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

Human Research Program Space Radiation Program Element Approved for Public Release: April 6, 2016 National Aeronautics and Space Administration Lyndon B. Johnson Space Center Houston, Texas

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CURRENTCONTRIBUTINGAUTHORS:

ZaranaPatel,PhDWyleScienceTechnology&Engineering,Houston,TXJaniceHuff,PhDUniversitiesSpaceResearchAssociation,Houston,TXJanapriyaSaha,PhDUniversitiesSpaceResearchAssociation,Houston,TXMinliWang,MDUniversitiesSpaceResearchAssociation,Houston,TXSteveBlattnig,PhDNASALangleyResearchCenter,Hampton,VAHongluWu,PhDNASAJohnsonSpaceCenter,Houston,TXPREVIOUSCONTRIBUTINGAUTHORS:

JaniceHuff,PhDUniversitiesSpaceResearchAssociation,Houston,TXFrancisCucinotta,PhDNASAJohnsonSpaceCenter,Houston,TXReference for original report: Human Health and Performance Risks of Space ExplorationMissions,(JancyC.McPheeandJohnB.Charles,editors),NASASP-2009-3405,2009.

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TableofContentsI. RISKOFCARDIOVASCULARDISEASEANDOTHERDEGENERATIVETISSUEEFFECTS

FROMRADIATIONEXPOSURE 4II. EXECUTIVESUMMARY 4III. INTRODUCTION 5A. DescriptionofDegenerativeRisksofConcerntoNASA 6B. CurrentNASAPermissibleExposureLimits 7

IV. EVIDENCE 8A. Ground-basedEvidence 8

1. Cataracts 82. CardiovascularDiseases 103. DigestiveandRespiratoryDiseases 184. EvidenceforOtherAge-RelatedEffectsCausedbyRadiation 215. RadiationEffectsonEndocrineFunction 236. MusculoskeletalSystem 237. Endometriosis 24

B. SpaceflightEvidence 241. CataractsinAstronauts 242. CardiovascularDiseaseinAstronauts 273. Influenceofgenetic/individualsusceptibilityontheDegenerativeRisk 294. Summary 29

V. COMPUTER-BASEDSIMULATIONINFORMATION 29VI. RISKINCONTEXTOFEXPLORATIONMISSIONOPERATIONALSCENARIOS 31A. ProjectionsforSpaceMissions 31B. SynergisticEffectswithotherFlightFactors 32C. PotentialforBiologicalCountermeasures 33

VII. GAPS 35VIII.CONCLUSION 36IX. REFERENCES 37X. TEAM 50XI. LISTOFACRONYMS 51

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I. PRDRiskTitle:RISKOFCARDIOVASCULARDISEASEANDOTHERDEGENERATIVETISSUEEFFECTSFROMRADIATIONEXPOSURE

Degenerative tissue (non-cancer or non-central nervous system [CNS]) effects, such ascardiovascular disease, cataracts, and digestive and respiratory diseases, are documentedfollowingexposurestoterrestrialsourcesofionizingradiation(e.g.,gammaraysandx-rays).Inparticular, cardiovascular pathologies such as atherosclerosis are ofmajor concern followinggammarayexposure.Thisprovidesevidenceforpossibledegenerativetissueeffectsfollowingexposurestoionizingradiationintheformofgalacticcosmicrays(GCR)orsolarparticleevents(SPEs) expected during long-duration spaceflight. However, the existence of low dosethresholdsanddose-rateand radiationqualityeffects, aswell asmechanismsandmajor riskpathways,arenotwell-characterized.Degenerativediseaserisksaredifficulttoassessbecausemultiplefactors,includingradiation,arebelievedtoplayaroleintheetiologyofthediseases.Dataspecifictothespaceradiationenvironmentmustbecompiledtoquantifythemagnitudeof this risk to decrease the uncertainty in current permissible exposure limits (PELs) and todetermineifadditionalprotectionstrategiesarerequired.

II. EXECUTIVESUMMARY

Occupationalradiationexposurefromthespaceenvironmentmayresultinnon-cancer

or non-CNS degenerativetissue diseases, such as cardiovascular disease, cataracts, andrespiratory or digestive diseases. However, the magnitude of influence and mechanisms ofactionofradiationleadingtothesediseasesarenotwellcharacterized.RadiationandsynergisticeffectsofradiationcauseDNAdamage,persistentoxidativestress,chronic inflammation,andaccelerated tissue aging and degeneration, which may lead to acute or chronic disease ofsusceptibleorgan tissues. Inparticular, cardiovascularpathologiessuchasatherosclerosisareof major concern following gamma-ray exposure. This provides evidence for possibledegenerativetissueeffectsfollowingexposurestoionizingradiationintheformoftheGCRorSPEsexpectedduringlong-durationspaceflight.However,theexistenceoflowdosethresholdsanddose-rateandradiationqualityeffects,aswellasmechanismsandmajorriskpathways,arenot well-characterized. Degenerative disease risks are difficult to assess because multiplefactors, including radiation, are believed to play a role in the etiology of the diseases. Asadditional evidence is pointing to lower, space-relevant thresholds for these degenerativeeffects,particularlyforcardiovasculardisease,additionalresearchwithcellandanimalstudiesis required toquantify themagnitudeof this risk, understandmechanisms, anddetermine ifadditionalprotectionstrategiesarerequired. The NASA PELs for cataract and cardiovascular risks are based on existing humanepidemiologydata.Althoughanimalandclinicalastronautdatashowasignificant increase incataracts followingexposureanda reassessmentofatomicbomb (A-bomb)data suggestsanincrease in cardiovasculardisease fromradiationexposure,additional research is required tofullyunderstandandquantifytheseadverseoutcomesatlowerdoses(<0.5Gy)tofacilitateriskprediction.Thisriskhasconsiderableuncertaintyassociatedwith it,andnoacceptablemodelforprojectingdegenerative tissue risk is currently available. Inparticular, risk factors suchas

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obesity, alcohol, and tobaccouse canactas confounding factors that contribute to the largeuncertainties. The PELs could be violatedunder certain scenarios, including following a largeSPE or long-term GCR exposure. Specifically, for a Mars mission, the accumulated dose issufficientlyhighthatepidemiologydataandpreliminaryriskestimatessuggestasignificantriskforcardiovasculardisease.

Ongoingresearchinthisareaisintendedtoprovidetheevidencebaseforaccurateriskquantification to determine criticality for extended duration missions. Data specific to thespace radiation environment must be compiled to quantify the magnitude of this risk todecrease theuncertainty in current PELs and todetermine if additional protection strategiesare required.New research results could lead to estimates of cumulative radiation risk fromCNS and degenerative tissue diseases that, when combined with the cancer risk, may havemajor negative impacts on mission design, costs, schedule, and crew selection. The currentreport amends an earlier report (Human Research Program Requirements Document, HRP-47052,Rev.C,datedJan2009)inordertoprovideanupdateofevidencesince2009.III. INTRODUCTION

Theenvironmentoutsideoftheshield-likeatmosphereandmagnetosphereoftheEarth

containsseveraltypesofradiation.Mostoftheparticlesininterplanetaryspacearederivedfromthesolarwind,whichproducesaconstantfluxoflow-energyparticles.However,dangerousandintermittentsolarparticleevents(SPEs)canproducelargequantitiesofhighlyenergeticprotonsandheavyions.Galacticcosmicrays(GCR)representanadditionalparticleconstituentofspaceradiation and emanate from outside our solar system. GCR is comprised of mostly highlyenergeticprotonswithasmallcomponentofhigh-Z,high-energy(HZE)nuclei.Researchershavepredictedthatanastronautwillreceiveatotalbodyexposureofapproximately300-450mGy,or1to1.3Sv,fora3-yearmissiontoMars,andthesenumberswillincreaseintheeventofaSPE(Guoetal.2015;Köhleretal.2014).

Exposure to ionizing radiation affects cells and tissues either by directly damagingcellular components or by producing highly reactive free radicals from water and otherconstituents of cells. Both of these mechanisms can produce sufficient damage to cause celldeath, deoxyribonucleic acid (DNA) mutation, or abnormal cell function (Li et al. 2014). Theextentofdamageisgenerallybelievedtodependonthedoseandthetypeofparticleandtofollow a linear response to radiation dose for initial induction of damage for high andmoderate radiation doses, but it is extremely difficult tomeasure for lower doseswhere theshape of the dose response curve is less well-defined andmay be affected by non-targetedeffectsthataredifficulttodistinguishfromnormalcellularoxidativestress(Lietal.2014).

Because HZE nuclei are the components of space radiation that have the highestbiologicaleffectiveness,theyarealargeconcernforastronautsafety.HZEnucleiproducehighlyionizingtracksastheypassthroughmatter. Inaddition,they leavecolumnsofdamageatthemolecular levelwhen they traverseabiological system–damage that isdifferent in severityand complexity from the damage that is left by low-linear energy transfer (LET) radiationsourcessuchasgamma-andX-rays (DuranteandCucinotta2008).HZEnuclei impartdamagethrough the primary energetic particle and secondary delta-ray electrons as well as fromfragmentationeventsthatproduceaspectrumofotherenergeticnuclei,protons,neutrons,

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andheavy fragments (Wilsonetal. 1995). Therefore, a largepenumbraofenergydepositionextendsoutwardfromtheprimaryparticletrack.The lackofepidemiologicaldataandsparseradiobiologicaldataontheeffectsoftheseHZEnucleileadstoahighlevelofuncertaintyinriskestimatesforlong-termhealtheffectsafterexposuretoGCRandSPEs.

NASAhasfundedseveralpreviousreportsfromtheNationalAcademyofSciences(NAS)andthe National Council on Radiation Protection and Measurements (NCRP) that providedevidencefortheradiationrisks inspace.TheNCRPischarteredbytheU.S.CongresstoguidefederalagenciessuchasNASAontherisk fromradiationexposurestotheirworkers.Reportsfrom the NCRP and the National Research Council (NRC) on space radiation risks are thefoundation for how NASA views the wide scientific body of evidence that is used for itsresearchandoperationalradiationprotectionmethodsandplans.RecentreportsofparticularrelevancetothisEvidenceReportincludeNCRP2000,NCRP2006,NAS/NRC2008,NCRP2010,and NCRP 2014. The International Commission on Radiological Protection (ICRP) has alsoreleased guidance and reviews, with ICRP 2007 and 2012 being of particular importance.Additionally, the UK Health Protection Agency recently reviewed the subject of radiation-inducedcirculatoryrisk(HealthProtectionAgency2010).

A. DescriptionofDegenerativeRisksofConcerntoNASAThe effects of protracted exposure to low dose rates (< 20 mGy/h) of protons, HZE

particles,andneutronsoftherelevantenergiesfordosesupto≈0.5to1Gy(correspondingtoexposuresestimatedfordesignreferencemissions indeepspace)ondegenerativeconditionsof the circulatory and other organ systems are of concern. Current Mars design referencemission exposure estimates vary between 0.25 and 0.5 Gy from GCR, with shielded SPEexposures on the order of 0.15 to 0.5Gy to internal body organswithin a typically shieldedspacecraft. Approximate relative dose (Gy) contributions to total organ exposure from GCRinclude protons delivering ~50-60% of the dose, alphas delivering approximately 10-20%,heaviesof 3<Z<9contributing~5-10%,heaviesofZ>10contributing~5-10%,andsecondaryradiation(e.g.,neutrons,pions,andmuons)contributingontheorderof10%ofthetotaldose.Themajordegenerativeconditionsofconcernthatcouldpotentiallyresultfromspaceradiationexposureareasfollows:

• Degenerative changes in the circulatory system, including cardiovascular diseases(ischemic heart disease (IHD), atherosclerosis), cardiomyopathy, and cerebrovascularandperipheralarterialdiseases,leadingtostroke

• Cataractformation• Otherdiseasesrelatedtoacceleratedagingeffects,includingprematuresenescenceand

fibrosis• Immuneandendocrinesystemdysfunction• Other possible degenerative diseases of concernmay include respiratory or digestive

diseases;however,aclearbaseofevidencehasyettobeestablishedforspace-relevantexposures.

