NOTE: End date changed to 2/4/2022 per PI and Space Radiation element (Ed., 3/17/21)

NOTE: End date is 2/4/2021 per PI (Ed., 11/7/19)

The goal of this proposal is to reduce uncertainties in the estimation of particle radiation carcinogenesis from galactic cosmic radiations (GCR). Our approach is to use the existing data on Harderian gland tumorigenesis from investigations of individual high-atomic number, and high-energy (HZE) ion beams to predict outcome of mixed ion chronic GCR exposures, and then measure Harderian gland and lung dose-dependent tumor data for such exposures. We will compare some of the measured cancer prevalence outcomes of a GCR-simulated exposure with the theoretical predictions based on experiments with individual ion beams. Our main hypothesis is that HZE carcinogenic effects are LET- (linear energy transfer) and dose-dependent and not additive at low particle doses due to the contribution of non-targeted effects. Completion of the proposed GCR studies using a mouse strain that has already been well characterized with a low spontaneous tumor background will allow a significant test of modeling approaches used to estimate carcinogenesis risk from a simulated GCR beamline.

Harderian Gland (HG), lung tissues, and other tissues with gross abnormalities were collected, fixed, and processed to slides for histological evaluations. To ensure that microscopic disease is discovered in the HG gland, each gland that is embedded in the blocks was step sectioned to exhaustion. Whenever possible, portions of the HG and lung tissues were snap frozen and stored at -20oC for future analysis. Other major organs such as kidneys, liver, lung, spleen, and brain were frozen and fixed for downstream processing or for sharing with other NASA investigators.

During necropsy, bone marrow lymphocytes from 10 animals in each group were extracted, cultured, and fixed on slides. Slides were shipped to Dr. Megumi Hada’s laboratory for fluorescent in situ hybridization (FISH) staining with chromosomes 1, 2, and 4 whole chromosome probes to determine long-term aberration prevalence in these animals.

Rolls of colon tissues from 10 animals in each group were harvested, fixed with formalin, and processed to slides. The slides were shipped to Dr. Jerry Shay’s laboratory for colon polyp assessment. No colon tumors were found either in control or irradiated animals. Ovarian tissues were collected, fixed, and shipped to Dr. Ulrike Lederer’s laboratory for analysis. Sample analysis work is in progress and results will be reported in the next progress report.

In silico prediction with incremental effect synergy theory of 3-HZE ions was modeled, based on results for 2-ion beams (Huang et al., LSSR 25:107-118, 2020, and Huang & Sachs, LSSR 26:173-174, 2020). Calculations and estimates were made assuming non-targeted effect (NTE) + targeted effect (TE) action, but assuming TE only action gave similar results:prevalences of ~23% for 30 cGy, and ~36% for 60 cGy total doses. Synergy theory modeling of the actual tumor prevalences using TE modeling indicated that there were higher values than predicted- Level 1* synergy at 30 cGy, while TE + NTE modeling showed Level 2* synergy at 30 cGy.

At scheduled necropsy, bone marrow-derived lymphocytes from 10 animals in each group were cultured, fixed, and shipped to our collaborator, Dr. Megumi Hada for FISH chromosome aberration (CA)-scoring. Results showed that the percent of apparently simple and total exchanges and the number of color junctions were significantly elevated 16 months after radiation for both dose regimes of the 3 HZE ion exposures, although the % complex exchanges were not significantly different from the controls. These results speak to persistent long-term space radiation effects in the bone marrow hematopoietic compartment that resulted in the accumulation of damaged cells with simple exchanges, but not those with complex exchanges.

B. Six-ION GCRsim Study: We irradiated animals to a single total dose of 100 cGy of a 6-ion GCRsim in the Spring of 2018. Here we report outcome data on tumor histology, prevalence, synergy modeling, and chromosome aberrations (CA) in bone marrow lymphocytes at 16-months post exposure.

