Radiation measurements in the International Space Station, Columbus module, in 2020-2022 with the LIDAL detector.

The Light Ion Detector for ALTEA (LIDAL) is a new instrument designed to measure flux, energy spectra and Time of Flight of ions in a space habitat. It was installed in the International Space Station (Columbus) on January 19, 2020 and it is still operating. This paper presents the results of LIDAL measurements in the first 17 months of operation (01/2020-05/2022). Particle flux, dose rate, Time of Flight and spectra are presented and studied in the three ISS orthogonal directions and in the different geomagnetic regions (high latitude, low latitude, and South Atlantic Anomaly, SAA). The results are consistent with previous measurements. Dose rates range between 1.8 nGy/s and 2.4 nGy/s, flux between 0.21 particles/(sr cm2 s) and 0.32 particles/(sr cm2 s) as measured across time and directions during the full orbit. These data offer insights concerning the radiation measurements in the ISS and demonstrate the capabilities of LIDAL as a unique tool for the measurement of space radiation in space habitats, also providing novel information relevant to assess radiation risks for astronauts.

Quality assurance for the use of computational methods in dosimetry: activities of EURADOS Working Group 6 'Computational Dosimetry'.

Working Group (WG) 6 'Computational Dosimetry' of the European Radiation Dosimetry Group promotes good practice in the application of computational methods for radiation dosimetry in radiation protection and the medical use of ionising radiation. Its cross-sectional activities within the association cover a large range of current topics in radiation dosimetry, including more fundamental studies of radiation effects in complex systems. In addition, WG 6 also performs scientific research and development as well as knowledge transfer activities, such as training courses. Monte Carlo techniques, including the use of anthropomorphic and other numerical phantoms based on voxelised geometrical models, play a strong part in the activities pursued in WG 6. However, other aspects and techniques, such as neutron spectra unfolding, have an important role as well. A number of intercomparison exercises have been carried out in the past to provide information on the accuracy with which computational methods are applied and whether best practice is being followed. Within the exercises that are still ongoing, the focus has changed towards assessing the uncertainty that can be achieved with these computational methods. Furthermore, the future strategy of WG 6 also includes an extension of the scope toward experimental benchmark activities and evaluation of cross-sections and algorithms, with the vision of establishing a gold standard for Monte Carlo methods used in medical and radiobiological applications.

Dose-averaged LET calculation for proton track segments using microdosimetric Monte Carlo simulations.

PURPOSE: There is an increasing interest in calculating linear energy transfer (LET) distributions for proton therapy treatments in order to assess the influence of this quantity in biological terms. Microdosimetric Monte Carlo (MC) simulations are useful tools to calculate dose-averaged LET, as this has been broadly proposed as the most adequate quantity to characterize these biological effects. However, a straightforward uniform sampling of the scoring site turns out to be computationally unaffordable. In contrast, some issues have been pointed out with the more efficient weighted sampling approach, frequently used in literature. Here, we address the issues associated with the latter method and propose adequate corrections to achieve reliable calculations of dose-averaged LET values from microdosimetry. METHODS AND MATERIALS: Proton track structures have been simulated with Geant4-DNA considering two different approaches. One version employs a uniform sampling for placing the spherical site and is used as the reference. The other one uses a weighted sampling by considering the spatial distribution of transfer points. Some corrections are proposed for calculating a dose-averaged LET comparable to the reference case. An additional MC approach is proposed to obtain the weighted mean of the energy imparted per electronic collision of the proton within the site, the δ 2 function, related to the straggling distribution, as an intermediate step in the LET calculation. RESULTS: Energy imparted per event distributions are different when employing either sampling methods, due to the different geometrical randomness. We have found an agreement below (0.15 ± 0.05) keV/µm in the worst case for uniform and weighted methods in dose-averaged LET values when the weighted sampling results are corrected according to our proposal. Our analysis is restricted to spherical sites of 1 and 10 µm diameter and monoenergetic beams in the range from 2 to 90 MeV. CONCLUSIONS: This work shows a reliable and computational-efficient method to perform calculations of track segment dose-averaged LET using MC simulations for proton therapy beams, including the necessary considerations for obtaining the straggling distribution characteristics. The validity of this approach remains as long as the stopping power of the proton can be considered as constant along its track within the site.