Note that risks to the central nervous system (CNS) may also involve degenerativeconditions,buttheyaretreatedasastand-aloneriskcategorybyNASAandaredescribedintheEvidenceReporttitled“RiskofAcuteandLateCentralNervousSystemEffectsfromRadiation

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Exposure” found at http://humanresearchroadmap.nasa.gov/Evidence/reports/CNS.pdf(Nelsonetal.2015).

B. CurrentNASAPermissibleExposureLimitsPermissibleexposurelimits(PELs)forshort-termandcareerexposurestospaceradiation

havebeen approved by the NASA Chief Health and Medical Officer, who also sets the re-quirements and standards formission design and crew selection. Tables 1 and 2, which aretakendirectlyfromNASA-STD-3001,Volume1,rev.A(NASA2014), listthecurrentshort-andlong-termPELs for non-cancer effects (Table 1; in mGy-Equivalents or mGy) and relevantrelative biological effectiveness (RBE) values (Table 2). The lifetime limits for cataracts andheartdiseaseareimposedtolimitorpreventrisksofdegenerativetissuediseases.ThecurrentPELs are based on recommendations from NCRP 2000, which defines a threshold as anexposure belowwhich clinically significant effects do not occur. However, the ICRP recentlyredefinedtheirnotionofathresholddoseasthedoserequiredtocausea1%incidenceofanobservableeffect(ICRP2007and2012).Inparticular,ICRP2012includednewerevidenceandnoted a lower threshold for both cataractogenesis and cardiovascular effects from ground-basedradiationexposure,withthepreviousthresholdof2Gylowereddownto0.5Gy.NCRP’slatestupdatetotheirPELrecommendationsincommentary23(NCRP2014)states:“Aresearchprogramthatprovidesadditionalscientificandtechnicaldatamayleadtotheneedforfurtherdefinition of acceptable levels of radiation risk, for example to take into account additionalhealth effects and the difference in mission scenarios, resulting in more restrictive missionlimits. At this time, NCRP does not recommend any specific radiation protection limit forexploratorymissions.”

Table1.DoseLimitsforShort-TermorCareerNon-CancerEffects(inmGy-Eq.ormGy)(NASASTD3001RevA).Note:RBEsforspecificrisksaredistinctasdescribedbelow.

Organ 30-day limit 1-year limit Career

Lens* 1,000 mGy-Eq 2,000 mGy-Eq 4,000 mGy-Eq

Skin 1,500 mGy-Eq 3,000 mGy-Eq 6,000 mGy-Eq

BFO 250 mGy-Eq 500 mGy-Eq Not applicable

Heart** 250 mGy-Eq 500 mGy-Eq 1,000 mGy-Eq

CNS*** 500 mGy 1,000 mGy 1,500 mGy

CNS*** (Z ≥ 10) – 100 mGy 250 mGy *Lenslimitsareintendedtopreventearly(<5yr)severecataracts,e.g.,fromasolarparticleevent.Anadditional

cataract riskexistsat lowerdoses fromcosmic rays for sub-clinical cataracts,whichmayprogress to severetypesafteralonglatency(>5yr)andarenotpreventablebyexistingmitigationmeasures;however,theyaredeemedanacceptablerisktotheprogram.

**Circulatorysystemdosescalculatedastheaverageoverheartmuscleandadjacentarteries.***CNSlimitsshouldbecalculatedatthehippocampus.

Because NASA has established short-term dose limits to prevent clinically significantdeterministichealtheffects,includingperformancedegradationinflight,thesedoselimitsand

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accumulated evidencewill be reviewed by NCRP in the next five years to establishwhetherthere are sharp thresholds or theremay still be some risk at lower doses. This deterministicapproach,which uses an estimate of threshold doses for cardiovascular and cataract risk, isquitedistinctfromthatforcancerrisklimits, inwhichaprobabilisticassessmentoftheriskismadeusingaprojectionmodel.Giventhetrendofincreasinglylowerthresholddoses,itislikelythatasimilarstochasticapproachwillbeneededinthefuturefordegenerativerisks. Table2.RBEforNon-CancerEffectsaoftheLens,Skin,BFO,andCirculatorySystems(NASASTD3001RevA).

Radiation Type Recommended RBE

b Range 1 to 5 MeV neutrons 6.0 (4-8) 5 to 50 MeV neutrons 3.5 (2-5) Heavy ions 2.5

c (1-4) Protons > 2 MeV 1.5 -

aRBEvaluesforlatedeterministiceffectsarehigherthanthoseforearlyeffectsinsometissuesandareinfluencedbythedosesusedtodeterminetheRBE.

bThereareinsufficientdataonwhichtobaseRBEvaluesforearlyorlateeffectsbyneutronsofenergies<1MeVorgreaterthanabout25MeV.

c There are few data on the tissue effects of ions with a Z>18, but the RBE values for iron ions (Z=26) arecomparabletothoseforargon(Z=18).OnepossibleexceptioniscataractofthelensoftheeyebecausehighRBEvaluesforcataractsinmicehavebeenreported.

IV. EVIDENCE

A.Ground-basedEvidence1. Cataracts

a.Cataractstudieswithlow-LETradiationThe development of ocular cataracts, which is a degenerative opacification of the

crystallinelens, is a well-recognized late effect of exposure to ionizing radiation.Comprehensivereviewsoftheevidenceforradiation-inducedcataractsincludeNCRP2006and2014, aswell as ICRP2012.The first reportsofradiation-inducedcataractsappearedearly inthe20thcentury,shortlyafterthefirstX-raymachinesweredeveloped(Rollins1903).It isnowclearthatradiation-inducedcataractsexhibitrelationshipsbetweenradiationdoseanddiseaseseverity, as well as between dose and latency. Evidence for this link comes,most notably,from survivors of radiotherapywho receivedhighdoses (>5Gy)of ionizing radiationusingXrays,gamma-rays,andprotonbeamsforoculartumors(Ferrufino-PonceandHenderson2006;Blakely et al. 1994; Gragoudas et al. 1995) and from individuals who received whole-bodytherapeuticradiation(Belkacémietal.1996;Dunnetal.1993;Frisketal.2000).

Evidence of radiation exposure leading to cataract formation (moderate- to low-dosegamma-rayexposures)comesfromepidemiologicaldatafromA-bombsurvivorsfollowedintheLifeSpanStudy(LSS)conductedbytheRadiationEffectsResearchFoundation(RERF).This isa

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longitudinalstudyofJapanesesurvivorsofthebombingsofbothHiroshimaandNagasaki,whichremainsoneofthemostvaluableandinformativeepidemiologicalstudiesforevaluatinglong-termhealtheffectsofradiationexposure(Prestonetal.2003).

Among the A-bomb survivors, the frequency and severity of cataracts are dose-dependent. Severity refers to the size and loss of visual acuity due to the cataract or thepresence of conditions requiring lens implants to prevent blindness. Symptoms appeared assoonasseveralmonthsafterexposureforseverecasesandseveralyearsafterexposureforless-severe cases. The frequency of cataractswas related to the proximity of the subject to thehypocenteroftheatomicbomb.Apossiblethresholddosewasoriginallyestimatedtobeintherangeof0.6to1.5Gy(Junketal.1998;OtakeandSchull1982,1991),butanon-thresholddosemodelhasbeenproposed inmorerecentreports (Neriishietal.2007). Inaprospectivestudythatfollowedthedevelopmentofradiation-inducedcataractsinworkerswhowereexposedtoradiationduringtheeffortstocleanupaftertheChernobylnuclearpowerplantdisaster,itwasfound that posterior subcapsular or cortical cataracts were present in 25% of the examinedindividuals. The investigatorsestimated that thedose effect threshold for cataract formationfollowingradiationexposureislessthan1Gy(Worguletal.2007).

As noted by Blakely et al. (2007a, 2010), published data on radiation-induced humancataractsarelimitedinpredictingtheriskfromchronicexposuretolowdosesofprotonsorlowfluencesofheavyions,suchasthoseencounteredinspace,becauseofthepossiblequalitativedifferencesineffects.However,studiesonprotonexposuresincancerpatientssuggestanRBEnearone for protons exceptnear theBraggpeak,where the LET is significantly higher (ICRP2012). Studies of cataracts in astronauts provide important insights as described below(Cucinottaetal.2001;Jonesetal.2007;Chylacketal.2009,2012).

b.CataractStudieswithProtons,Neutrons,andHZENucleiAlthoughthelargestbodyofinformationonradiation-inducedcataractogenesiscomes

from studies using low-LET radiation sources, substantial data also describe the induction ofcataractsinavarietyofanimalspeciesbydifferenttypesofparticleradiationsourcesthataresimilar to those that are encountered in space, including protons and high-LET particleradiation. The U.S. Air Force (USAF)/NASA Proton Bioeffects Project was an effort to identifydelayed or late effects of X rays, electrons, andprotons of differing energies on the long-termhealthofacolonyofRhesusmonkeys.Asubpopulationoftheprimatesthatwerestudied intheUSAF/NASAprojectwasmonitoredforabout30years for lateeffects, includingcancer,cataracts,andshorteningoflife.Analysesoftheseprimatesforsignsofcataractogenesisbegan20 years after exposure, and significant opacifications of the eye lens were seen in thesemonkeys20 to24yearsafterexposure to55-MeVprotonsat1.25Gyandhigher levels. Theresultsthatwereobtainedfromtheseexperimentssuggestthatthedose-responserelationshipfor inductionofcataractsbyprotons is similar to that seenwith low-LET radiation (Lettetal.1991;Coxetal.1992).Thesefindingsaresupportedbyotherstudiesoncataractformationinanimalmodelsusinghigh-energyprotonbeams(Niemer-Tuckeretal.1999;Fedorenko1995).In many studies of heavy ions, cataractogenesis that was induced by individual high-LETcomponentsofthespaceradiationspectrumwasanalyzed.Theconclusionsderivedfromthesestudies are that a trend exists for a decrease in the latency between exposure and theappearanceofcataractlesionsandthatthisdecreaseinlatencyoccursatlowerdosethresholds

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forheavyionscomparedtolow-LETx-raysandprotons.Table3listsrepresentativestudiesfordifferentheavy ionspecies.Studies inanimalsshowedanage-dependentsensitivity,withtheyoungeranimalsexhibitingalowerdosethresholdforcataractinductionthantheolderanimals(Coxetal.1992).

Table3.ReferencesforCataractogenesisStudiesConductedwithHigh-LETRadiation

High-LETComponent

SelectedReferences

Neutrons Ainsworth 1986; Riley et al. 1991; Worgul et al. 1996;Christenberryetal.1956

Argon Merriametal.1984;Lettetal.1980;Worgul1986;Abrosimovaetal.2000;JoseandAinsworth1983

Neon Lettetal.1980;Abrosimovaetal.2000;JoseandAinsworth1983Iron Brenner et al. 1993; Lett et al. 1991; Medvedovsky et al. 1994;

Rileyetal.1991;Taoetal.1994;Worgul1986;Worgul1993;Davisetal.2010

Protons Niemer-Tuckeretal.1999;Fedorenko1985;Lettetal.1991;Coxetal.1992

2. CardiovascularDiseases

a.EpidemiologicStudiesTheassociationbetweenhighdosesofradiationexposureandcardiovasculardamageis

wellestablished.Patientswhohaveundergone radiotherapy forprimarycancersof theheadandneckandmediastinalregionshaveshownanincreasedriskofheartandvasculardamageandlong-termdevelopmentofradiation-inducedheartdisease.Thesedataarewell-detailedinseveralreports(NCRP2006and2014;ICRP2012;HealthProtectionAgency2010).

