Attachment 1 The NEPA Advisory Medical Advisory Panel. "Tabulation of Available Data Relative to Radiation Biology" Report No. NEPA 1019-1ER-17. July 20, 1949. Oak Ridge, Tennessee. 46p. FAIRCHILD Engine and Airplane Corporation Tabulation of Available Data Relative to Radiation Biology OSD1.941207.057 GIF OAK RIDGE, TENNESSEE Tabulation of Available Data Relative to Radiation Biology Compiled for NEPA 1949 Submitted by The NEPA Medical Advisory Panel TABLE OF CONTENTS page The NEPA Medical Advisory Panel................................iv Introduction....................................................1 Summary.........................................................4 Histogenetic and Genetic Effects Table I.......9 Effect of Irradiation upon Gonads Table II.....10 Incidence of Leukemia Table III....11 Hematological Effects Other Than Leukemia Table IV.....13 Acute Total Body Irradiation of Rats with 250 KVP - Hematological Effects Table IV-A...15 Embryological Effects of Irradiation Table V......16 N - r Ratio Table VI.....17 Mortality Table Table VII....18 Mortality-Chronic X-Radiation 3r-10r per Day Table VIII...19 Longevity Table IX.....21 Effect of Radiation - Human Cases Table X......21 Effect of Total Body Irradiation - Human Cases Table X-A....23 Comparison of Radiation Effect by Total Dose - 26 Cases Table X-B....28 Techniques Employed for Total Irradiation Table X-C....29 Summary - Polycythemic and Leukemic Patients Living 1 Year or More Table X-d....31 Chemical Aspects Table XI.....33 Appendix General Background........................................35 Genetic Changes in Human Sperm and Eggs, Caused by a Single Exposure of 300 r or Less................36 General Results and Discussion............................40 Induced Mutation Rate.....................................41 Note and References.......................................42 i TABULATION OF AVAILABLE DATA RELATIVE TO RADIATION BIOLOGY Submitted By The NEPA Medical Advisory Panel Members and Consultants: Chairman Andrew H. Dowdy, M.D., Los Angeles, California Secretaries W. A. Selle, Ph.D., Galveston, Texas Rupert S. Anderson, Ph.D., Vermillion, South Dakota Members Simeon T. Cantril, M.D., Seattle, Washington Robley D. Evans, Ph.D., Cambridge, Massachusetts G. Failla, D.Sc., New York, New York Hymer L. Friedell, M.D., Cleveland, Ohio Joseph G. Hamilton, M.D., Berkeley, California R. R. Newell, M.D., San Francisco, California Robert S. Stone, M.D., San Francisco, California Stafford L. Warren, M.D., Los Angeles, California Raymond E. Zirkle, Ph.D., Chicago, Illinois Titus C. Evans, Ph.D., Iowa City, Iowa Lauren R. Donaldson, Ph.D., Seattle, Washington Consultant Members From The Atomic Energy Commission Austin M. Brues, M.D., Chicago, Illinois Alexander Hollaneder, Ph.D., Oak Ridge, Tennessee A. L. Holland, Jr., M.D., Oak ridge, Tennessee L. F. Nims, Ph.D., Upton, Long Island, New York Shields Warren, M.D., Washington, D.C. Wright Langham, Ph.D., Los Alamos, New Mexico ii INTRODUCTION The NEPA Division of the Fairchild Engine and Airplane corporation, operating under the joint sponsorship of the United States Air Force and the Bureau of Aeronautics of the Navy Department, and working with the cooperation of the Atomic Energy Commission, has been given the responsibility of conducting analyses and experimental investigations leading toward the assessment of the feasibility and practicality of applying nuclear energy to the propulsion of aircraft or missiles of military importance, and also to study the servicing problems connected therewith. Since power reactors must be shielded to protect personnel in their vicinity against nuclear radiations, and since large masses are required for their shielding, the shield becomes one of the most critical items of weight in the design of the nuclear power plant for the inhabited type aircraft, and hence has a very important bearing on the design, the size, and the cost of the airplane itself. Shield weight becomes of less significance in the design of the unmanned types of aircraft. Certainly an accurate knowledge is needed of all criteria upon which various shielding designs will be based. For the inhabited types of aircraft, the permissible levels of exposure of radiation of the operating personnel will establish an important design requirement for the shield. The levels of exposure of ionizing radiation as established for civilians during peacetime conditions and prevailing at stationary piles or in research laboratories are not applicable to the military aircraft problem. Since the effects of radiation on the human body are to some extent cumulative, the permissible levels of exposure of the laboratory worker and technician are quite small, and rightly so, since they are based on possible daily exposures over a period of many years. Crews of nuclear aircraft on the other hand need only to be exposed to radiation for a limited number of flying hours during the conduct of a military campaign. In order to obtain the best information available at present on the effects of various doses of ionizing radiation on the human body, as well as to formulate any necessary additions to the national program of radiobiological research, the NEPA Project has formed, with the cooperation of the Atomic Energy Commission, an Advisory Panel of experts in the fields of biology, radiobiological research, the NEPA Project has formed, with the cooperation of the Atomic Energy Commission, an Advisory Panel of