ISOPTWPO Today

N OVEMBER 2014, N O 13

ISOPTWPO Today

PAMELA ANN MELROY (COLONEL, USAF, RET.) NASA ASTRONAUT (FORMER) Ms. Pamela Melroy joined DARPA in January 2013 after serving as the acting Deputy Associate Administrator and Director of Field Operations in the Federal Aviation Administration’s Office of Commercial Space Transportation. As acting Deputy Associate Administrator, she was responsible for developing human commercial spaceflight safety guidelines and oversaw interagency policy coordination with the White House, NASA, and the Department of Defense on space policy. As Director of Field Operations, she was responsible for overseeing and growing activities from three to six field offices supporting operational safety oversight, licensing and inspection of commercial space activities.

Formerly, Ms. Melroy served as the Deputy Director, Orion Space Exploration Initiatives at Lockheed Martin Corporation from August 2009 until April 2011. Prior to her position at Lockheed Martin, she was selected as an astronaut candidate by NASA and held several key positions within the NASA shuttle program from 1994 until 2009, including Crew Module Lead on the Columbia Reconstruction Team, Deputy Project Manager for the Columbia Crew Survival Investigation Team, and Branch Chief for the Orion Branch of the Astronaut Office. She served as pilot on two shuttle missions (STS-92 in 2000 and STS-112 in 2002), and was the Mission Commander on STS-120 in 2007. She was the second woman to command a space shuttle mission. She has logged more than 924 hours (38+ days) in space.

Ms. Melroy was commissioned through the Air Force ROTC program in 1983 and attended Undergraduate Pilot Training at Reese Air Force Base in Lubbock, Texas, graduating in 1985. She flew the KC-10 for 6 years at Barksdale Air Force Base in Bossier City, La., as a copilot, aircraft commander and instructor pilot. Ms. Melroy is a veteran of Operations JUST CAUSE and DESERT SHIELD/DESERT STORM, with more than 200 combat and combat support hours. In June 1991, she attended the Air Force Test Pilot School at Edwards Air Force Base, Calif. Upon graduation, she was assigned to the C-17 Developmental Test Program, where she served as a test pilot until her selection for the Astronaut Program.

She retired from the Air Force in February 2007.

Ms. Melroy holds a Bachelor of Arts in Physics and Astronomy from Wellesley College and a Master of Science in Earth and Planetary Sciences from the Massachusetts Institute of Technology. — Image Credit:NASA

Human Space Flight Edition

Radiation Carcinogenesis in Astronauts In space, astronauts are exposed to ionizing radiation that is quantitatively and qualitatively different from terrestrial radiation. This environment includes protons and high-Z high-energy (HZE) ions together with secondary radiation, including neutrons and recoil nuclei that are produced by nuclear reactions in spacecraft materials or tissue. Astronauts who are on missions to the ISS, the Moon or Mars are exposed to ionizing radiation with effective doses in the range of 50 to 2000 mSv (milli-Sievert) projected for possible mission scenarios. Similar doses from terrestrial radiation sources, such as gamma-rays and X-rays, are associated with an increased risk for development of cancer.

Therefore, occupational radiation exposure from the space environment may increase cancer morbidity or mortality risk in astronauts.

Astronauts are exposed to protons and high energy and charge (HZE) ions, along with secondary radiation including neutrons and recoil nuclei that are produced by nuclear reactions in spacecraft or tissue. The nuclear charge of the galactic cosmic radiation (GCR) extends from hydrogen to uranium; however, nuclei heavier than iron (Z=26) are infrequent.

The energy spectrum of the GCR peaks at about 85% of the speed of light, or 1 GeV per nucleon in energy units, and consequently these particles are so penetrating that shielding can only partially reduce the doses absorbed by the crew. The number of nuclei per unit area is denoted by the fluence, F. The large ionization power of HZE ions with Z>2 makes them the major contributor to the risk, in spite of their lower fluence than protons. The absorbed dose (D; measured in Gy) is the amount of energy deposited per unit mass of material and is calculated from the fluence by multiplying it by the linear energy transfer (LET), L, such that D = F × L. Because the types of radiation in space are diverse in how they deposit energy, absorbed dose is a poor descriptor of biological effects. If the same biological effect (for example, same cell survival or mutation frequency) is induced by a reference radiation (for example, X-rays) dose DX and by a dose Dt of a test radiation (for example, HZE ions), then the ratio DX /Dt is defined as relative biological effectiveness (RBE) of the test radiation. The RBE depends on several parameters, including LET, particle velocity and charge, dose and doserate, biological endpoint and oxygen concentration. To estimate biological effects it is customary to scale the absorbed dose by a quality factor Q(LET), which is estimated from the measured RBE values for late effects. Q ranges from 1 at low LET (<10 keV/µm) to 30 at high LET (around 100 keV/µm), and then decreases at very high LET values because of what is called over-kill or wasted energy. The quantity H = D × Q is called the dose equivalent and is measured in sievert (Sv).

