Search NASA⌕ Search

Engineering topics

Cucinotta, Francis

Publications and source records attributed to Cucinotta, Francis.

Modeling Clustered DNA Damage by Ionizing Radiation Using Multinomial Damage Probabilities and Energy Imparted Spectra

Simple and complex clustered DNA damage represent the critical initial damage caused by radiation. In this paper, a multinomial probability model of clustered damage is developed with probabilities dependent on the energy imparted to DNA and surrounding water molecules. The model consists of four probabilities: (A) direct damage of sugar-phosphate moieties leading to SSB, (B) OH− radical formation with subsequent SSB and BD formation, (C) direct damage to DNA bases, and (D) energy imparted to histone proteins and other molecules in a volume not leading to SSB or BD. These probabilities are augmented by introducing probabilities for the relative location of SSB using a ≤10 bp criteria for a double-strand break (DSB) and for the possible success of a radical attack that leads to SSB or BD. Model predictions for electrons, 4He, and 12C ions are compared to the experimental data and show good agreement. Thus, the developed model allows an accurate and rapid computational method to predict simple and complex clustered DNA damage as a function of radiation quality and to explore the resulting challenges to DNA repair.

Biochemistry & Molecular Biology↗

Evidence Report: Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure

Occupational radiation exposure from the space environment may result in non-cancer or non-CNS degenerative tissue diseases, such as cardiovascular disease, cataracts, and respiratory or digestive diseases. However, the magnitude of influence and mechanisms of action of radiation leading to these diseases are not well characterized. Radiation and synergistic effects of radiation cause DNA damage, persistent oxidative stress, chronic inflammation, and accelerated tissue aging and degeneration, which may lead to acute or chronic disease of susceptible organ tissues. In particular, cardiovascular pathologies such as atherosclerosis are of major concern following gamma-ray exposure. This provides evidence for possible degenerative tissue effects following exposures to ionizing radiation in the form of the GCR or SPEs expected during long-duration spaceflight. However, the existence of low dose thresholds and dose-rate and radiation quality effects, as well as mechanisms and major risk pathways, are not well-characterized. Degenerative disease risks are difficult to assess because multiple factors, including radiation, are believed to play a role in the etiology of the diseases. As additional evidence is pointing to lower, space-relevant thresholds for these degenerative effects, particularly for cardiovascular disease, additional research with cell and animal studies is required to quantify the magnitude of this risk, understand mechanisms, and determine if additional protection strategies are required.The NASA PEL (Permissive Exposure Limit)s for cataract and cardiovascular risks are based on existing human epidemiology data. Although animal and clinical astronaut data show a significant increase in cataracts following exposure and a reassessment of atomic bomb (A-bomb) data suggests an increase in cardiovascular disease from radiation exposure, additional research is required to fully understand and quantify these adverse outcomes at lower doses (less than 0.5 gray (SI unit for ionizing radiation dosage, i.e. one joule of radiation energy per one kilogram of matter)) to facilitate risk prediction. This risk has considerable uncertainty associated with it, and no acceptable model for projecting degenerative tissue risk is currently available. In particular, risk factors such as obesity, alcohol, and tobacco use can act as confounding factors that contribute to the large uncertainties. The PELs could be violated under certain scenarios, including following a large SPE (solar proton event) or long-term GCR (galactic cosmic ray) exposure. Specifically, for a Mars mission, the accumulated dose is sufficiently high that epidemiology data and preliminary risk estimates suggest a significant risk for cardiovascular disease. Ongoing research in this area is intended to provide the evidence base for accurate risk quantification to determine criticality for extended duration missions. Data specific to the space radiation environment must be compiled to quantify the magnitude of this risk to decrease the uncertainty in current PELs and to determine if additional protection strategies are required. New research results could lead to estimates of cumulative radiation risk from CNS and degenerative tissue diseases that, when combined with the cancer risk, may have major negative impacts on mission design, costs, schedule, and crew selection. The current report amends an earlier report (Human Research Program Requirements Document, HRP-47052, Rev. C, dated Jan 2009) in order to provide an update of evidence since 2009.

