AcuteAcute RadiationRadiation EffectsEffects AcuteAcute RadiationRadiation EffectsEffects

HumanHuman datadata generatedgenerated primarilyprimarily from:from:

“ AtomAtom BombBomb survivorssurvivors

“ MarshalleseMarshallese accidentaccident victimsvictims

“ AccidentsAccidents atat nuclearnuclear installations,installations, e.g.,e.g., ChernobylChernobyl AcuteAcute RadiationRadiation EffectsEffects

“ TheThe RadiationRadiation AccidentAccident RegistryRegistry maintainedmaintained byby thethe RadiationRadiation EmergencyEmergency AssistanceAssistance CenterCenter atat OakOak RidgeRidge NationalNational LibraryLibrary hashas documenteddocumented 403403 radiationradiation accidentsaccidents fromfrom 19441944--19991999

“ OfOf these,these, 1919 involvedinvolved nuclearnuclear reactors,reactors, 303303 involvedinvolved radiationradiation devices,devices, andand 8181 isotopesisotopes

“ ResultedResulted inin 120120 deaths;deaths; 3030 inin thethe US,US, 22 inin GB,GB, 3232 inin thethe formerformer USSRUSSR ProdromalProdromal RadiationRadiation SyndromeSyndrome

“ RefersRefers toto earlyearly symptomssymptoms seenseen afterafter exposureexposure toto highhigh-- intensityintensity radiationradiation

“ VaryVary withwith respectrespect toto timetime ofof onset,onset, severity,severity, andand durationduration

“ DosesDoses ofof ~~ 3030 GyGy individualsindividuals willwill exhibitexhibit allall phasesphases ofof thethe syndromesyndrome withinwithin 55--1515 minmin ofof exposureexposure

“ SevereSevere prodromalprodromal syndromesyndrome usuallyusually associatedassociated withwith poorpoor prognosisprognosis ProdromalProdromal RadiationRadiation SyndromeSyndrome

SignsSigns andand symptomssymptoms divideddivided intointo 22 mainmain groupsgroups

A. GastrointestinalGastrointestinal:: anorexia,anorexia, nausea,nausea, vomitingvomiting etc.etc.

B. NeuromuscularNeuromuscular:: easyeasy fatigability,fatigability, fever,fever, andand hypotension.hypotension. ProdromalProdromal RadiationRadiation SyndromeSyndrome

Neuromuscular Gastrointestinal Signs and Symptoms to be expected at ~ 50% Lethal Dose Easy fatigability Anorexia

Vomiting

Additional Signs to be expected after Supralethal Doses Fever Immediate diarrhea

Hypotension CharacteristicsCharacteristics ofof ProdromalProdromal andand LatencyLatency PeriodsPeriods asas FunctionFunction ofof DoseDose

Dose (Gy) Onset (h) Duration (h) Latency 0.5-2.0 6 or more <24 3 weeks or longer 2.0-3.5 2-6 12-24 2-3 weeks

3.5-5.5 1-2 24 1-2.5 weeks

>5.5 Minutes to 1 48 2-4 days

¾Time of onset of prodromal syndromes inversely related to dose ¾Duration and severity of prodromal syndromes directly dose-dependent CerebrovascularCerebrovascular SyndromeSyndrome

Total body dose of approx. 100 Gy γ rays will cause death in a few hours

N.B. All organs severely damaged and would cause death if the person survived long enough

“ Cerebrovascular damage occurs rapidly, causing death within 24-48h. See severe nausea and vomiting within minutes, followed by disorientation, respiratory distress, diarrhea, seizures, coma, and death

“ Pathogenesis thought to be massive edema leading to severe brain dysfunction CerebrovascularCerebrovascular SyndromeSyndrome

1964:1964: 3838 yearyear--oldold--manman workingworking inin aa 235UU recoveryrecovery plantplant waswas involvedinvolved inin nuclearnuclear accident;accident; receivedreceived totaltotal dosedose ofof ~88~88 GyGy (22(22 GyGy neutrons,neutrons, 6666 GyGy γγ rays)rays)

RecalledRecalled seeingseeing aa flash,flash, hurledhurled backwardsbackwards butbut diddid notnot loselose consciousness.consciousness. RanRan fromfrom scenescene ofof accidentaccident toto anotheranother buildingbuilding 200200 yardsyards awayaway

ComplainedComplained ofof abdominalabdominal crampscramps andand headaches,headaches, vomited,vomited, waswas incontinentincontinent withwith bloodybloody diarrhealdiarrheal stools.stools. NextNext dayday patientpatient comfortablecomfortable butbut restlessrestless CerebrovascularCerebrovascular SyndromeSyndrome

OnOn secondsecond dayday conditioncondition deteriorateddeteriorated

“ VictimVictim becamebecame restless,restless, fatigued,fatigued, apprehensive,apprehensive, shortshort ofof breath,breath, greatlygreatly impairedimpaired vision,vision, hypotensivehypotensive

“ SixSix hourshours beforebefore deathdeath becamebecame disoriented,disoriented, bloodblood pressurepressure couldcould notnot bebe maintainedmaintained

“ DiedDied 4949 hh afterafter accidentaccident GastrointestinalGastrointestinal SyndromeSyndrome

TotalTotal bodybody exposureexposure ofof approx.10approx.10 GyGy γγ raysrays leadsleads toto thethe GIGI syndromesyndrome

“ Symptoms:Symptoms: nausea,nausea, vomitingvomiting andand severesevere diarrheadiarrhea

