Professor John Roderick Cameron's Influence on Radiation Safety in Terrestrial and Space Environments.

Professor John Roderick Cameron (1922-2005) stands out as a trailblazer in the field of medical physics, whose innovative work has deeply influenced radiation protection and the broader medical radiation field through sound technical judgment and insight. Best known for inventing the bone densitometry device, his pioneering efforts have reshaped modern medical practices far beyond his initial breakthroughs. Cameron's explorations extended into the realms of space biomedical science and models of terrestrial radiation, areas where his insights continue to resonate today. As the Emeritus Professor of Medical Physics at the University of Wisconsin-Madison and a founding member of the American Association of Physicists in Medicine, Cameron laid crucial groundwork for safety standards in environments with high natural radiation levels. His leadership was instrumental in advancing thermoluminescence dosimetry, radiation measurement, and image quality assurance, driving progress in both academia and clinical practices. Moreover, through establishing Medical Physics Publishing, Cameron played a pivotal role in spreading vital research and educational materials across the fields of health physics and medical physics. This commentary reflects on Cameron's far-reaching contributions, highlighting his critical work in space radiation research and terrestrial radiation models-key to the future of interplanetary travel and potential human settlement on planets like Mars. His research in areas of high background radiation, like Ramsar, Iran, has been fundamental in developing strategies for biological protection in space, which are essential for ensuring astronaut safety during long-duration space missions. We honor Professor Cameron's profound legacy, celebrating his visionary spirit and the lasting impact of his contributions on generations of scientists in radiation science.

Chromosomal damage, gene expression and alternative transcription in human lymphocytes exposed to mixed ionizing radiation as encountered in space.

Astronauts travelling in space will be exposed to mixed beams of particle radiation and photons. Exposure limits that correspond to defined cancer risk are calculated by multiplying absorbed doses by a radiation-type specific quality factor that reflects the biological effectiveness of the particle without considering possible interaction with photons. We have shown previously that alpha radiation and X-rays may interact resulting in synergistic DNA damage responses in human peripheral blood lymphocytes but the level of intra-individual variability was high. In order to assess the variability and validate the synergism, blood from two male donors was drawn at 9 time points during 3 seasons of the year and exposed to 0-2 Gy of X-rays, alpha particles or 1:1 mixture of both (half the dose each). DNA damage response was quantified by chromosomal aberrations and by mRNA levels of 3 radiation-responsive genes FDXR, CDKN1A and MDM2 measured 24 h post exposure. The quality of response in terms of differential expression of alternative transcripts was assessed by using two primer pairs per gene. A consistently higher than expected effect of mixed beams was found in both donors for chromosomal aberrations and gene expression with some seasonal variability for the latter. No synergy was detected for alternative transcription.

Light flashes and other sensory illusions perceived in space travel and on ground, including proton and heavy ion therapies.

Most of the astronauts experience visual illusions, apparent flashes of light (LF) in absence of light. The first reported observation of this phenomenon was in July 1969 by Buzz Aldrin, in the debriefing following the Apollo 11 mission. Several ground-based experiments in the 1970s tried to clarify the mechanisms behind these light flashes and to evaluate possible related risks. These works were supported by dedicated experiments in space on the following Apollo flights and in Low Earth Orbit (LEO). It was soon demonstrated that the LF could be caused by charged particles (present in the space radiation) traveling through the eye, and, possibly, some other visual cortical areas. In the 1990s the interest in these phenomena increased again and additional experiments in Low Earth Orbit and others ground-based were started. Recently patients undergoing proton and heavy ion therapy for eye or head and neck tumors have reported the perception of light flashes, opening a new channel to investigate these phenomena. In this paper the many LF studies will be reviewed, presenting an historical and scientific perspective consistent with the combined set of observations, offering a single comprehensive summary aimed to provide further insights on these phenomena. While the light flashes appear not to be a risk by themselves, they might provide information on the amount of radiation induced radicals in the astronauts' eyes. Understanding their generation mechanisms might also support radiation countermeasures development. However, even given the substantial progress outlined in this paper, many questions related to their generation are still under debate, so additional studies are suggested. Finally, it is also conceivable that further LF investigations could provide evidence about the possible interaction of single particles in space with brain function, impacting with the crew ability to optimally perform a mission.

