I

IPrepared by

U.S. Department of EnergyOffice of Energy Research

Office of Program AnalysisWashington, DC 20585

nnl? /F. R-- 0275 -VO1.2 l“ FM M

August 1986

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This report is a companion docu-ment to Health and EnvironmentalResearch: Summary of Accomplish-ments, DOE/ER-0194, published inMay 1983. The information for bothreports was gathered in 1982 and1983. These reports are intendedto foster an awareness of a publiclyfunded health and environmentalresearch program chartered nearly40 years ago, of its contributionstoward the National goal of safeand environmentally acceptableenergy development, and of ap-plications of its findings towardthe improvement of human health.This program, administered by theOffice of Health and EnvironmentalResearch, is one of many researchactivities of the U.S. Department ofEnergy. Over the years, it has beena part of other Federal agencies re-sponsible for the National energymission. Its evolution has been areflection of changes in time,pubiic priorities, and public law.But throughout, there has remaineda consistency of purpose: to seeka fundamental understanding ofthe health and environmentalaspects of emerging energy tech-nologies and to establish the bodyof knowledge necessary to theirdevelopment and utilization con-sistent with the public health andsafety.

The story of this research programcan be told through its accomplish-ments. Several of the more signif-icant accomplishments have beenchosen here for illustrative pur-poses, including some whosevalue have far exceeded the costof the research program itself. How-ever, regardless of the measure ofits economic benefit, the basicmotivation for the program re-mains to serve the public interestthrough health and environmentalresearch. In the pages that follow,the selected accomplishments aregrouped and reviewed within eachof several areas of research. It isuseful, first, to recall the originsand development of the program.

DISCLAIMER

This report was prepared as an account of work sponsored by an agenq of the UnitedStates Government. Neither the United States Government nor any agency thermf, norany of their empioy% makeany warranty, expmssor impiie&or ~ illly legalliabili-ty or mqmnsiity for the accuracy, complete- or usefulness of any informatio~ appa-~ Prodm% or Processdisdosedjor represents that its use would not infringeprivately_n*kWm~Wti~~lc~tip_pqor~m@&de _ trade- manufacturer, or otherwise does not Wessariiy COmtituteor

4 IecOmmmdadqimply its endoraemen or fhvoringby the United States Governmentorany agency thereof. The views and opinions of authors expreswl herein do not aemssar.ily state or reflect those of the United States Government or any agency thereof.

DISCLAIMER

Portions of this document may be illegibleelectronic image products. Images areproduced from the best available originaldocument.

r .

ExeidveSummary

This is an account of some of theaccomplishments of a 40-year-oldhealth and environmental researchprogram performed in NationalLaboratories, universities, andresearch institutes. Under thesponsorship of the Federal agen-cies that were consecutivelyresponsible for the Nationalenergy mission, this research pro-gram has contributed to theunderstanding of the humanhealth and environmental effectsof emerging energy technologies.

Both direct and indirect societalbenefits emerged from the newknowledge provided by the healthand environmental research pro-gram. In many cases, the privatesector took this knowledge andapplied it well beyond the missionof supporting the defense andenergy needs of the Nation. in-dustrial and medical applications,for example, have in several in-stances provided annual savingsto society of $100 million or more.Collectively, the diffusion of thisknowledge has resulted in annualsavings to the Government and tothe public that are several timeslarger than the cumulative cost ofthe entire program itself.

The form of this presentation is,in fact, through “snapshots”-examples of significant, tangibleaccomplishments in each of theareas at certain times to illustratethe role and impact of the re-search program. The program’sworth is not necessarily confinedto such accomplishments; it ex-tends, rather, to its ability to iden-tify and help solve potentialhealth and environmental pro-blems before they become critical.This anticipatory mission hasbeen pursued with an approachthat combines applied problemsolving with a commitment to fun-damental research that is long-term and high-risk.

The narrative of this research pro-gram concludes with a perspec-tive of its past and a prospectuson its future.

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Contents Origins of the Research ProgramEmerging Energy Technologies

Identification of Human Health EffectsNuclear TechnologySynthetic FuelsResponding to Hazardous Events

Detection and Measurement of Human Health EffectsCell Sorting and Blood AnalysisFast Test for Cancer-Causing ChemicalsAnalyzing Complex Mixtures for Toxic AgentsPredicting Pollution Pathways in the Atmosphere

Identification and Evaluation of Environmental EffectsRiverine EcologyEcology of the Continental ShelfTracing Pathways of Nuclear Wastes in the Life CycleRadioisotope TracersPlant MetabolismLand Reclamation

Detection and Measurement of Environmental EffectsDetecting Change Over the Ages

Nuclear MedicineTechniques that Aid in Diagnosis

Thallium-201 for Diagnosis of Heart DiseaseTechnetium-99m for Diagnostic ScanningGallium-67 for Diagnosis of Hodgkins Disease

Instruments That Aid in DiagnosisThe Scintillation CameraScanning lnstruments—PETInstrument Standardization

Treat mentiodine-131 Therapy for HyperthyroidismL-dopa Treatment for Parkinson’s Disease

The FutureAPPENDIX. The Health and Environmental Research

5

Program

t

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Origins of theResearchProgram

The origins of the Office of Healthand Environmental Research(OHER) trace back to the outsetof World War II and the establish-ment of nuclear research centersunder the “Manhattan Project.”The first formal program began in1942 as a Health Division, estab-lished by Dr. Arthur Holly Com-pton, Director of the University ofChicago Metallurgical Laboratory.Already a Nobel laureate for hiswork on X-ray scattering, Dr.Compton recognized the unprece-dented hazards posed by radiationto wartime workers at the labora-tory. With the perspective of ahalf-century of earlier experiencewith X-rays and radium, he and hiscolleagues could well appreciatethe dangers, as well as the possi-bilities, of atomic radiation. Bio-medical programs were soonestablished at Oak Ridge, Tennes-see, and in the Manhattan Projectat large, and it is fortunate thatthese were able to attract themost competent physicians andmedical researchers in the field ofthe biomedical effects ofradiation.

Like the Curies and otherpioneers in the field of radiation,those who sought to protect thehealth of their colleagues couldunderstand, more than others,that the phenomenon that so con-cerned them was, at the sametime, an opportunity. Theygrasped its significance andforesaw the promise of radiationand nuclear medicine as a newmeans for medical diagnosis andtreatment. This promise has beenfulfilled. Today, radiophar-maceuticals are produced andpackaged in myriad forms and arein widespread use; for example,radiopharmaceutic”als containingthallium-201 ions were admini-stered for the diagnosis of heartdisease to 370,000 patients in1981.

In providing the first legislativebasis for the health research pro-gram through the Atomic EnergyAct of 1946, the Congress over-looked neither the opportunitiesnor the dangers presented byradiation. In the Act the Congressdirected the Atomic Energy Com-mission (AEC) to

7

. . . make contracts,agreements, arrangements,grants-in-aid, and loans . . .for the utilization of fis.sionable and radioactivematerials for medicine andhealth purposes . . .

and for

. . . the protection of hea/thduring research and productionactivities . . .

The need for a highly qualifiedgroup of research administratorswas foreseen to fulf iII this broadcharter. Thus, the Division ofBiology and Medicine was estab-lished, and Dr. Shields Warren,Professor of Pathology at HarvardUniversity, was named its firstDirector. Under Dr. Warren, theDivision laid down the outlines ofa vigorous research effort of fun-damental studies in the life scien-ces; in applied areas to ensureindustrial hygiene in Commissionfacilities, as well as for the publichealth and safety; and in fosteringthe rapid growth of nuclearmedicine.

The responsibility for administer-ing this program was assigned tothe Energy Research and Develop-ment Administration (ERDA),which succeeded the AECthrough the Energy Reorganiza-tion Act of 1974. However, the oilembargo had underscored theneed for developing a wide rangeof energy options and tech-nologies in addition to nuclear,and this need was reflected in thenew agency’s mission. Therefore,this Act additionally charged theERDA Administrator with theresponsibility of

. . . engaging in and support-ing environmental, physical,and safety research related tothe deve~opment of energysources and utilizationtechnologies.

These responsibilities wereassumed by the Agency’s Divisionof Biomedical and EnvironmentalResearch, which initiated a signifi-cant program of non-nuclear

esearch, focusing on the develop-ment of fossil fuels and renew-ible energy sources. At the sameime, a broad range of legislation*strengthened and expanded the‘ationale for ERDA’s program of~ealth and environmental research)y establishing a regulatory frame-tvork by which the results of this‘esearch could be integratedIirectly into the planning and~evelopment of energytechnologies.

41though ERDA was relativelyshort-lived, these research func-:ions were retained intact by thelew Department of Energy (DOE),established in 1977. Within the3epartment today, these respon-sibilities have been carried on by3HER.

Nhat, then, has been the netresult of OHER’S history of chang-ing roles and mandates? A centralmission has evolved, requiring theintegration of three fundamentalareas of study: (1) the “source,”w potentially toxic agent of con-oern; (2) its “transport,” or pathhorn its point of release; and (3)the “effects” that it may produceupon populations and the en-vironment.

The first of these areas of studyinvolves the understanding andcharacterization of the material,pollutant, or agent of concern.Despite the seemingly limitedscope of this phase of study, itcan lead to unexpected rewards ofa much broader nature. For exam-ple, the OHER mandate under theAtomic Energy Act required anunderstanding of radiations ofvarious kinds and their interac-tions. This, in turn, created a needfor the development of a host ofradiation detection instruments,some of which became essentialto the field of nuclear medicine,as noted later.

The second facet of the mission—source transport—began as an ef-fort to understand the paths that

●This legislation, beginning with theNational EnvironmentalPolicy Act in1969, included the Clean Air Act, SafeDrinkingWater Act, Toxic SubstancesControl Act, and the ResourceCon-sewation and RecoveryAct.

8

night be taken by radioactivenaterials through the environ-ment. But, as the range of energy)ptions under development in-:reased, the transport of materialsrom other technologies—coal flyish, combustion gases, syntheticuel components—also cameJnder study.

rhe final segment of OHER’S in-egrated mission is to detect thelature and extent of any possible~anger to man and his environ-ment from the potentially toxic)ource materials. Once again, in-tial research in this area was con-‘ined to radiation biology, the>tudy of mechanisms and magni-tudes of effects produced by‘adiation. These studies included:he uptake and distribution of“radioactivematerials in animalsmd man to determine potentialtoxicity. This knowledge, when~oupled with developments inIuclear instrumentation, providedthe basis for the parallel develop-ment of nuclear medicine. Thelatter was but one of the new~irections in research to receiveits impetus from radiation biology.The quest for answers to themysterious response of cellulardeoxyribonucleic acid (DNA) toradiation spawned an unparalleledresearch program in basicgenet its.

Thus, the objective of the OHERmission has been straightforward—to perform fundamental researchm the energy-related triad ofsource-transport-effect and to in-tegrate its basic findings towardthe solution of practicalquestions.

The OHER Program employs amultidisciplinary “team” of nearly1000 scientists in specializedfacilities that have come to beregarded as National resourcesfor biomedical and environmentalresearch. (Table 1). For example,in FY 1985 other Federal, State,and local agencies, and private in-dustry invested over $115 millionin DOE laboratories to conducthealth and environmental researchto help address their own missionneeds. Additional research sup-ported by the OHER Program isconducted at some 100 academic

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rable 1. Health and EnvircmrnentalResearch ~aborat6ries

1. Multi program LaboratoriesArgonne National Laboratory

(ANL)Brookhaven National Laboratory

(BNL)Lawrence Berkeley Labclratory

(LBL)Lawrence Livermore National

Laboratory (LLNIL)Los Alamos National Laboratory

(Los Aiamos)Oak Ridge Nationad Laboratory

(ORNL)Pacific Northwest Laboratory

(PNL)Savannah River Laboratory

2. OH ER-Dedicated LaboratoriesEnvironmental Measurements

LaboratoryInhalation Toxicology Research

InstituteOak Ridge Associated Univer-

sitiesUniversity of California, Davis

Laboratory for Energy-RelatedHealth Research

University of California, LosAngeles Laboratory ofBiomedical and Environmen-tal Sciences

University of California, SanFrancisco Laboratory ofRadiobiology and En-vironmental Headth

University of Georgia, SavannahRiver Ecology Laboratory

University of Rochester Bio-medical Laboratory

University of Utah RadiobiologyLaboratory

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campuses, hospitals, and otherresearch institutions. Hundreds ofOHER-funded scientists hold aca-demic appointments and serve asimportant resources in the formaleducation of the Nation’s scien-tists, engineers, and physicians.Many of the research projectssupported at the laboratories alsoserve as vehicles for trainingpredoctoral students, as well aspostdoctoral investigators. In addi-tion, opportunities are providedfor research collaboration withvisiting scientists who stay for ex-tended periods of time.

Throughout its history OHER’Sphilosophy has been to encourageprompt dissemination of research”results at scientific meetings andin the scientific literature. Scien-tists currently supported by theprogram make nearly 2000 presen-tations each year at technicalmeetings and document theirwork in more than 2000 journal ar-ticles that have been peer-reviewed prior to publication.

In addition to the intellectual andscientific resources which havemade these advances in knowl-edge and technologies possible,the National Laboratories possessmultiuser facilities that are havinga major impact on the rate ofprogress in elucidating the struc-ture of biological molecules. Suchstructural determinations are aprerequisite for solving moleculardesign problems; for example, themodification of proteins so thatthey have a specified type of ac-tivity. Moreover, the unparalleledcomputational resources availableat the laboratories and the broadcapability to exploit them fullyalso provide the environmentnecessary for major advances inpredicting small molecule struc-ture and activity, which are centralto identifying mutagens and car-cinogens and designing drugs andvaccines. Together, these struc-tural biology activities will providethe firm foundation crucial tomaintaining America’s competitiveadvantage in private sector bio-technology during the comingdecades.

The funding for the Biological andEnvironmental Research Program

is shown in Table 2, which alsodefines extensively the organiza-tional structure of OHER. As inany large-scale research program,activities being conducted varyfrom year to year as existing proj-ects are completed and new proj-ects or lines of investigation openup. A synopsis of the principalresearch activities currently underway is presented in the Appendix.

The following descriptions of pro-gram accomplishments provide aglimpse of some of the more tan-gible products of the OHER re-search process. Having providedthe background for the presenta-tion of these products, somecaveats are in order.

As in any other research enter-prise, there is a continuum of ef-fort, and a “snapshot” of selectedOHER Program accomplishmentscan easily create a distorted viewof the overall workings of the pro-gram. It has already been notedthat while many of the accom-plishments described have provedto be of considerable economicimportance, that is not necessarilya measure of the effectiveness ofthe research within the context ofthe OHER mission, nor is it a fac-tor in shaping its research agen-da. The course of research iscomplex and can lead to a num-ber of “dead ends,” as well as tosuccesses and breakthroughs. Aseemingly fruitless effort cansometimes be useful by virtue ofits indication of more productivepathways, and one of the ac-complishments described, whicheventually ended in a treatmentfor Parkinson’s disease, providesa case in point. Basic research, akey part of the program, is long-term and often not immediatelyand measurably beneficial. Yeteven in the event of no immediateproduct, the insights gained intothe operation of biological proc-esses improve our capability toanticipate or predict how thesystem will respond to new oruntested events for which dataare sparse or unavailable. Thebone-marrow transplantation workundertaken early in the program isan example of basic research thatultimately provided much of theinformation that supports the

current state-of-the-art for organtransplantation work in medicine.

Thus, in summarizing the accom-plishments of a research programdesigned for a mission as far--reaching as that of OHER, itsworth should not be judged solelyon the basis of economic benefitor immediate applicability. Theresult of research may be a tangi-ble product (e.g., a nuclear scan-ner or radiopharmaceutical) ofreadily calculable value. But the“product” may also be the answerto the riddle of self-repair to cellinjury, the mechanism by which aparticle is transported, or the defi-nition of the risk of bone cancerfrom radiostrontium. Thus, it isequally valid to judge the benefitof a research contribution interms of its reduction of uncer-tainty or its description of apreviously unknown mechanism.These criteria have been in con-sonance with the energy develop-ment missions of OHER’S parentagencies (AEC, ERDA, and DOE),which, in an anticipatory manner,have made use of its research toprevent, modify, or mitigate poten-tial health and environmental ef-fects before an emerging tech-nology reaches maturity. The con-trast between the anticipatorynature of OHER research and thatwhich is conducted by the regu-latory agencies is readily apparentfrom the differing content and ob-jectives of their respectiveresearch programs. The ultimategoal of the research program is,therefore, not so much to find ef-fects as it is to aid in their pre-vention. The extent to which thatgoal is realized is the true meas-ure of its benefit to the Nation.

The following sections containdescriptions of selected, definitiveresearch contributions resultingfrom the program—accomplish-ments of the many individuals inNational Laboratories, universities,and research institutes who con-duct this work under contract toOHER. In some instances theresearch has been cofunded or isnow pursued under auspices otherthan OHER.

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Table 2. Funding for Biological and Environmental Research(Dollars in Millions)

.l &

Research AppropriationsFY 1984 FY 1985

Human health research to quantify risks of lateeffects of acute and chronic exposures viaepidemiological studies of workers and thegeneral population and to develop methods todetect and measure latent disease induction oridentify highly susceptible individuals

Health effects research in biological systems todefine experimentally dose-response relationshipsand the factors influencing carcinogenic, muta-genic, and toxicological risks of energy-relatedexposures; and basic biological research toelucidate the mechanisms by which physical andchemical agents may cause their effects

Environmental research to determine the mech-anisms that control and influence totalecosystems and the cyling of energy by-productsthrough them

Physical and technological research to characterize.energy-related emissions to which humans maybe exposed and improve measurement anddosimetry instrumentation

Health and environmental risk analysis of emergingenergy technologies

Nuclear medicine: research to develop new radio-isotopes, labeled compounds, clinical procedures,and visualization devices for improved diagnosis,treatment, and study of human diseases

co:Program direction

Total operatingCapital equipment and construction

Total

25.6

57.0

23.8

27.6

1.8

20.8

24.8

59.5

21.3

35.4

0.0

21.8

12.43.3

173.310.7

184.0

13.33.5

179.610.9

190.5

‘C02 research is managed by the Basic Energy Sciences Program staffbut is budgeted under the ‘Biological and Environmental Research Pro-gram. C02 research is not discussed in this report.

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EmergingEnergy -TechnologiesOBJECWE: Through Research,Examine the Potential for AdverseEffects on Human Health and theEnvironment from EmergingEnergy Technologies.

It is the purpose of this Act...to advance the goals of resfor”ing, protecting, and enhancingenvironmental quality andassuring public health andsafet~...

.—Sec. 102, Public Law 95-91

The functions which theSecretary shall assign...shal~include..~onducting a compre-hensive program of researchand development on the en-vironmental effects of energytechnologies and programs...;

—Sec. 203, Public Law 95-91

This new organization act iden-tified, for the Department ofEnergy (DOE), responsibilities forpublic health and safety that werevirtually identical to those of theAEC in its nuclear developmentand production programs andERDA in its development ofenergy conservation and bothnuclear and non-nuclear energy-supply technologies. In all threecharters the intent of Congresswas cleac to foster a better under-standing of the potential Iy adverseeffects on human health and theenvironment of emeraina enercwtechnologies. The dr~m~tic di~lo-cations following the oil embar-goes of 1973 and 1979 gaveimpetus to the development of theemerging technologies—syntheticand renewable, as well as nuclear,fuels—and, thus, added to theurgency of these responsibilities.

Identification of HumanHealth Effects

Early in the OHER Program, con-cerns centered around the re-sponses of humans and animalsexposed to radiation. Specific ex-periments to measure radiation ef-fects were initiated and led veryquickly to the realization that torecognize damage, scientists firsthad to understand the structureand functioning of healthy cells,tissues, animals, and, ultimately,humans. The resulting researchprogram would make, and contin-ues to make, major contributionsto biology, medical diagnosis and

:reatment, ecological science,genetics, biophysics, immunology,3NA repair, and the study of the>auses of cancer, to mention only~ few of the affected and enrichedscientific areas.

The next decades could see a ris-ing potential for new pollutants’from such technologies as oilshale and synthetic oil from coalw from diesel emissions. ‘Ttiemovement of these pollutantsthrough the air, land, and waterand possibly back to human be-ings would have to be evaluated.It is important to understand theability of the environment to breakdown, detoxify, and absorb theresiduals from these new chem-icals. Testing their ability to causecancer, mutagenic effects, or .“somatic damage is also needed tohelp minimize health and environ-mental effects. The time whenguidance can be most helpful andleast expensive is before billionsof dollars are invested in newenergy technologies.

Finally, shou’d the unexpectedoccur, the OHER has developedcapabilities to respond to emer-gency situations and realisticallyassess the potential public healthhazards of toxic releases to the at-mosphere. These systems wereoriginally designed to predict fall-out from atmospheric nuclearweapons testing but have evolvedinto an especially effective atmo-spheric-dispersion forecasting forchemical releases as well.

Nuclear Technology The biolog-ical and medical research programinitiated during the World War II“Manhattan Project” has spon-sored extensive research studiesand measurements to determinethe mechanisms and extent ofradiation effects on human healththrough direct studies on exposedhuman populations and by experi-ments on animals, tissues, cells,and individual molecules of in-terest. Data on the health impactsof different types and levels ofradiation exposure, the interactionof radiation with living tissue, andthe manner in which radioisotopesare taken up into the body havebeen evaluated and used to deter-mine the risks posed by radiation

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to industrial workers and the gen-wal public. Such risk analyseshave been used in the develop-ment of industrial hygiene prac-tices, radiation exposure controlguidelines, and regulatory criteriafor the location, design, andoperation of nuclear facilities.From the collective effort, a newscientific discipline, radiation biol-ogy, emerged and revolutionizedthe study of biological, ecological,and medical systems. Radiationbiology has increased our under-standing of fundamental proces-ses by enabling greater quantifi-cation of results through new in-struments and techniques and byapplying the multidisciplinaryskills of physical and biologicalscientists to vital questions ofhealth, illness, and life.

Ovemlew Major research and edu-cation programs to study radiationand its effects were first under-taken in the 1940’s and 1950’s.These programs provided system-atic assessments of the immedi-ate or genetic effects of variouslevels and types of radiation onboth humans and animals. Mostdata on radiation risk before thistime had been estimated frommeasures of effects in persons in-volved in diagnostic and medicalX-ray irradiations or from specialstudies dealing with issues suchas the effects of radium ingestedby workers painting watch dials.The epidemiological study of thelong-term effects on the survivorsof Hiroshima and Nagasaki beganwith the establishment of theAtomic Bomb Casualty Commis-sion, now called the RadiationEffects Research Foundation.Their studies provided initial. infor-mation on a wide range of dosesof ionizing radiation from manyradioactive isotopes, includinginformation on those common tothe defense and nuclear powerindustries.

By the 1960’s, comparative evalua-tions of health risks from radio-nuclides in defense and energyproduction included studies ateach stage of these industries,from mining and productionthrough storage and disposal ofnuclear material. Insights gainedfrom these studies permitted the

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correlation of results from cells,mimals, and humans to providensight into the biological impactsof radiation. Moreover, they pro-fide the scientific informationrequired to establish realistic ex-posure limits for both nuclear in-~ustry workers and the generalpopulation.

The primary unresolved issue inhuman health-effects studies isthe effect of long-term exposureto low levels of radiation. Over thenext decade the study of health~ffects will benefit from its firstdirect information as many of theworkers urider study complete ex-pected latency periods (time fromexposure to possible cancer on-set). Any variations from popula-tion norms will provide first-handdata for drawing conclusionsabout radiation effects. Withoutthis confirming evidence, healtheffects from low-level exposureswould continue to be based on in-direct information of three kinds:(1) the lack of adverse effects inthe workers under study, (2) esti-mates obtained from the use ofanimals as substitutes for humans,and (3) data from the studies ofJapanese atomic bomb survivorsexposed to medium-to-high levelsin a single exposure event. Thus,although enough data for positiveconfirmation may be 10 or moreyears away, the fact that the esti-mates have held year after year forthe last 35 years has allowed in-dustries involved with radiation togain increasing confidence in thestandards by which they operate.

The next sections will outline theresearch areas undertaken byOHER in an attempt to gain aworking understanding of thepotential human health effectsfrom nuclear technologies. Thecomplementary research efforts ofradiation biology, epidemiology,and animal studies support theevaluation of public and workerexposure standards. These sec-tions are followed by a sample ofthe benefits that have accruedfrom OHER research in humanhealth effects.

Radiation Biology Radiationbiology is the study of the effectsof radiation on biological systems.

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The emergence of radiation biol-~gy as a major area of scientificresearch resulted fronn the estab-lishment of the AEC and its Divi-sion of Biology and Medicine[later called the Office of Healthand Environmental Research).Large-scale programs designed toexamine the biological effects ofatomic radiation were initiated ata number of the OHER-supportedlaboratories, including those atOak Ridge, Brookhaven, Argonne,Los Alamos, and Hanford F}acificNorthwest Laboratory (PNL), aswell as within several nonglovern-ment institutions, notably theUniversities of California, Floches-ter, and Utah, and the LovelaceFoundation (Inhalation ToxicologyResearch Institute). A smaller pro-gram of university-based, contract-supported research was alsoinstituted.

Undoubtedly, one of the mi~jor im-pacts on the expansion of biologyin the 1950’s and 1960’s resultedfrom the close interaction amongphysicists, engineers, biologists,and physicians at the radiationbiology laboratories. interdiscipli-nary research and training withadded emphasis on quantificationwere very effective in bringingabout rapid advances in bcthbasic and applied aspects ofquantitative biology and medicine.The general trend towards quan-titative biology can be seen in theincreased emphasis placedl onphysics, chemistry, and physicalchemistry content in biologycourses taught at the universitylevel. The value of a solid back-ground in physical science to thebiological or medical student isnow wel I accepted.

Discoveries within the fielcl ofradiation biology have had a majorimpact in many areas of science:genetics, biophysics, immunology,nucleic acid structure and func-tion, DNA repair, cell biology, andcancer research. Radiation biologyresearch provided the basis formajor advances achieved inresearch related to human healtheffects, environmental effects, andnuclear medicine, all discussedelsewhere in this report. Some ad-ditional examples willl serwe to il-lustrate the breadth clf impact of

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radiation biology on biomedicalresearch: basic ‘and applied in-vestigations in molecular biology,cellular biology, genetics, and themechanisms involved in the devel-opment of cancer.

The continuity and diversity of lifeforms depend upon the replication(duplication of genetic material),the recombination (the exchangeof genetic material, to yield geneticdiversity), and the repair (the re-moval of darnage resulting fromenvironmental agents or from mis-takes in replication) of DNA. WhenDNA repair mechanisms are func-tioning normally, cell survival in-creases while the mutation rateand the probability of cancer orother abnormal changes in tissuesresulting from exposure to radia-tion or a toxic chemical decreases.The discovery of DNA repair, alandmark achievement, was a di-rect outcome of OH ER-supportedinvesti,gati.ons in radiationbiology—in this case, research onthe genetic effects of ultravioletlight.