Liketheevidencedescribedforcataractogenesis,themajordrivingevidencethatprovesa linkbetween ionizing radiation exposure and the development of degenerative heart andvasculaturechangescomesfromprospectivestudiesthatfollowthelong-term,radiotherapy-related effects in cancer survivors. These patients received relatively high therapeutic doses(~5–50Gy)oflow-LETthoracicradiationinthecourseoftherapyforcancersofthehead,neck,andmediastinal regions, such as Hodgkin’s lymphoma and breast cancer (Prosnitz et al. 2005;Darbyetal.2005;Carveretal.2007;Swerdlowetal.2007;Mulrooney2009;Darbyetal.2013).There is a dose-dependent increase in the development of a wide variety of cardiovasculardiseases, including acute and chronic pericarditis, coronary artery disease, cardiomyopathy,valvulardisease,andconductionabnormalities,intheseindividuals.ThestudyofDarbyetal.(2013) reported the relationship of the risk of ischemic heart disease after breast cancerradiotherapytoradiationdosetotheheartandtoothercardiacriskfactors.Figure1showsthelineardose-dependentrelationshipbetweenexposureandexcessrelativerisk (ERR)basedontheirfindings,withtheriskincreasing7.4%foreverygrayofexposureatthesehighdoses.

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Figure1.RateofMajorCoronaryEventsAccordingtotheMeanRadiationDosetotheHeartComparedwiththeEstimatedRatewithNoRadiationExposuretotheHeart(Darbyetal.2013).*ReproducedwithpermissionfromtheNewEnglandJournalofMedicine-CopyrightMassachusettsMedicalSociety.

Within 5 years after radiotherapy, the frequency of major coronary events starts to

increaseinalinearmannerwithnoapparentthresholdandcontinuesforatleast20yearsafterradiationexposure.Womenwithcardiacriskfactorsatthetimeofradiotherapyhavegreaterabsoluteincreasesinriskfromradiotherapythanthosewithout(Darbyetal.2013).Thesehighdoses (>5Gyexposures) areassociatedwithdamage to the structuresof theheart and tothe coronary, carotid, and other large arteries, including marked diffuse fibrotic damage,especiallyofthepericardiumandmyocardium,pericardialadhesions,microvasculardamage,and stenosis of the valves (Little 2013). Mechanisms of damage involve cell killing orinactivationoflargenumbersofcellswhichcausefunctionalimpairment.

Atmoderatedosesof radiationexposure,between0.5and5Gy,otherevidence thatsupports a link between the occurrence of cardiovascular disease and radiation exposure isderived from prospective studies of A-bomb survivors who received moderate doses ofradiation (0–2Gy), aswell as fromoccupationally exposedworkerswho received continuouslow-doseexposure(Shimizuetal.2010;McGaleandDarby2008;Darbyetal.2005;Yamadaetal.2004;Prestonetal.2003;Hayashietal.2003).InA-bombsurvivorswhoareenrolledintheLifeSpan Study (LSS), the development of health effects has been extensively studied throughcontinuous longitudinalhealthassessments.TheaveragedosesthatwerereceivedbytheA-bomb survivors (Preston et al. 2003) are similar to the effective doses for an InternationalSpace Station (ISS) mission (50-100mSv for 6-month stays) and somewhat lower than theeffective dose that is expected for aMarsmission (1 to 1.3 Sv). A significant dose-responserelationshipexistsforhypertension,stroke,andheartattackinsurvivorswhowereexposedatlessthan40yearsofage;theirERRisestimatedtobe14%perSv.However,theexistenceofa

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thresholddosecannotbeexcluded for risks thatareassociatedwithdoses thatare less than0.25 Sv (Table 4). At these moderate doses, mechanisms of action are thought to involveatherosclerosis,potentiallythroughinflammation,oxidativestress,endothelialdysfunction,andcellularsenescence(HealthProtectionAgency2010).Table4.EstimatesofExcessRelativeRiskperSievertforNon-cancerdeathsfromtheLifeSpanStudyoftheAtomicBombSurvivors(Prestonetal.2003).

Cause

ERRperSv

Deathsa

Estimatednumberofradiation-associateddeaths

Allnon-cancerdiseases (0–139,240–279,290–799)

0.14(0.08;0.2)b 14,459 273(176;375)b

Heartdisease(390–429) 0.17(0.08;0.26) 4,477 101(47;161)Stroke(430–438) 0.12(0.02;0.22) 3,954 64(14;118)

Respiratorydisease(640–519) 0.18(0.06;0.32) 2,266 57(19;98) Pneumonia(480–487) 0.16(0.00;0.32) 1,528 33(4;67)

Digestivedisease(520–579) 0.15(0.00;0.32) 1,292 27(0;58) Cirrhosis(571) 0.19(–0.05;0.5) 567 16(–2;37)

Infectiousdisease(000–139) –0.02 (< –0.2;0.25)

397 –1(–14;15)

Tuberculosis(010–018) –0.01(<–0.2;0.4) 237 –0.5(–2;13)

Otherdiseasesc(240–279;319–389;580–799) 0.08(–0.04;0.23) 2,073 24(–12;64) Urinarydiseases(589–629) 0.25(–0.01;0.6) 515 17(–1;39)aDeathsamongsurvivorsbetween1968and1997.b90%confidenceinterval(C.I.).cExcludingdiseasesofthebloodandblood-formingorgans.

Foroccupationallyexposedworkers,suchasemployeesofnuclearpowerfacilities,data

are mixed at this range of moderate doses (0.5-5 Gy). A study of U.S. workers who wereexposed to radiation at doses below 1 Sv in nuclear power plants showed a significantcorrelationbetweenradiationdoseanddeathfromcardiovasculardisease(Howeetal.2004).However,similarstudies(Table5)haveshowneitherrisksthataremoresimilartothosefortheA-bombsurvivorsornoincreasedrisk.RecentanalysesofMayakworkerdatarSimonettoetal.2014and2015)showahighlystatisticallysignificanttrendinthedose-responserelationshipforischemicheartdiseaseandcerebrovascularevents.Theyalsoadjusted formajor lifestyle riskfactorssuchassmokingandalcoholuse.However, thesestudiesarealsounique inthat theyincludedpopulationswithinternalradiationexposuresfrominternallydepositedradionuclidessuchasplutonium.Furtherstudiesarewarranted,asevidencesuggeststhatasimilartrendispresent at dosesbelow0.5 Sv (Vrijheid et al. 2007). Finally, follow-up studies of the healthrisks in Chernobyl recoveryworkers also show an increased risk for cardiovascular diseases;however, the contribution oflifestyle factors to this risk estimate cannot be eliminated at thispoint,andfurtheranalysisisneeded(Ivanovetal.2006;McGaleandDarby2005).

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Table5.OccupationalStudiesandCirculatoryDiseaseMortality(Hoel2006).

OccupationallyExposedPersons

Study Workers(Circulatorydeaths)

ERRperSv Comments

U.K.radiologists(Berrington2001)U.S.radiologists(Matanoski1975)U.S.radiologytechs(Hauptmann2003)NuclearworkerstudyIARC3countrystudy(Cardis1995)U.S.powerreactors(Howeetal.2004)Mayakworkers(Bolotnikova1994)Chernobylemergency(Ivanov2001)

2,698(514)30,08490,284(1,070)95,673(7,885)53,698(350)9,373(749)65,095(1,728

<00.20.01–0.420.268.30.010.79

TimetrendincancerbutnotinCVDTimetrendincancerbutnotinCVDTimetrendinbothstrokeandCHD5%works>0.2Sv2%workers>0.4Sv95%C.I.:(2.3,18.2)Exposures0to0.35Sv

CHD=coronaryheartdisease;CVD=cardiovasculardisease;IARC=InternationalAgencyforResearchonCancer.Table6.ERRcoefficientsforcirculatorydiseasesasaresultofexposuretolow-levelradiation≥5yearsearlier,bydisease(Littleetal.2012).

aAnalysisbasedonmorbidityfromIHD(ischemicheartdisease),witha10-yearlag.bAnalysisbasedonmortalityfromheartfailureandotherheartdisease.cAnalysisbasedonmortalityfromheartfailure.dAnalysisbasedonmorbidityfromCVA(cerebrovasculardisease),witha10-yearlag.eAnalysis based onmorbidity from hypertension, disease of arteries, arterioles and capillaries, veins, lymphatic

vessels,andlymphnodes.fAnalysisbasedonmortality from rheumaticheartdiseaseandcirculatorydiseaseapart fromheartdiseaseand

CVA.gAnalysisbasedonmorbidityfromhypertension,hypertensiveheartdisease,andaorticaneurysm. In a comprehensive and systematic review by Little et al. (2012), information wassummarized on circulatory disease risks associated with moderate- and low-level whole-body

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ionizing radiation exposureswith criteria ofwhole-body radiation exposures and a cumulativemeandoseof<0.5Svorexposureatalowdoserate(<10mSv/day).Althoughmeancumulativeradiationdoseswere≤0.2Gyinmostoftheexaminedstudies,thesmallnumbersofparticipantsexposedtohighcumulativedoses(≥0.5Gy)drivetheobservedtrendsinmostcohortsinthesehigherdosegroups. Table6 summarizesERR coefficients for circulatorydiseasesas a resultofexposureto low-levelradiation≥5yearsearlier,bydisease.Analysessupportedanassociationbetweencirculatorydiseasemortality(excessriskofIHD)andlowandmoderatedosesofionizingradiationabove>0.5Gy(Littleetal.2012).Datawerenotstatisticallysignificantatlowerdoses.Thismaybedue to statistically significantheterogeneityacrossexposedpopulations (Japaneseatomic-bomb survivors compared with a Western cohort of largely European/Americanpopulations).Thislackofsignificancemayalsobepartlyduetouncontrolledconfoundingfactors,suchaslifestyleandgeneticfactors,withinthemanystudiesincludedinthemeta-analyses.

Currently, a large-scale effort known as the Million Worker Study is underway toevaluate late health effects associated with low dose, low dose-rate ionizing radiationexposure.ThisepidemiologystudyofUSradiationworkersandveteranswillprimarilyfocusoncancer mortality but will also address causes of death due to cardiovascular andcerebrovasculardiseaseandshouldprovideimportantinformationrelatedtodose-rateeffectsthatisnotcurrentlyavailablefromtheA-bombsurvivorstudieswheretheexposurewasacute(Bouvilleetal.2015).Molecularepidemiology(Abend2015,Kreuzer2015)stratagiesarealsobeingutilizedtosupplementthebodyofepidemiologicaldatainordertoprovideinsight intobiological mechanisms and risk estimation at low doses.At these low doses <0.5 Gy, themechanisms of action may involve non-targeted effects, monocyte killing, and kidneydysfunction.Ina2003analysisof992patientstreatedfortesticularcancer,thosewhoreceivedmediastinalradiotherapyshowedasignificantincreaseintheirriskforacardiacevent(Huddartetal.2003).Morenotably,patientswhoreceivedintradiaphragmaticradiotherapy(irradiationbelow thediaphragm,excluding theheart) still hadhigher risk compared to controls.Withalowestimatedheartdoseof0.75Gy,theauthorssuggestedradiationnephropathy,leadingtohypertension,maybeapartialcausefortheirelevatedriskofCVD.MorerecentstudiesofthesurvivorsoftheA-bombsofWorldWarIIinJapansuggestthattheincreasedriskofcirculatorydiseasefromacuteexposurestogamma-raysatlowtomoderatedoses(upto3Gy)isrelatedtorenaldysfunction,withconcomitantchangesinbloodpressureandinflammation(Adamsetal.2012;Sera2013).Adamsetal.(2012)reportedthataquadraticdoseresponsemodelbestfitstheirdata,whichisconsistentwiththefindingofShimizuetal.(2010)andtheobservationsof Little et al. (2008), who reported that inflammation was not increased after low-doseradiationexposure(<0.5Gy).WorkbyLenarczyketal.(2013)inratsshowedcomparablelevelsof cholesterol (total,HDL, LDL,and triglycerides) compared to sham-irradiatedcontrolswhenthe kidneyswere shieldedduring irradiation (10Gy gamma).Additional research is currentlybeingconductedtoinvestigatethisroleofthekidneyinradiation-inducedCVDatlower,space-relevantdoses(Bakeretal.2015).