We found significantly increased HG tumor prevalence in GCRsim irradiated animals when compared to the controls (p=0.026). Although benign adenomas are the dominant tumor-type, the HG in 1 control animal was found to be a lymphoma while 1 animal in the irradiated group had a HG carcinoma.

We found changes in lung tumor incidence and pathology in 6-ion-GCRsim-irradiated animals but the change was not significant when compared to the controls (p=0.41 obtained by Fisher’s exact test). Although benign adenomas are also the dominant tumor-type in the lungs, there were more carcinomas in the GCRsim irradiated animals than in the controls.

In addition to the HG and lung tumors, ovarian tumor incidences were also elevated in the irradiated animals. No spontaneous tumors were found in the control cohort. A variety of tumors, including luteoma (with luteal-like cells that are bigger than a corpus luteum and compresses the surrounding tissue), mixed tumors, lipoma, cystadenomas, tubulostromal adenomas, and granular cell tumors that are either benign or malignant were found in the GCRsim irradiated animals. Other sporadic tumors in the GCR-irradiated animals include renal tubule adenomas, pituitary adenoma.

Professor Rainer Sachs and his University of California Berkeley team completed theoretical modeling of the data obtained in the 6-ion beam GCRsim Harderian Gland tumor prevalence study, to test for synergy or antagonism. A modern synergy theory, Incremental Effect Additivity (IEA), was used, for the reasons detailed in the paper by Huang et al. and its web supplement (Huang et al., LSSR 25:107-118, 2020).

Tumor prevalence results of the 6-ion beam exposure with a total mixture dose of 100 cGy was measured to yield HG tumor prevalence of ~23.5%. The curves and confidence intervals (CI) assumed HZE NTE action dominates at very low doses, so that there is a smooth, but very steep, highly concave increase of prevalence from 0 dose to very small doses. Swift light ion effects were modeled by a single Incremental Effect Additivity (IEA) curve prediction for the prevalence if no synergy or antagonism is present among the components of the mixed beam, and a 95% CI, which was calculated appropriately, taking adjustable parameter correlations into account. Our results suggest synergy is more likely than antagonism, since the actual tumor prevalence lies above the predicted IEA line. However, because the error bar of the data point overlaps the CI band, the data indicate—no significant synergy among the 6 beams.

The results from the analysis of murine CA in bone marrow of mice harvested at 16 months post irradiation with the 6-ion GCRsim beam mixture by Dr. Hada and her team showed that there was a significant increase in % total (p=0.007 obtained by Mann-Whitney test) and simple exchanges (p=0.007 obtained by Mann-Whitney test), but no significant increase in complex exchanges (p=0.74 obtained by Mann-Whitney test) in the 6-ion GCRsim exposure when compared to the unirradiated controls.

The goal of this proposal is to reduce uncertainties in the estimation of particle radiation carcinogenesis from galactic cosmic radiations (GCR). Our approach is to use the existing data on Harderian gland tumorigenesis from investigations of individual high-atomic number, and high-energy (HZE) ion beams to predict outcome of mixed ion chronic GCR exposures, and then measure Harderian gland and lung dose-dependent tumor data for such exposures. We will compare some of the measured cancer prevalence outcomes of a GCR-simulated exposure with the theoretical predictions based on experiments with individual ion beams. Our main hypothesis is that HZE carcinogenic effects are LET- (linear energy transfer) and dose-dependent and not additive at low particle doses due to the contribution of non-targeted effects. Completion of the proposed GCR studies using a mouse strain that has already been well characterized with a low spontaneous tumor background will allow a significant test of modeling approaches used to estimate carcinogenesis risk from a simulated GCR beamline.

A. THREE HEAVY ION BEAM STUDY

A total study cohort of ~ 3-month old 419 female CB6F1 mice (including 52 sham-treated controls) were shipped to Brookhaven National Laboratory (BNL). Animals were sham-treated or exposed to a 3- heavy ion mixed beam (260 MeV/u Si, 1 GeV/u Ti, and 600 MeV/u Fe) during NASA Space Radiation Laboratory (NSRL) 19A delivered in rapid sequence to a total dose of 30 cGy, or 60 cGy.