“ SeenSeen withinwithin 33--1010 daysdays ofof irradiation.irradiation. ProlongedProlonged diarrheadiarrhea indicatesindicates poorpoor prognosis,prognosis, withwith deathdeath occurringoccurring inin aa fewfew daysdays

“ NoNo humanhuman hashas survivedsurvived aa dosedose ofof >10>10 GyGy MechanismMechanism ofof GastrointestinalGastrointestinal SyndromeSyndrome HematopoieticHematopoietic SyndromeSyndrome

“ Total body exposure of 3-8 Gy leads to expression of the hematopoietic syndrome

“ Dose limiting organ is the bone marrow

“ Again have sterilization of precursor cells, leading to diminished supply of mature blood cells

“ Critical period not seen for several weeks, due to lag between the natural turn-over time of the mature cells and subsequent inadequate supply from reduced precursor cell population. HematopoieticHematopoietic SyndromeSyndrome

“ PeakPeak incidenceincidence ofof deathdeath fromfrom hematopoietichematopoietic syndromesyndrome occursoccurs atat ~~ 3030 daysdays afterafter exposureexposure

“ DeathDeath cancan bebe observedobserved upup toto 6060 daysdays

“ Thus,Thus, expressexpress LDLD50 forfor humanshumans asas LDLD50/60

“ DoseDose appearsappears toto bebe inin thethe orderorder ofof 44 GyGy HematopoieticHematopoietic Syndrome:Syndrome: ExperimentalExperimental DataData TreatmentTreatment ofof RadiationRadiation AccidentAccident VictimsVictims

TreatmentTreatment optionsoptions dependdepend onon exposureexposure dosedose

<< 44--55 Gy:Gy: ObservationObservation TreatTreat specificspecific symptomssymptoms e.g.,e.g., antibioticsantibiotics forfor infectionsinfections BloodBlood transfusionstransfusions ifif requiredrequired TreatmentTreatment ofof RadiationRadiation AccidentAccident VictimsVictims Dose > 5 Gy:

“ Person will likely die from hematopoietic syndrome if untreated

“ Use antibiotics and keep patient in isolation to prevent infection

“ Animal studies suggest using antibiotics can increase LD50 twofold

“ Aim to provide time for the bone marrow to regenerate TreatmentTreatment ofof RadiationRadiation AccidentAccident VictimsVictims

Can also give bone marrow transplants: “ Results appear controversial, appears to be a very narrow therapeutic window, between 8-10 Gy BMTBMT afterafter ChernobylChernobyl AccidentAccident

“ Following Chernobyl accident, 202 persons were admitted to Clinical Hospital 6 in Moscow within 4 days of explosion

“ 105 received an estimated total-body dose of ≥1-2 Gy

“ 33 initially considered to have received a dose of ≥6 Gy and were potential candidates

“ 8 subsequently excluded when cytogentic analyses indicated probable doses of < 6 Gy (7 recovered, 1 died from skin burns) BMTBMT afterafter ChernobylChernobyl AccidentAccident

“ 1010 personspersons whowho receivedreceived dosedose ≥≥66 GyGy excludedexcluded duedue toto extensiveextensive nonhemataologicnonhemataologic damage,damage, mainlymainly burnsburns

“ RemainingRemaining 15:15: 11 receivedreceived aa fetalfetal liverliver ratherrather thanthan BMT,BMT, 11 refused,refused, 1313 receivedreceived BMTBMT 44--1616 daysdays afterafter thethe accidentaccident BMTBMT afterafter ChernobylChernobyl AccidentAccident

“ Only 2/13 (doses of 5.8 and 9.0 Gy) survived, began regenerating their own bone marrow on day 28

“ 5 died mainly from burns, although 3 had GI damage and 1 radiation pneumonitis

“ 3 died mainly from radiation pneumonitis

“ 2 died from graft-versus-host disease

“ 1 died from acute renal failure and adult respiratory distress syndrome. GrowthGrowth FactorFactor StimulationStimulation ofof BoneBone MarrowMarrow ProliferationProliferation

“ PostPost--irradiationirradiation stimulationstimulation ofof cellcell proliferationproliferation inin thethe bonebone marrowmarrow predictedpredicted toto bebe advantageousadvantageous >> 4040 yearsyears agoago byby LajthaLajtha (1960)(1960)

“ RecentRecent animalanimal experimentsexperiments usingusing hematopoietichematopoietic growthgrowth factorsfactors andand thethe clinicalclinical experienceexperience fromfrom thethe treatmenttreatment ofof accidentalaccidental radiationradiation exposureexposure inin Goiania,Goiania, BrazilBrazil (1987)(1987) areare supportivesupportive ofof thisthis farsightedfarsighted predictionprediction GoianiaGoiania AccidentAccident

SeptemberSeptember 1313 1987,1987, Goiania,Goiania, CentralCentral BrazilBrazil

“ ApproxApprox 250250 peoplepeople exposedexposed toto aa 137CsCs sourcesource fromfrom anan abandonedabandoned RTRT unitunit

“ 1414 individualsindividuals showedshowed bonebone marrowmarrow depression,depression, 88 developeddeveloped acuteacute radiationradiation syndromesyndrome GoianiaGoiania AccidentAccident

“ 8/148/14 receivedreceived GMGM--CSFCSF iviv

“ NoneNone receivedreceived BMTBMT

“ GMGM--CSFCSF treatmenttreatment notnot startedstarted untiluntil 2323--4848 daysdays afterafter initialinitial andand 1919--3737 daysdays afterafter finalfinal exposureexposure

“ 44 dieddied fromfrom hemorrhagehemorrhage andand infectioninfection