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NASA NTRSDate not supplied

More than RBE: Exploring Two Decades of Space Radiation Quality and Carcinogenesis Research and How NASA Manages Cancer Risk

NASA’s Space Radiation Element (SRE), both as a stand-alone entity and as part of the Human Research Program, has invested heavily into investigating how the different qualities of radiation and low dose rates relevant to the space environment and how these factors effect long term carcinogenesis risk. NASA’s current model to assess astronaut excess cancer risk due to radiation exposure utilizes data generated from both in vitro and in vivo models to inform quality factor and dose-rate functions that scales risk estimates originally established from human cohorts exposed to terrestrial radiation, most notably the Lifespan Study of atomic bomb survivors (LSS). As part of an effort to update these quality function, the SRE hosted a workshop in on radiation quality in September 2021 and a workshop on dose-rate at NASA HRP’s Investigators’ Workshop in February 2022 where current and former grantees presented data that could potentially be incorporated into assessing carcinogenic risk. This presentation is intended to both inform the broader research community of the outcome of those workshops and generate a discussion as to what biological data should be generated to better inform NASA’s risk estimates. Additionally, NASA’s current risk disposition for cancer assessment will be discussed and clarified. We look forward to hearing feedback from the Radiation Research Society community!

Brock J Sishc↗
NASA NTRS2005

DNA Damage by Ionizing Radiation: Tandem Double Lesions by Charged Particles

Oxidative damages by ionizing radiation are the source of radiation-induced carcinogenesis, damage to the central nervous system, lowering of the immune response, as well as other radiation-induced damages to human health. Monte Carlo track simulations and kinetic modeling of radiation damages to the DNA employ available molecular and cellular data to simulate the biological effect of high and low LET radiation io the DNA. While the simulations predict single and double strand breaks and base damages, so far all complex lesions are the result of stochastic coincidence from independent processes. Tandem double lesions have not yet been taken into account. Unlike the standard double lesions that are produced by two separate attacks by charged particles or radicals, tandem double lesions are produced by one single attack. The standard double lesions dominate at the high dosage regime. On the other hand, tandem double lesions do not depend on stochastic coincidences and become important at the low dosage regime of particular interest to NASA. Tandem double lesions by hydroxyl radical attack of guanine in isolated DNA have been reported at a dosage of radiation as low as 10 Gy. The formation of two tandem base lesions was found to be linear with the applied doses, a characteristic of tandem lesions. However, tandem double lesions from attack by a charged particle have not been reported.

Huo, Winifred M.↗
NASA NTRS2003

Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects

The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.

Review, Tutorial↗
NASA NTRS1996

Possible effects of protracted exposure on the additivity of risks from space radiations

Conventional radiation risk assessments are presently based on the additivity assumption. This assumption states that risks from individual components of a complex radiation field involving many different types of radiation can be added to yield the total risk of the complex radiation field. If the assumption is not correct, the summations and integrations performed to obtain the presently quoted risk estimates are not appropriate. This problem is particularly important in the area of space radiation risk evaluation because of the many different types of high- and low-LET radiation present in the galactic cosmic ray environment. For both low- and high-LET radiations at low enough dose rates, the present convention is that the addivity assumption holds. Mathematically, the total risk, Rtot is assumed to be Rtot = summation (i) Ri where the summation runs over the different types of radiation present. If the total dose (or fluence) from each component is such that the interaction between biological lesions caused by separate single track traversals is negligible within a given cell, it is presently considered to be reasonable to accept the additivity assumption. However, when the exposure is protracted over many cell doubling times (as will be the case for extended missions to the moon or Mars), the possibility exists that radiation effects that depend on multiple cellular events over a long time period, such as is probably the case in radiation-induced carcinogenesis, may not be additive in the above sense and the exposure interval may have to be included in the evaluation procedure. It is shown, however, that "inverse" dose-rate effects are not expected from intermediate LET radiations arising from the galactic cosmic ray environment due to the "sensitive-window-in-the-cell-cycle" hypothesis.