Radiation Assessment Detector (RAD) Investigation Radiation Assessment Detector (RAD) on the Mars Science Laboratory(MSL) is an energetic particle detector designed to measure a broad spectrum of energetic particle radiation.The Mars Science Laboratory Science Team has ISOPTWPO Today c International Space Agency(ISA)

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Human Space Flight Edition presented initial analysis of radiation data acquired by the rover’s Radiation Assessment Detector during the Cruise from Earth to Mars.

After being launched atop an Atlas V Rocket from Cape Canaveral Air Force Station on November 26, 2011, MSL’s RAD Instrument was activated to gather radiation data from deep within the Spacecraft. RAD activation occurred on December 6, 2011. As part of cruise operations, RAD data was downlinked to Earth every 24 hours for subsequent analysis by the instrument team. Because the instrument was hidden inside the Rover and its Aeroshell which was protected by the Cruise Stage, RAD was able to characterize the radiation environment Astronauts would encounter in their way to Mars inside a Spacecraft. This enables it to record so called secondary particles - these are particles that result from collisions of primary radiation particles coming from space with spacecraft materials. Secondary Particles can be more dangerous to humans than primary particles, but often go undetected as previous missions were outfitted with Radiation Assessment Instruments directly exposed to space. Just one week after activation of the instrument, RAD already showed four times the radiation it detected during launch preparations in Florida.

On its way to Mars, RAD was able to observe major events such as Coronal Mass Ejections."Curiosity has been hit by five major flares and solar particle events in the Earth-Mars expanse," said Don Hassler of the Southwest Research Institute in Boulder, Colorado that manages the instrument.

While analyzing the data with respect to the instrument’s position inside MSL, it was found that only the strongest radiation storms have made it inside to RAD and that charged particles penetrating the spacecraft’s shell were slowed down and fragmented by their interaction with the spacecraft’s metal skin. "It’s not only the walls that matter, however," Hassler noted "The spacecraft’s hydrazine tanks and other components contribute some protection, too." Data acquired during Cruise will enable scientists to find out what shielding effects each major component such as tanks, shielding materials and other parts, are providing. On July 13, 2012, the RAD instrument was turned off in preparation for landing.

This chart shows the entire Particle Flux Record acquired by RAD from December 6, 2011 to July 13, 2012. Five spikes are clearly visible and correspond to 5 solar particle events. The inset covers ten days in March 2012 during which a X5.4-class Solar Flare occurred. This Coronal Mass Ejection occurred on March 7 was registered by the Advanced Composition Explorer (ACE) Spacecraft shortly thereafter. ACE is located in Sun-Earth Lagrange Point 1 which is 1.5 Million Kilometers from Earth. MSL was significantly further away from the Sun and from Earth at that point, explaining why RAD detected the increased particle flux later than ACE. The graph shows that MSL’s hull was able to provide significant shielding from the impinging radiation - the Red Line representing ACE measurements consistently remains above the proton flux average detected by RAD. On Earth, we often associate radiation exposure with fallout from catastrophes such as Chernobyl and Fukushima.

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Human Space Flight Edition We sometimes worry over CAT scans, chest xrays or transcontinental flights. However, according to the Health Physics Society, the biggest source of radiation for most of us, by far, is inhaled radon, which comes from the natural decay of material present since the Earthâ&#x20AC;&#x2122;s formation. In open space, human beings continuously contend with intense solar and cosmic background radiation. Solar Energy Particles (SEPs) and Galactic Cosmic Rays (GCRs) turn a trip to Mars into a six month radiation shower.

The Mars rover Curiosity has allowed us to finally calculate an average dose over the 180day journey. It is approximately 300 mSv, the equivalent of 24 CAT scans. In just getting to Mars, an explorer would be exposed to more than 15 times an annual radiation limit for a worker in a nuclear power plant.

Data from Curiosity also demonstrated that landing only partially solves the problem. Once on the Martian surface, cosmic radiation coming from the far side of the planet is blocked. This cuts down detected GCRs by half. The protection from strong solar particles, though, is shoddy and inconsistent. Substantial variations in SEPs occur as the meager Martian atmosphere is tussled by solar wind. Radiation and its variations impact not only the planning of human and robotic missions, but also the search for extraterrestrial life. Without substantial atmospheric protection, powerful particles entering the air can penetrate straight into the Martian soil. On impacting the surface, the GCRs and SEPs from space produce cascades of other energetic particles. Of these newly produced particles, gamma rays and neutrons are easily capable of breaking molecular bonds in the soil, destroying evidence of past life, as well as any life that may be presently trying to survive there.

