446; Reprinted from the Archives of Pathology May 1967, Volume 83 Copyright 1967, American Medical Association 704636

Radiation Death From Cardiovascular Shock Following a Accident Report of a Second Death From a Newly Defined Humaii Radiation Death Syndrome

Herbert Fanger, MD, Providence, RI, and Clarence C. Lushbaugh, MD, Oak Ridge, 7env

Two case histories of nuclear radiation victims sidered secondary to cerebral and cerebellar are similar and reflect radiation-induced hypoten- damage. After exposure to more than 5.000 sion, vascular damage, shock, and death within R, most animals manifest a neurologic syn- Case K two days. Pathologic changes in one patient are drome; malaise, weakness, ataxia, and pros- Fig 1.-Position: described which show these two cases to repre- tration are progressive. Finally, such ani- ring tanks (approx sent a lethal subsyndrome the acute radiation criticality excursior of mals become unresponsive and die with con- the activities and syndrome, occurring in the dosage range between vulsive manifestations.2 Pathologic changes epicenters of the c the acute gastrointestinal and neurologic sub- tirnated distances fl syndromes. Because meningeal and cortical in such instances include meningeal leuko- face of the heart arc of changes occur as part of the vascular damage, cytic exudates, necrosis of cerebellar gran- tion the neutro exposure in patient terminal neurologic symptoms occur that lead io ular cells, oligodendroglial and cortical the suspicion of neurologic damage. Only mini- neurone lysis, and progressive cerebral deaths of some 1 mal neuronal damage and glial reaction were edema.3.4 This syndrome and its pathologic tims may pos~ present, however, and death apparently resulted basis has been defined in monkeys5 but not manner, clinic: from increased intracranial pressure, cerebral in man. first two days a anoxia, cardiac failure, and massive peripheral In man the hematologic syndrome has during the first edema. been documented by clinical and pathologic were not made studies of cases of intentional1 and acciden- Until the dea tal exposure to .l.6 The in this report, ( THREEMAJOR mechanisms of fatal ter- sequence of hematologic events is almost mination have been recognized in humans identical with that in animals, except for had been jnvoh which exposure after lethal radiation exposure: central nerv- temporal differences in the nadir and recov- rads, and had ous system injury; gastrointestinal mucosal ery of peripheral while lolood cell counts. manifest clinic. loss; and hematopoietic failure.1 At radia- There phenomena are delayed in man, so death syndromc tion exposure levels (300 to 800 R) which that his acute hematologic syndrome lasts Idaho Falls Re, are known to result in death of animals 60 days instead of 30 davs.6 3 These observa- received instan within 30 days or man within 60 days, death tions have been verified in normal man by rads or more occurs as a result of hemorrhage, infection, extensive study of the and Naga- u or died short11 and anemia secondary to hematopoietic in- saki atom bomb casual tie^,^ and the Los them.14 The 19, jury. Radiation between 1,000 and 3,000 R Alamos,5Jo Oak Ridge,l* and the Vinca ac- tim (patient I denudes the mucosa of the smal,l intestine, cidents.12 failed to manifa and results in septicemia and electrolyte im- The occurrence of the gastrointestinal age until imme balance causing death within five days in syndrome, on the other hand, is documented though he h: animals and within two weeks in man. At in man by only two cases: Accident Case exposures higher than 3,000 R, deaths in ani- LA-36 and the 1960 Russian suicide.l3 In 10,000 rads expl Just before des mals or man within 24 to 48 hours are con- these instances the total-body depth-dose tional, uncontrt distribution of 1,350 and 1,910 rads, respec- Accepted for publication Jan 27. 1967. movements. In From the Pathology Department, Rhode Island tively, was extremely uneven, but death OC- course and bec: Hospital, Providence, RI, and the Medical Division. curred in nine to ten days as predicted, coin- Oak Ridge Institute of Nuclear Studies, a unit of whole-body dos Oak Ridge Associated Universities, Tnc., Oak Ridge, cidental with intestinal mucosal denudation. topsy findings Tenn. No human deaths have been attributed Reprint requests to Oak Ridge Institute of Nu- syndrome werc clear Studies, Oak Ridge, Tenn 37830 (Dr. Lush- per se to the neurologic syndrome as it is minimal changl baugh). known in animals. Although the early tis and perivasc

Arch Path-Vol 83, May I967

io05435 RADIATION DEATH-FANGER & LUSHBAUGH 447

P‘ 34- ,,‘ GWNKOCYTES 0 CASE K M-

26 -

22 - I I- 510- e--- ”?- P ‘4- VI- Lwmocym usf K sbellar a 5,000 :.‘tL;.-hhC,, , Case cm Case IC syn- K P 02 6 10 14- I8 -22 TIME POST EXPOSURE IHJURSI I pros- Fig 1.-Positions of the two men, relative to stir. h ani- ring tanks (approximate relative scale) in which the Fig 2.-Changes in peripheral white blood cell count xiticality excursions accidentally occurred, showing and differentials in the two patients showing the early ;h con- the activities and bodily orientation of the men to complete disappearance of lymphocytes and extreme 9anges epicenters of the criticality excursions (asterisks). Es- leukocytosis. timated distances from the reaction to the anterior sur- leuko- face of the heart are shown. There was greater modera. gran- tion of the flux by water in the total-body severe cardiovascular changes and general- ortical exposure in patient K. ized edema seemed to account for his death ?rebra1 and to explain the protracted irrevocable rologic deaths of some Hiroshima and Nagasaki vic- shock from which this man suffered.15 The ut not tims may possibly have occurred in this absence in patient K of definitely primary manner, clinical observations during the neurologic injury similar to that previously le has first two days and postmortem examinations described in animals after massive doses of lologic during the first week after the detonations radiation2,.”,5 suggested that the two-day :ciden- were not made.9 death syndrome in man might be cardio- The Until the death of the man (P) described vascu1ar.l0 in this report, only one other person (K)10 almost Pathologic Details pt for had been involved in a radiation accident in recov- which exposure was known to exceed 4,000 The pathologic details of the Rhode Island :ounts. rads, and had survived sufficient time to radiation accident victim of 196416 are report- an, so manifest clinical symptoms of a two-day ed here at length, because they support the hy- lasts death syndrome.10 (The three victims of the pothesis that the neurologic syndrome in man, if it exists as such at all, is a terminal or sec- serva- Idaho Falls Reactor Test Site accident who received instantaneous doses of 1,000 kilo- ondary event in another death syndrome in- Ian by volving the cardiovascular system. A primary Naga- rads or more were killed instantly by blast or died shortly after medical aid reached neurologic radiation death syndrome in man :e Los apparently requires an integrated total-body them.14 The 1958 Los Alamos accident vic- ca ac- dose in excess of 10,000 rads and such a death is tim (patient K) survived 34 hours and yet to be observed. The Rhode Island patient ?stinal failed to manifest signs of neurologic dam- (P) received an estimated integrated whole- iented age until immediately before his death, al- body dose of about 8,800 rads,l7 roughly twice ; Case though he had received approximately as much as the Los Alamos man (K),IO more radiation than considered necessary to produce :.I3 In 10,000 rads exposure to the front of the head. h-dose Just before death he suddenly became irra- cerebellar granule cell necrosis in experimental tional, uncontrollable, and made convulsive animals within 24 hours of exposure.lJ0 ‘espec- The accidents in which the two men were in- Ith OC- movements. In spite of hypotensive clinical course and because of an estimated average volved were basically similar criticality excur- , coin- sions, which occurred when fissionabIe material whole-body dose in excess of 4,500 rads, au- iation. in process of being reclaimed was unintention- topsy findings of the so-called neurologic ibuted ally caused to flow into unsafe geometric vol- syndrome were anticipated. Instead, only s it is umcs (Fig 1).In both accidents the man was minimal changes of mild meningeal vasculi- early close to a tank containing the extracting fluid. tis and perivascular edema were seen, while In Rhode Island, the tank was open at the top, I Arch Path-Vol 83, May 1967 448 RADIATION DEATH-FANGER & LUSHBAUGH