NASA Discipline Number 45-10↗
NASA NTRS2003

Radiation-induced second cancers: the impact of 3D-CRT and IMRT

Information concerning radiation-induced malignancies comes from the A-bomb survivors and from medically exposed individuals, including second cancers in radiation therapy patients. The A-bomb survivors show an excess incidence of carcinomas in tissues such as the gastrointestinal tract, breast, thyroid, and bladder, which is linear with dose up to about 2.5 Sv. There is great uncertainty concerning the dose-response relationship for radiation-induced carcinogenesis at higher doses. Some animal and human data suggest a decrease at higher doses, usually attributed to cell killing; other data suggest a plateau in dose. Radiotherapy patients also show an excess incidence of carcinomas, often in sites remote from the treatment fields; in addition there is an excess incidence of sarcomas in the heavily irradiated in-field tissues. The transition from conventional radiotherapy to three-dimensional conformal radiation therapy (3D-CRT) involves a reduction in the volume of normal tissues receiving a high dose, with an increase in dose to the target volume that includes the tumor and a limited amount of normal tissue. One might expect a decrease in the number of sarcomas induced and also (less certain) a small decrease in the number of carcinomas. All around, a good thing. By contrast, the move from 3D-CRT to intensity-modulated radiation therapy (IMRT) involves more fields, and the dose-volume histograms show that, as a consequence, a larger volume of normal tissue is exposed to lower doses. In addition, the number of monitor units is increased by a factor of 2 to 3, increasing the total body exposure, due to leakage radiation. Both factors will tend to increase the risk of second cancers. Altogether, IMRT is likely to almost double the incidence of second malignancies compared with conventional radiotherapy from about 1% to 1.75% for patients surviving 10 years. The numbers may be larger for longer survival (or for younger patients), but the ratio should remain the same.

Review, Tutorial↗
NASA NTRSDate not supplied

The Potential Outcome Model: Explaining Low-Dose Radiobiology through an Epidemiologic Lens

One of the major challenges in understanding space radiation-induced carcinogenesis is the uncertainty from translating radiobiological research in cellular and animal models to humans, especially at doses below 100 mSv. Biological studies have shown a host of potential outcomes at lowdoses in animal and cellular models. The existence of non-targeted effects as bystander and abscopal effects is well-documented from clinical research and basic science1,2,3. While some studies have shown increased effects at low doses, others have shown evidence of hormetic bystander effects, where radiation exposure may be beneficial4,5,6. Despite these varied and diverse findings, epidemiologic studies largely support the linear-no threshold (LNT) assumption used by radiation protection guidance7,8. Translational animal-to-human models have predominantly considered ratio values such as the relative biological effectiveness (RBE) and dose and dose-rate effectiveness factor (DDREF) that rely on the assumption of LNT rather than implementing specific dose-response shapes in the low-dose region, and translational cell-to-human models are uncommon. The sufficient component cause model presents an opportunity to examine biological findings at low doses from an epidemiological lens9. In this model, exposures “sufficient” to cause an outcome of interest are presented in pie charts, such that when all slices of a pie chart are fulfilled, the outcome will occur. Multiple pie charts may exist for a single outcome, illustrating individual differences9. In 1988,Greenland and Poole adapted the sufficient component cause model to incorporate interaction with other exposures (such as genetics or lifestyle factors)10. They show that a range of biological processes are possible in a population, but that an epidemiologic study will only reveal the mean outcome from the population at large10,11. Using this construct, the multiple outcomes presented in radiobiological models to date can be explained in the context of epidemiologic studies. This presentation aims to demonstrate a causal framework that can integrate radiobiological and epidemiological models to date. It is intended as a conversation starter to spur future research.

C M Milder↗
NASA NTRSDate not supplied

The Sufficient Component Cause Model Explaining Low-Dose Radiobiology through an Epidemiologic Lens

One of the major challenges in understanding space radiation-induced carcinogenesis is the uncertainty from translating radiobiological research in cellular and animal models to humans, especially at doses below 100 mSv. Biological studies have shown a host of potential outcomes at low doses in animal and cellular models. The existence of non-targeted effects as bystander and abscopal effects is well-documented from clinical research and basic science1,2,3. While some studies have shown increased effects at low doses, others have shown evidence of hormetic bystander effects, where radiation exposure may be beneficial4,5,6. Despite these varied and diverse findings, epidemiologic studies largely support the linear-no threshold (LNT) assumption used by radiation protection guidance7,8. Translational animal-to-human models have predominantly considered ratio values such as the relative biological effectiveness (RBE) and dose and dose-rate effectiveness factor (DDREF) that rely on the assumption of LNT rather than implementing specific dose-response shapes in the low-dose region, and translational cell-to-human models are uncommon. The sufficient component cause model presents an opportunity to examine biological findings at low doses from an epidemiological lens9. In this model, exposures “sufficient” to cause an outcome of interest are presented in pie charts, such that when all slices of a pie chart are fulfilled, the outcome will occur. Multiple pie charts may exist for a single outcome, illustrating individual differences9. In 1988,Greenland and Poole adapted the sufficient component cause model to incorporate interaction with other exposures (such as genetics or lifestyle factors)10. They show that a range of biological processes are possible in a population, but that an epidemiologic study will only reveal the mean outcome from the population at large10,11. Using this construct, the multiple outcomes presented in radiobiological models to date can be explained in the context of epidemiologic studies. This presentation aims to demonstrate a causal framework that can integrate radiobiological and epidemiological models to date. It is intended as a conversation starter to spur future research.

