Triage Proceedings.vp:CorelVentura 7 · 2011-05-13 · dressed the issues and highlighted the...

TRIAGETRIAGEof Irradiated

Personnel

AnArmed Forces Radiobiology

Research InstituteWorkshop

25-27 September 1996

Proceedings

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Standard Form 298 (Rev. 8-98)Prescribed by ANSI Std Z39.18

Proceedings

TRIAGEof IrradiatedPersonnel

Edited by:

Glen I. Reeves, M.D.

David G. Jarrett, M.D.

Thomas M. Seed, Ph.D.

Gregory L. King, Ph.D.

William F. Blakely, Ph.D.

AnArmed Forces Radiobiology

Research InstituteWorkshop

25–27 September 1996

Armed Forces Radiobiology Research Institute

8901 Wisconsin Avenue

Bethesda, MD 20889-5603

This and other AFRRI publications are available to qualified users from the Defense TechnicalInformation Center, Attention: OCP, 8725 John J. Kingman Road, Suite 0944, Fort Belvoir, VA22060-6218; telephone (703) 767-8274. Others may contact the National Technical InformationService, 5285 Port Royal Road, Springfield, VA 22161; telephone (703) 487-4650. AFRRI publicationsare also available from university libraries and other libraries associated with the U.S. Government’sDepository Library System.

For information about this publication, write Armed Forces Radiobiology ResearchInstitute, 8901 Wisconsin Avenue, Bethesda, MD 20889-5603, USA, or telephone011-301-295-0377, or send electronic mail to [email protected]. Findmore information about AFRRI on the Internet’s World Wide Web athttp://www.afrri.usuhs.mil.

AFRRI Special Publication 98-2Printed March 1998

Cleared for public release; distribution unlimited.

The workshop, “Triage of Irradiated Personnel,”sponsored by the U.S. Army Office of the SurgeonGeneral, was conducted at the Armed Forces Radio-biology Research Institute (AFRRI) on September25–27, 1996. This workshop focused on a reassess-ment of the radiation medicine section of Chapter 4,Medical Aspects of Nuclear, Biological and Chemi-cal Warfare, of Army Field Manual 8-10-7: HealthService Support in a Nuclear, Biological and Chemi-cal Environment.Sixty-five speakers and guestsfrom the United States, Germany, Netherlands,Canada, United Kingdom, and France addressed thethree issues: (1) operational effectiveness of exposedpersonnel with and without other injuries who re-ceive medical care in Army echelon I and echelon IImedical facilities, (2) operational effectiveness ofpersonnel with multiple exposures (assuming a pre-vious total dose of <1.5 Gy), and (3) methods for es-timating exposure in personnel who receiveantiemetics before or shortly after exposure.

Over the course of the 3-day workshop the followingfour sessions were conducted:

Session I. Background.An overview of doc-trine and laboratory capabilities in a forwardmedical field environment and an assessmentof the future operational capabilities offorward-deployed medical units and support-ing laboratories.

Session II. Estimation of Exposure UsingBlood Markers and Clinical Indicators.Assessment of the accuracy, sensitivity, andreliability of monitoring blood-cell responsesand other clinical indicators, particularly ifnau-sea and vomiting have been reduced or elimi-nated by the administration of antiemetics.

Session III. Predicting the Effects of Multi-ple Radiation Exposures. Assessment ofthe accuracy, reliability, and validity of animaland human data that have been used to predictthe outcome of exposure scenarios.

Session IV. Forward-Field Bioindicators forDose Assessment: Possible Alternatives.Evaluation of the status of several possible al-ternatives to peripheral blood counts and pro-dromalsymptoms for field-dose assessment.Selected candidate assays were evaluated;characteristics included (1) negligible post-sampling incubation, (2) rapid processingsuitable for a high degree of automation andhigh throughput, (3) low-threshold and broaddose-range capability, (4) relatively noninva-sive sample collection, and (5) equipmenthardware for which components are or soonwill be available.

At the conclusion of each session a panel of invitedspeakers and AFRRI subject-matter experts dis-cussed the presentations and session findings. Audi-ence participation generated several questions andcomments. The final morning summary session ad-dressed the issues and highlighted the workshopconclusions as well as the remaining uncertainties.

The findings of this workshop are intended for useby U.S. Army medical planners, particularly thoseinvolved in the configuration, deployment, and lo-gistics of forward-field medical facilities (echelon Iand II). These Summaries do not necessarily reflecteither current or future Army doctrine. It must be em-phasized that triage is a dynamic process that in-cludes prioritization at each iteration. The initial cate-gorization and treatment delivered to the patient willrequire and receive reevaluation as the patient’s clini-cal course develops and as echelons of available careand resources change. Physicians at each echelon ofcare will determine appropriate management basedprimarily on their clinical impression of the patient’scondition and what means of intervention appearbest suited to favorably influence the course of dis-ease. Laboratory studies, including physical dosime-try—no matter how accurate—are used to supportclinical judgment, not substitute for it. One finalpoint: triage is NOT a decision based on militaryutility to “treat or not treat.” It is a decision on how

iii

Preface

best to use both personnel and materiel resources tomaximize treatment foreverypatient and to achievefavorable clinical outcomes for as many patients aspossible. Although the concept of triage is generallycited in a military medical context, it is ade factopractice in every busy emergency room and in everymajor disaster, civilian or military.

The success of this workshop is directly attributableto the excellence and expertise of the participants. Inaddition, each session chairman deserves praise for

the formidable amount of preparation and knowl-edge—without which this workshop could not havesucceeded. COL David G. Jarrett, M.D., USA, Ses-sion I Chairman; Dr. Thomas M. Seed, Session IIChairman; Dr. Gregory L. King, Session III Chair-man; and Dr. William F. Blakely, Session IV Chairman,deserve high praise for the success of this endeavor.

This project was funded by the Department of theArmy Surgeon General, Directorate of Health CareOperations.

GLEN I. REEVESCol, USAF, MC, SFSWorkshop Coordinator

iv

Contents

Summary of Session I

Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Summary of Session II

Estimation of Exposure Using Blood Markers andClinical Indicators. . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Summary of Session III

Predicting the Effects of Multiple Radiation Exposures. . . . . . . . 15

Summary of Session IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Forward-Field Bioindicators for Dose Assessment:Possible Alternatives. . . . . . . . . . . . . . . . . . . . . . . . . . 21

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Appendices

Appendix A. Session I. . . . . . . . . . . . . . . . . . . . . . . . . A-1

Appendix B. Session II. . . . . . . . . . . . . . . . . . . . . . . . B-1

Appendix C. Session III. . . . . . . . . . . . . . . . . . . . . . . . C-1

Appendix D. Session IV. . . . . . . . . . . . . . . . . . . . . . . . D-1

Appendix E. List of Attendees. . . . . . . . . . . . . . . . . . . . . E-1

v

1


Background

David G. Jarrett, COL, MC, USAChairman

Armed Forces Radiobiology Research Institute, Bethesda, MD

• Operational Capabilities of Army Forward Medical FacilitiesGary C. Norris, LTC, MSC, USADirectorate of Combat and Doctrine DevelopmentArmy Medical Department (AMEDD) Center and SchoolFort Sam Houston, TX

• Overview of Current Operational PolicyRobert Mosebar, COL, MC, USA (ret)Directorate of Combat and Doctrine DevelopmentAMEDD Center and SchoolFort Sam Houston, TX

• Field Laboratory CapabilitiesSamuel J.P. Livingstone, Maj, MSC, USAFWilford Hall Air Force Medical CenterAndrews Air Force Base, MD

• Status and Limitations of Physical Dosimetry in the Field EnvironmentDavid A. Schauer, LCDR, MSC, USNNaval Dosimetry CenterNavy Environmental Health Center DetachmentBethesda, MD

• NATO Policy and Guidance on Antiemetic UsageRobert KehletDefense Special Weapons AgencyAlexandria, VA

• Review of Potential Biomarkers of Radiation ExposureDr. Clive L. GreenstockRadiation Protection BranchAtomic Energy Commission Limited, Chalk River LaboratoriesChalk River, Ontario, Canada

Overview

The goal of Session I was to provide background in-formation and a starting point for the many physi-cians and researchers who are not acquainted withthe capabilities and limitations of providing medicalcare away from a permanent medical facility. Thecurrent and near-future deployable medical unitswere discussed and an overview of potential radia-tion biomarkers was presented.

Introduction

TheUnitedStatesArmymustbeprepared toeffectivelyuse soldiers in a radiologically contaminated environ-ment during small-scale operations that include acci-dents and terrorist activity and in the event of a nuclearconflict. Current doctrine is based on scenarios of coldwar transition to nuclear war and the resultant mass-casualty medical requirements. Early return to combatduty would be practiced for all soldiers who are nomi-nally performance capable. Significant morbidity andmortality of radiation casualties would not occur untilafter the arrival of reinforcements. Isolated radiationinjury does not necessarily cause significant immediatedisability; and truly effective therapy for radiologi-cally injured soldiers is considered improbable in a totalnuclear war scenario. However, low- to mid-range ra-diation injury presents a unique problem as acutesymptoms can be debilitating but are preventable withadequate prophylaxis. If left untreated, the hemato-logic intermediate-term (i.e., 2 to 6 weeks) effects ofthis same radiation injury would become devastating.

In view of the significant advances in the treatmentof hematologic injury as well as changes in militaryoperational requirements, a review of current doc-trine is mandatory. The purpose of this section wasto present to scientists the medicalcapabilities of de-ployable units to ensure that recommendations forimplementing triage mechanisms will bepractical.

