Simulating galactic cosmic ray effects: Synergy modeling of murine tumor prevalence after exposure to two one-ion beams in rapid sequence

Huang, Edward Greg; Wang, Ren-Yi; Xie, Li-Yang; Chang, Polly Y.; Yao, Gracie; Zhang, Borong; Ham, Dae Woong; Lin, Yimin; Blakely, Eleanor A.; Sachs, Rainer K.

doi:10.1016/j.lssr.2020.01.001

Cited by 16 publications

(34 citation statements)

References 26 publications

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“…Published results will inform our understanding of the sensitivity of biological response to the exact composition of the selected mixed-field particle species, to the order of ion delivery, to the possibility of synergy among components of the mixed GCR, and to the timing of beam delivery. Early results investigating synergy between various GCR ion beams on the prevalence of murine Harderian gland tumorigenesis have been published [30], which illustrate the importance of considering the physics of space radiation interactions in tissue, such as the information presented here in the development of the simulator, to interpret biological responses to mixed-field exposures and ultimately NASA GCR simulations.…”

Section: Plos Biologymentioning

confidence: 91%

“…Given the continuous low-dose rates found in space (<1 mGy/day), challenges remain in simulating the galactic cosmic ray environment in Earth-based analogs [4]. Modeling is expected to play a key role in interpreting and translating biological results from acute (high dose rate) and fractionated exposures to the protracted [35] and mixed-field [30] exposures humans see in space.…”

Section: Plos Biologymentioning

confidence: 99%

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NASA’s first ground-based Galactic Cosmic Ray Simulator: Enabling a new era in space radiobiology research

et al. 2020

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With exciting new NASA plans for a sustainable return to the moon, astronauts will once again leave Earth's protective magnetosphere only to endure higher levels of radiation from galactic cosmic radiation (GCR) and the possibility of a large solar particle event (SPE). Gateway, lunar landers, and surface habitats will be designed to protect crew against SPEs with vehicle optimization, storm shelter concepts, and/or active dosimetry; however, the ever penetrating GCR will continue to pose the most significant health risks especially as lunar missions increase in duration and as NASA sets its aspirations on Mars. The primary risks of concern include carcinogenesis, central nervous system (CNS) effects resulting in potential in-mission cognitive or behavioral impairment and/or late neurological disorders, degenerative tissue effects including circulatory and heart disease, as well as potential immune system decrements impacting multiple aspects of crew health. Characterization and mitigation of these risks requires a significant reduction in the large biological uncertainties of chronic (low-dose rate) heavy-ion exposures and the validation of countermeasures in a relevant space environment. Historically, most research on understanding space radiation-induced health risks has been performed using acute exposures of monoenergetic single-ion beams. However, the space radiation environment consists of a wide variety of ion species over a broad energy range. Using the fast beam switching and controls systems technology recently developed at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory, a new era in radiobiological research is possible. NASA has developed the "GCR Simulator" to generate a spectrum of ion beams that approximates the primary and secondary GCR field experienced at human organ locations within a deepspace vehicle. The majority of the dose is delivered from protons (approximately 65%-75%) and helium ions (approximately 10%-20%) with heavier ions (Z � 3) contributing the remainder. The GCR simulator exposes state-of-the art cellular and animal model systems to 33 sequential beams including 4 proton energies plus degrader, 4 helium energies plus degrader, and the 5 heavy ions of C, O, Si, Ti, and Fe. A polyethylene degrader system is used with the 100 MeV/n H and He beams to provide a nearly continuous distribution of lowenergy particles. A 500 mGy exposure, delivering doses from each of the 33 beams, requires approximately 75 minutes. To more closely simulate the low-dose rates found in

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Section: Plos Biologymentioning

confidence: 91%

Section: Plos Biologymentioning

confidence: 99%

NASA’s first ground-based Galactic Cosmic Ray Simulator: Enabling a new era in space radiobiology research

et al. 2020

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“…Since astronauts who travel on interplanetary space missions such as a trip to Mars and back will be exposed to a mixture of different radiation types, it is important to use the information on dose response shapes and magnitudes for individual components of this mixture to predict the effects of the entire mixture. A novel and powerful method for generating such predictions, under the assumptions of no synergy and no antagonism between the effects of all components, was developed by Sachs et al 19,22,23 . This new approach, called incremental effect additivity (IEA), is reliable for non-linear dose response shapes, such as those encountered in this analysis.…”