Cell cycle studies using agentssuch as radioactive thymidine (3H-thymidine) and radioactive iodine(iodine-125) have led to increasedunderstanding of DNA replication,DNA repair, and the genetics andbiochemistry of specific phases ofthe cell life cycle. In addition,many effects of endogenous andexogenous environmental agentson these cellular functions havebeen determined. Drawing on thisresearch, more rational and scien-tific uses of chemotherapy for themanagement of cancer and otherproliferative diseases have beenformulated and adopted.

The ability to perform many of theprocedures in molecular biologynow common in laboratoriesthroughout the world clearlyresulted from earlier work on radio-active precursors of DNA, as wellas from the development of techni-ques for manipulating, isolating,and analyzing radiation-damagedDNA. Today, these techniques arebeing put into practical use ingenetic engineering for the produc-tion of insulin, growth hormones,and other biological materials ofgreat utility to mankind. Another

consequence of the early studiesof DNA synthesis is the current in-terest in human genetic diseasesassociated with defects in theDNA repair mechanism or in theproteins that, along with DNA,form the genetic material of livingcells, known as chromatin.Diseases of this type include xero-derma pigmentosa, ataxia telangi-ectasia, Bloom’s syndrome, andFanconi’s anemia.

Knowledge of DNA repair andother cell cycle phenomena arosefrom attempts to understandradiobiological phenomena. Theconcepts and methodologies ofDNA repair research have nowbeen extended to two other impor-tant areas of biological research—the study of the chemical causesof cancer and aging. The connec-tion between the chemical andradiological causes of cancerarises from the important discov-ery that the modes of repair ofchemical damage in DNA ofhuman cells mimic either ultra-violet damage and repair or radia-tion damage and repair. Hence,DNA repair is a general phenom-enon, not one peculiar to ‘radiation.Active repair of DNA in bacterial ormammalian ceils treated withpotential mutation or cancer-causing substances, mutagens orcarcinogens, respectively, is takenas evidence of DNA damage and isthe basis for several rapid tests foragents that cause harm or destroygenes. The use of bacteria thatlack the ability to repair damage toDNA in such tests, for example,the Ames test, enhances by ordersof magnitude their sensitivity fordetecting cancer-causingchemicals.

In 1974 researchers at the Brook-haven National Laboratory (BNL)made the intriguing finding thatthe ability of cultured cells fromdifferent mammalian species tocarry out the repair of ultraviolet-induced DNA damage increased asthe life span of the species in-creased. Human cells are verygood at excision repair mousesells are poor. The notion thatthere is a correlation between ag-ing and DNA repair ability wasderived from early experiments atOak Ridge National Laboratory

(ORNL) on the accumulation ofsingle-strand breaks in the DNAof tissues of old mice. This areaof new and fruitful research wasopened up by OHER support forradiation biology and DNArepair.

Radiation biology has had massiveimpacts on human medicine sincethe late 1940’s, as discussed in thesection entitled “Nuclear Medi-cine.” We can get a glimpse of itssignificance in another importantarea of medicine from two sum-maries on the use of bone marrowtransplantation in contemporarymedical treatment. Bone marrowtransplants were first used as atreatment for radiation-induceddamage to blood-forming cells inbone marrow. R. A. Good writing inThe New England Journal ofMedicine in 1982 said, “Indeedmore than 20 previously fataldiseases can now be successfullytreated with bone marrow trans-plantation. These disorders rangefrom genetically determined severecombined immunodeficiencydiseases to acute Ieukemias.”Similarly, E. Beutler of The Journa/of the American Medical Associa-tion in 1981 pointed out, “Untilrecently, our mind-set was that leu-kemia was not curable.” In selectedleukemia patients and under ap-propriate circumstances,

the vast majority (well over 90’Yo)survive the transplantation pro-cedure and the extent of morbiditydoes not differ great/y from thatassociated with ordinary inductionchemotherapy Despite the occur-rence of graft-vs-host disease andoccasional relapses, the overall curerate of this selected group of pa-tients seems to be between 700/0and 80°7’0.

Epkfemlology of Radkzflon hPOSUfWQuantitative data havebeen produced from epidemiologicstudies of the genetic (on thegerm or reproductive cells) andsomatic (on the body as a wholeor on cells other than germ orreproductive cells) effects ob-sewed in humans exposed toradiation. These data allow theestablishment of upper-boundestimates of the genetic risk andnumerical estimates of thesomatic risk of such exposures.

13

N a more basic scientific level,“esearch in molecular epidemiol-ogy on understanding the molecu-ar basis of predisposition towardmd resistance to damage by‘adiation and toxic chemicals nows extremely promising. The iden-tification of populations that areparticularly susceptible or resist-ant to certain types of insults isnot only of the greatest signifi-~ance to medical sciences, but itwill have a major positive impactm Federal regulatory activities byproviding data for setting healthstandards that take into accountboth variations in the populationmd the doses to which human~opulations are ordinarily~xposed.

The study of atomic bomb surviv-ors in Japan has provided the bestwailable estimates of the risk oftarious types of cancer resultingfrom exposure to external low-energy radiation. Some of the char-acteristics that make this studyparticularly useful are as follows:

1. The survivors are the only largepopulation with a wide range ofwhole-body exposures, or ex-posure over the entire body.

2. The population was compara-tively random with respect tohealth and work history.

3. An elaborate dosimetry programhas yielded individual doseestimates for major organs.

4. The family registration systemof Japan ensures 100 percentfollowup on mortality.

Although intensive study has beenunder way for over 30 years, thepast decade has seen the idemtification of new potential cancersites and revisions of previousestimates of risk. Most recently, areassessment of calculated gam-ma and neutron dose received byindividuals has led to a majorchange in the carcinogenic, orcancer-producing, role assigned toneutrons and to a modest revisionin estimates of gamma doses.

A series of epidemiological stud-ies designed to detect geneticeffects among the offspring ofatomic bomb survivors has shownno statistically significant differ-

.

ence between them and the~ffspring of groups not exposedto the radiation. The geneticstudies have provided valuableassurance that the use of animaldata (see section on “AnimalStudies’~ does not seriouslyunderestimate the effect onhuman populations. The epidemi-ological results are consistentwith the mouse data and alsoallow us to confidently place anupper bound on the level ofsomatic effects in irradiatedhumans.

Although the study of bomb sur-vivors was the predominant factorin developing a quantitative ‘esti-mate of the effects of variouslevels of exposure, i.e., a dose-response relationship for radi-at ion-induced cancer, it has in-herent limitations, notably that thedata were compiled from a singleexposure at a high dose rate andthe population samples are notlarge enough to define with anyconfidence the risk of very lowdose rates. These factors madequestionable the extrapolation ofthe dose-response curve to lower,prolonged exposures without addi-tional information. Moreover,animal studies had shown that theresults of high doses of lowenergy-transfer radiation (lowenergy particles or gamma radia-tion) received over a short periodof time are of far more conse-quence than the same dose re-ceived over a long period of time.As a result, studies of industrialworkers were begun by the AECas early as 1964. The initiastudies of Hanford and otherDOE-contractor employees havesubsequently been expanded toinclude naval shipyard workersand soldiers present at nuclearweapons tests in Nevada. Theresults to date have reinforcedthe low risk that would bepredicted for workplace externalexposures.

The AEC initiated a study ofradium-dial painters subjected toradiation from internal radiumdeposits accumulated in the erabefore the health effects of radia-tion exposure were generallyknown. Radium emits high energyalpha-particles and a gamma ray.

,

rhese epidemiological studies~ave provided the primafy basis‘or setting all such standards fol‘adium and for transuranic ele-nents such as plutonium, whichNso emit alpha-particles and gafna rays. Epiderniological r’esear[m chronic internal exposure ha:more recently been expanded tonclude plutonium workers, atseveral DOE facilities. Results o[his ongoing work halve corrobo-rated the adequacy of current>tandards for these alphasmitters.

dnhnal Studbs Impcwtant infor-mation about the risks from ex-~osure to radiation has beenSerived from large-scale animal~xperiments. These studies detemined the potential cancer orgenetic effects from internallydeposited radionuclides or fromsxternal radiation an~drevealed tImportance of the rate with whitthe radiation is received, as wellas the relative biological effec-tiveness of different types ofradiation.

Because there was minimialhuman data on the effects oflong-term exposure to low level:~f radiation, animal ciata ftad toplay a significant role inestimating guidelines forallowable human exposure to diFerent types of radiation. 13etwe[1956 and 1966, three large studi~on mammals were conducted todetermine (1) the latent effects [plutonium exposure in dogs androdents, (2) the relative toKicity (strontium-90 and radium-226deposited in the skeletons ofhumans and other mammals, an(3) the genetic effects of extermradiation in mice. By 1974 ten mjor animal experiments were inplace to determine tlhe uptake,metabolism, dosimetry, and earland late effects of exposure tomost major fission products ofconcern. There were also con-cerns about the importance ofchemical forms of plutonium administered by different exposur(routes and the importance of dc(quantity and rate) of externalgamma ray or fission enetrgyneutrons in the induction of Iattsomatic or genetic effects.

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Following are five examples ofsome df the sludies developed toinvestigate these important” issues:

1. Relation of Human and AnimalEffects of Bone-Seeking Radio-nuc/ides. The radium-dial-paintersstudy provided a quantitativeepidemiological data base forhumans exposed to, and carry-ing gradedbody burdens of, thenatural bone-seeking radio-nuclide radium-226. By obtain-ing comparable data forradium-226 in a long-livedanimal species (dog), a radiationeffects ratio (RER) for radium-226 can recalculated as follows:

Z~Ra-effects (man)RER =

~Ra-effects (dog) ‘

Assuming the same interspe-cies relation holds true forother bone-seeking radionu-clides, such as plutonium-239,and using the following expres-sion, the data from the dogstudies can be used to estimatethe potential hazards from theseradionuclides to humans:

z~Pu-effects (man)= RER x ‘gPu-effects (dog).

These studies provide vital datafor predicting human risks ofradiogenic bone cancer from im-portant man-made radionuclides,which are already present in ourbiosphere. The data derivedfrom these experiments havedemonstrated that the presentguidelines are scientificallydefensible for radiation ex-posure by workers and thegeneral population.

2. Determination of Dose-Rate Ef-fects of External Sources onRadiation Risks. Most of theearly data on radiation riskestimation were derived fromstudies of people involved indiagnostic and therapeuticmedical X-ray exposure.Although there was strongevidence that low dose rates orprotracted radiation exposurewas less harmful than high-dose-rate single exposures, nosystematic assessment andmeasurement of the magnitudeof the dose-rate effectivenessfactors had been made for

either heritable or geneticeffects or for delayed toxicolog-ical effects and cancer induc-tion. OHER-supported studiesshowed that genetically dif-ferent mouse strains respondedsimilarly to the varying doserates. These findings promptedstudies in which gamma andneutron irradiation would becompared as a function of doserate.

3. Potential Health Risks inNuclear Research, WeaponsPrograms, and Power Produc-tion. Multispecies animal ex-periments were initiated inseveral laboratories to validatethe acceptability of standardsand guidelines for radionuclidesproduced by nuclear fission:Priority among the fission prod-ucts was established based ontheir relative fission yields, theirhalf-lives, and their propensity,due to the metabolic character-istics of the exposed animal, tobe deposited and retained inspecific organs of the body.These studies showed thatradiation responses could bealtered by different routes of ex-posure, by differences in local-ized dose and dose rate, and byother variables such as thechemical characteristics of theradioactive compound and thetype of radiation produced byits decay products. Develop-ment of nuclear power reactorsled to expansion of the OHEReffort to include evaluation ofimportant radionuclides en-countered at each significantstage of the nuclear fuel cycle,from uranium mining throughstorage and disposal of nuclearwaste.

A major fraction of OHER’Sresearch has involved animal ex-posures by inhalation, one ofthe most significant routes ofexposure for products of the fis-sion process, especially pluto-nium. These animal studieswere instrumental in developingmodels describing the distribu-tion and fate of various solubleand insoluble aerosols in thelungs, including movement toremote critical organs at dif-ferent times after exposure.

Determination of the Genetic Ef-fects of Radiation in Mice. Until1947 estimates of the genetichazards of radiation were basedentirely upon the data derivedfrom the fruit fly (Drosophila).Because it was essential to ob-tain information on a mam-malian species to provide acloser correlation with man andbecause a genetic study re-quires data over many genera-tions, a long-term, verylarge-scale study of radiation-induced genetic effects in micewas begun. Pending definitiveresults from the epidemiologicalstudies discussed earlier, theresults of the mouse studiesstill provide the basis for ourestimation of genetic risk tohumans.

The large mouse study requiredthe development of new tech-niques and methods for detect-ing radiation-induced mutation.One of these, the specific locusmethod, has found wide applica-tion in determining how muta-tion rate varies with changes inradiological and biological pa-rameters such as dose rate,dose fractionation, total dose,radiation quality, sex, stage inthe cell life cycle, and age atexposure. The specific locusmethod is also being applied tothe study of the processes bywhich some chemicals causemutations, called chemicalmutagenesis, and to the possi-ble effects of energy-related andother environmental pollutants.

It was found that the mousewas considerably more sensitivethan the fruit fly to the induc-tion of mutations by large,rapidly administered (acute)doses of radiation. This resultwas an important factor in thesubsequent lowering of recom-mended permissible levels forhuman exposure to radiation.Additionally, it was discoveredthat the level of mutations pro-duced in male and female micewas different over a range ofdose rates. in males this wasmanifested by a one-third reduc-tion in mutation rate when thesame dose was absorbed at alow, as compared with a high,

15

rate of exposure. It was alsofound that the germ cell in thefemale mouse is so resistant tomutation induction by radiationthat no significant increase overnaturaiiy occurring, spontane-ous mutation rates has beendetected in the irradiatedanimai.

These iast two findings togethersuggested that genetic risk inman is only about one-sixth ofwhat it was estimated to bewhen radiation exposure limitswere based on high dose-rateresuits and on the assumptionthat femaies and maies wereequaiiy sensitive. Although thefindings did not iead to the rais-ing of permissible levels ofradiation exposure, they did pro-vide a cogent argument for nofurther iowering of permissibleIeveis.

5. Supporting Animal Studies. Tointerpret experimental resuits, itwas necessary to understandthe natural changes occurringin animals being studied, that isto study the roie of aging andto gain a better understandingof the biological process ofaging itself. Strong support wasgiven to recording and anaiyzingspecific biological parameterssuch as brain mass, metaboiicrate, body temperature, andbody mass—important param-eters that correlate with andserve as actuarial predictors oflongevity in animal species. Thewhite-footed field mouse andthe common laboratory mousewere particularly usefui in thisregard. Although these twospecies are similar in colora-tion, form, and size, the fieldmouse has a iifespan of neariy8 years whiie the laboratorymouse seldom lives longer than3 years. Additional aspects ofaging and iongevity are beingexpiored and inciude immuno-logic factors and possible rela-tionships between the agingprocess and ceiiuiar DNA repair.

Evaluation of Exposwe Wtentiaito Workers and the Pubiic De-tailed information on appropriateindustrial hygiene practices wasdeveloped to ensure safe operation

16

~f industries that use radiationsources and radioactive isotopesand to ensure public safety. Thisinformation was deveiopedthrough major OHER-supportedresearch and educational pro-grams in the areas of radiationmonitoring; dosimetry and tox-icoiog~ air, water, and soiianaiysis; bioassay; and health riskand analysis. These are nowbroadly inciuded in the fieid ofheaith physics.

To evaiuate radiation exposures ofworkers in nuciear industries,health physicists needed devicesto measure radiation from externaisources and bioassay methods todetermine the amounts of radioac-tivity that may have been takeninto the body. Personai dosimeterswere developed, first from radia-tion sensitive fiim and then fromthermoluminescent crystais. Bio-Iogicai assay or bioassay tech-niques were developed that usedradiation counters that measureradiation absorbed by the body,excretion assays, and biomathe-matical models of the metabolismof internai iy deposited radio-nuclides. These techniques haveprovided working lifetime recordsof external radiation exposuresand the amounts of radioactivitythat may have been taken into thebody. Exposure records are avaii-abie today for most workers inindustries using radioactive proc-esses or equipment and can beused to evaiuate the potential foran individual developing aradiation-reiated injury.

Extensive research programs wereinitiated and expanded to developmodels needed to project thedispersion of radioactivity in theenvironment and its uptake andretention by peopie. Modeis arecurrently available to predict trans-port of radioactivity through air,groundwater, and soii. Other bio-logical research programs haveproduced modeis to project thetransfer of radioactive isotopesthrough food pathways to man andtheir uptake from food, water, andair.

Large research and educationalprograms were established duringthe 1940’s and 1950’s to study

radiation concern$ of thq future.Graduate ievei training programswere begun at the University ofRochester, Harvard University,Vanderbilt University, and theUniversity of California, amongothers. They were also coupled toresearch programs at sevelrai Na-tional Laboratories supported bythe AEC. The majority of trainedhealth physicists working in nu-ciear industries today are grad-uates of these programs.

The radiation monitoring instru-ments, measurement techniques,and models described above arethe major tools used by heaithphysicists in industry and Govern-ment safety programs to evaiuatehuman radiation exposures atoperating plants and facilities.They were mainly developed inDOE-supported research programsand have been used for manyyears to provide expc)sure recordsand risk evaluations for radiationworkers and members of thegeneral public. The nuclear in-dustry is unique amcmg industriesthat handle potentially toxic sub-stances because of the state ofdevelopment of its detailedmethods to characterize or docu-ment human exposures.

Currenti y, about 200,000 peopie inthe United States have occupa-tions that involve handiincl radia-tion sources and radioactiveisotopes. Their safety depends onproper application of radiation ex-posure standards and the abilitiesof health physicists to measureand record exposures. Thus, themost important uses of technol-ogy developed in radiationresearch programs supported byDOE and its predecessor agencie:are in industrial hygiene and radiation safety.

BenefMs of Nuclear TechnologyResearoh The bulk c)f worldwideregulatory and envircmrnentalassessment act ion rlegardingnuciear power is based iargely onthe body of knowiedge acquired iithe OHER Program.

A concrete exampie of a i)enefit athis information is to UnitedStates electric power consumersin a recent decision by Federal

*

regulators to, maintain standardsin the workplace at the same levelas those maintained for the past25 years. It can be estimated whata given reduction in the worker ex-posure limit would cost; and, thus,what value these studies have hadfor the consumer/taxpayer. For ex-ample, a reduction of the annualworker exposure limit from thecurrent 5 rem●/year to 0.5 rem/yearwould cost the Government andindustry nearly $2 billion/year. Inboth commercial and DOE facili-ties, moreover, the increase innumber of work crews required toreduce exposure times would, inturn, increase cumulative ex-posure because each workerreceives some fraction of his orher exposure during the non-productive time spent in removingcontaminated protective gear. Thegreater the frequency of suchchanges, the greater cumulativeexposure to perform the sameamount of work. For a 0.5-rem/yearlimit, the Atomic Industrial Forumestimates an increase of 5400man-rems/year for the power-reactor industry and an increaseof 2300 man-rems/year for DOE’svarious programs. While there issubstantial uncertainty in thefinancial evaluation of increasedradiation exposure, the 7700 man-rems/year increase is certainlysignificant.

Because research supported byDOE and its predecessor agencieshas put industrial radiation protec-tion practices on a firmer scien-tific basis, these practices canreadily be defended in legal ac-tions taken against the UnitedStates Government and its con-tractors. OHER’S research doesnot serve as part of Governmentadvocacy but, rather, provides ascientific basis upon which claim-ants’ injuries can be assessed andequitable decisions can bereached. One example involved aclaim against the DOW ChemicalCompany, Rockwell International,and the United States Governmentfor $200 million in damages al-leged to have been caused by

●The amount of ionizing radiation re-quiredto produce the same biologicalEffect as one Roentgenof high-penetrationX-rays.

plutonium spilled at the RockyFlats nuclear weapons facility be-tween 1959 and 1965. Smallamounts of plutonium were blownby the wind into neighboringlands. The claim, filed in 1975 inDistrict Court in Denver, Colorado,was dismissed in May 1982because the Government, and itscontractors were able to demon-strate acceptably to al I partiesthat the level of plutonium outsideof the Rocky Flats facility did notrepresent a significant hazard.

Our understanding of the role ofdose rate in risk estimation wassignificantly enhanced by theanimal studies. Studies on mice,for example, demonstrated for thefirst time that for the same cumu-lative dose of radiation, fewer mu-tations and cancers are producedin animals receiving low dose rateexposures than in those receivingthe same exposure at a high rate.Furthermore, it was shown thatthe same total amount of radiationdelivered in smaller increments tomice was less damaging thanwhen delivered as a single ex-posure. These data showed thatmammals other than man arecapable of repairing damage tocells involved in transmitting thegenetic information from onegeneration to the next. A carefulevaluation of the same endpointsfrom the radiation exposures ofmice, dogs, and man has provideda model for the scaling of radia-tion effects between the species.Animal studies are also providinginformation on differences inradiation sensitivity as a functionof the age when irradiated. Thepositive contribution is to providesound scientific data that areessentiai for those charged withdeveloping guidelines for the pro-tection of human health.

The radiation biology research pro-gram and the appiied studies inradiation effects continue to hoidgreat promise of a better under-standing of biological processesand of treatments and therapiesfor a number of human diseases.Research to date has led to a hostof theories on the possible causesof genetic diseases, birth defects,aging, and cancer, as well as to

advances in immunology and treat-ment. Much of this research mayeventually resoive the question ofthe existence of a threshoid forradiation damage.

Simple discoveries, such as theuse of tritium-labeled thymidine asa DNA precursor, were instrumen-tal in helping characterize DNAreplication and recombination inmammaiian ceiis, as well as theproperties of the different phasesof the cell cycle. A knowledge ofsuch phases is important not onlyin the estimation of mutagenicand carcinogenic risk, but aiso inradiation therapy as weil.

Synthetic Fuels Human epidemio-Iogical studies provide the mostdirect information for developingrelationships between levels of ex-posure and health risks. However,these studies are rareiy avaiiabiefor industrial products not alreadyon the market, as is the case forthe products of such technologiesas oii shaie or synthetic oil fromcoal. Thus, laboratory studies aregenerally undertaken to providethe needed information. Theseusually begin with studies usingbacteria and mammalian cells incultures (see Fast Test for Cancer-causing Chemicals in “Detectionand Measurement of Human HealthEffects”) and may progress to ex-posures of whoie laboratory ani-mals by skin painting, inhalation,or ingestion. Because costs ofthese studies increase markedlywith the level of complexity, mostelaborate life-span studies usinglaboratory animais are undertakenonly when the less costly cell cul-ture assays indicate a potentiallyimportant human health concern.

Mathematical methods are aisobeing developed to combine theresuits of short-term bioassaytests, whole animal studies, andhuman epidemiology to predictthe health risks associated withnew chemicai substances. Withthese methods the toxic potentialof new substances is determinedthrough comparison with othersubstances that act in simiiarways and for which human healthrisks have been measured. Humanhealth risks can thus be estimatedper unit of exposure, providing the

17

nformat ion necessary to establishreasonable human exposureguidelines.

Research on the health risksassociated with exposures tosubstances produced in coal con-version and oil shale recoveryprocesses will also provide a firmbasis for the development of ex-posure control guidelines forworkers in these industries. It isimportant for the orderly develop-ment of safe working conditionsthat the health-effects researchprecede the large-scale deploy-ment of fuel production facilities.

Coa/ Gas/t/@XkwJ Procedureshave been developed and theirvalidity demonstrated for (1)analyzing chemical toxicants incompound mixtures, (2) monitoringhuman and environmental ex-posures, and (3) mitigating ex-posures and their effects. Theseprocedures have been proven ef-fective in characterizing the toxicchemical species in the processand effluent streams of coal gasif-ication pilot plants and processdevelopment units.

Mstory Epidemiological informa-tion on workers in turn-of-the-century coal gasification plants (inEngland and Japan) and morerecent experience in coking opera-tions indicated that a coal gasifi-cation industry might presentsignificant potential for adversehuman health effects (e.g., in-creased incidence of lung andbladder cancer). Likewise, thetremendous amounts of coal thatwould be consumed in a gasifica-tion industry suggested that theentire conversion system hadpotential to create a number ofadverse environmental impacts.

In the mid-1970’s OHER initiated abroad program of health and en-vironmental studies at operatingcoal gasification developmentunits and pilot plant facilities toobtain definitive information onthe potential health effects ofmodern coal gasification technol-ogy. These studies, which usestate-of-the-art toxicological andecological testing methods andprocedures, are coordinated withand complementary to, studies

18

supporting the development of ad-vanced high-Btu and low-Btu coalgasification technology.

Studies to identify and character-ize the extent of toxins in gaseousproducts from coal focused on thepotentially carcinogenic organiccompounds in process streamsand effluents. Ecological studiesaddressed the effects of air emis-sions, liquid effluents, and solidwaste disposal. Industrial hygienestudies included workplace moni-toring, medical surveillance, andevaluations of the adequacy ofmeasures to limit exposures andeffects. Finally, an initial riskassessment of coal gasificationwas performed.

Benefits As a direct result of thestudies at pilot plants, toxicolog-ical evaluation of process streamsand effluents from full-scale gas-ifiers can be limited to screeningtests for most streams. Detailedanalysis is necessary only forthose streams or stream compo-nents with previously identifiedtoxicity. This practical researchhas established that (1) the muta-genicity of organic compounds islimited principally to chemicalscalled the higher molecular weightpolynuclear aromatic hydrocar-bons, making it necessary tostudy and characterize the toxicityof less than 1 percent of thematerial found in most processstreams, and (2) the more volatilehydrocarbons found in the pro-cess stream (e.g., naphtha with upto 1000 tons/day output) do notcontain new toxins, need notcome under Toxic SubstancesControl Act regulations, and thuswill not require extensive tox-icological study.

This means that it should bepossible to design facilities torecover these commerciallyvaluable chemicals rather thanburn them as in-plant fuels or todispose of them as waste mate-rials. The evaluation of processstreams for toxins has also beengreatly simplified by the develop-ment of sophisticated proceduresfor separating the complex coal-derived products and isolating andidentifying toxic chemicals. Newinstruments for vapors and iiquids

,

~ave been developed and field-tested for monitoring confam-‘nation by polynuclear aromaticHydrocarbons in the workplace.These instruments provide aSimple method for directlywaluating exposure and canmonitor the effectiveness o’Fmitigating procedures, whichis almost impossible without suchinstrumentation.

Ecological studies have indicatedthat the effects of atmosphericemissions on vegetation decreasewith decreasing humiclity. Thus,judicious site selection criteriacould yield economies, in emissionControl requirements without sac-rificing air quality.

Evaluation of environmental con-trol technologies has provicled in-formation that will permit healthand safety considerateions to be in-corporated in process design. In alow-Btu industrial gasifier, com-mercially available cleanupdevices have been shc)wn to beeffective in removing materialsof health and environmentalconcern. On the other hand,solvent extraction of wastedwater from tar-producing gas-ifiers does not completely re-move all products of potentialconcern; further treatment maybe required before discharge tothe environment. Similarly,leaching of the large amount ofsolid waste produced in acommercial-scale facillity might inthe long term have adverse en-vironmental effects even thoughthe concentration of toxins in thewaste is low.

As a result of the knowledgegained through this program, thescope of health and environmentalstudies required at any future full-scale commercial facilities will begreatly reduced, information ontoxic substances and their loca-tion in the product or wastestream is avai Iable, validatedmethodologies are avi~i Iable forobtaining meaningful data,sophisticated procedures for ~isolating and identifying toxinshave been developed, and many ofthe problems that can beprevented by careful plant designare known.