Military Medical Care at Far-ForwardEchelons

Military medical care is designed to be delivered as farforward as is practical. This doctrine maximizes thereturn to duty of individuals with minor injuries and

makes a positive impact on battle outcome. Theearly evacuation of casualties requiring prolongedtreatment concomitantly minimizes the individualcasualty's morbidity and frees forward-medical re-sources to concentrate on short-term care. Nocur-rent method is available to rapidly assess an indi-vidual's degree of radiologic injury, and as ra-diation is not likely to result in immediate mortality,triage is primarily based on other criteria. Thosesoldiers in whom radiation injury is suspectedwould require evacuation to the hospital level forevaluation.

Initial treatment may be provided by the combat life-saver, a combat soldier trained in advanced first aidtechniques. The first medical treatment (echelon I)is provided by the combat medic and his supervisingbattalion aid station (BAS), which has a physicianand a physician's assistant. No laboratory or radio-logic equipment is available at the BAS. The two ba-sic choices are either treatment to allow return of thecasualty to duty or stabilization for evacuation toechelon II or III. At echelon II (the medical com-pany), rudimentary laboratory services and x-raycapability are available as are holding beds for pa-tients who are expected to return to duty within awell-defined short time frame. Interventional sur-gery can be placed at this level as an augmentationmodule when additional forward capability is deemedpractical. Echelon III is the first hospital facility andhas the capabilities for true blood-cell counting andlimited chemistry. Most patients who are evacuatedto this level will proceed up the evacuation chain andwill not return to duty soon. The next echelon ofevacuation will be to a theater-level medical facility,a fixed-base facility, or a continental U.S. (CONUS)hospital. See Fig. 1 for possible routes of medicalevacuation from the far-forward field.

The Theater Army Medical Laboratory (TAML) isan independent field laboratory capable of providingregional support that includes clinical laboratoryref-erence testing for biochemical, toxicological,bacte-riological, mycological, and parasitological agents.It is also capable of gross and microscopic pathologysupport. Its medical defense tactical applications in-clude confirmation of endemic disease and sus-pected radiological, chemical, and biological war-fare agents. Future plans include replacement of theTAML with an Area Medical Laboratory (AML),

2

Triage of Irradiated Personnel Proceedings

which is smaller and requires less logistical support(diminished footprint); the rapid diagnostic and chem-istry test capabilities will be relocated to echelon IImedical companies. The AML will then be focuseddirectly on battlefield health-hazard assessment.

Current Operational Policy

Symptoms of radiation injury will usually not bemanifest at acute doses of less than 100 cGy but willbe progressively more intense and more rapid in on-set with higher radiation doses. Most soldiers whoreceive low to midrange radiation doses (100–300cGy) will have symptoms of nausea and vomitingwithin several hours of exposure and are conse-quently less tactically effective. They are then sig-nificantly more prone to further traumatic injury asthey can less proficiently operate weapon systems,

defend themselves, and press the attack. Primaryclinical guidance for triage of radiation casualtieswith unknown dose is based on symptoms during theprodromal period. This is the interval between timeof exposure and cessation of nausea and vomiting.Radiation exposure dose is estimated based on thetime interval between exposure, symptom onset, andsymptom severity. To diminish the individual sol-dier's morbidity and performance degradation, thedevelopment of a safe prophylactic drug for thenausea and emesis of significant radiation injurywas necessary. Use of this medication would pre-vent individual capability degradation and wouldconsequently diminish the overall casualty rate byallowing tactical mission completion. Unfortu-nately, eliminating these symptoms rules out themedical officer's ability to clinically estimate ra-diation exposure without research-level diagnosticmodalities.

3


TAML(Theater Army Medical

Laboratory)

Infusion pump & controllerIV setBlood substitute

Personnel Status Monitor relaysposition and vital signs

Casualty

Forward Surgical Team

BDE Medical CoW/FWD Surgical

Team

Combat Zone Hospital

USAF StagingFacility

Resuscitation essentials

E CH E L ON IBuddy aidCombat lifesaverCombat medic

Buddy aidCombat lifesaverCombat medic

E CH E L ON I IEmergency abdominaland thoracic surgeryEmergency abdominaland thoracic surgery

E CH E L ON I I I

Advanced Medical Hospitals

Battalion Aid StationPhysician/PA

DJARR1.CDR

Casualty evacuation

Information transfer

Fig. 1. Routes of medical evacuation from the far-forward field.

Status and Limitations of PhysicalDosimetry in the Field Environment

Peacetime occupational radiation exposures aremonitored using thermoluminescent dosimeter(TLD) systems accredited by the National Volun-tary Laboratory Accreditation Program (NVLAP).These systems are designed for centrally located andcontrolled programs and are not suitable for field op-erations. War-time dosimetry is based and con-trolled at the unit level. The primary individualdosimeter system currently fielded is the high-rangephotoluminescent AN/PDR-75. This system con-sists of the ruggedized DT-236 wristband dosimeterthat is capable of measuring cumulative neutron andgamma-ray doses in the range of 0–999 cGy and theCP-696 nondestructive dosimeter reader. The CP-696 is issued to company-sized units, and results arerecorded at company level. The system is not con-sidered a medical-issue item, and dosimeters are notroutinely distributed to deploying soldiers. Futuredosimetry systems include the platoon-basedAN/UDR-13, a direct-reading dose-rate meter and atotal gamma-plus-neutron dosimeter. Next-generation systems should include the capability ofteledosimetry that allows remote monitoring of indi-vidual dose-rate exposure.

Current NATO Policy and Guidance onAntiemetic Usage

The North Atlantic Treaty Organization (NATO)project group (PG-29) has recommended grani-setron as the deployable radiation emesis preventiondrug of choice. NATO members will develop indi-vidual operational plans for implementation underthe draft Standardization Agreement (STANAG4510). Under draft STANAG 4511, multiple pro-phylactic antiemetic medications and regimenswere evaluated prior to adoption of granisetron.

Two drugs exceeded the criteria (shown below),granisetron and ondansetron. The former was adopteddue to a better technical profile and the operationaladvantage of once daily oral administration.

Review of Potential Biomarkers ofRadiation Exposure

The human body is the ultimate dosimeter, andmeasurable changes in tissues and biosamples arethe most important indicators of whole-body dose.Two types of biodosimeters are possible: biophysi-cal indicators that are direct measures of absorbed

4


Approval by individual national pharmaceutical regulatory authorities.

Effective antiemetic for radiation doses up to 10 Gy.

Rapidly effective after a single self-administered oral or auto-injectable dose.

Compatible with other normal prophylactic and emergency therapeuticmeasures.

No militarily significant side effects, and no potential for abuse.

Effective in extremes of climate without compromising individualenvironmental conditioning.

Packaged for 1-week dosages utilizable by individuals in protectiveequipment.

Minimum of 36-month shelf life stability between 0 and 50 degrees Celsius.

Summarized NATO criteria for an acceptable antiemetic

dose and are not influenced by repair mechanisms,and biological indicators that record absorbed doseby a biological manifestation of radiation exposure.A biophysical indicator, such as electron spin reso-nance (ESR), is instrument-based and is usuallymore amenable to automation. It is analogous to aphysical personal dosimeter. A biological dosimetercan include physiological, hematological, bio-

chemical, immunological, and cytological assays.Consequently, it measures the biologically relevanteffects of radiation to estimate the effective dose re-ceived. Testing usually requires experienced techni-cians to minimize method variabil i ty andsubjectivity for reliable dose estimation. Relevantportions of this talk are summarized in subsequentsessions.

5


7


Estimation of Exposure Using Blood Markersand Clinical Indicators

Thomas M. Seed, Ph.D.Chairman

CDR Michael E. Dobson, LTC Daniel C. Garner,LT Tracy B. Kneisler, and Dr. Mark H. Whitnall

Session Panelists


• Alterations of Hematological Parameters by RadiationNiel Wald, M.D.Department of Environmental and Occupational Health, Graduate School ofPublic HealthUniversity of Pittsburgh, Pittsburgh, PA

• Prediction of Clinical Course Through Serial DeterminationsHauke Kindler, D. Densow, T. M. FliednerInstitute of Occupational and Social Medicine, University of Ulm, Ulm, Germany

• Dose Estimation Using Lymphocyte Depletion KineticsRonald E. Goans, Elizabeth C. Holloway, Mary Ellen Berger, Robert C. RicksRadiation Emergency Assistance Center/Training Center (REAC/TS)Oak Ridge Institute for Science and EducationOak Ridge, TN

• Fatigability and Weakness as Clinical Indicators of ExposureGeorge H. AnnoPacific-Sierra Research CorporationSanta Monica, CA

Overview

This session's goal was to examine the usefulnessand practicality of attempting to assess—for the pur-pose of triage—early clinical and blood-cell re-sponses that would occur in irradiated militarypersonnel operating within radiation contaminatedfar-forward battlefields.1

The operational necessity to rapidly and accuratelyassess the physiological responses induced by ra-diation exposure and the possible concomitantnegative impact on troop performance (and to alesser extent, long-term medical complications andsubsequent treatment protocols), provided theorientation for this session's presentations andtopics.

The session featured four presentations by invitedexperts who spoke on various aspects of radiation-induced blood alterations, the clinical responses,and their applicability as clinical indicators formedical triage of irradiated military personnel in thefar-forward field.2 Two presentations (by Drs. NielWald, University of Pittsburgh, and Hauke Kindler,University of Ulm) provided overviews of thetemporal and exposure-dependent hematologicalresponse patterns of acutely irradiated individuals.An additional presentation (by Dr. Ron Goans,REACT/S, Oak Ridge) focused on the biodosimet-ric potential of assessing lymphocyte depletion ki-netics. The fourth presentation (by George Anno,Pacific-Sierra Research Corp.) discussed the possi-bility of using the clinical responses of fatigabilityand weakness asearly indicators of the extent ofradiation exposure.