After irradiation, animals were shipped to the vivarium at Lawrence Berkeley National Laboratory (LBNL) for 16-month long-term housing and maintenance, until their scheduled necropsy at SRI International on the first two weeks in August 2020. Tumor tissues were collected and fixed for potential down-stream analysis.

Harderian Gland, lung tissues, and other tissues with gross abnormalities were collected, fixed, and processed to slides for histological evaluations. Other major organs such as kidneys, liver, lung, spleen, and brain were frozen and fixed for downstream processing or for sharing with other NASA investigators.

Samples derived from bone marrow from 10 animals in each group were sent to Dr. Megumi Hada’s laboratory for fluorescent in situ hybridization (FISH) staining with chromosomes 1, 2, and 4 whole chromosome probes to determine long-term aberration prevalence in these animals. Slides of colon tissues derived from 10 animals in each group were shipped to Dr. Jerry Shay’s Laboratory for colon polyp assessment. Fixed ovarian tissues were to Dr. Ulrike Lederer’s Laboratory for analysis. Sample analysis work is in progress and results will be reported in the next progress report.

B. SIX-ION GCRsim STUDY

We irradiated animals to a single total dose of 100 cGy of GCRsim in the Spring of 2018. The irradiation procedures were described in the 2019 progress report. The study design is summarized briefly here.

Protons 250 MeV-60cGy (60%) + Helium 228 MeV/u-20 cGy (20%) + Oxygen 350

MeV-10 cGy (10%) + Silicon 260 MeV/u-2.5 cGy (2.5%) + Titanium 1 GeV/u-2.5 cGy

(2.5%) + Iron 600 MeV/u-5 cGy (5%)

This 6-ion combination is compliant with the requirements stated in the NASA Research Announcement where protons will contribute to 50%-60% of the total dose, 10%-20% of the dose contribution will be from alphas, 5%-10% of the contribution will be from HZE ions of 3>Z>9, and 5%-10% of the contributing dose will be from HZE ions of Z>10.

B.1 Chromosome Aberrations: One of the key observations from the analysis of murine chromosome aberrations from the bone marrow of the mice harvested at 16 months post-irradiation is the significantly increased heterogeneity in chromosome exchanges/100 cells in the mice exposed to the 6-ion beams (p=0.007 by Fisher’s exact test), compared to the sham-treated controls. A significant increase in simple exchanges (p=0.007 by Fisher’s exact test), while no significant increase in complex exchanges (p=0.74 by Fisher’s exact test) were found after exposure to the 6-ion beams, as well as the variability between individual mice. These observations will require follow up in order to confirm our speculation that the cells with complex exchanges are diminished in significance, due to their loss during the 16-month period post-treatment.

B.2. Synergy Modeling of the 6-Ion Beam GCRsim Results: We completed theoretical modeling of the data obtained in the 6-ion beam GCRsim Harderian Gland tumor prevalence study, to test for synergy or antagonism. A modern synergy theory, Incremental Effect Additivity (IEA) was used, for the reasons detailed in Huang, EG, RY Wang, L Xie, P Chang, G Yao, B Zhang, DW Ham, Y Lin, EA Blakely and RK Sachs (2020). "Simulating galactic cosmic ray effects: Synergy modeling of murine tumor prevalence after exposure to two one-ion beams in rapid sequence." Life Sci Space Res (Amst) 25: 107-118 and its web supplement.

The 6-ion beam exposure with a total dose of 100 cGy was measured to yield a Harderian Gland tumor prevalence of 23.5% above background.

We used synergy theory analysis to estimate the IEA prediction and confidence intervals (CI) for the prevalence if no synergy or antagonism is present among the components of the mixed beam. Our analysis assumed that for HZE non-targeted effect, action dominates at very low doses. The 95% CI was calculated appropriately, taking adjustable parameter correlations into account. Incorrectly neglecting parameter correlations gives a substantially wider 95% Ci and leads to an unduly pessimistic estimate of the upper 95th percentile height that NASA emphasizes. We compared the IEA prediction with the data. We found that the measured prevalence was slightly higher than the predicted prevalence but there was no significant synergy or antagonism among the components of the six-ion mixture. This result was consistent with our expectations.