BIOINFORMATIC ANALYSIS OF DOSE- AND TIME-DEPENDENT miRNome RESPONSES.

The advent of new 'omics' techniques determined a massive boost in the measurement of the whole spectra of molecules within cells, favoring promising new radiobiological studies at low doses. The main aim of this work was to assess the radiation-induced perturbations of miRNA profiles and their temporal dynamics. Human Umbilical Vein Endothelial Cells were irradiated with low doses of γ-rays. At different time points post-irradiation, cells were harvested and miRNAs isolated. A full mapping of the miRNA sequences via Next-Generation-Sequencing analysis was performed followed by bioinformatic analyses. Pathway enrichment analyses on the differentially expressed miRNAs focused both on the averaged effects of different doses over the 24-h experiment and on the altered temporal dynamics of the miRNA profiles. These complementary analyses provided a picture of the dose- and time-dependent miRNAs responses, allowing to better explore the candidate biomarkers linked to radiation exposures and their corresponding pathways and functions.

INNOVATIVE SOLUTIONS FOR PERSONAL RADIATION SHIELDING IN SPACE.

Personal radiation shielding is likely to play an important role in the strategy for radiation protection of future manned interplanetary missions. There is potential for the successful adoption of wearable shielding devices, readily available in case of accidental exposures or used for emergency operations in low-shielded areas of the habitat, particularly in case of solar particle events (SPEs). Based on optimization of available resources, conceptual models for radiation protection spacesuits have been proposed, with elements made of different materials, and the first prototype of a water-fillable garment was designed and manufactured in the framework of the PERSEO project, funded by the Italian Space Agency, leading to the successful test of such prototype for ease of use and wearability on-board the International Space Station. We present results of Monte Carlo calculations offering a proof-of-principle validation of the shielding efficacy of such prototype in different SPE environments and shielding conditions.

A New Standard DNA Damage (SDD) Data Format.

Our understanding of radiation-induced cellular damage has greatly improved over the past few decades. Despite this progress, there are still many obstacles to fully understand how radiation interacts with biologically relevant cellular components, such as DNA, to cause observable end points such as cell killing. Damage in DNA is identified as a major route of cell killing. One hurdle when modeling biological effects is the difficulty in directly comparing results generated by members of different research groups. Multiple Monte Carlo codes have been developed to simulate damage induction at the DNA scale, while at the same time various groups have developed models that describe DNA repair processes with varying levels of detail. These repair models are intrinsically linked to the damage model employed in their development, making it difficult to disentangle systematic effects in either part of the modeling chain. These modeling chains typically consist of track-structure Monte Carlo simulations of the physical interactions creating direct damages to DNA, followed by simulations of the production and initial reactions of chemical species causing so-called "indirect" damages. After the induction of DNA damage, DNA repair models combine the simulated damage patterns with biological models to determine the biological consequences of the damage. To date, the effect of the environment, such as molecular oxygen (normoxic vs. hypoxic), has been poorly considered. We propose a new standard DNA damage (SDD) data format to unify the interface between the simulation of damage induction in DNA and the biological modeling of DNA repair processes, and introduce the effect of the environment (molecular oxygen or other compounds) as a flexible parameter. Such a standard greatly facilitates inter-model comparisons, providing an ideal environment to tease out model assumptions and identify persistent, underlying mechanisms. Through inter-model comparisons, this unified standard has the potential to greatly advance our understanding of the underlying mechanisms of radiation-induced DNA damage and the resulting observable biological effects when radiation parameters and/or environmental conditions change.

A COMPARISON BETWEEN X-RAY AND CARBON ION IRRADIATION IN HUMAN NEURAL STEM CELLS.