Space agency-specific standards for crew dose and risk assessment of ionising radiation exposures for the International Space Station.

The Partner Agencies of the International Space Station (ISS) maintain separate career exposure limits and shared Flight Rules that control the ionising radiation exposures that crewmembers can experience due to ambient environments throughout their space missions. In low Earth orbit as well as further out in space, energetic ions referred to as galactic cosmic radiation (GCR) easily penetrate spacecraft and spacecraft contents and consequently are always present at low dose rates. Protons and electrons that are trapped in the Earth's geomagnetic field are encountered intermittently, and a rare energetic solar particle event (SPE) may expose crew to (mostly) energetic protons. Space radiation protection goals are to optimize radiation exposures to maintain deleterious late effects at known and acceptable levels and to prevent any early effects that might compromise crew health and mission success. The conventional radiation protection metric effective dose provides a basic framework for limiting exposures associated with human spaceflight and can be communicated to all stakeholders. Additional metrics and uncertainty analyses are required to understand more completely and to convey nuanced information about potential impacts to an individual astronaut or to a space mission. Missions to remote destinations well beyond low Earth orbit (BLEO) are upcoming and bestow additional challenges that shape design and radiation protection needs. NASA has recently adopted a more permissive career exposure limit based upon effective dose and new restrictions on mission exposures imposed by nuclear technologies. This manuscript reviews the exposure limits that apply to the ISS crewmembers. This work was performed in collaboration with the advisory and guidance efforts of International Commission on Radiological Protection (ICRP) Task Group 115 and will be summarized in an upcoming ICRP Report.

Microgravity-Related Changes in Bone Density and Treatment Options: A Systematic Review.

Space travelers are exposed to microgravity (µg), which induces enhanced bone loss compared to the age-related bone loss on Earth. Microgravity promotes an increased bone turnover, and this obstructs space exploration. This bone loss can be slowed down by exercise on treadmills or resistive apparatus. The objective of this systematic review is to provide a current overview of the state of the art of the field of bone loss in space and possible treatment options thereof. A total of 482 unique studies were searched through PubMed and Scopus, and 37 studies met the eligibility criteria. The studies showed that, despite increased bone formation during µg, the increase in bone resorption was greater. Different types of exercise and pharmacological treatments with bisphosphonates, RANKL antibody (receptor activator of nuclear factor κß ligand antibody), proteasome inhibitor, pan-caspase inhibitor, and interleukin-6 monoclonal antibody decrease bone resorption and promote bone formation. Additionally, recombinant irisin, cell-free fat extract, cyclic mechanical stretch-treated bone mesenchymal stem cell-derived exosomes, and strontium-containing hydroxyapatite nanoparticles also show some positive effects on bone loss.

The role of oxygen and the Goldilocks range in the development of cataracts induced by space radiation in US astronauts.

This article explores the role that oxygen levels in US spacecraft from 1961 to 1998 have on the development of cataracts induced by space radiation in astronauts and whether oxygen levels are well accounted for in experimental studies examining cataractogenesis. The first epidemiological report in 2001 linked an increased risk of the primary types of cataracts, and nuclear cataract alone, for astronauts with higher lens doses. However, later studies of US astronauts in 2009 and 2012 reported a higher risk of cortical cataract and posterior subcapsular cataract, but not for nuclear cataract. Firstly, it is postulated that the high oxygen level atmospheres of spacecraft employed before 1976 were a factor in promoting nuclear cataract. The high oxygen levels of hyperbaric oxygen therapy are reportedly associated with nuclear cataract, and the low intraocular oxygen levels of diabetic patients are possibly linked to their higher risk of posterior subcapsular cataract and cortical cataract. Secondly, it is hypothesized that the normal hypoxic environment of the lens and lens epithelial cells (LECs), and all stem/progenitor cells in general, have an optimal Goldilocks range of oxygen levels. Too high a lenticular oxygen level increases oxidative stress and radiosensitivity due to the oxygen effect. Whereas too low an oxygen tension also increases oxidative stress and disrupts LEC differentiation. Even so, a focused literature search of the PubMed database of in vitro experiments with LECs shows that studies rarely account for the hypoxic state of the normal lens, whether ionizing radiation is a factor or not. It is therefore recommended that ocular physioxic levels should therefore be considered when designing in vitro studies to better understand the progression of cataractogenesis on long-duration missions to the Moon and Mars.