experts in the fields of biology, radiobiology, biophysics, medicine and genetics. The composition of this Panel is listed on Page iv of this report. Their wealth of experience in various fields of specialization eminently qualifies them for their responsibilities. Since no one knows precisely how much radiation the average human can reasonably tolerate, it became NEPA's task to seek out these answers. Initially, we are interested in obtaining radiobiological data which will make possible the prediction of immediate and delayed reactions of the human body exposed to various levels of whole-body radiation. It was realized at the outset that figures representing radiation levels for specific physiological effects in man could not be arrived at solely on the basis of detailed data on laboratory animals and that only rough estimates can be made from the limited information available. iii At the first meeting of the NEPA Medical Advisory Panel, held in Chicago June 23, 1948, it was decided to survey as comprehensively as possible the present knowledge of the biological effects of ionizing radiations and to prepare a summary of data that would furnish useful information to the NEPA Project. Many months were spent in the collection, compilation, evaluation and revision of the data presented herewith in tabular form, and the task represents the concerted effort of a number of individuals whose assistance is acknowledged elsewhere. The work of assembling the available data was done by a subcommittee to which all members contributed not only the results of their own work, but in some instances tables which were compiled by workers who are not members of the Panel. Due to the special conditions prevailing in the Atomic Energy field with respect to security, all credits and references could not be given in full in an unclassified report of this character. After the pertinent exposure data had been compiled in tabular form, the committee met to assess the data and to form their conclusions into a broad scale of the expected biological effects of various single doses of radiation on the human body. These conclusions are presented in the summary of this report. Certain difficulties arise in attempting to transfer radiobiological data obtained on lower animals to man. The problem of assessing the amount of damage which will result to the human body exposed to various levels of mixed radiation is complicated by the following: 1. A single acute dose of total-body radiation is more damaging than a similar total dose given fractionally or repeated in smaller doses. 2. The total-body dose of radiation received as an acute or fractional exposure varies from animal to animal and from one member to another of the same species. 3. It is difficult to evaluate radiation damages from neutrons in the terms of roentgen equivalents, since the N to r ratio varies from tissue to tissue and from one animal to another. 4. It is difficult to estimate accurately the energy spectrum of neutrons emerging through the shield of a chain reactor. 5. It is difficult to evaluate the additive effects of gamma rays plus neutrons in an exposure of mixed radiation. It is, therefore, impractical on the basis of present data to predict with great accuracy what will happen to human beings exposed to mixed radiations such as are anticipated from power piles. While some data on the effects of whole-body radiation on man have been obtained, these are few and fragmentary, and, for the most part, have been obtained on sick individuals. some information of questionable value has been obtained as result of occasional accidents and mass exposures, such as occurred at Hiroshima and Nagasaki, obviously the dosage in those cases could not be accurately determined. Such data have not been included in the present compilation. The estimates of predicted radiation injury to man are based largely upon experimentation on lower animals, empirical observations and clinical investigation. Since there are many blank spaces in our data on lower animals, however, extrapolation to man cannot be made with assurance, but informed estimates can be reached. It is hoped that the efforts of the committee in preparing these data will be of interest to other groups working on similar or related aspects of atomic energy and radiation biology, and that this preliminary report will form the basis for extended studies. It is our intention to add to these data and to revise and refine the estimates on human injury as additional information is obtained. This information will be compiled and published when circumstances warrant. In the meantime, we believe the estimates given are as accurate as can be made from available data. iv The Project wishes to express its sincere appreciation to the members of the NEA Medical Advisory Panel for their work, and in particular to its Chairman, Dr. Andrew Dowdy, upon whose broad shoulders fell the additional burdens of Committee Administration. With the exception of this introduction, this Report was prepared by the NEPA Medical Advisory Panel. General Manager v SUMMARY I. Genetics (Table I) A. Mice The genetic hazard in mice is approximately 1% of bad sperm per 100 r. This value apparently excludes recessive and dominant or chromosome mutations with small effects. Donald Charles). See Appendix, page 37, paragraph 3. B. Drosophila 1. 50 r doubled mutation frequency of control group. 