Glioblastoma multiforme (GBM) is characterized by a poor prognosis and a median survival of ~12-18 months. GBM is usually managed by neurosurgery followed by both chemotherapy and radiotherapy. Since GBM develops resistance to conventional therapies, treatment with C-ions is promising to completely eradicate the tumoural mass. During cranial irradiation, exposure of healthy tissues is inevitable. Because of the presence of neural stem cells, a deep investigation on the effects of C-ion irradiation with respect to X-ray induced damage is mandatory to allow a better definition of treatments. In this work, the comparison of X-rays and C-ion irradiation-induced effects on human neural stem cell, focusing on multiple endpoints, such as cell viability, cytokine secretion and spheroid formation is presented. Results show different temporal and dose responses of human neural stem cells to the different radiation qualities, suggesting different underpinning mechanisms of radiation-induced damages.

WHAT ROLES FOR TRACK-STRUCTURE AND MICRODOSIMETRY IN THE ERA OF -omics AND SYSTEMS BIOLOGY?

Ionizing radiation is a peculiar perturbation when it comes to damage to biological systems: it proceeds through discrete energy depositions, over a short temporal scale and a spatial scale critical for subcellular targets as DNA, whose damage complexity determines the outcome of the exposure. This lies at the basis of the success of track structure (and nanodosimetry) and microdosimetry in radiation biology. However, such reductionist approaches cannot account for the complex network of interactions regulating the overall response of the system to radiation, particularly when effects are manifest at the supracellular level and involve long times. Systems radiation biology is increasingly gaining ground, but the gap between reductionist and holistic approaches is becoming larger. This paper presents considerations on what roles track structure and microdosimetry can have in the attempt to fill this gap, and on how they can be further exploited to interpret radiobiological data and inform systemic approaches.

A water-filled garment to protect astronauts during interplanetary missions tested on board the ISS.

As manned spaceflights beyond low Earth orbit are in the agenda of Space Agencies, the concerns related to space radiation exposure of the crew are still without conclusive solutions. The risk of long-term detrimental health effects needs to be kept below acceptable limits, and emergency countermeasures must be planned to avoid the short-term consequences of exposure to high particle fluxes during hardly predictable solar events. Space habitat shielding cannot be the ultimate solution: the increasing complexity of future missions will require astronauts to protect themselves in low-shielded areas, e.g. during emergency operations. Personal radiation shielding is promising, particularly if using available resources for multi-functional shielding devices. In this work we report on all steps from the conception, design, manufacturing, to the final test on board the International Space Station (ISS) of the first prototype of a water-filled garment for emergency radiation shielding against solar particle events. The garment has a good shielding potential and comfort level. On-board water is used for filling and then recycled without waste. The successful outcome of this experiment represents an important breakthrough in space radiation shielding, opening to the development of similarly conceived devices and their use in interplanetary missions as the one to Mars.

AT THE PHYSICS-BIOLOGY INTERFACE: THE NEUTRON AFFAIR.

We present predictions of neutron relative biological effectiveness (RBE) for cell irradiations with neutron beams at PTB-Braunschweig. A neutron RBE model is adopted to evaluate initial DNA damage induction given the neutron-induced charged particle field. RBE values are predicted for cell exposures to quasi-monoenergetic beams (0.56 MeV, 1.2 MeV) and to a broad energy distribution neutron field with dose-averaged energy of 5.75 MeV. Results are compared to what obtained with our RBE predictions for neutrons at similar energies, when a 30-cm sphere is irradiated in an isotropic neutron field. RBE values for experimental conditions are higher for the lowest neutron energies, because, as expected, target geometry determines the weight of the low-effectiveness photon component of the neutron dose. These results highlight the importance of characterizing neutron fields in terms of physical interactions, to fully understand neutron-induced biological effects, contributing to risk estimation and to the improvement of radiation protection standards.

Exploring innovative radiation shielding approaches in space: A material and design study for a wearable radiation protection spacesuit.