Consideration should also be given to cataract monitoring as a potential window onother degenerative effects caused by space radiation exposure. Hu et al. (2001) put forth a“commonsoilhypothesis”thattheremaybecommonpathwaysbetweenthedevelopmentofcataracts andCVD, suggesting that oxidative damage fromamore generalized agingprocessmay responsible for both. This has been reiterated in several other studies linking cataracts

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withincreasedriskofCVD(Kesseletal.2006;Kleinetal.2006;Nemetetal.2010).InarecentreviewbyWongetal.in2014,evenkidneydiseasewaslinkedwithoculardiseasethroughthecommonsoilhypothesiswith thesuggestion that sharedvascular risk factorsandpathogenicmechanisms act as a basis for both. Given the well-documented effects of radiation onincreased oxidative stress and noting that cataract formation is ameasurable, direct diseaseendpoint resulting from space radiation exposure in humans, monitoring of cataracts inastronauts may have benefit in providing information on radiation quality, progression andlatency.Cataractsmayrepresentaveryusefulbiomarkerforradiation-inducedcardiovasculareffects.

In summary, these observations are supportive of a threshold dose for circulatorydiseaseriskfromradiationofapproximately0.5Gyofacutelydeliveredgamma-rays.However,it is not knownhow the thresholdmight bemodified for other radiationqualities, dose-rateeffects,orindividualsensitivity.Forhealthyworkerswhorefrainfromtobaccouseandhaveanormal bodymass index (BMI) andmoderate alcohol use, a higher thresholddosewouldbepredictedbasedontheoreticalconsiderations.Incontrast,theepidemiologicalmeta-studiesofLittleetal.(2012)andSchollnbergeretal.(2012)areconsistentwithanincreasedriskbelowa0.5 Gy threshold. Additionally, the Health Protection Agency 2010 report identified severalother possible mechanisms, such as mitochondrial dysfunction and DNA damage, throughwhichradiationexposuremaycausecirculatorydamage,leavingtheexistenceofathresholdanopenquestion.

b.ExperimentalDatafromAnimalandCellularStudiesandMechanismsofDamageSystematic studies on the progression of radiation-induced heart diseases were first

conductedinrabbits(FajardoandStewart1970)andrats(YeungandHopewell1985;Lauketal.1985)withhighdosesof X-rays in the rangeof 10 to20Gy. Similar studieswere conductedusingheavyionsduringthecourseoftheJANUSprogramatArgonneNationalLaboratory,inwhich ultrastructural studies of themouse heart and vasculaturewere performed after theanimals had been irradiated with neutrons. The results of the studies were compared withresultsfromirradiatingmicewithlow-LETradiationandshowedvesselmorphologicalchanges,includingmarkedfragmentationofvascularsmoothmusclelayersandanincreaseindepositionofextracellularmatrix invesselwalls, similar to thechangesobserved inanimalsofadvancedage(Yangetal.1976,1978;Stearneretal.1979).Changesinthecoronaryarteriesandaortaat18 months post-exposure were greater in animals receiving fractionated neutron exposurescompared to the single-exposure group. Opposite results were observed for the gamma-ray-exposedanimals,withsingledoseexposuresbeingmoreeffectivethanfractionatedexposures.RBEsforneutroneffectsincreasedwithdecreasingdoseordosefractionation,withRBEvaluesexceeding100withprotractedexposures(Yangetal.1978).Similarresultswerefoundinearlystudies with low doses of Ne and Ar ions (Yang and Ainsworth 1982). Studies on theatherogenicchanges thatareassociatedwith irradiationwereconducted indogs tocomparetheeffectsoffractionateddosesoffastneutrons(15MeVavg.)withthoseoflow-LETphotons.TheRBEofneutronswasestimatedat4to5fromthesestudies(Bradleyetal.1981).

More recently, studies aimed at defining the mechanisms by which radiation inducesheartdiseaseswereconductedusingatherosclerosis-proneanimalmodels.Increasedoxidativestress(fromtheformationofreactiveoxygenspecies[ROS])andpromotionofinflammationhave

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beenimplicatedaspossiblemechanismsbywhichradiationpromotesatherogenesis.Forexample,accelerated formation of aortic lesions occurred in a dose-dependent manner in x-ray-irradiatedC57BL/6mice fedahigh-fatdiet (Figure2),while smaller lesionswereobserved intheirirradiatedtransgeniclittermatesthatover-expressedCuZn-superoxidedismutase,whichisexpected to decrease chronic oxidative stress and lead to a decreased susceptibility todegeneration (Tribble et al. 1999). The lowest dose in these studieswas 2Gy. Impairment innitricoxidesignaltransductionmayalsocontributetodegenerativevascularchanges(Solovievet al. 2003). In another study (Stewart et al. 2006), radiation was shown to accelerate theformation of macrophage-rich inflammatory atherosclerotic lesions in atherosclerosis-pronemicelackingthegeneforapolipoproteinE(apoE-/-).Thesemiceweregivenasinglehighdoseofgamma-rays(14Gy)totheneck,supportingthenotionthatradiationpromotesdegenerativeheartdiseases thoughan inflammatorymechanism.Khaledetal. (2012)showedthateven intheabsenceofincreasedsurfaceexpressionofVCAMandICAM-1onhumanaorticendothelialcells, radiation at doses of 15 Gy with x-rays induced chemokine-dependent signaling thatresultedinincreasedadhesivenessofthecells.

Figure 2. Dose-Dependent Effects of Ionizing Radiation on Aortic Lesion Formation in Fat-fed Mice(repeated-measuresanalysisofvariance:P=0.02)(Tribbleetal.1999).

Atdoseslessthan0.5Gy,theresponseoftheApoE-/-modelismorecomplex.Mitchell

et al. (2011) analyzed aortic lesion frequency, size, and severity as a function of gamma-raydose, dose rate, and disease state. This study revealed nonlinear responses with a complexcombinationofprotectiveanddetrimentaleffectsdependingondoserateanddiseasestage,withmaximumeffectsoccurringbetween25and50mGy(Mitchelletal.2011).Mitchelletal.(2013)followedthatworkwithsimilarresults(protectiveanddetrimentaleffects)inanApoE-/-mousemodelwith reduced p53 function. Additionalwork in the samemodel using low andhigh dose rates again shows a non-linear dose response with moderate doses of 30 cGyexhibitingpersistentvasculardamage(Mancusoetal.2015).

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Exposurewith high doses of 56Fe ions showed a similar pattern of accelerated lesiondevelopment in this ApoE-/- mouse model (Yu et al. 2011), which is associated with earlyimpairment of normal vascular reactivity (Yu et al. 2011; White et al. 2014). In a YucatanminipigmodelusedforinvestigatingSPEeffects,acalculatedheartdoseof0.35Gywith6MeVelectronsover3hoursalsoresultedinimpairedvascularrelaxation(Sanzarietal.2015).

Usingwildtypeanimals,Soucyetal.(2011)showedchronicvasculardysfunctionduetoradiation-inducedxanthineoxidase-dependentROSproductionandnitrosoredox imbalance inrats after 1 Gy 56Fe particle irradiation, a particularly damaging component of the GCRspectrum.Atdosesas lowas0.1Gyof 28Si ions, changes inapoptosis andmarkersof chronicinflammationwereobservedinhearttissueofadultmaleCBA/CaJmiceupto6monthsfollowingexposure(Tungjaietal.2013).Similarly,Sasietal.(2015)irradiatedC57Bl/6NTacmiceorbone-marrow-(BM-)derivedendothelialprogenitorcells(EPCs)with0.9Gyofprotonsor0.15Gyof56Fe ions and showed early (5-24h) and delayed (28 days) apoptosis in the mice and non-targetedeffectsinthecells.Inthesamemousemodelirradiatedwith0.5Gyofprotonsor0.15Gyof56Feions,cardiacfibrosisandhypertrophywasstillobservedatlatetimepoints(upto10months).However,functionalmarkersofcardiacphysiologywerenotimpairedcomparedwithcontrolsatthosetimepoints(Yanetal.2014).Nickelirradiationinhumanumbiliicalveincellsat0.5,2,and5GyresultedinpersistentDNAdamage24hoursafterexposure,dysregulationofthecellcycle,andincreasedsecretionofinflammatorycytokines(Becketal.2014).Insummary,substantial evidence fromhuman epidemiology data and animal studies suggests thatlow-LETradiationstronglyimpactsthedevelopmentofdegenerativeheartandcardiovasculardiseasesat doses above 0.5 Gy, which may be related to the overall acceleration of age-relatedprocesses.Itisstillanopenquestionastowhetherthereisariskbelow0.5Gyandhowdoserate and radiationqualitymodify theoverall radiation response.Humanepidemiologydataare subject to large errors due to inconsistencies in organ dose evaluations and, moreimportantly,intheunderstandingoftheroleoflife-stylefactors.Circulatorydiseaserisksmaybe impactedby factors suchas smoking status,obesityandnutrition,alcohol consumption,andstresstoamuchlargerextentthancancerrisks.Humanepidemiologyanalysisoftenlackscorrections for these confounders. These considerations will be vitally important forastronauts becauseof their longevity andbecausedefinitive evidence for a healthyworkereffect is present (Cucinotta et al. 2013a). Additionally, data on these same effects ofirradiationwithprotonsorheavyionsareclearlylacking,andthefewstudieswithHZEparticlesto date have used doses higher than those present in space and often used animals pre-disposedtoheartdiseasethatwerefedahigh-fatdietnotreflectiveofthestatusanddietofastronauts.TheCenterforSpaceRadiationResearch(CSRR),awardedin2014bytheNationalSpaceBiomedicalResearchInstitute(NSBRI),isa3-yearresearchconsortiumcentralizedattheUniversityofArkansasforMedicalSciencesthatwasfundedtogenerateresearchtofillsomeofthese noted knowledge gaps. They will be utilizing cell and animal models (mice, rats, andrabbits) with protons, HZE, and gamma-ray controls to further characterize this risk ofradiation-inducedcardiovasculardisease.

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3. DigestiveandRespiratoryDiseasesEvidence for the development of late complications to the respiratory and digestive

systemarelargelyderivedfromtheLSSstudyoftheJapaneseA-bombsurvivors.AnearlyRERFpublication reported a significant increasing trend with dose in mortality from digestivediseases for the period 1950-1985, with liver cirrhosis being the major digestive disease(Shimizu et al. 1992). Several follow-up surveys that included non-cancer deaths haveconfirmed theearly findingsofdigestivedisease risks in theA-bombsurvivors (Shimizuetal.1999; Preston et al. 2003). Figure 3 shows results fromPreston et al. (2003) for the ERR fordeathvs.doseforseveraldiseases,includingdigestiveandrespiratorydiseases.

