Attendees Radiation Effects Section Medical Advisory Group

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AEC, Germant own Cincinnati General Hospital / National Academy of Sciences Project Officer, Medical Applications LT Herbert J. Mitchell, MSC, USN Project Officer, Medical Effects

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Subtask Number and Title : Radiation Effects i n Man: Manifestations and Therapeutic Efforts NNER RMD 4.009 Agency Having Technical Supervision: Defense Atomic Agency Performi n q Work : Departnent o f Radi ol ogy , University of Cincinnati College of Medicine: Contract No. DASA Ol-69-C-0131 Pri nci pal I nves ti aator - Name (total funding up t o Prior FY) $ 406,882 Estimated completion date: 1975 Requi renent and/or Jus ti f i cation: As nucl ear weapons are deployed about the worl din increasi n g numbers and as the peaceful use of atomic energy similarly spreads, the need t o acquire detailed knowledge about human radiobiology becomes more and more urgent. I t is i n this direction that our research efforts have been concentrated fora number of years. that extrapolation of radiation results from animals t o man i s of only limited value and therefore we have concentrated upon radiation effects inpatients,with only limited animal experimentation. to obtain information of practical value in the diagnosis and therapy of radiation injury as we pursue our radiobiological studies. Ithas become increasingly apparent O u r goal has been The proposed investigations contained herein continue our acquisition of data on clinical manifestations o f radiation injury,alterations in DNA metabolism, evaluation of bone marrow reserves after irradiation, and psychological effects of radiation especially on cognitive functions. newly undertaken include evaluation of certain serum enzymes a n d of chromosome aberrations as biological radiation dosimeters , the use of tri tia ted thymidine incorporation into lymphocytes for the same purpose, and electron microscopic investigations of radiation damage i n human leukocytes.

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Cooperative studies with AFRRI will continue for investigation of plasma bound neutral hexoses as predictors of radiation sensitivity. Our own studies of glycoprotein changes after irradiation will also be radiation do siret ers of burns and trauma t o ascertain that our findings are specific for radiation injury, since soldiers in nuclear warfare may be exposed toall three types o f injury. \.le shall also continue t o examine the effects on our biological These studies are perforfled, as noted i n previous years, on patients who are given total and partial body irradiation as treatment for metastatic malignancy i n place of systemic chemotherapy where the latter is of queso f the College of I.ledicine in regard toits therapeutic value and informed consent of a l l subjects so treated has been obtained. The study design has been approved by the Research Connittee Several net;! areas wi 11 be i nves tiga ted. These i ncl ude an approach t o the prevention of the graft versus host syndrome i n homologous bone marrow transplantation now t h a t the auto1 ogous marrow transplant has proven successful in our hands. chemical diet to alter the acute radiation syndrome i n man, correlating this with the alterations which this diet causes i n fecal flora. !de also plan t o investigate the ability of a synthetic I tem 7. Research ldork Units : 1. a . DASA 01-69-c-0131. Radiation Effects i n Man: Mani fes tati ons and Therapeuti c Efforts 2 . Department of Radiology Edward 8. Sil b erste in, M.D. 4 . Continuation of Existing \lork.Unit: Yes 5. Estimated Interim Report Date: 1971 6 . Estimated Completion Date: 1975 7 . Estimated Final Report Date: 1975

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Agency: University o f Cincinnati College of Continuation o f Existing Contract: Yes Medicine, C i nci nnati General Hospi tal, Synopsis of Research Proposal : body radiation given for therapeutic purposes i n the huinan being. The effects being studied are clinical, hematological, biochemical, These studies are designed t o obtain data from whole and partial a . Selection of Patients Patients selected f o r study will be those who are t o receive partial or total body irradiation in the treatment of metastatic mal i gnancy from vari ous pri mary si tes. neoplasm which may be t r e a t e d uy internal radiation such as carcinoma of the thyroid o r prostate and tumors for which there is effective systemic chemotherapy, such as carcinoma o f the breast and prostate. w i 11 have s tab1 e hematologi c values a1 though they may have received local radi ati on previ ous ly . These primary si t e s excl ude Each patient serves as his own control i n our study. This i s possible because the patients are stable both clinically and i n respect to all labperiod and then the patient receives one o r two days of sham irradiation. Post-irradiation observations are then made at intervals of one t o three days unti1 cl ini cal and laboratory values become stable. Two t o four observations are made i n the pre-irradiation Some o f the patients will be hospitalized on the Tumor o r Medical blards of the Cincinnati General Hospital a n d others will be placed in the Clinical Research Center o f this newly constructed facility. In many situations the irradiated individual will be followed entirely on a n out-patient basis. Si nce who1 e-body radi ation is occasional ly uti l i zed i n chi ldren, an opportunity t o study such patients i n the Clinical Research Center of Children's Hospital occurs about 1-2 times per year. During the pre-irradiation period, the patient ' s records are reviewed by the physicians t o be certain that the contribution of the uoderlying disease can be evaluated accurately. One o r two sham irradiation s are given t o pei-nii t accurate dosimetry, obtain cooperation by the patient and evaluate psychological factors induced by the environment o f the irradiation facility.