We present a design study for a wearable radiation-shielding spacesuit, designed to protect astronauts' most radiosensitive organs. The suit could be used in an emergency, to perform necessary interventions outside a radiation shelter in the space habitat in case of a Solar Proton Event (SPE). A wearable shielding system of the kind we propose has the potential to prevent the onset of acute radiation effects in this scenario. In this work, selection of materials for the spacesuit elements is performed based on the results of dedicated GRAS/Geant4 1-dimensional Monte Carlo simulations, and after a trade-off analysis between shielding performance and availability of resources in the space habitat. Water is the first choice material, but also organic compounds compatible with a human space habitat are considered (such as fatty acids, gels and liquid organic wastes). Different designs and material combinations are proposed for the spacesuits. To quantify shielding performance we use GRAS/Geant4 simulations of an anthropomorphic phantom in an average SPE environment, with and without the spacesuit, and we compare results for the dose to Blood Forming Organs (BFO) in Gy-Eq, i.e. physical absorbed dose multiplied by the proton Relative Biological Effectiveness (RBE) for non-cancer effects. In case of SPE occurrence for Intra-Vehicular Activities (IVA) outside a radiation shelter, dose reductions to BFO in the range of 44-57% are demonstrated to be achievable with the spacesuit designs made only of water elements, or of multi-layer protection elements (with a thin layer of a high density material covering the water filled volume). Suit elements have a thickness in the range 2-6 cm and the total mass for the garment sums up to 35-43 kg depending on model and material combination. Dose reduction is converted into time gain, i.e. the increase of time interval between the occurrence of a SPE and the moment the dose limit to the BFO for acute effects is reached. Wearing a radiation shielding spacesuit of the kind we propose, the astronaut could have up to more than the double the time (e.g. almost 6 instead of 2.5 h) to perform necessary interventions outside a radiation shelter during a SPE, his/her exposure remaining within dose limits. An indicative mass saving thanks to the shielding provided by the suits is also derived, calculating the amount of mass needed in addition to the 1.5 cm thick Al module considered for the IVA scenario to provide the same additional shielding given by the spacesuit. For an average 50% dose reduction to BFO this is equal to about 2.5 tons of Al. Overall, our results offer a proof-of-principle validation of a complementary personal shielding strategy in emergency situations in case of a SPE event. Such results pave the way for the design and realization of a prototype of a water-filled garment to be tested on board the International Space Station for wearability. A successful outcome will possibly lead to the further refining of the design of radiation protection spacesuits and their possible adoption in future long-duration manned missions in deep space.

Comprehensive track-structure based evaluation of DNA damage by light ions from radiotherapy-relevant energies down to stopping.

Track structures and resulting DNA damage in human cells have been simulated for hydrogen, helium, carbon, nitrogen, oxygen and neon ions with 0.25-256 MeV/u energy. The needed ion interaction cross sections have been scaled from those of hydrogen; Barkas scaling formula has been refined, extending its applicability down to about 10 keV/u, and validated against established stopping power data. Linear energy transfer (LET) has been scored from energy deposits in a cell nucleus; for very low-energy ions, it has been defined locally within thin slabs. The simulations show that protons and helium ions induce more DNA damage than heavier ions do at the same LET. With increasing LET, less DNA strand breaks are formed per unit dose, but due to their clustering the yields of double-strand breaks (DSB) increase, up to saturation around 300 keV/µm. Also individual DSB tend to cluster; DSB clusters peak around 500 keV/µm, while DSB multiplicities per cluster steadily increase with LET. Remarkably similar to patterns known from cell survival studies, LET-dependencies with pronounced maxima around 100-200 keV/µm occur on nanometre scale for sites that contain one or more DSB, and on micrometre scale for megabasepair-sized DNA fragments.

The origin of neutron biological effectiveness as a function of energy.