An additional follow-up study of the A-bomb survivors for the period 1998-2003waspublished in 2012 (Ozasa et al. 2012). As of 2003, 3394 A-bomb victims died of digestivediseases,withanERRof0.11(-0.01,0.2)/Gy(Ozasaetal.2012).Whenthenon-cancerdiseasemortality is divided between the early period (1950-1965) and late period (1966-2003), ERRshowedmarginaldifferencesbetweentheperiods,asshowninthedose-responserelationshipinFigure4.Fordigestivediseasedeathsinthelateperiodalone,theERRwasfoundtobe0.20(0.05,0.38),suggestingapossible latedevelopmentofthediseases;however, intheanalysis,livercirrhosis,amajordigestivedisease,didnotshowanyincreasewithradiationexposure.

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Figure 3. Dose-response functions for non-cancer deaths from the LLS study of A-bomb survivors(Prestonetal.2003).

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Figure4.Comparisonofdose-responsecurves for theearlyperiod(dashed line)and lateperiod(solidline)fornon-cancerdiseases(Ozasaetal.2012).

Fortherespiratorysystem,thereisaclearassociationbetweenhigh,therapeuticdosesofradiationanddevelopmentoflungdiseases,includingacutepneumonitisandchronicfibrosis(Choietal.2004).Atthelowerdoselevelsrelevanttospacetravel,datafromtheA-bombsurvivorsagainprovidemostoftheevidenceforrespiratorydiseasesduetoexposuretoexternal,acutelow-LETradiation.Respiratorydiseasesobservedinthiscohortincludechronicobstructivepulmonarydisease(COPD),pneumonia/influenza,andasthma.AccordingtothelatestpublishedresultsfromtheLSSstudyfortheperiod1950-2003,theERRperGyforrespiratorydiseaseswas0.21(0.10,0.33),withpneumoniabeingthemajorcauseofdeath(Ozasaetal.2012).However,inamoredetailedexaminationoftheLSSdatathatincludedadditionaladjustmentsforindicationsofcardiovasculardiseaseand/orcancer,theonlyrespiratorycomplicationthatremainedsignificantwasanexcessriskforpneumonia/influenza(Phametal.2013).AnanalysisoftheMayakworkercohortbyAzizovaetal.(2013)alsoindicatedamarginallysignificantraisedERR/Gyfromexternaldoseforchronicbronchitis,butwithmanyconfoundingfactorssuchasinternaldose,smokinghabits,andpoorworkingconditions.

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There is no evidence for the association of charged particle exposure with digestivediseasesandverylittleevidenceforthedevelopmentofrespiratorydiseasesatthedosesanddose rates that are relevant to space travel. A recent study investigated the late effects ofgamma-rays, protons, 56Fe, and 28Si ions on the lungs of mice approximately 2 years post-exposure and revealed histopathological abnormalities and changes in markers of oxidativestress inthelungtissueofmiceatdosesas lowas0.1Gy56Feand0.1Gy28Si ions.However,thesealterationswereassociatedwithchanges in functionalparameters,asapproximatedbysystemicoxygenationlevels,onlyathigherdosesthatarenotspace-relevant(Christofolodouetal.2015).

In summary, acute exposure to gamma-rays may increase the risk of non-cancermortalityfromdigestiveandrespiratorydiseases.However,availableepidemiologicalevidenceislimitedandconfoundedbytheimpactofotherlifestylestressorsandmisdiagnoses,makingthe level of these risks unclear. Additionally, because the association between low doseradiation exposure and digestive and respiratory diseases is only evident in isolated groups,cautionintheinterpretationofthesefindingsiswarranted(Littleetal.2013). 4. EvidenceforOtherAge-RelatedEffectsCausedbyRadiation

Manyofthecellularandphysiologicalchangesinorgansystemsthatareassociatedwiththe normal aging process are shown to be accelerated by radiation exposure. These includechanges in immune and endocrine function, fibrosis, and cellular senescence. Examples ofstudiesshowingradiationeffectsonmarkersofagingincludethefollowing(NCRP2006):

• Studiesofstructuralchangesinspecificorgans• Generallifespanlongevitystudiesthatareperformedinanimalmodels• Analyses of biochemical and molecular markers of cellular aging, including oxidative

damage,inflammation,andcellularsenescence

Thepossibilityofradiation-inducedacceleratedagingwasnotedveryearlyoninfollow-upstudiesoftheA-bombsurvivors(Andersonetal.1974),anditisnowclearlyestablishedthatthe survivors are at an increased risk of developing age-related conditions, most notably,diseasesofthecirculatorysystem,cataracts,alteredimmunesystemfunction,andchangesininflammatorymarkerstatus(Kusunokietal.2008;Hayashietal.2012).AlthoughexposuretoHZE particles occurs at low fluences during space travel, accumulated molecular changesresulting from long-term exposure have been found that are similar to those seen in agedanimals(Mandaetal.2008;Pouloseetal.2011).

a. Mechanisticcandidatesandbiologicalprocessesofradiation-relatedaging Possible aging mechanisms include oxidative stress (e.g., free radicals produced in

intracellularandextracellularwater),somaticDNAmutations,shortenedtelomeres,declineinendocrineandimmunefunction,increasedinflammationandfibrosis,andstemcellexhaustion.RadiationexposureisassociatedwithenhancedoxidativestressandoxidativedamagetoDNA,proteins,andlipids,whichmaypromotechronicinflammation,cellularsenescence,prematureaging, and development of age-related diseases (Li et al. 2014). Radiation-induced oxidative

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stressalsodisruptsintracellularsignalingandcell-to-cellcommunication,leadingtoacceleratedage-dependentdecline(Troskoetal.2005).

b. PrematureCellularSenescenceRadiation exposure is associated with increased cellular senescence of two types:

replicative senescence,mediated through DNA damage and telomere dysfunction (Shay andWright2005;Toussaintetal.2002),andstress-inducedprematuresenescence(SIPS).SIPScanresult from sub-lethal exposure to a variety of stressors including ionizing radiation andoxidative stress, and does not involve telomere dysfunction. Both types of senescent cellsexhibit p53-dependent cell cycle arrest and share features such as a flattened and enlargedmorphology, an increase in acidic betagalactosidase activity, and chromatin condensation(Funayama and Ishikawa 2007; Caino et al. 2009), as well as secretion of proinflammatorymediators and other bioactive compounds as part of the SASPs (senescence associatedsecretoryphenotype)whichconsistsofawidevarietyof inflammatorymediatorsandgrowthfactorssuchasIL-6,IL-8,IL-1,Gro-α,HGF,MCPsandMMPs(Renetal.2009).Otherhallmarksof senescent cells, such as DNA-SCARs (DNA-SCARS: distinct nuclear structures that sustaindamage-induced senescence growtharrest) andanalysis of pathways controlling this processarebeingcharacterized(Rodieretal.2011;Salminenetal.2012).

c.DefectiveStemCellFunctionandAgingStem cells in all tissues are of fundamental importance because they support tissue

homeostasis,whichistheabilitytomaintainnormaltissuefunctionandinvolvesformationandreplacement of tissue-committed cells fromadult tissue resident stem cells. A decline in thenumber or functional capability of stem cellswill impair the ability of the body to form andreplacecommittedcells,withpotentiallydeleteriouscostsfortissuemaintenance.Studiesthatwere conductedusing low-LET irradiation inmousemodelshave shownadecline in the totalnumberofcellsandan increase inthenumberofcellswiththesenescentphenotype inbonemarrowstemcellsafterradiotherapyandchemotherapy.Thesechangesmaycontributetothelong-term deficits in bone marrow function that occur after these treatments (Wang et al.2006).

d.EffectsofHighLETRadiationonAgingRadiation-inducedagingiswelldocumentedwithhighdosesoflow-LETradiation,whilelow

doses of low-LET radiation have been shown to stimulate cells to gain adaptive responsesresultinginresistancetoaging,definedas“radiationhormesis,”withtheimplyingmechanismsof strengthened cytoprotective and restorative functions (Mattson 2008, Maynard 2011).Nevertheless,high-LETradiationproducesmoreclusteredlesionsandgenomicinstabilitythanlow-LETradiationandendogenoussourcesofROS(Lietal.2014).High-LETradiationalsohasanenhancedability todamage the telomeres thatareatoneendofeachchromosomeandarebelieved to be involved in the aging process (Durante et al. 2006). Since telomeres areextremely sensitive toROS, cellsexposed tohigh-LET radiationaremoreprone to senescence.Some investigators report very high levels of telomere deletion in the progeny of humanlymphocytesafterirradiationwithlowdosesofironnuclei(Duranteetal.2006).Bailey(2007)is

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studying changes to telomeres as a function of radiation quality. Possible quantitativedifferencesbetweenlow-andhigh-LETradiation-induceddamagecausetelomereshorteningorprematuresenescenceandarethusaconcernforspaceradiationriskassessment.Withgammaexposuresatlowandhighdoserates,Yentrapallietal.(2013)alsosuggestincreasedprematureendothelialsenescenceafterirradiation.5. RadiationEffectsonEndocrineFunction

The endocrine system controls hormone production, secretion, metabolism, andlevelsincirculatingblood.Age-relatedchangesintheendocrinesystemoccurinolderpeopleandresult in a decreased capability of the system to respond to the internal environment. Thehypothalamusisresponsibleforreleasinghormonesthatstimulatethepituitarygland.Duringaging, individuals suffer impaired secretion of some hypothalamic hormones and directradiation effects on the thyroid and pituitary glands, as well as subtle effects on thehypothalamic-pituitary-adrenalaxisandthehypothalamic-pituitary-gonadalaxis.Thepituitarygland, thyroid, and gonads have been found to be sensitive to radiation (Niazi 2011; Nishi2011).Radiation-inducedatrophyoftheendocrineglandshasbeenreported,occurringafewweeksafterradiationexposure(Nishi2011). Inthefollow-upstudyofthenuclearaccident inChernobyl, childhood autoimmune thyroid diseasewas extensively observed (Eheman 2003).Residents in Chernobyl and nearby areas were found to have lower sympathetic activity,adrenalcorticalactivity,andbloodcortisol levels.Acceleratedsexualdevelopment in femaleshasbeen reported,and the concentrationof gonadotropichormones inbloodwas increased(Leonova 2001). In addition, hyperparathyroidism was reported in the A-bomb survivors(Fujiwaraetal.1992;Prestonetal.2002).A-bombradiationexposureperturbedtheprocessesinvolved in T-cell homeostasis, whichmay result in the acceleration of immunological aging(Kusunoki2008).