104, on into a sapling - though the twiligl quate for the othe About 30 minutes an ambulance ar CASE I( a CbSE P speaking coherent1 during violent crar -1 YI - L., -606 himself onto the st IW I Y Y ambulance. At ti HMCT _-----A -5c a r facilities and stafl

rC4SEK the largest general aCASEP ? he arrived about Z -30 y 98- C4SE K ;L 2 OCAS P g - trip he suffered w“e IIIIIIlIIIIlillllflIfII0 0 4 8 12 16 20 24 28 32 36 43 44 nausea, vomiting, ( 97 III’lf11 1~~1~1~1111111 4 8 12 16 20 24 28 32 36 40 44 TIME POST EXPOSURE IHOURSI The details of his TIME POST EXPOSURE [HOURS) Fig 4.-Parallel changes in peripheral blood hemato- and therapy has E Fig 3.-Fluctuations in rectal temperatures of the crit and hemoglobin values in the two patients. An : men. The early high fevers rapidly subsided. initial hemoconcentration was corrected by intravenous the time of his fluids in both patients and recurred only in patient P. room, the frequenc intestinal colic ha a propeller was stirring the contents, and criti- quieted complete1 cality occurred as the contents of an elongated meaning of 7-ray alarms, ran down three phine. polyethylene bottle 10 cm in diameter were flights of stairs, went through the proper build- Initial Geiger-c poured into the tank. This nuclear criticality ing exit, and ran to an egress in the perimeter from the body rea accident occurred at a United Nuclear Corpo- fence. Upon reaching this station, he shed all ity of 80 mr/hr, wl ration Plant at Wood River Junction, RI, on his clothing contaminated with radioactive ma- 45 mr/hr. Some 1 July 24, 1964. In Los Alamos, the criticality terial, laid his film badges down, and ran 150 was due to induct was initiate6 when the operator (K) activated yards across a field to an emergency shack. an electric stirrer, which created a circulation These actions required only a few minutes. and interstitial fl fission-product co in the tank that concentrated fissionable ma- When a security guard met him at the shack, The induced terial (dissolved in a floating layer of solvent the victim showed no signs of distress other hair. immiscible in water) in a vortex around the than those usually (ax~~c~t~dfrom excitement body and estimate the inte propeller shaft. Although this tank was en- and exertion. Five to ten minutes after the acci- closed so that none of its contents escaped, the dent, however, the patient developed severe thcrmal neutron f the criticality cer blue flash of ionized oxygen, the shock wave, griping abdominal pains, accompanied by nau- dent.16.17 and an immediate burning sensation made pa- sea, vomiting, and bloody diarrhea. At about tient K assume that he was injured by acid re- the same time the guard noted that the whites Comparative C1 leased from an explosion. The patient P was of patient P’s eyes wcrc turning bright red and cidents occurred knocked down when he saw the blue flash and his skin began to appear acutely “sunburned.”. miles) apart and was showered with solutions containing fission During the next 15 minutes he vomited and body doses that products. He did not suffer any illusions of had diarrheal stools about five times. During (dose of patient being burned and did not experience immediate one of these episodes, as he was going away tient P - 8,800 prostration, but correctly interpreting the from the shack to relieve himself. he ran head- were so similar th support the thesis Fig 5.-Temporal fluctuations in systolic and diastol- longed period in which a diastolic pressure could not resent a prcvious ic blood pressures in patient K (left), and patient P be discerned. radiation syndror (right). Death in each instance was preceded by a pro- syndrome is due vascular rather tl I 11 as suggested in tk 150 - raised by the gro vations in the secc brevity the two CI under the headin Pressure and Th Hematology.-‘ blood cell, grand are shown in Fig showed the progi phopenia typical t mals. The early I 40 shown by both TIME POST EXPOSURE IHOURSI TIME P05‘ EXPOSURE (HOURS)

Arch Path-Vol 83, May 2967 RADIATION DEATH-FANGER & LUSHBAUGH 449

on into a sapling four inches in diameter, al- though the twilight was still more than ade- quate for the other men to distinguish objects. About 30 minutes after the accident occurred, an ambulance arrived. Patient P was then speaking coherently, and was only incapacitated during violent cramping evacuations. He helped himself onto the stretcher and was placed in the ambulance. At the first hospital inadequate facilities and staff directed the ambulance to the largest general hospital of the region where he arrived about 30 minutes later. During this trip he suffered from recurring episodes of nausea, vomiting, diarrhea, and cramping pains. The details of his subsequent hospital course !mato- and therapy has been reported at length.16 By Fig 6.-Comparing the rate of infusion of pressor :s. An drugs into the two patients. Height of each arrow indi- enous the time of his admission to the emergency cates the amount of drug injected at that time into ent P. room, the frequency and intensity of his gastro- fluids that were running intravenously at various rates. intestinal colic had largely subsided but were The curving solid lines sum the amount of pressor drugs infused. three quieted completely with intramuscular mor- mild- phine. neter Initial Geiger-counter readings four inches dall from the body recorded a maximum radioactiv- ma- ity of 80 mr/hr, which was reduced by a bath to L 150 45 mr/hr. Some of this residual radioactivity hack. was due to induced "Na activity in the blood I2 utes. and interstitial fluids, but most was due to IO lack, fission-product contamination of his skin and hair. The induced radioactivities of his whole- Ither Y xKXAR LACT4lE rnent body sodium and hair sulphur were used to Y QPLASMA acci- estimate the integrated whole-body dose, the .D6 thcrmal , and bodily orientation to o WOW PLUS ?vere I-ARTERENOL nau- the criticality center at the time of the acci- dent.lG.17 .bout I I 1 0 10 20 30 40 hites Comparative Clinical Courses.-The two ac- TICTIF WST EXPOSUREEXPDbunc (HOURS1gnuunar and cidents occurred about five years (and 2,500 Fig 7.-Amount of various fluids administered per ed.". miles) apart and resulted in integrated total- os or intravenously in relation to time after radiation and body doses that differed by a factor of two exposure of the two patients. iring (dose of patient K+4,900 rads; dose of pa- way tient P --.8,800 rads). The clinical courses Fig 8.-Temporal course of amount of fluid lost after eatl- were so similar that they are contrasted here to exposure on the assumption that fluid loss in the im- support the thesis that these two patients rep- mediate prodromal radiation reaction of the two men was similar and approximated two liters. Oliguria in i not resent a previously undescribed human lethal patient K was more extreme, but in both fluid loss radiation syndrome. The possibility that this failed to balance fluid intake (Fig 7) syndrome is due fundamentally to widespread vascular rather than primary cardiac damage as suggested in the reports on patient K1"10 is

raised by the gross and histopathologic obser- 14 - vations in the second patient P. For the sake of brevity the two courses have been summarized 12-

under the headings of Hematology and Blood M- Pressure and Therapy. d WMITUS 8- URINE Hematology.-The changes in total white DI Dl4RWIEA CbSE P blood cell, granulocyte and lymphocyte counts f LEVINE TUBE are shown in Fig 2 for patients K and P. Both +- showed the progressive leukocytosis and lym- phopenia typical of heavily irradiated mam- mals. The early disappearance of lymphocytes I I I I I 0 10 PO 30 40 shown by both thesc men has become well TIME POST EXPOSURE MURS)