An open discussion followed the presentations inwhich presenters and audience alike examined andprovided comment, not only on the accuracy, sensi-tivity, and reliability of these measured, well-documented clinical and hematological endpoints,but also on the practicality of such assessmentsgiven the constraints of a narrow time window (24-hr postexposure), the possibility that antiemeticswere given, and the far-forward medical echelon Iand II settings.

The general consensus was that under such con-straints (time, technology, and echelon setting)these blood and clinical indicators are not adequatefor initial triage in the far-forward field. First-linetriage would be better served by the application ofphysical dosimetry, rather than by blood/clinicalindicator-based biodosimetric procedures.3 The lat-ter procedures would serve a more useful function insecondary triage processes during which clinicalmanagement/treatment decisions can be made.

Presentation Details and Comments

Comparisons of attributes of the three bloodmarker-based assays, along with a single clinical-indicator assay, are presented in Table 1.

Blood Markers in Estimating Exposure

A single parameter assessment strategy, offered byDr. Ron Goans (ORISE, Oak Ridge, TN), is basedon monitoring the rate of lymphocyte depletionduring the initial 24-hr postexposure period. Thisbiodosimetric tool seems to provide a moderately

8


1Triage processes discussed relate solely to military operations under battlefield conditions, and not to possible early processing

of civilian casualties by civilian medical doctors following a nuclear accident.2An additional presentation relevant to this topic of early hematopoietic response indicators was made by Dr. L.G. Filion

(University of Ottawa, Canada) during Session IV. For details of this presentation, the reader should refer to Appendix D,

which contains the appended text of this work.3Proposed use of physical dosimetry in forward fields of operation is not intended to supplant the need for medical evaluation by

either the medic in the field or by the physician in a higher echelon care facility, but only as a means to more effectively sort

minimally exposed “duty-ready” troops from those troops deemed “suspect” and perhaps “duty unfit” due to moderate-to-heavy

exposures and associated performance and health status degradations.

reliable and consistent but fairly crude assessment ofacutely delivered whole-body exposures.4 It has thestrongest biodosimetric potential in the far-forwardfield of operation of various assays described duringthis session. The technique, however, is limited interms of threshold doses to approximately 1 Gy andto approximately 2–3 Gy in terms of resolving dis-tinct exposure levels within the range of detection,i.e., ~1–10+ Gy. The relatively short time (6–8 hrs)for assay development is a major advantage;whereas the requirement for multiple sampling andthe uncertainty of confounding factors (biologicalwarfare (BW)/chemical warfare (CW) agent expo-sures, combined wound/burn injuries, physiologicalstress, etc.) represent major disadvantages.

reliable and consistent but fairly crude assessment ofacutely delivered whole-body exposures.4 It has thestrongest biodosimetric potential in the far-forwardfield of operation of various assays described duringthis session. The technique, however, is limited interms of threshold doses to approximately 1 Gy andto approximately 2–3 Gy in terms of resolving dis-tinct exposure levels within the range of detection,i.e., ~1–10+ Gy. The relatively short time (6–8 hrs)for assay development is a major advantage;whereas the requirement for multiple sampling andthe uncertainty of confounding factors (biologicalwarfare (BW)/chemical warfare (CW) agent expo-sures, combined wound/burn injuries, physiologicalstress, etc.) represent major disadvantages.

Thisassay techniqueshouldbeconsideredonly in termsof its dosimetric attributes, and not as a diagnostictool upon which treatment decisions are based.

Two multiparameter strategies for the hemato-logic assessment of the “acute radiation syndrome(ARS)” were presented—one by Dr. Niel Wald ofthe University of Pittsburgh, and another by Dr.Hauke Kindler of the University of Ulm (Ulm, Ger-many). Both strategies were designed to segregateradiation-exposed individuals into distinct severitylevels (five levels) of radiation injury (ranging fromminimal, nonlethal, to severe, definitively lethal),thus, providing the clinical rationale for subsequenttreatment options.

Dosimetric assessment was not the primary objec-tive of these assessments per se; although crude esti-mates of exposure levels can indeed be determinedbased on characteristic blood response profiles.5

The approach outlined by Wald involves rankedanalyses of the degree of exposure-dependent

9


Table 1. Comparison of attributes of hematological/clinical indicator-based assays.

Attributes Assay types

No. endpoints 1-parameter

Hematologic-based

3-parameter 9-parameter

Clinical-based

F/W

No. samples required ³3 ³6 ³6? >1?

Predictor functionBiodosimeter

function

weakmoderate

strongweak

strongweak

very weaknegligible

Threshold doseResolutionRange of detection

~1Gy~2Gy

~1–10+Gy

~1Gy~2–3Gy

~1–10+Gy

~1Gy~2–3Gy

~1–10+Gy

~<1Gy~2–3Gy?

~1–10+Gy?

Validation of test yes yes yes ?

Development time £24hrs 1–5d 4–7d £24hrs

Confoundersinfluence-stress-combined injury-BW/CW

yes+

+

+

yes-±

±

yes-±

±

yes+±

+

Meets far forward-field use requirements no no no no

4The utility of such “lymphocyte” depletion-type assays to accurately and reliably estimate radiation exposure levels has been ac-

tively debated and questioned, especially within the community of physicians and researchers specializing in radiation hematology.5Clinical assessments based on blood-cell counts should be used first and foremost to estimate both the extent of hematopoietic injury,

as well as the capacity for injury repair, and should provide the basis for rational, medically-based, treatment decisions. Extracting

prognostically useful information from simple blood-cell responses is quite possible but is clearly and absolutely time dependent.

hematologic abnormality. The assay is based on theserial assessment and abnormality scoring of nineindividual blood parameters (hemoglobin levels,erythrocyte counts, hematocrit values, erythrocytesedimentation rates, reticulocyte counts, total leuko-cyte counts, absolute neutrophil levels, lymphocytecounts, and platelet levels) and, in turn, the foldingof the individual abnormality scores into a singlescore of hematopoietic injury.

The major advantage of this approach is its strongpredicator function of clinical outcome; whereas itsmajor disadvantages are the relatively long develop-ment times (~1–5 days) and low resolution of thedose-dependent clinical responses.

The ARS assessment approach presented by Kindleris similar to Wald's approach, in terms of its multi-parameter nature, but employs fewer parameterswhich are analyzed individually and not in aggre-gate at distinct times over the course of the initialweek followingexposure.Thisassessmentprocesshasbeen labeled the “sequential diagnosis” technique.

Response profiles for given parameters were basedon a detailed, retrospective study of 543 ARS patientrecords from the International Computer Databasefor Radiation Exposure Case Histories (ICDREC).These profiles were used in determining patientmanagement/treatment decisions. It should be notedthat the majority of cases (390/543 or 71%) exhib-ited minimal injury profiles and required no specifictreatment for radiation injury. The next largestgroup (101/543 or 18%) had substantial levels of in-jury but were clearly treatable with standard clinicalsupport and cytokine therapy. Only a minor group(52/543 or 9%) exhibited radiation injuries so severeas to require intense, technologically complex levelsof support (e.g., marrow transplantation).

Based on data presented by Kindler, reliable assess-ments of injury severity can be made within a 4- to7-day window if blood granulocyte, lymphocyte,and platelet levels are sequentially monitored (at 6-hr intervals during the initial 36-hr postexposure pe-riod). However, accurate dose-dependent injury as-sessment within the targeted 24-hr postexposureperiod is not possible using this assay procedure.

The multiparameter assessment (sequential diagno-sis) procedure developed by the Ulm group (led byProfessor T.M. Fliedner) has strong prognostic ca-pabilities and can provide a solid basis for subse-quent medical management and treatment decisions.When compared to Wald's “folded multiparameter”scoring assay, this procedure enjoys roughly thesame sensitivity (~1 Gy), resolution (~2–3 Gy), aswell as the overall range of detection (~1–10+ Gy).The major weaknesses (in terms of its biodosimetricpotential) are again the long development times (~4to 7 days) and the requirement for multiple sampling.

Clinical Indicators in Estimating Exposure

A physiological-based model using empirical obser-vations of the well recognized radiation associatedclinical syndrome of fatigability and weakness(F/W) were presented by Mr. George Anno ofPacific-Sierra Research Corporation. This syn-drome was discussed, not only in terms of elicitingradiological and temporal parameters, but also as avery early (<24 hrs) indicator of the magnitude andoccurrence of radiation exposure.

This discussion was driven by underlying questionsas to whether F/W can serve as a reliable, meaning-ful indicator of radiation exposure if the prominentclinical indicators of nausea and vomiting arestripped away by the application of antiemetics. Theconsensus answer to this question was clearly andsimply—no.

The F/W model, founded on a lymphocyte-depletion kinetics construct, seems to provide rea-sonably consistent exposure-dependent responseprofiles (comparing “observed” to “expected” re-sponse profiles). This consistency along with earlyassessment times of 24 hrs or less and the prospect ofindirectly quantifying the highly subjective F/W pa-rameter through a simple lymphocyte count are allattractive attributes. Nevertheless, near-term appli-cation of the F/W modeled parameter to triage in theforward field is extremely doubtful, due not only tothe uncertainty of individual response variations(lack of confidence intervals) but also to the uncer-tainty of the basic mechanism(s) governing the F/Wresponse.

10


Discussion and Conclusions

This session, with its focus on “blood markers andclinical indicators,” primarily addressed the thirdissue raised in Chapter 4 of theArmy Field Manual8-10-7: Methods for Estimating Exposure in Per-sonnel Who Have Received Antiemetics Before orShortly After Exposure.

In principle, both the single- and multiparameter-hematologic methods described during this sessioncan be used to provide estimates of exposure withinirradiated personnel regardless of whether antiemet-ics have been given.