The goal of this proposal is to reduce uncertainties in the estimation of particle radiation carcinogenesis from galactic cosmic radiations (GCR). Our approach is to use the existing data on Harderian gland tumorigenesis from investigations of individual high-atomic number, and high-energy (HZE) ion beams to predict outcome of mixed ion chronic GCR exposures, and then measure Harderian gland and lung dose-dependent tumor data for such exposures. We will compare some of the measured cancer prevalence outcomes of a GCR-simulated exposure with the theoretical predictions based on experiments with individual ion beams. Our main hypothesis is that HZE carcinogenic effects are LET- (linear energy transfer) and dose-dependent and not additive at low particle doses due to the contribution of non-targeted effects. Completion of the proposed GCR studies using a mouse strain that has already been well characterized with a low spontaneous tumor background will allow a significant test of modeling approaches used to estimate carcinogenesis risk from a simulated GCR beamline.

Dr. Megumi Hada and her team (Andrew Beitman and Jordan Rhone) completed 9 cave entries exposing human blood, and human epithelial cells and fibroblasts. Dr. Hada exposed sets of her samples to each of the 6-ion beams alone, followed by the 6-ion sequence at the dose fractions to be used for the mice totaling 100 cGy, as well as half and quarter proportional total doses of 50 cGy and 25 cGy. The Blakely/Chang group followed with the irradiation of 136 female, CB6F1 mice of 100-120 days of age in 7 hours on May 2nd, 2018 from 1:06pm to 8:00pm. Each animal received a sequence of 60 cGy 250 MeV protons, 20 cGy 228 MeV/u He, 10 cGy 350 MeV/u Oxygen, 2.5 cGy 260 MeV/u Si, 2.5 cGy 1,000 MeV/u Ti, and 5 cGy 600 MeV/u Fe within an approximately 24 min period. Eight mice were whole-body irradiated in each of 17 cave entries. The automated delivery of mixed ion beams by Adam Rusek and his team at Brookhaven National Laboratory (BNL) represents a major leap forward in NSRL capabilities.

2—We harvested tumors and tissues from two large animal cohorts totaling 400 mice in 2018. In February, we necropsied animals from the single or dual-ion beam studies from NSRL16C, and in August, from the 350 MeV/u Oxygen ion dose response of NSRL17C. Both cohorts included harvesting of murine bone marrow cells for later chromosome analysis. This was an enormous effort, and was successfully completed on time and on budget. The results were quite striking.

CHROMOSOME ABERRATIONS (DUAL BEAMS). Murine chromosome aberrations in the bone marrow of mice harvested at 16 months post irradiation were analyzed. Animals were either sham-treated (controls) or irradiated with 60 cGy of protons (H) alone, 40 cGy of Silicon ions alone, or 60 cGy of protons followed by 40 Gy of silicon ions, 40 cGy of protons followed by 30 cGy of iron ions, or 20 cGy of silicon ions followed by 20 cGy of iron ions. The number of simple and complex exchanges were measured in each of 4 - 5 mice in group. One of the key observations was the significant increased heterogeneity in chromosome exchanges/100 cells in the mice exposed to dual ion beams. Both simple and complex exchanges increase after exposure to HZE ions, as well as the variability between individual mice. These observations will require follow up in order to understand any potential correlations with tumor outcome.

OXYGEN ION HG TUMORIGENESIS DOSE RESPONSE. The 350 MeV/u Oxygen ion Harderian Gland tumorigenesis prevalence dose response data were shown to nest between the 670 MeV/u Neon ion data (LET of ~25 keV/µm and the 228 MeV/u Helium ion data (LET of ~1.6 keV/µm). These preliminary data are consistent with our expectations. A manuscript is in preparation.