Astronauts Plasma-Derived Exosomes Induced Aberrant EZH2-Mediated H3K27me3 Epigenetic Regulation of the Vitamin D Receptor.

There are unique stressors in the spaceflight environment. Exposure to such stressors may be associated with adverse effects on astronauts' health, including increased cancer and cardiovascular disease risks. Small extracellular vesicles (sEVs, i.e., exosomes) play a vital role in intercellular communication and regulate various biological processes contributing to their role in disease pathogenesis. To assess whether spaceflight alters sEVs transcriptome profile, sEVs were isolated from the blood plasma of 3 astronauts at two different time points: 10 days before launch (L-10) and 3 days after return (R+3) from the Shuttle mission. AC16 cells (human cardiomyocyte cell line) were treated with L-10 and R+3 astronauts-derived exosomes for 24 h. Total RNA was isolated and analyzed for gene expression profiling using Affymetrix microarrays. Enrichment analysis was performed using Enrichr. Transcription factor (TF) enrichment analysis using the ENCODE/ChEA Consensus TF database identified gene sets related to the polycomb repressive complex 2 (PRC2) and Vitamin D receptor (VDR) in AC16 cells treated with R+3 compared to cells treated with L-10 astronauts-derived exosomes. Further analysis of the histone modifications using datasets from the Roadmap Epigenomics Project confirmed enrichment in gene sets related to the H3K27me3 repressive mark. Interestingly, analysis of previously published H3K27me3-chromatin immunoprecipitation sequencing (ChIP-Seq) ENCODE datasets showed enrichment of H3K27me3 in the VDR promoter. Collectively, our results suggest that astronaut-derived sEVs may epigenetically repress the expression of the VDR in human adult cardiomyocytes by promoting the activation of the PRC2 complex and H3K27me3 levels.

Female astronauts: Impact of space radiation on menopause.

Space travel has different effects on the reproductive capacity of women compared to men. The radiation exposure intrinsic to deep space travel causes destruction of some of a woman's primordial follicles. Data suggests that a typical Mars mission may reduce a women's ovarian reserve by about 50%. This has consequences to a woman's reproductive capacity and, more significantly, decreases the time interval to her menopause. A reduced time interval to menopause is associated with earlier mortality. Estrogen replacement therapy and cryopreservation of a female astronaut's oocytes may be used to address these issues. However, cortical tissue freezing provides advantages to more directly compensate for these workplace complications. Cortical tissue freezing especially provides advantages if there are plans to reproduce in an extraterrestrial location.

Biological Protection in Deep Space Missions.

During deep space missions, astronauts are exposed to highly ionizing radiation, incl. neutrons, protons and heavy ions from galactic cosmic rays (GCR), solar wind (SW) and solar energetic particles (SEP). This increase the risks for cancerogenisis, damages in central nervous system (CNS), cardiovascular diseases, etc. Large SEP events can even cause acute radiation syndrome (ARS). Long term manned deep space missions will therefor require unique radiation protection strategies. Since it has been shown that physical shielding alone is not sufficient, this paper propose pre-flight screening of the aspirants for evaluation of their level of adaptive responses. Methods for boosting their immune system, should also be further investigated, and the possibility of using radiation effect modulators are discussed. In this paper, especially, the use of vitamin C as a promising non-toxic, cost-effective, easily available radiation mitigator (which can be used hours after irradiation), is described. Although it has previously been shown that vitamin C can decrease radiation-induced chromosomal damage in rodents, it must be further investigated before any conclusions about its radiation mitigating properties in humans can be concluded.

Emerging Role of Exosomal Long Non-coding RNAs in Spaceflight-Associated Risks in Astronauts.

During spaceflight, astronauts are exposed to multiple unique environmental factors, particularly microgravity and ionizing radiation, that can cause a range of harmful health consequences. Over the past decades, increasing evidence demonstrates that the space environment can induce changes in gene expression and RNA processing. Long non-coding RNA (lncRNA) represent an emerging area of focus in molecular biology as they modulate chromatin structure and function, the transcription of neighboring genes, and affect RNA splicing, stability, and translation. They have been implicated in cancer development and associated with diverse cardiovascular conditions and associated risk factors. However, their role on astronauts' health after spaceflight remains poorly understood. In this perspective article, we provide new insights into the potential role of exosomal lncRNA after spaceflight. We analyzed the transcriptional profile of exosomes isolated from peripheral blood plasma of three astronauts who flew on various Shuttle missions between 1998-2001 by RNA-sequencing. Computational analysis of the transcriptome of these exosomes identified 27 differentially expressed lncRNAs with a Log2 fold change, with molecular, cellular, and clinical implications.