2. Induced sex-linked lethal mutation in Drosophila in single exposure of 24 r-1000 r is linear and equal to 0.0019% per r. (Spencer and Stern) II. Histogenetic (cytogenetic) Table (I) A. Rats 1. Chromosome breaks in intestine and lymphs nodes are at least 9% per 100 r (probably 18%). (Charles) B. Mice 1. Inhibition of mitotic activity in mouse epidermis is 100% with r and 60% with 5 r. (Knowlton & Hempelmann, quoted by Langham) C. Neuroblast of grasshopper. 1. The mitotic rate at 8 r drops to approximately 1/2 and at 64 r to zero. Recovery within a few hours. (Hollaender) III. Gonads (Table II) A. Dogs 1. 1.0 r/day, 6 days/week results in temporary aspermia at 9 mons. in 50% of males. Partial recovery 4 mos. post-irradiation after 1 year continuous irradiation. 2. 3.0 r/day, 6 days/week to accumulated total of 1320 r-female conceived and delivered 6 normal pups. (Boche) B. Homo sapiens 1. 625 r (fractional) to ovary produced permanent sterility. 2. 500 r (fractional) to ovary produced permanent sterility in 94%. (Peck et al.) 1 IV. Leukemia (Table III) A. Rats 1. 0.1; 0.5; 1.0 and 10.0 t/day, 6 days/week (x-rays) produced leukemia in 1.0%; 2.0%; 3.0% and 12.0%, respectively. (Rochester) 2. 0.11N and 1.7N/day, 6 days/week produced 4.0% and 16.0%, respectively. (Biochemical) B. Physicians 1. Incidence in physicians is 0.53% as contrasted to 0.39% in general population. (Henshaw) 2. Incidence in radiologists is 3.9% as contrasted to 0.44% in physicians other than radiologists. (Ulrich) V. Haemarology (acute radiation) (Tables IV; IV-A) A. Rats 1. 25 - 100 r results in transient lymphopenias down to 30%. (Brues & Dowdy) 2. 100 r results in appreciable transient reduction in reticulocytes, platelets, and neutrophils. (Dowdy) 3. 300 r results in approximately 16% temporary reduction in Rbc. and Hb. (Dowdy) B. Humans, acute (Table X) 1. 60-120 r produce inconsistent mild to moderate lymphopenias which in some instances last 164 days. (CH-3868, LAMS No. 808) 2. 18 r and above results in increased number of refractile bodies in the lymphocytes. (LAMS No. 808) 3. 60-120 r produce inconsistent mild reduction in neutrophils. (CH-3868, LAMS No. 808) C. Humans* semi-acute (Tables X; X-A; X-B; X-C; X-D) 1. 87.5 r (in 8 Rx over 9 days) resulted in reduction (delayed-80-120 days) Hb, platelets, and lymphocytes. (CH-3868) 2. 300 r (in 22 Rx over 33 days) marked lymphopenia, neutropenia, and slight bone marrow depression. (CH-3868) 3. 502 r (in 5 Rx over 30 days) produced profound lymphopenia, neutropenia, with transfusion required. (CH-3868) _________________________________ * (1) C. W. Wilson; Radiology, 46: 364, 1946 (2) Supplement to Acta Radiological, 1946-48 2 D. Animals, chronic (Table IV) 1. 1 t/day, 6 days/week for 1-2 years produced no unequivocal alteration in peripheral blood picture. Probably at critical level, however. (Dowdy) 2. 3 t/day, 6 days/week (dog), first detectable blood change in reticulocytes and lymphocytes at accumulated dose of 282 r. (Dowdy) 3. 1.7 N/day, 6 days/week (dog), accumulated doses of 25 N-50 N, first change in platelets, lymphocytes, and neutrophils. (Dowdy) 4. 10 r/day, 6 days/week (dog), accumulated dose (60- 120 r, reduction in lymphocytes and neutrophils. (Dowdy) 5. 10 r/day, 6 days/week (dog), accumulated dose 960 r, first drop in Rbc. and Hb. (Dowdy) 6. 1.7 N/day, 6 days/week (dog), accumulated dose 385 N, Rbc.drop. (Dowdy) VI. Embryology (Table V) A. Rats 1. 50 r to 10 day gravid uterus - no effect. 2. 100 r to 10 day gravid uterus-results in increased reabsorption, reduced fetal weight, eye and lens abnormalities, and in some instances other developmental processes. (Wilson) B. Mice 1. 200 r (whole body radiation) to 2 - 17 day gravid uterus resulted in pronounced effects characteristic of embryo age. 100 r suggests similar effects. (Russell, quoted by Hollaender) VII. N-4 Ratio (based on mortality) (Table VI) A. Acute: 1 N = 5 - 12.5 r B. Chronic: 1 N = 6 - 21 r VIII. Mortality (Tables VII; VIII; IX) A. Acute, LD. 50 1. In warm-blooded mammals, the spread is from 200 r to 790 r. (Table VII) B. Chronic (dog) 1. 10 r day, 6 days/week. 50% mortality at accumulated dose of 1440 r. 3 dogs survived 5000 r. 2. 6/t/day, 6 days/week. 50% mortality at accumulated dose of 2940 r. 3 5 dogs survived 3000 t. 3. 3 r/day, 6 days/week. 7 out of 9 were surviving at 1500 r. C. Chronic (rat, mouse, guinea pig) 1. 10 t/day, 6 days/week (rat). 50% survival at accumulated dose of 3500 r. 2. 8.8 r/8-hour day (mouse). 50% survival at accumulated dose of 4400 r. Guinea pig, 50% survival at accumulated dose of 2300 r. Acute* Exposure Estimated Results to Humans Exposed to Filtered, 200-1000 KVP X-Rays, Measured in Air The estimates given below apply to the average normal individual. It should be borne in mind that there is considerable variations in individuals' susceptibility to radiation. A. 25 r and below; no detectable clinical effects. 1. From animal experiments it would appear that if man behaves like the mouse and drosophila, there will be, due to radiation, a genetic effect which is much smaller than the spontaneous rate of mutations. In other words, the combined result of the spontaneous and the radiation-induced genetic abnormalities would be slightly increased but much less than double the spontaneous rate alone. 2. Delayed effects** possible but highly improbably. B. 50 r; slight, transient reductions in lymphocytes and neutrophils. No other clinically detectable effects. 