The sensitivity, resolution, and range of detectiondisplayed by these assays are reasonable and proba-bly would be effective as supplemental proceduresfor triage under select conditions. For example, therapid one-parameter/lymphocyte-depletion kineticsassay might be suitable to provide rough estimatesof radiation casualty numbers needed for medical lo-gistics; whereas the slower, more prognostic multi-parameter assays (3- and 9-parameter assays) mightbe effectively applied for determining the extent ofinjury and subsequent treatment options. However,the utility of these procedures for triage in aforward-field operation is questionable. This con-cern was raised principally by Dr. Robert H. Mose-bar, a recently retired chief medical operationsplanner (U.S. Army Medical Department Center,Fort Sam Houston, Texas) and by others in the audi-ence as well. The constraints of time, medical re-sources, and the operation itself seem to precludeuse of these assays. The status of existing blood-analysis technology restricts these assays to a mini-mum echelon II facility—a facility designed forhigh throughput of short-term emergencies, and notfor the prolonged sequential monitoring required by

these hematologic assays, especially the multi-parameter-based assays.6

Nevertheless, the multiparameter hematologic as-says and their strong prognostic attributes are abso-lutely essential, perhaps not in the very early phasesof triage but a little downstream in the process.These assays are essential in determining the sever-ity of radiation-induced injuries and the probabilityof organ-system repair and recovery. Such determi-nations provide the basis for subsequent treatmentdecisions.

In contrast to the hematologic assays, it is extremelydoubtful that the clinical F/W response assay, as itcurrently stands, can provide a useful vehicle for es-timating exposure levels, regardless of whether an-tiemetics are administered. The highly subjectivenature of the F/W clinical response and the lack ofquantitative methods for determining its measure-ment, effectively rules out the use of this endpoint asa biodosimeter.

The aforementioned operational problems of usingthe F/W bioassay in the initial triage of radiation-injured personnel in far-forward combat environ-ments led to considering physical dosimetry as apossible interim solution to the rapid (<24 hrs)throughput requirements for the initial phase of thetriage process.7Dosimetry could be rapidly read, ex-posure levels estimated, and casualty probabilitiesdetermined—all in an echelon II facility. With thesedose estimates, troops with registered doses (free-in-air) of 1.5 Gy or greater, would be medicallyevacuated to an echelon III facility for clinical andhematologic evaluations on which subsequent treat-ment decisions would be based. Troops with esti-mated exposures oflessthan 1.5 Gy (as assessedby initial physical dosimetry) or lacking subsequent

11


6The suggestion was offered that with the advent of new technology (in the form of hand-held blood cell analysis units) the above

mentioned shortcomings of the hematologic assays in far-forward fields of operation might be largely overcome. With such hand-

held units, medics should be able to perform these hematologic assays on putatively injured troops directly in the field (or in an eche-

lon I facility) with high efficiency and accuracy. However, it needs to be noted that the utility of applying such advanced monitoring

devices in far-forward fields of operation has been seriously questioned by several radiation hematologists.7The suggested use of physical dosimetry in the initial phases of the triage process is intended to supplement, not to minimize, nor

eliminate the need for full symptomatologic assessment by the field medic or physician in a forward-field care facility. Physical do-

simetry is suggested as a possible solution to the substantial problem imposed by the constraints of time, resources, and casualty-care

logistics under battlefield conditions. See footnotes 1, 3, and 5 for additional comments.

clinical/hematologic indicators of radiation injury(assessed in the echelon III facility) would be sentback to duty.

The remaining two issues addressed by the work-shop, namely, (1) operational effectiveness of irradi-ated personnel, and (2) operational effectiveness ofpreviously exposed personnel, were only brieflyconsidered, specifically in terms of the expectedperformance decrement following onset of selectedclinical syndromes (upper/lower gastrointestinaland hematologic syndromes). Changes in opera-tional performance caused by radiation exposureneed to be considered within a temporal frameworkof both “early effects” (less than 24 hrs) and “lateeffects” (>24 hrs, days to weeks). In terms of the lat-ter, the consensus was clear: The prognosticallyuseful hematologic assays relate to long-term per-formance and not to short-term capacity, due to thedelayed onset (days to weeks) of the potential,performance-degrading hemopathologic responses(granulocytopenia and thrombocytopenia, with in-creased susceptibility to infection and uncontrolledbleeding).

The dose-dependency of decreased performance un-der acute radiation exposure scenarios has been ex-tensively studied and modeled (as indicated in theSession III presentation by Dr. Gene McClellan ofPacific-Sierra Research Corp.). However, the ap-propriateness of these models, either in terms oftheir basic biology or to the triage process itself, wasnot fully addressed.

Early changes in operational performance can beelicited by induction of the F/W syndrome. Even atfairly moderate radiation doses, where long-termsurvival would be expected, there is rapid onset (<~3hrs) of a moderately intense F/W response with thepotential to degrade short-term performance (<24hrs). In this regard, there was general agreementamong workshop participants that (1) the F/W syn-drome is a very real and important component ofperformance and (2) its induction and expression isgoverned by a standard set of radiological parameters.However, there was also agreement that the F/W re-sponse is highly subjective and resists quantitation.

This restricts the assignment of confidence intervalsto F/W response components (threshold, magnitude,intensity) and, in turn, limits its power and utility asa “folded parameter” in the model of radiation-associated performance degradation.

Recommendations

1. Physical dosimetry should be the principal tool inthe initial assessment of radiation exposure levelsreceived by military personnel operating withinfar-forward fields of operation.7

1.1. Exposure estimates would be carried out inan echelon II facility and would be usedsolely for logistical purposes and not fortreatment decisions.

1.2. Personnel with estimated exposures of 1.5cGy or greater (free-in-air doses) would bemedically evacuated to an echelon III facil-ity for confirmation of performance/healthdegrading radiation exposure. Personnelwith estimated exposures of less than 1.5cGy would be deemed fit and would be re-turned to duty.

2. Application of the slower developing, highlyprognostic, multiparameter hematologic assaysshould be restricted to echelon III facilities. Theseassays would be applied to (a) confirm initial expo-sure assessments made by physical dosimetry infar-forward fields of operation, (b) assess the ex-tent of radiation injury to the vital lymphohemato-poietic system and, (c) provide the basis forsubsequent treatment decisions.

3. The possibility of far-forward fielding the singleparameter lymphocyte-depletion assay for biodo-simetry needs to be reconsidered and delayed un-til (a) its efficacy is more thoroughly evaluated,(b) confounding factors affecting assay perform-ance are more fully determined, and (c)hardened,hand-held electronic blood cell countingdevicesbecome available.

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3.1. Comprehensive testing of the assay and theinstrument will be required prior to any con-sideration of fielding.

4. F/W syndrome should not be considered as anadequate substitute for the more demonstrativeclinical indicators (nausea and vomiting) of ra-

diation exposure, regardless of whether anti- e-metics are involved.

4.1. Improved methods to better quantitate F/Ware needed to support radiation-associatedperformance decrement evaluationmodels.

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15


Predicting the Effects of Multiple Radiation Exposures

Gregory L. King, Ph.D.Chairman

André Dubois, M.D., Ph.D., LTJG Matthew Hamilton, MSC, USN,Michael R. Landauer, Ph.D., and G. David Ledney, Ph.D.

Session Panelists


• Large Animal Radiation ExperimentsE. John Ainsworth, Ph.D.Armed Forces Radiobiology Research InstituteBethesda, MD

• Estimating Lethality Risks for Complex Exposure PatternsBobby R. Scott, Ph.D.Lovelace Research FoundationAlbuquerque, NM

• An Integrated, Physiologically-Based Model of Human Response to MultipleExposures

Gene McClellan, Ph.D.Pacific-Sierra Research CorporationArlington, VA

• Operational Performance Decrement After Radiation ExposureGeorge H. AnnoPacific-Sierra Research CorporationSanta Monica, CA

Overview

This session’s goal was to describe the impact on theoperational effectiveness of military personnel whohave received multiple radiation exposures within arelatively short time frame and who have not beenmedicated. Participants were asked to estimate theeffects of two low-dose radiation exposures—without medication—on the human response by ei-ther mathematical models or extrapolation frompublished human and animal data. While the mathe-matical models provided useful general predictions,most of the workshop participants agreed that fur-ther validation of these models was necessary. Thepanelists and participants also agreed that no animalmodel completely predicts the effects of acute, pro-tracted, or multiple radiation exposures in man; andthat fatigability and weakness would worsen withmultiple radiation exposures regardless of the frac-tionation interval between exposures. An effort wasmade to incorporate the data and models that werepresented into a table for use in theU.S. Army FieldManual 8-10-7, Health Service Support in aNuclear, Biological, and Chemical Environment.

Introduction

The goal of this session was to describe the injuriesof military personnel who have been exposed tomultiple radiations within a relatively short timeframe and who do not receive medication, as well as todescribe the impact of these radiation injuries on op-erational effectiveness. Due to the paucity of humandata that directly bear on this issue, the session focusedon assessing the accuracy, reliability, and validityof both animal and human data that have been usedto predict outcomes from such scenarios. Because ofthe infinite possibilities of scenarios for multiple-radiation exposures, the participants were requestedto limit their presentations and analyses to two spe-cific time-related scenarios that had varied radiationdoses. Both scenarios were for two radiation expo-sures separated by 7 days. The first exposure was amidline-total dose (MTD) of 0.7 Gy, given promptly(Scenario 1) versus a protracted dose over the courseof 7 days (Scenario 2). The second exposure for bothscenarios was a variable prompt dose: 0.5, 1.5, or 3.0Gy. In general, military personnel exposed to a dose

of 1.5 Gy or greater will not be allowed exposure to asecond radiation incident. Thus, the lower 0.7-Gyradiation dose was chosen for the first exposure.