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Fig 11: Fig 9.-Right ventricular myocardium showing inter- Fig 10.-Subepicardial myocardium from the anteri- treme intr. stitial leukocyte exudation and edema (hema.oxylin or portion of the base of the right ventricle showing toxylin ant and eosin, X 400). granularity caused by interfibrillar edema of the cardiac muscle (hematoxylin and eosin, X 400). known as an ominous prognostic sign of supra- autopsy lethal total-body irradiation.1 Both men showed initially had an extremely low blood pressure of patie the granulocytosis thought to be due to an out- (40/10) which never reached normotensive lev- post mc pouring of these cells from boLe marrow and els (Fig 5, left). Patient P was hypertensive findings other tissue reserves in response to wide- (Fig 5, right) on hospital admission but within phopoiel spread tissue damage. Increase in temperature six hours required vasopressor drugs to combat terstitial as shown in Fig 3 may be another reaction to the steady decline in his blood pressure (Fig descript circulating protein breakdown products and 6). In both men, a relatively stable, but lower alteratio postdiarrheal loss of fluid. The progressive than normal, systolic pressure was maintaina- changes in hematocrit and hemoglobin are ble during the first postirradiation day chiefly inspectic shown comparatively in Fig 4. The major cause by vasopressor drugs and intravenous fluids muscula of the different initial levels of the blood values (Fig 7). but diastolic pressures were often massive in the two men may be related to the altitudes difficuIt to measure. After their initial fluid of skel at which they lived and died-7,000 feet at Los losses in their attacks of vomiting and diarrhea exuded I Alamos and sea level in Rhode Island. Both, both men were oliguric (Fig 8) during the first forearm however, showed postexposure hemoconcentra- day in spite of large amounts of intravenous source o tion. This was followed by a return to normal fluids. Patient 17 regained some urinary func- swollen, hematocrit levels, but in spite of 14 liters of tion during the second day. Electrocardio- fluid administration to patient K and 9 liters to bow. Pi graphic changes in both men were similar,1j~1~ process. patient P, neither man showed signs of hemodi- reflecting (retrospectively) a developing rela- lution but tended to hemoconcentratc. This tive left ventricular preponderance, pericardial lar intei progressive leakage into expanding extravascu- effusion, and myocarditis. Terminally, both were bi: lar spaces was particularly obvious clinically. men had low unstable blood pressures, which effusion Blood Pressure Changes and Therapy.-The were difficult to measure. Patient P had no dis- ably mi. severity of the shock syndrome from which cernible blood pressure for five hours before Cardi these men suffered is illustrated graphically in death. pericard Fig 5-8. These figures show the blood pressure Iowish f changes, fluid output, and fluids and vasopres- Postmortem Observations on the r sor drugs administered in attempts to combat the hypotensive and oliguric courses. Patient K Lushbaughls has previously reported the clotted

Arch Path-Vol 83, May 1967 RADIATION DEATH-FANG ER & LUSHBAUGH 451

I

Fig 11.-Typical medium-sized artery showing ex- Fig 12.--Srnall meningeal vein collared by exudated interi- treme intracellular edema of the smooth muscle (hema- polymorphonuclear leukocytes (hematoxylin and eosin, owing toxylin and PAS, )( 400). X 400). xdiac autopsy findings of patient K. The autopsy abrupt transition from faint vascular injec- ;sure of patient P was performed seven hours tion of the upper anterior right ventricular : Iev- post mortem. The most conspicious gross pericardium to vivid hyperemia of the ad- wive findings related to the cardiovascular, lym- jacent root of the aorta. Microscopically, ithin phopoietic and hemopoietic systems, and in- fibrin and polymorphonuclear leukocytes mbat terstitial tissues and spaces. The following were scattered in patchy fashion in the epi- (Fig cardium of the right ventricle, auricle, ower descriptions are limited to only pathologic aina- alterations considered important. External and atrium. Polymorphonuclear neutrophils iiefly inspection revealed a thick set, exaggerated were dispersed singly and in groups between Iuids muscular appearance, which proved due to muscle fibers, usually near blood vessels, often massive subcutaneous and interstitial edema and there was slight interstitial edema (Fig fluid of skeletal muscle. Cutaneous incisions 9). Muscle necrosis was not observed. -rhea exuded a copious flow of clear fluid. The left Mesothelial cells varied in appearance, be- first forearm and hand, which were closest to the ing sometimes swollen and prominent, or now source of radiation (Fig 1),were maximally shrunken and having pyknotic nuclei. func- swollen, turgid, and cyanotic up to the el- Subepicardial myocardial cells were finely rdio- 15.16 bow. Pitting edema overlay the olecranon reticulated or granular as though the myo- rela- process. In addition to extensive extravascu- fibrils were dispersed in the sarcolemmal rdial lar interstitial accumulations of fluid, there sheaths by intracellular edema (Fig lo). both were bilateral hydrothorax and pericardial Most of the medium-sized arteries ap- rhich effusion. Ascites was present but unexplain- peared pale histologically, because of swol- 1 dis- ably minimal. . len smooth muscle layers (Fig 11). This in- efore Cardiovascular System.-A serofibrinous tracellular edema in smooth muscle was also pericarditis was manifested by 100 ml of yel- Seen in the muscle coats of the small and lowish fibrin-flecked fluid and fibrin deposits large intestine where the ganglionic cells of on the right atrium and ventricle. This fluid the intramuscular plexuses were similarly the clotted on standing in vitro. There was an affected. The irregular staining and vacuola-