1. Incidence of radiation-induced genetic abnormalities is expected to be approximately the same or smaller than the spontaneously occurring abnormalities. 2. Delayed effects possible but serious effects on the average individual very improbable. C. 100 r; at this level, nausea and fatigue may be a problem. Reductions in lymphocytes and neutrophils with delayed recovery. Above 125-150 r, vomiting may become a problem. 1. Incidence of radiation-induced genetic abnormalities, which are quantitatively proportional to the dose, will probably still be comparable to or somewhat greater than those occurring spontaneously. _________________________________ * Received within twenty-four hours. ** The expression, "delayed effects", as used here, refers to any harmful effects attributable to radiation on the recipient of the radiation and manifested at any time subsequent to the period when acute reactions may occur. 4 2. Delayed effects, in summation, would be expected to shorten to shorten the life expectancy of man on the average by not more than about 1% from all causes, assuming that limited observations on animals can be extrapolated to man. D. 200 r; at this level, fatalities, 2-6 weeks after exposures, might occur in a small portion of the irradiated individuals. Nausea, vomiting, and fatigue will probably occur in most persons within 24 hours. Definite depression of practically all blood elements, reduced vitality, in most cases with a convalescent period of 3 to 6 months. Temporary sterility in some cases and possibly permanent sterility in rare instances. 1. Incidence of radiation-induced genetic abnormalities will be expected to be at lest twice as frequent as the spontaneously occurring abnormalities. 2. Delayed effects--that these would be of major consequent in a small percentage of individual would seem very probably. E. 400; it would be expected that virtually everyone would be immediately incapacitated by such an amount of radiation, and many would never recover completely. Some deaths would occur in 2 to 6 weeks. 5 Table I HISTOGENETIC AND GENETIC EFFECT Type Species Reference Radiation Application Mice LAMS(1) X-ray Acute Report No. 808 Mice " " " Grass- Hollaender Gamma " hopper Oak Ridge & x-ray Rat Charles 250 KVP " Rochester x-ray Mice " " Chronic 0.1-10r/day 6 days/wk Mice " " " Drosophila Stern and X-ray Acute (fruit fly) Spencer Female irradiated II-188-5524 Observed Results Gene Chromosome Dose Mutation Breaks Recovery 5r to 325 r 35r = 5 hr. to epidermis 325r = 6 days 35r to adrenal, Gave 50% lymph node, and reduction jejunum 5r (neuroblast - Transient Recognizable studied) reduction in mitoric rate 100r At least 9% increase Dominant In sperm 0.4% per 100r 25r-1000r rate Sex-linked of 10/r.min. lethal Remarks Mitotic reduction *5r=60% reduction 325r = 100% reduction Gave 50% reduciton Recognizable reduction in mitoric rate Probably 18% In sperm In sperm **Linear * Control, no radiation: 168 mitoses per 100,000 cells. ** At 50r, the mutation frequency was doubled that of the control. Induced mutation rate =.0019 % per r. (1) Knowlton and Hempelmann, Science, 107; 625, 1948. 6 Table II EFFECT OF IRRADIATION UPON GONADS Type Species Reference Radiation Application Dog Boche Rochester 250) Kvp. Total body No. 5936 1000) 6 days/week " " " " " " " Aspermic 50% after 9 mos. " " " " Women (1) Peck ? 200 Kvp. Local to ovary et al fractional " " " " Observed Results Dose Recovery Period Remarks ? Sperm reduction 0.1 t/day Partial - 4 weeks post-irradiation " 0.5 t/day " " Aspermic 50% 1.0 r/day Partial recovery Animal ir- after 9 mos. 4 mos. post- radited irradiation for one year " 3 r/day --- Approxi- 6 t/day & mately 50% 10 r/day aspermic 100 Rx Sterility 6225 r (depth None Permament dose) sterility " " " " Note: One female dog became pregant after 3 r x 440 Rx or 1320 (6 pups - all normal) Ref: (1) Peck, W. S., T., Kretzmar, M. R., Brown, W. F. Castration of Female by Irradiation. Radiology 34:1176, 1940 7 Table III INCIDENCE OF LEUKEMIA Type Species Reference Radiation Application Rats Rochester X-ray Chronic Wistar Seminars ( 250 KVP) total body (a) (1000 KVP) irradiation Rats Rochester Neutrons Chronic Wistar and Bio- total body Strain chemical irradiation Research Female Lorenz et Gamma Rays Chronic total Mice at (b) total body, LAF1 8 hrs./day Physicians Henshaw Not given -- *(1) Radiologists Ulrich Not given -- *(2) Dose Min. Detect. Max. Detect. Observed Results 0.1 t/day 10.0 t/day 0.1 r/day 1% 6 da./wk 6 da./wk 0.5 r/day 2% 1.0 r/day 3% 10.0 r/day 12% 0.11 N/day 1.7 N/day 0.11 N/day 4% 6 da./wk 6 da./wk 1.7 N/day 16% 0.0 r/day 600 days 0.11 r/day 700 days 1.1 r/day 600 days 2.2 r/day 600 days 4.4 r/day 480 days 8.3 r/day 360 days -- -- 0.53% Physicians 0.39% General population -- -- 3.9% Radiologist 0.44% Other physicians, not radiologists Recovery Remarks --- Rats exposed for 2 years --- Rats exposed for 1 year Overall incidence about 45% in the first five groups; about 70% in the last group 1933-1944: Physicians dying of leukemia as compared to general population 8 References for Table III (a) In Wistar strain of rats, breeding colony of 20,000 - 30,000 rats, no spontaneous leukemia were observed at Rochester between 1943 and 946. -- A. H. Dowdy (b) Lorenz, Egon, et al. Biological Studies in the Tolerance Range, Radiology, 49; 274, 1947. (c) Henshaw, P.S., Hawkins, .W. Incidence of Leukemia in Physicians, J. N. Cancer Inst., 4:339-346, 1944. (d) Ulrich, Helmuth. The Incidence of Leukemia in Radiologists, New England J. of Med., 234: Jan., 1946. Other