1 MILITARY AND CIVIL DEFENSE ASPECTS OF THE IN MAN

HERBERT B. GERSTNER, M. D. Deportment of

58-6

Air University SCHOOL OF AVIATION MEDICINE, USAF RANDOLPH AFB, TEXAS November 1957 MILITARY AND CIVIL DEFENSE ASPECTS OF THE ACUTE RADIATION SYNDROME IN MAN

From a compatative analysis of human data derived from nuclear accidents, Japanese bomb casualties, and radiotherapy patients, emerges the clinical picture of the acute radiation syndrome with its three subdivisions - hematopoietic, gastrointestinal, and cerebrai forms. Dependency of the picture on dose level and individual susceptibility is discussed, and the therapeutic management is outlined. Since penetrating represents a potential casualty-causing agent, problems facing the practical physician under catastrophic conditions are evaluated.

In an address to the 62d Annual Convention o/ the Association of Military Surgeons o/ the United States held in November 19.55, hlaior General lames P. Cooney, Deputy Surgeon General o/ the Army, stated (I): “In the past ten years a great deal o/ effort has been spent in trying to understand and teach various detailed eflects o/ nuclear weapons. Some of the effort has in- volved discussions of detailed physics and mathematics relating to the bomb and the micm- following the detonation. This approach has led to a preoccupation with details that will not help us as medical people to solve the casualty problems. In addition. the preoccupation with these details has resulted in the creation of an aura of mystety around the weapon that has prevented the average individual from understanding the things that are essential to him and to his neighbor if they are to survive.”

INTRODUCTION difficult to arrive at an objective and sen- sible judgment. Now that nuclear energy is already producing electricity, propelling ships, and forming the The present report, restricted to the acute basis for devastating weapons, and now that effects of human whole-body exposure to long-range ballistic missiles capable of carrying penetrating ionizing radiation, attempts a nuclear warheads can be assumed to exist, every- realistic evaluation of facts as they are known body concerned with practical medicine is at this time. Clinical features essential from compelled to acquaint himself with effects of the standpoint of the practical physician and ionizing radiation on man. Widespread ignorance the medical officer have been emphasized, of these effects may be attributed to the fact that while those of more academic interest have presently known parts of the data are too widely been omitted or treated cursorily. Such an dispersed over numerous protessional journals, endeavor to present to the practitioner a coherent or hidden in practically inaccessible documents, and unified clinicopathologic concept on which to allow easy composition of a comprehensive to base his actions, necessarily must involve picture; also, the factual evidence is frequently oversimplifications that, with increasing infor- clouded by emotional and political consid- mation, may be subject to revision. erations. Under these circumstances it IS In case of accidental or intentional nuclear Received for publication on 19 July 1957. explosions, an estimate can be made of the

1 50-6 air dose of penetrating ionizing radiation to within 2 or 3 days, hospitalization becomes which a group of persons has been exposed. necessary. Manifestations of severe bone marrow The physician then called into action will depression - characterized hematologically by face two questions of paramount importance: leukopenia, thrombocytopenia, and anemi a - (1) Is it possible, from the air dose, to predict appear in the form of frank hemorrhages, purpura, the fate of the exposed persons-that is, to susceptibility to infection (especially in the arrive at a reasonably correct prognosis? oral cavity), fever, and other signs and symptoms (2) Is it conceivable, from the air dose, to associated with such disorders of the blood anticipate for a population the degree and the picture. This phase of aplastic anemia cul- time course of the ensuing disease, and thereby minates about the 30th day when the patient to estimate the medical requirements - personnel, passes through a critical state. Thereafter hospital beds, and supplies? recovery starts and becomes obvious between the 40th and 50th days; when fever disappears, THE “TYPICAL” ACUTE RADIATION SYNDROME infectious lesions in the oral cavity heal, and Exposure to a sufficient amount of penetrating the blood picture approaches normal values. x-ray, gamma, or neutron radiation causes Convalescence begins after the 60th day and in man characteristic clinical sequelae -the is followed by resumption of work and normal acute radiation syndrome. This complex of life approximately 3 months postexposure. signs and symptoms, unfolding along a rather According to their chronologic sequence, fixed time schedule, forms a peculiar picture four distinct stages of the acute radiation that is as well defined as “lobar pneumonia” syndrome can thus be established -namely, or “typhoid.” prodromal, latent, bone marrow depression or The most conspicuous features of the “typical” aplastic anemia, and recovery phases (fig. 1 radiation-induced disease are as follows: Within and ref. 2). Of course. the “typical” disease, 2 hours after exposure, complaints pointing as described above. will be subject to variation to an “upset stomach” develop rather abruptly; and modification brought about essentially by anorexia, nausea, and malaise are predominant two factors -dose and individual susceptibility. and are accompanied by listlessness, drow- Before these modifications can be discussed, siness, and fatigue. Deterioration of the indi- however, a survey must be made of the material vidual’s general condition progresses rapidly on which the analysis is based. and leads to profuse vomiting, extreme weakness, or even prostration. This early reaction cul- ORIGIN OF DATA USED FOR EVALUATION minates about 8 hours after exposure and then subsides rather quickly. On the 2d postradiation The largest group of persons exposed to day, nausea and occasional vomiting persist nuclear radiation is represented by the popu- but the general condition is markedly improved; lations of Hiroshima and Kagasaki. Careful on the 3d postradiation day all compiaints and comprehensive clinical (2, 3) as well as have disappeared. To avoid confusion, the pathologic (3, 6) observations are available. burst of eariy signs and symptoms should noc Although these data are outstanding for estab- be designated as “radiation sickness” but lishing consequences of human exposure to rather as “initial reaction” or as the “prodromal ionizing radiation, they are of rather limited phase” of the acute radiation syndrome. After value for deriving dose-effect relationships, dissipation of prodromal effects, the patient since frequently even a rough estimate of the is asymptomatic and capable of performing dose is impossible. Subsequently, reference normal work, or even of exerting strenuous to the Japanese bomb casualties appears under physical effort. This favorable state, the the abbreviation JBC. On 1 March 1954, the tt latent period,” may extend to the 19th or 20th test explosion of a hydrogen device at Bikini postradiation day, when a new phase is entered Atoll accidentally exposed 28 Americans and rather abruptly. As in the acute onset of an 239 Marshallese to fallout radiation. Deter- infectious disease, the patient experiences minations oi dose and clinical sequelae are chills, malaise, a feverish feeling, fatigue, well documented (5, 6, 7). According to the and shortness of breath on exertion. Again the four islands on which these persons were general condition deteriorates rapidly and, located, four dose groups can be formed that 58-6 will subsequently be designated as h~/,(Utirik), numbering of the patients. On 2 June 1952, at .M/, (Ailinginae), Ai/, (Rongcrik), and All, (Ronge- the Argonne National Laboratory, 4 persons lap Atoll). During the same test shot, 23 were exposed to neutron and gamma radiations Japanese aboard a fishing boat were also ex- released by the accidental excursion of a water- posed to fallout radiation. This group, for moderated critical assembly. Doses and clinical which dose and clinical sequelae are relatively pictures have been well established for each well known (8, 9, lo), will subsequently be individual patient (13). These cases will be designated as IF. designated as A,, A,. A,, and A,. At the Geneva Two nuclear accidents occurred at the Los Conference on Peaceful Uses of Atomic Energy, Alamos Scientific Laboratory. Uncontrolled fis- Guskova et al. (14) reported 2 Russian cases sion reactions caused the inadvertent exposure of the acute radiation syndrome as the result of 10 persons to complex ionizing radiation. of a short gamma and neutron irradiation, after Detailed analysis of dose (11) and clinical the rules of operating an experimental reactor course (12) are available for 9 of these cases. had been violated. These 2 patients, for whom They will be designated as LA, . . . LA,,, dose and clinical course are well reported, keeping the indices identical with Hempelmann’s will be designated as R, and R,.