BesidesA-bombradiationexposure,variousendocrinesystemshavebeenaffectedbyradiationtherapy(ICRP2012)aswell,e.g.,adenomas,whicharehyperplasiasintheparathyroidgland,areobservedinpatientswhoaretreatedwithlow-LETradiationatdosesthatarebelow1Gy(Tezelmanetal.1995;Tisseletal.1985)andintheA-bombsurvivors(Fujiwaraetal.1992;Prestonetal.2002).Variousendocrinesystemseffectshavebeenencounteredfromradiationtherapy(ICRP2012);however,mostofthedataarederivedfromhighexposures,whichareofquestionablerelevanceforspaceradiation.6. MusculoskeletalSystem

ICRP 2012 reports that “radiation effects observed in bone and skeletal muscle arepredominantlylateeffectsthatappearmonthstoyearsafterradiationexposure.Whilematureboneisrelativelyradioresistant,growingboneismoreradiosensitive,andmeasurablegrowthdelay can be expected after relatively low doses of radiation. Hence, while musculoskeletalradiation effects are aminor issue inmost adult patients with cancer, they remain amajorprobleminchildhoodcancersurvivors.”Therearecurrentlynohumandataatspace-relevantdosesshowingalong-termradiation-inducedeffectonthemusculoskeletalsystem(NCRP2006,ICRP2012).Althoughsomeanimalandcellwork investigatingtheeffectsofHZEradiationonmuscle(Bandstraetal.2009;Shtifmanetal.2013)andbone(Willeyetal.2008;Alwoodetal.2010; Yumoto et al. 2010) has been reported, they all demonstrate transient or short-term

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effects, or no effect of low dose HZE radiation. Overall, the evidence at lower doses is notsufficienttodeterminetheexistenceofexcessriskformusculoskeletaldiseases.7. Endometriosis

An additional effect of irradiation thatwas revealed by the proton bioeffects studiesthat were conducted in Rhesus monkeys was a significant increase in the risk of developingendometriosis, which is an abnormal growth of the uterine lining. This disease occurred inabout25%ofallof theunirradiated femaleprimatesand inmorethan50%of the irradiatedprimates.Although it isnotnormally life-threatening inhumans, this conditionproved fatal inseveral of the animals beforeproper treatmentplanswereput into effect. Endometriosiswasevidentevenwhenrelatively low-energyprotons (32MeV;penetrating toadepthofabout1cm)and lowdoseexposures (0.2 to1.13Gy)wereused (Yochmowitzetal.1985;FantonandGolden, 1991). As very few humans have been exposed to high-LET radiation, other healtheffectsmayarisethathavenotbeendocumentedtodateforterrestrial formsofradiationatlowtomoderatedoses(<2Gy).

B.SpaceflightEvidenceTheNASSpaceScienceBoardfirstreviewedspaceflight issues in1967(NAS/NRC1967)

andrevisitedtheseissuesin1970(NAS/NRC1970).Thesereviewsledtotheestablishmentofdose limits thatwereused atNASAuntil 1989. Extensive reviewsof humanandexperimentalradiobiologydataforspaceriskswerealsoprovidedtoNASAin1989,2000,and2006viaNCRPreports(NCRP1989,2000,and2006).The1989and2000NCRPReportsledtoupdatesoftheNASAdoselimits.Theissuesofcataractsanddegenerativetissueeffectsarediscussedinmanyofthesereports.Reviewsonotherdegenerativeriskshavebeengivenmorepriorityinthemorerecentofthereports.Themorerecentreviewssuggestthatthresholddosesmaybelowerthanpreviouslyestimatedordonotoccur,especially forhigh-LETradiation.Amajorquestionalsoremains regarding the categorization of these risks as deterministic vs. stochastic,which hasmajorimplicationsforradiationprotection.

The most recent external report of the evidence of space radiation effects waspublishedin2006bytheNCRP(NCRP2006).Thestatedpurposeofthisreportwastoidentifyanddescribe the information that is needed to make radiation protection recommendations forspacemissionsbeyondlowEarthorbit(LEO).Thereportcontainsacomprehensivesummaryofthecurrentbodyofevidence for radiation-inducedhealth risksandmakes recommendationsonareasrequiringfurtherresearch.Forthenon-cancer,lateeffectsofradiation,theauthorsofthis report recommendthatexperimentsbeconductedusingprotractedorextendedexposuretimesandlowdoseratesofprotons,heavyions,andneutronsinenergyrangesthatarerelevanttospaceradiationexposurescenarios.Specifically, theauthorsof the report recommend thatanalysesshouldbeconductedontheeffectsofprotractedexposuresonthelens,whole-bodyvasculature, gastrointestinal tract, gonadal cell populations, and hematopoietic and immunesystems,aswellasfertility.1. CataractsinAstronauts

Cucinotta et al. (2001) reported epidemiological evidence for an exposure-dependentincreaseintheriskofcataractformationinastronauts.Healthrecordsfor295astronautswho

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were enrolled in theNASA Longitudinal Study of AstronautHealth,which spansmore than3decades,wereevaluatedforincidenceandtypeofcataract.Datawereanalyzedforastronautageatthetimeatwhichthecataractappearedorthedurationbetweenthefirstmissionandcataractappearance (Figure5).Astronautsweregroupedby individualoccupational radiationexposurerecordsthatallowedfortheseparationofexposuresfromlow-LETdiagnosticx-rays,atmospheric radiation that was received during aviation training, and exposure that wasreceivedduring space flight.Thesedata revealan increasedcataract incidence inastronautswhohaveahigherlensdose-equivalent(averageof45mSv)ofspaceradiationrelativetothatof other astronautswith zero or low lens doses (average 8mSv). These studies also show asignificantassociationbetween radiationqualityandcataract incidence.Astronautswho flewon high-inclination (>50 deg) and lunarmissions, which are associated with a higher flux ofhigh-LETheavyions,hadahigherincidenceofcataractformationthanthosewhoflewonlow-inclinationmissions, inwhicha largeproportionof thedose is from low-LET trappedprotons.Furtherevidenceforthelinkbetweencataractformationandexposuretospaceradiationwaspresentedina2002studyofcosmonautsandastronauts(Rastegaretal.2002),inwhichatrendforincreasedopacificationintheposteriorcorticalandposteriorcapsuleregionsofthelenswasevident inagroupofcosmonautsandastronautscomparedwith thecontrols.Asastronautswere screened for vision at entry into the Astronaut Corps andwere observedwith distinctmethods,comparisonstootherstudiesareinconclusive.Infact,itisverylikelythatastronauts,prior to theirexposure tospace radiation,haveabaseline incidenceofcataracts that iswellbelowthatofmembersofthegeneralpopulation.

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Figure 5. Results regarding the probability of survival without cataracts vs. time after the first spacemission for NASA astronauts in a low-dose group (closed symbols) with a lens dose below 8 mSv(average 4.7mSv) and a high-dose group (open symbols)with a lens dose above 8mSv (average 45mSv).Errorbarsindicatestandarderrorsofthemean.Theupperpanelisforallcataracts,andthelowerpanel is for non-trace (vision-impairing or large-area) cataracts. Only cataracts occurring after a firstspacemissionareincluded(Cucinottaetal.2001).

Morerecently, theNASAStudyofCataracts inAstronauts (NASCA) (Chylacketal.2009a,

2012) studied cataracts in a population of 224 astronauts and a comparison group of 200ground controls from the LSAH and military aviators using clinically validated objectivemeasures of posterior subcapsular (PSC), cortical, and nuclear cataracts. Amajor goal of theNASCAstudywasto investigatewhethertheratesofprogressionofcataractswere increasedbyspaceradiation.NASCAconfirmedtheassociationbetweenspaceradiationandcorticalandPSCcataracts.Thelongitudinalphaseofthestudyrequired5lensexamspersubject;however,the study ended early after an average of 3.7 exams per subject. Evenwith the incomplete

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studydata,theprogressionratesforcorticalcataractswereshowntobeassociatedwithspaceradiationexposures(Chylacketal.2012).

TheNASCAcross-sectionalanalysesofbaselinedata (Chylacketal.2009) revealed (a)themedian size andvariance in sizeof cortical opacitiesweregreater inexposedastronauts(P=0.015); (b)within-astronaut group PSC severity (area)was greater in subjects exposed tohigher radiation doses (P=0.016); (c) galactic cosmic radiation (GCR) was possibly linked toincreasedPSCarea(P=0.056)andthenumberofPSCcenters(P=0.095);and(d)norelationshipwas found between density (severity) of C opacification and space radiation exposure. Thelongitudinalanalysesrevealedthefollowing:(a)theestimatedmedianrateofprogressionofCopacificationwasanincreaseC%-areaopacityof0.25/yr/Svinexposedastronauts(P=0.062);(b) neither the area of PSC opacification nor the increase in numbers of centers of PSCopacificationwassignificantlyassociatedwithspaceradiationexposure(yes/no)(however,theNASCA results were influenced by the absence of a large number of PSC cases amongastronautsduetolensimplantsorotherreasonsasdescribedinthereport);(c)withinthetimeframeof the study, therewasnoevidence that space radiationexposure is related to fasterratesofincreaseinvariousmeasuresofNopacification;and(d)noimpactofspaceradiationonvisualacuitywasapparentovertheapproximately5yearsoffollow-uptime.

Theseobservations,alongwithseveralotherepidemiological studies (seeTable2.4ofICRP2012),havebeenusedby the ICRP tosupporta recommendation fora lower lensdoselimitforradiationworkers(ICRP2012).TheverylowdosesatwhichincreasedratesofcorticalcataractswereobservedandthelikelihoodthatPSCwouldalsobeincreasedsuggestthatthepossibilityofvision-impairingopacitiescouldoccur for themuchhigherdoses tocrew (up to40-foldhigher thanNASCAaverage lensdoses)within the timelineofa3-yearMarsmission.However,NCRP2014notesthat“theannuallimittothelensoftheeyeforradiationworkersinthe United States is 0.15 Sv (150mSv) (equivalent dose), although the European Union hasrecentlymodified their annual limit for the lens of the eye to 0.02 Sv (20mSv) (equivalentdose), averaged over 5y, based on the recommendation from ICRP (2012). ICRP (2012)recommendedthischangebasedonnewevidence,frombothhumanandanimalstudies,thatsupportsa lowradiationdoseforthe inductionofcataracts.Thereremainsdiscussiononthesuitabilityofthisrevisedlimitandparticularlyhowitcanorwillbeappliedinmedicalsituationsandperhapsbyextensiontospacemissions.”2. CardiovascularDiseaseinAstronauts

Reynolds and Day (2010) and Cucinotta et al. (2013a) provided evidence that U.S.astronautsshouldbeconsideredtobeatlowerriskforcirculatorydiseasesandenjoyalongerlifespan compared to the average U.S. population. This is borne out by analysis of Kaplan-Meirsurvival curves (Figure 6) and standardmortality ratios (SMRs) (Table 7),where the cohort ofNASA astronautswas compared to the averageU.S. population and populations ofU.S. neversmoker(NS),U.S.normalweight(NW),orU.S.NS-NWmodelpopulations(Cucinottaetal.2013a).Theresultsarestronglyindicativeofahealthyworkereffectforastronauts,astheyshowalongerlongevityandreducedSMRforcirculatorydiseasescomparedwiththeaverageU.S.populationandaremoresimilartoapopulationofNSamongNWindividuals.

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Figure6.Kaplan-MeiersurvivalversusageforastronautsandpayloadspecialistscomparedtoU.S.malesandprojections fornever-smoker,NW,andNS-NWmales. The leftpanel includesoccupationaldeathsrelatedto flightaccidentsor training,andtherightpanelcensorsoccupationaldeaths (Cucinottaetal.2013a).

Table 7. Standard mortality ratio for astronauts and payload specialists relative to other modelpopulationsforcoronaryheartdiseaseandstroke(Cucinottaetal.2013a).

Comparison SMR

Astronautsvs.U.S.average 0.33[0.14,0.80]Astronautsvs.NSaverage 0.43[0.18,1.04]Astronautsvs.NWaverage 0.47[0.19,1.12]Astronautsvs.NS-NWaverage 0.67[0.28,1.62]

It is also interesting to note the differences in SMRs for death from circulatory diseasesbetween NASA astronauts and Soviet/Russian cosmonauts. Reynolds et al. (2014) reportedthat:“Cosmonautshaveonly11%theriskofdeathduetoanycausecomparedtothegeneralpopulation(forwhomcirculatorydiseaseisamajorkiller),butareatmorethanthreetimestheriskofdeath fromcirculatorydiseasecompared toU.S.astronauts.”Thishighlightsagain thepotentialheterogeneityfoundwithindifferentpopulationsthatcancontributetoconfoundingfactorsinepidemiologicalanalyses.