References Furth; J. and Furth, O. B. Neoplastic Disease Produced in Mice by General Irradiation with X-rays. Incidence and Types of Neoplasm, Amer. J. Cancer, 28:54-65, 1936. Carman, R. D. and Miller, A. Occupational Hazards of Radiologists with Special Reference to Changes in the Blood. Radiology, 3:408-419, 1924. Evans, W. H. and Roberts, R. E. Splenomedullary Leukemia in X-ray Workers, with Discussion of Previously Discussed Cases. Lancet, 2:748-751, 1928. Nielsen, J. Chronic Occupation Ray Poisoning: discussion based on case of leukemia in radium worker. Acta Rad., 13:385, 1932. Warren, S. and Dunlap, C. F. Effects of Radiation on Normal Tissues. III. Effects of Radiation on Blood and Hemopoietic Tissues, including. Spleen, Thymus, and Lymph Nodes. Arch. Path., 34:562-608, 1942. Dublin, L. I. and Spiegalman, M. Mortality of Medical Specialists. J.A.M.A., 137:1519, 1938-1942. 9 Table IV HEMATOLOGICAL EFFECTS OTHER THAN LEUKEMIA Type Species Reference Radiation Application Dog Rochester X-ray ( 250 KVP Chr. total body Seminar (1000 KVP 6 days/wk " " " " " " " " " " " " " " " " Rabbit " " " " " " " " " " " Monkey " " " Dog Biochemical Fast Neutrons Chr. total body Foundation irradiation 6 days/wk " " " " " " " " Dose Amt. Accum. Observed Results 10r/day-96r Accumulated Rbc drop, at accumulated dose 960r 10r/day-960r " HB drop, at accumulated dose 960r 3r/day-282r " Reticulocytes drop 6r/day-564r " Platelet ) Total Wbc ) drop Absolute Neutrophils ) 3r/day-282r " Absolute Lymphocytes drop 10r/day-960r " Rbc drop 10r/day-720r " Platelet drop 10r/day-240r- " Total Wbc ) 300r Absolute Neutrophils) drop Absolute Lymphocytes ) 10r/day-60r- " Total Whites ) 120r Absolute Neutrophils) drop Absolute Lyphocytes ) 1.7N/day-385N " Rbc drop 1.7N/day-26.5N " Platelet drop 1.7N/day-25.0N " Total Wbc ) drop Absolute Neutrophils ) Recovery Period Remarks --- 10 Table IV (continued) HEMATOLOGICAL EFFECTS OTHER THAN LEUKEMIA - continued Type Species Reference Radiation Application Dog Biochemical Fast Neutrons Chr. total body Foundation irradiation 6 days/wk Rabbit " " " " " " " " " " " " " " " Rat " " " " " " " " " " " Rabbit Hogen and X-ray Acute total body Sacher CH-3754 Dose Amt. Accum. Observed Results 1.7N/day-45N Accumulated Absolute Lumphocytes drop 1.7N/day-32N " Rbc and Hb drop 1.7N/day-50N " Total Wbc drop 1.7N/day-75N " Absolute Neutrophils drop 1.7N/day-25N " Absolute Lymphocytes drop 1.7N/day-60N " Rbc drop 1.7N/day-15N " Total Wbc ) Absolute ) drop Lymphocytes ) 1.7N/day-25N " Absolute Neutrophils drop 50-150r " Detectable effects upon haematological elements Recovery Period Remarks Note: Analysis of original data incomplete. Results indicated above are tentative. Note: In special Los Alamos Report No. 808, Knowlton reports studies on 10 workers exposed during the course of their work and studied for 77 weeks and compared with 24 non-exposed workers over the same period of time. The average accumulated exposure was 16 r; the average drop in total Wbc. was 12-13% absolute neutrophils drop was 10-11%; and the absolute lymphocyte drop was 16- 17%, as compared to a 3% lymphocyte drop in unexposed personnel, Neutrophil control 0%. Total Wbc. of controls 0-1% drop. 11 Table IV-A ACUTE TOTAL BODY IRRADIATION OF RATS WITH 250 KVP HEMATOLOGICAL EFFECTS (DOWDY) Occurrence, Blood hours post- Extent of Element Dose in r radiation Depression Min. detectable 300r 225 hours 16% RBC Max. depression 600r 240 " 66% Min. detectable 300r 243 " 16% Hb. Max. depression 600r 245 " 70% Reticu- Min. detectable 100r 75 " 36.8% locytes Max. depression 600r 75 " 100% Min. detectable 100r 225 " 20% Platelets Max. depression 700r 225 " 90% Absolute Min. detectable 100rr 75 " 15% Neutrophils Max. depression 600r 75 " 100% Absolute Min. detectable 25r 16 " 15% Lymphocytes Max. depression 500r 23 " 100% Duration of Recovery, hours Duration of Depression post-radiation Recovery 225 hours 150 hours 150 hours 210 " 450 " 150 " 208 " 450 " 150 " 205 " 450 " 150 " 0+ " 75 " 0+ " 203 " 277 " 165 " 0+ " 225 " --- 225 " 450 " >600 " 82 " 157 " 60 " 215 " 285 " 200 " 4 " 20 " 5+ " 225 " 225 " 375 " 12 Hours post-irradiation to recovery and per cent recovery 600 hours 100% 600 hours 68% 600 hours 100% 600 hours 70% 75 hours 193% 442 hours 145% 600 hours 100% 600 hours 30% 217 hours 129% 485 hours 129% 25 hours 107% 600 hours incomplete Note: (1) It is difficult to determine the point where minimal detectable effects are real; therefore, considerable error. (Dowdy) (2) Error in picking maximal depression is substantial as several hundred roentgen may be required to depress the count from 90% to 100%. Furthermore, recovery times and per cent recovery times are obtained from surviving animals only. (Dowdy) (Stearner, reported by Brues) "Blood response of rats given 100 r total body x-ray shows a fall in lymphocytes of 70% to 75% of control count with recovery in about 10 days. No effect noted on heterophils. At 25 r, rat lymphocytes fall 30% at one day and are recovered at ILLEGIBLE days." 13 Table V EMBRYOLOGICAL EFFECTS OF IRRADIATION Species Reference Criteria Organ or System Type Radiation Rat Wistar Wilson Rochester Resorption Not stated, thought Project Rate Growth to be 120 Kvp., Rat " Resorption, " Rat " Reduction wt. of fetus " Rat " Eyes malformed Lens malformed " Rat " Resorption Decreased wt. fetus Eye deformity " Chinook Salman Donaldson L.D. 50 -125 days Abnormal eye development 200 Kvp Mouse *Hollaender Viability at birth Size at birth External characters 250 Kvp Skeleton Application Dose in r Results Remarks Local through operative wound to one uterine horn 50 Negative first Radiation given 10 days post-conception 72 hours days postconception " 100 + .72 hrs " " 100 + .72 hrs. " " 100 + 72 hrs. Also G.U. tract and heart retarded " 200 Resorption + + Reduction + + (wt) Eyes ++ + Total body 1000 Eyed embryos irradiated Total body A great variety 2 - 17 days irradiation of of changes in gravid mice mother 200-500 all criterim, depending upon stage irradiated and on dose *Hollaender states that that preliminary data indicate that 100 r gives similar striking changes. Note: All these data are preliminary and incomplete. 