LATENT PHASE

I I\ I I

DAYS I WEEKS POST EXPOSURE I POST EXPOSURE

FIGURE 1 Schematic drawing showing the typical clinicai course of the acute radiation syndrome (hematopoietic tom). The platelet count would parallel the WBC, while lymphocytes wuld decline earlier and recover later.

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course is trivial. Case A,, on the ‘15th day man, at least not in the low dose ranges, until after exposure, displayed in the right eye, they can be founded on strong affirmative ob- immediately inferior to the limbus of the optic servations. Tolerance to additional small disc, a very small, flame-shaped hemorrhage amounts of irradiation will practically be normal. (a in table I) that disappeared one month later. In this respect the National Committee on Radi- The ,i!/,group showed indications of a slight ation Protection and Measurement (28) declares: depression of leukocytopoiesis (b) since lympho- “An accidental or emergency dose of 25 rems cyte and thrombocyte counts were somewhat ( equivalent man) to the whole body, lower than those of the controls, especially occurring only once in the lifetime of the person, around the 29th postexposure day when the shall be assumed to have no effect on the maximal effect on the peripheral blood elements radiation tolerance status of that person.” must be expected to occur. Case LA9 felt At the Chalk River Conference (quoted from nauseated (c in table I) several hours after ref. 29) it was agreed that no manifest permanent the accident but ascribed this symptom to injury is to be expected for a single exposure nervousness and apprehension. Among the of the whole body equivalent to 25 r or less, VDA cases only one patient reported a brief with a possible exception in the case of pregnant episode of nausea on the day of treatment, women. Evidently, as far as the exposed while the rest were completely asymptomatic. individual is concerned, doses up to 50 r do In connection with the Manhattan Project, 3 not present clinical problems; however, they healthy volunteers received 21 r of x-radiation may assume significance for future generations to the whole body: they showed neither hema- it large numbers of the younger population have tologic changes nor any other adverse effect been irradiated. Animal experiments suggest (18). The same was true in a group of cancer that doses of 30 to 50 r will probably double the patients, with the exception of a slight decline spontaneous mutation rate in man. Since most in lymphocytes occurring rather consistently of the mutations are undesirable, this increased at doses of 40 r or higher (19). In summary, rate may be a real problem for the nation as a then, if can be stated that the dose range from whole. However, much more information is ’ 0 to 50 r is subthreshold {or the acute radiation required before the size of the potential genetic syndrome and presents no medical problem in hazard can be realistically assessed. emergency situations. From a purely military standpoint, a recent British publication (26) Dose range: 51 - 100 r concludes that at this level no serious disability As revealed by the corresponding section is to be expected and that the irradiation can of table I, this dose range is subthreshold for be ignored, apart from recording its occurrence. the acute radiation syndrome, and the clinical Although a thorough discussion of possible sequelae are consistently trivial; however, a late effects and genetic consequences ol few sporadic individuals with high radiosen- exposure to ionizing radiation does not belong sitivity snow indications of a beginning, though to the objectives of the present report, a few clinically insignificant, depression of leuko- remarks appear appropriate at this time. All cytopoiesis: between the 3d and 6th week the evidence, supplied by thousands of patients lymphocyte count is well below normal, while having received therapeutic doses in this the granulocytes decrease to slightly subnormal range and by bomb and accident data so far values. in case LA, the total leukocyte count as they can be evaluated today, points to the had fluctuated between 5,500 and 8,000 cells fact that acute reactions, if existing at all, per cubic millimeter prior to the accident; will completely disappear and that perfect after exposure it showed a typical initial period recovery will occur. Shields Warren, in the of instability (fig. 1) and then declined gradually foreword to reference 12, states: “The story to a minimum of 5,000 around the 20th day of the survivors shows that an individual can (d in table I). Among the MI, population, only be exposed to a large dose of radiation and one member showed mild prodromal symptoms still return to a productive vigorous life.” The with nausea (e) during the first 2 days post- concepts of accelerated aging and shortening exposure. The group means for WBC, neutrophils, of life span (27), as derived from contradictory and lymphocytes appeared to be slightly sub- animal experiments, should not be applied to normal (/) throughout several months, while 58-6 the platelets showed a definite minimuin between persons (1, m). Consistently, however, these the 20th and 30th postradiation days. From a changes are so moderate in degree that they clinical standpoint, however, these changes can be handled ambulatorily and, therefore, were inconspicuous, the maximal depression do not pose clinical problems. Three additional of the total white count being somewhat below patients exposed to 120 r remained asympto- 5,000 in 3 cases only. Between the 27th and 42d matic (18). Hence, conclusions parallel those postexposure days there occurred an epidemic gruen {or the previous dose range. of upper respiratory diseases (g, h) which most Dose range: 151 -200 r likely was unrelated to irradiation. Epilation This most important range is well documented and skin injuries (i) definitely were conse- as revealed by the corresponding section in quences of direct contact with fallout material. table 11. Dose and clinical course have been On the 3d postradiation day case A, vomited established for two relatively large groups - MI, on several occasions and had four loose (i) and iZ.1D24. Since these data represent rhe best stools. These effects were believed to be mani- ones known for man, some detailed discussion festations of anxiety and tension rather than appears appropriate. The typical acute radiation of a reflections true prodromal phase. Findings syndrome, evolving in its four phases along in the .ill, group (iz) essentially paralleled a rather fixed time schedule (fig. l), was clearly those of the 1\11, population; however, there noticeable in approximately 70 percent of the was no case with prodromal symptcms, and MI, group and in 90 percent of the MDA patients. neither epilation nor skin lesions developed Among the MI, population, about two-thirds because of early decontamination. The 26 experienced nausea and one-tenth reported patients of the MDA series as well as 4 addi- vomiting and loose stools. Without therapy cases to r com- tional exposed 60 (18) were these effects had subsided by the 3d post- pletely asymptomatic with the exception of a radiation day. The bone marrow depression slight decrease in lymphocytes occurring in the phase varied in degree from trivial to moderate. latter cases. in summary, then, it can be stated In all of the exposed persons both platelet that doses between 51 and 100 r will cause, it at count and total white blood cell count decreased all, but trivial and transitory clinical changes and were at a minimum between the 25th to the posing no medical problem. According to present- 30th and between the 40th to the 45th day, day knowledge these mild acute effects. are respectively. More revealing, from a clinical followed by complete recovery and return to standpoint, are the following findings: Of the normal life. Nevertheless, additional irradiation entiie population 10 percent reached platelet should be restricted as much as possible since values of less than 65,000; 50 percent attained a lowering of radiation tolerance may persist. a WBC of less than 4,000; and 10 percent fell As to this dose range a British publication to a WBC of less than 1,50O/mm.’ However, (26) concludes approximately as follows: Slight, even the patients showing the most pronounced but not incapacitating, illness may occur in a depression must still be considered as border number of cases. There is no need to break off line between moderate and serious since they an important military mission; however, as did not develop definite clinical complications soon as convenient, the exposed men should and remained physically active; frank hemor- be placed under medical observation for bo rhages and purpura were absent; blood transfusion days, and symptoms should be treated as they was not required. The epidemic of upper respir- one-half year, arise. Afterwards, for about atory diseases that spread through the Marshall monthly blood counts should be performed. Islands between the 27th and 42d postexposure days (n, 0) caused, in the group with low Dose range: 101 -150 r leukocyte counts, neither greater incidence Although, as shown by the corresponding nor clinical signs and symptoms of greater section of table I, observations are too few to severity than in the other groups. Therefore, allow a definite statement, the MDA data in agreement with radiotherapeutic experience, suggest the following: The acute radiation Cronkite et al. (7) conclude that such degrees syndrome, with well-developed prodromal and of radiation-induced bone marrow depression bone marrow depression phases, becomes are still well tolerated, and that coincidence noticeable in about one-third of the exposed between epidemic and height of radiation