Coal Liquefaction Less costlytechnologies can be used to con-trol the toxic side effects of coalliquefaction processes while stillmeeting health standards likely tobe established for the direct coalliquids industry. The carcinogenicand mutagenic activities of coal-derived liquids from numerous li-quefaction processes occur onlyin a fraction of the liquid productand can be reduced through proc-ess modifications.

HMOW In the early 1970’s, interestin producing liquids from coal asa means of reducing United Statesdependence on foreign oil sourceswas heightened. However, thepossibly deleterious effects (e.g.,lung, skin, and scrotal cancers) ofcoal processing and, perhaps, pro-ducts were known to both in-dustry and Government agenciesinterested in developing coal li-quefaction processes. Great carewas taken in research anddevelopment (R&D) facilities tominimize the exposure of workersto process stream materials. In ad-dition, careful medical surveillanceprograms were carried out tomonitor the health of workers inpilot plants. Concern by industryand Government regulatory agen-cies led to preliminary commercialplant designs that would reducethe exposure of workers to all pro-cess stream materials and fugitiveemissions. However, there werelingering concerns that excesscosts were being incurred in safe-ty systems and that equal or bet-ter worker safety could beobtained in a more cost-effectiveway.

To obtain the data necessary toevaluate the potential healthimpacts of coal liquefaction, abroad-based research program wasundertaken to examine materialsfrom a number of different coal li-quefaction processes. Substantialeffort was directed toward usingsimple tests to screen for possi-ble carcinogens and mutagens.Other studies investigated the oraltoxicity and teratogenic potential,or the ability to cause fetal malfor-mations, of the materials.

Benefits The tests demonstratedthat coal liquefaction products

with boiling points below approx-imately 650 “F were not activebiologically. This was true whenthe tests measured mutations inmicrobial changes in cells takenfrom mammals. Further examina-tion showed that both the. mutat-ions and cancers observedresulted from fractions boilingabove the 650 “F to 700 “F range.Moreover, the rates of occurrenceincreased markedly in fractionsthat boiled above 800 “F.

It appeared, therefore, that miti-gating procedures might be applied to a more limited set ofmaterials than had been previous-ly thought possible, with corre-sponding cost savings. For.example, for a SRC-11(Solvent-Refined Coal) fuel oil blend (withboiling points ranging from 350”Fto 900”F), materials boiling above700 ‘F represent about 25 percentof the total mass of material inthe blend, and materials boilingover 800 “F represent less than 10percent. Thus, only the heaviest10 to 20 percent of the productstream required treatment. It alsoappeared that hydrotreatment, acommon petroleum-refining in-dustrial process of hydrogenationusing catalysts, might be effectivein neutralizing the biologically ac-tive materials. Studies using theAmes assay or mammalian celltransformation assays indicatethat hydrotreatment is effective inreducing the biological activity ofcoal-derived liquids. Skin-paintingstudies demonstrated thathydrotreatment dramaticallyreduces the potential for causingcancer.

This research also led to the defi-nition of components acting aspotential agents causing skincancer. These are tentatively iden-tified as compounds known aspolyaromatic amines (PAA) andpolynuclear aromatics (PNA).Although test data are incomplete,they provide a basis for morespecific monitoring and the devel-opment of more reliable criteriafor preventing worker exposure topotentially cancer-causingmaterials.

Research results also have an in-fluence on the conceptual market-

ing strategy for coal liquids. Aninitial approach was to market thehigh-boiling materials as boilerfuels. As a result of the research,a second strategy has been iden-tified, namely to market productswith boiling points below 750”Ffor use without further treatment.Under this approach, the higherboiling materiais wouid be con-sidered for use as in-piant energysources or as candidates forhydrotreatment to iower their boii-ing points.

The substantial difference be-tween the capitai and operatingcosts of hydrotreating aii versuspart of the materiai with high boii-ing points (heavy distiiiate) pro-vides the basis for quantifying aportion of the potentiai benefitsassociated with OH ER research.Four sets of capitai and annuaioperating costs deveioped by theChevron Research Company forthe SRC-ii process (a nominai50,000-barreis/day piant) werestudied, inciuding hydrotreatingthe whoie heavy distillate andhydrotreating oniy that fraction ofthe heavy distillate boiling above750 “F. For the Phase Zero design,SRC-ii produces about 11,000 bar-rels/day of heavy distillate prod-uct. Materiai boiiing above 750 ‘Famounts to 2700 barrels/day. Theestimated cost savings per yearfor a single SRC-11piant vary from$98 to $174 miiiion for capitaicosts and from $7 to $14 miiiionfor annuai operating costs. Theprojected cost savings per barreiof product produced are in therange of $0.69 to $1.14.

Risk Anaiysis Risk anaiysis is asystem of principles, practices,and procedures that uses the in-formation generated in scientificexperiments to estimate thepotential heaith and environmentaiconsequences of man’s activities.It is this measure, a probability orchance of an effect occurring, thatis needed by poiicymakers, regula-tory bodies, and insurance groupsto formuiate goais, criteria, andstandards. Such estimates haveproved particularly usefui whereatmospheric particies pose theprincipai concern, as in the ex-hausts of automotive dieseis and

19

>Iectric power plants. Moreover,vhat began as developing meth-]ds for estimating the health ef-ects of particles and sulfates‘ounctapplication in a wide rangeIf analyses of the risks of other]ollutants.

Fva/uafion of Health Risb frvm~tmospheric Particles A com-xehensive body of information is>eing developed to evaluate thelealth risks associated with thenhalation of atmospheric particles“eleased from energy-relatedndustries.

rhe human health risks associated~ith exposure to atmospheric)ollution depend on many factors,ncluding the physical and chem-cal composition of the pollutants,:heir transport and transformationn the environment, the amounts:hat may be inhaled or ingested bylumans, and their toxicity. DOE-wpported research is playing anmportant role in identifying the>ollutants of greatest concern, thenanner in which they can enter:he body, and their potential for>ausing adverse health effects.rhe research provided methods forcharacterizing and evaluating>missions from different types of>oal combustion plants, coal con-version processes, oil shale recov-try, and the use of petroleumfuels in diesel and gasolinemgines. In some cases, new in-Nruments were invented, forsxample, a family of particlesamplers for use under normal at-mospheric conditions and at hightemperatures and pressures. Newtechniques were also developedIor chemical fractionation andidentification of pollutants and for~haracterization of their toxicities.

WsforyWork dealing mainly withradioactive aerosols began in thelate 1950’s at the University ofRochester, PN L, and the LovelaceFission Product Inhalation Labora-tory (now the Inhalation ToxicologyResearch Institute). This researchwas expanded after 1970 to includestudies of aerosol particles origi-nating from many different energy-producing, consuming, and con-servation activities. These studieshave examined the ranges of parti-cle sizes that can be inhaled by

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humans and test animals, toascertain the fractions that de-posit in the respiratory tract, andthe potential mechanisms of theirtoxicity. Several such studies arenow under way but will requireseveral years to complete becauselifetime observations of largegroups of laboratory animals ex-posed to the toxic substances arenecessary.

Each research project evaluates asingle energy technology and esti-mates the risks resulting fromhuman exposures to its products,by-products, and waste products.This research integrates diversetypes of information, most ofwhich has been developed in DOE-supported health and environmen-tal research programs, on pol-lutant sources, characteristics,movement through the environ-ment, human exposures, andhealth effects. These analyses areexpected to provide the informa-tion necessary for cost-effectiveregulation of future energy indus-tries, including models of expo-sure and risk from atmosphericparticulate.

At present, the estimation ofhealth risks from particles emittedby energy technologies is a compl-icated and uncertain processbecause of incomplete informationregarding which components of at-mospheric articulate matter aretoxic and may cause illness ordeath in humans. As the toxicityof atmospheric particles becomesbetter understood, this informationcan be combined with knowledgeof the atmospheric dispersion ofparticles to decrease the uncer-tainty involved in projecting thehealth risks that energy technol-ogies might pose to the generalpopulation.

BeneMs Two major benefits ofresearch to evaluate the healthrisks associated with exposureatmospheric particles follow.

to

1. Development of the scientific imformation base. The fossil fuelsresearch program has focusedmainly on characterizing emis-sions from electricity-generatingpower plants and light-duty vehicles used in road transportation,

2.

These two categories of energyuse account for nearly 50 per-cent of the emissions of regu-lated pollutants in the UnitedStates. The physical and chem-ical characteristics of theseemissions are now well known.

The research program has alsocontributed greatly to an under-standing of the depositicm,retention, and health effects ofatmospheric pollutants in gen-eral. It is now known that futureregulations should be aimed atcontrolling respirable-size par-ticles, that is, those with aero-dynamic diameters below 10microns. It is also known thatsulfur dioxide emissions con-tribute greatly to the formationof sulfate particles, which aremostly in the small respirableparticle-size range. Automobileemissions have alsm beenshown to be respirable. Thisknowledge, along with the rank-ing of the toxicity of variousrespirable particles., is crucial tothe development of cost.effective pollution controlguidelines.

Development of atmosphericdispersion models. An importantaspect of evaluating the healthand environmental impacts ofnew pollution sources is pro-jecting the atmospheric concen-trations of pollutants in nearbypopulated areas. This must beaccomplished before new indus-trial sources are permitted.Mathematical models have beendeveloped for projecting the at-mospheric dispersion of pollu-tants; an example of theseefforts is the Handbook on At-mospheric Diffusion publishedin 1982 (Steven R. Hanna et al.,DOE/Technical InformationCenter, DOE/TIC-11223). Al-though the value of theseresearch programs lies in thedevelopment of new knc)wl-edge, it appears reiasonalbleto assume that the enforce-ment of air quality standardswould be on a “trial-and-error I

basis” if acceptable means ofprojecting environrnental disper-sion of pol Iutants ‘were notavailable.

Evaluation @ Pubiic Heaith Risksfrom’ Diese[ Engine Exhaust Thepublic health risks associated withexposure to diesel engine exhaustwere evaluated based on informa-tion on the physical and chemicalcharacteristics of diesel engine ex-haust, the transport of particlesand gases in the atmosphere, andthe potential health effects ofdiesel emissions. Health riskswere stated in terms of the in-creased probabi Iity of personsliving in congested urban areasdeveloping chronic respiratorydiseases or cancer. This risk eval-uation is being used to focusrelated health effects research pro.grams on areas where uncertain-ties remain about the effects ofemissions from light-duty dieselvehicles.

History The attraction of diesels islargely that they achieve 10-25percent higher fuel efficienciesthan equivalent-sized gasolineengines and, thus, can make animportant contribution to reducingU.S. dependence on foreignsources of oil. However, becausecurrent diesel engines emit morevisible smoke and odors thangasoline engine vehicles, concernhas been expressed that they mayalso involve new health risks. in-deed, particles emitted by dieselengines have been found to con-tain small amounts of knowncancer-causing chemicals, whichalso have been shown to be muta-genic when tested in cell cultures.These particles are small enoughto be inhaled by humans and de-posited in the lungs. Althoughthese are both signs of a potentialhealth risk, epidemiological stud-ies of workers who were exposedto high concentrations of emis-sions from diesel buses ingarages showed no detectable in-crease in lung cancer incidence.

To understand this apparentanomaly, mathematical modelswere used to predict future airconcentrations of diesel exhaustin congested urban areas. Rela-tionships between exposure con-centrations and health risks weredeveloped by combining theresults of short-term bioassaytests, whole-animal studies, andhuman epidemiological studies.

Because human epidemiologicalstudies of workers exposed todiesel exhausts were not sensitiveenough to detect changes incancer rates of the general popu-lation, the mathematical modelsused results of human epidemio-Iogical studies of populations ex-posed to coke-oven emissions,cigarette smoke, and urban soot.All of these represent exposuresto the combustion products offossil fuels that are similar todiesel emissions in their physicaland chemical characteristics.

Overall, the health risk evaluationconcluded that future diesel light-duty vehicles are n“otlikely to in-crease significantly the risks ofdeveloping respiratory diseases orcancer over those already presentfrom atmospheric pollution. Theprojected risks were also muchless than those associated withcigarette smoking or exposure tolevels of cigarette smoke that arecommonly found indoors. Thepotential reductions in health riskthat could be achieved with pollu-tion controls on diesel vehicleswere also evaluated.

Benefits The analysis performedfor OHER is being used to (1)guide the development of researchprograms aimed at directly meas-uring the relationships betweenlevels of exposure and risk, (2)identify populations that may beat greatest risk from future dieselemissions, and (3) formulate cost-effective emission control stand-ards for future light-duty dieselvehicles. The health risk analysiswas incorporated into the Environ-mental Protection Agency’s (EPA’s)summary publication Toxico/ogica/Effects of Emissions from DieselEngines [J. Lewtas, Developmentsin Toxicological and EnvironmentalScience 10, 1982 (Elsevier SciencePublishing Company)].

The health risk analysis indicatedthat if 20 percent of the light-dutyvehicles in the United States wereto use diesel engines, fewer than400 lung cancers/year would likelyoccur as a result of exposures todiesel engine exhaust—even if nofurther emission controls wereapplied to reduce particulate ex-haust. Fewer than 200 lung

cancers/year are projected if theproposed post-1985 emissionstandards reduce current particu-late emissions by about 50 per-cent. This increased incidencewould be a small fraction of the100,000 lung cancers that alreadyoccur in the United States eachyear.

Thus, the research program devel-oping risk analysis for the health“effects of diesel engine exhausthas provided information that canserve as a basis for the cost-effective regulation of vehicleemissions.

Evacuation of Pubiic Heaith Risksfmm Atmospheric Suifates A prob-abilistic health-damage functionthat yielded a “best” estimate forincreased mortality as a result ofexposure to atmospheric sulfateparticles, which included a con-fidence interval expressing therange of uncertainty of the esti-mate, was derived.

History Of the various pollutantsproduced in the combustion of ‘fossil fuels, the chemically trans-formed products of sulfur dioxideand atmospheric sulfates havebeen of particular concern withrespect to potential increases inhuman mortality. Numerous epi-demiological studies have beenconducted, generating a broadrange of sometimes conflictingresults. These studies wereassessed for scientific validity andthen aggregated into a singleprobabilistic function that ex-presses the uncertainty of the in-formation available.

This probabilistic health-damagefunction has now become stand-ard in the air pollution health im-pact literature, and the generalmethodology has been extendedto a broad range of risk assess-ment and policy analysis applica-tions. The function has served asan important tool in educatingpolicy makers and the generalpublic regarding the potentialhealth impacts of future emis-sions. A recent state-of-the-artassessment of fossil fuel combus-tion stated that the probabilisticfunction might be regarded as thebest available indication of the

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magnitude of the effect of air pol-lution on health. In addition, thefunction was selected by the Of-fice of Technology Assessment foruse in estimating the health ef-fects of sulfur dioxide emissions.

f?eneflts Concern about the healthand environmental impacts ofsulfur dioxide emissions has beenevident in bills placed before theUnited States Senate. One suchbill required a reduction of sulfurdioxide emissions from about 22.5million to 12.5 million tons/year inthe states bordering on and eastof the Mississippi River (a reduc-tion of about 45 percent of 1980emissions), while another requireda total emissions reduction ofabout 8.2 million tons annually inthese states. Although these billswere aimed primari Iy at reducingthe environmental damage causedby acid rain, they also have impli-cations for human health. In re-sponse to these bills and hearingson revision of the Clean Air Act of1970, the Office of TechnologyAssessment prepared a technicalreport for Congress on sulfur diox-ide emissions. The health impactsportion of that report is based onthe probabilistic sulfate/particledamage function. The cost of theemissions reductions specified inthe first bill was estimated torange from $3.9 billion to $4.9billion/year (1981 dollars) and thecost of the second bill to rangefrom $2.6 billion to $3.1 billion/year. In a separate study the Con-gressional Budget Office esti-mated that simply maintainingcurrent sulfur dioxide emissionsstandards would cost $36.5 billion(1981 dollars) in capital costs and~05&billion in annual operating

To bring these numbers into per-spective, the probabi list ic sulfatedamage function was used to es-timate the health impacts of bothbills. The reduction in excessdeaths that might result from areduced level of emissions wascalculated along with the invest-ment costs required to meet thereduced levels. The cost per deathaverted was found to vary in the90 percent confidence range, from$59,000 to infinity, with the medianat $180,000 to $230,000.

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With a method available to quan-tify potential sulfate healtheffects, both proponents andopponents of emissions-controllegislation are able to generatewidely varying, but defensiblehealth-impact estimates to supporttheir respective positions. Generalacceptance of the probabilisticdamage function enables decisionmakers to place extreme estimatesin perspective and provides themwith a common basis for compar-ing alternate regulatory optionsand approaches.

Responding to HazardousEventsEvents in recent years,such as the reentry of Cosmos942 and the atmospheric testingof nuclear weapons by foreignpowers, have led to the develop-ment of a capability to react tosuch possible emergencies andevaluate their consequences. Twocomplementary systems that pro-vide such a capability were devel-oped under the OHER researchprogram and are operational today.Both were initiated in the 1960sbecause of concern about falloutfrom atmospheric testing ofnuclear-weapons.

Atmospheric Release AdvisoryCapabMfyThe ARAC is a vali-dated system for predicting thetransport and dispersion of sub-stances released into the atmos-phere. ARAC provides real-timeanalysis and interpretation ofthe dispersal of atmosphericreleases of potential Iy harmfulsubstances that are used tosupport on-site decisions. Outputcontaining position- and time-dependent concentrations isprovided by telephone lines touser terminals, telecopiers, andcomputers.

ARAC can independently predictthe dispersion of materials re-leased simultaneously fromseveral locations. The real-timeestimation results from a predic-tion of the concentration of thetoxic material in the atmosphere.ARAC includes (1) the ability touse a variety of dispersion modelsthat range from complex to sim-ple; (2) the capability to includeterrain effects; (3) a centralizedcomputer facility with access to

terrain data for any’ location in theUnited States; (4) the ability to useterrain information from outsidethe United States; and (5) accessto real-time data on local weatherconditions and winds {Noft.

Inputs to ARAC are (1) the types ofsubstances released, (2) the quan-tities of material released overtime, and (3) the altitude of therelease. If these factors are notknown quantitatively, preselectedapproximations can be usecl incalculations. With these inputs,supplemented by current meteoro-logical data and the internall ter-rain data base, ARAC can initiateits predictions. The AFIAC systemis activated through direct re-quests from ARAC sites anc~through DOE headquallers fornon-ARAC sites.

Those users who are dlirectlyconnected to the ARAC systemare able to make fastelr and moreaccurate predictions. LLsercostsvary according to equipmentavailability, software, and interfacebut generally range from $10,000to $55,000 (not including man-power costs) for initial install-ation and 4 to 5 months ofoperation.

Wsfofy The ARAC project wasinitiated as a result of AEC~ con-cerns regarding the fate of radio-active debris from nuclear tests inthe 1960’s. Originally, the projectfocused on fallout and Iong.rangetransport and diffusion (thousandsof kilometers) to ensure that theUnited States did not violate inter-national agreements by nucleardebris from the Nevadia Test Sitecrossing National boundaries. Thiscapabi lity was improved, verifiedby measurements, and expandedto include real-time predictions.

In 1972 the AEC decidled todevelop a real-time assessmentcapability for accidental radioac-tive releases from industry. TheARAC project was initiated byLawrence Livermore NationalLaboratory (LLNL) in 1!373.Current-ly, ARAC is being upgraded tostate-of-the-art technology, and thestaff is expanding to 24-hourcoverage for Federal and stateemergency response support,

Benefits ARAC is supported direct-y b~ subscribers who are con-;erned about both nuclear andIon-nuclear releases. ARAC’S sub-scribers include the followingagencies:

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DOE. Several DOE sites are tieddirectly to the ARAC system:Savannah River, Rocky Flats,Mound Laboratory, LLNL, andSandia National LaboratoriesLivermore (SNLL).Department of Defense (DOD).DOD was scheduled to haveabout 50 sites tied into ARACby 1984.Federal Aviation Administration(FAA). The FAA found ARAC tobe very responsive in providinginput for the development of airtraffic advisories subsequent toforeign atmospheric nucleartests.Federal Emergency Manaw-ment Admini~tration -(FEMAL FEMA cwovided SUDDOrt

5.

6.

for New York and California “andthe commercial nuclear powerplants at Rancho Seco and ln-dian Point to tie into ARAC.ARAC will be used to providecalculations of estimated dis-persion for use in emergencyplanning.Environmental ProtectionAgency (EPA). ARAC providedEPA with an independent (ver-sus power company) source ofinformation during the con-trolled krypton release atThree Mile Island (TMl) in July1980.Nuclear Emergency SearchTeam (NEST). DOES NEST relieson ARAC for assessments asso-ciated with nuclear extortionthreats.

ARAC provides analyzed informa-tion in circumstances where thepaucity of data could lead deci-sion makers to overrespond,resulting in an unnecessarilyexpensive emergency evacuation,or underrespond, leading to acompromise of public health andsafety. To date almost all of theARAC applications either indicatedno threat to public health andsafety, thereby avoiding unneces-sary evacuations, or were used inmanaging the release to minimizeoverall risk.

\n example of a major benefit ofhe use of ARAC was at the TMImclear power plant. Even thoughrMl was not tied into ARAC, DOEJut the system into service. ARAC~as operational during the first‘ew days of the accident and pro-~ided dispersion calculations tohe DOE Emergency Operations2enter, the DOE emergency-‘esponse site commander, andNuclear Regulatory CommissionNRC) representatives. The ARACcalculations indicated that anwacuation of the population~round TM I was not necessary.rhis evaluation was consistentwith other calculations and recom-mendations; and, therefore, nogeneral evacuation was ordered.14RACalso supplied the FAA withjose calculations for the Harris-~urg airport, which allowed of-ficials to avoid closing the airport.In addition, ARAC was employedto help manage the controlledrelease of radioactive krypton inJuly 1980 by tracking the releaseand advising EPA regarding thebest ground sites for portablemonitors and routes to be flownby sampling aircraft. Good agree-ment was found between themodel calculations and the obser-vations. Fewer monitoring stationswere required because of ARAC’Suse. ARAC was also used in apostaccident detailed analysis ofpopulation dose around TMI forthe President’s Commission onthe accident.

Less tangible but very importantbenefits have been reported byDOE site users. SDecificallv, ARAChas been of great. benefit in assur-ing local, state, and Federal of-ficials responsible for protecting~ublic health that they have anadequate capability tb respond toaccidental releases. Some of theDOE users have conducted publictours of their ARAC site facilities,receiving press and televisioncoverage.

Fallout Forecasting Fallout fore-casting is a system for collectingdata on nuclear detonations, alert-ing users of nuclear events, andproviding forecasts of the atmos-pheric spread of the radioactivedebris. The National Oceanic andAtmospheric Administration

NOAA) is responsible for pro-Iiding the forecasts to users. To‘ormulate these forecasts, NOAAJses meteorological input pri-marily from the Air Force and30E.

rhe detonation of a foreignluclear device during peacetime[riggers a coordinated Federalresponse to ensure maintenance~f public health and safety.Through a multiagency memoran-dum of understanding, the follow-ing responsibilities have been~stablished:

1. NOAA collects data from the AirForce and DOE to develop theofficial fallout forecast; this

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3.

serves as the basis for allpublic announcements on themovement of airborne radioac-tivity and areas of potential rain-out of nuclear debris.The Air Force provides classi-fied data to NOAA on nucleardebris samples, including thelocation, time, altitude, andconcentration of airbornesamples.DOE gathers information on thenature of the nuclear detonation(such as location, time, yield,and height) and reports this in-formation to NOAA for input tothe fallout forecast. DOE alsoprovides NOAA with advisoriesreleased by its ARAC center atLivermore, California. Data col-Iected from radiation measure-ments at DOE facilities aremade available to user agencies.

History OHER has sponsored fall-out research at the NOAA AirResearch Laboratory since 1952.The fallout forecasting system wasdeveloped in response to generalpublic concern about the potentialhazards of foreign nuclear detona-tions. It was a natural outgrowthof the Laboratory’s research in at-mospheric transport and disper-sion, which became the focalpoint of the forecasting when theinteragency fallout response teamwas formally established in 1976.Since that time the fallout fore-casting element of the researchprogram has cost approximately$300,000. OHER currently providesfunding as necessary to maintainits operational status.

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I

ii(I(iiI

I

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Be‘al)f‘ators[iaWIyD(DrFE

‘nefifs The primary benefit of thelout forecasting is its triggeringa network to alert officials in~iation-sensitive industries.ice the news of a nuclear eventreleased, NOAA notifies the Na-mal Association of Photographicmufacturers (NAPM), EPA (usual-a joint announcement with)E), FAA, NRC, the Food andug Administration (FDA), and[MA.

lch organization responds ac-,rding to the needs of its users.merally, the actions taken arewentive in nature. The kinds of~blems prevented and the ac-res taken as a result of the alerttwork and subsequent forecasts> user-specific.

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The photographic industry isconcerned about potentialdamage to sensitive materialsduring manufacture. The mostsensitive are scientific platesand X-ray film. NOAA alertsNAPM, which in turn notifies 16member-plant officials (DuPont,Kodak, 3M, and Polaroid, for ex-ample). If radiation levels risesufficiently, filtered air andwater may be recirculated toavoid contamination from exter-nal sources. Only in the early1950s (from United States tests)has fallout been severe enoughto damage materials and causea production shutdown.The EPA (a) disseminates toFederal agencies and the gen-eral public predictions fromNOAA on pathways of contam-inated air-mass movements overthe United States and areas ofpossible rainout of radioactivematerials and (b) activates thestandby portions of the Environ-mental Radiation Ambient Moni-toring System (ERAMS). EPAalso recommends necessaryradiation surveillance or protec-tive actions to appropriate stateagencies.The FAA uses data from NOAA,the Air Force, and DOE to devel-op air traffic advisories for ap-propriate air traffic controlcenters, airman’s informationcenters, and airlines regardingairspace that should be avoidedbecause of potential or actual

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5.

radioactive contamination.These advisories depend mostheavily on Air Force and ARACinformation.NRC is concerned about thepossibility that fallout may trig-ger on- or off-site monitors atnuclear faci lit ies. Local severeweather following a nuclear testcan cause monitors to showsignificant increases in radia-tion levels that can be confusedwith a radiation leak from areactor. NRC alerts all reactorfacilities and has therebyavoided costly power plantshutdowns that might last fromhours to weeks at a potentialcost of $500,000/day.FDA receives information fromNOAA regarding the probablelocation of fallout contamina-tion and consults with EPA con-cerning radiation surveillanceand protective actions. FDAthen provides guidance to stateand local Governments regard-ing appropriate responses forevaluating and preventinghazardous radioactive contami-nation of foods and animalfeeds, as well as guidance onthe control and use of suchproducts should they becomecontaminated.

Detection andMeasurement ofHuman Health Effects

No area of science can developvery far without special tools,methods, and instruments. Duringthe early stages of a science,observation with available instru-ments is usually sufficient. Atsome point, it becomes necessaryto measure events that have notbeen measured before. A new tech-nology often provides the meansof developing new, more efficientor more cost-effective instrumentsthat find applications outside theoriginal thrust of the research.