14 Table VI N - r RATIO Species Reference Criteria Organ or System Type Radiation Mice Evans & Failla Haemogram Fast Neutrons Mice " Haemogram Survival time 80 t/day;10 N/day Mice Evans, T. C. (1) Mortality; Haematology; Gonads; Lens of Eye 1.4 N/day Rat Rochester and Biochemical, Mortality Fast Neutrons X-ray Rabbit " " " Dog " " " Mice Zirkle (2); Fast Neutrons Roper; Riley; X-ray Stapleton; CH-2571, " Mice & " Rabbits CH-3839 " " Application Remarks Total body, acute 1N = 8 r Total body, fractional 1N = 8 r (approx.) Total body, fractional 1N = 12 - 15 r Total body, cronic 1N = 8 - 21 r " 1N = 12 - 16 r " 1N = 6 - 14 r Total body, Fast neurons and acute gamma rays completely additive (acute radiation) " 1 n = 5 - 12 1/2 r or gamma rays (1 n = 2.5 reps). (1) Evans, T.C. Effects of Small Daily Doses of Neutrons on Mice, Radiology, 50:811-833, 1948 (2) Mitchell (Brit. J. Radiology, 20:368, 1947) found 1 rep of neutrons equivalent of 32 + 8.6 r of gammas when the doses were delivered in one or two days. 15 Table VII MORTALITY TABLE Taken from Report By Robert Boche Species Reference Application Radiation Dose Time Guinea Ellinger (4) " 200 KVP 200 r Pig Henshaw (5) Dog Cole et al. (6) " 200 KVP 300 r Dog Rochester expt. " 1000 KVP 335 r No. 5980 Mouse Ellinger (4) " 200 KVP 400 r Mouse Henshaw (5) " 200 KVP 450 r C3H Mouse Henshaw (6) " 200 KVP 600 r LAF Monkey Rochester " 250 KVP 500 r Report No. 5980 Rat cole et al. (6) " 200 KVP 590 r Rat Rochester " 250 KVP 650 r Wistar Report No. 5980 Hampster Rochester " 250 KVP 700 r Report No. 5980 Rabbit Hagen et al. (7) " 200 KVP 790 r Man (4) Ellinger, F. Radiology, 4:125-142, 1945. (5) Henshaw, P.X. J. Natl. Cancer Inst., 4:485- 501, 1944. (6) Cole, K. s. et al., Metallurgical Laboratory, University of Chicago, 1944. (7) Hagen, Jacobsen, Murray and Lear, Metallurgical Laboratory University of Chicago, 1944. 16 Table VIII MORTALITY CHRONIC X-RADIATION 3 r = 10 r PER DAY Type Species Sex Reference Radiation Application Boche Rochester Total body Dog No. 1 F No. 5939 1000 KVP 6 days/wk " No. 2 F " " " " No. 3 F " " " " No. 4 F " " " " No. 5 M " " " " No. 6 M " " " " No. 7 M " " " " No. 8 M " 250 KVP " " No. 9 F " " " " No. 10 F " " " " No. 11 M " " " " No. 12 F " " " " No. 13 M " " " " No. 14 M " " " " No. 15 M " " " " No. 16 M " " " " No. 17 M " 1000 KVP " " No. 18 M " 250 KVP " " No. 19 F " 1000 KVP " " No. 20 M " " " " No. 21 M " " " " No. 22 M " " " " No. 23 F " 250 KVP " Total r r per received day at death Remarks 10.0 r 1200 " 3310 " 1340 " 2540 " 3590 " 1240 10 dogs or 50% dead " 1830 3 dogs were alive at at accumulated dose 5000 r (2 M and 1 F) of 1140 r " 1300 " 1320 " 1110 " 1270 " 1440 " 1070 " 2660 " 1150 " 1870 1 F alive at 5000 r 3.0r 1199 2 M and 2 F living at 1500 r " 1305 3 F living at 1500 r 6.0r 2940 " 2304 " 2064 " 2214 1 F alive at 3000 r " 1908 3 M and 1 F alive at 3000 r 17 Table IX LONGEVITY Type Species Reference Radiation Application Rat Boche X-rays 250 Within 10-15 min 11-188-5936 1000 KVP per dose 0 0.10/day, 6 wk 0.5 " " 1.0 " " 10.0 " " Rat " " " " Dog " " " " Rabbit " " " " Mouse Henshaw's X-rays * data 250 V Mouse Lorenze et Gamma Rays 0.0 /8 hr/day al. Radiology, 0.115 " " 49:274, 1947 1.1 " " 2.2 " " 4.4 " " 8.8 " " Guinea " " 0.1 " " Pig 1.1 " " 2.2 " " 4.4 " " 8.8 " " Mice Henshaw's X-rays 0 r per week C3H data given by 200 KV *25 " " Boche No. 5936 50 " " 75 " " 100 " " 125 " " Observed Accumulated Dose at Results Half Survival in r Remarks Mean Death Time 85.8 weeks 0 81.7 " 48 76.7 " 230 76.9 " 460 58.3 " 3500 Factor related to life-span decrease 2.4x10-4 2.1x10-4 1.1x10-4 2.0x10-4 690 days half survival 780 " " " 690 " " " 760 630 " " " 1390 600 " " " 2640 500 " " " 4400 75% survival (1100 days) 1100 day half survival 1200 960 " " " 2100 540 " " " 2400 150 " " " 2300 45.8 weeks, Mean Death Time 36.8 " " " " 920 34.6 " " " " 1730 27.1 " " " " 2032 L.D. 50 x 450 r 23.9 " " " " 2390 19.2 " " " " 2400 *Dosages are in equal fractions 5x/wk., i.e., 5rx5, etc. 18 Table X EFFECT OF RADIATION HUMAN CASES Type Case Age Reference Radiation Application 1. 53 CH-3868 400 KVP Total body acute 60 r 2. 75 " " " 3. 59 " " " 4. 72 " " " 5. 57 " " Total body acute 27 r 6. 61 " " Total body acute 120 r 7. 65 " " " 8. 54 " " " 9. 73 " 270 KVP Fractional total body 502 r Nov 26-Dec 20 10. 67 " " Fractional total body 300r in 33 days 11. 25 " " 87.5 r total body. In 8 daily treat- ments 12. 35 " " 7 r total body 13. 23 " " q. day for 3 15. 