7 5H-6

that the rnaxiinai bone marrow depression will p redom 1 n ant I y ti e 111 atopoi e t i c ti e p res s 1 on su c- occur 4 to h weeks postexposure. and it was cumb, if ‘it all. during the critical period ex- still considered sate to continue whole-body tendin? irom 3 to (1 weeks postirradiation (32). irradiation, with intervals ot only a tew days Iri summary, ther~, it cu71 be stated that zn between each exposure, as long as the leukocyte li-lr! dose range /win 400 tu 600 T the ciznicai count did not fall below 2,50O/mn1.~ Thus the Cuursc CJ/ the acute radiation svndronie is pre- authors were completely surprised when about domznnntiy grave. ~:pLO 500 T, the bone marrow 3 we e k s po st t r eatinent g r anu i o c y t e s di s appeared lt>]Ury sliil determines clinlcai picture and’ “almost completely,” thrombocytes were “hardly outcome, whereas at higher doses direct damage present,” hemorrhage from gum and nose ap- 10 ti^^ cpitbelzum oj the gastrointestinal tract peared, and petechial bleeding in the skin becomes more and inore the decisive /actor became evident. kloreover, fever and infection brangin5 auout (1 /ulminating course 01 rhe complicated this picture of “agranulocytosis” disease - the ~nstrointestznal /orm the acute and caused death of the patients between 3 and radiation svnd’ronl e. 7 weeks after cessation of radiotherapy. In addition, much of the /l?C data can be assumed The gastrointestinal form of the acute radi- to fall in this dose range; there exist also ation syndrome is illustrated by one of the numerous animat experiments that allow cau- nuclear accidents. LA, (12, 33). The scientist t iou s extrapol a ti on. involved was performing critical mass tiecer- When all the direct and indirect evidence minations. For that purpose two pieces of is taken into account. the following inference bomb material, hemispheres the size ot a split may be made: co about 500 r, the ciinical baseball mounted on a rack, were siowiy pushed course of the acute radiation syndrome is largely toward each other. Pleutrons from an outside determined b), radiation effects on the lymphoid source triggered in the fissionable material tissue and the bone marrow -the most radiosen- chain reactions that became more intense with sitive cell groups of the adult individuai. narrowing air gap. Just before reaching the Temporary depression of the gonads need not critical distance -and thus before an explosive be considered in this regard since no serious build-up oi chain reactions occurred -the constitutional reactions are involved. At doses hemispheres had to be separated. One day the above 500 r, however, direct radiation damage to bomb materials accidentally came too close the epithelium of the gastrointestinal mucosa - together and the reaction in the critical assembly the next cell group in radiosensitivity -becomes began to “run away,” emitting massive amounts a decisive factor. In the generative centers of penetrating ionizing rays. The scientist of the jejunal and iliac crypts, particularlj., was exposed to a combined neutron, gamma, and radiation causes arrest of mitotic activity. roentgen radiation oi about 2,000 r to the whole This production block of viable new ceils, body. He experienced nausea within a few combined with decay of already existins cells. minutes. and he vomited before reaching the leads to denudation of the intestinal wall (30). hospital about 60 minutes later. During the Functionaily. the structural chanye has several next few hours vomiting increased in frequency serious consequences. As shown by Brecher and one loose diarrheai stool was passed. From and Cronkite (jl), water and eleccrolyte ioss 12 hours postexposure onward these prodromal into the lumen of the alimentary tract may be reactions ceased completeiy, and the general so severe as to cause vascular collapse. condition began to improve. The patient re- Furthermore, denudation of the mucosa together mained in satisfactory condition until the 6th with a defense mechanism weakened by bone day when a grave deterioration took place marrow depression, leaves the organism wide abruptly. The WBC fell precipitously to very open to invasion by toxic substances and low values; the low-grade fever existing since bacteria. These factors, singly or combined, the day of the accident rose suddenly above are responsible for the fulminating clinical 102OF.; nausea, vomiting, and darrhea re- course of the disease. In the fulminating forms appeared; and signs of a severe paralytic ileus a clear latent phase is no longer present, and developed. The patient’s major complaint was death may occur at any time during the first abdominal distention. No peristaltic sounds 3 weeks postexposure, while patients showing could be heard. By gastric suction 10 liters

