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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 NTRS1993

Automated System for Early Breast Cancer Detection in Mammograms

The increasing demand on mammographic screening for early breast cancer detection, and the subtlety of early breast cancer signs on mammograms, suggest an automated image processing system that can serve as a diagnostic aid in radiology clinics. We present a fully automated algorithm for detecting clusters of microcalcifications that are the most common signs of early, potentially curable breast cancer. By using the contour map of the mammogram, the algorithm circumvents some of the difficulties encountered with standard image processing methods. The clinical implementation of an automated instrument based on this algorithm is also discussed.

Bankman, Isaac N.↗

NASA NTRS2001

Cancer Risk Assessment for Space Radiation

Predicting the occurrence of human cancer following exposure to any agent causing genetic damage is a difficult task. This is because the uncertainty of uniform exposure to the damaging agent, and the uncertainty of uniform processing of that damage within a complex set of biological variables, degrade the confidence of predicting the delayed expression of cancer as a relatively rare event within any given clinically normal individual. The radiation health research priorities for enabling long-duration human exploration of space were established in the 1996 NRC Report entitled 'Radiation Hazards to Crews of Interplanetary Missions: Biological Issues and Research Strategies'. This report emphasized that a 15-fold uncertainty in predicting radiation-induced cancer incidence must be reduced before NASA can commit humans to extended interplanetary missions. That report concluded that the great majority of this uncertainty is biologically based, while a minority is physically based due to uncertainties in radiation dosimetry and radiation transport codes. Since that report, the biologically based uncertainty has remained large, and the relatively small uncertainty associated with radiation dosimetry has increased due to the considerations raised by concepts of microdosimetry. In a practical sense, however, the additional uncertainties introduced by microdosimetry are encouraging since they are in a direction of lowered effective dose absorbed through infrequent interactions of any given cell with the high energy particle component of space radiation. Additional information is contained in the original extended abstract.

Richmond, Robert C.↗

NASA NTRS1998

Cancer Detection Device

Ratcom, Inc., has joined NASA Johnson Space Center in an active program to develop cytometry capabilities for space station freedom. This agreement results from a cooperative program that NASA entered into with the American Cancer Society to aid in cancer prevention, diagnosis, and treatment. The flow cytometer is used by cancer researchers to make cellular measurements.

Source record↗

NASA NTRS2002

Cancer Risk-Assessment of Radiation Damage in Ataxia Telangiectasia Heterozygous Human Breast Epithelial Cell Cultures

This paper describes the study of the markers of cellular changes that are found during the onset of carcinogenesis. Several of the biological factors are markers of stress response, oncoprotein expression, and differentiation factors. Oxidative stress response agents such as heat shock proteins (HSPs) protect cells from oxidative stresses such as ionizing radiation. The onocoprotein HER-2/neu, a specific breast cancer marker, indicates early onset of cancer. Additional structural and morphogenetic markers of differentiation were considered in order to determine initial cellular changes at the initial onset of cancer. As an additional consideration, all-trans retinoic acid (RA), a differentiation agent, was considered because of its known role in regulating normal differentiation and inhibiting tumor proliferation via specific nuclear receptors. This paper discusses study and results of the preliminary analyses of gamma irradiation of AT heterozygous human breast epithelial cells (WH). Comparisons are also made of the effects various RA concentrations post-irradiation.

Lisa C. Applewhite↗

NASA NTRS2001

Space Radiation Cancer Risks and Uncertainties for Mars Missions

Projecting cancer risks from exposure to space radiation is highly uncertain because of the absence of data for humans and because of the limited radiobiology data available for estimating late effects from the high-energy and charge (HZE) ions present in the galactic cosmic rays (GCR). Cancer risk projections involve many biological and physical factors, each of which has a differential range of uncertainty due to the lack of data and knowledge. We discuss an uncertainty assessment within the linear-additivity model using the approach of Monte Carlo sampling from subjective error distributions that represent the lack of knowledge in each factor to quantify the overall uncertainty in risk projections. Calculations are performed using the space radiation environment and transport codes for several Mars mission scenarios. This approach leads to estimates of the uncertainties in cancer risk projections of 400-600% for a Mars mission. The uncertainties in the quality factors are dominant. Using safety standards developed for low-Earth orbit, long-term space missions (>90 days) outside the Earth's magnetic field are currently unacceptable if the confidence levels in risk projections are considered. Because GCR exposures involve multiple particle or delta-ray tracks per cellular array, our results suggest that the shape of the dose response at low dose rates may be an additional uncertainty for estimating space radiation risks.