C M Milder↗
NASA NTRSDate not supplied

Biological Space Radiation Countermeasures to Enable Long Duration Exploration Missions

NASA’s career radiation limit for astronauts is 600 mSv. Currently planned missions beyond low Earth orbit (LEO) will expose crew to at least double that amount of radiation (for Mars missions). Therefore, to enable long duration exploration, countermeasures need to be deployed to reduce the long-term health outcomes of space radiation exposure. Limitations to the ability of spacecraft to shield against the high energy charged particles of the space radiation environment necessitate alternative methods to reduce overall space radiation risk for carcinogenesis. Recent successes in the arenas of Acute Radiation Syndrome (ARS) and clinical radiotherapy have demonstrated the efficacy of compound-based/biologicals in reducing the detrimental long term health outcomes associated with space radiation exposure. In recent years, the Space Radiation Element has funded the investigation of several such compounds including Avasopasem Manganese, CDDO-Me, Metformin, and γ-tocotrienol. The demonstrated efficacy of these compounds in reducing carcinogenesis, central nervous system, and cardiovascular disease risks demonstrate the need for, and potential benefit of, a robust countermeasure identification and development program with an initial starting suite of compounds available to validate others. The authors would also like to present highlights of a recent Space Radiation Element sponsored issue of Life Sciences in Space Research entitled “Breaking the Limit” on this specific topic.

Space Radiation↗
DOE OSTI2024

Dosimetric and biological impact of activity extravasation of radiopharmaceuticals in PET imaging

The increasing use of nuclear medicine and PET imaging has intensified scrutiny of radiotracer extravasation. To our knowledge, this topic is understudied but holds great potential for enhancing our understanding of extravasation in clinical PET imaging. This work aims to (1) quantify the absorbed doses from radiotracer extravasation in PET imaging, both locally at the site of extravasation and with the extravasation location as a source of exposure to bodily organs and (2) assess the biological ramifications within the injection site at the cellular level. A radiation dosimetry simulation was performed using a whole-body 4D Extended Cardiac-Torso (XCAT) phantom embedded in the GATE Monte Carlo platform. A 10-mCi dose of 18 F-FDG was chosen to simulate a typical clinical PET scan scenario, with 10% of the activity extravasated in the antecubital fossa of the right arm of the phantom. The extravasation volume was modeled as a 5.5 mL rectangle in the hypodermal layer of skin. Absorbed dose contributions were calculated for the first two half-lives, assuming biological clearance thereafter. Dose calculations were performed as absorbed doses at the organ and skin levels. Energy deposition was simulated both at the local extravasation site and in multiple organs of interest and converted to absorbed doses based on their respective masses. Each simulation was repeated ten times to estimate Monte Carlo uncertainties. Biological impacts on cells within the extravasated volume were evaluated by randomizing cells and exposing them to a uniform radiation source of 18 F and 68 Ga. Particle types, their energies, and direction cosines were recorded in phase space files using a separate Geant4 simulation to characterize their entry into the nucleus of the cellular volume. Subsequently, the phase space files were imported into the TOPAS-nBio simulation to assess the extent of DNA damage, including double-strand breaks (DSBs) and single-strand breaks (SSBs). Organ-level dosimetric estimations are presented for 18 F and 68 Ga radionuclides in various organs of interest. With 10% extravasation, the hypodermal layer of the skin received the highest absorbed dose of 1.32 ± 0.01 Gy for 18 F and 0.99 ± 0.01 Gy for 68 Ga. The epidermal and dermal layers received absorbed doses of 0.07 ± 0.01 Gy and 0.13 ± 0.01 Gy for 18 F, and 0.14 ± 0.01 Gy and 0.29 ± 0.01 Gy for 68 Ga, respectively. In the extravasated volume, 18 F caused an average absorbed dose per nucleus of 0.17 ± 0.01 Gy, estimated to result in 10.58 ± 0.50 DSBs and 268.11 ± 12.43 SSBs per nucleus. For 68 Ga, the absorbed dose per nucleus was 0.11 ± 0.01 Gy, leading to an estimated 6.49 ± 0.34 DSBs and 161.24 ± 8.12 SSBs per nucleus. Absorbed doses in other organs were on the order of micro-gray (µGy). The likelihood of epidermal erythema resulting from extravasation during PET imaging is low, as the simulated absorbed doses to the epidermis remain below the thresholds that trigger such effects. Moreover, the organ-level absorbed doses were found to be clinically insignificant across various simulated organs. The minimal DNA damage at the extravasation site suggests that long-term harm, such as radiation-induced carcinogenesis, is highly unlikely.