10 58-6 of a green fluid with fecal odor and appearance one-seventh of the total number of injured per- were aspirated within a 24-hour period. In sons escaped both mechanical lesions and burns, spite of continuous gastric suction, parenteral but received radiation doses sufficient to fluid supply, blood transfusions, and antibiotic cause clinically significant sequelae (35). treatment, the deterioration progressed swiftly These patients entered medical care in two to beginning circulatory collapse on the 8th day waves. The first one, comprising predominantly and death on the 9th postexposure day. At persons exposed at a distance of less than autopsy, the most striking changes were found 1,000 meters from the hypocenter, began to in the small intestine. “IC was distended, flabby appear within a few days after the attack; and filled with dark brown semi-liquid material. its start merged with the influx of the numerous The vessels were intensely congested, and there casualties showing combined injuries. In this were numerous petechial hemorrhages on the first wave, severe gastrointestinal disturb- serosal surface. The mucosal surface was ances - tenacious anorexia, vomiting, and di- edematous and deep red, particularly in the arrhea associated with extreme weakness - were region of the jejunum wnere, in addition, the most conspicuous, predominating the entire surface was covered with a membranous - clinical course. At the end of the first green exudate that could be stripped off in postattack week, serious leukopenia had devel- sheets” (12). Histologic examination showed oped in the patients still living and was complete erosion of the jejunal and iliac epi- complicated by high fever as well as profuse thelium with loss of the superficial submucosal bleeding in almost every organ. Purpura, bloody layers. The denuded surfaces were covered by diarrhea, bleeding from the gum, epistaxis, exudate containing masses of bacteria that, in hematemesis, and hemoptysis, In chis order the ulcerated portions, had invaded the intestinal of frequency, were the most common forms of wall. In essence, the anatomic diagnosis was blood loss (3, 34, 37). In one group of then as follows: Diffuse membranous and ulcera- autopsies, subarachnoid hemorrhage was seen tive enterocolitis associated with aplasia and in 60 percent of the cases (35). The first depletion of bone marrow, lymph nodes, and wave of casualties had very poor prognosis; lymphatic system in spleen and gastrointestinal the clinical course was fulminating; practically tract. all of these patients died within 2 weeks postexposure from dehydration with vascular HIROSHIMA AND NAGASAKl collapse, or fatal bleeding, or septicemia. At 0815 hours on 6 August 1945, an atomic The wave of radiation casualties bomb was detonated approximately 2,000 feet entered medical care about 3 to 4 weeks after above the city of Hiroshima, and 3 days later the attack. Since by that time the worst at 1102 hours another one was exploded over aonfusion had subsided and the improvised the city of Nagasaki under essentially the clinical facilities had been much improved, same conditions. Most of the population were and since the Japanese medical personnel either on the streets or in their rather lightly had begun to understand the etiology of the constructed homes and business establish- unfamiliar disease (34), clinical observations, ments. In Hiroshima 7’0,000 to 80,000 persons laboratory examinations, and hospital records died, and at least as many were injured. Since obtained on these patients, as compared to 72 of the 190 medical doctors residing in those on patients of the first wave, were the city perished, and since most of the much more complete and reliable. Generally, hospitals were destroyed, catastrophic con- exposure had occurred in open air or in ditions ensued with respect to care and Japanese-type housing at a distance of 1,000 treatment of the injured (34). It is under- to 2,000 meters from the hypocenter; in the standable that during the first week only occasional instances where the distance had the most critically injured patients could been less than 1,000 meters the individuals be retained and observed closely in the had been sheltered by heavy concrete buildings. improvised clinical facilities. Most of these This second wave of casualties displayed cas,.alties, showing combinations of mechanical the “typical” acute radiation syndrome. A wounds, thermal burns, and radiation injury, brief prodromal phase of 3 days’ duration was succumbed rapidly (2, 3, 34, 35). Perhaps followed by a latent period lasting about 3 556 weeks. During that time rnosc of the patients the 5th and 6th week by cessation of the continued to work: frequently they participated pharyngitis followed by disappearance of in the strenuous duties of clearing the rubbish petechiae and fever, and finally by healing of the city. In only a few instances was there oi the ulcerative lesions. This improvement a record of persisting weakness and easy was associated with an increase in cir- tatipability. Approximately 2 weeks after the culating leukocytes and platelets, while red attack. the hair of the scalp became loose; cell count and hemoglobin content of the this &as considered an ominous sign (34). blood generally continued to decline. reaching A tea. days later general malaise. fever, the minimum around the 6th and 8th week. purpura, and other typical complications com- !4 o sc p a t i en t s he c am e corn pl e te 1y a s y m p t o m a ti c pelled the patient to seek hospital admission. at 3 months following the attack. Hachiya. direccor of the Hiroshima Communica- Comparison of the ]OC data with che tions Hospital, describes in his diary (34) experience gained from radiotherapy and nuclear the following case as characteristic: The accidents ieads ro several important con- 28-year-old female patient had been inside clusions. The first wave of casualties ob- ;1 solid building at 700 meters from the hypo- viousl!. represents the fulminating form of center. Shortly after the bombing. she developed the acute radiation syndrome with direct weakness. nausea. vomiting , g enera1 111 a1 aise . radiation damape to the gastrointestinal ep- and diarrhea. Tao days later these complaints itheliurr as the determining patho,cenic factor. had vanished and physical scrength as well as It then tolloas that these patients must have appetite heFan to return. Thereatter, she ate been exposed to air doses in excess of 500 r. plenty and did iipht uork. although some The second wave of casualties evidently fatigue and malaise persisted. On the 13th represents che typical form of the acute day. while combing, she noticed large amounts radiation syndrome with hematopoietic depres- of loose hair. Recognizing chis as a portentous sion as the deternining pathogenic factor. sign. she asked for a physical examination on These patiencs, therefore, must be assumed the 22d day. Nothing abnormal was found to have been exposed to air doses ranging with the exception of severe weakness, epilation froni 200 to 500 r. These conclusions, com- of about tao-thirds ot the scalp area, and pelling iis far as the clinical symptomatology marked leukopenia. She kas admitted to the is concerned. do not agree with dose estimates hospital where her condition deteriorated calculated tron: physical considerations. These swiftly. In days postattack the sequence oi calculations do yield doses higher than 500 r events was as follows: 25th. petechiae and for the area described around the hypocenter severe malaise; Zf>th,anorexia. increase in size by a radius of 1.000 meters, but they arrive and number of petechiae. and tever of ac only 15 r for .I distance of 2,000 meters 101.5.; 3Zd: weak pulse, and further enhance- where the ciinical picture demands at least men[ of petechial bleeding: 37th. death. 200 r. This obvious discrepancy between Survej, of the entire /r:C data rcvealed 2 rnedicai and physical dose estimates has rather uniform clinical course tor patients a 1 re ad >. a t tract e d attention and specula ti on of the second wave (2, 3, I, 32, 37, Zh, 78, 39). about its cause (40). In the present report, Around the 20th day after the bombing, general precluding the treatment of technical dosimetric malaise, pharyngeal pain, and ascending problems. this interesting phenomenon cannot unremittent fever appeared. Kithin a fen be analyzed. The physical factors involved days. petechiae and ulcerative lesions ot have been re-examined in a recent study of lips, mouth, and pharynx became rnaniiest. the bomb data (41). L-eukopenia and thrombocytopenia were most pronounced between the 3d and 5th week postexposure. During this period, representing SUMMARY OF DOSE-EFFECT RELATIONSHIP, clinically the critical phase of the illness, AND DEFINITION OF CLINICAL THRESHOLD severe hemorrhage and overwhelming respir- OR HOSPITALIZATION DOSE IN MAN atory or enteric infection caused the death &hen for a large group of whole-body of about 50 percent of the patients. In the irradiated animals the mean survival time is survivors, recovery was heralded between plotted as a function of dose, the graph does

12 58-6 not proceed in a smooth curve but forms been treated earlier), an attempt must noa three distinct steps (42). Furthermore, it can be made to predict and describe for man the be shown chat these steps reflect three dif- cerebral form of the disease as it emerges ferent pathogenic mechanisms. Death is caused, from animal experiments. Keakness, drowsi- in the low dose range, by hematopoietic de- ness, and listlessness - components of the pression; in the middle dose range, by gastro- prodromal complex already at low-level irra- intestinal denudation and inflammation; and diation- will develop within 1 hour after in the high dose range, by failure of the exposure and will proceed swiftly to severe central nervous system. Although the cor- apathy, prostration, and lethargy. Over this responding data are largely unknown for man, progressive loss of physical and mental they can be extrapolated with reasonable activity is superimposed, particularly during accuracy from clinical findings and animal the first 3 hours postexposure and at doses observations. Because of the close agreement of radiation-induced effects among the various species of the mammalian class, man can be expected to show the three-step survival- 64 r-- time curve depicted in figure 2. Correspondingly, three dfferent types of clinical pictures should exist, and the acute rahation syndrome z- should be subdivided, as shown in table 111, I 16 into hem a topoieti c, gastrointestinal, and cere- + bral forms. In man, the hematopoietic form A 4 of the disease is rather weii established - based -> a- > on a sufficient number of careful observations; II 3 the gastrointestinal form is but vaguely * 4- z understood since only two nuclear accidents 4 W fall in this range and since /BC records of 2 early cases are not complete; and the cerebral 2- form is completely unknown because (1) per- sons of the /OC group who w'ere close,enough 11 I I 1 I 3 to the hypocenter to receive such high doses, 100 200 400 800 1,600 3,200 6,400 necessarily experienced also lethal thermal DOSE IN ROENTGENS burns or mechanical injuries and (2) patients of this group were lost during the confusion FIGURE 2 of the first 3 days postattack without examina- ,Wean survival time o/ u large group o/ persons tion and recording. exposed to various arriounts 01 zonizing rauiation. For the sake of completeness (the hemato- 7tie curve is extrapolated /or man lroni clinical poietic and the gastrointestinal forms having uata and animal ex/Jerzments.