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Human Space Flight Edition

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Human Space Flight Edition

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Human Space Flight Edition

Biological dosimetry in the ENEIDE Mission on the International Space Station Space radiation represents one of the major health hazards to crews of interplanetary missions. As the duration of space flight increases, according to International Space Station (ISS) and Mars mission programs, the risk associated

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Human Space Flight Edition with exposure to ionizing radiation also increases. Although physical dosimetry is routinely performed in manned space missions, it is generally accepted that direct measurement of biological endpoints (biological dosimetry) is necessary for a precise assessment of radiation risk in extraterrestrial activities. Chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) are particularly suitable to this purpose, as they can provide estimates of both equivalent radiation dose and risk.

Cytogenetic analysis performed on PBL chromosomes from the Italian astronaut R. Vittori involved in two different 10-day missions on the ISS (Marco Polo Mission, April 2002, and ENEIDE Mission, May 2005). Blood samples from the astronaut were collected before and after flight, and after six months follow up from Marco Polo mission.

CAs were measured by FISH in mitosis as well as in prematurely condensed chromosomes (PCCs). In addition,blood samples were exposed to X-rays in vitro and cytogenetic damage was evaluated to investigate whether the space environment alters the sensitivity of human cells to ionizing radiation.

Pre- and post- flight samples for ENEIDE Mission and follow-up samples for Marco Polo Mission were analyzed.

ENEIDE mission occurred 3 years after Marco Polo mission, and were both short missions (10 days). To obtain statistically significant CA data, an appropriate number of cells were analyzed ( â&#x2C6;ź 2000 for 0 Gy samples and â&#x2C6;ź 1000 for > 1 Gy samples). Images of metaphase and PCC spreads were automatically acquired and stored for subsequent analysis by a computerized system. Aberrations observed in chromosomes 1 and 2 are reported in Table 1.

To evaluate the possible alteration of cellular response to ionizing radiations, whole blood was exposed to 1-5 Gy X-rays before and after the mission. Chromosome aberrations were measured in metaphases and PCCs (Figure 1a-d).

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Human Space Flight Edition

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Human Space Flight Edition

Similar results were obtained after exposure to Îł rays of blood samplesâ&#x20AC;&#x2122; astronauts involved in short missions [7].

Intra-individual variations in radio sensitivity can be significant, but they cannot be related to the space flight. A dose-response curve from follow-up sample for Marco Polo mission is also shown in Figure 1b, together with the previous pre- and post-flight data reported elsewhere [5]. The follow-up data show a reduced radio-sensitivity compared to both pre- and post-flight Marco Polo data. This may be seen as a result of an increased radio resistance conferred by the permanence in space. This observation is consistent with data reported by Durante et al. [8] in Russian cosmonauts, also showing evidence for a possible acquired radio-adaptation. The yield of baseline chromosomal aberrations in the blood not exposed on Earth (Fig. 2) was not modified after Marco Polo or ENEIDE mission and this is consistent with the low dose absorbed in these short-term space missions. However, while no significant alterations ISOPTWPO Today c International Space Agency(ISA)

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Human Space Flight Edition are observed in metaphase samples, a slight increase is measured in PCC. This may reflect the occurrence of slowly cycling aberrant cells undetectable at mitosis and caused by the high-LET space radiation.

Figure 3: Multi-fluorescent chromosome map of a cell exposed to cosmic radiation.

ALTCRISS(Alteino Long Term monitoring of Cosmic Rays on the International Space Station) The Altcriss project aims to perform a long term survey of the radiation environment on board the International

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Human Space Flight Edition Space Station. Measurements are being performed with active and passive devices in different locations and orientations of the Russian segment of the station. The goal is to perform a detailed evaluation of the differences in particle fluence and nuclear composition due to different shielding material and attitude of the station.

The Sileye-3/Alteino detector is used to identify nuclei up to Iron in the energy range above â&#x2030;&#x2C6; 60 MeV/n. Several passive dosimeters (TLDs, CR39) are also placed in the same location of Sileye-3 detector. Polyethylene shielding is periodically interposed in front of the detectors to evaluate the effectiveness of shielding on the nuclear component of the cosmic radiation.

Biomarkers of Space Radiation Risk Ionizing radiation elicits a number of detectable changes at the molecular, cellular and physiological level in exposed organisms. These biological parameters have been called biomarkers. Based on methods and end points, biomarkers have been classified in a number of different ways.

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Human Space Flight Edition

Brooks[11] identified three different classes: biomarkers of exposure,sensitivity and disease. Biomarkers of exposure are biological parameters for which a dose-response relationship can be established [12] and can be broadly referred to as biodosimeters. Biomarkers of sensitivity are genetic markers associated with an increase in the individual susceptibility to radiation damage. For instance, people who are heterozygotes for ataxia telangiectasia mutated gene (ATM) may be hypersensitive to radiation compared to the normal population. ATM heterozygosity would then represent a biomarker of sensitivity.