Large Animal Radiation Experiments

This presentation summarized numerous fractionated-radiation experiments that were performed prior to1975 on sheep, swine, goats, and dogs at the U.S.Naval Shipyard in San Francisco, California, and onnon-human primates at the School of Aviation Medi-cine in San Antonio, Texas. All of the experimentsused two radiation exposures of varying doses andwere designed to determine animal recovery or“residual injury” from the first radiation dose. Theendpoints in most experiments were LD50/30 or LD50/60

survival data; and the early indicators for radiationexposure had to be inferred from the LD50 data, per-sonal experience, and from examining the differencesamong species. In general, the first radiation dose wastwo-thirds of the LD50/30 or LD50/60 value for a givenanimal species and was delivered at different doserates for many of the experiments. The second anddifferent radiation dose was delivered at varying in-tervals. This general experimental design did not al-low for extrapolation to the lower, more survivabledoses suggested for the scenarios described for thisworkshop. The overall conclusions were that variousspecies show quite varied LD50/30values in response toan acute dose of ionizing radiation. Furthermore, therecovery of each species from the first radiation dose,as measured by survival to a second radiation dose,also varies across species. It was emphasized that theresidual injury observed in some species in responseto the second radiation dose could not be predictedfrom hematological measures. The discussion cen-tered on the issue of which radiation response in aparticular animal species might best correlate withthe human response. The general consensus was thatno single species is an ideal correlate.

Estimating Lethality Risks for ComplexExposure Patterns

This presentation described a mathematical modelthat could predict the hematopoietic lethality for hu-mans exposed to complex dose-rate patterns of

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gamma rays. An analysis of the model, background,and definitions were also presented. The model isdose-rate dependent and was developed from dataaccrued from both laboratory animals and humans.In the context of this workshop, the major limitationof the model is that it can estimate lethality only ifthere is either no recovery or full recovery from theinitial irradiation. Thus, predictions for survival can-not be accurately made if partial recovery or residualinjury to the first radiation exposure exists. Again,since lethality is an endpoint of this model, the earlyindicators of radiation injury in humans had to be in-ferred. The probability of lethality is the indicator ofperformance decrement. Despite this limitation, themodel can provide useful predictions for estimatingthe upper and lower limits of radiation exposure un-der the multiple radiation scenarios described in theworkshop.

With the limitations of either no or full recovery, theresults calculated for the two scenarios showed thatthere should be no risk of hematopoietic deaths in ei-ther scenario, provided the second radiation dose didnot exceed 0.5 Gy. If the second radiation dose ex-ceeded 0.5 Gy, the risk for hematopoietic death in-creased; but importantly, the lethality risk wasexclusively due to thesecond radiation dose. In abrief comparison across species, the model showedthat the ordinal value estimated for the radiosensitiv-ity of humans to a prompt radiation dose falls be-tween that of mice and dogs—which in turn aresimilar to goats and swine. The model also showedthat the value estimated for the relative recovery ca-pacity in humans falls near those values for sheepand goats. As emphasized in the previous presenta-tion, data showing the necessary survivable end-points are unavailable for the non-human primate.To its credit, the model does allow for the inclusionof protection and susceptibility factors such aswounds, burns, and medical support.

An Integrated Physiologically BasedModel of Human Response to MultipleExposures

This presentation provided an overview of theRadiation-Induced Performance Decrement (RIPD)software program that describes certain radiation

effects in humans—thus calculating the severity ofillness and the residual performance capability fornumerous radiation scenarios. This mathematicaland computer model uses several differential equa-tions to describe and predict radiation effects undervarious conditions. Each sign and symptom of themodel is based on changes in biological endpointsthat occur in response to radiation, such as the clear-ing of humoral toxins, the cellular kinetics of the in-testinal mucosa, and the kinetics of lymphocytes,cytokines, and bone-marrow cells. One limitation ofthe model appears to be that three of the symptomcategories (nausea and vomiting, diarrhea, and fati-gability and weakness) and the mortality incidenceare based on independent kinetic models, while theother symptom categories (fluid loss, infection andbleeding, and hypotension) are slaved to these otherkinetic models. Time restrictions prevented furtherexplanation of the biological validity of this interde-pendence among the symptom categories. Althoughsome of the kinetic models were derived from ani-mal studies, and others from human data, the outputfrom the animal data in the RIPD model were ad-justed to match the human response. Another limi-tation of the RIPD model is that its dose-rate de-pendence under some conditions appears to be anextrapolation of the acute response to a prompt irra-diation that is then protracted over time. Time didnot allow for presentation of specific examples ofthese conditions. Without further clarification, itwas thus unclear which specific endpoints measuredin the RIPD model reflected results from specific ra-diation dose-rate studies, and which endpoints wereextrapolated from the results seen after a prompt ra-diation dose. It was noted that some data for the pro-dromal aspects of the model were obtained fromexpert opinion and from questionnaires given tomilitary personnel. The questionnaires were designedto establish correlations between symptoms (includ-ing their severities) and task performance, not be-tween radiation dose and performance. While suchinput may be important to developing and establish-ing the model, this approach adds a degree of subjec-tivity to the model. To the credit of the RIPD model,some aspects of these prodromal responses have beenvalidated in human studies on sea-sickness.

Two other important points were made during thegeneral discussion of this model. First, the RIPD

17


model cannot provide an accurate estimate of thethreshold radiation dose for some of the earlysigns/symptoms of radiation exposure. Second, itwas noted that under fractionated radiation condi-tions, fatigability and weakness did not show a spar-ing effect to that fractionation. One attendeeremarked and cited some older clinical literature de-scribing results from fractionated radiation expo-sures that might provide useful data to incorporateinto the model. While well received, the overall im-pression by the attendees was that this model re-quires further validation with other animal models,especially for multiple-dose scenarios.

Operational Performance DecrementAfter Radiation Exposure

This presentation described in detail the “opera-tional performance” defined for the RIPD model in amilitary setting and further described how the se-verities of the various manifestations of radiationsickness alter performance. Numerous illustrationsshowed how performance levels with 95% confi-dence limits for specific tasks (e.g., for a member ofa tank gun crew vs. a tank commander) varied withdose and time after exposure. Due to time con-straints, this presentation did not provide details onthe multiple-radiation scenarios that were suggestedin advance. However, and of perhaps greater impor-tance, operational effectiveness was evaluated in re-sponse to the presence or absence of an antiemetic.Since the human response to antiemetics varies con-siderably, and a complete set of human data undersuch conditions is unavailable, the speaker wasasked to assume 100% efficacy of the antiemeticdrugs to give the best-case scenario. The datashowed, depending on the task, that nausea andvomiting were the primary causes of performancedegradation; and that operational effectivenesscould be improved by an antiemetic. However, theprevious presentation showed that fatigability andweakness did not show a sparing effect to multipleradiation doses. Thus, some clarification is neces-sary to determine the degree to which fatigabilityand weakness vs. nausea and vomiting contribute toperformance degradation after multiple exposuresto radiation.

Discussion

The discussion centered on issues involved in theconstruction of Table 2,Effects of a Second Radia-tion Dose on Combat Effectiveness of Military Per-sonnel, that could hypothetically be used in theArmy field manual. As seen in the table, the first ra-diation doses in a multiple radiation scenario areplaced in two bands (1–70 cGy and 71–140 cGy)and are identical to those radiation dose bands cur-rently described inArmy Field Manuel 8-10-7. Byconsensus, it was agreed that if this first dose was< 70 cGy (either prompt or protracted), military per-sonnel would remain combat effective as long as thesum of it and the second dose did not exceed 150cGy. This should be true for short intervals of up to14 days. Beyond 14 days, the panelists and audiencecould not determine whether personnel could be ex-posed to a greater second dose. That is, even at lowradiation doses, it is unclear whether the biologicalrepair mechanisms would render a human the sameas if he or she had never been irradiated. Regardless,lymphocyte counts should be followed in such indi-viduals. Again by consensus, the participants agreedthat if the first dose were protracted and > 70cGy,any prompt second dose at any time interval after thefirst dose would likely evoke partial to full perform-ance decrement in military personnel. This reflectsone of the major points gained from this portion ofthe workshop: the symptoms of fatigability andweakness do not show a sparing effect after fraction-ated radiation. The workshop participants agreedthat the authors of the Army field manual shouldprovide, if possible, military medical personnel witha definition, operational or otherwise, of radiation-induced fatigability and weakness so that medicscan distinguish this symptom from battle fatigue.From the aforementioned table, it also can be dis-cerned that there are not enough data to estimatewhat level-III clinical remarks might be most salientfor such irradiated personnel. However, under suchmultiple-dose scenarios; it is possible that some ofthe serial measures of biological dosimetry exploredin other portions of the workshop could provide in-valuable assistance to the field medic.

It became readily apparent from the presentations inthis session that no single animal species is the best

18


model for the radiation response in humans. More-over, very little data exist that describe the survivalof the non-human primate after irradiation, espe-cially in response to multiple exposures to radiation.Since the non-human primate may be the best ani-mal model to substitute for humans, there shouldbe further studies with them using fractionatedradiation scenarios.

As a side point, it was suggested that the ArmedForces Radiobiology Research Institute should be-come a central repository for older government datathat deal with radiation studies and should also in-clude newer collections of human radiotherapydata.This would provide a central database that could beaccessed by future generations of radiation biologists.