NASA Discipline Radiation Health↗

NASA NTRS2001

Fatty acid regulates gene expression and growth of human prostate cancer PC-3 cells

It has been proposed that the omega-6 fatty acids increase the rate of tumor growth. Here we test that hypothesis in the PC-3 human prostate tumor. We found that the essential fatty acids, linoleic acid (LA) and arachidonic acid (AA), and the AA metabolite PGE(2) stimulate tumor growth while oleic acid (OA) and the omega-3 fatty acid, eicosapentaenoic acid (EPA) inhibited growth. In examining the role of AA in growth response, we extended our studies to analyze changes in early gene expression induced by AA. We demonstrate that c-fos expression is increased within minutes of addition in a dose-dependent manner. Moreover, the immediate early gene cox-2 is also increased in the presence of AA in a dose-dependent manner, while the constitutive cox-1 message was not increased. Three hours after exposure to AA, the synthesis of PGE(2) via COX-2 was also increased. Previous studies have demonstrated that AA was primarily delivered by low density lipoprotein (LDL) via its receptor (LDLr). Since it is known that hepatomas, acute myelogenous leukemia and colorectal tumors lack normal cholesterol feedback, we examined the role of the LDLr in growth regulation of the PC-3 prostate cancer cells. Analysis of ldlr mRNA expression and LDLr function demonstrated that human PC-3 prostate cancer cells lack normal feedback regulation. While exogenous LDL caused a significant stimulation of cell growth and PGE(2) synthesis, no change was seen in regulation of the LDLr by LDL. Taken together, these data show that normal cholesterol feedback of ldlr message and protein is lost in prostate cancer. These data suggest that unregulated over-expression of LDLr in tumor cells would permit increased availability of AA, which induces immediate early genes c-fos and cox-2 within minutes of uptake.

NASA Discipline Cell Biology↗

NASA NTRS2000

Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

NASA Program Fundamental Space Biology↗

NASA NTRS1999

Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such understanding is critical in extrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool for such extrapolation.

Non-NASA Center↗

NASA NTRS2005

Managing Lunar and Mars Mission Radiation Risks: Cancer Risks, Uncertainties, and Shielding Effectiveness - Part 1

This document addresses calculations of probability distribution functions (PDFs) representing uncertainties in projecting fatal cancer risk from galactic cosmic rays (GCR) and solar particle events (SPEs). PDFs are used to test the effectiveness of potential radiation shielding approaches. Monte-Carlo techniques are used to propagate uncertainties in risk coefficients determined from epidemiology data, dose and dose-rate reduction factors, quality factors, and physics models of radiation environments. Competing mortality risks and functional correlations in radiation quality factor uncertainties are treated in the calculations. The cancer risk uncertainty is about four-fold for lunar and Mars mission risk projections. For short-stay lunar missins (<180 d), SPEs present the most significant risk, but one effectively mitigated by shielding. For long-duration (>180 d) lunar or Mars missions, GCR risks may exceed radiation risk limits. While shielding materials are marginally effective in reducing GCR cancer risks because of the penetrating nature of GCR and secondary radiation produced in tissue by relativisitc particles, polyethylene or carbon composite shielding cannot be shown to significantly reduce risk compared to aluminum shielding. Therefore, improving our knowledge of space radiobiology to narrow uncertainties that lead to wide PDFs is the best approach to ensure radiation protection goals are met for space exploration.

Cucinotta, Francis A.↗

NASA NTRS2007

Space Radiation Cancer Risks

Space radiation presents major challenges to astronauts on the International Space Station and for future missions to the Earth s moon or Mars. Methods used to project risks on Earth need to be modified because of the large uncertainties in projecting cancer risks from space radiation, and thus impact safety factors. We describe NASA s unique approach to radiation safety that applies uncertainty based criteria within the occupational health program for astronauts: The two terrestrial criteria of a point estimate of maximum acceptable level of risk and application of the principle of As Low As Reasonably Achievable (ALARA) are supplemented by a third requirement that protects against risk projection uncertainties using the upper 95% confidence level (CL) in the radiation cancer projection model. NASA s acceptable level of risk for ISS and their new lunar program have been set at the point-estimate of a 3-percent risk of exposure induced death (REID). Tissue-averaged organ dose-equivalents are combined with age at exposure and gender-dependent risk coefficients to project the cumulative occupational radiation risks incurred by astronauts. The 95% CL criteria in practice is a stronger criterion than ALARA, but not an absolute cut-off as is applied to a point projection of a 3% REID. We describe the most recent astronaut dose limits, and present a historical review of astronaut organ doses estimates from the Mercury through the current ISS program, and future projections for lunar and Mars missions. NASA s 95% CL criteria is linked to a vibrant ground based radiobiology program investigating the radiobiology of high-energy protons and heavy ions. The near-term goal of research is new knowledge leading to the reduction of uncertainties in projection models. Risk projections involve a product of many biological and physical factors, each of which has a differential range of uncertainty due to lack of data and knowledge. The current model for projecting space radiation cancer risk relies on the three assumptions of linearity, additivity, and scaling along with the use of population averages. We describe uncertainty estimates for this model, and new experimental data that sheds light on the accuracy of the underlying assumptions. These methods make it possible to express risk management objectives in terms of quantitative metrics, i.e., the number of days in space without exceeding a given risk level within well defined confidence limits. The resulting methodology is applied to several human space exploration mission scenarios including lunar station, deep space outpost, and a Mars mission. Factors that dominate risk projection uncertainties and application of this approach to assess candidate mitigation approaches are described.