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3. InfluenceofGenetic/individualSusceptibilityontheDegenerativeRadiationRisk

As noted above, the differences between population cohorts, including genetic,environmental, and lifestyle factors, can contribute significantly to variations in risk betweenthosepopulations.Itisverylikelythatindividualgeneprofilesmightinformandinfluencerisks.The NCRP 2010 report details this potential impact of individual genetic susceptibility onradiation-inducedrisksforastronautsandrecommends“thatnogenetictestingofastronautsbecarriedoutatthistime.Theprobabilityofindividualastronautshavinggeneticsusceptibilityfactorsforradiation-inducedcancerorotherradiation-induceddiseasesislow.”Thisisbecausehuman genetic disorders, such as ataxia telangiectasia (ATM), ATM-like disorder, Nijmegenbreakage syndrome, severe combined immune deficiency (SCID), ligase IV syndrome, andSeckelsyndrome,arealldisordersthatarerareandhavephenotypesthatarereadilyapparentand therefore not likely to be present in the astronaut population (NCRP 2010, ICRP 2012).NCRP 2010 concludes that “it is generally not possible to predict an individual’s inherentgeneticsusceptibilitytothelong-termriskofcancerorotherdiseasesassociatedwithradiationexposure.” This is partly because of the relatively little amount of information available onspecificgeneticcharacteristicsthatareknowntoaffecttheriskofradiation-inducedcancersornon-cancerhealtheffectsinhumansandpartlybecauseofthedearthofdataforHZEeffects.However,withtherecentadvancesingenomicsresearchand“omics”dataingeneral,itislikelythat current and future researchwill provide for an avenue to predict the risks of radiationbasedongeneticsusceptibility.

4. Summary

In summary, the link between exposure to acute doses of 0.5Gy ormore of ionizingradiationandthedevelopmentofdegenerativediseasesisclearlyestablished,whilethehealthrisks of low-dose and low-dose-rate ionizing radiation remain largely unknown. These risksaremoredifficulttoassessbecausemultiplefactorsarebelievedtoplayaroleintheetiologyofthediseases(BEIRVII2006).Similarly,nohumandataareavailableontheeffectsofhigh-LETradiationonthedevelopmentofdegenerativeheartandcardiovascularcomplications.

V. COMPUTER-BASEDSIMULATIONINFORMATION

Computermodels of radiation-induced degenerative risks have been proposed and are

beingdevelopedatthistime.Epidemiologicaldataareseverelylacking,precludinganapproachthatissimilartothosethatwereusedtoprojectcancerrisks.Onlyafewbiologicalmodelsthatdescribe thedegenerativeprocesses that are causedby ionizing radiation and thatwould beneededtoformacomputermodelareavailable.Thisisprobablybecausetheseprocessesarelessstudiedthanradiationcarcinogenesisandare,inmanycases,complicatedbyotherlifestylefactors that influence the disease process. A mechanistic model for radiation-inducedatherosclerosiswasproposedbyLittleetal.(2009).Basedonexperimentallyderivedparameters,theassumptionthattheexcesscardiovascularriskseenintheepidemiologydataisprimarilyduetoatherosclerosis,aswellasseveralotherassumptionsnotedinthepaper,themodelsuggestsalineardoseresponsedowntorelativelylowdoses.

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Thereareothersystemsbiologyapproachesavailableforthemathematicalmodelingofcardiovasculardisease;althoughtheydonotincluderadiationeffects,theymaybemodifiedtodescribe radiation-induced degenerative risks.MacLellan et al. (2012) reviewed systems-basedapproachestomodelingcardiovasculardiseases.Ramseyetal.(2010)alsoproposedasystems-biologyapproachtoatherosclerosisinvolvinginteractingsystemsatmultiplelevelsandincludinggeneticandenvironmentalfactors(Figure7).Finally,insilicomodelingofatherosclerosisisbeingdevelopedbytheNIHinconjunctionwithEntelosandtheBiomarkerConsortiumandwillresultinapubliclyaccessiblemodelthathasthepotentialformodificationtoincluderadiationexposureas a risk factor (http://www.fnih.org/work/research-partners/atherosclerosis-computer-modeling-metabolic-disorders).

Figure7.Systemsbiologyapproachtomodelingatherosclerosis(Ramseyetal.2010).

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VI. RISKINCONTEXTOFEXPLORATIONMISSIONOPERATIONALSCENARIOS

A. ProjectionsforSpaceMissionsNo existing biophysical model projects all degenerative risks for the entire range of

particle typesand energies that are found in space. The large RBEs that are found in the fewstudies that have been performed suggest that organ dose-equivalent based on radiationqualityfactorscanbeusedtomakeafirstapproximationforriskestimates;however,theshapeofthedose-responsecurveforspecificdiseasesanddose-ratemodifiersisunknown.Dose-ratemodifiers could be higher than those observed for cancer risks because of the possibility ofthresholdeffects.Cucinottaetal.(2013b)presented%REIDassessmentsforextendedLEOandexploratory missions, including the prediction of a combined cancer and circulatory disease%REIDforaMarsmission.Theauthorsusedtheexcessrelativerisk(ERR)resultsofLittleetal.(2012)andnotedthattheinclusionofthecirculatorydiseaseriskincreasedtheoverallriskby40% from cancer alone and reduced the overall age at exposure dependence of the %REID(Table8).

Table8.Safedaysindeepspace(definedasthemaximumnumberofdayswiththe95%CIbelowtheNASA3%REIDlimit)formalesandfemalesatdifferentagesatexposure(Cucinottaetal.2013b). NCRP2014notesthatthisapproachforcombiningcancerandcirculatorydiseaserisksiscomprehensivebutshouldbeconsidered“preliminary”,largelyduetotheassumptions“ofriskinthelow-dosedomainforcirculatorydiseasethatarefarfromconclusive.”TheestimatesforERR per Sv, which were provided by studies of the A-bomb survivors, arenot sufficient toestimateriskforastronautsbecausearisktransferapproachisneededtogetherwithestimatesof RBE and dose-rate modifiers. Additionally, there is significant heterogeneity betweendifferentpopulations-thebaselineriskofcoronaryheartdisease(CHD)isseveral-foldlargerintheU.S.thaninJapan,whiletheriskofstrokeiscomparable.NCRP2014suggeststhat“itwouldbe preferred to have less heterogeneous andmore comparable populations to generate riskcoefficients.”Todeterminethecancerrisks,theNCRPsuggestsusingmultiplicativeandadditivetransfer models to transfer risks between populations.” Thus, “it is essential that additionalexperimentaldatawithHZEparticlesbeacquiredusing relevantmodel systemsand relevantdoses to provide robust input to refine the currentmodel of cardiovascular risk from spaceradiation”(NCRP2014).

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B. SynergisticEffectswithotherFlightFactorsThe space environment includes many other stressors besides radiation, such as

microgravity,alteredoxygenlevelsandcircadianrhythms,nutritionaldeficiencies,andimmunedysregulation. These are currently unknown modifiers of cardiovascular and degenerativetissuediseaserisksfromspaceradiation.Fewreportshavebeenpublishedthatdirectlyaddresssynergisticeffectsofnon-radiationriskfactorsontherisksfromspaceradiation.

Forexploration-classmissions,NASAhasproposedtousevaryinglevelsofoxygeninthevehicles(Norcrossetal.2013).Thisraisestheissueofwhat,ifany,effectstheseoxygenlevelsmayhaveonradiation-induceddegenerativediseases.Hyperbarichyperoxia(increasedoxygenlevelsatpressureshigher thatatmosphericconditions)hasbeenusedasaradiosensitizer forcancerradiotherapy.However,conditionsofhyperoxiawouldonlybepresentduringEVAs(4.3psiaand85-100%O2),whicharecharacterizedbymildhypobarichyperoxiaandshortdurationson the order of hours. Currently, there are no plans for long-term exposure to high O2concentrationsathyperbaricpressuresinanyofNASA’sdesignreferencemissions(Norcrossetal.2013).Therefore,theeffectsoftheplannedhypobarichyperoxiaonthisriskarelikelytobenegligible.Thedifferencebetweenhyperbaricornormobaricandhypobarichyperoxiashouldbenotedaswell.Onestudypublishedresultsshowingoxidativelungdamagefromsynergiesofexposuresofradiationandhyperoxiadescribedas“relevant”tospacetravel(Pietrofesaetal.2013). However, exposure conditions were not relevant to the space environment; low-LETgamma radiation was used at high doses (total dose of 3 Gy), and the hyperoxia was in anormobaric environment, not the proposed hypobaric hyperoxia that is planned for NASA’smissions.

Conversely, there may be some benefit to the use of a hypoxic environment formitigatingradiationeffects.Theproposedvehicleexplorationatmosphereof8.2psiaand34%oxygen presents a mildly hypobaric hypoxic environment and would only be used in theexploration habitat during high EVA frequency portions of a mission. A standard sea-levelatmosphere (14.7 psia/21%) would be used for the transit to and from the explorationdestination (moon,Mars,asteroid) (Norcrossetal.2013).Additionally,previous researchhasshown that the body will acclimatize to this type of mildly hypobaric, hypoxic environmentstartingafterapproximately2weeksofexposure (Powelletal.2000;BarrattandPool2008).Giventherelativelyshortexposuretimesinthishypobarichypoxicenvironment,italsoseemslikelythattheeffectsofthesetypesofoxygenlevelsarenegligible.

Immunedysregulationhasbeennotedduringexposuretoshortperiodsofmicrogravity(Crucianetal.2015).However,nostudieshaveevaluatedthecombinedeffectsofradiationandmicrogravity over long periods relevant to the degenerative risks. One study by Zhou et al.(2012)specificallyinvestigatedtheeffectsofmicrogravityandradiationontheimmunesystemusingahindlimbsuspensionmousemodelandgammaorprotonradiation.Theyconcludedthatsynergies were present, but the time points for data collection were all less than a week.Similarly, Alwood et al. (2010) and Yumoto et al. (2010) irradiated, hind-limbunloadedmicewithironionsbutonlyexaminedeffectsatshorttimepointsdaysafterirradiation.Prisbyetal.(2015) also evaluated vasodilator response in skeletal muscle after gamma irradiation andunloadingandnotedimpairedrelaxationbutagainatshorttimepoints.Itremainstobeseenwhether any long-standing effects will occur from microgravity and radiation exposurecombined.

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TheCSRR,establishedbyNSBRIin2014,willconducta3-yearfocusedresearchefforttoinvestigate theeffectsof space radiationoncardiovasculardisease.Additionally,aportionoftheirresearchwillincludetheinvestigationofcombinedstressorsofmicrogravityandSPE-likeproton exposures to provide insight into early, acute effects on the hematopoietic system,heart,andretina.

C. PotentialforBiomedicalCountermeasuresMuchof the indirect cell damageproducedby ionizing radiation ismediated through

reactive oxygen species (ROS) that are immediately generated from the interaction of thechargedparticlewithwaterandothercellcomponents(Lietal.2014).Excessiveproductionoffree radicals produces oxidative damage to cellular structures,which includes proteins,DNA,and lipids, and contributes to the radiation-induced degenerative changes that are associatedwithaging,cardiovasculardisease,andcataractformation.ThisextensiveROSprofilecanalsoinduce persistent metabolic changes that result in a chronic inflammatory response. Thesubsequentrecruitmentofinflammatorycells,suchasmacrophages,whichalsogenerateROSand pro-inflammatory signals, feeds into a loop of oxidative stress, inflammation, and celldamage (Zhao and Robbins 2009). The identification of safe and effective agents that willprotect and mitigate against these effects of radiation exposure is a high priority both forradiotherapypurposes,wherethesparingofnormaltissueiscritical,andforthehealthofthegeneralpublicintheeventofaterroristattackwithnuclearweapons(Kennedy2014).