TABLE 111 1 he acute raa'iatzon synarome

Cerebral Gastrointestinal Hernatonoietic form form form

I Threshold dose 2,000 r 500 r Ij 100 r

Characteristic Convulsions; Diarrhea; fever; Leukopenia; signs and tremor; disturbance of purpura; symptoms ataxia; electrolvte hemorrhage; 1et h argy balance infection

Time of '?Jithin 2 i['ithin 2 , Within 2 death weeks I months 58-0 in excess of 5,000 r, ii disturbance of thc such char hospitalization becomes necessary inotor system. In short intervals seizures for an appreciable number of persons among will occur either in form of generalized A large irradiated group. When ;I military muscle tremor, or ataxic movements, or full- installation or a city has been exposed to blown epileptoid convulsions of the grand a known air dose, the medical counter- mal type (43). Patients who survive the measures for a dose beneath the “hospital- convulsive phase will be prostrate and som- ization threshold” will be different from the nolent, and will expire within 2 or 3 days one above it. In the first case, psychologic postexposure. The anatomic substrace for reassurance and taking KBC counts, as a pre- the progressive loss of physicai and mental cautionary measure, may be the only things activity must probably be sought in wide- required. In the second case, elaborate steps spread inflammatory foci that begin to can be taken to prepare beds and medical develop within 1 hour after irradiation. supplies for the anticipated number of These nonbacterial radiation-induced reactions casualties since. owing to its relatively long form the pictures of meningitis, encephalitis, latent phase, the actual disease will starc and vasculitis, and are soon associated with several Reeks postexposure. Therefore, good brain edema. The convulsive seizures, on organization and logistics may be of primary the other hand, are most likely related to importance. From the previous analysis of pyknosis occurring in the granule cell layer data - showing that the hospitalization thresh- 01’ the cerebellum within 2 hours post- old lies near an air dose of 200 r-figure 1 exposure (32, 43). was designed for “typical” cases exposed Obviousl) the three characteristic torms to various amounts ot radiation. of the acute radiation syndrome will be separated from each other b!, broad dose RELATIVE IRRELEVANCE OF TYPE OF ranges of transition where mixed effects will PENETRATING IONIZING RADIATION result. These more complex clinical pictures, FOR THE CAUSATION OF THE however, become explainable when the pure ACUTE RADIATION SYNDROME forms are understood clearly. From a practical To the medical officer the physical aspects medical standpoint, it should be reiterated of the radiation problem appear, at first glance, that, so far, the pure hematopoietic form and to be of embarrassing complexity. Biologic clinical pictures representing a transition injury may be inflicted by high-speed par- from the hemacopoietlc toward the gastroin- ticles, the various types of which are steadily testinal form have predominantly been en- increasing with progressing knowledge of countered in bomb explosions and nuclear the nuclear structure, and it may also be accidents. For future disasters it may be induced by high-energy photons covering the assumed that these forms again will repre- electromagnetic wave spectrum from ultra- sent the major medical problem; the ensuing violet to the hardest gamma radiation. sections will, theretore, be restricted to Yoreover. a specified amount of radiant further analysis of these pictures only. energy may be cransterred to the organism Ionizing radiation, as many other phys- within seconds as in exposure to the atomic ical and chemical factors brought about or bomb, or it may be transmitted over a period in t e n si f i ed by modern ci vi1 i za t i o n , i s s u ppo sed of time measured in days, weeks, or even years to be biologically harmful regardless of as in exposure to fallout from the hydrogen dose. Obviously, it is only a matter of time bomb. Finally, the radiation source may be until there exist laboratory methods refined located at various distances from the sub- enough to detect the minute functional changes ject, or it may be attached to the skin as possibly induced by very low doses. Such in fallout Contamination, or it may have its alterations, unless usable as biologic dosim- seat in internal organs as a consequence eters, have no bearing on the casualty of ingestion or inhalation of radioactive problem. Also negligible are the minor substances. From a practical medical stand- systemic reactions occurring in the low dose point, fortunately. this complexity can be range. Ychat really matters is the threshold reduced to but a few realistic situations. dose beyond which the clinical course is Although one case of suicide with large

14 58-6

IO S P ITA L I Z AT I ON REQUIRED

HOSPITAL1Z ATlOF NOT REQUIRED

E X POSUR E POSTEXPOSURE FIGURE 3

amounts of thorium->( proves that the typical decreased by less than 6 perc’ent (45): acute radiation syndrome can be elicited by &hen the time of exposure is extended beyond the uptake of radioactive substances (44), 4 days, however, the air dose necessary to present-day experience indicates that internal cause the acute radiation syndrome increases irradiation from fallout material is much too appreciably with length of exposure time. small to trigger the acute radiation syndrome Therefore, to avoid drastic systemic reac- or to influence its course (32). Fxternal tions, radiotherapy applies fractionated doses, irradiation, when composed of soft roentgen, each partial dose being separated from the alpha, or beta rays, %ill be absorbed pre- next one by an interval of several weeks. 1 dominantly in the skin and will produce in Observations on patients treated with the this organ inflammatory reactions frequently Heublein technic (16) also demonstrate that progressing to ulcerative lesions. This dis- the clinical tolerance threshold drifts to I ease - the acute radiation dermatitis - has higher dose levels for protracted exposure as been excellently described as a consequence compared to one of less than 4 days’ duration. of fallout contact (?), but it cannot be covered Craver (20) reaches the conclusion that in the present report. External irradiation, advanced cancer patients withstand up to when composed of hard roentgen, gamma, 300 r total-body exposure when given over neutron, or other penetrating rays, will cause a period from 20 to 30 days and that the the acute radiation syndrome. The severity of lack of systemic effects, other than those the clinical reaction is essentially the same, caused by the progressing disease, indicates regardless of whether a certain dose is that such doses may be well tolerated by delivered within a microsecond or over a healthy persons. A dose of 300 r, given in period oi 4 days; an estimate shows that in one continuous course for IO days, produces the latter case the “biologic efficiency” is definite responses and is about the highest