Finally, biomarkers of disease are those biological events that can be used to anticipate the clinical diagnosis of a specific illness. In the case of carcinogenesis, these biomarkers have also been called intermediate end points of cancer, i.e. a detectable lesion, or a cellular or molecular parameter with some of the histological or biological features of preneoplasia or neoplasia. There is no need for a causal relationship between the intermediate end point and the disease, although biomarkers that are part of the multistep process leading from initiation to the occurrence of invasive cancer are obviously perceived as more relevant.

Electron spin resonance (ESR) of tooth enamel is recognized as the bioindicator with the highest precision in dose reconstruction. Disadvantages of ESR are the high cost and bulkiness of the readout instrument and especially the invasiveness of the method, which requires extraction of the teeth of the exposed individual. Use of portable spectrometers for assessing accumulated dose in vivo could have practical application in space radiation biodosimetry, but at present the limits of detection of in vivo ESR are about 2 Gy. None of the other biological indicators of exposure are very satisfactory for the low-dose, chronic radiation exposure that occurs during space missions. Molecular techniques based on scoring of residual DNA damage, mutations and gene expression offer great promise for biomonitoring, but more research is needed to validate these methods.

At present, cytogenetic assays such as micronuclei, dicentrics and FISH (also in combination with premature chromosome condensation) are widely used methods accepted in the field as the most reliable for biological dose estimation.

All tests performed so far in astronauts after return from long-term space missions in LEO have detected significant increases in the yield of chromosome aberrations compared to preflight background , and these increases are attributed to space radiation exposure.

However, a large interindividual variability was found in the biological measurements, and this variability had no correspondence with the measured dose. It is possible that this variability is caused by differences in individual radiosensitivity, with genetic and/or physiological background, but the experimental uncertainties are so high that simple statistical fluctuations can explain the results. The main problem with cytogenetic dosimetry at low doses is the large statistical errors associated with each measurement.

Even for long-term missions on the Space Station, radiation doses are close to the sensitivity threshold of the method.

Aberrations in lymphocytes are rare events, and thousands of cells must be scored to achieve a good statistical confidence.Despite the statistical errors, biodosimetry measurements can be used to test the estimates of the dose equivalent for each crew member. Measurements of chromosome translocations are particularly suitable for this purpose, because these aberrations are relatively stable, can be transmitted through mitosis, and can be scored quickly and accurately using FISH painting. A large and accurate chromosomal aberrations dosimetry program was started at NASA Johnson Space Center about 10 years ago.

Preflight calibration curves are measured for individual astronauts, exposing blood samples in vitro to Îł rays. Preflight in vitro calibration curves are then used to convert the measured yield of chromosome translocations into equivalent dose. This estimate is then compared to results from physical dosimetry, i.e. with independent measurements of skin dose by thermoluminescence dosimeters and LET spectra by tissue-equivalent proportional chambers, correction of skin to bone marrow dose, and calculation of the average quality factor using ICRP recommendations.

Results gathered so far in the NASA study show a fair agreement between chromosomal aberrations and physical dosimetry-derived doseequivalent estimates, although large statistical uncertainties are associated to the biological dose estimates.

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Human Space Flight Edition

Risk estimates from biological dosimetry in Table 2 are relative to single, long-term missions in LEO, where the cytogenetic test was performed shortly before and after the mission. From these measurements, we have estimated a lifetime risk starting with physical dose and using the NCRP approach . However, the results of the biological test will differ if the samples are obtained at longer intervals after exposure. Cancer risks estimated in the ESCH study did not change with the time elapsed after the chromosomal aberrations test was performed , but in that case the test subjects were basically healthy individuals with no overexposures to clastogenic agents. This is not so for astronauts, who receive an overexposure to radiation (in LEO, the dose rate exceeds terrestrial levels by a factor of 100 or more) during the mission. The exposure is repeated after some time if the crew member is involved in multiple space flights, or it can last many months in the case of long sojourns on the Space Station or interplanetary missions.

Under such conditions, the output of the biological test will change with time from the exposure. By way of illustration, dicentrics and translocations induced during a mission to Mars can be estimated by following the elegant calculation published by Obe and coworkers[14] and using the scenario of a 30-month exploratory mission to Mars presented in the recent ESA HUMEX study[15].

Cytogenetic biomarkers appear to be the most reliable indicators of both radiation dose and risk. Several research studies have measured chromosomal aberrations in the blood lymphocytes of crew members who were involved in LEO space missions.If chromosomal aberrations are measured shortly before and after single,long-term space flights in LEO, dose and risk estimates are in the same range as those expected from physical dosimetry and standard models derived from terrestrial data.This basically implies that the current standards for radiation protection in LEO are sound. Nevertheless, the output of the cytogenetic test is dependent upon the sampling time, and the radiationinduced chromosomal damage produced in multiple space flights does not appear to be additive.