DNA strand breaks↗
NASA NTRS2017

Mind the Gap: Exploring the Underground of the NASA Space Cancer Risk Model

The REID quantifies the lifetime risk of death from radiation-induced cancer in an exposed astronaut. The NASA Space Cancer Risk (NSCR) 2012 mode incorporates elements from physics, biology, epidemiology, and statistics to generate the REID distribution. The current model quantifies the space radiation environment, radiation quality, and dose-rate effects to estimate a NASA-weighted dose. This weighted dose is mapped to the excess risk of radiation-induced cancer mortality from acute exposures to gamma rays and then transferred to an astronaut population. Finally, the REID is determined by integrating this risk over the individual's lifetime. The calculated upper 95% confidence limit of the REID is used to restrict an astronaut's permissible mission duration (PMD) for a proposed mission. As a statistical quantity characterized by broad, subjective uncertainties, REID estimates for space missions result in wide distributions. Currently, the upper 95% confidence level is over 350% larger than the mean REID value, which can severely limit an astronaut's PMD. The model incorporates inputs from multiple scientific disciplines in the risk estimation process. Physics and particle transport models calculate how radiation moves through space, penetrates spacecraft, and makes its way to the human beings onboard. Epidemiological studies of exposures from atomic bombings, medical treatments, and power plants are used to quantify health risks from acute and chronic low linear energy transfer (LET) ionizing radiation. Biological studies in cellular and animal models using radiation at various LETs and energies inform quality metrics for ions present in space radiation. Statistical methodologies unite these elements, controlling for mathematical and scientific uncertainty and variability. Despite current progress, these research platforms contain knowledge gaps contributing to the large uncertainties still present in the model. The NASA Space Radiation Program Element (SRPE) defines the knowledge gaps that impact our understanding of the cancer risks. These gaps are outlined in NASA's Human Research Roadmap [4], which identifies the research questions and actions recommended for reducing the uncertainty in the current NSCR model and for formulation of future models. The greatest contributors to uncertainty in the current model include radiation quality, dose rate effects, and the transfer of exposure-based risk from other populations to an astronaut population. Future formulations of the risk model may benefit from including other potential sources of uncertainty such as space dosimetry, errors in human epidemiology data, and the impact of microgravity and other spaceflight stressors. Here, we discuss the current capabilities of the NSCR-2012 model and several immediate research needs, highlighting areas expected to have an operational impact on the current model schema. The following subway-style route map outlines the NSCR-2012 model (Green Line), emphasizing the research gaps in the Human Research Roadmap for risk of radiation-induced carcinogenesis (Stops on Dashed Lines). The map diagrams how these research gaps feed specific portions of the model.

Chappell, L. J.↗
NASA NTRSDate not supplied

Biological Space Radiation Countermeasures to Enable Long Duration Exploration Missions

NASA’s career radiation limit for astronauts is 600 mSv. Currently planned missions beyond low Earth orbit (LEO) will expose crew to at least double that amount of radiation (for Mars missions). Therefore, to enable long duration exploration, countermeasures need to be deployed to reduce the long-term health outcomes of space radiation exposure. Limitations to the ability of spacecraft to shield against the high energy charged particles of the space radiation environment necessitate alternative methods to reduce overall space radiation risk for carcinogenesis. Recent successes in the arenas of Acute Radiation Syndrome (ARS) and clinical radiotherapy have demonstrated the efficacy of compound-based/biologicals in reducing the detrimental long term health outcomes associated with space radiation exposure. In recent years, the Space Radiation Element has funded the investigation of several such compounds including Avasopasem Manganese, CDDO-Me, Metformin, and γ-tocotrienol. The demonstrated efficacy of these compounds in reducing carcinogenesis, central nervous system, and cardiovascular disease risks demonstrate the need for, and potential benefit of, a robust countermeasure identification and development program with an initial starting suite of compounds available to validate others. The authors would also like to present highlights of a recent Space Radiation Element sponsored issue of Life Sciences in Space Research entitled “Breaking the Limit” on this specific topic.