15 58-6 times the following day; thcreafrer he became uncomplicated and led to the birth of two healthy asymptomatic with the exception of light nausea babies at full-term. Since the first of these children on the 3d postradiation day. This favorable con- was born in January 1955, conception must have dition persisted for 3 weeks. On the 24th post- occurred in April 1954, that means between 1 and radiation day, low grade fever and profound pan- 2 months postexposure. The hematologic findings cytopenia began to develop. Soon multiple gluteal on this patient (compiled in table IV) show a pro- abscesses as well as ulcerating lesions involving nounced minimum of platelets around days 26 and gingiva and hard palate appeared and progressed 30, while a corresponding sharp dip of the WBC in spite of treatment with penicillin, streptomycin, probably was obscured by the intercurrent infection an d t e tr a cy c 1in e h y droc b 1ori de ( a c hro m y c in ”) . F i na 1 1y of the upper respiratory tract. after beta-hemolytic micrococcus pyogenes (var. uureus) resistant to tetracycline hydrochloride had This case history is of particular interest been found on culture, improvement took place because it demonstrates that a dose close to under administration of erythromycin. The patient the clinical threshold may cause nausea fol- became afebrile on the 51st day postradiation; lowed by definite hematologic alteraAons; soon thereafter the infectious lesions began to whereas, general condition, feeling of well- heal, and the leukocyte count rose to 2,300 from being, physical activity, and capability to a previous minimum of iOO/mm.’ bear children are not affected. ROLE OF PENETRATING IONIZING RADIATION Fallout from thermonuclear device (history of AS A CASUALTY -CAUSING AGENT a clinically subthreshold case). This 26-year-old mother of four children, a native of the Rongelap Although the atomic explosions over Japan Atoll, was exposed to about 175 r of penetrating may have had revolutionary impact on military fallout radiation as an aftermath of the thermonu- and political pianning, their influence on clear test explosion at Bikini on 1 March 1954. medical concepts was far less striking. In many respects, the problems posed by the Approximately 4 to 5 hours after the explosion, great number of casualties were not essen- a white material of snowlike appearance fell upon tially different from those observed after the island located 120 miles from Bikini. The large-scale bombing raids with conventional natives, not aware of the significance of these explosives. Ionizing radiation was a minor “snowflakes” that continued to fall for about 1 hour, complication: heat and blast were reall) carried on their everyday life in the lightly con- devastating. From a military medical stand- structed palm houses and out of doors. At 50 hours point, therefore, atomic bombs could be after the explosion, evacuation was executed bv conceived as huge conventional bombs with air and surface transportation to the Kwajalein some unusual side effects. It was the explosion Naval Station. Here, clothes were removed and of the first hydrogen bomb at Bikini in 1954 laundered, while skin and hair were washed re- that revolutionized medical thinking. The peatedly with fresh water and soap. aftermath of this event can still be felt. and On the day following the fallout, this particuiar its full meaning must be recognized by every- patient was nauseated but did not vomit; she also body concerned with medical problems under experienced itching and burning of the skin pre- catastrophic conditions. Emphasized by the sumablv caused by direct contact with fallout accidental exposure of the hlarshall Island material. These complaints soon disappeared and population and the Japanese fishermen, the at the time of evacuation, 2 days after the be- Bikini explosion demonstrated that ionizing ginning of exposure, she was feeling well. This radiation can become the casualty-causing favorable general condition, interrupted by a brief agent. Fallout from the bomb may cover episode of upper respiratory infection, persisted thousands of square miles and deposit radio- throughout the entire observation time of 3 months active material of sufficient activity to be during which period she gained 2 pounds in weight. suprathreshold for the acute radiation syndrome. At several follow-up examinations, covering 3 years This means that a military installation or a to the present time, no diseases other than occa- city situated hundreds of miles away from a sional colds were reported, and no complaints hydrogen bomb explosion will experience interpretable as radiation effects were disclosed. neither thermal nor blast effects, and may She has had two additional pregnancies that were not even have knowledge of the disaster.

18 58-6

TABLE IV Eirect vi expvsure to penetrating fallout radiation on white blood cell and piatelet counts 01 a 26-year-via rernale native of Rongelap Atoll

Platelets in expo sure total UHC total UBC ,000/~~.~

9 6.2 1 57 I 35 150 12 5.2 I 65 I 21 - 15 5.9 71 23 160 18 5.8 1 65 I 33 105 I 22 6.8 57 40 120 1 26 3.3 59 29 60 I 30* 10.0 i 64 I 32 50 33 5.7 I 54 1 38 130 39 5.9 76 , 22 160 43 4.1 I 50 1 48 240 47 4.5 1 62 36 180 51 3.8 46 50 135 I 54 3.0 I 43 I 51 120 , ~ 62 6.3 - - 160

2 years 9.0 63 I 34 188 - __ _- ‘Upper rcspirarory infection.

Yet, owing to the prevailing meteorologic a large amount of neutron and gamma radia- conditions, several hours after the explosion, tion is released and transmitted to the fallout may descend upon the area and expose earth below. At ground level the intensity its population to high amounts of penetrating of this “initial nuclear radiation,” emitted ionizing radiation. Quite in contrast to Hiro- within the first minute, will be determined shima and Nagasaki, the medical practitioner essentially by the inverse square law and would then face a type of mass casualty the absorption in air. At the point of completely different from that seen after explosion, a temperature of several million conventional bomb attacks, and the counter- degrees exists and vaporizes the highly measures would have to deviate correspondingly. radioactive fission products as well as the Although the fallout problem has been thrust unsplit fissionable material, casing, and other into medical and public attention by the first parts of the weapon. These hot gases form a hydrogen bomb explosion, it should be pointed highly luminous sphere -the “fireball” - that out that the phenomenon is not necessarily quickly expands to a diameter of about 200 characteristic of this type of weapon (in the feet for the atomic bomb and to 8,000 feet present report the popular term “hydrogen for the hydrogen bomb. As the fireball bomb” has been used as a synonym for the (rising with a rate of roughly 250 to 150 feet more general designation thermonuclear per second) cools, the vapors condense and bomb”). The difference between atomic and the highly radioactive bomb debris is dispersed hydrogen bomb, in this respect, is one of in the upper layers of the troposphere. The degree rather than of kind. Furthermore, fine radioactive particles are then carried the amount of fallout depends strongly on over appreciable distances and slowly de- the physical conditions under which a scend to earth. Recause of its considerable nuclear explosion occurs. Two extreme pos- dispersion and late descent, this “world- sibilities will be considered. First, the wide fallout” conveys only minute amounts bomb explodes at a relatively high altitude of radioactive material to the unit of surface above ground. In the process of detonation, area and the thereby emitted “residual nuclear 58-6 means it would refer to the dose shown by ized during the first 2 days after exposure. the worn by each individual. Six Of course, this might not be feasible under percent of this population would require pre- catastrophic conditions where the short period cautionary surveillance only; whereas 94 of hospitalization might not justify the percent would have to be hospitalized at efforts required to transfer a large number the end of the latent phase. Sixty-eight of casualties; however, these persons would percent of the population are expected to certainly require close medical attention. enter a serious clinical course followed pre- The large influx of patients to hospitals dominantly by complete recovery; while 26 could be expected to occur 2% weeks post- percent are expected to exhibit a grave clinical exposure. At the height of the disease-4 to 5 course ending frequently in death. weeks postirradiation -about 50 percent of the population would require hospital treat- From the standpoint of medical logistics, ment. Thereafter, the number of in-house it is important to estimate incidence, onset, patients would be expected to decline rather and duration of hospitalization as anticipated rapidly, with the last patient leaving the for an exposed population. When the data on hospital at 10 weeks postexposure. In a dose dependency of the clinical course similar fashion, figure 7 may be used to (discussed earlier) are combined with those estimate incidence, onset, and duration of on individual susceptibility, n graphic repre- hospitalization for other dose levels. It sentation of such an estimate can be obtained must be stressed that the curves of figure 7 (fig. 7). To demonstrate the significance of are based largely on extrapolation. Therefore, figure 7. it shall be assumed that a large future additional information will make cor- population has been exposed to 250 r. For rection possible, but adjustments are ex- this dose, figure 7 indicates that approximately pected to affect only minor details without 25 percent of the people would be hospital- changing the basic design of the figure. TIME OF HOSPITALIZATION n r W