These observations do not necessarily reflect a technical limitation of the biomarker (total chromosomal aberrations, or reciprocal translocations) but provide an individual risk assessment rather than the average risk estimate based solely on absorbed dose. As in the case of individuals who quit smoking at a certain age after years of chronic exposure to carcinogens in the cigarette smoke, radiation relative risks decrease with time after exposure, and the decrease is likely to show a large interindividual variability caused by physiological, environmental and genetic factors.

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Human Space Flight Edition Space radiation does not induce a significant increase of intrachromosomal exchanges in astronauts’ lymphocytes The measurements of intrachromosomal exchanges in lymphocytes from 11 astronauts following space missions on the ISS are reported. The recent method of high-resolution multicolor banding (mBAND) was selected to be used to detect intrachanges in chromosome 5 from peripheral blood lymphocytes obtained both before and after the flight.

The interchanges were also measured using Giemsa-staining and multicolor FISH (mFISH) in the same samples.

Blood samples were obtained before and after the flight from a total of 11 astronauts who flew between the years 2002 and 2004. Four astronauts returned to Earth after only 1 week, while the others remained on the Space Station for about 6 months. Radiation doses are around 2 mGy for short-term flights, and up to 60 mGy for the 6-month missions. Using a quality factor of 2.4 for space radiation in LEO, we estimate an equivalent dose of around 5 mSv for astronauts 0-3 and 150 mSv for astronauts 4-10.

In most astronauts’ samples sufficient metaphases could be scored in FPG-stained preparations from 48 h cultures.

In cases were the cells were delayed in cultivation we also scored first in vitro metaphases from 72 h cultures. The yield of dicentrics scored in Giemsa-stained or mFISH samples pre- and post-flight is reported in Table. No dicentrics were measured pre-flight, and a statistically significant increase is reported post-flight, when data for all astronauts are pooled.

A translocation, as visualized by mFISH, in astronauts’ samples is shown in Fig. 1. Translocations reported in Table include both reciprocal and incomplete types. The sample size is smaller in these mFISH experiments than for those relative to dicentrics analysis, and no significant increases could be detected for the induction of translocations within the statistical limitations of the sample. No complex-type exchanges were observed in a total of 3590 cells analyzed by mFISH.

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Human Space Flight Edition

Intrachromosomal exchanges were measured in chromosome 5 by mBAND. Figure 2 shows a normal pair of chromosome 5 from astronautsâ&#x20AC;&#x2122; lymphocytes after mBAND. The analysis by mBAND failed to identify any inversion in 2800 images of chromosome 5 from the lymphocytes of the eight astronauts analyzed(Table).

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Human Space Flight Edition

Table shows the aberration frequency data pooled for all astronauts, and the upper 95% confidence limit. Dicentrics are the only structural rearrangement displaying a statistically significant increase in the postflight samples compared to the pre-flight ones. The frequency of translocations is not significantly higher in post-flight samples, even if the analysis is limited to longterm flights. However, the sample size is small in this mFISH study as compared Ë? 3 whole-chromosome probes, and where a statistically significant increase in to other studies using FISH with 2U translocations has been detected after long-term space flights. No increase is observed in inversions, and the 95% upper confidence limit for this aberration in chromosome 5 is around 0.3% in the post-flight samples.

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Human Space Flight Edition

Cytogenetic damage in the blood lymphocytes of astronauts: Effects of repeat long-duration space missions Chromosome damage in peripheral blood lymphocytes is the most widely used biomarker of accidental or occupational radia-tion exposure, and space missions of a few months or more on theInternational Space Station (ISS) can induce measureable increasesin the yield of chromosome damage in the blood lymphocytes ofastronauts. NASA uses this cytogenetic data to validate and develop risk-assessment models for characterizing excess healthrisk from space radiation exposure.

The ISS has been continuously occupied since 2000 and during this period long-duration missions have increased from about 3 months to around 6 months. Several astronauts have now participated in second ISS increments, and this has raised concern aboutthe cumulative risk across these missions. It is still unclear if radiation effects in space are simply additive and studies of chromosome damage may provide insight into this issue. Since mono-centric chromosome aberrations, or so-called stable aberrations, do not impose mechanistic interference to cell division and have a higher probability of survival after cell division compared with unstable aberrations (acentric or multicentric aberrations) they are commonly believed to persist in peripheral blood cells for many year safter homogenous whole body irradiations.

One study shows large inter-individual differences in the temporal response of chromosome aberration yields after spaceflight, with pooled statistical data indicating no significant decay with time after flight. Pooled data for total exchanges (which includes unstable exchanges) showed a slight decay in yield of total exchanges thatis more significant at later sampling times. In contrast, a study of Russian cosmonauts reported a lack of correlation between time in space or absorbed dose and translocation yield, although no individual time dependence of translocations was presented and the number of cells assessed for each individual was low. Temporal studies of dicentrics from individual cosmonauts involved in multiple long duration missions show a rapid decline in the interval between flights and a decreasing radio-sensitivity was observed after repeated space flights.