The mathematical models presented were sophisti-cated and summarized most of the existing informa-tion on human radiation effects. They are useful asworking hypotheses for future testing. Unfortu-nately, much of the human data used to derive themodels are from events in which uncertainty existsconcerning radiation dose, dose distribution, andeven the clinical parameters. The panelists and otherparticipants did not have adequate time to evaluatetheir validity for the overall human response to ra-diation. The chairman and panelists of this sessionbelieve that scientific peer reviews of the models

would benefit the authors and developers of thesemodels. These models need further work beforeconclusions can be derived for establishing militarystandards for triage. Such work should focus on vali-dating the models across several species, with spe-cial emphasis on validating the effects of multipleradiation exposures.

Recommendations and ResearchDirections

The panelists and participants in this sessionrecommended that (1) Table 2,Effects of a SecondRadiation Dose on Combat Effectiveness of MilitaryPersonnel, should assume that no confoundingvariables exist (e.g., combined injury, infection,exposure to a threat agent); (2) physical dosimetersshould be issued to personnel at risk of a second ex-posure; (3) field commanders should be made awarethat the fatigability and weakness response does notshow recovery; (4) multiple-radiation exposurestudies should focus on end points other than lethal-ity; (5) radiation studies should address the effects ofother combined injuries, such as physical trauma orinfection; and (6) an attempt should be made toquantitate fatigability and weakness in eitherhumans or in an animal model to approximate thehuman response.

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Table 2. Effects of a second radiation dose on combat effectiveness of military personnel.

1st dose Prompt 2nd dose

Prompt orprotracted1

Time intervalbetween doses

Maximum2nd doseallowed2

Expectedperformance

capability of unitField

symptomsLevel III clinical

remarks

1–70 cGy

Protracted1, 3

71–140 cGy

1–14 days>14 days

1–7 days>7 days

149–80 cGy?

79–10 cGy?

Combat effective

Partial/fulldecrement

Mild nauseaand vomiting

Fatigability andweakness,greater nauseaand vomiting

Mildly decreasedlymphocytes,platelets, andgranulocytes—monitor lymphocytecount

?

1All individuals are considered combat effective after the 1st dose, from Table 4-1, FM 8-10-7.2Maximum total dose received should not exceed 1.5 Gy.3This group should receive no further radiation exposure after 1st dose.

21

Summary of Session IV

Forward-Field Bioindicators for Dose Assessment: Possible Alternatives

William F. Blakely, Ph.D., and Thomas M. Seed, Ph.D.Chairmen

Pataje G.S. Prasanna, Alasdair J. Carmichael, Narayani Ramakrishnan,David A. Schauer1, and Clive L. Greenstock2

Session Panelists

Armed Forces Radiobiology Research Institute, Bethesda, MD,1Naval Dosimetry Center, Navy Environmental Health Center Detachment, Bethesda, MD,

and2Atomic Energy of Canada Limited (AECL), Chalk River, Ontario, Canada

• NATO Perspectives on Biological Indicators of Radiation ExposureDr. Govert P. van der SchansTNO Prins Maurits Laboratory, Rijswijk, Netherlands

• Radiation-Induced Apoptosis in Human LymphocytesDr. Douglas R. BorehamAECL, Chalk River, Ontario, Canada

• Halo-Comet AssayDr. Juong Gile Rhee, Jie Liu, Mohan SuntharalingamUniversity of Maryland Medical School, Baltimore, MD

• Radiation Damage in the Hematopoietic SystemDr. Lionel G. FilionUniversity of Ottawa, Ottawa, Canada

• Automated Cytogenetic Assays in a Field Environment: Consideration of the Halo-CometAssay

Mr. Harry L. LoatsLoats Associates, Westminster, MD

• Potential Use ofIn VivoElectron Paramagnetic Resonance, Electron Spin Resonance (EPR,ESR) forIn VivoDosimetry Under Field Conditions

Dr. Harold M. SwartzDartmouth Medical School, Hanover, NH

• EPR-Based Dosimetry and Its Present Suitability for Field UsageDr. Arthur H. HeissBruker Instruments, Inc., Billerica, MA

Overview

The goals of Session IV were to evaluate the statusof several alternatives to peripheral blood countsand prodromal symptoms for forward fieldradiation-dose assessment. The suitability of se-lected biochemical-based (DNA single strandbreaks), cytogenetic-based (apoptosis, halo-comet),and biophysical-based (free radicals in solid matrixmaterials) bioindicators of radiation exposure wasevaluated. The current status of fielding systems toautomate the measurements was also evaluated. Thesession consensus was that no one assay is presentlysuitable for military use. It was also recommendedthat a research program be implemented to evaluatethe development of a multiassay strategy character-ized byin vivoevaluation studies, acute versus pro-tracted radiation exposures, and critical comparisonsbetween techniques with the greatest potential forboth robust dosimetric capability and automation.Table 3 shows the classes of bioindicators, the type ofassays, and the presenters.

Introduction

Suitable forward-field bioindicators should exhibitthe following characteristics: (1) negligible post-sampling incubation, (2) rapid processing suitablefor a high degree of automation and high throughput,(3) low-threshold, broad dose-rate, and variableradiation quality capability, (4) relatively noninva-sive sample collection, and (5) equipment hardwarefor which components are or soon will be available.

Dr. Clive L. Greenstock's (AECL, Chalk River, On-tario, Canada) review of potential biomarkers of ra-diation exposure (presented in session I) providedexcellent background. In addition, Dr. Govert P. van

der Schans, chairman of the Bioindicator subgroupof NATO Research Study Group No. 23/Panel VIII(Assessment, Prophylaxis, and Treatment of Ioniz-ing Radiation Injury in Nuclear Environments), pro-vided a brief summary of related research efforts. Henoted the limitations inherent to dose assessmentmethods involving lymphocyte counts and chromo-some aberrations. Dr. van der Schans said the NATOgroup is studying the use of dextran sulfate to stimu-late resting immune cells in peripheral blood as wellas their dose-dependent cytogenetic-based responseand the micronucleus assay. Further progress withcytological dosimetry is possible using prematurechromosome condensation (PCC), chromosomepainting using hybridization probes, and automateddata collection and analysis using a metaphasefinder. However, these techniques are inherentlytime consuming, subjective, and labor intensive. Inaddition, the analysis of more than five samples perday is problematical unless the assay is automated.

Presenters for Session IV were selected to permit aninspection and review of potential bioindicatorsfrom a broad spectrum or class of candidates (Table4). All presenters were asked to address the statusand practicality of fielding an automated dose-measurement system. The seven presentations inSession IV were each limited to 20 minutes and re-flected an intent to bridge the gap between scienceand industry. Representatives from two science-application companies, Mr. Harry L. Loats (LoatsAssociates, Westminster, MD) and Dr. Authur H.Heiss (Bruker Instruments, Inc., Billerica, MA),gave presentations on automated cytogenetic assaysand EPR-based dosimetry, respectively.

An open discussion evaluating and comparing thevarious biomarkers for radiation exposure followedthe presentations.


22

Table 3. Class of bioindicator, type of assay, and presenter.

Class Assays Presenter(s)

Biochemical

Cytogenetic

Biophysical

DNA single-strand breaks

Apoptosis

Halo-comet

Free radicals in solidmatrix (EPR)

van der Schans

Boreham; Filion

Rhee; Loats

Swartz; Heiss

Possible Alternative Bioindicators forDose Assessment

Biochemical

The use of an immunochemical-based method to de-tect radiation damage to DNA appears to offer thepossibility of providing the necessary requirementsof a fast, simple, direct biological indicator using ablood sample. The assay involves using specificmonoclonal antibodies against DNA single-strandbreaks attached to the surface of multiwell plates.Small volume blood samples (3ml) are diluted in al-kali to unwind the DNA at single-strand breakagesites. The blood samples are neutralized and soni-cated to release single-strand fragments. The frag-ments as antigens are allowed to form complexeswith the coated monoclonal antibodies; and thecomplexes are conjugated with alkaline phos-phatase and incubated with an FITC-labeled sub-strate—the fluorescent intensity of which is directlyproportional to the amount of single-strand frag-ments which in turn is proportional to the radiationexposure. The assay requires only small samples,takes 1–2 hours, does not require cell culture, andhas a lower limit of detection of ~0.2 Gy.

Because of rapid DNA repair,in vivosamples mustbe collected immediately after exposure (<1 hour) ora much lower sensitivity is achieved—since DNAstrand-break damage is rapidly repaired. In a practi-cal situation (the far-forward field), the reliable

lower limit of detection is probably 1–2 Gy—takinginto account the wide variation in individual radio-sensitivities and the controls' baseline level DNAbreaks. Morein vivo tests are required to validatethis promising potential biodosimeter and to com-pare acute versus chronic or protracted exposures aswell as the varying effects that result from differ-ences in radiation quality.

Cytogenetic

Apoptosis Assay.Dr. D. R. Boreham addressed thepossibility of using apoptotic death in humanperipheral-blood lymphocytes as a biological do-simeter and reviewed the steps involved in humanlymphocyte apoptosis—a rapid, sensitive, repro-ducible biological response to low-dose radiationexposure. Although most research involves assaysrequiring cell culture, the kinetic changes involvedin the process of apoptosis offer the possibility of us-ing apoptosis as a potential biological dosimeter,provided that a blood sample is obtained withinhours of human exposure. The characteristic DNAfragmentation is detected using either the comettechnique, byin situ terminal deoxynucleotidyltransferase (TdT) assay, or the fluorescence analysisof DNA unwinding (FADU) assay. Forin vitro ex-posures the induction of apoptosis is proportional todose; the lower limit of detection is ~ 0.05 Gy. Over-all radiation-induced DNA damage is repairablewith a half-life of ~1 hour. After about 4 hourspostexposure, the ordered DNA fragmentation

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Table 4. Selected list of alternative bioindicators.