The understanding of the impact of radiation quality in early and late responses of biological targets to ionizing radiation exposure necessarily grounds on the results of mechanistic studies starting from physical interactions. This is particularly true when, already at the physical stage, the radiation field is mixed, as it is the case for neutron exposure. Neutron Relative Biological Effectiveness (RBE) is energy dependent, maximal for energies ~1 MeV, varying significantly among different experiments. The aim of this work is to shed light on neutron biological effectiveness as a function of field characteristics, with a comprehensive modeling approach: this brings together transport calculations of neutrons through matter (with the code PHITS) and the predictive power of the biophysical track structure code PARTRAC in terms of DNA damage evaluation. Two different energy dependent neutron RBE models are proposed: the first is phenomenological and based only on the characterization of linear energy transfer on a microscopic scale; the second is purely ab-initio and based on the induction of complex DNA damage. Results for the two models are compared and found in good qualitative agreement with current standards for radiation protection factors, which are agreed upon on the basis of RBE data.

Energy dependence of the complexity of DNA damage induced by carbon ions.

To assess the complexity of DNA damage induced by carbon ions as a function of their energy and LET, 2-Gy irradiations by 100 keV u(-1)-400 MeV u(-1) carbon ions were investigated using the PARTRAC code. The total number of fragments and the yield of fragments of <30 bp were calculated. The authors found a particularly important contribution of DNA fragmentation in the range of <1 kbp for specific energies of <6 MeV u(-1). They also considered the effect of different specific energies with the same LET, i.e. before and after the Bragg peak. As a first step towards a full characterisation of secondary particle production from carbon ions interacting with tissue, a comparison between DNA-damage induction by primary carbon ions and alpha particles resulting from carbon break-up is presented, for specific energies of >1 MeV u(-1).

Investigation of radiation-induced multilayered signalling response of the inflammatory pathway.

Ionising radiation exposure of cells might induce the perturbation of cell functions and, in particular, the activation or inhibition of several important pathways. This perturbation can cause the deregulation of both intra- and extra-cellular signalling cascades (such as the inflammatory pathway) and alter not only the behaviour of directly exposed cells but also the neighbouring non-irradiated ones, through the so-called bystander effect. The aim of the present work was to investigate the complex nonlinear interactions between the inflammatory pathway and other strictly interlaced signalling pathways, such as Erk1/2 and Akt/PKB, focusing on the radiation-induced perturbation of such pathways in the dose range of 0-2 Gy. The results show how radiation affects these interconnected pathways and how confounding factors, such as the change of culture medium, can hide radiation-induced perturbations.

The ANDANTE project: a multidisciplinary approach to neutron RBE.

UNLABELLED: The usual method for estimating the risk from exposure to neutrons uses the concept of relative biological effectiveness (RBE) compared with the risk from photons, which is better known. RBE has been evaluated using cellular and animal models. But this causes difficulties in applying the concept to humans. The ANDANTE project takes a new approach using three different disciplines in parallel: Physics: a track structure model is used to contrast the patterns of damage to cellular macro-molecules from neutrons compared with photons. The simulations reproduce the same energy spectra as are used in the other two approaches. Stem cell radiobiology: stem cells from thyroid, salivary gland and breast tissue are given well characterised exposures to neutrons and photons. A number of endpoints are used to estimate the relative risk of damage from neutrons compared with photons. Irradiated cells will also be transplanted into mice to investigate the progression of the initial radiation effects in stem cells into tumours in a physiological environment. EPIDEMIOLOGY: the relative incidence rates of second cancers of the thyroid, salivary gland and breast following paediatric radiotherapy (conventional radiotherapy for photons and proton therapy for neutrons) are investigated in a pilot single-institution study, exploring the possible design of a multi-institution prospective study comparing the long-term out-of-field and in-field effects of scanned and scattered protons. The results will be used to validate an RBE-based risk model developed by the project, and validate the corresponding RBE values.

Radiosensitivity in lymphoblastoid cell lines derived from Shwachman-Diamond syndrome patients.