The instruments developed inOHER programs have found spe-cialized applications in hospitalsand clinical laboratories, researchlaboratories, Government, and in-dustry. They have brought trueautomation, as opposed to mech-anization, to the areas of cell

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counting and blood:chemistryanalyses. The methods and pro-cedures of short-term bioassays,fast tests for screening materialsfor potential cancer-calusingagents, have revolutionized tthefield of testing new chemicals forpotential hazards.

Instruments originally designed tomeasure radiation doses to biolog-ical systems are now found inoperating power reactcmsandmetal recovery plants, as well asin the delicate interior of electronmicroscopes. The concepts of per-sonal badges and on-tlhe-spotdosimeters are providing new waysto further increase employee safe-ty in chemical processing facili-ties. The United States has a wayto track and measure the path ofdangerous substances relea~sedtothe atmosphere shoulcj an a\cci-dent or mishap occur.

In the 1960’s the emphasis of en-vironmental research shifted tothe support of a civilian nuclearindustry, and research efforts weredirected toward perceived prob-lems of nuclear power plani:s.Although all types of power plantsrelease heat to the rivers used tosupply their cooling water, 1he ef-fect of the increased heat releasesfrom the Iaraer nuclear Dowerplants need;d to be understood.Plans to construct ocean-ccioied,off-shore reactors focusedresearch on the Continental Shelfand near-shore areas amd providedvaluable information for norl-nuclear energy development, suchas ocean thermal energy conver-sion (OTEC), and information nec-essary to evaluate ocean wastedisposal. Research in the c!/clingof transuranic elements (man-made elements heavier thanuranium, primarily plutonium) inthe environment turned to the con-cern about their potential uptakeby crops such as wheat, corn, soy-bean, and root crops.

Efforts to understand the innpactof radioactive materials inadver-tently introduced into the ecosys-tem by nuclear bomb tests led toa clearer understanding of howecosystems operate. The ccm-trolled use of radioisotopes tofurther this understanding has

incre~ed our knowledge of thefate of nonradioactive hazardouswaste, the metabolism of plants,and many other subjects.

The extremely high detectability ofradioactive atoms makes themeasy to trace as they movethrough nature’s cycles andmigrate from one place to another.Their known decay rates, decayproducts, arid ratios have led togreater understanding of physical,biological, and climatic processesover whole ecosystems and ofbiological and life processes atthe microscopic level. This use ofradioactive tracers enabled man tounderstand the process of photo-synthesis vital to plant growth andfood production.

In the 1970’s health and environ-mental research in AEC and itssuccessor agencies broadened tosupport all energy sources anduses. Basic research on toxic sub-stances and cancer-causingagents focused on applying knownmethods to new substances. New,unique concerns, such as reclaim-ing of land affected by stripmining, were brought forward tobe addressed and solutionsidentified.

Cell Sorting and Blood AnalysisTwo devices for biological analysiswidely used in laboratories, hos-pitals, and clinics are the flowcytometer and the centrifugal fastanalyzer. The flow cytometer wasdeveloped in 1965 to distinguishcells damaged by radiation fromnormal cells. Since then, the meth-ods used for cell sorting and theirapplications have continued to in-crease. Today the flow cytometeris used routinely for performingcomplete blood counts (its great-est single application), detectingcancer and monitoring its treat-ment, detecting genetic abnor-malities, and isolating specificchromosomes for analysis of theirgenetic composition.

The centrifugal fast analyzer alsohad its beginnings in the searchfor tools to measure radiation ef-fects in humans. The analyzer,which exploits advances for proc-essing uranium made in centrifugetechnology in the 1960’s, can

handle a large number of samplesfor automated analysis simultane-ously. It is used principally to testblood and other body fluids fordiagnostic purposes.

Flow Cytometry The flow cytom-eter characterizes and sorts in-dividual cells, permitting themeasurement of cellular propertiesand changes in those propertieson an individual rather than on apopulation-average basis. The cellsare suspended in a fluid dropletstream flowing past one or moreoptical or electronic sensors thatmeasure cel I characterist its.Typically, for characterization, acell is stained with ‘a fluorescentdye and passed through a focusedlaser beam. The fluorescent lightemitted from the cell is analyzedand recorded. Cell sorting is arelated procedure in which drop-lets with particular characteristicsin the stream are charged elec-trostatically and then diverted.This separates relatively purepopulations of the selected cellsfrom the main sample.

The advantages of flow cytometryand cell sorting over other tech-niques include:

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Rapid analysis of single cellsand subcellular components(10,000/second versus about100/minute with a microscope),Statistical analysis of largenumbers of individual cells,Rare cell identification (one cellin 10 million can be detected),Greatly enhanced resolution(the 9 percent difference in theDNA content of human maleversus female cells can bemeasured),Simultaneous analysis of manyparameters of individual cells,andSorting of selected cells atrapid rates.

HlstoryThe first device capable ofseparating biological cells wasdeveloped in 1965 by M. J. Fulwy-Ier at Los Alamos National Labora-tory (LLN L) as part of researchinto the effects of plutonium radia-tion. The flow cytometer wasdeveloped to provide a means ofrapidly scanning for and separat-ing cells damaged by radiation.

Further developments in theanalysis of cell populations werebased on optical phenomena suchas absorption, light scattering, andfluorescence. The first sorterbased on fluorescence analysiswas developed in 1972. Almostsimultaneously, a multiparametercel I/particle separator was devel-oped. Recent developments in thefield of flow cytometry and flowsorting have stressed the use ofnew or improved sensors for cellphysical and chemical properties.Analytical capabilities such asthe development of low-resolutionmorphological information (celland nuclear size, chromosomelength, and location of thechromosome constriction) offerthe potential to detect impor-tant genetic defects and low-Ievel background mutationalevents.

Since 1964 at Los Alamos and1972 at LLNL, flow cytometry” R&Dhas totaled about $6.5 million(1982 dollars).

Four companies currently offerflow cytometry systems at anaverage cost of about $100,000 persystem. The number of instru-ments in place is estimated at350. All companies contactedbelieve that there is a stronggrowth market for flow cytometersand are investing in newdevelopments.

llenefifs The flow cytometer cellsorter, originally intended toseparate radiation damaged cellsfrom normal cells, has been usedextensively as both a biologicaland clinical research tool. Its ma-jor commercial potential, however,lies in its capability for automateddiagnosis and economical popula-tion screening in the fields ofhematology, immunology, cancer

I diagnosis, and genetics.

More recently, improvements inthe method have permitted thecreation of a chromosome-specificDNA library which scientistsbelieve will advance the course ofhuman genetics by a decade; anadvance which will certainly be amajor step forward in the diag-nosis and treatment of geneticdiseases.

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cC(indirOisar

lfemato/ogry. Complete bloodcounts, which are performedroutinely in the clinical labora-tory, represent the single largestcurrent application of flowcytometry. Several dedicated,single-purpose commercial ma-chines have been developed forthis purpose. Reticulocyte andplatelet counting are examplesof two recent developmentsthat are moving immediately in-to the clinical consultinglaboratory. The efficacy of diag-nosis and radiotherapeutic andchemotherapeutic treatment ofleukemia is being assessed byflow cytometry./mmuno/ogy. The clinical signif-icance of circulating mono-clinal B-lymphocytes in non-Hodgkin’s Iymphoma hasrecently been demonstrated.Accurate monitoring of new pa-tients and those in remission isbeing performed, and definitivemarkers useful in determiningthe results of therapy and theprognosis for relapse have beendeveloped.Onto/ogy. Considerable efforthas been directed to modifyingthe basic flow cytometric in-strument to allow automation ofPap smear analysis for detect-ing cervical cancer. The ob-jectives are to reduce costs,increase the information con-tent ,and statistical reliability ofthe tests, and increase thenumber of early detections.Genetics. Several genetic abnor-malities involve chromosomeduplication beyond the normalhuman complement of 46 chro-mosomes. Flow cytometry isused not only to detect thesegross changes in the number ofchromosomes, which typicallyresult in severe mental retarda-tion, but also to detect moresubtle polymorphic events thatpromise the first means of diag-nosing several inheritablediseases.

enirlfugal Fast Analyze~ Themtrifugal fast analyzer is anstrument used for medicalagnostic purposes to performIutine and special blood chem-try tests in hospitals, clinics,Id research laboratories.

The centrifugal -fast analyzer testsmultiple samples simultaneously.It is built around a flat rotor withnumerous sets of wells arrangedradially. Measured quantities ofthe samples and reagents are in-troduced into individual wellstoward the center of the rotor.Centrifugal force mixes each sam-ple and its reagent and movesthem into transparent reactioncells at the periphery of the rotor.During each revolution a time-synchronized measurement ismade of light transmittance, color,fluorescence, or other relevardproperty. The course of the chem-ical changes in each reaction ceilis monitored by an on-line com-puter, and analytical results aredeveloped simultaneously for allsamples on the rotor. The result-ing data are stored, interpreted,and provided to the laboratorytechnician very rapidly. One runof the analyzer performs thesame analysis on from 1 to 42samples.

H/sfory R&D of the centrifugal fastanalyzer was an outgrowth of Na-tional Laboratory expertise inbiological sciences and separa-tions science. The original fundingfor the project was shared by theNational Institute of General Med-ical Sciences and the AEC. Theoriginal name of the device, GeM-SAEC, is an acronym of these twocontributors. The National Aero-nautics and Space Administration(NASA) provided support from 1974to 1976 for a zero-gravity cen-trifugal fast analyzer. Invention ofthe centrifugal fast analyzer is at-tributed to Dr. Norman G. Ander-son while he was Director of theMolecular Anatomy Program atORNL in 1968.

The original GeMSAEC systemreceived the Industrial ResearchMagazine 1R-1OOAward as 1 of the100 most significant new tech-nical products of 1969. A second1R-1OOAward was awarded in 1977for the portable, miniaturized, cen-trifugal fast analyzer developed atORNL.

Transfer of the analyzer to industryoccurred very rapidly. In late 1968and early 1969, representatives ofElectro-Nucleonics, Inc., Union

Carbide Corporation, and theAmerican Instrument Company ap-plied for and were granted royalty-free licenses from AEC to com-mercially produce a centrifuflalfast analyzer. Today, five domesticcompanies sell centrifugalanalyzers. Both industry and DOEresearchers have made major con-tributions to its continued devel-opment analyze~ for example,improved sample handling, minia-turization, and microchemistrytechniques to save reagent costsand laboratory workspace and per-mit improved blood analyses inareas such as pediatrics and geri-atrics, where only small samplesare obtainable.

Benefits Major markets for thle cen-trifugal fast analyzer are hospitalsand laboratories with lc~w-to-medium dai Iy test volumes. Theseinclude small-to-moderate-sizedhospitals, specialty laboratories inlarge hospitals, and commerciallaboratories. Major advantages ofthe centrifugal fast analyzer are it~throughput capacity, flexibility toperform any type of assay, concurrent ability to perform economical-ly single tests and batches clftests, and ability to perform lemer-gency tests. At the time of its in-troduction, the centrifugal fastanalyzer represented a :25to 50percent cost savings over thediscrete analyzers then available.The centrifugal fast analyzer alsorepresented an 80 percent cc~stsavings over the manual methodsthat predominated in srnall-to-medium-sized hospitals, Then, asnow, existing continuouls-flowanalyzers perform a fixed balteryof tests (a “profiIe”) for less costthan a centrifugal analyzer, butthis economy is only ok)tainable bya laboratory that has a Ihighenough volume of tests to justifypurchasing the larger, more expen-sive continuous-flow instrument.

The significant benefits arisingfrom the development of cen-trifugal fast analyzers include:

1. Introduction of true automationto clinical chemistry (as differ-ent iated from mechanization);

2. Improved precision fcw certaintests, thus eliminating the needto retest;

26

3. Availability of test techniquesnot .~eadily avaiIable wit h otherequipment;

4. Data reduction in “real time” us-ing an on-line computer

5. Flexibility to serve institutionshaving small-to-medium testingloads; and

6. Cost savings to users.

Sales of the centrifugal fastanalyzer are estimated by industrysources to be at least 500 units/year, amounting to approximately$25 million/ year. Industry sourcesindicate that the current numberof centrifugal fast analyzers inoperation is about 4000 in theUnited States and as many as10,000 worldwide at purchasedprices ranging from $20,000 to$70,000. While there are no sta-tistics on the number of tests per-formed with the analyzer, twoestimates are available: (1) approx-imate y 175,000 tests per year peranalyzer and (2) 10 to 25 percentof the 2 to 4 billion clinical chem-istry tests performed in a year,probably closer to 10 percent ofthe total tests.

Owners indicated that they save 10to 30 cents/te’st performed on cen-trifugal fast analyzers, mostly inreagent costs. Applying these fac-tors to 300 million tests/yearyields the estimated savings of$30 to $90 million/year.

Fasf Tesf for Cancer=CausingChemicals Short-term cell bio-assays are used as inexpensive,fast screens prior to more costlyanimal tests in screening chem-icais for cancer-producing or ceii-aitering characteristics. A numberof tests are included within thescope of short-term ceii bioassays.

One of the most wideiy used is atest using speciai strains of thebacterium Sa/mone//a deveiopedby Dr. Bruce Ames of the Universi-ty of California at Berkeiey. Theuniqueness of this test invoivesthe use of a mutant strain of thisbacterium that is unabie to pro-duce the amino acid histidine,which is necessary for its repro-duction. if the chemicai beingscreened causes the organism toundergo a genetic change thataiiows it to produce histidine and,

therefore, reproduce itself, thenthe chemicai is considered amutagen and potentiai cancer-causing agent. The mutationalpotency of the chemicai undertest is expressed in terms of thenumber of growing bacterial col-onies that are observed after aperiod of incubation. The equip-ment required is minimai and asingle technician can perform anumber of tests in a day.

Because a negative Ames testdoes not absolutely ensure that acompound is inactive in humans, a“tiered” strategy in which the nextieveis of testing may include mam-malian ceils in tissue culture andacute animai studies is oftenemployed. Although not quite assimpie or inexpensive as theAmes test, such assays are stiiiorders of magnitude quicker andcheaper than iong-term, whoie-animai testing.

Chromosomai aberration andsister chromatid exchange meas-urements are common bioassaysperformed with cuitured mam-maiian ceiis. These assays are runeither on ceiis grown in tissuecuitures or on bone marrow ceiis,spermatogonia (a ceii structurethat precedes development of asperm), or lymphocytes (a whitebiood cell formed in lymph nodesand severai other organs) from ex-perimental animals and humandonors.

lffstory Although short-term cellbioassays are most commoniyused for measuring the responseto chemicai agents, the majoritywere deveioped from radiationstudies sponsored by OHER. Theirroots iie in two areas of investi-gation in radiation biology—chromosomai effects and genetictoxicology.

Scientists in the OHER-supportedlaboratories were the first toreaiize that the induction ofchromosome aberrations—otherthan normal changes in genesmanifested as mutations causedby the abnormal breaking and re-ioining of chromosomes—couidbe used as a biological dosimeter.This was first demonstrated by ex-posing cells from a plant that is

extremely sensitive to radiationdamage to radioactive ciouds dur-ing the atomic bomb test, Opera-tion Greenhouse, in 1951. Later itwas found that chromosomai aber-rations in lymphocytes couid alsobe used to measure dose. Addi-tional studies, combined with ad-vances in the science of somaticceii genetics, were instrumental indeveloping the mammalian cellassays noted above.

Genetic toxicology—the study ofthe nature, effects, and detectionof radiation and chemicais ongenes and, thus, on the character-istics passed from one generationto another—is a new fieid of sci-ence that developed from thediscovery of DNA repair. Studiesby Rasmussen and Painter at theRadiobioiogicai Laboratory, Univer-sity of California at San Francisco,in the 1970’s demonstrated thatexposure to radiation (and othertoxins) caused some DNA to un-dergo unscheduled DNA (repair)synthesis (UDS), and that this UDSis quite separate from the normaisynthesis p,ocess in DNA. Thisobservation forms the basis of thecommoniy used UDS assay. Theabiiity to construct and character-ize bacteria with deficient DNA-repair mechanisms was a cruciaistep on the path to the Ames test.

Beneflfs The testing of new prod-ucts using short-term ceii bio-assays has resuited in reducedcosts and increased productivity.Many different new substanceshave been created and introducedto the environment in recent years,some of which have the potentialto cause genetic damage. Beforethe early 1970’s, animai testingwas the only accepted means ofevacuating a substance for car-cinogenic activity. With the adventof the Ames test and other short-term ceii bioassays, however, ithas become possibie to test sub-stances for mutagenic or carcino-genic potentiai far more rapidiyand cheaply. The Ames test, forexampie, presentiy costs $1000 to$1500 and takes only 48 hours.These bioassays are used routine-ly by many drug and chemicaifirms to screen substances forpotential mutagenic activity before

27

arge expenditures are made to de-felop them into marketablexoducts.

4 measurable benefit of the Amesand similar tests is the amount of,money manufacturers save bywoiding the development of po-tentially hazardous products. Be-cause drug and chemical firms arethe most active users of short-term bioassays, a very rough esti-mate of benefits can be developedbased on calculating the amountof development money saved as aresult of

A=

uVhere

A=D=

Fm =

T=

prescreening:

(

DxFm _Tl–Fro )

net annual benefits,annual R&D outlays bydrug and chemical firms,fraction of compoundsshelved as potentialmutagens, andannual cost of bioassays.

An estimate of the annual R&Doutlays by drug and chemicalfirms is contained in the NationalScience Foundation publicationResearch and Development in in-dustry 1979. The figure is $1.99billion in 1979, or about $3.3 bil-lion in 1982 dollars. Based on aninformal survey of a number offirms, 5 percent appears to be afair estimate for the fraction ofcompounds found to be potentialmutagens. Dr. Ames estimatedthat over 3000 laboratories world-wide use his test routinely, result-ing in an estimate of $35 millionto the annual cost of bioassays.This results in an estimated an-nual cost savings of some $140million/year in 1982 dollars.

Use of these low-cost tests toscreen existing products that havenever been examined for muta-genic potential represents a poten-tial future benefit. Thousands ofman-made compounds are current-ly in use. To date EPA has inven-toried under the Toxic SubstancesControl Act over 60,000 such com-pounds that have never been testecfor carcinogenic potential. Becaus(the present capacity for animaltesting in the United States is lim-ited to a few hundred compounds

28

per year, short-term cell bioassaysare the only feasible means ofscreening these substances.

Analyzing Complex Mixtures forToxic Agents By the early 1960s,existing instruments were reach-ing limits that would adversely af-fect important areas of health andenvironmental research and prog-ress in increasing industrial safety.Two such limits were the inabilityto determine the elemental com-position of nonradioactive mix-tures suspected of containingtrace amounts of toxic materialsand the inability to ascertain theisotopic composition of complexmixtures of radioactive elementssuch as those being encounteredin nuclear reactors and laboratoryanalysis. Solutions to both ofthese problems emerged from theOHER research program. The firstsolution, a semiconductor X-rayspectrometer, has been widely ap-plied to detect pollutants in theenvironment, identify unknown

] materials in the scrap metal andmetal manufacturing” industries,and to locate sites for examinationby electron microscopes. The sec-ond solution, a high-resolutiongamma-ray spectrometer, is com-monly used for identifying theelements in the cooling water ofnuclear power plants that causeradioactivity, logging oil wells,studying distant planets, andanalyzing laboratory samples.

Semiconductor X+ay Spectmm=eter (SXRS)This instrument iswidely used in industry, medicine,and scientific research to deter-mine the elemental composition ofnonradioactive materials. TheSXRS is a member of the family ofX-ray fluorescence spectrometersand is also known as the energy-dispersive X-ray spectrometer.

The SXRS has three primary com-ponents: a radiation source, asemiconductor detector, and aprocessor. The radiation sourcecan be any material or device thatemits X-rays; an isotope of ironthat naturally emits X-rays is fre-quently used. X-rays from thesource are directed at the sampleto be analyzed, causing the sam-ple to emit other X-rays. The semi-conductor detector is made of

silicon with lithium adcled (lithium~rifted into it) to obtain the~esired detection capability. When(-rays enter the detector, the‘esulting interaction or ionizationxoduces current pulses that are~irectly proportional to the energyof the X-rays from the sample. Theprocessor, an electronic logic cir-suit, counts the number of pulsesand records the patternl of X-rays,the distribution of measuredmergies. Because each elementemits a unique pattern of X-rays,the elemental composition of thesample is identified. The typicalwtput produced by the processoris a table showing the percentagecomposition of the sample.

History X-ray fluorescence spec-trometers have been in use sincethe 1930’s, when the wavelength-dispersive X-ray fluorescence(WDXRF) spectrometer was devel-oped. However, the WDXRF spec-trometer has limited resolutionand can only analyze one elementat a time. It is, thus, a very costlymethod, particularly when a largenumber of elements must be ana-lyzed. Older methods of cherhicalanalysis, particularly wet chem-istry, which is very slow and de-structive, were still predominant in1960.

Research on alternative methodswas undertaken on a large scale inthe 1950’s in the Unitecl States andother countries. The electronicproperties of silicon and germa-nium were discovered during thisperiod, and the first silicon detec-tor was developed in 1960. Thelithium-drifting process, which per-mitted construction of detectorsthick enough to totally absolrb theX-rays, was developed in 1960 and1961.

These first semiconductor detec-tors provided improved resolutionto distinguish element% but theassociated electronic processorswere too poor to maintain thleresolution. From 1963 to 1969,research to improve the associ-ated electron ics was undertaken.By 1965 a high-resolution SXRSwas developed. During this period,improvements in the detectcrs andfurther development of the entireX-ray detector system also took

I

.

place. New ap@ications were ex-plored as scientists realized thatthe SXRS could potentially beused in industry and medicine inaddition to laboratory analysis.Commercialization of the SXRSbegan in 1965, primarily to univer-sity, Government, and corporatelaboratories. Between 1970 and1973, trace-element analysis im-provements were made atLawrence Berkeley Laboratory(LBL). Improvements were alsomade in the speed of analysissuch that a complete analysis of atypical sample now took less than1 minute.

Approximately 8300 commerciallymanufactured SXRS units arepresently in use in the UnitedStates. Of these, 2500 units arestand-alone analysis systems thatinclude the radiation source,detector, and processor. The usersof these systems fall into threecategories: (1) industry; (2) com-mercial laboratories; and (3) Gov-ernment, academic, and medicallaboratories. The remaining 5800SXRS units are attached to scan-ning electron microscopes.

About 350 of the 2500 stand-aloneSXRS systems are used in thescrap metal, steel and metalmanufacturing, and durable manu-facturing industries. All of theseunits are located in the productionarea and are used as part of theproduction process. Approximately1000 SXRS systems are used incommercial laboratories wherethey are typically one of manyelemental analysis instrumentsused away from the actual produc-tion process.

The remaining 1150 of the stand-alone systems are used both forresearch and analysis of traceelements in patient specimens inNational, university, and hospitallaboratories.

The SXRSS attached to scanningelectron microscopes assist themicroscope in plotting a “map” ofa surface; the elemental composi-tion of each small area is deter-mined separately, and the peaksand valleys are identified. Theseinstruments are widely used inboth commercial and Government/

university/medical laboratories.They are used frequently in qualitycontrol of ball bearings, airplanebodies, and machine parts, as wellas in new materials research.

Eight factors are responsible forthe large number of SXRS units inuse and the wide variety of uses.

1. The SXRS analyzes all elementsof a given sample simultaneous-ly, thereby providing a completeelemental composition of thesam pie.

2. The SXRSS measurement accu-racy is tenths of parts permillion.

3. The SXRS provides informationrapidly, typically in 10 to 30seconds.

4. The SXRS is nondestructive.5. The SXRS is flexible and can be

programmed to analyze singleelements in less than 5seconds.

6. The SXRS can use portabledetector attachments, and eventhe non-portable units requirelittle floor space.

7. The SXRS system requires littleadditional maintenance.

8. The SXRS does not usually re-quire skilled personnel.

Benef/ts The benefits of SXRSdevelopment are twofold: (1) re-duction in the cost of analyzingmaterials compared with otherelemental analysis techniques and(2) availability of information nototherwise obtainable.

The cost savings accumulatedthrough 1982 by industrial andcommercial users provide some in-dication of the benefits of SXRSdevelopment. SXRS users werecontacted and asked to estimatethe 1982 cost savings that couldbe attributed to the SXRS, Averageannual savings for five usergroups—scrap, steel/metals, manu-facturing, commercial (nonre-search), and commercial (R&D)—were estimated to total $88million/year in 1982.

High-resolution Gamma=raySpeohornetry Gamma-ray spec-trometry is a method of detecting,characterizing, and monitoringgamma radiation. The developmentof lithium-drifted germanium[Ge(Li)] and high-purity germanium

[Ge(HP)] solid-state semiconductordetectors and improvements in theassociated electronics have revolu-tionized the field of gamma-rayspectrometry, particularly withrespect to energy applications.

As a result of their much higherresolution (the ability to distin-guish between gamma rays of dif-ferent energies), germaniumspectrometers have replaced othertypes of gamma-ray spectrometersin many uses. They are now com-monly used in nuclear powerplants, industry, and research in-stitutions for identifying theelements in reactor cooling watersthat cause radioactivity, loggingoil wells, studying distant planets,and analyzing biological and labo-ratory samples.

History Until about 1970 the devicemost frequently used for gamma-ray spectrometry was the scintilla-tion spectrometer. The most wide-ly developed scintillator is asodium iodide crystal that emitslight when penetrated by gammarays. The light is collected andconverted to an electrical signalby a photomultiplier tube. Thescintillation spectrometer is an ef-ficient detector of gamma rays.However, the resolution of thescintillator is not fine enough todistinguish between isotopesemitting gamma rays of verysimilar energies. The need for aspectrometer with higher resolu-tion in physical and biologicalbasic research was the primary im-petus for germanium spectrometerdevelopment.

The first germanium gamma-raydetector was developed in 1962 asa result of Federal (non-OHER),private, and foreign-sponsoredresearch. The original instrumentwas inferior to the scintillator inboth resolution and efficiency. im-proved resolution was achieved in1963 through OHER-sponsoredresearch at LBL, BNL, and ORNL.

By 1971 the results of OHERresearch were twofold. First, theprocess of drifting the germaniumcrystal with lithium was improved,which considerably enhanced theresolution of the detector. Second,the associated signal processing

29

system was developed further sothat the resolution of the detectorwas not degraded by the pro-cessor. During this period, theGe(Li) detector surpassed thescintillator in resolution, and itsuse in research applicationsbecame widespread. These detec-tors, however, had to be manufac-tured and operated at very low(cryogenic) temperatures.

Research on the development ofGe(HP) detectors was initiated atLBL and General Electric (GE). Thefirst high-purity germanium detec-tors were sold by GE in 1974.These detectors still needed to becooled during operation but notduring manufacture and storage.Manufacturing and operating costsfell as a result.

The ability to work with the ger-manium at room temperature alsopermitted the construction ofmultidetector systems. By con-necting as many as ten detectorsto a single processing unit, the ef-ficiency of the germanium detec-tor array can be increased withoutsacrificing resolution. These multi-detector arrays are ideally suitedto situations such as medicalresearch and power plant environ-mental monitoring. Between 1975and 1982, Ot-tER funded develop-ment of these multidetector arraysat LBL.