Cucinotta, Francis A.↗

NASA NTRS2003

A Virtual Bioinformatics Knowledge Environment for Early Cancer Detection

Discovery of disease biomarkers for cancer is a leading focus of early detection. The National Cancer Institute created a network of collaborating institutions focused on the discovery and validation of cancer biomarkers called the Early Detection Research Network (EDRN). Informatics plays a key role in enabling a virtual knowledge environment that provides scientists real time access to distributed data sets located at research institutions across the nation. The distributed and heterogeneous nature of the collaboration makes data sharing across institutions very difficult. EDRN has developed a comprehensive informatics effort focused on developing a national infrastructure enabling seamless access, sharing and discovery of science data resources across all EDRN sites. This paper will discuss the EDRN knowledge system architecture, its objectives and its accomplishments.

knowledge systems↗

NASA NTRS2011

CPRIT/Johnson Space Center, September, 2011 (Cancer Prevention and Research Institute of Texas)

JSC researchers study carcinogenesis, cancer prevention and treatment along with epidemiological (primarily retrospective and longitudinal) studies, modeling, and interactions with the environment such as radiation, nutritional, and endocrine changes related to space flight along with behaviors such as smoking. Cancer research is a major focus for human space flight due to the exposure to space radiation which consists of particles of varying charges and energies, and secondary neutrons. The JSC laboratories collaborate with investigators from the U.S. as well as our European and Japanese partners. We use accelerator facilities at the Brookhaven National Laboratory, Loma Linda University and Los Alamos National Laboratory that generate high energy charged particles and neutrons to simulate cosmic radiation and solar particle events. The research using cultured cells and animals concentrates on damage and repair from the level of DNA to organ tissues, due to exposure to simulated space radiation exposure, that contribute to the induction of leukemia and solid tumors in most major tissues such as lung, colon, liver and breast. The goal of the research is to develop a mathematical model that can predict cancer morbidity and mortality risks with sufficient accuracy for a given space mission.

Davis, Jeffrey↗

NASA NTRS2011

Space Radiation Cancer Risk Projections and Uncertainties - 2010

Uncertainties in estimating health risks from galactic cosmic rays greatly limit space mission lengths and potential risk mitigation evaluations. NASA limits astronaut exposures to a 3% risk of exposure-induced death and protects against uncertainties using an assessment of 95% confidence intervals in the projection model. Revisions to this model for lifetime cancer risks from space radiation and new estimates of model uncertainties are described here. We review models of space environments and transport code predictions of organ exposures, and characterize uncertainties in these descriptions. We summarize recent analysis of low linear energy transfer radio-epidemiology data, including revision to Japanese A-bomb survivor dosimetry, longer follow-up of exposed cohorts, and reassessments of dose and dose-rate reduction effectiveness factors. We compare these projections and uncertainties with earlier estimates. Current understanding of radiation quality effects and recent data on factors of relative biological effectiveness and particle track structure are reviewed. Recent radiobiology experiment results provide new information on solid cancer and leukemia risks from heavy ions. We also consider deviations from the paradigm of linearity at low doses of heavy ions motivated by non-targeted effects models. New findings and knowledge are used to revise the NASA risk projection model for space radiation cancer risks.