Patel, Zarana↗

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↗

Depth Dose Distribution Study within a Phantom Torso after Irradiation with a Simulated Solar Particle Event at NSRL

The adequate knowledge of the radiation environment and the doses incurred during a space mission is essential for estimating an astronaut's health risk. The space radiation environment is complex and variable, and exposures inside the spacecraft and the astronaut's body are compounded by the interactions of the primary particles with the atoms of the structural materials and with the body itself Astronauts' radiation exposures are measured by means of personal dosimetry, but there remains substantial uncertainty associated with the computational extrapolation of skin dose to organ dose, which can lead to over- or underestimation of the health risk. Comparisons of models to data showed that the astronaut's Effective dose (E) can be predicted to within about a +10% accuracy using space radiation transport models for galactic cosmic rays (GCR) and trapped radiation behind shielding. However for solar particle event (SPE) with steep energy spectra and for extra-vehicular activities on the surface of the moon where only tissue shielding is present, transport models predict that there are large differences in model assumptions in projecting organ doses. Therefore experimental verification of SPE induced organ doses may be crucial for the design of lunar missions. In the research experiment "Depth dose distribution study within a phantom torso" at the NASA Space Radiation Laboratory (NSRL) at BNL, Brookhaven, USA the large 1972 SPE spectrum was simulated using seven different proton energies from 50 up to 450 MeV. A phantom torso constructed of natural bones and realistic distributions of human tissue equivalent materials, which is comparable to the torso of the MATROSHKA phantom currently on the ISS, was equipped with a comprehensive set of thermoluminescence detectors and human cells. The detectors are applied to assess the depth dose distribution and radiation transport codes (e.g. GEANT4) are used to assess the radiation field and interactions of the radiation field with the phantom torso. Lymphocyte cells are strategically embedded at selected locations at the skin and internal organs and are processed after irradiation to assess the effects of shielding on the yield of chromosome damage. The initial focus of the present experiment is to correlate biological results with physical dosimetry measurements in the phantom torso. Further on, the results of the passive dosimetry within the anthropomorphic phantoms represent the best tool to generate reliable data to benchmark computational radiation transport models in a radiation field of interest. The presentation will give first results of the physical dose distribution, the comparison with GEANT4 computer simulations based on a Voxel model of the phantom, and a comparison with the data from the chromosome aberration study.

Berger, Thomas↗

Space Radiation and Exploration - Information for the Augustine Committee Review

Space radiation presents significant health risks including mortality for Exploration missions: a) Galactic cosmic ray (GCR) heavy ions are distinct from radiation that occurs on Earth leading to different biological impacts. b) Large uncertainties in GCR risk projections impact ability to design and assess mitigation approaches and select crew. c) Solar Proton Events (SPEs) require new operational and shielding approaches and new biological data on risks. Risk estimates are changing as new scientific knowledge is gained: a) Research on biological effects of space radiation show qualitative and quantitative differences with X- or gamma-rays. b) Expert recommendations and regulatory policy are changing. c) New knowledge leads to changes in estimates for the number of days in space to stay below Permissible Exposure Limits (PELS).

Cucinotta, Francis↗

M-BAND Study of Radiation-Induced Chromosome Aberrations in Human Epithelial Cells: Radiation Quality and Dose Rate Effects

The advantage of the multicolor banding in situ hybridization (mBAND) technique is its ability to identify both inter- (translocation to unpainted chromosomes) and intra- (inversions and deletions within a single painted chromosome) chromosome aberrations simultaneously. To study the detailed rearrangement of low- and high-LET radiation induced chromosome aberrations in human epithelial cells (CH184B5F5/M10) in vitro, we performed a series of experiments with Cs-137 gamma rays of both low and high dose rates, neutrons of low dose rate and 600 MeV/u Fe ions of high dose rate, with chromosome 3 painted with multi-binding colors. We also compared the chromosome aberrations in both 2- and 3-dimensional cell cultures. Results of these experiments revealed the highest chromosome aberration frequencies after low dose rate neutron exposures. However, detailed analysis of the radiation induced inversions revealed that all three radiation types induced a low incidence of simple inversions. Most of the inversions in gamma-ray irradiated samples were accompanied by other types of intra-chromosomal aberrations but few inversions were accompanied by inter-chromosomal aberrations. In contrast, neutrons and Fe ions induced a significant fraction of inversions that involved complex rearrangements of both inter- and intrachromosomal exchanges. The location of the breaks involved in chromosome exchanges was analyzed along the painted chromosome. The breakpoint distribution was found to be randomly localized on chromosome 3 after neutron or Fe ion exposure, whereas non-random distribution with clustering breakpoints was observed after -ray exposure. Our comparison of chromosome aberration yields between 2- and 3-dimensional cell cultures indicated a significant difference for gamma exposures, but not for Fe ion exposures. These experimental results indicated that the track structure of the radiation and the cellular/chromosome structure can both affect radiation-induced chromosome aberrations.