Arch Path-Vol 83, May 1967 452 RADIATION DEATH-FANGER & LUSHBAUGH

Fig 15.-Mucosa ani Fig 13.-Esophagus with extreme hyperemia and Fig 14.-Autoradiogram of the skin showing abun- Ion. The most superft interstitial edema of connective tissue, and acanthotic dant tracks in the emulsion from a-particles emitted desquamated. Lamina appearance of desquamating epithelial lining. Basal from fission-product contaminants entrapped in the its lymphoid complem cells are less evident than normally (hematoxylin and keratinized horny layer (hematoxylin and eosin, edematous. No mitotic eosin, x 400). x 200). submucosal edema is x 100). tion of the intestinal smooth muscle was Respiratory Tract.-Congestion of the most suggestive of hydropic degeneration or trachea, bronchi, and lung parenchyma was haled fission produ fluid imbibition. A possible fatty change was accompanied by intra-alveolar and intersti- but autoradiogran looked for, but the Sudan 111 fat stain was tial edema. Microscopic examination showed showed abundant negative. Persistent alkaline phosphatase an irregular desquamation of epithelium of emitting substance activity of capillary endothelium of small the airway passages and hypersecretion of layer. intestine was demonstrable 15 hours after their mucous glands. Necrosis and desqua- Gastrointestinal death. mation of the tracheal epithelium was prom- the cardioesophagc In many areas, polymorphonuclear leuko- inent and the denuded basement membrane (Fig 13) and a fer cyte exudation was found where it could be was irregularly widened and hyalinized. the stomach. Sub considered only evidence of primary en- Macrophages, which were rarely multinu- prominent gastric dothelial damage.- The small venules of the cleated but occasionally vacuolated, were thickened colonic meninges are an excellent example of this frequently dispersed in alveoli and contained scopically, the epi change>* for they were collared by neutro-; black particulate debris in a brown cyto- to a variable de phils in the absence of demonstrably dam- plasm. In some pneumatocytes, the PAS down to the rectu aged tissue (Fig 12). stain demonstrated material resistant to sali- a smear of intesti. Hyperemia was especially prominent in vary amylase. Tests for metachromasia with numerous epitheli subepithelial capillaries of the respiratory toluidine blue at pH 2.5 and pH 4.5 were ty was found at ai tract and esophagus (Fig 13) where the cap- negative as was the Sudan 111 fat stain. ‘I morphonuclear ne illaries were enormously dilated with blood The ferric ferrocyanide reaction inconstant- large lymphocyte in which crenated and fragmented erythro- ly demonstrated hemosiderin. Smooth muc- 4 but reduced frequ cvtes could be demonstrated. Thrombi con- cle cells in the media of the pulmonary intestinal tract; bl taining erythrocytes were not found any- arteries were vacuolated and edematous. completely absen where but leukocytic “thrombi” occluded Surprisingly, a terminal aspirative broncho- As in other sib small venules in central portions of the cere- pneumonia could not be demonstrated. Con- denuded of lym~ bral white matter. tamination of the respiratory tract by in- a retidoendothe

Arch Path-Vol 83, May 1967 RADIATION DEATH-FANGER & LUSHBAUGH 453

Fig 15.-Mucosa and submucosa of descending co- ing abun- Fig 16.-Pancreas showing edematous interstitial lon. The most superficial epithelial cells have been connective tissue and a focus of necrotic and degener- s emitted desquamated. Lamina propria .appean to have lost d in the ating acini with infiltrating leukocytes (hematoxylin its lymphoid complement and to be contracted but and eosin, X 128). d eosin, edematous. No mitotic activity is present. Remarkable submucosal edema is evident (hematoxylin and eosin, x 100). small residual amount of nuclear debris. of the Liver.-The liver was enlarged and heavy ma was haled fission products was not demonstrated (weight 2,370 gm), owing to congestion, intersti- but autoradiograms of the skin (Fig 14) confirmed microscopically. In addition, showed showed abundant tracks from a-particle there was fatty metamorphosis and rare ne- :lium of emitting substances in the epidermal horny crosis of individual liver cells. The sinusoids ?tion of layer. contained increased numbers of polymor- desqua- Gastrointestinal Tract.-The mucosa at phonuclear neutrophils with nuclei frequent- s prom- the cardioesophageal junction was congested ly altered by increased lobulation, pyknosis, tmbrane (Fig 13) and a few petechiae were found in and irregular outline. ilinized. the stomach. Submucosal edema produced Pancreas.-Although grossly not abnor- nultinu- prominent gastric rugae and a remarkably mal, the histologic changes were impressive. 3, were thickened colonic mucosa (Fig 15). Micro- A patchy alteration of pancreatic acinar epi- ntained scopically, the epithelium had desquamated thelium was manifested by shrinkage of n cyto- to a variable depth from the esophagus cells, pyknosis of nuclei, and eosinophilia of ie PAS down to the rectum. This was confirmed by cytoplasm (Fig 16). In some acini there to sali- a smear of intestinal contents that revealed was vacuolization of cytoplasm, as well as sia with numerous epithelial cells. No mitotic activi- karyorrhexis and complete disappearance of .5 were ty was found at any level. Histiocytes, poly- cells. Duct epithelium was rarely desqua- t stain. morphonuclear neutrophils, eosinophils, and mated and a few polymorphonuclear neutro- )nstant- ' large lymphocytes occurred with variable phils appeared in duct lumen. The islets of ' :h muc- but reduced frequency in the mucosa of the Langerhans were uninvolved, except for a monary intestinal tract; but small lymphocytes were rare cell showing nuclear pyknosis. Poly- matous. completely absent. morphonuclear neutrophils and monocytes Nroncho- As in other sites, lymphoid follicles were in small numbers had infiltrated the edema- d. Con- denuded of lymphocytes and consisted of tous interstitial tissue. Leukocytes were pres- \ by in- a reticuloendothelial skeleton containing a ent within necrotic acinar cells in some areas.

Arch Path-Vol 83, May 1967 454 RADIATION DEATH-FANGER h LUSHBAUGH

Fig 17.-Thymus gland showing epithelial remnant Fig 19.-Spleen shows former site of lymphoid nod- resembling a basalar layer differentiating into squamoid ule consisting of a periarterial tuberculoid nodule in Fi: 20.-Vertebr cells (hematoxylin and eosin, X 400). condensed reticulum containing pyknotic lymphoid depleted sinusoids ( nuclear partcles and phagocytic cells of the sinusoidal only a few axumu Fig 18.-Reticuloendothelial follicular center in a reticulum (hematoxylin and eosin, X 400). an occasional mega’ mediastinal (hilar) lymph node, appearing as the “tu- (hematoxylin and el bercle” of a heavily irradiated lymph node. Pyknotic Thymus.-Although the thymus gland nuclear remnants surround it. Anthracotic pigment- sis. Sinusoids C( laden macrophages are at upper left, and granulocytes was not distinguishable grossly, and micro- neutrophils anc and erythrocytes are in a sinus at upper center and swpic sections revealed extensive fat re- right (hematoxylin and eosin, X 400). Spleen.-The placement and atrophy commensurate with was flabby gros the patient’s age, lymphocyte depletion was of acute massivr impressively complete. Polymorphonuclear puscles could r leukocytes were present in minute cystic spondingly, the foci. Hassall’s corpuscles and epithelioid phocytes was m cells were intact. The denuded peripheral were adjacent t epithelial layer was so condensed that it preserved hype appeared arranged in columnar palisade cells (Fig 19) fashion, and looked remarkably like a basal disrupted lymp epithelium differentiating into a squamoid maining pykn epithelium (Fig 17). spersed were Lymph Nodes.-Hilar lymph nodes were clear neutropli of average size and anthracotic pigment dis- and reticular c colored them. Lymph nodes in the mesen- frequency and t tery were calcified. Microscopically, there Central arteria was a markedly diminished lymphocyte con- thickening. OCC tent. The sites of the follicles consisted of tive tissue wa hypertrophied reticuloendothelial nodules the altered foll surrounded sparsely by shrunken, pyknotic pulp were poor lymphoid cells and nuclear debris. Reticu- Patchy areas v loendothelial cells were intact throughout hemorrhage, bi the lymph nodes and evidenced phagocyto- supportive con