Space Radiation↗
NASA NTRS2015

Prototype Biology-Based Radiation Risk Module Project

Biological effects of space radiation and risk mitigation are strategic knowledge gaps for the Evolvable Mars Campaign. The current epidemiology-based NASA Space Cancer Risk (NSCR) model contains large uncertainties (HAT #6.5a) due to lack of information on the radiobiology of galactic cosmic rays (GCR) and lack of human data. The use of experimental models that most accurately replicate the response of human tissues is critical for precision in risk projections. Our proposed study will compare DNA damage, histological, and cell kinetic parameters after irradiation in normal 2D human cells versus 3D tissue models, and it will use a multi-scale computational model (CHASTE) to investigate various biological processes that may contribute to carcinogenesis, including radiation-induced cellular signaling pathways. This cross-disciplinary work, with biological validation of an evolvable mathematical computational model, will help reduce uncertainties within NSCR and aid risk mitigation for radiation-induced carcinogenesis.

Terrier, Douglas↗
NASA NTRS2018

Abortive Apoptosis and Its Profound Effects on Radiation, Chemical, and Oncogene-Induced Carcinogenesis

Traditionally apoptosis and the apoptotic machinery have been deemed as anti‐carcinogenic because of their presumed roles in eliminating damaged or unwanted cells. However, recent work from our laboratory and others have shown that the established paradigm is deeply flawed. The fundamental flaw is the assumption that apoptosis, once initiated, is irreversible and invariably leads to cell death. However, there is increasing evidence that cells can survive activation of the apoptotic cascade. This new revelation about abortive apoptotic cells can dramatically change our assessment of the biological roles of apoptosis. In this brief review, we will cover some of the original studies that report the "undead" apoptotic cells and how they lead to unexpected new roles for apoptotic factors in space radiation and other stress induced genetic instability and carcinogenesis. We will also review exciting new discoveries on the association among abortive apoptosis, spontaneous DNA double strand breaks, DNA damage response, and stemness of cancer cells.

Liu, Xinjian↗
NASA NTRS1999

[Radiation Anticarcinogenesis by Thiazolidine Pro-drug]

The original goal of this work was to determine the capacity of selected aminothiols to modulate radiation induced cytotoxicity, mutagenesis and carcinogenesis in a human mammary epithelial cell line. The conclusions from this work are that WR-1065 is the "gold standard" for protection against radiation induced cytotoxicity, mutagenesis and carcinogenesis. While a potent radiation protector, WR-1065 is cytotoxic in vitro and in vivo. Our rationale for a study of the thiazolidine pro-drugs was that these compounds are neither toxic in vitro or in vivo. The results obtained during this funding period indicate that the thiazolidine pro-drugs are as potent as WR-1065 as protectors against radiation induced mutation induction, and thus presumably against radiation induced carcinogenesis. Our results indicate that the thiazolidine prodrugs are excellent candidates to test as non-toxic anticarcinogens for protecting astronauts from cancer induction during space travel.

Warters, Raymond L.↗
NASA NTRS2010

Influence of Ionizing Radiation on Stromal-Epithelial Intercellular Communication in Esophageal Carcinogenesis

Esophageal cancer is the 6th leading cause of cancer death worldwide. Its development is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. An association with ionizing radiation exposure is revealed by the high excess relative risk for squamous cell carcinoma of the esophagus observed in the survivors of the atomic bomb detonations in Japan. It is also seen as a secondary malignancy in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely curable. The stromal microenvironment plays an essential role in the maintenance and modulation of normal epithelial cell growth and differentiation and cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibroblasts (Okawa et al., Genes & Dev. 2007. 21: 2788-2803). We examined how radiation treatment of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. Chemotactic and haptotactic migration of epithelial cells stimulated by conditioned media from irradiated fibroblasts was measured using assays conducted in Transwell cell culture chambers. Our results using low LET radiation showed a dose-dependent increase in migration of epithelial cells when exposed to conditioned media from irradiated vs. non-irradiated fibroblasts. We also observed enhanced invasion through a basement membrane simulant. To identify chemotactic proteins secreted by irradiated stromal fibroblasts, we used antibody capture cytokine arrays and have identified several proteins as candidates. Increased secretion of these factors by irradiated fibroblasts was confirmed using ELISA. We are currently analyzing the contribution of these individual factors on epithelial migration and invasion, as well as their influence on cell survival and DNA repair. Studies using high-LET radiation will help determine radiation quality effects on these processes. These results should further our understanding of the mechanisms by which radiation impacts the tissue microenvironment and how it influences cancer development processes.

Patel, Zarana S.↗