a 90 UJ 80 m 70 0

0 40 , 30

L-W 201

I

EXPOSURE POSTE XPOSURE FIGURE 7 1 Estimate o/ zncidence a?id' duration o/ bospitdization /or populations exposed to various amounts o/j~enetrating ionizing radiation. 5a-6

INTERRELATIONS BETWEEN SIGNS, SYMPTOMS, contrast. high fever developing within 2 weeks AND DOSE LEVEL postexposure is a poor sien. 'Kith great probability it indicates gastrointestinal in- "hen a group of persons has been exposed volvement since, most likely, it is a con- to an unknown dose ot penetrating ionizing sequence of bacterial toxins or of bacterial radiation, diagnosis ana prognosis must be invasion originating from the alimentary based on developing signs and symptoms; tract. The clinical course then must be the most important ones will be briefly dis- expected to be grave and the outcome very cussed and evaluated. dubious. Nausea and vomiting Absence of these prodromal effects is of Epilation eminent prognostic signiiicance. It indicates, Loss of hair, when definitely caused by with high probabilit!,l that the air dose was penetrating ionizing radiation, and not by less than 100 r, that the ensuing clinical alpha or beta emitters contained in fallout course will be trivial in most cases, and contamination of the skin, indicates an air that need for hospitalization will not dose in excess of 300 r. It is common arise. On the other hand, presence of these radiotherapeutic experience that about 300 r prodromal effects, even very early after are the smallest dose to cause temporary exposure, does not imply poor prognosis, as epilation. This sign is of prognostic im- frequently stated. It strongly indicates, how- portance for two reasons: (1) Generally it ever, an air dose in excess of 100 r and, becomes noticeable as early as the end of therefore, development of the acute radiation the 2d postexposure week; that means it syndrome in most instances. Severity and appears about 1 week before start of the outcome of the disease cannot be predicted actual disease, thus allowing sufficient time from time of onset and deeree of initial for precautionary measures. (2) After an reactions since the two complexes are only exposure to more than 300 r a serious or loosely related. Nevertheless, persons showing grave clinical course must be expected; prodromal symptoms should be closely watched hence, epilation is the forerunner to the tor the appearance of further manifestations need for hospitalization. Therefore, all per- of the radiation insult. sons observing excessive loss of hair after Latent phase exposure to penetrating ionizing radiation Onset of the disease after a ?-week latent should be kept under close medical surveillance. period, following remission of the initial reaction, heralds the typical uncomplicated Diarrhea hematopoietic form of the acute radiation Although transitory loose stool or diarrhea syndrome. In the majority of cases complete may occur occasionally as part of the pro- recovery may be achieved by proper manage- dromal reaction, they are not characteristic ment of the patients. Conversely, when a traits of the uncomplicated acute radiation clear latent phase is not evident, or when syndrome. Opposing statements probably are its duration is much shorter than 3 weeks, derived from the fact that diarrhea was the early development of the illness foretells rather frequently observed among Hiroshima a grave clinical course probably complicated and Nagasaki casualties. Close scrutiny by gastrointestinal involvement. Prognosis reveals, however, the widespread existence is then poor. of this disturbance in the population of the two cities even before the attack. Nuclear Fever accident and radiotherapeutic data prove Stepwise ascending fever starting around beyond any doubt (see tables I and 11) that the 20th day postexposure, even when associ- diarrhea does not belong to the symptomatology ated with petechial and frank hemorrhage as of the hematopoietic form of the acute radiation well as with oropharyngeal infection, is typical syndrome. Contrariwise, early and persistent for the pure hematopoietic form of the acute (liarrhea, when definitely not caused by mal- radiation syndrome and does not necessarily nutrition or accidental infection, is a rather compromise its favorable outcome. In sharp serious sign. Very likely, it indicates 5E-6 exposure [o more than 400 r and the ex- described by Cronkite (50, 51), the ensuing istence oi severe gastrointestinal damage. brief survey essentially summarizes his views, Prognosis is, at best, dubious. with minor additions and modifications. Leukopen io Prodromal complex As long as the total white blood cell Most important is psychologic reassurance count stays above 2,50O/mm.’, overt disease emphasizing the transient nature of the dis- is not anticipated. Such a degree of radiation- turbance as well as its relative insignificance induced leukopenia is, in general, well with respect to the actual injury. In more tolerated and, with the exception of increased serious cases, additional administration of fatiyability, does not seriously affect physical sedatives is indicated -for example, chlor- activity. Lhen the count ranges between promazine hydrochloride in oral doses of 2,500 and 1,000/mm.3, the typical acute radia- 25 mg. every 6 hours. Only occasionally will tion syndrome will appear in most instances. vomiting be so profuse as to necessitate Close attention is required with regard to parenteral replacement of fluid. the development of purpura, hemorrhage, and Cerebral form infection. Under proper treatment, prognosis No experience is available excepting the is favorable. Counts below l,OOO/mm.’ always fact that in animal experiments heavy will be associated with a serious or grave sedation eliminates convulsive seizures. clinical course. The fact that in Hiroshima and Nagasaki leukopenias of such degree Gas trointes tino I form generally- heralded fatal outcome, is appli- Since the alimentary tract will not tolerate cable only to practically untreated cases anything other than small quantities of under catastrophic conditions. With suitable fluid. parenteral nutrition is mandatory. treatment in modern hospital facilities, even N’ater and electrolyte equilibrium must be WBC values as low as 100/mm.3 may be maintained by large amounts of intravenous handled successfully, as demonstrated by saline-glucose, plasma, and balanced elec- radiotherapy patients and nuclear accident trolytes. Around the end of the 1st post- victims. It should be reiterated that in the exposure week, when high fever and infection pure hematopoietic form of the acute radia- are expected to occur, antibiotic treatment tion syndrome the minimal N’BC is encountered should be started. Excellent nursing care between weeks 4 and 6, and the cell drop and aseptic technic are paramount. Frank frequently occurs rather abruptly. Therefore, hemorrhage, anticipated during the 2d week, in all persons suspected of havins been ex- will require transfusions of fresh whole blood. posed to appreciable amounts of penetrating Hematopoietic form ionizing radiation, hematologic examination Infection being the principal complication, must be performed regularly for 3 months, careful examination of body temperature and with particular emphasis on the critical oral cavity are necessary, particularly from time period extending from the 20th to the the 3d postexposure week onward. The 40th day postexposure. slightest evidence of infection is an indica- Lymphope n ia tion for beginning antibiotic treatment. Cronkite The following dose ranges are probably does not recommend prophylactic administra- indicated by the lymphocyte count during tion of antibiotics because of two hazards -sen- the first 48 hours postexposure; less than sitization of the patient, and development 50 r, when there is no significant decrease; of bacterial resistance. Purpura and frank less than 100 r, when the decrease is mild; hemorrhage require repeated transfusions of and a dose in excess of 100 r, when the fresh whole blood or separated platelets and lymphocytes fall below 50 percent of leukocytes. Frequency and amount of trans- normal values. fusions will be determined by the blood count. It may be worthwhile to try additional TREATMENT OF THE ACUTE RADIATION procedures in accordance with the usual SYNDROME management of agranulocytotic disorders. Since the therapeutic management of the Figure 8 presents a graphic survey of the acute radiation syndrome has been ably acute radiation syndrome in its hematopoietic 58-6 form. The temporal relationship has been transient, as are radiation-induced epilation depicted for clinical course and therapeutic and azoospermia. Therefore, the therapeutic methods as applied in the IF group and the goal must be to help the patient overcome the MDA series. relatively short period of time during which Some remarks concerning the effectiveness his own organism is not able to supply the of the outlined therapy, especially that of the critical cell elements. Hence, the transfusion hematopoietic form, should be added. The procedures represent an actual substitution frequently advanced concept of the treatment therapy. This fact can be demonstrated as purely symptomatic is too pessimistic. strikingly in animal experiments. In rats the Hematopoietic depression and denudation of minimal white blood cell count occurs around the the gastrointestinal mucosa generally are 8th day postexposure. Parabiosis between an