Arch Path-Vol 83, May 1967 RADIATION DEATH-FANGER & LUSHBAUGH 455

ioid nod- Fig 21.-Kidney showing infraglomerular epithelial lodule in Fl; 20.--Vertebral bone marrow showing Cellularly reflux, a histologic finding associated with terminal oliguria and hypotension" (hematoxylin and eosin. lymphoid depleted sinusolds dilated with erythrocytes. containing 400). inusoidal only a few accumulations of pyknotic nucleated cells, x an occasional megakaryocyte, and reticular macrophage Fig 22.-Testicular tubule in distorted edematous (hematoxylin and eosin, X ZOO). intertubular connective tissue. Germinative epithelium appears to have an embedding artifact but changes gland sis. Sinusoids contained polymorphonuclear typical of necrosis of spermatogonia and chromatolysis micro- neutrophils and eosinophils (Fig 18). and injury of the chromatin of spermatocytes and chro- fat re- matids are present (hematoxylin and eosin, )( 400). Spleen.-The spleen weighed 110 gm and te with was flabby grossly. appearance was that on was Its of acute massive blood loss. Malpighian cor- nuclear puscles could not be identified and. corre- cystic spondingly, their usual complement of lym- thelioid phocytes was missing. The central arterioles nipheral were adjacent to prominent nodules of well- that it preserved hypertrophied reticuloendothelial ialisade cells (Fig 19). Only a few shrunken or a basal disrupted lymphocytes were among the re- uamoid maining pyknotic nuclear debris. Inter- spersed were eosinophils, polymorphonu- es were clear neutrophils, plasma cells, histiocytes, ent dis- and reticular cells. Phagocytosis varied in mesen- frequency and erythrophagocytosis was rare.

1, there Central arterioles showed hyaline intimal rte con- thickening. Occasionally hyalinized connec- sted of tive tissue was present in the center of nodules the altered follicles. The sinusoids and red yknotic pulp were poorly defined by nucleated cells. Reticu- Patchy areas were congested appearing like mghout hemorrhage, but in most areas the reticular gocyto- supportive connective tissue of the spleen

Arch Path-Vol 83, May 1967 456 RADIATION DEATH-FANGER & LUSHBAUGH was condensed, especially, as seen with the damage in spermatids and spermatocytes, from primary I PAS stain. Polymorphonuclear neutrophils evidenced by nuclear pyknosis and cyto- tral nervous sy! were frequent in the blood of both the red plasmic vacuolization. The spermatogonia subsyndrome 4 pulp and large blood vessels. were pyknotic, swollen, or unidentifiable as drome of max Bone Marrow.-Grossly the bone marrow to type. The germinal epithelium was sepa- both men occw of the sternum, ribs, vertebral bodies, and rated from the basement membrane and in- for this letha femoral heads was thin, liquid, and a clear, terstitial edema was massive (Fig 22). courses and pa bright red. Former islands of erythromyelo- Brain.-Grossly the brain was normal and port the mncl poiesis (Fig 20) were identifiable chiefly by microscopic changes were minimal. There examples of tE the presence of fixed reticular phagocytes was acute swelling of Penfield. Oligodendro- drome. Both I containing small amounts of nuclear debris. glia and astrocytic nuclei showed clear dence symptom Megakaryocytes with pyknotic distorted nu- spaces around them with wisps of stainable ease, but the ah clei could also be seen adjacent to sinusoids cytoplasm bridging them. Occasional fields of neuronal lysi dilated by erythrocytes and to interstitial showed more microglia than usual. The en- contrast to the ; spaces filled by stainable edema fluid. A few dothelial cells of capillaries sometimes were Iar inflammatox cells appearing like primitive stem cells prominent. Cerebellar granule cells dld not ular exudates ai were found along with scattered small cells show necrosis or any decrease in number. widespread else with pyknotic nuclei. Mitoses were absent Diffusely scattered extravascular polymor- bodies-suggest and no accumulations of cells that suggested phonuclear leukocytes were increased in the toms in these p continuing cellular proliferation could be meninges and around some of the cortical lar damage and found. Fat cells were unaltered. blood vessels (Fig 12), slightly greater in ment rather th Thyroid.-The gross appearance of the amount than the infiltrations seen in the upon the centri thyroid was normal except for a minute cal- vi-cers. Severe intrad cific nodule in the left lobe. Microscopically, Review of these sections was made by a ing histologic ci a rare acinus contained polymorphonuclear panel of consultants in neuropathology: vious study of a leukocytes in the colloid and brown pigment Samuel P. Hicks, MD, Ann Arbor, Mich; tion dosage rar in the epithelial cells. David Sohn, MD, New York; F. Stephen cardiac damage ; Parathyroid.-The parathyroid glands Vogel, MD, Durham, NC; Harold W. Wil- lesion responsibl showed no abnormality except ectopic thy- liams, MD, Providence, RI; Mary Ambler, sis, however, w: mic tissue showing changes similar to those MD, Providence, RI; and Wolfgang Zeman, that the myoca in the mediastinal thymus. MD, Indianapolis. All were in general agree- sensitive than tl Kidneys-The kidneys were moderately ment that cytologic evidence for primary although studier swollen but otherwise not abnormal and neuronal and granule-cell damage was mini- y-irradiation on showed only slight degenerative changes. mal or questionable, while vascular changes of animals fail t The glomeruli were normal but displaced and meningeal leukocytic exudation were recent studies ir by proteinaceous fluid that distended the present but mild in comparison to the de- onstrates that tl glomerular space. Reflux of proximal tubu- gree of these changes in monkeysl8 and of the subdivisi lar epithelium19 into Bowman’s space over- lower animals irradiated at the level of this syndrome into h lying the capsular epithelium were found patient’s exposure. and neurologic (Fig 21). Epithelium in proximal convolut- size the “domin; ed tubules and rarely in other parts of the Comment damage at doses diovascular calk nephron, showed isolated foci of necrosis Pathologic changes are described here in tal-body doses b and nuclear degeneration. Small amounts a man who died 49 hours after receiving sal ulceration of an unknown yellowish-brown pigment the highest estimated neutron-y whole-body ha (? lipochrome) were present within the epi- radiation dose (8,800 rads) in human expe- of fluid and elec thelium of the proximal convoluted tubules rience.16 They confirm and extend those ic lesions are ( and thick loops of Henle. previously reported in a man who died 33 experiments in AdrenaIs.-These glands were congested hours after about half as large a radiation that doses of ra but otherwise not altered. in the range where some previous animal ex- hypotension whc Testes.-Grossly the testes were not re- perimentation suggests that the mode of body are ineffec markable. A review, by a biologist special- death in both patients should have resulted heart with the 1 izing in histologic evidence of radiation in- exposure in a simiIar nuclear criticality acci- radiation of the I jury in the human testes, revealed great dent.10.16 The exposures of both men were tension in dogs