23 " " days Lymphocytes Neutrophils Other + reduction + reduction None + rise followed + rise followed + platelet fall by + reduction by + fall 28th-71st day + fall + fall None + reduction None None + reduction None None No effect Sl. increase None + reduction + temporary Platelets reduced reduction at 24 - 48 hours + reduction most + rise + decrease in Rbc. marked 35th day and Wbc. + reduction " rise + rise in platelets 2nd-14th day ++++ Starting after ++++ Starting Nausea & vomiting after 2nd Rx after 2nd Rx 1, 2, 6th Rx +++ +++ + depression bone marrow + reduction + reduction Rbc. and Wbc. + reduction None None None Remarks Ca epiglottis. Reduced lymphocytes for 157 days. Ca tonsillar pillar and fossa. Lymphocyte fall persisted 151 days. Ca epiglottis. Ca right breast. Lymphocyte fall transient. Ca epiglottis. Ca larynx. Lymphocytic reduction not marked. Ca larynx. Ca epiglottis (1) - Change not impressive Ca hand with metastasis. 3750 cc. transfusion 26th and 30th day. Chr. rheumatoid arthritis. Arthritis. None (Total 3 cases) (1) No radiation nausea observed in case receiving 60 or 120 r acute doses 20 Table X continued EFFECT OF RADIATION HUMAN CASES - continued Type Case Age Reference Radiation Application - - Rochester 1000 KVP Estimated 25 r total body from overhead tube 1. - LAMS Clinical Total body No. 808 limit Estimated 290 r overhead tube 2. - " " Estimated 18 r 3. - " " " 880 r 4. - " " " 86 r 5. - " " " 65 r 6. - " " " 22 r 7. - " " " 18 r 8. - " " " 14 r Lymphocytes Neutrophils Other None None Dates estimated at mid-torso. +++++ reduction +++++ reduction Epilation, anemia, thrombocytopenia, gross testis damage No reduction No reduction Normal ++++ reduction ++++ reduction Nausea, vomiting, Gastric distress Normal Normal Normal + reduction + reduction Normal Normal Normal + reduction Normal Normal Normal Normal Remarks Does estimated at mid-torso. Death 25th day. (2) Aplastic bone marrow. Still normal 10 mos. post-irradiation. Death 9th day. Normal 2 years post-exposure. Normal 15 mos. post exposure. Normal Normal Normal (2) Of the Los Alamos cases, all but case 7, and case 8. revealed increase in refractile bodies in the lymphocytes. (3) All doses, cases 1-6 inclusive, subject to revision. 21 Table X-A EFFECT OF TOTAL BODY IRRADIATION HUMAN CASES Submitted by Dr. R. S. Stone Cases 1-29 CH - 3863 Cases 30-32 UCRL - 41 (Stone and Low Beer) Application Elapsed Daily Total Case Age Radiation Days Dose Dose 1. 23 200 KV 27 15 321 2. 33 200 KV 58 50 394 3. 58 200 KV 24 10 295 or 20 4. 61 100 KV 89 30 367 200 KV 5. 29 100 KVx10 59 10 291 200 KVx18 6. 64 200 KV 25 10 244 or 20 7. 36 100 KVx23 35 10 295 200 KVx3 or 15 Lymphocytes Neutrophils During Rx After Rx During Rx After Rx Fluctuate from 25 days after ++++ 4 days after ++++ increase + decrease Fluctuations ++++ decrease to 60 days after 60 days after ++++ decrease + decrease ++++ increase Fluctuate from + decrease ++++ increase to ++++ decrease Fluctuate from ++++ increase ++ decrease ++ decrease ++++ increase + increase to ++++ decrease Fluctuate from ++ decrease Fluctuate Low in 50 days + increase at end of Rx mostly up to +++ decrease to +++ gradual re- +++ recovery +++ decrease turn to normal in 180 days Down to Fluctuate from ++++ decrease + increase to ++++ decrease Down to Fluctuate from +++ decrease ++++ increase to ++++ decrease Other such as RBC, etc. Remarks Poor subject, Hodgkins Disease with fluctuating blood counts. Followed 48 days. Poor follow-up (cooperation poor) Followed 130 days. Recovery of count in 90 days for PMN - by end of treatment for lymphocytes. Followed 154 days No good because too much local treatment and not enough blood counts ++ fluctuation in PMN for 600 days. Otherwise complete recovery. Followed 834 days. Followed only 36 days and received local x-ray therapy during that time. Followed 36 days 22 Table X-A continued EFFECT OF TOTAL BODY IRRADIATION HUMAN CASES - continued Cases 1-29 CH - 3863 Cases 30-32 UCRL - 41 Application Elapsed Daily Total Case Age Radiation Days Dose Dose 8. 46 200 KV 22 15 302 9. 66 200 KV 16 20 300 10. 51 200 KV 16 20 300 11. 63 200 KV 17 20 300 12. 47 200 KV 17 20 313 13. 66 200 KV 15 20 258 14. 38 1000 KV 5 20 100 Lymphocytes Neutrophils During Rx After Rx During Rx After Rx Down Rx Low level Fluctuating ++++ decrease ++++ decrease continued increase to Lowest level ++++ 18th day after end of Rx Decrease to Did not re- Fluctuate Low of 630 ++++ turn pre-Rx from ++ in- 22 days after until 315th crease to end of Rx day ++++ decrease Fluctuating but Low of 620 Fluctuate Low of 805 on frequently 9 days after ++ increase 30th day after ++++decrease end of Rx to ++ Rx. Recovery decrease 60th day Fluctuating Recovery 56 Fluctuate Recovery by 55, mainly down to days after from ++ in- but tended to ++++ decrease end of Rx crease to ++ fluctuate at max. decrease low level Always down Not complete Fluctuate Fluctuate Greatest recovery in mostly + up mostly below decrease +++ 46 days normal Always Remained Fluctuate ++ decrease decreased down less than + in 10 days ++ to +++ either up or down Always Rapid Fluctuate Mostly decreased Recovery Most increase down + or ++ + or ++ + or ++ Other such as RBC, etc. Remarks In 32 days followed after Rx. PMN and lymphocytes did not recover. Followed 74 days. Lymphocytes and PMN continued low most of the time. Lymphocytes returned to normal by 43rd day after Rx. PMN returned to normal by 60th day. Lymphocytes and PMN frequently low. Followed 1946 days. Lymphocytes generally low for about 2 years, but tend to be higher. Polys tended to be low for 2 years. Followed 1650 days. Not sterilized in 46 days. Reports from other Physician showed "norma" blood 10 months after Rx. Followed 46 days. Lymphocytes did not return to 3500 level. Polys remained lower after Rx. Followed 784 days. Lymphocytes tended to fluctuate below pre-R x level. Polys tended to fluctuate below pre-R x level, Followed 79 days. 23 Table X-A continued EFFECT OF TOTAL BODY IRRADIATION HUMAN CASES - continued Cases 1-29 CH - 3863 Cases 30-32 UCRL - 41 Application Elapsed Daily Total Case Age Radiation Days Dose Dose 15. 