Cucinotta, Francis A.↗

NASA NTRS2017

Determination of the Risk of Radiation-Associated Circulatory and Cancer Disease Mortality in a NASA Early Astronaut Cohort

Of the many possible health challenges posed during extended exploratory missions to space, the effects of space radiation on cardiovascular disease and cancer are of particular concern. There are unique challenges to estimating those radiation risks; care and appropriate and rigorous methodology should be applied when considering small cohorts such as the NASA astronaut population. The objective of this work was to determine if there was sufficient evidence for excess risk of cardiovascular disease and cancer in early NASA astronaut cohorts. NASA astronauts in selection groups 1-7 were chosen; this relatively homogeneous cohort consists of 73 white males, who unlike today's astronauts, maintained similar smoking and drinking habits to the general US population, and have published radiation doses. The participants flew in space on missions Mercury through Shuttle and received space radiation doses between 0-74.1 milligrays. Cause of death information was obtained from the Lifetime Surveillance of Astronaut Health (LSAH) program at NASA Johnson Space Center. Mortality was compared with the US male population. Trends of mortality with dose were assessed using a logistic model, fitted by maximum likelihood. Only 32 (43.84 percent) of the 73 early astronauts have died. Standard mortality ratios (SMRs) for cancer (n=7, SMR=43.4, 95 percent CI 17.8, 84.9), all circulatory disease (n=7, SMR=33.2, 95 percent CI 13.7, 65.0), and ischemic heart disease (IHD) (n=5, SMR=40.1, 95 percent CI 13.2, 89.4) were significantly lower than for the US white male population. For cerebrovascular disease, the upper confidence interval for SMR included 100, indicating it was not significantly different from the US population (n=2, SMR = 77.0, 95 percent CI 9.4, 268.2). The power of the study is low and remains below 10 percent even when risks 10 times those reported in the literature are assumed. Due to small sample size, there is currently insufficient statistical power to evaluate space radiation exposure effects on mortality in NASA astronauts. In addition to a comprehensive longitudinal study of NASA astronauts, a research strategy of low dose epidemiology data integration with cell and animal studies should be utilized for space radiation risk assessment in the astronauts.

Elgart, S. R.↗

NASA NTRS2018

Track Structure and the Quality Factor for Space Radiation Cancer Risk

A major risk from exposure to space radiation is the induction of cancer and it is from estimates of this risk that the maximum career flight times of NASA space crew members are restricted by a permissible exposure limit. For the purpose of demonstrating compliance with the career limit, NASA has developed a cancer risk projection model for exposure-induced fatal cancer, in which the formulation and numerical values of the quality factor (QFNASA) are substantially different from those of the quality factor (Q) or radiation weighting factor (wR) routinely applied for radiation protection on earth. The quality factor is used to account for the increased effectiveness of radiations of high linear energy transfer (LET), compared to the effectiveness of low-LET γ-rays derived from epidemiological studies of the atomic-bomb survivors. The need for a special approach for space radiation is dictated by the special characteristics of the charged particles from solar radiation and especially the charged particles of high energy and charge (HZE) in galactic cosmic rays (GCR). This article considers aspects of radiation track structure in relation to the relative biological effectiveness (RBE) of HZE particles and the quality factor used for space radiation. The NASA quality factor (QFNASA) is composed of two terms, which can be interpreted as broadly representing the low- and the high-ionization-density components of the HZE particle tracks. These are discussed in turn as they relate to available experimental evidence on the biological effectiveness of such components. Also briefly described are subsequent published proposals for a reformulation of the quality factor to relate more directly to the acute γ-ray exposures from the atomic bombs and for further refinement of the parameter values (and their uncertainties) that determine the shape of the quality factor function. Other recent developments are also mentioned.