Shwachman-Diamond syndrome is an autosomal-recessive disorder characterised by bone marrow failure and a cumulative risk of progression to acute myeloid leukaemia. The Shwachman-Bodian-Diamond syndrome (SBDS) gene, the only gene known to be causative of the pathology, is involved in ribosomal biogenesis, stress responses and DNA repair, and the lack of SBDS sensitises cells to many stressors and leads to mitotic spindle destabilisation. The effect of ionising radiation on SBDS-deficient cells was investigated using immortalised lymphocytes from SDS patients in comparison with positive and negative controls in order to test whether, in response to ionising radiation exposure, any impairment in the DNA repair machinery could be observed. After irradiating cells with different doses of X-rays or gamma-rays, DNA repair kinetics and the residual damages using the alkaline COMET assay and the γ-H2AX assay were assessed, respectively. In this work, preliminary data about the comparison between ionising radiation effects in different patients-derived cells and healthy control cells are presented.

Reaction mechanism interplay in determining the biological effectiveness of neutrons as a function of energy.

Neutron relative biological effectiveness (RBE) is found to be energy dependent, being maximal for energies ∼1 MeV. This is reflected in the choice of radiation weighting factors wR for radiation protection purposes. In order to trace back the physical origin of this behaviour, a detailed study of energy deposition processes with their full dependences is necessary. In this work, the Monte Carlo transport code PHITS was used to characterise main secondary products responsible for energy deposition in a 'human-sized' soft tissue spherical phantom, irradiated by monoenergetic neutrons with energies around the maximal RBE/wR. Thereafter, results on the microdosimetric characterisation of secondary protons were used as an input to track structure calculations performed with PARTRAC, thus evaluating the corresponding DNA damage induction. Within the proposed simplified approach, evidence is suggested for a relevant role of secondary protons in inducing the maximal biological effectiveness for 1 MeV neutrons.

Mechanisms of the induction of apoptosis mediated by radiation-induced cytokine release.

The aim of the present work was to investigate the mechanisms of radiation-induced bystander signalling leading to apoptosis in non-irradiated co-cultured cells. Cultured non-transformed cells were irradiated, and the effect on the apoptosis rate on co-cultured non-irradiated malignant cells was determined. For this, two different levels of the investigation are presented, i.e. release of signalling proteins and transcriptomic profiling of the irradiated and non-irradiated co-cultured cells. Concerning the signalling proteins, in this study, the attention was focussed on the release of the active and latent forms of the transforming growth factor-ß1 protein. Moreover, global gene expression profiles of non-transformed and transformed cells in untreated co-cultures were compared with those of 0.5-Gy-irradiated non-transformed cells co-cultured with the transformed cells. The results show an effect of radiation on the release of signalling proteins in the medium, although no significant differences in release rates were detectable when varying the doses in the range from 0.25 to 1 Gy. Moreover, gene expression results suggest an effect of radiation on both cell populations, pointing out specific signalling pathways that might be involved in the enhanced induction of apoptosis.

In vitro γ-ray-induced inflammatory response is dominated by culturing conditions rather than radiation exposures.

The inflammatory pathway has a pivotal role in regulating the fate and functions of cells after a wide range of stimuli, including ionizing radiation. However, the molecular mechanisms governing such responses have not been completely elucidated yet. In particular, the complex activation dynamics of the Nuclear transcription Factor kB (NF-kB), the key molecule governing the inflammatory pathway, still lacks a complete characterization. In this work we focused on the activation dynamics of the NF-kB (subunit p65) pathway following different stimuli. Quantitative measurements of NF-kB were performed and results interpreted within a systems theory approach, based on the negative feedback loop feature of this pathway. Time-series data of nuclear NF-kB concentration showed no evidence of γ-ray induced activation of the pathway for doses up to 5 Gy but highlighted important transient effects of common environmental stress (e.g. CO2, temperature) and laboratory procedures, e.g. replacing the culture medium, which dominate the in vitro inflammatory response.