Influence of Microgravity on Apoptosis in Cells, Tissues, and Other Systems In Vivo and In Vitro.

All life forms have evolved under the constant force of gravity on Earth and developed ways to counterbalance acceleration load. In space, shear forces, buoyance-driven convection, and hydrostatic pressure are nullified or strongly reduced. When subjected to microgravity in space, the equilibrium between cell architecture and the external force is disturbed, resulting in changes at the cellular and sub-cellular levels (e.g., cytoskeleton, signal transduction, membrane permeability, etc.). Cosmic radiation also poses great health risks to astronauts because it has high linear energy transfer values that evoke complex DNA and other cellular damage. Space environmental conditions have been shown to influence apoptosis in various cell types. Apoptosis has important functions in morphogenesis, organ development, and wound healing. This review provides an overview of microgravity research platforms and apoptosis. The sections summarize the current knowledge of the impact of microgravity and cosmic radiation on cells with respect to apoptosis. Apoptosis-related microgravity experiments conducted with different mammalian model systems are presented. Recent findings in cells of the immune system, cardiovascular system, brain, eyes, cartilage, bone, gastrointestinal tract, liver, and pancreas, as well as cancer cells investigated under real and simulated microgravity conditions, are discussed. This comprehensive review indicates the potential of the space environment in biomedical research.

From international ophthalmology to space ophthalmology: the threats to vision on the way to Moon and Mars colonization.

PURPOSE: To report the ophthalmological risks of space travel. METHODS: The literature about the effect of microgravity and cosmic radiation on the human eye has been reviewed, focusing on the so-called "spaceflight related neuro-ocular syndrome (SANS)", and possible remedies. RESULTS: The eye is the major candidate to suffer from the adverse space conditions, so much so that SANS is the main concern of the National Aeronautics and Space Administration (NASA). SANS, that affects astronauts engaged in long-duration spaceflights, is characterized by optic nerve head swelling, flattening of the posterior region of the scleral shell, choroidal folds, retinal cotton wool spots, and hyperopic shift. Even if it seems related to an increased volume of the cerebrospinal fluid in the brain and the optic nerve sheaths, its pathogenesis is still unclear. In addition, cataract is related to the effect of galactic cosmic rays on the lens. Centrifuges, pressurizing chambers, and mechanical counter-pressure suits have been advanced to counteract the upward fluid shift responsible for the SANS syndrome. Shields with a high content of hydrogen, magnetic shielding systems, and wearable radiation shielding devices are under study to mitigate the exposure to galactic cosmic rays. CONCLUSIONS: Since 1961, the year of the first manned mission outside the Earth, history has shown that the human being may venture in space. Yet, visual impairment is the top health risk for long-duration spaceflight. Effective remediation is mandatory in anticipation of long space missions and Moon and Mars colonization.

Poor Understanding of Radiation Profiles in Deep Space Causes Inaccurate Findings and Misleading Conclusions.

The radiation environment in deep space, where astronauts are behind the shelter provided by the Earth's magnetosphere, is a major health concern. Galactic cosmic rays (GCR) and solar particle events (SPE) are two basic sources of space radiation in the solar system. The health risks of exposure to high levels of space radiation can be observed either as acute and delayed effects. Zhang et al. in their recently published paper entitled "γ-H2AX responds to DNA damage induced by long-term exposure to combined low-dose-rate neutron and γ-ray radiation" have addressed the effects of different cumulative radiation doses on peripheral blood cell, subsets of T cells of peripheral blood lymphocytes and DNA damage repair. These researchers exposed animals to low dose rate 60Co-rays at 0.0167 Gy h-1for 2 h/d and 252Cf neutrons at 0.028 mGy h-1for 20 h/d for 15, 30, or 60 consecutive days. They reported that the mRNA of H2AX increased significantly, and showed a positive correlation with dose. Despite strengths, this paper has several shortcomings such as poor definition of low dose radiation as well as space and reactor radiation environments. Another shortcoming of this paper comes from this point that blood cell studies do not represent the biological effects of ionizing radiation on the total body. Moreover, the effects of the human immune system and DNA repair mechanisms are not included in the study. The role of pre-exposures and induction of adaptive response phenomena in decreasing the risk of radiation in deep space missions are also ignored.