Hada, Megumi↗

Distribution of Chromosome Breakpoints in Human Epithelial Cells Exposed to Low- and High-LET Radiations

The advantage of the multicolor banding in situ hybridization (mBAND) technique is not only its ability to identify simultaneously both inter- and intrachromosome exchanges, but also the ability to measure the breakpoint location along the length of the chromosome in a precision that is unmatched with other traditional banding techniques. Breakpoints on specific regions of a chromosome have been known to associate with specific cancers. The breakpoint distribution in cells after low- and high-LET radiation exposures will also provide the data for biophysical modeling of the chromatin structure, as well as the data for the modeling the formation of radiation-induced chromosome aberrations. In a series of experiments, we studied low- and high-LET radiation-induced chromosome aberrations using the mBAND technique with chromosome 3 painted in 23 different colored bands. Human epithelial cells (CH1 84B5F5/M10) were exposed in vitro to Cs- 137 rays at both low and high dose rates, secondary neutrons with a broad energy spectrum at a low dose rate and 600 MeV/u Fe ions at a high dose rate. The data of both inter- and intrachromosome aberrations involving the painted chromosome have been reported previously. Here we present data of the location of the chromosome breaks along the length of chromosome 3 in the cells after exposures to each of the four radiation scenarios. In comparison to the expected breakpoint distribution based on the length of the bands, the observed distribution appeared to be non-random for both the low- and high-LET radiations. In particular, hot spots towards both ends of the chromosome were found after low-LET irradiations of either low or high dose rates. For both high-LET radiation types (Fe ions and neutrons), the breakpoint distributions were similar, and were much smoother than that for low-LET radiation. The dependence of the breakpoint distribution on the radiation quality requires further investigations.

Hada, Megumi↗

Expression of Genes Associated with DNA Damage Sensing in Human Fibroblasts Exposed to Low-dose-rate Gamma Rays

Understanding of the molecular response to low-dose and low-dose-rate radiation exposure is essential for the extrapolation of high-dose radiation risks to those at dose levels relevant to space and other environmental concerns. Most of the reported studies of gene expressions induced by low-dose or low-dose-rate radiation were carried out on exponentially growing cells. In the present study, we analyzed expressions of 84 genes associated with DNA damage sensing using real time PCR in human fibroblasts in mostly G1 phase of the cell cycle. The cells were exposed continuously to gamma rays at a dose rate of 0.8 cGy/hr for 1, 2, 6 or 24 hrs at 37 C throughout the exposure. The total RNA was isolated immediately after the exposure was terminated. Of the 84 genes, only a few showed significant changes of the expression level. Some of the genes (e.g. DDit3 and BTG2) were found to be up or down regulated only after a short period of exposure, while other genes (e.g. PRKDC) displayed a highest expression level at the 24 hr time point. The expression profiles for the exposed cells which had a smaller portion of G1 cells indicated more cell cycle signaling and DNA repair genes either up or down regulated. Interestingly, the panel of genes changed from radiation exposure in G1 cells is different from the panel in cells having less G1 arrest cells. The gene expression profile of the cells responding to low-dose-radiation insult apparently depends on the cell growth stage. The response pathway in G1 cells may differ from that in exponentially growing cells.

Zhang, Ye↗

NASA Strategy to Safely Live and Work in the Space Radiation Environment

This viewgraph document reviews the radiation environment that is a significant potential hazard to NASA's goals for space exploration, of living and working in space. NASA has initiated a Peer reviewed research program that is charged with arriving at an understanding of the space radiation problem. To this end NASA Space Radiation Laboratory (NSRL) was constructed to simulate the harsh cosmic and solar radiation found in space. Another piece of the work was to develop a risk modeling tool that integrates the results from research efforts into models of human risk to reduce uncertainties in predicting risk of carcinogenesis, central nervous system damage, degenerative tissue disease, and acute radiation effects acute radiation effects.

Cucinotta, Francis↗

Painting Analysis of Chromosome Aberrations Induced by Energetic Heavy Ions in Human Cells

This viewgraph presentation reviews some of the techniques used to analyze the damage done to chromosome from ion radiation. Fluorescence in situ hybridization (FISH), mFISH, mBAND, telomere and centromereprobes have been used to study chromosome aberrations induced in human cells exposed to low-and high-LET radiation in vitro. There is some comparison of the different results from the various techniques. The results of the study are summarized.

Wu, Honglu↗

Micronuclei Induction in Human Fibroblasts Exposed In Vitro to Los Alamos High-Energy Neutrons

High-energy secondary neutrons, produced by the interaction of galactic cosmic rays with the atmosphere, spacecraft structure and planetary surfaces, contribute to a significant fraction to the dose equivalent in crew members and passengers during commercial aviation travel, and astronauts in space missions. The Los Alamos Nuclear Science Center (LANSCE) neutron facility#s ICE House 30L beamline is known to generate neutrons that simulate the secondary neutron spectra of earth#s atmosphere. The neutron spectrum is also similar to that measured onboard spacecraft like the MIR and International Space Station (ISS). To evaluate the biological damage, we exposed human fibroblasts in vitro to the LANSCE neutron beams without degrader at an entrance dose rate of 25 mGy/hr and analyzed the micronuclei (MN) induction. The cells were also placed behind a 9.9 cm water column to study effect of shielding in the protection of neutron induced damages. It was found that the dose response in the MN frequency was linear for the samples with and without shielding and the slope of the MN yield behind the shielding was reduced by a factor of 3.5. Compared to the MN induction in human fibroblasts exposed to a gamma source at a low dose rate, the RBE was found to be 16.7 and 10.0 for the neutrons without and with 9.9 cm water shielding, respectively.