Section: Resultsmentioning

confidence: 99%

“…We used the modeled dose responses for each radiation type to predict the biological effect of a mixture of these radiations. This was done using the new and powerful IEA synergy theory 19,22,23 for a mixture with radiation type proportions relevant for a mission to Mars. The results (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…To solve this problem, Sachs et al recently developed an improved synergy theory approach called incremental effect additivity (IEA) 19,22,23 . The IEA methodology uses the dose response of each component radiation to accurately predict the effect of a mixture of these components, under the assumptions of no synergy and no antagonism between components, even for strongly nonlinear dose response shapes 19,22,23 . Deviations of measured results from IEA predictions can be interpreted as evidence for synergistic or antagonistic interactions between the effects of different radiation types.…”

Section: Incremental Effect Additivity (Iea) Synergy Theory Calculationsmentioning

confidence: 99%

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Quantitative Modeling of Carcinogenesis Induced By Single Beams Or Mixtures of Space Radiations Using Targeted And Non-Targeted Effects

Shuryak

Sachs

Brenner

2021

Preprint

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Ionizing radiations encountered by astronauts on deep space missions produce biological damage by two main mechanisms: (1) Targeted effects (TE) due to direct traversals of cells by ionizing tracks. (2) Non-targeted effects (NTE) caused by release of signals from directly hit cells. The combination of these mechanisms generates non-linear dose response shapes, which need to be modeled quantitatively to predict health risks from space exploration. Here we used a TE+NTE model to analyze data on APC(1638N/+) mouse tumorigenesis induced by space-relevant doses of protons, 4He, 12C, 16O, 28Si or 56Fe ions, or γ rays. A customized weighted Negative Binomial distribution was used to describe the radiation type- and dose-dependent data variability. This approach allowed detailed quantification of dose-response shapes, NTE- and TE-related model parameters, and radiation quality metrics (relative biological effectiveness, RBE, and radiation effects ratio, RER, relative to γ rays) for each radiation type. Based on the modeled responses for each radiation type, we predicted the tumor yield for a Mars-mission-relevant mixture of these radiations, using the recently-developed incremental effect additivity (IEA) synergy theory. The proposed modeling approach can enhance current knowledge about quantification of space radiation quality effects, dose response shapes, and ultimately the health risks for astronauts.

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Mathematical properties of Hand Incremental Effect Additivity and other synergy theories

Hanin

Xie

Sachs

2023

Math Methods in App Sciences

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Synergy theories for multi‐component agent combinations use 1‐agent dose‐effect relations (DERs), known from analyzing previous 1‐agent experiments, to calculate neither‐synergy‐nor‐antagonism combination DERs. Synergy theories are widely used in pharmacology, toxicology, and radiation biology. This article analyzes mathematical properties of one important synergy theory, proposed by John Hand in a little‐known article published in 2000 and here called Hand Incremental Effect Additivity (HIEA). In 2018, Hand's approach was reinvented in a radiobiology study that inadvertently overlooked his paper. We carefully state the assumptions required for mathematically rigorous development of HIEA and other synergy theories. Under these assumptions, studying synergy/antagonism between any number of agents can be done on a single 2d plot. We show that HIEA combination DER is in general not well‐defined in that it can “blow up” at finite total dose. We also formulate necessary and sufficient conditions on 1‐agent DERs preventing such pathology. Using weighted harmonic means, we study the betweenness property of HIEA synergy theory and demonstrate that Hand's combination DER has a systematic tendency for betweenness violation. On the positive side, we introduce the concept of a strongly dominant agent and show that the presence of such an agent ensures the betweenness property. We show also that the betweenness property holds for another major synergy theory, Loewe–Berenbaum Additivity. Our emphasis in this article on synergy theories that can handle any number of agents was motivated by applications to the study of toxic effects of galactic cosmic rays on astronauts during interplanetary travel.

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Simulating galactic cosmic ray effects: Synergy modeling of murine tumor prevalence after exposure to two one-ion beams in rapid sequence

Cited by 16 publications

References 26 publications

NASA’s first ground-based Galactic Cosmic Ray Simulator: Enabling a new era in space radiobiology research

NASA’s first ground-based Galactic Cosmic Ray Simulator: Enabling a new era in space radiobiology research

Quantitative Modeling of Carcinogenesis Induced By Single Beams Or Mixtures of Space Radiations Using Targeted And Non-Targeted Effects

Mathematical properties of Hand Incremental Effect Additivity and other synergy theories

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