Fig. 1 shows the time course of chromosome damage yields for each individual before and after their first and second long duration missions. The sample timing and duration between flights varied considerably. Plots are presented on the same scale for easier comparison. The first postflight samples were collected within a week or two after the missions and for most individuals a followup sample was collected 6-18 months later. It has been shown that peripheral blood lymphocytes collected the day of return from space show a severely reduced response to phytohemagglutinin(PHA), a chemical that is used to induce lymphocytes to undergo cell division, the mitotic index is drastically lower, and progression through the cycle is much slower than preflight. This phenomenon, which may be related to changes observed in the immune response and/or other stress and microgravity effects,seems to last only a few days. For this reason post flight sampling was restricted to 7-14 days after flight.

Fig. 2 shows the preflight in vitro dose response for gamma-ray induced chromosome damage in astronautsâ&#x20AC;&#x2122; blood lymphocytes.The first five plots represent dose responses for individual astronauts (A-E) measured before their first and second flight. Astronaut A has an additional measurement from samples collected before a short duration shuttle mission that occurred between ISS increments. The sixth plot is included for comparison and represents a combined plot of all preflight dose responses collected so far from the astronaut population. In the combined plot each symbol for a given dose represents a different individual. Dose response is similar for samples collected from the same individual at different times, where as the combined plot shows a wide spread of response for a given dose.

Table 1 shows the measured yield of translocations and total exchanges for each individual along with their radiation doses measured using personal TLDâ&#x20AC;&#x2122;s and cytogenetic biodosimetry data. In contrast to the biological dose, the TLD dose does not take into account the tissue self-shielding or biological weighting of the galactic cosmic rays and trapped radiation contributions to the individual doses. by comparing a linear weighted regression model of the

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Human Space Flight Edition individualâ&#x20AC;&#x2122;s preflight in vitro gamma ray dose response for chromosome damage with postflight yields. A "population average" method was also used to measure the biological dose using the weighted average of the linear coefficient of regression model of the dose responses for all the astronauts assessed so far (Fig. 2, last panel). In most cases a significant increase in the biological dose estimates was measured after each spaceflight.

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Human Space Flight Edition

No decrease in the individual yield of chromosome exchanges was observed between flights, with the exception of astronaut A where the yield of translocations decreased during the period between the first and second mission.

These data are consistent with a previous study of 16 individuals showing pooled data for mono-centric aberrations remain consistent with time after flight and only a slight decrease in total exchanges occurred after the first 220 days, although a large individual variation in temporal response was shown.

Comparison of data from pre-and post-flight samples shows an increase in chromosome aberration yield in all individuals after both the first and second flights. Astronaut A had a much smaller increase after the second flight compared to the first flight.However, physical dose measurements using this individualâ&#x20AC;&#x2122;s TLD badge show the dose was considerably less for the second flight(Table 1). Astronaut A also participated in a short duration shuttle mission between ISS increments, although this mission did not induce any measureable increase in the yield of chromosome damage. For the remaining four astronauts, the second mission induced a similar or greater increase in chromosome damage compared to the first, and personal TLDs measurements showed the radiation dose was either approximately the same or higher for the second flight compared to the first. For astronaut C, the yield of chromosome damage at the first sampling time after the second mission was not significantly different from preflight, whereas the two postflight follow up samples were both elevated compared to preflight.Because of the consistency in the yield of damage in the follow up samples, the second post flight analysis was used for dose measurements in this individual.

Data in Fig. 2 confirm that individual radiation response is similar before and several months after the first mission, and no radio-sensitivity changes could be detected at least in the case of in vitro dose response assessment. Whereas the dose response is similar for samples collected at different times from the same individual, inter-individual differences can be seen when comparing the response of each crewmember (Fig. 2A-E). A combined plot of all astronauts measured so far, a total of 34 individuals, shows a wide spread of response for a given dose (Fig. 2, last panel).This suggests an individual preflight dose response may be more accurate for assessing biological dose.

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Human Space Flight Edition Uncertainties in cancer projections For space radiation risk assessments, the major uncertainties in cancer prediction are: • Radiation quality effects on biological damage related to the qualitative and quantitative differences between space radiation compared to X rays • Dependence of risk on dose-rates in space related to the biology of deoxyribonucleic acid (DNA) repair, cell regulation, and tissue or organism responses • Predicting SPEs, including temporal, energy spectra, and size predictions • Extrapolation from experimental data to humans and between human populations • Individual radiation-sensitivity factors, including genetic, epigenetic, dietary, or "healthy worker" effects

The minor uncertainties in cancer risk prediction are: • Data on GCR environments • Physics of shielding assessments related to transmission properties of radiation through materials and tissue • Microgravity effects on biological responses to radiation • Errors in human data (statistical, dosimetry, or recording inaccuracies)