Clinical chemistry kits for low molecular weightproducts in body fluids

Immunochemical tests

Genetic engineering

• Electrolytes, creatine, taurine

• Prostaglandins, enzymes, metabolites,nucleotides

• Molecular/chemical biosensors

• Immunochemicals, antibody tests

• Cytokines, lymphocytes, hormones

• Membrane markers

• Cyclins, integrins, etc.

• Differential display (multiple gene expression)

• DNA probes (FISH, PCR, RFLP, mutationspectral analysis)

characteristic of active apoptosis becomes apparentand increases over 24 to 48 hours.

In-vivo exposures require the removal of lympho-cytes from the body as soon after exposure as possi-ble (within hours), otherwise apoptotic cells willdisappear as a result of phagocytosis. One techniquethat can potentially measure apoptosis is flowcytometric-based analysis of lymphocyte plasmamembrane changes—the early and critical events inapoptosis. Dr. Lionel G. Filion emphasized (see ses-sion II manuscript) the potential benefits from theuse of flow cytometry-based methodology. Clearlythe use of multiple parametric endpoints derivedfrom several distinct cell populations should pro-vide a significant improvement in clinical doseassessment.

Because individual radiation-induced apoptotic re-sponses vary greatly, this assay measures biologicalradiosensitivity rather than physical absorbed dose.Apoptosis has considerable potential as a future bio-dosimeter and is amenable to the development of afast, automated, clinical kit to test for radiation ex-posure using a small (0.1 ml) blood sample; how-ever,in vivo(animal or radiotherapy patient) testingis urgently required.

Halo-Comet Assay.Dr. J. G. Rhee presented resultsfrom a modified version of the “halo assay,” desig-nated the halo-comet assay. The halo-comet assayappears to quantify alterations of an individual cell'sDNA organization. Dr. Rhee used twoin vitro cul-tured mammalian cell lines for these studies. Aga-rose gels containing single cells, which had beenexposed to different doses of x-rays and various re-pair intervals, were prepared on glass slides. Follow-ing electrophoresis (pH-7 conditions), the cellpreparations were stained with propidium iodide.The dye was excited, and image data acquisition de-tected with fluorescent light (excitation: 545 nm,emission at 580 nm). Data were analyzed by imageanalysis. A linear increase of up to 6 Gy in the“amount of DNA pulled from the nucleoids” wassuggested by the results. Significant differences be-tween 0 and 0.5 Gy induced damage, with no repair,suggests that this assay is sensitive enough for triagepurposes. The analysis of residual damage after 30min of repair following exposure to 2 and 4 Gy of

x-raysindicated a significant difference betweenirradiated and control samples. This was evidenteven after 1 or 6 days of repair, indicating thatsome damage could still be measured after a timelapse. Dose-dependent alterations following frac-tionated doses (2 Gy x 3 days) were also observedafter 5 days of repair following the last fraction.These results should also be confirmed byin vivostudies.

The assay is rapid and can be automated by imageanalysis, which was the subject of Harry L. Loats'presentation. Loats presented a system based on thehalo-comet assay designed to automate cytogeneticassays in a field environment. The system compo-nents are based on the existing automated systemsproduced by Loats Associates, Inc., for clinical andresearch laboratory applications. To accommodatethe throughput requirements inherent in themilitary-field scenario, a parallel processor and mul-tichannel design was presented with characteristicsincluding (1) robotic slide selection and deliverysystem, (2) automated cell finder using non-fluorescent lighting, (3) a new technique for image-based low-light level range extension to provide dy-namic range extension for capturing the head andtail of the halo comet in the same image, and (4) adigital method to produce composite images from aseries of closely spaced images neighboring theplane of best focus.

The system uses off-the-shelf and proven hardwareand software, can be operated by non-specialist per-sonnel, and would be applicable to both forward-field and rear-support echelon facilities.

The detection system for dose assessment using thehalo-comet assay has distinct possibilities. It likelywill exhibit a broad dose range and can potentiallybe performed with blood, making the sample collec-tion relatively noninvasive. A halo-comet assay sys-tem has the potential to handle a large number ofsamples using automated image analysis; its rela-tively short assay time is a major benefit over alter-native biomarkers. The possible applicability of thisassay for use in human dose-assessment applica-tions needs to be explored with animal models andradiotherapy patients. However, studies addressingthe effect of individual variations in radiosensitivity

24


and effects from confounding factors (e.g., prior ex-posure to genotoxins, dose protractions, and differ-ent exposure scenarios) need to be performed.

Biophysical

Free Radicals in Solid Matrix Material.Free radi-cals in solid matrix can be measured by electron par-amagnetic resonance (EPR) spectroscopy, a wellestablished and accepted technique for determiningabsorbed radiation in cases of accidental radiationexposure. Dr. Harold M. Swartz and Dr. Arthur H.Heiss presented aspects of this subject. Dr. Swartzprovided results from EPR spectroscopy using toothenamel and bone dosimetry, although several alter-natives (clothing buttons, nail clippings) are pre-sented in his manuscript. Swartz also emphasizedthe need to investigate other biological sample sys-tems for EPR dosimetry measurements. The work-ings of the EMS 104 portable EPR analyzer,designed specifically for dosimetry purposes andnow in use in many clinical settings, was presentedby Dr. Heiss. In addition to using it for alanine do-simetry, Heiss presented additional potential usesfor this EPR instrument, including the red blood cellreceptor assay being developed at AFRRI by Dr.Alasdair Carmichael using spin-labeled insulin. Ap-plication of the Bruker EMS 104 for use in militaryforward-field applications was also discussed.

While EPR-based dosimetry has several desirablefeatures, there are also significant limitations. Therequirement to either assess in advance each individ-ual's radiosensitivity in relation to their solid matrixmaterial (teeth enamel, bone, etc.), or to establish adose response calibration curve from a test sample,restricts practical use of this approach for militaryapplications. This second approach requires a radia-tion source in the far-forward field laboratory;however, use of an isotope-based gamma-raysource forthis purpose is notadvisable in battlefieldapplications.

Other Bioindicators to Consider

Several other potential bioindicators were identifiedthat may have merit as alternative biomarkers formilitary forward-fielding as dose assessment assays

(Table 4). Unfortunately due to time constraints, dis-cussion of these assays was limited.

Discussion

Accomplishments

Advances in biotechnology, digital imaging, anddata handling and analysis can effectively eliminatemanual analysis procedures for biological dose as-sessment—which are subjective, time-consuming,and labor-intensive. Parallel development of equip-ment with improved fieldability characteristics(compact, rugged, portable multiplexing technologyto dramatically increase throughput with fewermoving parts) coupled with these radiation bioindi-cator assays is feasible. For example, the automationof cytogenetic assays (metaphase finder, imageprocessing, chromosome aberration/micronu-cleus/fluorescencein situhybridization (FISH)/pre-mature chromosome condensation (PCC scoring))were demonstrated. There is a need to develop alter-native persistentdamage endpoints (halo-comet,membrane markers,in vivoESR biological dosime-try) that do not require cell culturing. These assaysrequire tests of individual radiosensitivity withappropriatein vivovalidation.

Remaining Research Questions

These findings, along with contributions from work-shop participants, permitted a delineation of rele-vant remaining research questions. Several signifi-cant questions that were identified include the needto (1) improve existing assays or develop new assaysto make the process faster, simpler, more direct, anddefinitive, (2) look for mechanisms underlyingintraindividual and interindividual variability, (3)search for a radiation-specific response or signature,(4) carry out interlaboratory comparison, standardi-zation, and validation, (5) overcome the problem ofneeding prior knowledge of an individual's radiationhistory (dose-rate, LET, etc.) and baseline re-sponses, and (6) establish necessary criteria (andweigh the advantages and disadvantages) of a bio-logical doseindicator versus a biologicaleffectindicator.

25


Recommendations

The consensus of the session was that none of thedose assessment biomarkers has all of the featuresrepresenting the “ideal” assay; alternatively, a multi-assay approach represents the best design to meetmission requirements. To accomplish the goal offielding a practical dose-assessment assay, a re-search program should (1) concentrate future

experiments onin vivo testing (animals or ra-diotherapy patients), (2) compare results fromacuteversusprotracted exposures, (3) move to-ward standardized protocols using the samein vi-tro cell lines (preferably human), (4) carry outcritical comparisons between the techniques withthe greatest potential, and (5) develop combina-tions of assays performed sequentially or inparallel (preferable).

26


Executive Summary

Operational Effectiveness of ExposedPersonnel

The consensus was that personnel receiving radiationof 1.50 Gy or more should be evacuated to the rear,while most personnel can be returned to duty even afterexposure to a “significant” amount of radiation, up to1.50 Gy (free-in-air). All irradiated individuals will beat increased levels of susceptibility to morbidity andmortality from other illness and injury (e.g., communi-cable and infectious disease, mechanical and/or ther-mal trauma, etc.). Up to 30% of personnel receiving ex-posures approaching 1.50 Gy will be too clinically illto return to duty, and will require evacuation to anechelon III or higher-level facility. After recoveryfromthe acute effects, many will experience fatigue andweakness of varying degrees for up to several weeks,although they otherwise will be able to continue theirduties.Thedecision of whether to leave in place eitherindividuals or units that have been exposed to radia-tion is ultimately an operational—not a medical—decision. (Butseebelow, finalparagraphof thissection.)

An important point: The general consensus was thatclinical symptoms and hematological indicators areinadequate for initial triage in a forward-field setting,given the rapid time constraints, limited personnel andequipment, and potential use of prophylactic emeticsin this situation. First-line triage and dose assessment

would be better served by the application ofphysicaldosimetry. Clinical, serial hematological, and otherbiologicalparameterswill bemoreuseful insecondarytriage processes and in rearward medical facilities.