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The sham treatments will be followed i mediate ly by the whole o r partial body irradiation procedure employing a Cobal t-60 source. discussion of possible subjective reactions resulting from the treatment. Other physicians , nurses , techni ci ans and ward personnel are instructed not t o discuss syniptoms o r reactions with the patient, - c. Parameters t o be Investigated ( a ) Complete history and physical examination ( b ) Temperature, pulse and respiration ( c ) Body weight a t standard test times 2. Hematology and other Laboratory Tests platelets, reticulocytes , erythrocyte sedimentation rate, leukocyte reaction t o eti ochol anol one t o evaluate bone marrow Bone marrow--smear and block f o r microscopic pathological analysis a t regular Selected enzymes and other less frequently measured serum constituents i ncl uding gas troi ntes ti nal a1 kal i ne phosphatase, LDH isozynes , kinase, serum histamine, serum transfer r in, serum deoxycytidi ne deaminase , serum 5-hydroxyindole acetic acid, and pre- and post-radiation karyotyping f o r biologic dosimetry. T r i ti ated thymidi ne uptake by lymphocyte suspens i ons pre- and pos t-radi ation. His tochemi cal s tudi es . Electron microscopic studies of leukocyte 3.Bi ochemi cal studies i ncl udi ng tracer studies of isotopic ally tagged nucleosides i n treated humans. Comparison \ vith patients suffering burns and other

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4 . Bone marrow autotransplantation vii t h animal study of homotransplantation and prevention of graft versus host disease. 5. Use of a chemically defined synthetic diet t o a1 ter the gas tro in test i nal radi ati on syndrome and measure changes i n fecal bac6 . Psychiatric evaluation and testing. ( a ) Five minute verbal samples ( b ) Cli n i cal psychiatric interviews and rating scales Dos i met ry In previous studies the radiation beam has been directed horizontally ata wall 338 cm away with the patient midline a t 282 cm from the source. Under these circumstances the beam area f o r the 50% isodose curve a t the patient ' s midline has been a square with legs raised and head tilted slightly forward. Each lateral portal receives half the dose. o f Canada, Ltd) was installed. unit is 286 cm. The field size at 286 cm for this unit is 100 cm (90% isodose line) compared t o 75 cm (50% isodose line)for previous Eldorado 8Unit, thus providing a larger and a more homogeneous radi ati on field. The patient is placed in a sitting position A new Cobalt 60 teletherapy u n i t (Theratron Nodel 8, Atomic Energy The source t o mialine-trunk distance for this The dose rates as used i n the past of Dosimetry studies are in progress t o determine experimentally being placed i n selected bone spaces of an Alderson Rando phantom and the phantom then irradiated under simulated patient exposure hematologic f i ndi ngs observed for whole-body i rradi ation and for other conditions of partial body irradiation. 4nterp.retations of the effects of shielding portions o f "active" bone Thermoluminescence dosimeters (LiF) are These "active" bone marrow doses will be related t o the These data will aid i n Clinical and laboratory observations will continue as indicated above. There will be 3-5 observations made before radiation, daily observations afterwards f o r 3 days a n d then every 3 days as long as Comparisons will be made for partial vs. whole body, partial upper vs.partial lower, and trunk (sternum t o pubis) vs. partial irradiation of upper and lol$/er body. changes and biochemical changes will be followed. The frequency o f prodromal symptoms, hematological