Radiation affects cells and tissues either through direct damage to the cellular components or through the production of highly reactive free radicals from water . Both of these mechanisms can generate sufficient damage to cause cellular death, DNA mutation, or abnormal cellular function. The extent of damage is generally believed to be dependent on the dose and type of particle with a linear dose-response curve. This is true for high and moderate radiation exposure, but it is extremely difficult to measure for lower doses where it is not easy to discern the effects of radiation exposure from those that are triggered by the normal oxidative stress with which cells and tissues deal constantly. The HZE nuclei are unique components of space radiation that produce densely ionizing tracks as they pass through matter; when they traverse a biological system, they leave streaks or tracks of damage at the biomolecular level that fundamentally differ from the damage that is left by low-LET radiation sources such as gamma rays and X rays. In the nucleus of a cell, where the genetic material is stored, the traversal of a heavy ion can produce tracks of clustered DNA damage, as illustrated in figure 4-3.

HZE nuclei impart damage via the primary energetic particle as well as from fragmentation events that produce a spectrum of other energetic nuclei, including protons, neutrons, and heavy fragments; a large penumbra of energy deposition extends outward from the primary particle track . Secondary radiation that is produced in shielding materials can be controlled through the use of materials that have light atomic constituents (e.g., hydrogen and carbon).

However, a large percentage of secondary radiation is produced within tissue and is, therefore, not practically avoidable. Due to the large amount of energy that is deposited as these particles traverse biological structures, the HZE nuclei are capable of producing the greatest amount of cellular damage, which means that they are of great concern for astronaut safety. The lack of epidemiological data and sparse radiobiological data on the effects for these radiation types leads to a high level of uncertainty when formulating risk estimates of long-term health effects following exposure to GCRs and SPEs.

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Human Space Flight Edition

Types of cancer caused by radiation exposure A broad spectrum of tissue types contributes to the overall cancer risk that is observed with low-LET radiation (Table 4-2), including lung, colorectal, breast, stomach, liver, and bladder cancers as well as several types of leukemia, including acute myeloid leukemia and acute lymphatic lymphoma .

It is not known whether the same spectrum of tumors will occur for high-LET radiation as with low-LET radiation, and some differences should be expected. Relative biological effectiveness (RBE) factors describe the ratio of a dose of high-LET radiation to that of the X rays or gamma rays that produce the identical biological effect. RBEs that are observed in mice with neutrons vary with the tissue type and strain of the animal, which provides evidence that the spectrum of tumors in humans who are exposed to space radiation will be distinct from that in humans who ISOPTWPO Today c International Space Agency(ISA)

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Human Space Flight Edition are exposed to low-LET radiation. These likely differences are not described by the models that are used currently at NASA to project space radiation risks.

Current NASA permissible exposure limits Permissible exposure limits (PELs) for short-term and career astronaut exposures to space radiation have been approved by the NASA Chief Health and Medical Officer, and requirements and standards for mission design and crew selection have been set. This section describes the cancer risk section of the PELs. â&#x20AC;˘ Career Cancer Risk Limits The astronaut career exposure to radiation is limited to not exceed 3(REID) from fatal cancer. NASA policy is to assure that this risk limit is not exceeded at a 95level (CL) by using a statistical assessment of the uncertainties in the risk projection calculations to limit the cumulative effective dose (in units of Sievert) that is received by an astronaut throughout his or her career. These limits are applicable to missions of any duration in LEO and to lunar missions of less than 180 days duration. For longer missions that are outside LEO, further considerations of non-cancer mortality risks and approaches to reduce uncertainty in cancer risk projection models must occur before these missions can be safely assured. â&#x20AC;˘ Cancer Risk to Dose Relationship The relationship between radiation exposure and risk is both age- and gender-specific due to latency effects and differences in tissue types, sensitivities, and life spans between genders. These relationships are estimated using the methods that are recommended by the NCRP (NCRP, 2000) and more recent radiation epidemiology information. Table 4-1 lists examples of career effective dose (E) limits for an REID=3% for missions that are of 1-year duration or less. Limits for other career or mission lengths will vary and should be calculated using the appropriate life-table formalism. Tissue contributions to effective doses are defined below, as are dose limits for other career or mission lengths. Estimates of average life-loss that are based on low-LET radiation are also listed in Table 4-1; however, higher values should be expected for high-LET exposures such as GCRs.

Radiation Limits for Other Space Agencies The European Space Agency (ESA), Russian Space Agency (RSA), and Japanese Space Agency (JAXA) use dose limits for astronauts and cosmonauts largely based on the recommendations of the International Commission on Radiological Protection (ICRP) for ground-based works with some modifications for 30-day and annual limits for non-cancer effects. A series of flight rules and action levels is in place for the ISS based on real-time dosimetry, mission length, and prior crew exposures. Crew are not selected for missions if they are projected to exceed career limits at the end of any given mission.

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The Russian Space Agency (RSA) uses the following Dose limits.