Arch Path-Vol 83, May 1967 RADIATION DEATH-FANGER & LUSHBAUGH 457

:*, from primary to the cen- cmse over the required total-body dose is needed.23924 Cyto- tral nervous system, the so-called neurologic gonia subsyndrome of the acute radiation syn- The findings in this human case study )le as drome of mammals.1 Although death in and the previous Los Alamos one of mas- sepa- both men occurred within the expected time sive peripheral interstitial edema, cavitary id in- for this lethal mechanism, the clinical effusions, random organ edemas, and in- >. courses and pathologic findings do not sup- fl2m.atox-y states leads us to the conclu- 11 and port the conclusion that these deaths are sion that peripheral and organic vascular rhere examples of the neurologic radiation syn- damage was the dominant radiation lesion Nndro- drome. Both patients terminally did evi- underlying the hypotensive shock and rapid clear dence symptoms referable to cerebral dis- death within two days. Although these two inable ease, but the absence of a significant amount patients provide the only human medical fields of neuronal lysis or granule-cell pyknosis in evidence for it, this study, along with evi- ne en- contrast to the presence of meningeal vascu- dence from animals20 of severe vascular damage after total-body exposure 1,000 to I were lar inflammatory changes, perivascular ceI- to d not ular exudates and edema-all changes found 10,000 R, suggests a “vascular radiation sub- mber. widespread elsewhere throughout the whole syndrome” should be inserted into the radio- ymor- bodiessuggest that the neurologic symp- biologic concept of modes of death in the in the toms in these patients resulted from vascu- . The occurrence ztical lar damage and cerebral circulatory impair- of early transient hypotension at doses that ter in ment rather than primary radiation effects cause death later because of hematopoietic n the upon the central nervous system. and intestinal mucosal failure suggests that Severe intractable shock and accompany- systemic vascular damage may play a role in these subsyndromes as well. The absence of by a ing histologic cardiac changes’j in the pre- well defined central nervous system neuro- >logy: vious study of a human death in this radia- nal damage in these patients (K and P) sug- Mich; tion dosage range suggested that primary gests that for the neurologic subsyndrome in ephen cardiac damage might have been the etiologic lesion responsible for death.10 This hypothe- man to be due, as implied, to direct cerebral , Wil- or cerebellar damage, a prompt dose the nbler, sis, however, was based on the assumption to brain greater than 10,000 rads must be nec- eman, that the myocardium may be more radio- essary. This opinion finds some support in agree- sensitive than the blood vessels themselves, the precise studies of Zeman et al26 on the imary although studies on the effect of total-body mini- y-irradiation on the cardiovascular system histologic and enzymatic effects of micro beams of deuterons upon individual neu- anges of animals fail to lend this idea support. In rones and glial cells. It lends credence also were recent studies in a primate, Kunde120 dem- to Brown’s2Gexplanation for the anomalous Le de- onstrates that the widely accepted concept cerebral radiosensitivity of the burro, that 5 and of the subdivisions of the acute radiation If this syndrome into hematologic, gastrointestinal, dies a “neurologic” death according to and neurologic syndromes fails to empha- Trum2’ after exposure of its head to as little size the “dominance” of peripheral vascular as 200 R. Brown26 describes in these ani- damage at doses greater than 3,000 R. Car- mals extraordinary cerebral vascular damage diovascular collapse can occur from such to- with the production of meningeal vascu- ere in tal-body doses before gastrointestinal muco- litis, cerebral edema, and intracranial pres- sures in excess of 800 mm Hg, while ziving sal ulceration has time to cause massive loss histo- &-body logic evidence of primary cerebral neural of fluid and electrolyte and before neurolog- cellular damage is minimal. Acute intra- we- ic lesions are demonstrable. Furthermore, those cranial vascular damage may thus be an im- experiments in dogs21 and rabbits22 show ed 33 portant pathologic complex within the vas- iation that doses of radiation capable of causing cular radiation syndrome and explain in a1 ex- hypotension when administered to the entire part the past confusion of this syndrome de of body are ineffectual when confined to the complex with a neurologic one. 5Ult.d heart with the body shielded. Although ir- The development of a radiation vascular T acci- radiation of the head alone can induce hypo- lesion that leads acutely to fluid leakage and were tension in dogs and rabbits, a tenfold in- cel1,ular exudation or remotely to sclerosis,

Arch Path-vol 83, May 1967 458 RADIATION DEATH-FANGER & LUSHBAUGh

atrophy, and chronic circulatory impairment Schweitzer of heavy dosage of radation over tering of primitik obviously depends upon some synergism of the thorax with globules noted in the “myo- nective tiiue d total dose and rate of exposure. In these pa- plasm.” Gassman31 and W~lbach~~have in- degenerate fat cel tients (K and p),the total dose requirement dependently observed vacuolation of smooth teinaceous precipi was exceeded instantaneously and length of muscle cells in the media of arteries second- ma and residuum survival was determined by the acute vascu- ary to radiation exposure. Warren and The well-know lar damage and the rate of accumulation of Friedman33 have observed vacuolation of epithelium to radi intolerable amounts of extravascular fluid. smooth muscle in the irradiated intestinal present patient w The use of plasma in patient P instead of as tract. In radiation accidents, LatarjeF4 has such a short time much electrolyte solution as in patient K suggested that tissue changes in the heart to the degeneratic may be the reason P survived longer after a might be biochemically induced by toxic its separation frl greater dose. The primary vascular lesion tissue-breakdown products indirectly from was of interest as itself, however, was not definable by light whole-body damage. What total effect this the loss of cell adh microscopy nor by limited histochemistry. inltaceilular change in hydration may have Among the ato The congested capillaries were lined by en- upon myocardial and vascular contractility thelia1 cells in the dothelial cells that were rarely pyknotic or and Purkinje fiber conductivity is of course quently became di disrupted. These changes, difficult to distin- unknown. Electrocardiographic changes, clei, coarse chrom guish from artifact, were seen in the subcu- however, were minimal and seemed to reflect mitoses, but coml taneous tissues of the left hand and abdomi- chiefly pericardial iniiammatory changes. In found in the pres nal wall of P and the omentum of K,15 and support of this observation, in animals ra- supervened. The I rarely at other superficial sites in both. diation doses that cause hypotension are onstrated desqw Alkaline phosphatase, an enzyme that not accompanied by reduction in myocar- cells in the lumin: might be concerned with the transport of OS- dial contractility’o or electrocardiographic only equivocal ck motically active molecules** was demon- changes. The relative ineffectiveness of an- observed in the F strable in capillary endothelial cells for at giotensive drugs in these patients is paral- tim. least 15 hours after death, attesting to the leled by the unresponsiveness of the heavily It is especially radioresistance of this enzyme or the en- irradiated animal to levarterenol2” creatitis of the pre dothelial cell, or both. This “hardiness” The degree of pathologic changes in the ation damage, sin might be related to enzyme survival, intact other organs was, for the most part, as ex- creatitis has been ribosomal function capable of enzyme syn- pected from previous experience. The early severe radiation thesis, or continuous production of messen- disappearance of circulating lymphocytes alterations seen i ger ribonucleic acid and message transcrip- was correlated with the almost complete ab- do not resemble t tion, or several of these possibilities. On the sence in any tissue of cells recognizable as ly observed with other hand, this enzyme might not reflect normal small or medium-sized lymphocytes. rect effect of ma; the molecular level of the radiation damage, The peripheral granulocytosis during life and Warthin36 which could conceivably be appraised better was recognizable at death and its reflections changes in a pati by measuring lysosome development using were Seen as leukocytic inflammatory exu- heavy doses of rc acid phosphatase as a marker for hydrolytic dates in many organs, leukocytic thrombi, epigastrium. Aci enzyme activity.25 and bone-marrow depletion. Although Lie- duct epithelium I The vacuolation of subepicardial myocar- bow et a135 noted frequent mast cells and tion and necrosis dium aad smooth muscle in the intestines and erythrophagocytosis in lymph nodes and cytic infiltration. media of arteries was considered similar and spleens in atomic bomb casualties, this was The other epitl probably was produced by the same basic not the present experience. Phagocytosis of is that of the ren, mechanism. Although similar changes are nuclear debris was considerable, but eryth- bule. This lesior due to postmortem artifact, these alterations rophagocytosis was rare. Most impressive Councilman37 an of intracellular architecture can be caused was the efficiency of the reticuloendothelial epithelial reflux by altered osmolality, cell-membrane per- system in cleaning up cell debris. Only scant occurs when olig meability, and intracellular imbibition of nuclear fragments remained, either in extreme shortly k fluid. Similar changes in muscle, although lymphoid tissue or in bone marrow. P. Since it has no rare, have been previously described. Hart- The extreme damage to the bone marrow in a death from 1 man29 observed granular and vacuolar de- was consistent with previous experience in not present in p generation of myocardium in animals and severe radiation exposures. Cell population related in patient humans exposed to localized radiation of the was notably depleted, especially of imma- fore death during thorax. Warrenso cited a case reported by ture hemopoietic cells. Yet there was a scat-