Benefits Gamma-ray spectrometersare used primarily for gammaradiation monitoring and elementalanalysis of radioactive or neutron-activated materials. Accordingly,gamma-ray spectrometer users fallinto four main categories:

1. Nuclear power plants usegamma-ray spectrometers tomonitor the content of gas andliquid effluents and the environ-ment of the plant and to meas-ure the condition of the reactorfuel elements.

2. Laboratories (National, univer-sity, and commercial) usespectrometers to monitor theenvironmental conditions of thelaboratory and to perform ele-mental analyses.

3. Resource exploration com-panies use spectrometers inserial and ground surveillance

30

4.

and mapping and in wellholeiogging.Environmental monitoringorganizations (such as s~ateand local environmental protec-tion agencies) use spec-trometers to monitor levels ofradiation being emitted into theenvironment.

For users of gamma-ray detectorsand spectrometers who require ahigh level of resolution, the onlyalternative in these applications istime-consuming chemical separa-tions. The real choice to be madeby users, therefore, regards thedegree of resolution required.None of the competing detectorshas the resolving power of a Ge(Li)or Ge(HP) detector.

Discussions with representativesof gamma-ray spectrometer sys-tems and detectors indicated thatthe market is approximately $7 to$8 million annually. One majormanufacturer offered a distributionof units by type of usen

PercentUser of units

Public utility <loLaboratories 75Resource exploration 5Environmental monitoring 10

The major manufacturers of Ge(Li)and Ge(H P) detectors are CanberraIndustries, EG&G Ortec, andPrinceton-Gamma Tech Inc.

The use of germanium detectorsis most often justified by the needfor fast, high-resolution measure-ments. Fairly short scan times arereported for Ge(Li) detectors, rang-ing from 100 to 1000 seconds. Thetime for radiochemical analysis toperform the same analyses rangesfrom one-half day to several days.

Cost savings associated with us-ing germanium detectors were es-timated based on discussions withthe staff of approximately 20 utili-ties operating power reactors.Based on this survey, the annualcost saving in 1982 was estimatedas $21.2 million. Past savings wereestimated as $230 million (presentvalue). Almost all of these benefitsrepresent cost savings associatedwith measurements for which thealternative is radiochemistry.

It appears that other irnpo,rtant,but”difficult to quantify; benefitsare beino realized. For exam~le.much of-the scientific work ~n ‘nuclear physics could not be per-formed without the germani urndetector. Interestingly, a numberof isotopes have been discoveredby scientists using the Ge(Li)detector. The device is currerrtlvbeing used to determine wheth~rthe neutrino has mass,, Also, thegermanium spectrometer is nowa primary method of gi~mma,-rayspectrometry in astronomy.

/ndustrial Hygiene Monitors Theexpertise and methods in meas-UHTWW SCh?nCtX aCCllnNk3kd inthe nuclear energy program servedthe Nation well in the 1970’s whencomplex chemical mixitures be-came an area of vital concern inexploring the potential of syn-thetic fuels from coal. Lapel andpocket dosimeters for monil:oringexposure to polycyclic aromatichydrocarbons [(PAHs), known car-cinogens] were developed tc~meetthe needs of industrial hygiene.Sensitive instruments to measureskin contamination anc~spill spot-ters able to measure previouslyundetectable amounts of chemicalcontamination also emerged fromthe OHER Program. In addition tomonitoring devices, scientific pro-cedures such as biodirectedchemical analysis were developedto measure the carcinclgenic; andmutagenic properties c~fcomplexmixtures of chemicals derivedfrom coal liquefaction andgasification.

As part of the efforts slimed atdetecting toxic chemicals, asurvey of instrumentation for en-vironmental monitoring waspublished, and an instrument formonitoring concentrations of PAHcompounds, a hydrogen flucmidemonitor, and a portable elementalsurvey meter were developed. Thethree monitors are in the proto-type stage of development. Ahandbook The Survey of Ins fru-n?entation for EnvironmentalMonitoring* has been in use for

*LBL, Environmental InstrumentationGroup, Vol. 1(4), 1972-1980, JohnWiley and Sons.

several, years and will soon beissued by a private publisher. Thishandbook provides baseline refer-ence information to assist re-searchers and industrial hygienistsin selecting the appropriatemethod for measuring energy-related toxins.

Instrumentation under develop-ment will provide simple andpassive methods of monitoringworker exposure to hydrogenfluoride, more sensitive measure-ment of worker and skin contam-inat ion and work area surfacecontamination by PAHs, and anondestructive method of measur-ing formaldehyde emissions.These monitoring techniques ad-dress the critical health-relatedmeasurement needs associatedwith these toxic chemicals.

History The Industrial HygieneMeasurement Science and instru-mentation Program was initiatedto develop new or improved meas-urement tools and techniques toaddress a broad range of healthprotection problems. Since its in-ception in the late 1940’s, the pro-gram has focused on concernsassociated with chemical toxinsrelated to atomic energy defenseactivities.

With the creation of ERDA, thenDOE, and with broader missionsto cover all energy and conserva-tion measures, increased empha-sis has been placed on chemicalsrelated to energy development.These include PAHs, which areinherent in synthetic fuel produc-tion; hydrogen fluoride, an impor-tant chemical in DOE uraniumenrichment activities; trace ele-ments, which include respiratoryand inhalable toxic metal particu-Iates and vapors; and formalde-hyde, a potential carcinogen foundin materials used for buildingenergy conservation.

Benefits The major benefit of thismeasurement science and instru-mentation research is improved in-formation aimed at protecting thehealth of industrial workers andthe public. Advanced instrumentsare used to develop new and im-proved data to identify healthhazards. The use of overly con-

sepr~Iy,huIul

1.

2.

rvative and expensive healthotection measures or, converse-underestimation of the risks of

Iman exposure to chemical pol-tants is thereby avoided.

The survey of instrumentationfor environmental monitoring.This handbook was compiled byLBL to assist users in efficient-ly selecting appropriate instru-mentation. It is based onresponses by over 4000 users,including state and Federal en-vironmental agencies, analyticallaboratories, instrument manu-facturers, and technicallibraries. Separate volumes havebeen published on air, water,and radiation monitoringmethods, with each volumeorganized by pollutant. Thereare three major sections undereach pollutant. The first sectiondiscusses the reasons for moni-toring the properties of the pol-lutant, information on healthand environmental effects, andregulatory standards and re-quirements. The second sectiondescribes, compares, and con-trasts the principles used by thecommercially available instru-mentation methods. The thirdsection presents a one-pagesummary for each of the com-mercially available instruments.The water volume, with a cur-rent circulation of 4000 copies,has been purchased by most ofthe water pollution controlagencies in the United States.The volumes on radiation andwater have been published andmarketed by John Wiley andSons.Monitorirm of PAH compounds.The Spill spotter and the pas-sive vapor dosimeter provide thecapability to monitor routinelyand cost-effectively PAHs in theworkplace. The Spill Spotter is adevice that illuminates PAHswith light of a specific color,causing them to fluoresce. Theinstrument then measures thefluorescent light emitted. Theinstrument is a hand-heldoptics unit similar in size to asmall video camera and is con-nected to a small electronicsmodule. Easily changed excita-tion and emission filters provide

3.

4.

selective detection of classes oforganic compounds. This instru-ment also permits discrimina-tion between organic andinorganic compounds. The SpillSpotter is simpler and safer touse and provides quantitativeresults comparable to existingmethods. Its development wasrecognized by an 1R-1OOAwardin 1980.

The vapor dosimeter is a pas-sive air sampler that can beworn conveniently by the workeras a lapel badge or used as anarea monitor. It is a uniquedevice designed to measure theoveralI exposure to PAH com-pounds with three or more ringsand can measure dosages aslow as parts per billion. Thedosage is read by placing thebadge in an optical analyzer us-ing the room temperature phos-phorescence technique. Thepassive vapor dosimeter isfaster, simpler to use, and lessexpensive than existing instru-mentation. An IR-1OOAward in1981 recognized its invention.Hydrogen fluoride passivedosimete~ A hydrogen fluoridepassive dosimeter was devel-oped by ABCOR, Inc., undercontract to DOE. This monitor isused for industrial health moni-toring at the ABCOR enrich-ment facility. Uranium hexafluo-ride breaks down into uranylfluoride and hydrogen fluoridewhen it comes into contact withwater vapor in the air. Thisdosimeter detects the hydrogenfluoride reaction product andhas advantages over the ex-isting methods for measuringhydrogen fluoride. It is smalland simpler to use, and it canbe worn on the lapel. In addi-tion, it requires no pumps, im-pingers, sampling tubes, orcalibration. The collection ele-ment can be analyzed quicklyand easily with a fluoride-selective ion electrode. Further,it can be used either as a per-sonal or an area monitor.Portable elemental survey metezThe portable elemental surveymeter was developed undera DOE contract by ColumbiaScientific Instruments for rapid,

31

on-the-spot, elemental analysisof air particulate collected onfilters (including respirable andinhalable particulate) andvapors collected on membranesby chemical adsorption. It was ~designed to meet the accuracyrequirements for sampling inthe workplace. The samplingmethod is nondestructive andcan detect 23 elements. Thesurvey meter provides imme-diate elemental analysis of airparticulate and vapors presentin the work environment; thealternative is to send the sam-ples to an analytical laboratory.The meter can be used for rapidon-site checking of air contami-nants in the case of accidentalreleases, as well as for routinemonitoring purposes. For exam-ple, it can be used in the metal-lurgical and energy productionindustry to monitor weldingfumes (which contain toxicmetallic elements) or to meas-ure air contaminants found inother workplace environments.The device is portable and isenclosed in a small compactcarrying case. It uses a micro-processor-based, energy-dispersive, X-ray fluorescencetechnique to measure sequen-tially the concentrations ofselected sample elementswhose calibration parametersare stored in memory. Analysistime is on the order of 100seconds/element.

Predicting Poiiution Pathways inthe Atmosphere Although greatimprovements have been made inour understanding of the proc-esses that move pollutantsthrough the atmosphere anddeposit them in aquatic or ter-restrial ecosystems, an evengreater understanding is neces-sary to solve the problemspresented by acid rain and thechange in the heat budget of theearth caused by carbon dioxide in-creases. A step in this directionhas been made by the productionof stable, nontoxic tracer gas thatcan be released from source areasand detected at great distances.

Understanding and predicting pol-lutant transport are important

32

because it is a principal means bywhich health effects might be pro-duced in the public by an emerg-ing technology. The OHERresearch program pioneered themathematical modeling, or predic-tion, of pollutant behavior in theatmosphere because of the earlyresponsibility for understandingthe possible effects of radioactivecontamination. Models of themovement of materials throughand chemicals reaction in the airand soil are crucial to rationaldecisions related to citings oftoxic waste dumps and to optimaldecisions on mitigation to correctpast mistakes. However, the valid-ity of models and predictionsmust be tested, and OHER hasalso supported the development ofthe necessary tools forverification.

Although gas tracers have pro-vided valuable information of thiskind, it is also known that pollu-tant gases often interact withminute particle clouds (aerosols)from which the particles may bedeposited on the ground or be-come resuspended in air. Pollu-tants themselves may evenoriginate as aerosols. New instru-ments were needed to understandthe transport and cycling of par-ticles in streams, lakes, oceans,and the atmosphere. This needwas met by developing aerosoland particle analyzers for both at-mospheric and aquatic studies. To-day these analyzers form a vitalpart of the Nation’s ongoingresearch into the effects of air-borne chemical pollutants, notablyacid rain.

The major benefit of this researchhas been a sounder understandingof the relationships between pollu-tant releases and their concentra-tions in the human environment.information of this nature isessential to regulation of pollu-tants in the general interest andfor sound industrial planning.

Atmospheric 11’acersSeveralnonradioactive, chemically inertsystems have been developed totrace the dispersion of materialsreleased into the atmosphere.These include tracers, samplers,and extremely sensitive analyzers

that can detect materials at con-centrations as low as 2 parts perquadrillion (10-15).Such systemscan be used to trace dispersionsat ranges of over 100 kilometers.

Increased concern over the re-gional and international aspects ofair pollution has created a needfor reliable model calculations ofconcentrations as far as 1000kilometers from pollutant sources.Experimental verification of thesecalculations, as well as environ-mental assessments biased onmodel simulations, is essential toestablish the credibility of modelsof dispersion processes. One wayto verify the models is to trace themovement of actual rnaterialls inthe atmosphere. This requirescost-effective, nonreactive andnondepositing tracers for local(less than 100 kilometers), irlter-mediate (100 to 1000 kilometers),and long-range (greater than 1000kilometers) dispersion of pollu-tants. The tracers must also benonradioactive, nontoxic, and inex-pensive and have low natural back-ground to perform adequately.

Three sampling systems forperf Iuorocarbons have been devel-oped. The BNL automatic tracersampler was designed to be easilyportable (15 pounds), alutomatie,and reliable. Each sampler cantake a sequence of 23 samples ofair. The start/stop time, fiow rate,and total volume through thesampling tubes can be controlled.Each sampling tube contains 150milligrams of Ambersolrb, whichtraps all of the perfluorocarbon.The tracer is then recovered bythermal resorption from the sam-ple tubes and separated by !gaschromatography. An ek)ctrorl-capture detector provides meas-urement accuracy of lC)to 20 per-cent at concentrations as low as 2parts per quadrillion (backgroundconcentration) with an 8-litelrcapacity air sample.

A second sampler, the prototypecalled the “dual-trap salmplelr:combines both sampling andanalysis. Using two samplin!Jtubes, it simultaneously traps anew sample as it analyzes theprevious sample. This device canprovide analysis of one air sample

containing perfluorocarbon tracersevery 5 ‘m~n-utes.It can detectperfluorocarbon tracers at theirambient levels with 15 percentaccuracy essentially in real time.

The third prototype sampler is areal-time continuous monitor in-tended primarily for use in aircraftsampling. Air is drawn through acatalytic reactor that removes theoxygen and other electron absorb-ers, leaving the perfluorocarbonsand nitrogen in the remaining air.This air is passed directly to anelectron-capture detector that pro-vides continuous readout ofperfluorocarbon concentrationwith only a 3-second delay. Whencompleted, this sampler shouldyield accuracies of 0.1 parts/trillionin measuring perfluorocarbontraces.

History In the early 1970’s, the onlyavailable atmospheric tracer withacceptable physical propertieswas SF~. The difficulty in meas-uring trace amounts of SFGagainst natural and man-madebackgrounds limited its use-fulness to a range of about 150kilometers. Recognizing the needfor longer-range tracers, OHERinitiated research into two tracertypes:

1. Perf/uorocarbon tracer. Invest i-gations reported by 1974 in-dicated that a perfluorocarbontracer system could be devel-oped that would be ideal forlong-range dispersion studies.The NOAA Air Resources Labo-ratories contracted with Love-Iock to develop the threedifferent samplers as the firststep in the development of thenew tracer system. Prototype in-struments were delivered byLovelock in 1976. Since then thelaboratory has been workingclosely with DOE’s Environmen-tal Measurements Laboratory(EML) and BNL in a cooperativeeffort to develop a practicalperfluorocarbon system.

2. Heavy methane tracez Follow-ing the observation that aircontained an insignificantnumber of atoms with anatomic mass of 21, Los Alamosinitiated work in 1973 todevelop a tracer with that

atomic mass by synthesizingcarbon-13 and deuterium intoheavy methane, CDZ. Bothcarbon-13 and deuterium areavailable from other Los Alamosprograms. Concurrently, scin-tillation techniques for detec-ting single ions using massspectrometry were being devel-oped at the Atomic WeaponsResearch Establishment(AWRE), United Kingdom. Afterthe initial tests of heavy meth-ane tracers at AWRE were com-pleted, OHER funded thedevelopment of a mass spec-trometer analytical capability atLos Alamos to measure thetracer levels in ecologicalsamples.

Several field experiments havebeen conducted to test the per-fluorocarbon and heavy methanetracer systems. The most impor-tant of these were two demonstra-tions conducted in July 1980. Inthe first demonstration, SFGper-fluorocarbons and heavy methanetracers were released and sampledat distances of 100 and 600 kilo-meters. The second trial used onlyperfluorocarbons and SFGwithsampling only at 100 kilometers.

The key issue to be resolved bythe experiments was whether thetracers and the analysis systemswere similar; that is, if equalamounts of the two perfluorocar-bons were released, would equalamounts be detected at everylocation? Even more crucial werethe direct comparisons of differenttracers, such as the perfluorocar-bons and the heavy methanes.

The experiments proved that theperfluorocarbon and methanetracers behaved the same in theatmosphere, faithfully followingthe air motions and remaining inthe air streams out to 600 kilo-meters from the source. Consider-ing that the heavy methane andperfluorocarbon determinationsare conducted by totally differentanalysis techniques (mass spec-trometry for the methane and gaschromatography followed byelectron-capture detection for theperfluorocarbons), these resultsinspired confidence in both tracersystems.

BenefBs Atmospheric tracers are arecent development that may findapplications in several researchareas. These tracers allow thevalidation of computerized modelsto describe atmospheric transportand dispersion, as well as theinvestigation of fundamental as-pects of dispersion or dynamicmeteorology not accessible byother means.

These tracers will find applica-tions in facility siting and empiri-cal studies of specific situationswhere there is no adequate modelof the dispersion of emissions orwhen existing models are inade-quate because of the complexityof the terrain. For example, in a re-cent DOE study of drainage windsin complex terrain, the tracerswere used to determine thecapability of existing wind pat-terns to remove pollutants ventedfrom geothermal wells.

Aetvsol Instrumentation, DryDeposition, and Resuspension Inan effort to predict the fallout ofminute particles of radioactivedebris from weapons tests, re-search was undertaken in thescience and technology of aero-sols. Subjects studied include par-ticle behavior in the stratosphericair, tropospheric interactions withrain and snow, and deposition inlungs from inhalation.

Dry deposition is the process bywhich particles and gases aretransferred to the earth’s surfacefrom the air. Research into drydeposition has made possible thedevelopment of predictive modelsthat relate deposition velocity toparticle diameter. Although thesemodels still contain considerablepredictive error, the results aretypically an order-of-magnitude im-provement over earlier practice.

Resuspension is the process bywhich particles and gases becomereintroduced into the air from thecart h’s surface. Research into par-ticle resuspension has made pos-sible the development of modelsto predict resuspension rates,which are used as boundary condi-tions in air transport modelsneeded to reliably predict whatwill occur downwind.

33

Wstory Research on dry depositionstems from attempts in the 1960sto measure worldwide fallout ofradioactive debris from weaponstesting. Dry deposition on grazinglands was of particular concernbecause it introduced radioiodineinto the food chain. Researchersidentified the phenomenon anddeveloped a now widely usedsystem that collects dry and wetdeposition separately. The earlymonitoring efforts resulted in abody of data but also made clearthe inadequate understanding ofthe unde~lying physics. Theresults of OH ER-supported re-search into aerosol phenomenawas combined in 1973 with otheradvances in aerosol research andwith the emerging electronicstechnology to produce a new elec-trical aerosol analyzer for surface-Ievel use. Compared with thepreceding electrical analyzer, theprototype achieved an approximatesixfold reduction in size andweight. Recognizing its potential,TSI, Inc., an instrument manufac-turer, completed the design andengineered a reliable electronicspackage for the unit. After itsmarket introduction in 1974, theunit quickly became the standardmethod for measuring the numberand size of submicron-sized par-ticles or drops in aerosols.

flenetlls Over 200 units of the elec-trical aerosol-size analyzer havebeen sold since its introduction in1974j nearly one-half of thesesales have been to overseas cus-tomers. TSI supplied the followingapproximate domestic sales bycategory:

Numberof units Applications50-60 Air pollution monitor-

ing and research12-15 Diesel combustion

research and health ef-fects research

10-12 Military research onsmokes, obscurants,and aircraft condensa-tion trail suppression

Other applications include com-mercial smoke detector develop-ment and calibration, researchon commercial air filters and

34

demisters, sem,i,conductor cleanrooms, and particle-size control ofcarbon black in tire manufac-turing.

A number of health, safety, mili-tary, and industrial benefits areassociated with the use of elec-trical aerosol-size analyzers. Airpollution monitoring and researchbenefits include accuracy in quan-tifying airborne pollutants, identi-fying particles small enough to berespirable, and improving the abili-ty to enforce emission regulationsfor point sources. Benefits arisingfrom diesel combustion andhealth-effects research include theability to monitor more preciselythe diesel combustion exhaustand to evaluate more effectivelythe effect of design changes onexhaust products. Research onsmokes, obscurants, and aircraftcondensation trail suppressionenhances the survivability ofmilitary personnel and equipment.Industrial benefits include clean-room monitoring, leading to alower rejection rate of electroniccomponents and assemblies;particle-size control of carbonblack used in tire manufacturing,resulting in greater tire treadwea~and miscellaneous applications,such as smoke detector develop-ment and calibration, informationon the effects of pollutants onplant growth, and development ofcommercial air-cleaning filters anddemisters.

A sound understanding of thecomplex relationships betweenpollutant emissions and pollutantconcentrations in the environmentis essential for promulgatingsound environmental policy. In thisregard, research on dry depositionand resuspension can benefitsociety in one of two ways: by pro-viding basic data needed todemonstrate that human and en-vironmental exposures to harmfulaerosols are less than currentlybelieved or by demonstrating thatthe threats are greater than cur-rently believed. In the former case,society can benefit from this infor-mation by devoting fewer of itsscarce resources to emission con-trols, and in the latter case, itbenefits by taking actions toreduce emissions.

An additional benefit Ifromresearch on resuspension relatesto windblown soil erosion. “rhephysical processes of resuspen-sion and soil erosion are essen-tially the same. Hence, the resultsof research on resuspension canbe applied directly to the SIudyand prevention of windblown soilerosion.

Identification anclEvaluation ofEnvironmental Effects

The concerns resultin!~ fromenergy production andl use haveranged from disturbance of naturalsystems by mining, deforestation,and drainage to offshctre dri Iling,toxic waste disposal, thermaldischarges, and the ccmtaminationor pollution of sources of fc)od.Research initiated to gain anunderstanding of the effects offallout from weapons tests, poten-tial discharges from weapons pro-duction facilities, and pathwaysradioactive materials and otherenergy-related materials follow inmoving from their source to thesize of potential danger has beenexpanded to encompass pathwaysof substances through the foodchain, underground migraticln of.substances, as well as aspects ofradioecology, geology, and manyother fields.

Rlverlne Ecology “RiverineEcology” is the title given to agroup of studies and modelsdeveloped to understand anddescribe the environmental impactresulting from industrial heating ofriver water.

HistoryBeginning in the late 1940s,the environmental impi~cts clfonce-t hrough cooling c)f reactorsbuilt for the United States nuclearweapons program at SiavannahRiver and Hanford were the objectof research on riverine ecology bythe AEC Later, environmenti~l im-pacts resulting from once-throughcool ing of power reactorsprompted a major research pro-gram at Oak Ridge on riverineecology. The program focused onpower reactors in an effort to an-ticipate problems the nuclear in-dustry might face in complying

with the N,ational EnvironmentalPolicy Act and other environmentallaws. The problem of heating riverwaters is primarily nonradiologicalin nature and, thus, also germaneto coal-fired plants, pumped-storage reservoirs, and other oper-ations that have the potential tocause large-scale changes in riverconditions.

By reviewing and analyzing world-wide experience and by conduct-ing laboratory experiments,researchers were able to compile adata base on aquatic ecology im-pacts and establish criteria foraltering water quality. From thesedata was developed a set ofmodels of fish population dynam-ics, entrainment and impingementat plant intakes and discharges,and transport of water and en-trained fish and larvae. The focusof this research was on thestriped bass population of theHudson River, site of the IndianPoint Unit 2 nuclear plant. Later,the scope of the program was ex-panded, both in depth (to includemore detailed studies of factorsgoverning entrainment and im-pingement) and breadth (to in-clude studies of other fishpopulations).

Benefits This basic research onriverine ecology led to the devel-opment of a body of knowledgethat could be applied to a varietyof problems arising in the designand construction of large electricpower plants. The information wasused specifically to evaluate theneed for cooling towers plannedfor several power plants on theHudson River.

Riverine ecology research was in-strumental in the negotiatedresolution of the longstandingdispute over the impacts of powerplants at Indian Point (nuclear)and Bowline and Roseton (oil-fired)on the ecology of the HudsonRiver. At the time of the settle-ment (December 1980), EPA hadentered its fifth year of admini-strative deliberations over whetherthe plants would be required to beretrofitted with cooling towers.Previous studies had alleged thatthe plant’s emission of warmwater and its huge withdrawals

of river water for once-throughcooling would kill mature fish(through collision or impinge-ment) and would draw in and in-jure or destroy (entrain) juveniles,larvae, and eggs and, thus,, con-tribute to a serious depletion ofthe Hudson River population ofstriped bass.

The use of the models developedin the OHER research indicatedthat the impacts on striped basswere smaller than alleged butdeterminable. With the boundariesof the dispute settled, the partieswere able to reach a compromisesolution that served both theirplan and the public interest. Thisis, perhaps, the major significanceof the Hudson River case. Follow-ing its settlement, Russell Train,former EPA Administrator andmediator for the Hudson Rivercase, stated, “the settlementdemonstrates that acceptable ac-commodations can be reachedwhich effectively balance the en-vironmental and energy needs ofthe Nation . . . [through] media-tion and negotiation, rather thanby sole reliance on the moretraditional adversarial legalprocedures!’

Ecology of the ContinentalShelf The continental shelf, whichaccounts for less than 10 percentof the total ocean surface area,produces most of our seafood.This shallow perimeter of water offour coast receives nearly all of thecontaminants that wash off theland and flow downstream. Be-cause it is the more productive,the coastal area is more suscepti-ble to damage from pollution thanare deeper parts of the ocean.Research on the continental shelfwas initiated to determine the en-vironmental impact of effluentsfrom nuclear and fossil powerplants on coastal areas and alsoto predict the effect of energydischarges over the coastal zone.

The sea, like the lowest region ofthe earth’s atmosphere near thesurface, is self-cleansing. Thus, ithas a carrying capacity for con-taminants. We need to know thiscarrying capacity to be sure thatthe sea is not used beyond itscapabilities.

Hisfory The continental shelf pro-gram evolved from work that grewout of concern about nuclearfallout from weapons testing inthe Pacific. Work began in thedeep ocean, following the move-ment of the radionuclides fromEniwetok and Bikini in the Kuro-shio Current toward Alaska. Itsoon became apparent, however,that the primary route of radioac-tivity to humans from the oceanwas through seafood. Fallout onland was washed into the coastalzone, raising interest in the naturalprocesses that move contaminantsin this area.

The first integrated program dedi-cated to coastal transport wasbegun by DOE in 1975, usingoceanographers from Skidaway in-stitute, the University of Georgia,the University of Miami, and NorthCarolina State University. Thestudy began with an investigationof coastal currents that move dis-solved contaminants, specificallythe Gulf Stream that sendstongues of water twisting into thecoastal zone, causing quantities ofcontaminant-laden water to moveoffshore. The scientists thenmoved inshore to study themechanism driving freshwaterrunoff from rivers through the“dam” of saltwater offshore, carry-ing contaminated coastal waterout to the deep ocean. Their re-search has shown that the coastalzone is regularly flushed and thebuildup of contaminants is reducedperiodically.