3--In Silico Modeling of murine Harderian Gland tumorigenesis. It is currently unknown whether the GCR mixed field could demonstrate statistically significant synergy among its components. Synergy would increase risks for prolonged astronaut voyages in inter-planetary space. Prof. Ray Sachs and his team of 7 undergraduate Mathematics students at the University of California, Berkeley recently modeled the NSRL dual-beam HG tumor prevalence data. The methods were those introduced or summarized in the team's Radiat.Environ Biophys paper by Huang et al., 2019. These methods included the following: • Using their incremental effect additivity (IEA) synergy theory based on computer numerical integration of non-linear ordinary differential equations. • Analyzing IEA no-synergy/no-antagonism baseline dose-effect relation uncertainties by Monte Carlo sampling from variance-covariance matrices, thereby taking adjustable parameter correlations appropriately into account and getting appropriately narrow 95% CI. • Taking advantage of the IEA mix-mix principle to transfer uncertainties from matched one-ion analyses to mixture analyses, even when nominally one-ion NSRL beams are actually mixtures at the target due to intervening matter.

The single total dose dual beam Harderian Gland tumorigenesis data points we observed in our three separate dual-beam combinations have been compared to calculated incremental effect additivity synergy theory results with 95% CI. With the 60 cGy protons + 40 cGy silicon, and also the 20 cGy Si + 20 cGy Fe study, the observed mixture data points were slightly above the red IEA baseline representing no synergy or antagonism and extended beyond the CI, therefore the test of our hypothesis indicates there is no statistically significant synergy in these two cases. However, in the case of 40 cGy protons + 30 cGy Fe, unexpected significant synergy between proton and iron ion action is observed.

Additional theoretical modeling of the yield of human chromosome aberrations from single and mixed ion beams at NSRL is ongoing in collaboration with Dr. Megumi Hada.

4—Ongoing and upcoming plans: We plan to irradiate 2 total dose points (30 cGy, 60cGy) of a rapid sequence 3 HZE (260 Mev/u Si, 1 Gev/u Ti and 600 MeV/u Fe) beam mixture each contributing equal 10 cGy or 20 cGy dose fractions during NSRL19A in April 2019. This animal study of 420 mice is an important test of our hypotheses regarding the role of HZE non-targeted effects on tumorigenesis, and will bring our animal inventory up to 600. Mice irradiated in May 2018 during NSRL18A with a 6-ion mixed beam rapid sequence will be necropsied in November 2020 to harvest tumors, and to harvest bone marrow for chromosome aberration analysis.

Reference

Huang, EG, Lin, Y, Ebert M, Ham DW, Yunzhi C, and Sachs RK, Synergy theory for murine Harderian gland tumours after irradiation by mixtures of high-energy ionized atomic nuclei, Radiation and Environmental Biophysics. https://doi.org/10.1007/s00411-018-00774-x . 2019 Feb 2.

The goal of this proposal is to reduce uncertainties in the estimation of particle radiation carcinogenesis from galactic cosmic radiations (GCR). Our approach is to use the existing data on Harderian gland tumorigenesis from investigations of individual high-atomic number, and high-energy (HZE) ion beams to predict outcome of mixed ion chronic GCR exposures, and then measure Harderian gland and lung dose-dependent tumor data for such exposures. We will compare some of the measured cancer prevalence outcomes of a GCR-simulated exposure with the theoretical predictions based on experiments with individual ion beams. Our main hypothesis is that HZE carcinogenic effects are LET- (linear energy transfer) and dose-dependent and not additive at low particle doses due to the contribution of non-targeted effects. Completion of the proposed GCR studies using a mouse strain that has already been well characterized with a low spontaneous tumor background will allow a significant test of modeling approaches used to estimate carcinogenesis risk from a simulated GCR beamline.

1--Participated in NASA Space Radiation Laboratory (NSRL) 17C—Exposed a total (with unirradiated controls) of 171 female CB6F1 female mice to 350 MeV/amu Oxygen ions 0, 20, 40, or 80 cGy.