Is Telomere Length a Biomarker of Adaptive Response in Space? Curious Findings from NASA and Residents of High Background Radiation Areas.

Telomere length and stability is a biomarker of aging, stress, and cancer. Shortening of telomeres and high level of DNA damages are known to be associated with aging. Telomere shortening normally occurs during cell division in most cells and when telomeres reach a critically short length, DNA damage signaling and cellular senescence can be triggered. The induction of an adaptive response by space radiation was first documented in 2003. Telomere length alterations are among the most fascinating observations in astronauts and residents of high background radiation areas. While study of the chronic exposure to high levels of background ionizing radiation in Kerala, India failed to show a significant influence on telomere length, limited data about the NASA astronaut Scott Kelly show that exposure to space radiation can induce telomeres to regain length. Interestingly, his telomeres shortened again only a couple of days after returning to Earth. The difference between these situations may be due to the differences in radiation dose, dose-rate, and/or type of radiation. Moreover, Scott Kelly's spacewalks (EVA) could have significantly increased his cumulative radiation dose. It is worth noting that the spacewalks not only confer a higher dose activity but are also characterized by a different radiation spectrum than inside the space craft since the primary particles would not interact with the vehicle shell to generate secondary radiation. Generally, these differences can possibly indicate the necessity of a minimum dose/dose-rate for induction of adaptive response (the so called Window effect).

NK cell function is impaired during long-duration spaceflight.

Maintaining astronaut health during space travel is paramount for further human exploration of the solar system beyond Earth's orbit. Of concern are potential dysregulations in immunity, which could increase the likelihood of cancer and latent viral reactivation. Natural killer (NK) cells are critical effectors of the innate immune system, and their function and phenotype are important to immunosurveillance of nascent tumors and latent viral infections. We compared changes in NK cell phenotype and function in eight crew members who completed an ~6-mo mission to the International Space Station (ISS) with healthy controls who remained on Earth. Assessments were made before (180 and 60 days before launch), during [flight day + 90 days (FD+90) and 1 day before return (R-1)], and after the mission (at R+0, R+18, R+33, and R+66). These samples, plus an additional in-flight sample (FD+180), were collected from a crew member who spent 340 days (~1 yr) on the ISS. NK cell cytotoxic activity (NKCA) against K562 leukemia targets in vitro was reduced by ~50% at FD+90 in ISS crew but not controls. This decrease was more pronounced in "rookie" compared with "veteran" crew members. The ~1-yr mission crew member did not show declines in NKCA against K562 until late in the mission (R-1 and R+0). NK cell numbers, expression of activating and inhibitory receptors, target cell binding, and expression and degranulation of perforin and granzyme B were unaltered with spaceflight. Similarly, when we exposed an immortalized NK cell line (NK-92) to sera collected at different mission time points (before, during, and after flight), there was no effect on NKCA. This is the first study to report impaired NK cell function during long-duration space travel. Countermeasures may be needed to mitigate immune system impairment in exploration class mission crew during long-duration spaceflight missions. NEW & NOTEWORTHY Immune system impairment may inhibit future human space exploration missions to Mars. Natural killer (NK) cells are key components of immunity and vital for tumor surveillance and the prevention of latent virus reactivation. We report that NK cell function is impaired in astronauts during an ~6-mo orbital space mission compared with preflight levels and ground-based controls. Declines in NK cell function were more marked in first-time "rookie" fliers. Countermeasures are needed to preserve NK cell-mediated immunity during spaceflight.

The effect of competing risks on astronaut and cosmonaut mortality.