rn -1 FRANK HEMORRHAGE z . 0- PETECHIAL BLEEDING c I U 0 I -1 I a =F ,BODY TEMPERATUREI 0 U i ORO- PHARYNGIAL I I I u LCERAT IONS ] I > CHLORPROMAZINE I TRANSFUSIONS a U I oz I ANTI BlOTlCS w & I I I I "1~~~~lD00oo000000 BLOOD + E38 I 0 PLASMA I I I I I , I I I I 2 4 6v 2 4 6 8 10 12 14I EXPOSURE DAYS WEEKS POST EXPOSURE FIGURE 8 Schematic drawing showing the temporal relationship between clinical course and therapeutic management of the hematopoletic /om of the acute radiation syndrome.

25 38-6 irradiated and a nonirradiated rat will carry the rather well supported by data originating exposed animal through the bone marrow de- from radiotherapy, nuclear accidents, and pression phase when adequate cross-circulation atomic bomb explosions: Air doses up to 100 r exists between the 4th and 10th postexposure will be subthreshold for the acute radiation days; longer parabiosis does not add to the syndrome, and will thus be of no concern in beneficial effect (52). It is very likely that emergency situations. In the dose range markedly improved treatment of the acute radi- between 100 and 200 r, the acute radiation ation syndrome will soon be possible as a result syndrome, if it develops at all, will proceed of current research efforts -injection of bone in such a mild form that it can be handled marrow or spleen material, controlled cross- ambulatorily. The hospitalization threshold, transfusion with healthy donors, and isolation of a very important concept defined as that dose bone marrow-stimulating substances. level beyond which hospitalization becomes necessary for an appreciable number of Under the catastrophic conditions prevailing persons among a large exposed population, in Hiroshima and Nagasaki, the mortality of lies approximately at 200 r. Between 200 and the fully developed hematopoietic form was 400 r-perhaps even 500 r-the acute radia- 50 percent. Among those patients who were tion syndrome will be clinically significant treated at reasonably well equipped hospitals and will occur in its hematopoietic form, in Tokyo, the corresponding mortality was displaying a very characteristic time course 30 percent. With modern facilities, with suffi- almost independent of dose. Knowledge of cient types and amounts of antibiotics, and this time course should help in the advance with the rapidly advancing technics for the preparation for medical personnel, supplies, transfusion or exchange of fresh whole blood and housing facilities. Kith these steps taken or any desired constituent of it, a much lower and under proper therapeutic management, mortality rate can be achieved. the radiation-induced disease will have a A discussion of some additional medical favorable outcome in the overwhelming majority problems posed by nuclear disasters is contained of cases. All facts available disprove the in references 53 and 54. fatalistic or pessimistic approach frequently encountered. In emergency situations this SUMMARY AND CONCLUSIONS dose range represents a great and rewarding Since penetrating ionizing radiation has all challenge to the physician. Very little is the potentialities of becoming a major casualtv- known about doses above 500 r. Here, most causing agent, the peculiar clinical picture likely, a fulminating clinical course with caused by this new type of injurious factor gastrointestinal involvement will prevail, and must be understood. Only knowledge can help the outcome is at least dubious. Presently to dispel the many uncertainties and miscon- available facts are insufficient to either sup- ceptions surrounding the radiation problem. port or contradict the assumption that an Exposure of the whole body, or of a large acute exposure to 600 r is the highest one part of it, to sufficient amounts of penetrating corn pat i ble with human survival. ionizing radiation induces in man the acute The conclusion is that in a wide dose radiation syndrome. Clinical course and out- range man can overcome the acute radiation come of the disease are determined, in syndrome and return to a useful life. There essence, by two factors -dose and individual exists no account of the many thousand sur- susceptibility. At present, the factual evidence vivors of Hiroshima and Nagasaki who resumed is not strong enough to establish with high their previous occupation with full vigor, accuracy the interplay between these factors while there are several reports relating each in an exposed population. Since, therefore, case of leukemia, cataract, or neoplasm. most of the figures concerning incidence and Understandably, as any other severe disease, severity of radiation-induced injury must be the acute radiation syndrome may be followed based largely on extrapolations and estima- by late complications in a relatively small tions, their value is necessarily provisional percentage of cases. Further observations must and subject to revision when additional be made before an unbiased judgment is information becomes available. Nevertheless, possible about incidence and importance of the following broad statements seem to be late consequences of irradiation.

26 The author is deeply indebted to Dr. E. P. Cronkite in the present report. The author also expresses gratitude and Dr. R. A. Conard of the Brookhaven National Lab tor the support and advice of Colonel J. E. Picketing; oratory who furnished the case history ot one member of for the faithful assistance of M/Sgt. J. K. Walker, A/2C the Rongelap people and the data for table IV, and Peggy F. Reeves, and Mrs. hl. V. Sharp; and for the who kindly granted permission to include this material editorial help of Miss Helena Kay.

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10. Tsuzuki, :.1. Erfahrungen ueber radioaktive I?. I-ow-beer, B. V. 4., and R. S. Stone. Hematolog- Schaedigung der japanischen Fischer durch ical studies on patients treated by total-body Bikini-Asche. .‘hi’nch. med. Wschr. 97:988-99/1 exposure to x-rays. In National nuclear energy (1955). series, division IV, vol. 20, pp. 338-418 (1951).

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NOTE TO THE READER: It is requested that ony odditional information ond DroDosolr.. for change or expansion of the text be brought to the attention of the outhor to be considered in o second, more complete, report.

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