Biodosimetry, which has been performed on all ISS missions as well as for four astronauts on Mir missions, offers an alternative evaluation of organ dose-equivalents. Figure 4-6 shows results for the pre- and post-flight frequency of translocations, which are complex aberrations involving more than two chromosomes, and total exchanges. Total exchanges are increased post-flight over pre-flight values in all cases, and translocations increase in all ISS astronauts, but they did not increase for two astronauts: one who was returning from the Mir space station, and one who was on a Hubble repair mission. To test whether the overall frequency of complex aberrations was increased by space radiation, Cucinotta et al. (2008) pooled results into two groups: all ISS data, and all ISS data plus results from other NASA missions. The relative frequencies for complex aberrations and translocations were shown to be highly significant (P<10 â&#x2C6;&#x2019;4 ).

Figure 4-7 shows a summary of the crew doses for all NASA missions through the year 2007. The level of accuracy in effective dose determination and in the GCR environments suggests a high level of accuracy in predicting organ dose and dose-equivalencies for both lunar and Mars missions. The cancer projection model of NCRP Report No. 132 (NCRP, 2000), which can be applied to these effective doses, indicates REID values approaching 1% for many astronauts who have flown on ISS or the Russian space station Mir

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Human Space Flight Edition Reference: 1.Risk of Radiation Carcinogenesis,Human Research Program Requirements Document,HRP-47052, Rev. C, dated Jan 2009.

2.Website(http://www.astrobio.net/news-exclusive/calculated-risks-how-radiation-rules-mars-exploration/) 3.Hassler et al.,Mars’ Surface Radiation Environment Measured with the Mars Science Laboratory’s Curiosity Rover,2013.

DOI: 10.1126/science.1244797 4.Website(http://www.spaceflight101.com/msl-rad-science-reports.html) 5.Greco, O., Durante, M., Gialanella, G., Grossi, G., Pugliese, M.,Scampoli, P.: Biological dosimetry in Russian and Italian astronauts. Advanced Space Research vol 31, p. 1495 (2003) 6.Marco Durante and Francis A. Cucinotta,Heavy ion carcinogenesis and human space exploration,doi:10.1038/nrc2391.

7.Wu, H., George, K., Willingham, V., Cucinotta, F A.: Comparison of chromosome aberration frequencies in pre- and post-flight astronauts lymphocytes irradiated in vitro with gamma rays. Physica Medica vol. 17, p. 229 (2001) 8.Durante, M., Snigiryova, G., Akaeva, E., Bogomazova, A., Druzhinin, S.,Fedorenko, B., Greco, O., Novitskaya, N., Rubanovich, A., Shevchenko,V., von Recklinghausen, U., Obe, G.: Chromosome aberration dosimetryin cosmonauts after single or multiple space flights. Cytogenetic andGenome Research vol. 103, p. 40 (2003) 9.A. Bertucci, M. Durante, G. Gialanella, G. Grossi et al: Biological dosimetry in the ENEIDE Mission on the International Space Station.

10.Durante, M. Biomarkers of Space Radiation Risk. Radiat. Res. 164, 467-473 (2005).

11. A. L. Brooks, Biomarkers of exposure, sensitivity and disease. Int. J. Radiat. Biol. 75, 1481-1503 (1999).

12. A. L. Brooks, Biomarkers of exposure and dose: state of the art. Radiat. Prot. Dosim. 97, 39-46 (2001).

13.ICRU, Retrospective Assessment of Exposures to Ionizing Radiation. Report 68, International Commission on Radiation Units and Measurements, Bethesda, MD, 2002.

14. G. Obe, R. Facius, G. Reitz, I. Johannes and C. Johannes, Manned missions to Mars and chromosome damage.

Int. J. Radiat. Biol. 75, 429-433 (1999).

15. ESA, HUMEX: Study on Survivability and Adaptation of Humans to Long-Duration Exploratory Missions. ESA SP1264, ESTEC, Nordwijk, 2003.

16.M. Horstmann,M. Durante,C. Johannes,R. Pieper, G. Obe,Space radiation does not induce a significant increase of intrachromosomal exchanges in astronauts’ lymphocytes,Radiat Environ Biophys (2005) 44: 219-224.

17.K. Georgea,J. Rhoneb,A. Beitmana,F.A. Cucinottac,Cytogenetic damage in the blood lymphocytes of astronauts: Effects of repeatlong-duration space missions,2013.

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ISOPTWPO The ISOPTWPO is International Space Flight & Operations - Personnel Recruitment, Training, Welfare, Protocol Programs Office (International Space Academy). It is a division of the ISA organization.

Mr. Martin Cabaniss is director and Mr. Abhishek Kumar Sinha is Assistant Director of ISOPTWPO. Ad Astra ! To The Stars! In Peace For All Mankind !

Mr. Rick R. Dobson, Jr.(Veteran U.S Navy) â&#x20AC;&#x201D; International Space Agency (ISA)

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