Twomaintypesofcountermeasureshavebeenusedtoprotectnormalvasculaturefromionizingradiation: sulfhydryl or thiol compounds and antioxidants. Both of these classes ofcompoundsfunctionbyscavengingthefreeradicalsthatareproducedbytheinteractionofion-izingradiationwithwater.WR2721,whichisalsoknownasamifostineandgammaphos,isthebest-describedmemberof the sulfhydryl class and is theonlydrug that is approvedby theFoodandDrugAdministration(FDA)tohelppreventexcessdamagetonormaltissuesduringradiotherapy. Themechanism of action of this drug is thought to be the scavenging of freeradicals that are produced by radiation andH-atomdonation to protect against the damagethat is done by free radicals. This compound has been tested as a countermeasure for bothcataractformationandvasculardamage(Kador1983;Mooterietal.1996;Warfieldetal.1990;Plotnikovaetal.1988).RadicalscavengingvitaminssuchasCandEhavealsobeenshowntoprotect the lens and vascular system (Bantseev et al. 1997; Jacques et al. 1997; Taylor andHobbs2002).Inaddition,growthfactortreatmentshavebeenshowntodecreasebloodvesselstenosis (Fuks 1994). In allof these examples, the compounds were administered prior toradiationexposure.

Dietarysupplementsandantioxidantshavealsobeenusedasmitigators forradiation-inducedcataracts.Davisetal.(2010)showedthatexposureto1GeV/nucleonproton(3Gy)oriron-ion(50cGy)radiationsignificantlyincreasedthecataractprevalenceandseverityinCBA/Jmicetolevelsabovethebaselinelevelsofage-inducedcataractformationinthismousestrain.However, treatmentwitha soybean-derivedprotease inhibitoror anantioxidant formulationsignificantlyreducedtheprevalenceandseverityofthelensopacificationsinthemice2yearsafterbeingexposedtoheavyionradiation.

Similarly,theCenterforSpaceRadiationResearch(CSRR)willalsoinvestigatetheuseofgammatocotrienol,anisoformofvitaminE,asamitigatorforspaceradiation-inducedeffects

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onthecardiovascularsystem.γ-tocotrienolisapotentinhibitorofthecholesterolbiosynthesispathwayandhaspreviouslybeenshowtoactasaprotectiveagentagainstvascularradiationinjury due to high doses of whole-body gamma-ray exposures (Berbée et al. 2009), with asuggestedmechanismofactionofprotectionofendothelialcellfunctions(Berbéeetal.2012).TheCSRRwillusemicemodelstomeasureinvivoeffectsofγ-tocotrienolasamitigatoragainstcardiovasculareffectsoflow-dose,high-LETradiation.

Giventhechronicinflammatoryresponsethatmayoccurfromthelowdoseanddose-ratesexperiencedinspace,theuseofanti-inflammatorydrugsforthepreventionofradiation-inducedeffectsisalsoapossibility(Wilsonetal.(2011)usedcorticosteroidtherapytoimprovethe conditions of radiation-induced pneumonitis and pneumonopathy), but it should beapproached with caution. Consideration must be given to evidence pointing to immunedysregulation noted in microgravity (Crucian et al. 2015). The use of a long-term anti-inflammatorydrugmaysynergizewiththedepressedimmunefunctiontosignificantlyincreasetheriskofinfectionandevencardiovasculardisease(HsuandKatelaris2009). Anotherpotentialavenueforbiologicalcountermeasuresistheuseofstatins,aclassofpharmaceuticalscurrentlyusedtosloworpreventcardiovasculardisease.A recentstudyhasutilized simvastatin to mitigate the effects of radiation-induced cardiovascular disease(Lenarczyketal.2015),albeitafterveryhighdosesofwhole-body irradiation (10Gygamma-rays).Asidefrombiologicalcountermeasures,aerobictraininghasalsobeensuggestedasasafeapproach for potentialmitigation of CVD after radiotherapy or chemotherapy (Yu and Jones2015; Berkman and Lakoski 2015). In general, suggested cardioprotective strategies forradiation-induced coronary artery disease include early and frequent monitoring ofcardiovascularhealth (throughnon-invasive imaging techniques suchaselectrocardiography),management of traditional risk factors like hypertension and dyslipidemia through diet,exercise,andpharmaceuticals,andsurgicalinterventionasrequired(Cutteretal.2013).

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VII. GAPSCurrentresearchisfocusedonclosingthefollowingknowledgegaps:Degen - 1: How can tissue specific experimental models be developed for the majordegenerativetissuerisks,includingcardiovascular,lens,andothertissuesystems(e.g.immune,endocrine, respiratory and/or digestive) in order to estimate space radiation risks fordegenerativediseases?

Degen-2:Whatarethemechanismsofdegenerativetissuechangesinthecardiovascular,lens,digestive,endocrine,andothertissuesystems?Whatsurrogateendpointsdotheysuggest?

Degen - 3: What are the progression rates and latency periods for radiation-induceddegenerative diseases, and how do progression rates depend on age, sex, radiation type, orotherphysiologicalorenvironmentalfactors?

Degen - 4: How does individual susceptibility, including hereditary predisposition, alterradiation-induced degenerative disease processes and risk estimates? Does individualsusceptibilitymodifypossiblethresholddosesfortheseprocessesinasignificantway?

Degen - 5: What quantitative procedures or theoretical models are needed to extrapolatemolecular,cellular,oranimalresultstopredictdegenerativetissuerisksinastronauts?Howcanhumanepidemiologydatabestsupporttheseproceduresormodels?

Degen - 6: What are the most effective biomedical or dietary countermeasures to mitigatedegenerative tissue risks?Bywhatmechanismsare the countermeasures likely towork?AretheseCMsadditive,synergistic,orantagonistictootherRisks?

Degen-7:Aretheresynergisticeffects fromotherspaceflight factors (e.g.alteredgravity (μ-gravity), stress, altered circadian rhythms, altered immune function, or other) that modifyspaceradiation-induceddegenerativediseasesinaclinicallysignificantmanner?

Degen -8:Are there researchapproachesusing simulated space radiation that canelucidatethe potential confounding effects of tobacco use on space radiation circulatory disease riskestimates?

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VIII.CONCLUSIONTheassociationbetweenionizingradiationexposureandthelong-termdevelopmentof

degenerative tissue effects such as heart disease, cataracts, immunological changes, andpremature aging is well-established for moderate to high doses of low-LET radiation. Themajorityof this evidence is derived fromepidemiological studieson theA-bomb survivors inJapan,radiotherapypatients,andoccupationallyexposedworkersandissupportedbylaboratorystudiesusinganimalmodels(Blakelyetal.2010)andstudiesofcataractsinastronauts(Cucinottaetal.2001;Chylacketal.2009,2012).Therisksforthesediseasesfromlowdose-rateexposuresand HZE nuclei aremuchmore difficult to assess due to theirmultifactorial nature and longlatencyperiodswhereanimalsmustbeobserved;therefore,theserisksremaindebatableforISSor short-term lunarmissions but aremore likely in long-term lunar orMarsmissions. It alsoremainsunclearwhetherlow-dose(<0.5Gy)exposuresinfluencethesamebiologicalpathwaysthathavebeenshowntobeinvolvedindiseaseprogressionfollowingmoderate-tohigh-doseradiationexposures(Littleetal.2008).NASAhasestablishedshort-termdoselimitstopreventclinically significant deterministic health effects, including performance degradation in flight.ThesedoselimitsandaccumulatedevidencewillbereviewedbyNCRPinthenextfiveyearstoestablishwhethertherearesharpthresholdsorwhethertheremaystillbesomeriskat lowerdoses.Inthenear-term,celloranimalmodelsofdegenerativerisksneedtobedevelopedandapplied todetermine themechanismsof cardiovasculardiseaseandotherdegenerative risksandtodetermineappropriateriskassessmentdataformodels,includingtheexistenceofdosethresholds, role of individual susceptibility, relative biological effectiveness, and dose-ratedependencies for different space radiation ions at NASA Space Radiation Laboratory (NSRL)(GapsDegen1-4).Researchtoaddressthepossibleroleofchronicinflammationandincreasedoxidative stress associatedwith space radiation exposurewill also need to be conducted.Asmission duration increases, there could be degenerative risks to other tissues related todigestivediseasesandpulmonarychangesthatbecomeaconcern.Along-termgoalwillbetoconsidersuchpossiblechangesinanimalvalidationstudiesmadeattheextended-durationGCRfacility under development at NSRL (anticipated completion in 2016). The possibility ofsynergisticriskswithotherflightfactorsmustalsobeconsidered(GapDegen-7).

Space radiation is a large obstacle to mission success, and the long-term health ofastronautsandrecentevidencesuggeststhattheriskofdegenerativediseasesmaybeofmuchlargerconcernthanpreviouslythought.Therefore,theriskofdegenerativediseasespotentiallypresents a risk that is comparable to the already well-documented risks of mortality andmorbidityfromcancer.ItwillbeessentialtoobtainadditionalinformationtoaddresstheriskknowledgegapstosuccessfullymitigatethedegenerativerisktoastronautsforlunarandMarsmissions.

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X.TEAM

CURRENTCONTRIBUTINGAUTHORS:

ZaranaPatel,PhDCellandMolecularBiology,RadiationBiologyWyle,Houston,TXJaniceHuff,PhDCellandMolecularBiology,RadiationBiology,CancerBiologyUniversitiesSpaceResearchAssociation,Houston,TXJanapriyaSaha,PhDCellandMolecularBiologyUniversitiesSpaceResearchAssociation,Houston,TXMinliWang,MDCellandMolecularBiology,RadiationBiologyUniversitiesSpaceResearchAssociation,Houston,TXSteveBlattnig,PhDTheoreticalPhysics,MathematicalPhysicsNASALangleyResearchCenter,Hampton,VAHongluWu,PhDRadiationBiophysicsNASAJohnsonSpaceCenter,Houston,TX

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XI.LISTOFACRONYMS

A-bomb AtomicBombBEIR BiologicalEffectsofIonizingRadiationBFO Blood-FormingOrgansBMI BodyMassIndexCHD CoronaryHeartDiseaseCI ConfidenceIntervalCNS CentralNervousSystemCuZn Copper-ZincCVA CerebrovascularDiseaseCVD CardiovascularDiseaseDDREF Dose-andDose-RateEffectivenessFactorDNA DeoxyribonucleicAcidDDR DNADamageResponseEBIS ElectronBeamInjectorSystemERR ExcessRelativeRiskFDA FoodandDrugAdministrationGCR GalacticCosmicRaysGy GrayHZE HighChargeandEnergyIARC InternationalAgencyforResearchonCancerICRP InternationalCommissiononRadiologicalProtectionIHD IschemicHeartDiseaseISS InternationalSpaceStationLEO LowEarthOrbitLET LinearEnergyTransferLSAH LifetimeSurveillanceofAstronautHealthLSS LifeSpanStudyMeV MegaelectronVoltmGy milliGraymGy-Eq milliGray-EquivalentmSv milliSievertNAS NationalAcademyofSciencesNCRP NationalCouncilonRadiationProtectionandMeasurementsNRC NuclearRegulatoryCommissionNSRL NASASpaceRadiationLaboratoryNS NeverSmokerNW NormalWeightPEL PermissibleExposureLimitRBE RelativeBiologicalEffectivenessREID RiskofExposure-InducedDeathROS ReactiveOxygenSpeciesSMR StandardMortalityRatios

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SPE SolarParticleEventSv SievertUSAF U.S.AirForce