During the discussion Dr. Vic Bond, who was one ofthe physicians involved in caring for the Marshall-ese Islanders exposed to fallout in 1954, made animportant point regarding medical evaluation ofradiation-injured patients. The clinical presentationand course,not the physical dosimeter’s reading orother laboratory parameters, will determine the pri-ority and nature of treatment.

In interpreting Dr. Bond’s comments and his singleview graph (Fig. 2), the problem of placing relianceon physical dosimetry for medical assessment pur-poses stems from inherent differences in slopes of thedose-response functions for the primary biologicalendpoints of interest, namely fatality and injury se-verity (i.e., injury to organ systems, tissues, and se-lected target cells). Physical dosimetry best serves thenarrow, steeply-sloped “probability of fatality” dosefunction (Fig. 2.a), while serving poorly the broader,initially shallow-sloped “severity of injury” function(Fig. 2.b.) The integration of the two functions (fatal-ity vs. injury severity) tends to an extremely narrowwindow of expression of fatal-type responses, rela-tive to the overall extent of injury severity (Fig. 2.c).

27

100

50

0

100

50

0

100

50

0

dose dose

biological indicator of injury severity(%)

pro

babili

tyoffa

talit

y(o

rle

sser

effect)

(%)

bio

logic

alin

dic

ato

rof

inju

ryseverity

(%)

pro

babili

tyoffa

talit

y(o

rle

sser

effect)

(%)

A B

C

Fig. 2. Differences in slopes of the dose-response functions for the primary biologicalendpoints of interest.

As a result, the major fraction (and degree) of theinjury-severity response appears to be poorly repre-sented at the sublethal response levels. Accordingly,the use of physical dosimetry for medical triagewould be based on a fatality probability function,rather than on an injury severity function, and thuswould tend to ineffectively represent the degree oftreatable injury, measured more appropriately bybiomedical methods.

To summarize: physical dosimetry is required in tri-age at forward medical facilities, given the rapid (24hr.) time constraints and personnel and resourcelimitations, to determine if exposure was highenough (1.5 Gy or more) to require evacuation, andto determine the probability of lethality. Biomedicalresponse indicators become necessary, primarily atrearward facilities, to determine the severity of (sur-vivable) injury and the optimal clinical managementof the patient.

Operational Effectiveness of Personnelwith Multiple Exposures

There were three major consensus conclusions re-garding this topic: (1) No animal model completelypredicts the effects of either acute, protracted, ormultiple radiation exposures in humans; (2) fatigueand weakness are cumulative; and (3) physical do-simetry is required for personnel at risk of a secondexposure.

The models used to address this question need fur-ther experimental validation in terms of dose-rateand fractionation intervals. Large animal data havebeen used to develop human LD50 models, but thecorrelation of survival curves between species letalone between large animals and man, is not alwaysconstant. Marrow kinetics are certainly related tomortality, and the pathologic sequelae that contrib-ute to a fatal response; though there are probablyother factors besides marrow damage, even at thisdose range, that influence lethality.

Fatigue and weakness start at only 1 Gy, andthere is no apparent repair coefficient or fractiona-tion effect; i.e., the effects from multiple doses arecumulative. This also appears to be independent

of dose-rate effect, as well as for the interval be-tween discrete prompt doses. Emesis, however, isaffected by factors of dose rate and fractionation.In terms of marrow kinetics, repair does take place;the degree to which it occurs is dependent on ra-diation dose, dose rate, radiation quality, the vol-ume of marrow irradiated, and the species beingirradiated.

Estimating Exposure in Personnel WhoReceived Antiemetics Before orShortly After Exposure

The three symptoms currently used to clinically as-sess the degree of radiation exposure are nausea,vomiting, and diarrhea. Use of antiemetics before orshortly after known exposure clearly masks the re-sponse of the exposed person to radiation and couldactually improve operational effectiveness. Even so,there is individual variability in the effectiveness ofantiemetics. Although multiparameter hematologi-cal indices are probably not affected by the use ofantiemetics, there is no reliable clinical or labora-tory bioassay at echelon I and II facilities capableof exploiting this fact. Fatigue and weakness, evenif unaffected by antiemetics, are too highly subjec-tive to provide a reliable, reproducible, quantifi-able, and accurate measurement of exposure. Asmentioned earlier, physical dosimetry remains atpresent the only reliable tool for exposure esti-mates, regardless of whether personnel have re-ceived antiemetics. Accordingly we recommendthe following procedures:

1. Obtain a base level complete blood count anddifferential if exposure is anticipated.

2. Provide physical dosimetry, readable at thislevel, and make available for 100% of thetroops.

3. Perform serial blood counts as soon as possiblepostexposure.

4. Consider the above procedures carefullybefore ordering administration of prophy-lactic antiemetics. The decision to administerthese drugs must be made by the commander;

28


drugs should not be issued until exposure islikely and should not be taken until directed.

There are three areas of development for biologicaldose indicators that may become available at eche-lon I and II facilities in the near future: (1) develop ahand-held, durable electronic blood-cell countingdevice capable of performing either single or multipleblood cell (lymphocyte) depletion assays; (2) find,if possible, more reliable, precise, and quantifiablemeans of defining fatigability and weakness (whichwould also serve to better support radiationassoci-atedperformance decrement evaluation models); or(3) use hardened, automated, and sophisticatedcytogenetic (or other) assays (see final paragraph).

The application of multiparameter hematologic as-says as well as other assays in echelon III facilitiesand beyond is critically important. Assays at thislevel serve to confirm initial exposure estimatesmade by physical dosimetry, assess the extent ofinjury to the lymphohematopoietic system, andprovide the basis for therapeutic management.

One encouraging note is that there are near-termtechnologies that will provide additional bio-assays(besides serial lymphocyte and multi-parameter blood counts) at echelon III facilities.These include biochemical assays (radiation-induced single strand DNAbreaks), biophysicalassays (electron paramagnetic resonance (EPR)analysis of free radicals in solid matrix materi-als), and cytogenetic assays (apoptosis, halo-comet assays.) At present, the chief drawbacksfor most of these techniques are the high level ofskill required to run these generally time-consuming and labor-intensive procedures (withresultant low throughput) and their current un-suitability for field conditions (harsh environ-ment, mobility, ruggedness). Also, furtherresearch into individual radiosensititivity,in vivovalidation, results of acute vs. protracted expo-sures, etc., is required. With the near-term devel-opment of automation and field hardening, someof these procedures may become useful options—and perhaps can be used as far forward as echelonII facilities.

29

Executive Summary

Appendices

Appendix A. Session I

Appendix B. Session II

Appendix C. Session III

Appendix D. Session IV

Appendix E. List of Attendees

DISTRIBUTION LIST

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WALTER REED ARMY INSTITUTE OF RESEARCHATTN: DIVISION OF EXPERIMENTAL THERAPEUTICS

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AUTRE, INC.ATTN: PRESIDENT

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INSTITUTE OF PROTECTION AND NUCLEAR SAFETYATTN: L. LEBARON-JACOBS

INSTITUTE OF RADIOBIOLOGY, ARMED FORCESMEDICAL ACADEMY

ATTN: DIRECTOR

INTERNATIONAL CONSORTIUM FOR RESEARCH ON THE HEALTHEFFECTS OF RADIATION

ATTN: M. SPIRO

LOATS ASSOCIATES, INC.ATTN: H. LOATS

LOGICON RDAATTN: P. HARRIS

LOVELACE BIOMEDICAL AND ENVIRONMENTAL RESEARCHINSTITUTE

ATTN: B. SCOTT

MINISTRY OF DEFENCEATTN: DIRECTOR

NATIONAL COUNCIL ON RADIATION PROTECTION ANDMEASUREMENTS

ATTN: E. KEARSLEY

NATO HEADQUARTERS, DEFENCE SUPPORT DIVISIONATTN: DR. Y. COUTZAC

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OAK RIDGE ASSOCIATED UNIVERSITIESATTN: MEDICAL LIBRARYATTN: MEDICAL SCIENCES DIVISION

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RESEARCH CENTER OF SPACECRAFT RADIATION SAFETYATTN: DIRECTOR

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LABORATORY

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LABORATORY

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UNIVERSITY OF MINNESOTAATTN: R. ANDERSON

UNIVERSITY OF PITTSBURGHATTN: R. DAYATTN: N. WALD

UNIVERSITY OF ULMATTN: H. KINDLER

R. YOUNG

XAVIER UNIVERSITY OF LOUISIANAATTN: COLLEGE OF PHARMACY

NATO HEADQUARTERS, DEFENCE SUPPORT DIVISIONATTN: DR COUTZAC

This publication is a product of the AFRRI Information Services Division.Editor: David Marks. Graphic illustrators: Mark Behme and Guy Bateman.Desktop publisher: Carolyn Wooden.

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Proceedings: Triage of Irradiated Personnel

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Reeves GI, Jarrett DG, Seed TM, King GL, Blakely WF

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Armed Forces Radiobiology Research Institute

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13. ABSTRACT (Maximum 200 words)

AFRRI was tasked by the Army Office of the Surgeon General to answer operational questions concerning threeissues related to the triage of irradiated personnel deployed forward. These issues, and the workshop participants’consensus responses, are:

1 ) Effects of radiation injuries on exposed personnel, assuming Level I and Level II medical care andfacilities. Individuals receiving over 1.5 Gy should be evacuated; those receiving less than this amount may returnto duty. Even at this level, 30% of exposed personnel may be too ill to return to duty. Those who recover willexperience varying degrees of persistent fatigue and weakness. Dose assessment at this level is best served byphysical dosimetry.

2) Describe these effects in previously exposed personnel. Physical dosimetry is required for personnel who areat risk of a second exposure; no animal model completely predicts the effects of either protracted or multipleradiation exposure in humans. Fatigue and weakness in multiply exposed personnel will be cumulative.

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