Astronauts and cosmonauts have been reported to be at substantially lower age-specific risk of death from chronic disease (primarily heart disease and cancers) in comparison to the general populations of the United States and Russia, respectively. Yet, both groups have been at greater age-specific risk of death from external causes, mainly due to plane crashes and spacecraft accidents. In this study we tested the hypothesis that the reported reductions in mortality from natural causes result, to some degree, from survival bias created by early deaths from external causes. Statistical comparisons of baseline characteristics between cause-of-death groups showed no significant differences. Cause-specific survival curves showed no difference in long-term mortality from external causes among either astronauts or cosmonauts compared to Kaplan-Meier curves with censoring for competing causes. Cause-specific survival curves for natural causes suggested a possible upward bias in mortality estimates published thus far for both groups of space explorers. Differences in survival between Kaplan-Meier curves and the cause-specific survival curves were 7% and 5% for astronauts and cosmonauts respectively after 55 years. The data do not support the hypothesis that observed reductions in mortality from natural causes are due in whole or in part to bias created by deaths from external causes at young ages. The data imply that reports of cause-specific mortality for astronauts and cosmonauts may in fact systematically overestimate mortality rates, though these findings should be interpreted with caution as the data are thin at the extremes of follow-up time.

Commentary regarding: "The effect of simulated space radiation on the N-glycosylation of human immunoglobulin G1".

Deep space missions, including Mars voyages, are an important area of research. Protection of astronauts' health during these long-term missions is of paramount importance. The paper authored by Szarka et al. entitled "The effect of simulated space radiation on the N-glycosylation of human immunoglobulin G1" is indeed a step forward in this effort. Despite numerous strengths, there are some shortcomings in this paper including an incomplete description of the space radiation environment as well as discussion of the resulting biological effects. Due to complexity of the space radiation environment, a careful analysis is needed to fully evaluate the spectrum of particles associated with solar particle events and galactic cosmic radiation. The radiation source used in this experiment does not reproduce the range of primary galactic cosmic radiation and solar particle events particles and their associated energies. Furthermore, the effect of radiation interactions within the spacecraft shell and the potential effects of microgravity are not considered. Moreover, the importance of radioadaptation in deep space missions that is confirmed in a NASA report is neither considered. Other shortcomings are also discussed in this commentary. Considering these shortcomings, it can be argued that Szarka et al. draw conclusions based on an incomplete description of the space radiation environment that could affect the applicability of this study.

No evidence for an increase in circulatory disease mortality in astronauts following space radiation exposures.

Previous analysis has shown that astronauts have a significantly lower standardized mortality ratio for circulatory disease mortality compared to the U.S. population, which is consistent with the rigorous selection process and healthy lifestyles of astronauts, and modest space radiation exposures from past space missions. However, a recent report by Delp et al. estimated the proportional mortality ratio for ages of 55-64 y of Apollo lunar mission astronauts to claim a high risk of cardiovascular disease due to space radiation compared to the U.S. population or to non-flight astronauts. In this Commentary we discuss important deficiencies in the methods and assumptions on radiation exposures used by Delp et al. that we judge cast serious doubt on their conclusions.

The potential influence of the microbiota and probiotics on women during long spaceflights.

Humans have been exploring space for almost 55 years but space travel comes with many psychological and physiological changes that astronauts have to adapt to, both during and post flight missions. Now, with the reality of such missions lasting years, maintaining proper health of the flight crew is a high priority. While conditions such as nausea, bone loss, renal calculi and depression have been recognized, and approaches to medical and surgical care in space considered, the influence of the microbiota could be of added significance in maintaining astronaut health. While probiotics have long been part of the Russian cosmonaut diet, their use for specific health concerns of women has not been assessed. In this article, we explore the ways in which the microbiome may influence the health of female astronauts during long space flights, and present a rationale for the use of probiotics.

Cosmic radiation and cancer: is there a link?

Cosmic radiation can cause genetic and cytogenetic damage. Certain occupations including airline pilots and cabin crew are acknowledged to have a greater exposure to cosmic radiation. In a systematic search of MEDLINE, performed from 1990 to 2014, we analyzed clinical studies using the keywords: cosmic radiation, cancer, chromosome aberration, pilots and astronauts. Increased incidence of skin cancers among airline cabin crew has been reported in a number of studies and appears to be the most consistent finding. However, as with other cancers, it is unclear whether increased exposure to cosmic radiation is a factor in the increased incidence or whether this can be explained by lifestyle factors. Further research is needed to clarify the risk of cancer in relation to cosmic radiation.