In the Northeast, oceanographersfrom the Woods Hole Oceano-graphic Institution, Yale University,the University of California at LosAngeles, North Carolina StateUniversity, Columbia University,and Brookhaven National Labora-tory studied, and continue tostudy, the movement of naturalparticles and the manner in whichthey attract contaminants. The im-portance of this research washighlighted by the earlier dis-covery, in which DOE played animportant role, that many, indeedmost, pollutants tend to attachthemselves to particles that gradu-ally fall to the bottom of the sea.Also, since many of the particlesinvolved are photoplankton cells

35

rich in carbon, this line of re-search is important in understand-ing how carbon dioxide is beingremoved from the atmosphere andstored as deposits of organic car-bon in the ocean at the edge of ~the continental shelf.

Present research continues tostudy the processes that movecontaminants in the coastal zone.The scope of studies has been ex-panded to include the PacificOcean off California. Special in-terest is in those processes thattransport materials across theshelf and into deeper waters ofthe open ocean, where their directimpact with humans and naturalcoastal systems is minimized.

Benef/fs This continental-shelfdynamics program benefits manyusers, including:

c DOE. DOE is responsible forcleaning up several sites con-taining materials associatedwith earlier nuclear activitiesthrough the Formerly UtilizedSites Remedial Action Program.Data developed by the conti-nental-shelf dynamics programare a key element in decidingwhether sea disposal is safe.The program has also providedmodels to predict the fate ofspilled materials, such as theoil from the Argo-Merchant. Theinformation developed is alsoused by other agencies involvedin modeling oil spills. Moreover,the modeling capability providescrucial information required tosupport the leasing of offshoretracts for oil development.

● State and Federal regulatoryagencies and utilities. In Wash-ington and Oregon, the programidentified sites where industrialactivities might harm the razorclam fisheries. Work at theScripps Institution of Oceanog-raphy helped establish thechlorine release standard forthe California coast. Studies atthe University of Washingtonhave shown that mercury israpidly removed in coastalwaters and could, therefore, besafely released at higher levelsthan previously anticipated. Inthe past, floatable in municipalwastes drifted onto the beaches

36

●

of Long Island, closing morethan 100 kilometers of beachesand causing an estimated$20-million (1976) loss in thetourist and related industries.The coastal-shelf model pre-dicted the path of the wastesand showed that dumping far-ther off-shore or storing wastesfor later dumping during favor-able conditions could help avoidthese damages.fishing industry. Based on aconsid~ration o~ fronts, temper-ature, and upwelling, thecoastal-shelf dynamics workhelps determine where the fishare located. The impetus forfishery development was pro-vided by a NOAA Sea Grant, andthe information was provided bythe coastal-shelf dynamics pro-gram. Dockside values of finfish which landed in Georgiarose from less than $38,000/yearfrom 1969 to 1975 to over$230,000/year from 1976 to 1979.The program has similarlybenefited fin fisheries in SouthCarolina.

In 1976 there was a major kill ofshellfish along the New Jerseycoast with estimated damagesof $50 miIlion. The coastal-dynamics program investigatorsidentified the conditions andimplemented an early-warningsystem in case similar condi-tions recur. Fisheries expertsestimate this knowledge wouldenable them to save one-half ofthe shellfish. It is estimated thatthe peculiar oceanic conditionsthat lead to fish kills would oc-cur about one year in ten.

Tracing Pathways of NuclearWastes In the Life Cycie Smallamounts of transuranic elementsproduced by nuclear energy ac-tivities may move through the en-vironment and back to humans orother biological organisms. (Tran-suranic elements are those withatomic numbers greater thanuranium; they are radioactive andcan be toxic to humans.)

Hundreds of tons of transuranioelements, mostly plutonium, havebeen produced since World War IIas a part of nuclear weaponsproduction. Small losses to the

environment from processing haveoccurred. Such losses have beenstudied at the Savannah RiverLaboratory and the Savannalh RiverEcology Laboratory. Plutoniumemitted from a nuclear fuel sepa-rations pIant is followed throughthe aquatic and terrestrial environ-ments, and its dose to humansfrom ingestion is asse:>sed.

Plutonium particles from theSavannah River nuclealr fuel sepa-rations plant attach to dust par-ticles. Concentrations of theseparticles in the air provide poten-tial annual doses of less than 1percent of the natural backgroundat the plant boundary. Wheat,corn, soybeans, root crops, i~ndtobacco grown in plutcmium-containing soil—had the mcwtplutonium on the surfalces, not inthe edible part, of the plant. Thepotential dose from plutonium tohumans eating these crops aftermore than 20 years of SavannahRiver operation is less than fromnaturally occurring radioactivepotassium-40 in the same soil.

Measurements in sediments, biota,and water in estuarine systemsnear the Savannah River indicatethat plutonium concentrations inthis watershed are not differentfrom those of watersheds with nonuclear facilities, even though theSavannah River is near one of thehighest concentrations of nuclearfacilities in the United States.

The results of all transuranic cy-cling research up to 1980 havebeen compiled in a book entitledTransuranic Elements in theEnvironment: A Sumn?ivv of En-.vironmental Research on Trans-uranium Radionuclides Fun[jed bythe United States Depiirtment ofEnergy Through Calendar Year1979, [cd. by Wayne C Hanson(DOE Technical InformationCenter), DOE/TIC-2280(), 746p,1980]. These research results, pluslater scientific papers, form a valu-able data base on transuranic cy-cling in the environment. Perhapsequally important is the evolutionof a group of scientists whc~cananswer questions about trans-uranic elements that arise fromcivilian and military applicationsof nuclear technology.

Hisfory Befqre 1973 environmentalresearch’ into t~e behavior of thetransuranium elements was con-ducted on an ad hoc basis, usuallyin response to an accident, suchas the loss of nuclear material inmilitary aircraft accidents, or to“hot spots” found in the environ-ment, such as the discovery ofplutonium concentrations that ex-ceeded fallout levels (e.g., near theNevada Test Site). Short studieswere usually undertaken to de-scribe the distribution of pluto-nium and Assess the health hazardat the particular site. This informa-tion provided some basis for gen-eralized observations aboutenvironmental movement, butmost of the in-depth studies wereonly applicable to soils of highPH.

No concerted studies had beenmade of transuranic elementmovement through aquatic foodchains or the marine environment.Early studies did not addresswhether biological modification ofthe transuranium elements mightincrease their mobilization in theenvironment, with more movementto humans. To remedy these defi-ciencies, OHER initiated basicresearch activities covering allaspects of environmental transportfrom soil processes to ecos~stemcycling.

Bef?efifsThe major benefits of theinformation from OHER’S trans-uranic environmental cycling re-search are ut iIized by

1. Nuclear Standard-setting Agen-cies, both National and lnterna-

2.

tiona/. The results of researchon transuranic cycling representvirtually the sole source of suchdata which is vital to standardswriting bodies such as the Na-tional Council on Radiation Pro-tection for the United States,the National Radiation Protec-tion Board for the UnitedKingdom, the InternationalAtomic Energy Authority, andthe International Commissionon Radiation Protection.Defendants in Personal IniurvLitigation. The United States-and its contractors have been,and are being, sued by plaintiffswho claim damage caused by

3.

4.

R@tolchantivanusBeeabepr(inteltra

Th

::St[ic:iscdi:CuM(

transuranic elements and otherradioactive substances to whichthe plaintiffs were allegedly ex-posed. The body of scientificknowledge on transuranic ele-ments developed by OHER-sponsored research is beingused in such litigation. Thedamages sought in these suitscan be extremely large. In onesuch case, the punitive dam-ages sought were $4 billion.Hazardous Waste Managers. Themathematical models developedand validated for chemicalscontaining transuranic elementscan be applied to similar mate-rials in the environment. Specif-ically, the modeling of surfaceerosion, surface water transport,and sediment transport in thecanyons near Los Aiamos hashelped to determine remedialactions needed to deal withother forms of contamination inLos Alarnos County.Future Plutonium FacilityDesign and Operation. Thetransuranic cycling research atthe Savannah River Laboratoryand the Savannah River EcologyLaboratory has verified thattechnology exists for containingplutonium in operating nuclearfacilities. The environmentalassessment methodology anddata can be applied to othernuclear facilities where pluto-nium is of concern.

ldioisotope Tracers Radioiso-pe tracers can be used to followemical reactions in biologicald biomedical research. Radioac-‘e isotopes, such as carbon-14.d hydrogen-3 (tritium), can be;ed to “tag” organic molecules.?cause the tracer’s radiation islsiIy detected, its movement canI followed through the diverse‘ocesses and changes occurringthe biological or physical sys-

m containing the radioactiveacer.

ie following are examples of theIccessful application of radioiso-pe tracer techniques in theudy of ecosystems and biolog-al systems. The use of radio-otope tracers in medicalagnosis and treatment is dis-Issed in the section on “Nuclearedicine.”

Lh?kuges in Ecological SystemsUse of radioisotopes as chemicaltracers for food web (lateral foodchain linkages) and related studieswas developed to help understandand project the fate of radio-nuclides released to the atmos-phere in weapons tests and bynuclear production facilities.These techniques soon played akey role in ecosystem investiga-tions. In radionuclide studies, thetracers enabled researchers todistinguish the specific chains in,an ecological food web. With thisinformation they could trace thepathways and identify the proc-esses that concentrated radionu-clides as they moved from theenvironment to humans. Morebroadly, the successful use ofradiotracers in this research areaencouraged environmental scien-tists to use radiotracers for identi-fying and quantifying linkages inecological svstems that meviouslywere difficu~t, if not impossible,trace, thereby opening a wholenew range of understandingecology.

Hisfory A Rrime concern of the

to

AEC and public health agencieswas that radioactive materialsmight move and localize in the en-vironment, thereby becoming con-centrated before reaching humans.Recognizing that food webs werethe major unknowns in under-standing and predicting the fate ofradionuclides in the environmentand that radiotracers offer unusualpossibilities for distinguishingspecific pathways (food chains) inan ecological food web, AEC in-it iated a broad-based research ef-fort on radionuclides and foodwebs. This research led to anunderstanding that organisms inecosystems form feeding relation-ships and that these chains areusually limited to three or fourlinks. A radioisotope of an ele-ment may be transferred up a foodchain, concentrated, or discrim-inated against, at various levels, asit is passed to the next levelthrough feeding and being fedupon.

As investigations yielded quan-titative data on these processes,ecologists perceived the potential

37

to use mathematical models in ad-dressing the complexity anddynamics of ecosystems. By theend of the 1960s, ecosystemmodeling based on radiotracertechniques was recognized asuseful in addressing the Nation’senvironmental pollution problems.

Benefifs The analysis of foodchains with radiotracers confirmsthe importance of food in passingradionuclides to humans. Conse-quently, calculations and estima-tions of the radiological dose tohumans must take into accountthe behavior of radioisotopes infood chains. These data are crit-ical because the standards for therelease of radioisotopes to the en-vironment have become morestringent. In contrast to the earlydays of nuclear energy when esti-mates of release were based onlimited laboratory data, detailedquantitative information can nowbe provided on the rates of ac-cumulation and residence times ofradionuclides in a variety of organ-isms. This ability has provenextremely important in the prepa-ration of environmental assess-ments of proposed nuclearfacilities and has enabled radia-tion protection specialists toderive dose estimates.

Dynamics of Biological SystemsCarbon-14, which omits beta par-ticles with a half-life of 5770 years,with slight toxicity, and hydrogen-3(tritium), another beta emitter witha half-life of 12 years, are the twomost widely used radioactivetracers in biomedical research.Ninety-five percent of the biomed-ical research reported in leadingjournals involves the use of thesetracers. Research in biochemistry,physiology, and pharmacologyrelies on the continued use ofthese tracers.

Carbon-14 is the most popularisotope because of its favorablecombination of properties. H emitsbeta particles strong enough tomeasure—but weak enough tomake shielding unnecessary—andto give good definition in radio-graphs. Its long half-life makes itunnecessary to correct measure-ments for decay; and it is availablein adequate quantities, with

38

suitable levels OLradioactivity, andat low cost. Its toxicity is relative-ly slight and is not a problem inmost applications. Tritium hasbeen used mainly as an auxiliarytracer for carbon rather than as ahydrogen trace~ its shorter half-Iife offers some advantages.Isotopes of other elements, suchas hydrogen, nitrogen, oxygen,sulphur, and phosphorus, are ofsecondary interest but are valu-able for certain uses.

Hkfofy On June 14, 1946, in thejournal Science, an announcementwas made by Manhattan ProjectHeadquarters, Washington, D.C.,that:

Production of tracer and thera-peutic radioisotopes has beenheralded as one of the greatpeacetime contributions of theuranium chain reacting pile. Theuse of the pile will unques-tionably be rich in scientific,medical and technologicalapplications.

On August 2, 1946, the first ship-ment of reactor-produced radioiso-topes left ORN L. The compoundcontaining carbon-14 was sent tothe Bernard Free Skin and CancerHospital in St. Louis. This signal-ed the beginning of widely avail-able isotopes at reasonable costsfor persons trained in their use. By1962 ORNL had made over half amillion shipments of radioiso-topes. On July 31, 1964, there were1085 physicians in the UnitedStates licensed to use radioiso-topes in private practice and some1201 medical institutions licensedto handle radioisotopes.

Benefifs The use of carbon-14 inbiochemical analysis is widespread.

1.

2.

Carbon-14 glucose has replacedthe classic glucose tolerancetest in measuring the absorp-tion of glucose. Molecules“labeled” with carbon-14 arestructurally identical to thenonlabeled molecules andbehave exactly the same.Carbon-14-labeled COtT)DOUndShave simplified the study ofmetabolic diseases in manbecause only the amount ofcarbon dioxide labeled withcarbon-14 (14C02)in expi ratory

air needs to be’measured. Thismethod is easily applied usingcarbon-14-labeled tripalmitate ortrioleate to diagnose the malab-sorption of fat. Problems asso-ciated with radiochemical purityare avoided when carbor~-14compounds are used.

One of the most important ad-vances in medical dialgnos!s wasmade with the introductiorl oftissue biopsies, providing informa-tion that formerly could be ob-tained only at a postmortemexamination. Usual chemicalmethods can not be used blecauseof the small amount of tissue in-volved. Use of carbonl-14 provides asensitive, specific, and technicallyeasy measurement of biolcjgicalreactions in these iscdated tissues,by measuring 14C02liberated whentissues are incubated on surfacescontaining carbon-14.

Carbon-14 is used mainly for invitro, or test tube, studies of cellsincubated on various carbcm-l4-Iabeled surfaces. One developmentat the Johns Hopkins, UniversityHospital has been for rapid detec-tion of bacterial contamination invarious biological specimens. Forexample, blood or tissue sus-pected of harboring bacteria isplaced in a reaction vessel incontact with an appropriatecarbon-14-labeled material. The ap-pearance of 14COZin the gas abovethe reaction vessel will indlicatethe presence of bacteria morequickly than routine t]acteriolog-ical techniques.

Other advantages of carbon-14 andtritium are the long shelf-life ofradioactive-labeled cc~rnpounds;availability in relatively pure forms;the ease of attaching radic)activeatoms to proteins; and broad ap-plications in the production ofcomplex molecules with livingorganisms, drug metabolism,cytology, and enzyme assays.

Plant Metabolism A comp Ietemapping of the metabolic path-ways of carbon in the ~hotosyn-thesis process from the initialfixation of carbon dic)xide from theatmosphere to the production ofglucose by green plalnts wasdeveloped by Dr. Melvin Calvin and

associates at Berkeley from 1945to the Ihte 1950’s. In 1961 Dr. Calvinreceived the Nobel Prize in Chem-istry for this work.

History Once radioisotopes fromreactors became avaiIable in quan-tities sufficient for research in theearly 1950’s, AEC encouraged theuse of these isotopes and spon-sored a variety of research relatingto problems of fundamental signif-icance. The association with thefield of photosynthesis arosebecause the chemistry of metallic/organic compounds had been ap-plied to the purification of pluto-nium and uranium during theManhattan Project. Chlorophyll,the key molecule in photosyn-thesis, is one such metallic/organic compound and had beenan area of research for Dr. Calvinprior to his work on the ManhattanProject. AEC subsequently pro-vided both funding and isotopesto him for extensive fundamentalresearch on tracing the complexphysical and chemical processesinvolved in, or metabolism of,photosynthesis.

Other current directions of re-search, based upon understandingthe physics and chemistry ofphotosynthesis, include the devel-opment of devices to convert solarenergy directly into stable chem-ical forms and, on a longer-termbasis, to reduce carbon dioxide inthe atmosphere.

Beneflfs The scientific benefits ofthis work were twofold. First,understanding of the photosyn-thetic process was greatly en-hanced. This understanding of thedetailed biochemistry of the proc-ess laid the groundwork for fur-ther developments leading to anunderstanding of metabolic con-trols in plants. Such an under-standing was a prerequisite to anygenetically engineered plant mod-ifications and led to commercialapplications of chemicals specif-ically designed to accelerate plantgrowth and inhibit photorespiration.

The second early benefit was thedemonstration of powerful re-search techniques that have sincefound extensive use in studies of“both plant and animal metabolism.

These techniques include the useof radioactive carbon-14 as a tracerto provide detailed autoradio-graphs (pictures revealing thepresence of radioactive material,the film being laid directly on theobject to be tested) of the phys-ical movement of carbon atomsthrough tissues or samples andthe use of autoradiography com-bined with paper chromatography(the separation of mixtures intotheir constituents by preferentialadsorption by a solid, as a strip offilter paper) to identify the inter-mediate chemical products andenzymes associated with themetabolic path.

Extensive research has continuedat Berkeley and throughout theworld to further define photosyn-thesis, not only in terms of carbondioxide fixation, but also in termsof photochemistry, electron trans-port, and the metabolic mecha-nisms that regulate plantchemistry and structure subse-quent to the formation of glucose.The development of further meta-bolic understanding, the codevel-opment by other researchers of aspectrum of genetic engineeringtechniques that permits the inser-tion of gene fragments into singleplant cells, and the ability to growmany types of plants from a singlecell have made it possible to mod-ify selectively plant characteristics.

A potential future benefit ofresearch of this type is the trans-fer of the light-hydrocarbon manu-facturing capability of certaintropical species into plants thatcould be grown in the UnitedStates. Another possibility is thegenetic improvement of the effi-ciency of the photosynthetic proc-ess itself.

Land Reclamation The programin reclamation of surface-m! nedland was begun in 1975 and hasdemonstrated that reclamation ofsuch land is feasible both in thearid West and in the Midwest.

Hlsfory Two fundamental researchefforts in soil science and plantecology aim at understanding theprocesses leading to long-termchanges in soils and plants. Thisinformation is needed to define

whether restoration following stripmining of coal is acceptably com-plete. OH ER research focuses onplant competition, plant responseto salt and water stress, soil bio-chemical processes, nutrient avail-abiIity, and ecological processesQf long-term significance affectingplant succession on disturbedlandscapes.

The following examples of re-search efforts show that accept-able reclamation of surface-minedland is feasible.

Demonstration field plots at theJim Bridger Mine in westernWyoming show that areas withunstored topsoil deposited directlyon graded overburden can developa stand of naturally occurringnative plants 400 percent greaterthan that of a similar area coveredwith topsoil stored for 2 yearsprior to reapplication. Vegetationcover on the unstored topsoil plotalmost equaled that on unminedareas after 5 years. With this infor-mation, the Bridger Coal Companynow reapplies fresh topsoil when-ever feasible. Because of weatherand other factors, however, topsoilcannot always be deposited direct-ly on graded overburden but, in-stead, must be stockpiled. Howlong can topsoil be stored beforedegrading? In 1981 DOE built anexperimental topsoil stockpile,planted thousands of native plantseeds of known viability, and in-stalled tubes for sampling gas andmeasuring soil density. With peri-odic testing of the viability of theseeds in the pile, the maximumperiod of storage for acceptablelevels of seed germination is be-ing determined. Periodic changesin soil microbial activity areobserved in soil and gas samplesfrom the pile. Results suggest thatdirect reapplication will enableoperators to meet the 10-year re-vegetation period for arid sitesmandated by the Office of SurfaceMining, but use of stored topsoilmay not.

A second, related project is thedevelopment of “super plants”adapted to mined-land reclamationin the arid West. The hybrid nativeshrubs are in the genus Atriplex(saltbush and shadscale) and,

39

]Ianted in the dry saline/clay en-honment found on mined land athe Navajo Mine in the ForJrCor-lers region of New Mexico and:he Jim Bridger Mine in Wyoming,Iave survived better than any ex-sting native plants. Current effortsnclude the development of opti-mum cultural practices andmachine-harvesting methods forMriplex seed. Commercial produc-tion of large quantities of im-woved hybrid seed is possible in:he near future. A similar projectbrasconducted on prime farmlandrather than on arid desert) at theBurning Star Mine in southwesternIlinois.

Benefits Coal companies, underthe exemptions to current regula-tions allowed in some states, are>eginning to use these innovativeand reclamation methods. Pro-~osed changes in requirements by[he Office of Surface Mining willmake these new methods availableLOal I United States’ coal firms.

Current estimates indicate that asmuch as 45 percent of the strip-~able coal reserves in the mid-~estern United States lies beneathwime farmland used for crops,areas similar to the OHER testarea in southern Illinois. Themethod prescribed under the Fed-eral performance standards forreturning surface-mined land torow crop production is to removeand stockpile the topsoil, segre-gated by soil horizon, and thenreplace the horizons in theiroriginal order once mining is com-pleted and the overburden isregraded. Not only is this elabo-rate procedure very expensive, butresearch shows that it is counter-product ive.

The experiments performed at theBurning Star Mine in southern 11-Iinois have so far revealed no dif-ference in crop yield between seg-regated and mixed soi I materials:removing, storing, and replacingthe soil horizons did not increaseproductivity any more than dump-ing newly dug and mixed soilsfrom the bucket-wheel excavator(“wheelspoil”) directly onto pre-viously mined land in a singleoperation. The ANL land reclama-tion program has calculated the

40

:ost of the latter procedure as122,700/hectare in 1979, comparedo $61,800/hectare for the practicesnandated by the Office of Surfacedining.

f the above benefits are extrapo-lated for 20 years, the presentralue of the benefit would be $2.3)illion.

rhe amount of surface-mined coal‘rem western fields was about 200nillion tons in 1980 (assume thatvestern coal is mined at a rate ofj8,800 tons/hectare). The actual:ost of land reclamation at a typ-cal western surface coal mine, theIim Bridger Mine in Wyoming, is~bout $54,400/hectare, of which)arth-moving costs constitute~bout 75 percent. The direct-~pplication method would save~bout one-half of this latterimount or $20,400/hectare. The)otential benefits summed over 20rears would have a present value)f almost $600 million.

:heaper land reclamation offers ateast two other types of social)enefits of enormous significance:1) the environmental damages~voided, such as habitat destruc-tion, soil erosion, siltation ofMaterways, and visual degradation,md (2) the improved market posi-tion of an abundant domesticresource—coal—in relation toimported oil, and the associatedfavorable impact on the UnitedStates balance of payments andon National Security.

Detection and Measure-ment of EnvironmentalEffects

Detecting Change Over theAges The quantitative ratio of oneradioactive isotope of an elementto another isotope (radioactive orstable) of the same element canbe used to date or trace the move-ment of the material containingthose isotopes. The source of theradioactive isotopes may be geo-logic, continually generated natu-rally through cosmic-ray activity, orman-made, originating fromweapons-test fallout or accidentalreleases. Many questions can beaddressed using isotope ratios; for

)xample, the age,of volcanic ashm the ocean bottom, the rate ofJIacier building, the age of the4ntarctic ice, the age and source>f the water at the bottom of the>cean, groundwater age and mo-:ion, the speed of land ercsion,he speed of winds traversing the~tmosphere, and the exchimge‘ate from the stratosiphere of theNorthern hemisphere to that of:he Southern, to mention i~ few.

rwO important applications ofsotope ratios are the long-range:racing of effluents amd establish-ing a historical baseline for as->essing the impact cm the world>cosystem of the recent buildup>f radioactive and ncmradioactivesffIuents.

Wsfor’yBeginning in the 1950’s, the4EC undertook basic research.rsing isotope ratio analysis tech-niques to understanci the long-term dynamics of environmental~rocesses. For example, W. S.Broecker and his colleagues used>arbon-14/carbon-12 (’14CP2C)ratiosto estimate that the mean resi-~ence time of carbon dioxide inthe atmosphere is about 7’years.Bottom water in the Atlantic turnsover once in about 500 yeim andn the Pacific once in abOIJt 1000years.

In 1958 Goldberg suggested theuse of ionium/thoriurn ratios(NTh/23~h) to measure the ac-cumulation of deep-sea sediments,A year later, he disccweredsilicon-32 in marine sponges and, ~with it, determined the rate of ac-cumulation of silicious deposits.Perhaps his most important dis-covery, published in 1972, was theuse of lead-210 for di~ting glaciers,currently the most widely usedtechnique for dating recent (i.e.,the past 100 years) lake andcoastal marine sediments. In 1973he and his colleagues publishedon the use of 228Th/232Thtc~showthat many, if not most, lake andmarine sediments have mixed, in-dicating a greater than anticipatedrole of bottom-living organisms instirring up the bottom. OtherOHER contractors have sincefound “bomb plutonium” 5 to 15centimeters below thle surface ofsediments laid down over many

.

:entur~es,.hdipating a more dy-Iamic environment than previously)elieved. In 1976 Goldberg’s asso-ciates showed that radon-226>ould be used to help date sedi-ments of biological origin depos-ted over the past 5000 years.

Scientists (Harley and H. L.Jolchok) at the DOE Environmen-tal Measurements Laboratoryestablished the ratio of cesium-137md strontium-90 in fallout andJSt?d this information to determinelow quickly artificial radionuclides)enetrated and moved in oceanMaters and what factors (other~han radioactive decay) changedthe ratios. Oceanographers at Ore-gon State University measured Co-

lumbia River outflow to the sea byits chromium-51 content. Naturalradon measurements were used tostudy the movement of undergroumwater and the propensity of soil toretain introduced materials tojudge the safety of waste disposal;PNL measured the natural inter-change of materials between theair and seawater with beryllium-7.

Oceanographers at Hawaii andLivermore used fission products tomeasure the growth rate of corals.Woods Hole scientists usednatural radionuclides to measurethe absorption, resorption, andsettling, that is, the processes thatremove pollutants from the waterand place them in the sediments.

lenetlfs Knowledge of how quicklyhe air is purged of pollutants,low pollutants are swept out of:he ocean and into the sediments,TOWfast coastal waters flush, and~here the materials in rivers are~eposited provides important in-~ights into the ability of the en-vironment to accept human~astes. Thus, some basic issues:an be addressed: the carrying>apacity of nature’s major sinks;[he rate at which the land, air, andNater can accept civilization’s~astes; the time until cleansingmechanisms are operating; andthe time and manner in which~astes break down into compo-lent parts.

41

NuclearMedicineOBJECHVE: Develop to ItsHighest Potential the Applicationof Nuclear Science to theDiagnosis and Treatment ofHuman Disease.