Mullenax, Carol A.↗

NASA NTRSDate not supplied

BLOOD-BASED MULTI-SCALE MODEL FOR CANCER RISK FROM GCR IN GENETICALLY DIVERSE POPULATIONS

OBJECTIVES AND METHODS This project addresses the challenge of understanding and predicting individual radiation sensitivity by integrating genetics, demographics and biomarker characteristics across species (mice and humans). We hypothesize that ex vivo DNA repair response to GCR components is a central determinant of cancer risk from space radiation and can serve as a biomarker of radiation risk in combination with genetics. Automated image quantification of 53BP1+ radiation-induced foci (RIF) during the first 4-48 h post-irradiation was performed as a function of dose and LET in non-immortalized primary skin fibroblasts derived from 76 mice across 15 strains (5 inbred reference strains and 10 collaborative-cross strains) exposed to X rays (0.1, 1 and 4 Gy), 350 MeV/n 40Ar and 600 MeV/n 56Fe (1.1 and 3 particles/100μm2), as well as in peripheral blood mononuclear cells (PBMCs) from 768 healthy donors (matched ethnicity, 50/50 male/female, 18-70 years old) exposed to gamma rays (0.1 and 1 Gy), 350 MeV/n 28Si, 350 MeV/n 40Ar and 600 MeV/n 56Fe (1.1 and 3 particles/100μm2). QUANTIFICATION OF 53BP1+ FOCI IN VITRO AND ASSOCIATIONS TO IN VIVO RADIATION SUSCEPTIBILITY IN 15 MOUSE STRAINS We reported in vitro repair kinetic and repairable fractions of RIF for the 15 mouse strains and introduced a mathematical model for RIF as a function of time, dose and LET. We noted that the metabolic activity of cells modulates the RIF response, and we introduced the open access tool terRIFic (Tool for Enhanced Results of RIF In Cells, https://radbiolab.shinyapps.io/terrific/) to correct for such bias using confluence level. Notably, at 4h post-irradiation, RIF/Gy decreased with dose or LET: as the dose or LET increases, so does the proximity of DNA double-strand-breaks (DSB) and our data suggest that proximal DSBs are brought together inside isolated RIF for repair. The RIF/Gy trend was inverted at 24h, suggesting RIF with high DSB content are more difficult to repair. We showed that in vitro metrics correlate with in vivo measurements in the same 15 mouse strains, such as survival levels of immune cells or spontaneous cancer incidence, suggesting a relationship between the efficiency of DSB repair and cancer risk or radiation toxicity. In addition to the efficiency of repair and persistent RIF, the amount of spontaneous foci before irradiation was also found to be strain dependent. Finally, we performed genome-wide association study in the same 15 mouse strains using all RIF phenotypes measured in vitro, identifying genes of interest and validating RIF as an ideal biomarker for individual radiation sensitivity. BASELINE 53BP1+ FOCI PREDICTS INDIVIDUAL HUMAN RESPONSE TO GCR COMPONENTS Based on the analysis of radiation responses of 576 donor PBMCs (using quantification of 53BP1+ foci, oxidative stress and cell death), we observed a wide variability of subject- and LET-dependent radiation responses, with radiation-induced DNA repair foci increasing with LET, though oxidative stress being notably reduced by high-LET irradiation, potentially due to a switch between hydrogen peroxide and oxygen radical-based mechanisms. We identified a relationship between few spontaneous DNA foci at baseline and increased DNA repair after irradiation, accompanied by an alteration in immunoregulatory cytokine secretion, which might be adapted as biomarkers to predict ionizing radiation sensitivity. Among demographic variables, only latent cytomegalovirus infection and age were predictive of high baseline foci formation. Finally, we have performed low-throughput whole genome sequencing of all samples and are currently in the process of identifying the genes and pathways associated with low and high-LET ionizing radiation sensitivity in humans.

53BP1↗

NASA NTRS2020

Ensemble Methodologies for Astronaut Cancer Risk Assessment in the face of Large Uncertainties

A new approach to NASA space radiation risk modeling has successfully extended the current NASA probabilistic cancer risk model to an ensemble framework able to consider sub-model parameter uncertainty (e.g. uncertainty in a radiation quality parameter) as well as model-form uncertainty associated with differing theoretical or empirical formalisms (e.g. combined dose-rate and radiation quality effects). Ensemble methodologies are already widely used in weather prediction, modeling of infectious disease outbreaks, and certain terrestrial radiation protection applications to better understand how uncertainty may influence risk decision-making. Applying ensemble methodologies to space radiation risk projections offers the potential to efficiently incorporate emerging research results, allow for the incorporation of future (including international) models, improve uncertainty quantification for underlying sub-models developed against sparse experimental data, and reduce the impact of subjective bias on risk projections. Moreover, risk forecasting across an ensemble of multiple predictive models can provide stakeholders additional information on risk acceptance if current health/medical standards cannot be met or the level of knowledge doesn’t permit a specific risk or exposure limit to be developed for future space exploration missions. In this work, ensemble risk projections implementing multiple sub-models of radiation quality, dose and dose-rate effectiveness factors, excess risk, and latency as ensemble members are presented. Initial consensus methods for ensemble model weights and correlations to account for individual model bias are discussed. In these analyses, the ensemble forecast compares well to results from NASA's current operational cancer risk projection model used to assess permissible exposure limits and permissible mission durations for astronauts. However, a large range of projected risk values are obtained at the upper 95th confidence level where models must extrapolate beyond available biological data sets; closer agreement is seen at the median + one sigma due to the inherent similarities in available models. Future work, including the addition of new models and methods for statistical correlation between predictive members are discussed to define alternate ways of thinking about risk and ‘acceptable’ uncertainty with respect to NASA’s current permissible exposure limits.

space radiation↗