2--Animal husbandry continuing at Lawrence Berkeley National Laboratory (LBNL) for a total of nearly 400 animals from the single or two-ion beams from NSRL 16C and the animals from the Oxygen run during NSRL 17C run.

3--We have provided murine cardiac tissues collected from our previous Harderian Gland tumorigenesis studies that are currently listed in the NASA Tissue Archive to Dr. David Goukassian and continue to collaborate with him to conduct his NASA-funded research.

4--Murine Bone Marrow Harvest from 52 mice was conducted at 17-weeks post NSRL 16C irradiation for chromosome aberration study. However, the quality of the samples was not optimal and aberrations were not scorable, possibly due to the age and strain of the animals. The assay method was refined by optimizing the stimulating/blocking reagents and incubation conditions using the same strain of aged mice.

5--In collaboration with Dr. Megumi Hada, chromosome aberrations in human lymphocytes ex vivo, induced by single and mixed beam (H + Si) from NSRL 16C were recorded. The dose response of simple chromosome exchanges appears to be linear for H and Si, but the slope of the dose-dependent increase differs by a factor of ~6X. The H dose-response curve appears to be linear-quadratic. Slope of complex exchanges is steeper for Si than H by a factor of ~16X. Silicon-induced total exchanges appear to be linear with dose, proton exchanges appear to be linear quadratic with dose. Chromosome aberrations with mixed beams - consisting of different doses of H followed within 2 min by different doses of Si indicated that the chromosome aberration yield of simple exchanges in mixed beams in sometimes more than additive. The frequency and type of chromosome aberrations induced is dependent on the percentage of the dose from the proton versus the silicon beam. This biological system can detect 10 cGy differences in total dose.

6--In Silico Modeling of murine Harderian Gland tumorigenesis by Prof. Ray Sachs found substantially improved dose-effect relations for 1-ion beams, and confirmed: (a) our conjecture that 95% confidence intervals for baseline no-synergy (+ or -) are substantially tighter when correlations between calibrated model parameters are properly taken into account, (b) the well-known inapplicability of simple effect additivity as a baseline definition of no-synergy (+ or -) for a mixed radiation field when component Dose Effect Ratios (DERs) are highly curvilinear, e.g., are all highly concave at very low doses due to NTE. In addition, Prof. Sachs found a way to generate the mixture baseline DER of incremental effect that is now applicable to a “mixture of mixtures” theorem. This model is relevant because nominally 1-ion beams are usually themselves mixtures at the target, due, e.g., to mouse tissue fragmentation and self-shielding. He has also extended his synergy theory to one special case of constant chronic dose-rate lasting a year or more. Theoretical modeling of chromosome aberration work has progressed and a new paper was published online in December 2017 for print publication in the New Year.

7--Future plans: Necropsy and bone marrow harvest of 226 NSRL 16C mice (February 2018), and 171 NSRL 17A mice (August 2018). We also plan to irradiate a 6-ion mixed beam rapid sequence study in May 2018.

*Presentations:

1--Heidelberg Ion Beam Therapy Center, Heidelberg, Germany, Blakely, E., “Charged Particle Therapy”, 21 June 2017.

2--NASA Space Radiation Summer School, Brookhaven National Laboratory, Upton, New York, Blakely, E. “Space Radiation and Cataracts” on 22 June 2017.

3--NASA Space Radiation Summer School, Brookhaven National Laboratory, Upton, New York, Blakely, E. “Charged Particle Therapy” on 22 June 2017.

The goal of this proposal is to reduce uncertainties in the estimation of particle radiation carcinogenesis from galactic cosmic radiations (GCR). Our approach is to use the existing data on Harderian gland tumorigenesis from investigations of individual high-atomic number, and high-energy (HZE) ion beams to predict outcome of mixed ion chronic GCR exposures, and then measure Harderian gland and lung dose-dependent tumor data for such exposures. We will compare some of the measured cancer prevalence outcomes of a GCR-simulated exposure with the theoretical predictions based on experiments with individual ion beams. Our main hypothesis is that HZE carcinogenetic effects are LET- (linear energy transfer) and dose-dependent and not additive at low particle doses due to the contribution of non-targeted effects. Completion of the proposed GCR studies using a mouse strain that has already been well characterized with a low spontaneous tumor background will allow a significant test of modeling approaches used to estimate carcinogenesis risk from a simulated GCR beamline.