The phenomenon of radiation wasrecognized by early investigatorsto provide an opportunity for bothimproved health care and de-creased health risk. It was fore-seen that radiation provided aunique tool that, through applica-tion of the combined skills ofscientists from the fields ofphysics, chemistry, biology, andmedicine, could be made availablein forms convenient for use by themedical profession for the diag-nosis, as well as for the treatment,of human diseases. Nuclear medi-cine would make it possible tomonitor body functions, isolatethe causes and extent of diseases,and to treat these with methodsnever before possible.

Techniques that Aid inDiagnosis

Research programs sponsored byOHER have improved medicalscience’s capacity to diagnose cer-tain human illnesses. The use ofradioactive elements that preferen-tially concentrate in certain bodyorgans and that can be followedwith very sensitive radiation detec-tors acts to make the body’s inter-nal oraans visible to medicaldiagn~sticians. This combinationof selective radioisotopes andspecial instruments has decreasedmedical cost and simplified ormade more effective some pro-cedures. In general, radionuclidesare injected into the circulatorysystem, the resulting gamma emis-sions are viewed with radiationdetectors, and the detectedsignals are sent to a computer tobe transformed into the imagesused in making the diagnosis.

The development of radioisotopesand their application to diagnosis,therapy, and monitoring of humanhealth problems were accelerateddramatically by the formation ofthe AEC in 1947 and the establish-ment of a formal program to coor-dinate and expand efforts in thisfield. Nuclear reactors made itpossible to generate enormousquantities of suitable radio-nuclides that could be incor-porated into radiopharmaceuticalsat moderate cost. In August 1946the first reactor-produced isotopes

for civilian uses (carbon-14 forcancer research) were shippedfrom ORNL. At the same time,large quantities of radioiodinewere shipped to experimentersand clinicians; and in late 1946S. M. Seidlin, L. D. Marinelli, andE. O. Shory (J. American MedicalAssociation, 1946), announced thefirst effective treatment of thyroidcancer using iodine-130 andiodine-131.

Three examples of radionuclideswidely used in radiopharmaceu-ticals are thallium-201, technetium-99m, and gallium-67, whose usehas resulted in improved and lesscostly diagnosis with lower risk tothe patient. Other medically impor-tant radionuclides include iodine-123, ytterbium-169, xenon-127, andxenon-133.

Thallium=201 for Diagnosis ofHeart Disease Thallium-201 ion isa radiopharmaceutical used pri-marily for detecting cellulardamage and reduced blood flow tothe heart (ischemia). The thalliumions that have been injected in-travenously are taken up by var-ious organs in proportion to theblood supply of the particularorgan. Approximately 85 to 90 per-cent of the radionuclide passingthrough the heart or its blood ves-sels is extracted during each pass.Its use for heart imaging is basedon the relationship between thal-lium uptake and blood flow to thatregion and the integrity of thecells themselves. Therefore, re-duced thallium ion in the heartregion indicates either reducedblood flow, cell damage, or both.

Thallium scans can be performedimmediately after exercise or atrest. The combination of an abnor-mal exercise image in the pres-ence of a normal resting imageindicates reduced blood flow tothe heart. An abnormal exerciseimage that does not differ fromthe image at rest indicates previ-ous cell damage and scarring. Anabnormal exercise image that ismore abnormal than one noted atrest indicates both previous celldamage and reduced blood flow.

History Heart imaging with radioac-tive particles was performed in

43

dogs in 1966, and the feasibility ofdirect injection of radionuclidelabeled particles into humanhearts was demonstrated in 1970using radioiodine. With the directinjection technique, virtually allradioactivity was localized in the~eart and relative regional bloodlow could be determined precise-y. However, the inherent invasive-ness and risks involved limited theImplication of direct injection to)atients requiring cardiac:atheterizat ion.

:xercise-induced regional bloodlow among patients with coronaryirtery disease using intravenouslynjected potassi urn-43 andubidium-81 was demonstrated inhe early 1970s. Thallium-199 andnixed thallium isotopes were usedis imaging agents for heart mus-:Ie in the late 1960s under OHERwpport at the Franklin McLeanulemorial Research Institute. Sci-mtists at BNL developed the‘adiopharmaceutical productionechniques for thallium-201 anddemonstrated its use for heart im-iging in the mid-1970s. This ra-iionuclide is generated as the]y-product of a process that startsvith the bombardment by a parti-:Ie accelerator of stable thallium-!03 metal foils with protons.

rhe United States pharmaceuticalndust ry invested between $20 andF25 million in developing the~apacity to produce thallium-201.n 1981 about 370,000 thal Iium-201jeans were performed domes-tically.Thallium sales by the New:ngland Nuclear Corporationdone increased from $14 millionn 1979 to approximately $20nillion in 1981. Worldwide thalliumsales reached $28 million in 1980,Jp from $17 million in 1979.

Beneflfs The thalIium-201 exercisetesting has filled an important gapin the diagnosis of heart diseasebetween electrocardiograph (EKG)exercise tests and the moreinvasive, risky, and expensive angi-ography using cardiac catheteriza-tion. This is especially true forfemales because false positive fin-dings from exercise EKGs aremuch more frequent. Moreover, th~inherent invasiveness, risk, com-plexity, and cost of angiography

44

Jsing cardiac catheterizationveigh against its use to providehe necessary diagnostic informa-tion in a disease that affects overjOO,OOOAmericans each year. Thehallium examination not only ex-ends benefits to those patientsvho would not be able to with-}tand cardiac catheterization, butt also results in better selection]f those patients who require car-jiac catheterization.

rhe introduction of a new technol-ogy into an already well-developed)rocess produces an altered set of)enefits and costs. For example,~t the Johns Hopkins University+ospital between 1975 and 1977,57 percent of the women who had>ardiac catheterization to investi-~ate chest pain showed no evi-~ence of suspected coronary heartIisease. In these cases, coronarymgiography and simultaneous~atheterization were required to be;ertain that the women did notnave coronary heart disease. To-~ay, nuclear cardiology proce-dures, chiefly thallium-201 exercisetesting, have decreased this toless than 20 percent. Data fromJohns Hopkins also indicate theincreasing linkage of cardiaccatheterization to cardiac surgery,with nuclear examinations solvingnonsurgical diagnostic problems.The total National benefit hasbeen estimated at over $70miIIion/year.

lechnetium=99m for DiagnosticScanning Technetium-99m is a ra-dionuclide with a 6-hour half-life,favorable gamma-ray emissions,and no beta radiation. Dependingon the chemical form, it concen-trates in the liver and kidneys in afew minutes or in the skeleton in2 to 3 hours after intravenous ad-ministration, thus allowing imag-ing with minimal patient radiationdose. Use of technetium-99mscans to examine prostate cancerpatients identifies those—about25 percent of the total—for whomexpensive surgery or radiationtherapy could be replaced by lessexpensive hormone therapies suchas bilateral orchiectomy or exo-getieous estrogens.

Technetium-99m is considered tohave the best overall properties of

;urrently available radiorwclidesor imaging with a scintillation:amera (considering half-life of thadionuclide, patient radiationlose, gamma-ray energy, availabiliy, and cost). Accordingly, it isIsed in over 80 percent of nucleanedicine examinations of the‘arious body organs.

‘or routine diagnostic studies inidult patients, technetium-99m isadministered intravenously inloses of 10 to 20 millicuries.;tudies of the liver and kidney)egin immediately. For the skel-)ton, imaging is usually performe) to 5 hours later.

t has been estimated that one inour patients hospitalized (out of)7 million admissions/year) in theJnited States received a techne-ium-99m-labeled compoulnd as)art of the diagnostic process. Aleast 6 million studies are per-ormed annually. Industry is cur-‘ently producing teclnnetium-99m,rvithsales totaling $26nillion/year.

YistoryArt if icially produced tech-netium is usually obtained from~ctivated molybdenulm-98. Tech-netium was discovered by’ EmilioSegre and Glenn Sei~borg in 1938it Berkeley, California, in theaboratory of Ernest Lawrence.blolybdenum-99 and its daughterluclide, technetium-99m, were ob:ained as a result of the fissionwocess.

‘or many years the Imedic:alposs~ilities of the use of technetium-)9m were overlooked because ofts relatively short half-lifo (6Tours). However, L. G. Stang, Jr.md Richards (working at BNL) intented the radionuclide generate+in which the user could chemi-~ally separate the technetium-99[adionuclide from its longer livedradioactive parent, molybdenum-$This made possible the availabiliof the short-lived radionuclide atthose sites where a reactor wasnot available.

Stang and Richards advel’tisedboth molybdenum-99 andtechnetium-99m for sale (cmthecover of the Brookhaven catalog1960. In 1961 Beck published atheoretical study demonstrating

that the,oplim~ gamma-ray en-ergy for detecting brain tumors isbelow 200 kiloelectron volts, thuscalling attention to materials suchas technetium.99m. In 1963 Harperintroduced a series of importantcompounds labeled with thisnuclide. These compounds areused in medicine to diagnosedisease, aid in planning treatment,monitor the response to treatment,and elucidate the cause of thedisease. Technetium-99m-labeledcompounds amenable to bonescanning were introduced in theearly 1970s; labeled methylenedisphosphonate and related com-pounds are now the primaryagents used in bone scanningapplications.

Benefits Technetium-99m currentlyhas a broad range of diagnosticapplications, as shown in Table 3.One important application oftechnetium-99m is its use in bonescanning to detect the presenceof metastasis associated withcancer of the prostate.Technetium-99m replaces isotopesof strontium that have high radia-tion levels, long half-lives, andpoor physical properties, as wellas isotopes of fluorine-18, whichhas high energy gamma radiationand must be produced in acyclotron.

Table 3. Number of In VivoNuclear Medicine ExaminationsPerformed by Organ System, 1982

Examination Number of Millions

BrainBoneLiverLungThyroidKidneyHeartOther

Total

0.811.811.421.200.680.240.950.307.41

Source: Mettler, E A., et al., J. Nut.Med. 26(2),201-05, February 1985.

Cancer of the prostate is the mostcommon cancer in men over theage of 50. The median age for thedisease is 70. There are approx-imately 57,000 new cases and

25,000 deaths each year in theUnited States. Treatment for thedisease varies with the severityand advancement of the cancerand ranges from surgical removalof the prostate (prostatectomy), orradiation therapy in less advancedor localized cases, to hormonetreatment for relief from symp-tomatic pain in the more advancedor metastasized cases.

The use of technetium-99m bonescans enhances the diagnosticability for early identification.Thus, costly radical prostatectomysurgery or radiation therapy canbe avoided in patients with ad-vanced cases where symptomaticrelief is the appropriate treatment.Additionally, bone scans allow thephysician to respond to varioustherapies or disease progressionsafely and noninvasiveiy.

Prostatectomy has been used fordecades by pioneering institutionssuch as the John Hopkins Univer-sity Hospital as treatment for“curable” prostate cancer. Radia-tion therapy is an alternative treat-ment used by such major cancertreatment centers as Sloan Ketter-ing Memorial Institute and is be-coming more widespread.

A quantitative benefit oftechnetium-99m scanning wasderived by computing (1) the netprostatectomy costs and (2) thenet radiation therapy costsavoided. Averaging the net costsof the two treatments, assumingthat one-half of the patients wouldhave had prostatectomies and one-,half would have had radiationtherapy, yields an estimate of thecost benefit of about $92million/year.

Gallium-67 for Diagnosis ofHodgkin’s Disease Intravenouslyadministered radiopharmaceuticalscontaining gallium-67 emit highlypenetrating gamma rays (with ahalf-life of 78 hours) and concen-trate in tumors and abscesses.Gallium-67 was discovered at theBerkeley cyclotron in the late1930s and was demonstrated .clinically at Oak Ridge in the late1960s. A two-dimensional imagecalled a scintigraph is taken after48 hours, using either a whole-

body rectilinear scanner, a large-view gamma-ray camera, or a scan-ning. gamma-ray camera. Gallium-67 scintigraphy is of great value indiagnosing cancer of the lungsand peripheral lung tumors thataie not accessible by bronchos-copy. It is a valuable tool formonitoring response to chemo-therapy and radiation therapy. Theuse of gallium-67 for localizingabscesses is increasing and maysoon exceed its use for localizingtumors. Early detection of bone in-flammation (osteomyelitis) bygatlium-67 scintigraphy enablesphysicians to begin antibiotictherapy before extensive bonedestruction occurs. The early useof gallium-67 in investigating“fever of unknown origin” frequent-ly allows the physician to embarkon a more fruitful, cost-effectivesearch.

Currently, approximately one-halfof all gallium-67 studies are per-formed for abscess localizationand one-half for tumor diagnosis.In 1979 approximately 250,000gallium-67 scans were performedin the United States at a cost of$5 million.

WsforyThe development ofgallium-67 for use in detectingtumors and abscesses can betraced to the early 1950s, whenHC. Dudley at the Naval ResearchLaboratory (NRL) was conductingresearch on the toxicity of stablegaUium-71. In the course of thisresearch, it was noted thatgal,lium-71 has an affinity forosteogenic (bone-related) activity.This led to investigation by ORNL,BNL, and NRL into applications ofreactor formed gal lium-72 em-bedded in stable gallium-71 foruse in bone scanning. However,the short half-life (14 hours) andhigh energy of the gamma radia-tiofi (4 million electron volts) madethis approach unacceptable.

In 1968 gallium-67 in gallium-71was being evaluated as a newalternative for strontium-85 inbone scans. During this activityR. L. Hayes, C. L. Edwards, andothers at the Oak Ridge Associ-ated Universities observed thatgallium-67 in its carrier-free formconcentrates in tumors and

45

abscesses as well, permitting theirdetection via gamma-ray spectrog-raphy. This observation sparkedthe development and use ofgallium-67 for detecting tumors (J.Nuclear Medicine 13:92-100, 1972).

Benefits A single application ofgallium-67 scanning as part of adiagnostic package for detectingHodgkin’s disease demonstratesthe range of potential economicbenefits from the use of thisradioisotope. In the diagnosis ofHodgkin’s disease, patients areclassified into four stages basedon the number of lesions in thelymphatic system. In stage one,the disease usually involves onlyone lymph node region and isusually treated with radiotherapy.Stage two involves two or moreadjacent lymph node regionsabove the diaphragm and is alsousually treated with radiotherapy.Stage three involves lymph nodesabove and below the diaphragmand is treated with radiotherapy,supplemented by chemotherapy inselected cases. Stage four, charac-terized by more diffuse and dis-seminated involvement of thelymph nodes and other organs, isusually treated only by cherno-therapy, with only relief and nocure expected.

The benefit of gallium-67 scanningarises from the ability to discrimi-nate between advanced stagesthree and four of this disease andcan be estimated as the avoidedcost, about $10 million/year, ofradiotherapy for individuals classi-fied as stage four. Also importantis the use of gallium-67 in follow-up treatment to evaluate remissionor relapse, especially when con-fusing signs and symptomsappear. Symptomatic patientsfollowed yearly, for example, canhave recurrent disease thatgallium-67 studies allow to betreated early and possibly moreeffectively. Conversely, manyrelapse symptoms are found to befalsely positive and not indicativeof disease.

hwtruments Tha? Aid inDiagnosis

A key to novel and increased uses

of radioisotopes inmedicine has been

nuclearimproved in-

Xruments. Advances in imaging~quipment that resulted from the~ost-World War II explosion inAectronics and computer devel-opment had major impacts in im-woving detection sensitivity andthe range of diagnostic studiesthat could be performed. Thehigh-sensitivity Anger camerawith sodium iodide (thallium)scintillators accentuated thesignificance of such radioiso-topes as iodine-123 and techne-tium-99m, whose low particulateand gamma ray emissions areappropriate for camera use. Also,use of this modern imagingsystem allowed thallium-201 tobe developed and utilized fordiagnostic scanning of coronaryartery disease.

The advanced imaging equipmentallowed temporary concentrationsof radioisotopes in various organsto be measured with good multi-dimensional spatial resolution.Thus, in addition to organ struc-tural measurements, dynamicbody functions such as circula-tion and organ metabolism couldbe measured. The Positron Emis-sion Tomography (PET) scannerprovides a good illustration offunction-measuring capabilities.

When nuclear instruments werefirst developed by isolated groupsof research scientists in differentlaboratories and institutions, theabsence of standardization wasnot an important issue. However,as usefulness of these instru-ments increased, their usemoved to other laboratories andthe medical service industry. Thedemand grew accordingly, andthe total investment became large.Therefore, plug-to-plug compat-ibility of instruments from varioussources became both a scientificand an economic necessity. Toaddress this problem, the NuclearInstrument Module (NIM) systemwas developed under the OHERProgram to provide a basis forreplaceable plug-in instrumentsthat form modules in power sup-ply and instrument racks. TheComputer Automated Measure-ment and Control (CAMAC)

system which was tt~ providecompatibility at other electricalinterfaces and in data formats fol-lowed later and is now an interna-tional standard.

The $clntiiiation Cameral TheAnger scintillation ci~mera allowsthe image of a photcm (gammaray) source to be reconstructed.It is the most widely usedimaging device in nulclearmedicine woridwide, bein{~ usedfor 80 percent of the studieson patients in nuclear me(dicine.It was invented to replacemechanical scanning.

The Anger camera uses scin-tillation crystals and photomul-tipliers to obtain serial images ofthe distribution of a radioactivetracer within the bocly at varioustimes after the tracer is injectedintravenously. The di~ta are ana-lyzed and processed by a digitalcomputer and displayed on avideo screen to provide quan-titative information about regionalbiochemistry and physiolclgywithin virtually every organ of thebody.

The Anger camera consisls of alead, multihole, collimator, a 10-to 15-inch-diameter sodium iodidescintillation crystal, i~ two.dimen-sional photomultiplier tube arrayon the crystal face, and a posi-tioning logic network. The leadcollimator allows only thosephotons traveling in the preferreddirection (i.e., those that can gothrough the holes without beingabsorbed by the Ieadl) to strike thfcrystal and cause it to emit light.The photomultiplier tubes closestto the scintillation event (pulse oflight) produce the longest signal.An energy discriminator alllowsonly those photons associatedwith gamma rays of :speci’fiedenergy level to be detected.Thus, the camera prclduces asignal showing the positicm ofevery scintillation event withthe appropriate photon energy.A collection of these signials overtime produces an amalog image ofthe organ being viewed in theform of a two-dimensional pro-jection of the three-dlimervsionaldistribution of radioactivity withinthe patient.

46

.

lfWofy The scintillation camerawas invented by Hal Anger in 1958at the Dormer Laboratory, an AEC-sponsored facility. A number ofimproved versions of the camerahave been developed, buildingupon Anger’s original invention.Paul Harper of the FranklinMcLean Research Institute, devei-oped in the 1960s the scanningcamera concept that permitted thecamera’s field of view to be ex-tended to make whole body scan-ning possible. A new version ofthe camera permits rotationaround the long axis of a patient.Images acquired at a number ofangles around the patient areused with a computer for high-lighting three-dimensional charac-teristics of organs or structures ofinterest.

Bef?eflfi The nuclear cardiologyprocedures that’ use thallium-201and technetium-99m are performedalmost entirely with this camera.Thus, the numbers cited for pa-tients diagnosed and the benefitsassociated with thailium-201 andtechnetium-99m apply to theAnger camera as well. About onein four patients in Americanhospitals has an examinationwith the scintillation camera aspart of the process of medicaldiagnosis.

Anger cameras are now being in-terfaced with digital computersproduced by specialized nuclearmedicine manufacturers. Byenhancing the images produced,such computers allow improvedvisual interpretation. More im-portantly, because the images arestored in the computer as a matrixof numbers, quantification’ is pos-sible. Using mathematical modelsof physiological processes, thecombination of Anger camerasand computers permits nonin-vasive measurements that werenot previously possible.

In 1981, 6740 cameras were distrib-uted among hospitals of ail sizesin the United States.

Scanning instruments-PET PETscanning is a technique used innuclear medicine to provide vir-tually three dimensional images ofbody functions. The technique

measures the direction and inten-sity of gamma+ays from a positronemitting radiopharmaceutical inthe body.

Computer Assisted Tomography(CAT) scanning, which has beencalied the most important advancein medical diagnosis in a decade,uses X-rays and sophisticatedcomputer technology to provideviews of the body’s interior, reveal-ing in striking detail the anatomyand structure of various organs.PET scanning carries tomographyone step further, depicting the ac-tive functioning of body organs,such as biood flow and glucosemetabolism in the brain. Thus,PET represents “new” nuclearmedicine.

A person undergoing a PET scanbreathes or is injected with asmall amount of a radiopharma-ceutical labeled with a short livedradioactive isotope of some ele-ment that occurs naturally in thebody (such as oxygen, nitrogen, orcarbon). The radioisotope, pro-duced in a cyclotron, emits posi-trons while undergoing radioactivedecay. (Positrons are particles thathave the same mass as an eiec-tron, but a positive charge.) Thepositrons are attracted to elec-trons associated with the normalmatter in the body, and when theparticies meet (and annihilateeach other), two gamma rays (eachwith 511 kiloelectron voit ofenergy) are emitted in oppositedirections (180 degrees from eachother).

The gamma rays are detected us-ing a ring of radiation sensitivecrystais placed around the pa-tient’s head or body. When twogamma rays are detected by op-posing crystals at the same time(“in coincidence”), the site of an-nihilation is assumed to be aiongthe imaginary line joining the twocrystals. The set of such iinesdetected over time from differentpairs of crystals is fed to a com-puter, which reconstructs an im-age representing the internaldistribution of the radioisotope.The image of body function orstructure of interest is thendisplayed on a video terminal orrecorded on film.

HistoryThe first imaging device toexpioit the unique geometricalproperties of the positron-electronannihilation reaction using scintil-lation detectors was constructedwith OHER funding in 1953 byGordon Brownell at Massachu-setts General Hospital. The firstPET scanner (PETT) was built byMichel Ter-Pogossian and col-leagues at Washington Universityin St. Louis in 1974, with supportfrom the National Institutes ofHealth (NIH). Scanners subse-quently designed and built withsupport from NIH, DOE, and in-dustry include:

1. PETT Ill, IV, V, and VI atWashington University;

2. Dormer 280 crystal tomographat the University of California atBerkeleM

3. Emission Computed AxialTomograph (ECAT);

4. Neuro ECAT at the University ofCalifornia at Los Angeles(UCLA);

5. Neuro PET at NIH; and6. Other new tomographs at

Massachusetts GeneralHospital, the University ofTexas, and the University ofPennsylvania.

Several manufacturers, includingPositron Corporation (Houston,Texas), Cl~ Inc. (Knoxville, Ten-nessee), and Scanditronix(Sweden), now market PET scan-ners. The average cost of a unit isaround $1 million. Clinical applica-tions of PET have included imag-ing of the cardiac blood pool andbiood flow in the brain and heartby the Phelps (1976); imaging ofthe heart, lung, and brain by TerPogossian (1976) and Budinger(1979); and imaging of the cardiacblood pooi and blood flow by Hoff-man (1979).

BenefWs Perhaps the most excitinguse of the PET to date is to studybrain metabolism quantitatively. insuch studies, deoxyglucose, ananalog of giucose that is taken upby metabolically active areas ofthe brain as glucose, is Iabeiedwith carbon-n or fiuorine-18 andthen injected into a patient’sblood stream. PET provides three-dimensional views of the brainthat quantitatively reflect the rate

47

d which glucose is metabolized inIifferent regions of the brain.)ome remarkable findings have re-iuited from such studies

1

TIicinStsisiinNfii

InStthWIasthS(

1.

2.

Kuhl and colleagues at UCLAhave scanned the brains ofepilepsy patients, includingsome during seizures. The PETscans show that the brain cellsthat trigger a seizure are metabolically active during an at-tack. What surprised epilepsyspecialists is that these samebrain cells are less metabolical-ly active between seizures thanthey are in normal people. Thesignificance of this finding isas yet unknown.

The UCLA doctors also haveused PET to locate preciselythe trigger site of seizures inpatients where it could not bedetermined by other means.This has led to successfulsurgery in some previously in-operable cases.

NIH researchers have confirmeda theory that rare but deadlybrain cancers called g/iomas in-crease their metabolism whenthe speed of their growth in-creases. Doctors may delayoperating on such tumors intheir early stages because thesurgery itself can do seriousdamage to the brain. The prob-lem is that no good way nowexists to determine the growthrate of the cancers. PET couldbe the answer.

Istrument Standardization Twoandard instrumentation systems,Ie NIM and the CAMAC systems,ere developed and coordinatedi a result of efforts to improvele effectiveness and efficiency of>ientific instrumentation.

le NIM system provides mechan-al and electrical power supplyterchangeability of scientific in-:ruments and encourages a pon-derable degree of electricalgnal compatibility. MechanicalIterchangeabi Iity means that anyIM module (e.g., an amplifier) willt mechanically into any NIM binLframe for holding modules).Iectrical power supply inter-changeabilitymeans that any NIMIodule, when inserted into any

clm

48

~lM bin, will be connected to the>orrect power supply. CAMAC in->Iudes these features plus thecompatibility of digital signals andsignal transfer processing, systemnterconnections, interfacing to~omputers and other processors,md associated software.

NIM and CAMAC are now the prin-;ipal instrumentation systems usedthroughout the world in nuclearmd radiation physics, nuclear~hemistry, and nuclear medicine.Their use has also spread intoDther areas, including general lab-watory and industrial research andindustrial applications in processcontrol and automated testing.

The CAMAC specifications a~enow industrial standards world-wide, having been promulgated bythe American National StandardsInstitute (ANSI) and the Instituteof Electrical and Electronics Engi-neers (1EEE), as well as by the in-ternational ElectrotechnicalCommission (lEC).

Approximately 80 firms supplyNIM instruments and equipment.Over 50 firms manufacture CAMACequipment. Major manufacturersof NIM and CAMAC instrumentsestimated United States sales for1982 to be $23 million for NIM and$17 million for CAMAC The UnitedStates market for NIM accountsfor about 50 percent of the world-wide market, and the United Statesmarket for CAMAC accounts forabout 60 percent of the worldwidemarket.

H/story Prior to the development ofNIM and CAMAC, the users ofsolid-state nuclear instrumentationwere severely limited in their abil-ity to use the best available in-strumentation. Instruments fromdifferent manufacturers often wereneither electrically nor mechan-ically compatible. Consequently,the nuclear instrument user oftenhad to choose to bypass the mostappropriate instrument, to incurexcessive costs by replacing allmodules to obtain one newcapability, or to design expensivead hoc interface instruments.

In December 1963 the NationalBureau of Standards, under con-tract to AEC’S Division of Biology

md Medicine (now OtjER), urgedhat the National f..aboratoriesIevelop a module that could)ecome standard in all of thoseaboratories. Representatives ofhe National Laboratories met on‘ebruary 26, 1964, to establish the~lM Committee and assign‘responsibility for developing a}tandard module system. Pro-otype bins and modules w~erepro-kced by ORNL, LBL, and LLNL.rhe specifications for the NIMiystem were published in July1964.

4s automated and computer-linkedmclear instrumentaticm systems:ame into use, however, new com-patibility problems arc)se. in late1964 the Harwell Laboratory in%gland took the initiative to)rganize the development of2AMAC In 1967 responsibility for[he system development passed to:he European Standards or Nu->Iear Electronics (ESOINE) Com-nittee of European Laboratories,which initiated close collaboration~ith the United States NIM Com-mittee (still under OHER sponsor-ship): The ESONE NIM collabora-tion continues.