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A s indicated above, the doses for partial body radiation will be increased i n coniparison t o those used previously since the earlier dose 1 evels have been well tolerated. Comparison between patients will indicate trends in relation of different dose levels t o prodromal syinptorns. In previous studies i t has been noted that clinical syniptorns with partial body radiation are proportional t o the dose received a1 though heniatol ogi cal changes are e i t h e r minimal or absent. ' I n one patient receivins 300 rads of partial body radiation, a significant i n reference t o bone marrow reserves by etiocholanolone. these patients experience therapeutic benefit from the radiation, the use of higher doses of partial body irradiation is both justified and desirable. This effort will seek t o identify the dose range causing hernatologi cal changes simi 1 ar t o those observed with previously observed levels of whole body radiation. drop in white cell elements were noted. These changes will be evaluated bmSince some o f 1 . Eti och ol anol one Since February 1969 we have been employing etiochol anolone, a natural l y occurring steroid metabol ite,to measure the bone marrow reserves o f patients recei vi ng who1 e-body i rradi ation. This hormone injected intramuscularly causes a leukocytosis as granulocytes enter the peripheral blood stream from the bone marrow. in the total granulocyte count (neutrophi Is, stab cells, eosi nophi Is , basophils, plus som? less mature forms) exceeds 2,600 cells per cu/m within 16 t o 24 hours after a dose of etiocholanolone 0.10 mg. p e r kg body weight i s injected. The normal increment A 1 though radi ation - i nduced leukopenia has been observed for many years, the decrease i n granulocyte count i s not i mediate. However, our preliminary data indicate that bone marrow reserves of granulocytes are decreased while the patient ' s NI3C is still within normal limits. We have also been able t o observe a cyclic variation in the granulocyte reserve response after irradiation, with which we feel we will be able t o explain the partial marrow recovery noted frequently within two weeks after of the value of etiocholanolone i n evaluation o f marrow damage caused by partial as well as whole body irradiation. Further study i n this area will permit greater definition There continues t o be some controversy as t o the precise power function by which radiation dose i s related t o aberration yield. dosimetry available on our patients a t the Cincinnati General Hospital we plan t o continue our study o f chromosomes as a biologic dosimeter and redefine our dose-response curve with greater precision. Much older data has depended on 72 hour lymphocyte cultures whereas our more recent technique , involving 48 hour lymphocyte cultures after phytohemagglutini n stimulation should provi de clues t o some unanswered questions . Nith the accurate

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Ihe specificity of chroiiiosome aberrations, ring and di centric niation, as related t o radiation damage has never been questioned. I t is. that severe burns may alter the membranes o f the circulating cells and that red blood cells may also be injured by trauma, as i n "march hemokiiryotyping selected patients referred toour large Shrine r ' sBurn Hospital t o assess the frequency of chroriiosome breakage i n these patients. We plan similar studies i n patients suffering severe trauma i n cooperation with the Department of Surgery when we have adequate personnel f o r this purpose. Perhaps this is true o f lymphocytes as v!ell. We plan t o continue 3.Tri tia ted Thyclidine Studies We have initiated the study o f incorporation of tri tia ted thymidine i r! to lymphocytes before and imedi ately after whole-body irradiation. We plan t o extend these studies t o note the time course during which the i n - corporation of tri tia ted thymidine becomes normal andto evaluate the value of this test as a biologic dosirrieter. exqui site ly radiosensitive cell, thymidine i ncorporation may be a dosiReter of injury over a wide spectrum o f radiation dose. Since the lymphocyte i s such a n Because of the wide range o f histochemical tests available, one may study the appearance o f the different subcellular organelles under the light microscope. These include mitochondria, ribosomes, lysosoaes, as well as the cellular content o f glycogen, various fats and the phagocytic ability ologic correlates of rcdiation injury with the more sensitive electron microby the radiation doses employed we may then apply the appropriate histochemical stains t o determine if this damage seen on the electron microscope can also be picked u p by tests for the integrity of that cellular component which would be available i n the field. able include stains for glycogen, alkaline phosphatase, acid phosphatase, green-pyroni n , Sudan black, peroxidase, lactic acid dehydrogenase, succinic acid dehydrogenase, d i hydro-orotic acid dehydrogenase and several others. A more basic approach hotlever, is first to analyze the pathAfter we have identified which, i f any, of the organelles are affected Among the histochemical tests availRecent work i n this laboratory has proven the efficacy ofour technique plantation) with greater prevention o f radi ation-i nduced 1 eukopeni a than …