Arch Path-Vol83, May 1967 RADIATION DEATH-FANGER & LUSHBAUGH 459

1 over tering of primitive unidentified cells. Con- was measurable, and can not be attributed ‘myo- nective tissue damage was manifest by to primary radiation damage. ?e in- degenerate fat cells interspersed with a pro- This study was supported by the board of Trus- nooth teinaceous precipitate due to interstitial ede- tees, Rhode Island Hospital, and in part by the US Atomic Energy Commission. and- ma and residuum from necrotic tissue. Mrs. Gretchen Humason, Oak Ridge Institute of and The well-known vulnerability of germinal Nuclear Studies, Medical Division prepared special epithelium to radiation was borne out in the histologic preparations; Paul E. Steker, MD, Uni- m of versity of Pennsylvania, critically reviewed histo- &iMl present patient with changes manifested in pathology of these case studies; Arthur F. Jacques, 14 has such a short time after exposure. In addition photographer, and Barbara R. Barker, PhD, Rhode Island Hospital, prepared the photomicrographs and heart to the degeneration of germinal epithelium, autoradiographic studies. Miss Mavis Rowley, Re- toxic its separation from basement membranes search Associate, Pacific Northwest Research Foun- from was of interest as an additional example of dation. Seattle, reviewed histologic evidence of inju- ry to testes. Hospital records of Robert S. Grier, t this the loss of cell adherence due to radiation. MD, Los Alamos Medical Center, NM, and of JO- have Among the atomic bomb casualties, epi- seph S. Karas, Rhode Island Hospital, contributed ctility thelial cells in the gastrointestinal tract fre- materially to this study. The Medical Division, Oak Ridge Institute of Nuclear Studies, Inc., under con- murse quently became distorted with enormous nu- tract with the US Atomic Energy Commission, gave mges, clei, coarse chromatin network, and atypical permission to reproduce Fig 1-22. mitoses, but comparable changes were not reflect Generic and Trade Names of Drug e.In found in the present patient because death Is ra- supervened. The Los Alamos patient15 dem- Levarterenol-Leuophed. n are onstrated desquamated necrotic parietal locar- cells in the lumina of the gastric glands, but References .aphic only equivocal changes in this tissue were 1. Bond, V.P.; Fliedner, T.M.: and Archambeau, If an- observed in the Rhode Island accident vic- J.O.: Mammalian Radiation Lethality: A Disturb- paral- tim. ance in Cellular Kinetics, New York: Academic 3avily Press, Inc., 1965. It is especially difficult to ascribe the pan- 2. Langham, W., et al: Studies of the Effect of creatitis of the present patient to direct radi- Rapidly Delivered Massive Doses of Gamma-rays n the ation damage, since the occurrence of pan- on Mammals, Radiat Res 5:404-432, 195C. 3. Vogel, F.S.: “Effects of High-dose Gamma as ex- creatitis has been observed rarely even after Radiation on the Brain and on Individual Yeiir-*ns,” WlY severe radiation exposures. The cytologic in Haley, T. J., Snider, R. S., and Linde, S. M. XyteS alterations seen in the pancreas, however, (eds.): Response of the Nervous System to Ionizing Radiation: Proceedings of Znternational Symposium, te ab- do not resemble the pancreatitis occasional- Northwestern University Medical School, Sept 7-9, ble as ly observed with shock and must be a di- 1960, New York: Academic Press, Inc., 1962. 4. Bond, V.P., and Robertson, J.S.: Vertebrate ICyteS. rect effect of massive radiation dose. Case Radiobiology (Lethal Action and Associated Ef- g life and Warthin36 described such pancreatic fects), Ann Reu Nucl Sci 7:135-162, 1957. ctions changes in a patient who died weeks after 5. Haymaker, W., et al: The Effects of Lanthanum“o (Gamma) Radiation on the Central 7 exu- heavy doses of roentgen radiation over the Nervous System and Pituitary Gland of Macaque .ombi, epigastrium. Acinus cells were atrophic, Monkeys; A Study of 67 Brains and Spinal Cords 1 Lie- duct epithelium showed vacuolar degenera- and 77 Pituitary Glands, J Neuropath Erp Neurol 17:12-57, 1958. s and tion and necrosis, and there was lympho- 6. Hempelmann, L.H.; Lisco, H.; and Hoffman, ; and cytic infiltration. J.G.: The Acute Radiation Syndrome, A Study of Nine Cases and A Review of the Problem, Ann In- s was The other epithelial lesion of special note tern Med 36:279-510, 1952. Isis of is that of the renal proximal convoluted tu- 7. Davidson, H.O.: Biological Effects of Whole- eryth- bule. This lesion, originally described by Body Gamma Radiation on Human Beings (U), Baltimore: The Johns Hopkins Press, 1957, pp 101. essive Councilman37 and named infraglomerular 8. Fliedner, T.M.: Hamatologische Befunde Beim ,helial epithelial reflux by Waugh,Ig apparently Akuten Strahlen Syndrom, Strahlentherapie Son- scant derb 55:2541, 1964. occurs when oliguria and hypotension are 9. Oughterson, A.W., and Warren, S. (eds): Medi- 2r in extreme shortly before death, as in patient cal Effects of the Atomic Bomb in Japan, New P. Since it has not been described previously York: McGraw-Hill Book Company, Inc., 1956. 10. Shipman, T.L.: “A Radiation Fatality Re- arrow in a death from radiation damage and was sulting from Massive Overexposure to and Ice in not present in patient K, it must be cor- Gamma Rays,” in Diagnosis and Treatment of lation Acute Radiation Injury, proceedings of a scientific related in patient P with the five hours be- meeting sponsored by International Atomic Energy ma- fore death during which no blood pressure Agency and World Health Organization, Geneva, l scat- Arch Path-Vol 83, May 1967 -. 460 RAf?lATION JIEATH-”ANGER & LUSHBAUGH