BeneflfsThe benefits identifiedwith the NIM and CAMAC stand-ards include:

1. Flexibility and interchange-abilityy,

2. Optimization of systems,3. Ease of restructuring,4. Deferred obsolescence,5. Reduction of interfaces,6. Ready interchange between in-

stallations,7. Reduction of inventories,8. Increased utilization of in-

struments,9. Ease of serviceability,

10. Reduction of design coats, and11. Savings in software costs.

These advantages can be trans-lated into producer surplus or costsavings resulting from the use ofNIM and CAMAC equipment. An-nual benefits for 1982 were esti-mated to be $40 million. The pres-ent value of past and preseint costsavings associated with NI M andCAMAC between 1964 and 11982totals $1.9 billion. Major factorscontributing to these benefits are.

1. Fifty-percent reduction in datatransf& speeds;

2. Lower equipment costs (CAMACusers indicated that equipmentcost for a CAMAC system canbe 20 to 40 percent lower than ~the alternative); and

3. Reduced inventories (interviewswith National Laboratory per-sonnel indicate that for everyNIM or CAMAC model in inven-tory, at, least four of an alter-native instrument would have tobe in inventory).

lteatment

Nuclear medicine has promotednew medical treatments directlyand indirectly. Direct results havecome through the use of radioiso-topes that are specially producedand economical Iy avaiIable. Treat-ment procedures have been modi+fied by the involvement of abroadened range of scientificdisciplines such as physics, radia-tion health physics: and electronicengineering. These disciplinesbrought a new dimension tomedicine.

The direct use of radioisotopes in-cludes cobalt-60 for the treatmentof tumors, cesium to power im-planted heart pacemakers, and theuse of special radiation beams, aswell as complementary instrumen-tation. Economic availability alsogreatly enhanced the use of radio-iodine in thyroid treatment. Amongthe most recent experimentalresults is the treatment of tumorswith radioactive monoclinal anti-bodies. iodine-131 to treat hyper-thyroidism and thyroid adenomas(benign or low malignancy tumors)typifies the use of radionuclidesfor medical treatment.

The use of radioisotopes in diag-nosis allowed the tracing andunderstanding of body functions”(especially the immune and bloodsystems) not previously possible.These new understandings pro-moted the indirect benefits of newnonnuclear treatments, For exam-ple, studies to develop specific in-hibitors of protease enzymesresulted in the discovery of a com-pound that acts against thrombin,an enzyme that induces bloodclotting. The compound has been

patented and is used as an an-ticoagulant. Another example isthe development of L-dopa (levo-dopa) for the treatment of Park-inson’s disease.

iodine-131 Therapy for Hyper-thyroidism iodine-131 is a radioac-tive isotope that concentrates inthe thyroid gland and, thus, can beused in the diagnosis and treat-ment of thyroid disorder. Thisisotope has an 8-day half-life andemits high-energy beta particlesand gamma rays in the region of360 kiloelectron volts and higher.

Hyperthyroidism is a hypermeta-bolic state, caused by excessivelevels of circulating thyroid hor-mones, which contributes to avariety of clinical symptoms. Thedose of iodine-131 that concen-trates in the thyroid gland de-stroys abnormal, hyperactivethyroid tissue that is producingexcess hormone. This treatment,therefore, allows the gland toreturn to normal activity withoutsurgery, hospitalization, or adverseeffects on other tissues.

History In late 1939, J. G. Hamiltonand M. H. Soiey (University of Cali-fornia-Berkeleyj published a paperon the first use of iodine-131 in pa-tients with benign thyroid disease.In early 1941 the first patient wasadministered a therapeutic dose ofiodine-130 and iodine-131 at MIT,and in late 1941 iodine-131 wasused therapeutically against toxicgoiter disease at Berkeley. Inmid-1946 iodine-131 from nuclearreactor fission products was beingshipped from ORNL, and in late1946 iodine-131 was used bySeidiin for successful treatment ofmetastasized thyroid cancer. Untilthe mid-1960’s, iodine-131 was themain nuclide used for the diagno-sis of many diseases. After themid”-1960’s,many diagnostic usesof iodine-131 were supplanted bytechnetium-99m labeled com-pounds. iodine-131 is still extreme-ly important, however, in evalu-ating thyroid condition and thyroidcancer therapy, for studyingthyroid uptakes, and for thyroid”imaging.

Benefits Radioactive iodine-131 isused in about 12 percent of all

nuclear medicine procedures andis a good exmple of the use ofradioactive therapy. Over the past10 years at the Johns HopkinsUniversity Hospital, surgery forhyperthyroidism has decreaseddrastically from 3000 to 4000caseslyear to a current level of50/year. This reduction can be at-tributed to the use of nuclearmedicine therapy with iodine-131.

In the United States, radioactiveiodine is the preferred treatmentfor adults suffering from hyper-thyroidism. Because peak occur-rence of hyperthyroidism occursbetween the ages of 30 to 50, ap-proximately 85 percent of hyper-thyroid patients are now treatedwith radioactive iodine. The al-ternative medical treatments forhyperthyroidism are surgical re-moval of the thyroid gland anddrug therapy. Surgery is invasive,painful, and expensive and carriesa significant risk of complicationsand, possibly, death. Drug treat-ment can be long term, can haveserious side effects, and, in manycases, may still require subse-quent surgery. The comparativecosts (in 1982) of surgery andiodine-131 treatment reported for amedical teaching center were$7400 and $600, respectively. Thereported overall incidence ofhyperthyroidism in females andmales is, respect ively, 4.7/10,000and 1.06/10,000. Thus, the totalestimated savings in treatmentcost because of the use of iodine131 could be as high as $280million/year (based on the UnitedStates incidence of hyperthyroid-ism in 1980).

L-Dopa Treatment for Parkinson’sDisease L-dopa [(-)-3(3,4-dihydroxy-ophenyl)-L-adamine or Ievodopa] isan amino acid used in the treat-ment of Parkinson’s disease. Oraladministration of L dopa substan-tially slows the rate of progressionof the disease, reduces symptoms,and decreases the mortality rate.

Parkinson’s disease is a pro-gressive neurological disease thatproduces tremors, inability to planor initiate a movement, inability tocontrol movements, rigidity, anddisturbance of postural reflexes.The disease is characterized by a

49

marked deficiency of a chemicalcalled dopamine in the brain, thecause of which is unknown in themajority of cases. Parkinson’sdisease mainly strikes the aged,with onset between the ages of 50and 70 in two-thirds of the cases.However, a rare juvenile form alsoexists. The disease affects closeto one million persons, and thereare 50,000 new cases each year.

Following its clinical introduction,L-dopa quickly became the prefer-red treatment and remains so to-day in a number of derivativeforms. Although it does not curethe disease, it retards progresstoward complete debilitation sothat patients remain functional forseveral additional years. Symp-toms present at the initiation of L-dopa treatment are generallyreduced dramatically but reappeargradually, along with other symp-toms that may be associated withthe therapy.

in a broader context, L-dopa repre-sents a dramatic advance in thetreatment of diseases of the brain.It has provided a rational approachto medical treatment based onbrain biochemistry and has stimu-lated interest in research onneutral diseases based on similarbiochemical principles.

History In the early 1950’s, therewas widespread interest in thebiochemistry of trace metals, andthe use of radiotracers was devel-oping. Dr. George C. Cotzias ofBNL was searching for a researcharea employing radioisotopes oftrace metals to study the chemicaleffects of the metals in humansover long periods. Links betweenmanganese poisoning and Parkin-son’s disease had been discussedin the literature. Dr. Cotzias in-vestigated manganese-56 becauseit was easy to make and had anappropriate half-l ife.

Although it turned out that therewas not a good connection be-tween Parkinson’s disease andmanganese poisoning, several im-portant new areas of researchevolved from these studies. Onestemmed from Dr. Cotzias’sunderstanding, gained in hisresearch, of how the chemical

50

Table 4. Life Expectancy for Pre-L-dopa @nc&, ,Post-L-dopa Treatment

Age at Normal Life ExpectancyOnset of Life (Years)Disease Expectancy(Years) (Years) Pre-L-dopae Post-L-dopab Post-L-dopa

50 23 13 19 2060 15 8 11 12

‘Excessmortality rates calculated from Hoen and .Yahr, “319

Neurology 17,427-42 (1967).~Excessmoflality rates calculated by Macdowell, papaVaSilOUan(~ swe~?t, 1979,‘Excess mortality rates calculated by Diamond and Markham, 1979

balance in the body graduallychanged when a new substancewas introduced.

The deficiency of the amino aciddopamine in the brains of personssuffering from Parkinson’s diseasehad recently been discovered.Although it was not possible to in-troduce dopamine directly into thebrain, it had been postulated thatintravenous introduction of itsmetabolic precursor, levo-dopamine, might correct the braindopamine level. Short-term clinicaltrials were unsuccessful; however,they were inconclusive and pro-duced adverse reactions.

Dr. Cotzias recognized the needfor very gradual L-dopa administra-tion over long periods. The re-search hospital at BNL providedthe capability for the necessaryclinical trials, which proved suc-cessful. The first report of long-term L-dopa treatment waspublished by Dr. Cotzias in TheNew England Journal of Medicinein 1968, and a follow-up report onthe results of a 2-year clinicalstudy was published in the samejournal in 1969. A February 1969editorial described his work as“the most important contributionto medical therapy of a neurolog-ical disease in the past 50 years!’Dr. Cotzias received the Albert andMary Lasker Award for Experimen-tal Medicine in 1969.

Ber)eflts The two major benefitsassociated with the use of L-dopain the treatment of Parkinson’sdisease are extension of life ex-pectancy and delay of disability.

1. Extension of life expectimcy.Two studies provide a bi~sis formeasuring the effect of L-dopatreatment for increasing the lifeexpectancy of a patient. Thefirst study followecj a group of100 patients on L-dopa therapyfor 10 years beginning in 1968.During that period, 56 died,leading to a calculated excessmortality ratio of 1,54 for un-treated patients. The secondstudy surveyed a random sam-ple of 327 patients who werebeing treated with an L-dopaderivative over a 5-year periodand found an excess mcrtaiityratio of 1.42 for untreated pa-tients. These figures can betranslated into an individual lifeexpectancy extension fortreated patients with an as-sumed age of disei~se onset(see Table 4).

2. Delay of disability. L-dopa ther-apy has also been found to pro-duce moderate to markedimprovement in 50 to 75 percentof Parkinson’s disease pat ient’sability to function. Two studiesdemonstrate the initial improvem-ent and subsequent decay ofindependent performances ofpatients treated with L-dopa.

A disability index related tosymptons and ability to performnormal functions was calculatedat various times during the10-year period. For the 41 pa-tients who remained in thestudy throughout the period, th{average disability index im-proved initially, but at the endof 10 years, the index was the

.

same a$ that Rrior to treatment.However, although the indices hadthe same value and the impact onindependence was similar, thespecific disabilities at the end of10 years were not primarily motor-and tremor-related as in the initialsituation, but tended more towardinstability and dementia.

In a private communication, Dr.Thomas Presiozi of the JohnsHopkins University HospitalityNeurology Department confirmedthat about 80 percent of thedeaths of Parkinson’s disease pa-tients are actually due to causesunrelated to the disease or itseffects.

51

. .

The Future This account of selected accom-plishments over the 40-year pro-gram of energy-related health andenvironmental research only par-tially illustrates its role in fulfillingan important National need. Useof this style of presentation makesit difficult to convey the program’smost important characteristics: anevolutionary, integrated, and multi-disciplinary research commitment;a synergism between fundamentalscience and applied problem solv-ing; and an inevitable share ofscientific setbacks, as well asachievements. Thus, in reality theaccomplishments represent a con-tinuum of scientific developmentfrom the basic unraveling of bio-environmental processes and thecoupling of seemingly disparatefacts to their application tospecific problems.

These program characteristics, inturn, lend a distinct characteristicto the research itself; it drawscontinually upon an establishedbase of knowledge, the rewardsbecoming increasingly apparentfar downstream from the initialthought and investment. Thus, tolarge extent, the program’s futureaccomplishments are alreadyembedded in its studies of thepast and the present.

a

As a part of the evolving Nationalenergy mission, a responsiveresearch program has developedthe expertise and facilities re-quired for its newer roles. Theevolution continues, centeredaround a long term commitmentfundamental and basic research

to

and aimed at addressing problemsand issues of a high-risk naturewith an anticipatory rather than aregulatory approach. Of particular

importance to the future is thefact that the program’s multidisci-plinary talent and capabilities inunique, dedicated facilities con-stitute a valuable Nationalresource.

The research program is, therefore,as well equipped to meet futurechallenges as it was to meet pastchallenges. As our energy missioncontinues to evolve, with changingpatterns of energy demand andthe accompanying development ofresponsive new sources, it isreasonable to expect researchcontributions to assure safety, ac-ceptability, and compatibility withthe National goal.

The promise for the future, there-fore, lies within the Program’straditionally interactive and inter-disciplinary approach to complexproblems. New biophysical andchemical tools and techniques inbiomedical and environmentalresearch now make it possible toattempt unprecedented studieson cells, molecules, and proc-esses relevant to the triad. Thesetechnical advances, applied tobasic studies, will continue tocontribute answers to energy.related questions, as well as toincrease knowledge about causesand effects in biological systems.As in the search for radiationrepair mechanisms that led todiscoveries of DNA behavior andimportant theories of the nature ofhuman disease and its treatment,the Program’s research will con-tinue to lead in making funda-

I mental and practical contributionsin reducing uncertainties aboutthe health and environmentalaspects of emerging energytechnologies.

53

. .

AppendixThe HealthandEnvironmentalResearchProgram

The Office of Health and Environ-mental Research (OH ER) managesthe Department’s Biological andEnvironmental Research (BER)Program. The mission of OHER isto develop and sustain a highquality basic and applied researchprogram at the frontiers ofbiomedical and environmentalscience consistent with the mis-sion of the Department of Energy(DOE) and the objectives of theOffice of Energy Research. Morespecifically, the OHER programobjectives are based on thefollowing considerations:

1. OHER is the principal organi-zational unit within DOE forconducting research on environ-mental and human health ef-fects of energy strategies. Theobjective of these research pro-grams is to develop principlesand broadly generalizableknowledge that will be neededto address the wide range ofquestions that must inevitablybe faced by future generationsas well as by our own. OHER,therefore, is committed to usingthe most advanced scientificmethods and technologies toexplore the fundamental issuesbearing on assuring safe energyoperations, for example, themolecular and subcellular mech-anisms which underlie humancellular, genetic, and environ-mental pathology and toxicology.

2. The Office recognizes that theunique facilities and computa-tional capabilities, as well as in-terdisciplinary breadth anddepth of skilled scientists atthe National Laboratories, offerthe Nation an important oppor-tunity for addressing a widerange of important research anddevelopment problems. Pro-grams ‘in the area of nuclearmedicine have contributed sub-stantially to the health andeconomic well being of theNation. OHER is committed tofurther development of theseand other areas, such as bio-technology and related capitalintensive long term projects. instructural biology, which fullyutilize the human and techno-logical resources of theNational Laboratories.

3. OHER views the NationalLaboratory system, researchuniversities, and the private sec-tor, as members of the sameteam working toward the solu-tion of some of the Nation’smost important problems. TheOffice is, therefore, dedicated toencouraging synergism betweenthese three research sectors byvarious means, including stimu-lating access to advancedmultiuser research facilities atthe National Laboratories; thesupport of student fellowshipand faculty sabbatical programsfor collaborative research at Na-tional Laboratories; and thetransfer of tools and technol-ogies developed at the NationalLaboratories to the private sec-tor and universities.

To attain these goals, a number ofinterdependent research objectivesare addressed. The major objec-tives of the program are to:

1.

2.

3.

4.

5.

Develop new concepts, pro-cedures, and instrumentationfor detecting and measuringenergy related physical andchemical agents released intothe occupational and generalenvironment;

Characterize the long term at-mospheric transport and chem-ical transformation processes ofradionuclides and energy re-lated chemical effluents to im-prove estimates of dispersionand potential human exposure;

Elucidate the mechanisms thatcontrol natural ecosystems andthe processes that influencecycling of nutrients and energyrelated materials through ter-restrial and aquatic ecosystemsand to measure ecological ef-fects resulting from energyrelated stresses to better pre-dict environmental impacts andresiliency;

Quantify the late biological ef-fects of exposure to ionizingradiation through long termhuman and experimental animalresearch;

Resolve the uncertainties as-sociated with carcinogenic,

55

,

mutagenic, and toxic effects ofenergy related chemicals andcomplex mixtures of chemicals;

Define mechanisms involved inthe induction of biologicaldamage following exposure tolow levels of energy-relatedpollutants by supportingresearch on bimolecular struc-ture, gene function and control,genetic damage and repair, andcell transformation; and

Develop new approaches, in-struments, and methodology forthe improved diagnosis andtherapy of human diseases, andin the study of human physio-logical processes, including thebrain and heart.

rhe research is carried out in theollowing major program activities.

4ealth Effects Research This pro-]ram is primarily concerned withwaluating the delayed types of~ealth effects—tumors, heritable~efects, developmental effects,md damage to body organs—thatwe caused by chronic low-level ex-]osure to energy-related physicalmd chemical agents. The researchJtilizes molecular, cellular, andmimal test systems to obtain~uantitative data on dose response‘elationships and to develop anmderstanding of differences in\pecies sensitivity. Because credi-)1~ extrapolation of such data tonan requires a knowledge of thenechanism underlying the induc-:ion of adverse effects in different>pecies and because the produc-tion of delayed effects is not>Iearly understood, extensive uses made of generic and basic‘esearch to provide experimentalsystems, techniques, and insightsIaving the broadest application toneaith-risk prediction. Included isthe development of improvedbiological test systems and im-proved techniques for the extrapo-lation of experimental data toman.

Health effects research cutsacross virtually all of the energytechnologies. Areas of ongoingresearch include those that ad-dress health effects associatedwith the broad spectrum of ioniz-

56

2.

il g radiation and a variety ofe lergy-related chemicals, in-c Jding indoor air pollutants,F \Hs, and related compoundsa sociated with synthetic fuelsp oduction. Extensive research isc inducted to elucidate the mech-a lisms which cause cancers andn utations, metabolism of energy-rl Iated chemicals, and mech-a Iisms of DNA repair. Categoriesa research include:

1 Carcinogenesis (the productionof cancer)— Both establishedand developing energy tech-nologies produce or involvephysical and/or chemical agentsthat can cause human cancer.Carcinogenesis research em-phasizes evaluation of thetumor-causing potential of suchagents, detection and character-ization of carcinogens, elucida-tion of pathways and ways todetect formation and growth in-dicators of tumor, investigationsto correlate exposure condi-tions (carcinogen dose) withtumor incidence in animalpopulations, and elucidation ofmechanisms of carcinogenesis.

Because the production ofcancer is a complex processthat may include discrete initia-tion and promotion steps, re-search into cancer inductionoften involves the study of com-plex interactions among differ-ent causative agents. Emphasisis also being given to research-ing free radicals and other ox-idizing species that play a rolein both chemical and radiationcarcinogenesis.

Mutagenesis (the rwoduction ofmuta~ons)—Alteration of gen-etic material by physical andchemical agents may produceheritable defects as a result ofmutations in reproductive, orgerm, cells. Mutations in non-reproductive, or somatic, cellsmay result in cell modifications,leading to cancer or otherhealth effects. The mutagenesisresearch program emphasizesinvestigations of the mutagenicpotential of energy-relatedphysical and chemical agents;metabolism of chemical agentsin target cells; correlation of

mutation freqd’en~:~with level cexposure to a muitagen; evalua-tion of health consequencesthat mutations may produce atthe population level; measure-ment of chemical dama~getoDNA formation; and elulcidatiorof mechanisms of mutagenesisincluding the relationship ofmutagenesis to tumor induc-tion. Effects on germ cells(chromosomal modifications)are also studied in detail.

1.Systems damage--Many hazarcous environmental agents manifest their toxic potential by im-pairing one of the body’s func-tional systems. %Ch ellfects—particularly delayed impairmentof the respiratory, immune, ner-vous, reproductive, and bloodforming systems or the develo~ing embryo/fetal system —maylead to chronic disease with attendant health costs. The majoefforts in this research area in-clude the identification of earl)indicators of biolc)gical damag(interspecies comparison of major functional systems and theisensitivity to environmentalagents, the development of im-proved biological test systems,and the conduct of dbse re-sponse studies that supportrisk estimates for man.

L Basic research—This is a sub-stantial research effort aimed zproviding the mechanistic andconceptual foundation that isneeded to understand Ihowphysical and chernicai agentsinterfere with life processes.Emphasis is on molecular andcellular studies tc) elucidate thinormal structure and functionof key biological systems orprocesses. Included is researclin biophysics (structure ofmacromolecules and organ-elles), genetics (including DNAdamage and repair), and cellbiology (cell growth, cell dif-ferentiation, and cell regulation

Human Health and AssessmentThe Human Health alndAssessmcprogram supports research to prcvide information on the responseof individuals and human popula-tions to toxicants and the feasibil

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of using nuclear technologies inbiomedical applications.

1. Human health research—Thisprogram ascertains by epidemio-logic studies the potential spec-trum of human health problemsassociated with occupationaland environmental exposures toradiation and chemicals in DOEoperations and emerging energytechnologies. Investigators alsodetect and measure genetic andsignificant subclinical changesin exposed humans that canserve as early indicators of ia-tent disease induction or toidentify particularly sensitiveindividuals.

2. Medical applications of nucleartechnology—This program ex-ploits the Department’s interdis-ciplinary cadre of investigatorsand technological resources inphysical, chemical, and com-putational sciences to developand evaluate new approaches, in-struments, and methodology forthe improved diagnosis andtherapy of human diseases andin the study of human physio-logical processes. Current em-phasis is on the development,production, and evaluation ofnew radionuclides, labeled phar-maceuticals, radiation beams,imaging devices, and enrichedstable isotopes.

Physical and TechnologicalReseamh This is the physicalsciences component of the healthand environmental research pro-gram that addresses a broad rangeof fundamental and applied activi-ties. Many of the projects interactwith the biological and ecologicalcomponents of the program. Otherprojects involve the development ofexperimental techniques or ad-vanced measurement instrumenta-tion. The major areas addressedare the physical and chemical char-acterization of products and efflu-ents of new energy technologies,the transport and transformation ofpollutants in the atmosphere,measurement science, health andsafety, and the fundamentalmechanisms of pollutant interac-tion with environmental and bio-logical systems. Categories ofresearch activity include:

1.’Analytical Characterization—The

2.

3.

4.

distribution, concentration, andthe physical, chemical, andradiological properties of emis-sions and effluents associatedwith energy-technology proc-esses are determined. Fieldsampling and measurement andlaboratory studies provide de-tailed information on the chem-ical and physical properties ofcollected materials.

Atmospheric Transport andTransformation-This categoryincludes research to develop animproved understanding of mete-orological, chemical, and phys-ical processes that influence thetransport, transformation, andfate of gaseous and particulatespecies emitted into the atmo-sphere. Improved atmosphericdispersion models are devel-oped and validated through fieldexperimentation.

Measurement Science—Newconcepts and improved measure-ment systems required to ad-dress environmental, health, andsafety concerns related toenergy production are investi-gated. Research covers a broadscope of activities ranging fromthe basic science of measure-ments to the construction andevaluation of prototype instru-mentation systems.

Radiological Physics and Chem-istry-This is a fundamentalresearch program of radiologicalphysics and chemistry directedtoward understanding the entirechain of events from the initialradiation interaction process tothe eventual biological effect.Both theoretical and experimen-tal research investigate themechanisms of radiation energydeposition and transfer in sim-ple systems and extends thisunderstanding to more complexand biologically relevant systems.

Ecclcgical Research The eco-logical research program providesthe scientific information baseneeded for appropriate siting, oper-ation, and disposal of materialsfrom energy activities. To obtainthis information base, comprehen-sive basic research in terrestrial

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2.

Id aquatic systems is conducteddifferent climatic regions of thelited States and in off-shoregions along the eastern and>stern United States on mechan-ms that influence and controltal ecosystems. The research is~rriedout by integrating all~pectsof the physical andological sciences. This multi-sciplinary program includes ex-wts in soil science, plant science,limal biology, chemistry, geology,Id freshwater and marineiiences.

)search describes how energy by-oducts move and are acted upon‘ plants and animals in terrestrialid marine systems and identifiese major routes and rates ofinsfer of these by-products backhumans. Natural and energy-

Iated stresses are studied frome subcellular level to the com-unity level of ecosystems toNerrnine the rate andechanisms by which populations)d ecosystems disturbed by en-gy activities adapt or react toese stresses. Categories ofsearch opportunity include

Cycling of natural and energymaterials that include mobiliza-tion and movement of traceelements and compoundsthrough water bodies, soils,sediments, plants, and animals.Research into the cycling ofenergy introduced substances iscoupled to research into thecycling of normally requirednutrients to permit the mostappropriate cost effect ive meas-ures to be developed for redis-tribution and control of energymaterials in the environment.

Biologic responses derived fromcommunity structure, populationdynamics, and physiologicalecology research. Knowledge ofaccommodation by plants andanimals to natural stresses isused to allow energy-related ac-tivities to expand while takinginto consideration limits ofecosystem stress. Processes ofnatural succession are studiedto determine if disturbed land isbest left to natural revegetationor whether revegetation can beaccelerated or improved by

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scientific means. Research iscarried out on metabolic pro-esses that accumulate exposure!eve!s a!iowing ecosystems toexist without serious adverseimpacts.

Fuciiifies Facilities playing impor-tant roles for addressing radiationand energy-related chemicalissues include the RadiologicalResearch Accelerator Facility atColumbia University, the HealthPhysics Research Reactor atORNL, and the Janus Reactor atANL. These facilities provide aspectrum of relatively pureneutron beams over a wide rangeof doses and dose rates for stud-ies in radiation biology, radiationdosimetry, and for training activ-ities. The Environmental Measure-ments Laboratory (EM L) developsimproved techniques for radiolog-

ical and chemical measurementsto characterize the chemical andradiological content of atmos-pheric, soil, and water samplesand provides DOE with a rapidresponse capability for obtainingneeded field data. For example,EfvlL recent Iy completed a re-assessment of population dose inUtah from weapons testing basedupon their measurement of soiland water levels of cesium-137.

The National EnvironmentalResearch Parks (representing pro-tected sites around five NationalLaboratories with a diversity offlora, fauna, and climate) have fortwo decades served as outdoorlaboratories for quantifying eco-system responses to a wide rangeof energy activities, including coalcombustion, overhead transmis-sion lines, reactor operations, and

burial of radioactive Wastes.

A three-stage mass spectrometer,installed at the Savannah RiverLaboratory, provides accurate andprecise analysis of isotope ratiosfor very low levels of environmen-tal radionuciides, defining theirsource and time sequence of depfsition in terrestrial and aquatic ex!periments under field conditions.

Advanced flow cytometers, devel-oped at Los Alamos and LLN L, arcalso being used by DIOE and othersponsors to identify and separatespecific cell populations, and purifchromosomes for gene mappingstudies to produce template matericfor making chromosclme—specifichuman gene “libraries” for distribution to the scientific community.

*U. S. GOVERNMENT PRINTING Off ICE;1986- 491-176:4010958