Gersey, Brad↗

Radiation Risk Projections for Space Travel

Space travelers are exposed to solar and galactic cosmic rays comprised of protons and heavy ions moving with velocities close to the speed of light. Cosmic ray heavy ions are known to produce more severe types of biomolecular damage in comparison to terrestrial forms of radiation, however the relationship between such damage and disease has not been fully elucidated. On Earth, we are protected from cosmic rays by atmospheric and magnetic shielding, and only the remnants of cosmic rays in the form of ground level muons and other secondary radiations are present. Because human epidemiology data is lacking for cosmic rays, risk projection must rely on theoretical understanding and data from experimental models exposed to space radiation using charged particle accelerators to simulate space radiation. Although the risks of cancer and other late effects from cosmic rays are currently believed to present a severe challenge to space travel, this challenge is centered on our lack of confidence in risk projections methodologies. We review biophysics and radiobiology data on the effects of the cosmic ray heavy ions, and the current methods used to project radiation risks . Cancer risk projections are described as a product of many biological and physical factors, each of which has a differential range of uncertainty due to lack of data and knowledge. Risk projections for space travel are described using Monte-Carlo sampling from subjective error di stributions that represent the lack of knowledge in each factor that contributes to the projection model in order to quantify the overall uncertainty in risk projections. This analysis is applied to space mi ssion scenarios including lunar colony, deep space outpost, and a Mars mission. Results suggest that the number of days in space where cancer mortality risks can be assured at a 95% confidence level to be below the maximum acceptable risk for radi ation workers on Earth or the International Space Station is only on the order of 100-200 days. Approaches to reduce these unceI1ainties and mitigate risks are described.

Cucinotta, Francis↗

Space Radiation Cancer Risk Projections for Exploration Missions: Uncertainty Reduction and Mitigation

In this paper we discuss expected lifetime excess cancer risks for astronauts returning from exploration class missions. For the first time we make a quantitative assessment of uncertainties in cancer risk projections for space radiation exposures. Late effects from the high charge and energy (HZE) ions present in the galactic cosmic rays including cancer and the poorly understood risks to the central nervous system constitute the major risks. Methods used to project risk in low Earth orbit are seen as highly uncertain for projecting risks on exploration missions because of the limited radiobiology data available for estimating HZE ion risks. Cancer risk projections are described as a product of many biological and physical factors, each of which has a differential range of uncertainty due to lack of data and knowledge. Monte-Carlo sampling from subjective error distributions represents the lack of knowledge in each factor to quantify risk projection overall uncertainty. Cancer risk analysis is applied to several exploration mission scenarios. At solar minimum, the number of days in space where career risk of less than the limiting 3% excess cancer mortality can be assured at a 95% confidence level is found to be only of the order of 100 days.

Cucinotta, Francis↗

M-FISH Analysis of Chromosome Aberrations in Human Fibroblast Cells After In Vitro Exposure to Low- and High-LET Radiation

The recently commercialized multiplex fluorescence in situ hybridization (m-FISH) technique, which allows human chromosomes to be painted in 24 different colors, was used to analyze chromosome aberrations in diploid human fibroblast cells after in vitro radiation exposure. Confluent flasks of a normal primary fibroblast cell line (AG 1522) were irradiated at high dose rates with either gamma rays or 200 MeV/nucleon Fe ions (LET = 440 keV/micron), incubated at 37 C for 24 hours after exposure, and subsequently subcultured. A chemically induced premature chromosome condensation technique was used to collect chromosome samples 32 hours after subculture. Results showed that the fraction of exchanges which were identified as complex, i.e. involving misrejoining of three or more DSB, were higher in the Fe-irradiated samples compared with the gamma-irradiated samples, as has been shown previously using FISH with one or two painted chromosomes . The ratios of complex/simple type exchanges were similar for samples irradiated with 0.7 Gy and 3 Gy of Fe ions, although exchanges involving five or more breaks were found only in 3 Gy irradiated samples. The fraction of incomplete exchanges was also higher in Fe- than gamma-irradiated samples. Data on the distribution of individual chromosome involvement in interchromosomal exchanges will be presented.

Wu, Honglu↗