1--Oct 6, 2016-Irradiated 210 CB6F1 female mice using single-or two-ion beams (within 1.5 min separation) over a 5 hr period-(p alone; p+Si; p+Fe; Si+Fe), and 60 sham-irradiated controls. These animals will be used in Harderian gland and lung tumorigenesis, chromosome aberration, and tissue archiving studies.

2--Comparing human in vitro (and ex-vivo) with murine in vivo chromosome aberration yields (in coordination with M. Hada). Various chromosome aberration experiments, e.g., with mice or with normal human blood, fibroblast, and epithelial cells, were carried out in Oct. 2016 at NASA Space Radiation Laboratory (NSRL) with the goal of linking human in vitro data to murine in vivo responses.

3--A successful 17-week post exposure harvest of murine bone marrow metaphases has been completed and is being processed for chromosome aberrations.

• Reports and publications

1--Chang PY, Cucinotta FA, Bjornstad KA, Bakke J, Rosen CJ, Du N et al., Harderian Gland tumorigenesis: low-dose and LET response, Radiat Res 2016: 186:449-60. (NOTE: this publication is a product of prior funding, grant NNJ11HA94I "Harderian Gland Tumorigenesis: Low-Dose-, Low-Dose-Rate-, and LET-Response," and is listed with that project's bibliography.)

2--Siranart N, Blakely EA, Cheng A, Handa N, and Sachs RK. Mixed Beam Murine Harderian Gland tumorigenesis: Predicted dose-effect relationships if neither synergism nor antagonism occurs, Radiat Res. 2016: 186:577-591.

• Presentations

1--62nd Annual Meeting of Radiation Research Society, Kona, HI. Poster, Oct 16-19, 2016. A single low dose of particle radiations results in long-term perturbation of the gut microbiome, Mao JH, Karaoz U, Lim HC, JK Bielicki JK, Bjornstad KA, Rosen CJ, Brodie EL, Chang PY, and Blakely, EA.

2--American Society for Gravitational & Space Research (ASGSR), Cleveland, OH-Symposium Presentation-Oct 27, 2016. Radiobiological Applications of Single-Beam and Mixed-Beam NSRL Capabilities. Blakely EA, Sachs RK, Chang PY, Mao JH, La Tessa C, and Rusek A.

3--International Symposium Ion Therapy (ISIT), Milan, Italy – Hot Topics Debate, Nov 3-4, 2016. Proton, C-Ions (or Else)? Blakely EA, Tommasino, F, and Scifoni E.

4--NASA Human Research Program, Predicting and Simulating GCR-Induced Tumor Risk, Blakely E, Chang P, Mao JH, Bakke J, Grover A, La Tessa C, Snyder D, Bjornstad K and Sachs R, Jan 23-26, 2017.

The goal of this proposal is to reduce uncertainties in the estimation of particle radiation carcinogenesis from galactic cosmic radiations (GCR). Our approach is to use the existing data on Harderian gland tumorigenesis from investigations of individual high-atomic number, and high-energy (HZE) ion beams to predict outcome of mixed ion chronic GCR exposures, and then measure Harderian gland and lung dose-dependent tumor data for such exposures. We will compare some of the measured cancer prevalence outcomes of a GCR-simulated exposure with the theoretical predictions based on experiments with individual ion beams. Our main hypothesis is that HZE carcinogenic effects are LET- and dose-dependent and not additive at low particle doses due to the contribution of non-targeted effects. Completion of the proposed GCR studies using a mouse strain that has already been well characterized with a low spontaneous tumor background will allow a significant test of modeling approaches used to estimate carcinogenesis risk from a simulated GCR beamline.