Oct 17-21, 1960. International Documents Service, 24. Peng, M-T.; Chien, S.; and Gregersen, M.I.: Columbia University Press New York: 1961, pp Effect cf Large Doses of Head Irradiation in Dogs 113-133. Amer J Physiol 194:344-350, 1958. 11. Andrews, GA., et al: “ at 25. Zeman, W., et al: Chemical and Enzymatic the Y-12 Plant,” in Diagnosis and Treatment of Changes in Nerve Cells Irradiated With High Ener- Acute Radiation Injury, proceedings of a scientific gy Deuteron Microbeams, in Response of the Nerv- meeting sponsored by IAEA and WHO, Geneva, ous System to Ionizing Radiation: Proceedings of Oct 17-21, 1960. International Documents Service, an International Symposium, Northwestern Univer- Cclumbia University Press, New York 1961, pp sitv Medical School. Chicago. September 1960. Hal- 27-48. ey; T. J., and Snider, R. Sy (eds:), New York: Aca- 12. Jammet, H.P.: “Treatment of Victims of the demic Press, Inc., 1962. Zero-Energy Reactor Accident at Vinca, “in Diag- 26. Brown, D. G.; Sasmore, D.P.; and Jones, L.P.: nosis and Treatment of Acute Radiation Injury, Acute Central Nervous System Syndrome of Burros, prcceedings of a scientific meeting sponsored by in Response of the Neruous System to Ionizing IREA and WHO, Geneva, Oct 17-21, 1960, Intema- Radiation: Proceedings of an International Sym- tional Documents Service, Columbia University posium, Northwestern University Medical School, Press, New York: 1961, pp 83-103. Chicago: September 1960, Haley, T. J., and Snider, 13. Kurshakov, N.A. (ed): Sluchay Ostroy Luche- R. S. (eds.), New York. Academic Press, hc., 1962, voy Bolezni U Cheloveka (A Case of Acute Radia- pp 503-511. tion Sickness in Man), Gosudarstvennoe Izda- 27. Trum, B.F.; Rust, J.H.; and Wilding, J.L.: tel’stvo Meditsinskoy Literatury, Moskva: 1962, p Clinical Observations Upon the Response of the 150. Burro to Large Doses of External Whole Body 14. Petersen, D.F.: Neutron Dose Estimates in Gamma Irradiation, Aub Vet 8:131-136, 1952. the SGl Accident, Health Phys 9:231-232, 1963. 28. Tosteson, D.C.; Blaustein, M.P.; and Moulton, 15. Lushbaugh, C.C.: “Gross and Microscopic Pa- RH.: Phosphomonoesterase and Na + K Activated thology and Neuropathology,” in Acute Radiation ATPase, abstacted, Fed Proc 20:138, 1961. Death Resulting From an Accidental Nuclear Criti- 29. Hartman, F. W., et al: Heart Lesions Produced CQ~Excursion, Shipman, T. L. (ed.), J Occup Med by the Deep X-ray: An Experimental and Clinical (special suppl) 3:160-168,1961. Study, Bull Hopkins Hosp 41:36-61, 1927. 16. Karas, J.S., and Stanbury, J.B.: Fatal Radia- 30. Warren, S.: Effects of Radiation on Normal tion Syndrome From an Accidental Nuclear Excur- Tissues: VI. Effects of Radiation on the Cardiovas- sion, New Eng J Med 2’72755-761, 1965. cular System, Arch Path 34:1070-1079. 1942. 17. Petersen, D.F.: Rapid Estimation of Fast- 31. Gassman, cited by Warren, S: Effects of Radi- Neutron Doses Following Radiation Exposure in atkon on Normal Tissues: VI. Effects of Radiation Criticality Accidents: The 32 S (n, p) 32 P Reaction on the Cardiovasdar System, Arch Path 34A070- in Body Hair, in Proceedings of a Symposium on 1079, 1942. Personnel for Accidental High-Leuel Ex- 32. Wolbach, cited by Warren, S: Effects of Radi- posure to External and Internal Radiation, Vienna: ation on Normal Tissues: VI. Effects of Radiation March 8-12, 1965, IAEA, 1965, pp 217-233. on the Cardiovascular System, Arch Path 34:1070- 18. Vogel, F.S., et al: The Induction of Acute 1079, 1942. Morphological Changes in the Central Nervous Sys- 33. Warren, S., and Friedman, N.B.: Effeds of tem and Pituitary Body of Macaque Monkeys by Radiation on Normal Tissues: IV. Effects of Radia- Cobalt 60 (Gamma) Radiation, J Neuropath Exp tion on Gastrointestinal Tract, Including the Sali- Neurol 17:138-150, 1958. vary Glands, the Liver and the Pancreas, Arch Path 19. Waugh, D.; Schlieter, W.; and James, A.W.: 34:749-787, 1942. Infraglomerular Epithelial Reflux, Arch Path 7293- 34. Latarjet, R.: Discussion, p 176, in Diagnosis 96, 1964. and Treatment of Acute Radiation Injury, proceed- 20. Kundel, H.L.: The Effect of Gamma Irradia- ings of a scientific meeting sponsored by IAEA and tion on the Cardiovascular System of the Rhesus WHO, Geneva, Oct 17-21, 1960, International Docu- Monkey, Res 27:406418, 1966. ments Service, Columbia University Press, New 21. Phillips, S.J.; Reid, J.A.; and Rugh, R: Elec- York, 1961. trocardiographic and Pathologic Changes After Car- 35. Liebow, A.A.; Warren, S.; and DeCoursey, E.: diac X-irradiation in Dogs, Amer Heart J 68:524- Pathology of Atomic Bomb Casualties, Amer J 533,1964. Path 25:853-1027, 1949. 22. Gerstner, H.B., and Kent, S.P.: Early Effects 36. Case, J.T., and Warthin, A.S.: The Occurrence of Head X-irradiation in Rabbits, Radiat Res 6:626- of Hepatic Lesions in Patients Treated by Intensive 644,1957. Deep Roentgen Irradiation, Amer J Roentgenol 23. Gerstner, H.B., et aI: Effect of Head X-irradi- 12:27-46, 1924. ation in Rabbits on Aortic Blood Pressure, Brain 37. Councilman, cited by Waugh, D.; Schlieter, Water Content, and Cerebral Histology, Radiat Res W.: and James A.W.: InfragIomerular Epithelial 5:318-331, 1956. Rehux, Arch Path 7293-96, 1964.

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