) and risk surveillance by radiation monitoring (area monitoring, personal dosimeters, SPE alert). Age, gender, genetic predispositions and health and immune status are factors determining individual sensitivity and might be considered for crew selection for interplanetary missions. Ameliorative actions, including prophylactic treatment in order to lower the risk for chronic diseases, are under research and can be summarized as general recommendations for a healthy lifestyle. The treatment of acute radiation sickness encompasses e.g. administration of colony stimulating factors and symptomatic medication (antibiotics, anti-emetics, anti-diarrheic, anti-inflammatory drugs). Risk assessment for space radiation exposure is incomplete and many uncertainties concerning the biological effects of GCR remain. This is also reflected by the different exposure limits space agencies have set for their astronauts. To improve space radiation protection, active space radiation dosimeters, space weather prediction methods, and efficient shielding have to be developed and radiation measurements, including depth dose distribution in the human body, e.g. on the way to Moon and on the Moon surface are required. Mitigation of the effects of heavy ions is one of the most important challenges to be solved for the exploration of the solar system. The biological effects have to be further characterized and risk models should be updated accordingly.

Radiation-induced bystander effects (RIBE) are an acknowledged issue of radiation therapy. Radiation of tumor tissue has been shown to affect non-irradiated neighboring cells in a paracrine and endocrine manner. Transduction of bystander signaling though remains to be investigated in detail. A part of the transduction is the receptor-initiated activation of signaling pathways by secreted factors of the irradiated cell during irradiation damage response. This work focusses on the activation of the transcription factor Nuclear Factor κB (NF-κB) in bystander cells after irradiation.

Introduction: As a prerequisite for developing appropriate countermeasures to mitigate acute effects and late radiation risks for the astronaut and thereby enabling long-term human space flight, the cellular radiation response to densely ionizing radiation needs to be better understood. The biological effectiveness of accelerated heavy ions (which constitute the biologically most important radiation type in space) with high linear energy transfer (LET) for effecting DNA damage response pathways as a gateway to cell death or survival is of major concern not only for space missions but also for new regimes of tumor radiotherapy.

Introduction: As a prerequisite for developing appropriate countermeasures to mitigate acute effects and late radiation risks for the astronaut and thereby enabling long-term human space flight, the cellular radiation response to densely ionizing radiation needs to be better understood. The biological effectiveness of accelerated heavy ions (which constitute the biologically most important radiation type in space) with high linear energy transfer (LET) for effecting DNA damage response pathways as a gateway to cell death or survival is of major concern not only for space missions but also for new regimes of tumor radiotherapy.

There are two limiting factors for humans in space, namely microgravity and galactic cosmic radiation. For sake of improved risk assessment for astronauts, the cellular response to such ionizing radiation qualities that predominate in space (high linear energy transfer, LET) needs to be better understood. One of the key elements to be investigated is cell cycle control. It acts as a central element in DNA damage response as a switch for cellular decision making between life and death. Thus, cell death bypass mechanisms in DNA damage response of mammalian cells will be investigated after heavy ion exposure relevant for the space radiation environment. The dependency of relative biological effectiveness (RBE) on LET will be determined for different biological endpoints: cellular survival, the activation of transcription factors, identification of genes expressed in DNA damage response.