74 1000 KV 6 20 100 16. 66 1000 KV 6 20 100 17. 38 1000 KV 7 20 120 18. 55 1000 KV 5 20 100 19. 55 1000 KV 17 20 283 20. 36 1000 KV 17 20 300 21. 42 1000 KV 21 20 292 Lymphocytes Neutrophils During Rx After Rx During Rx After Rx Little change + decrease Up to a Slightly for 3 days + decrease low Mostly + Normal Mostly Down to a decrease slightly to ++ decrease + decrease ++ decrease Immediate Normal Normal by last day recovery fluctuation fluctuation ++ decrease Recovery Normal Normal by 39th day or slight fluctuation increase + total Low of 880 Marked Continued + decrease 90 days after fluctuations fluctuations finish of Rx. Fluctuating ++++ decrease Marked +++ decrease downward to on 4th day fluctuation on 4th day ++ decrease after Rx mostly down after Rx at end ++ decrease Gradual Below 1000 Fluctuating Low of downward to for 431 days but mostly ++ decrease +++ decrease slight on 25th decrease to post Rx day + decrease Other such as RBC, etc. Remarks Relatively little effect on polys and lymphocytes. Followed 88 days. Total WBC and polys lower - but more normal "after treatment. Lymphocytes normal. Followed 615 days. Practically no change. Followed 37 days. At 1 yr. and 2 yr. intervals the polys and lymphocytes + Total WBC were more normal than before Rx. Followed 100 days and then on the 386th and 655th. Lymphocytes below pre-treatment level almost constantly. Polys varied about the same during and after Rx. Followed 1071 days. Patient a drifter who did not return. Followed only 21 days. Lymphocytes never back to normal, but above 1200 after 755th day. Followed 1210 days. 24 Table X-A continued EFFECT OF TOTAL BODY IRRADIATION HUMAN CASES - continued Cases 1-29 CH - 3863 Cases 30-32 UCRL - 41 Application Elapsed Daily Total Case Age Radiation Days Dose Dose 22. 33 1000 KV 18 20 300 23. 48 1000 KV 19 20 302 24. 25 1000 KV 7 20 120 25. 32 1000 KV 2 20 40 26. 64 1000 KV 26 10 299 38 4 27. 45 1000 KV 27 10 301 200 KV 40 3 Lymphocytes Neutrophils During Rx After Rx During Rx After Rx ++ increase Low of 600 Slightly +++ decrease followed by 0n 23rd day downward by 23rd day slight post-Rx trend post-Rx decrease ++ increase Low of 160 Slight Generally followed by on 9th day fluctuation downward ++ decrease post-Rx up and down Low on 33rd day post-Rx ++ decrease Low of + decrease ++ decrease by end of Rx +++ decrease during Rx on 35th day on 35th day post-Rx post-Rx + decrease ++ decrease + fluctuation Above during Rx on 30th day up and down pre-Rx level near end post-Rx Gradual Gradual Occasional On 29th fluctuating increase to + decrease post-Rx day decrease to normal by ++ decrease +++ at end 62nd day of Rx post-Rx Other such as RBC, etc. Remarks Lymphocytes returned to pre-Rx level by 321st post-Rx day. Polys soon returned to normal levels. Followed 1344 days. Lymphocytes continued below 1000 all through post-Rx period. Polys gradually returned to normal levels. Followed 421 days. Lymphocytes back to normal by 49th days. Polys recovered by 49th day, but low thereafter. Followed 615 days. Complicated by previous x-ray. Followed only 2 days Lymphocytes recovered by 44th day post-Rx. Polys seldom below pre-Rx level. In normal range at all times. Followed 351 days. Lymphocytes stayed at or above pre- Rx level after 62nd post-Rx day. Polys tended to stay near pre-Rx level. Followed 585 days. 25 Table X-A continued EFFECT OF TOTAL BODY IRRADIATION HUMAN CASES - continued Cases 1-29 CH - 3863 Cases 30-32 UCRL - 41 Application Elapsed Daily Total Case Age Radiation Days Dose Dose 28. 52 1000 KV 17 5 298 200 KV 91 41 29. 68 1000 KV 15 5 278 200 KV 68 37 30. 59 100 KV 36 10 298 31. 58 100 KV 36 10 299 32. 58 100 KV 19 20 303 Lymphocytes Neutrophils During Rx After Rx During Rx After Rx Occasional On 5th Occasional Fluctuating + decrease post-Rx day + decrease around ++ decrease Normal Fluctuating +++ decrease Occasional ++ decrease down to 2 days ++ decrease 2 days after +++ decrease after Rx generally last Rx near end downward generally of Rx upward Occasional Around Fluctuate Trend to ++ decrease ++ decrease from fluctuate Trends to for 54 days + decrease considerably fluctuate to ++ more near increase end Fluctuate ++ decrease Fluctuate Fluctuate from 2 days after from around + increase Rx + increase Pre-Rx to to value + decrease + decrease ++ decrease Slowly Trend to be but upward low even fluctuate up before Rx and during Rx Other such as RBC, etc. Remarks Lymphocytes and polys near normal level. Followed 913 days. Lymphocytes did not recover to pre- Rx value. Polys only once reached pre-Rx value. Followed 351 days. Lymphocytes rose to +++ increase and stayed pre-Rx values. Polys tend to be normal or slightly low. Followed 771 days. Lymphocytes tend to higher values. Polys vary around pre-Rx value. Followed 716 days. Lymphocytes recovery by 107 post-Rx day. Polys tend to stay on same low value as below Rx. Followed 674 days. 26 Table X-B COMPARISON OF RADIATION EFFECT BY TOTAL DOSE 26 CASES Submitted by Dr. R. S. Stone 1. 2. 200 & 100 Kv 200 Kv 300r 300r 2 pts. 9 pts. sig + sig - sig + sig - RBC - - - 1 pt Conclusion HGB - - - - of treatment WBC - - 1 pt - course PMN - - 2 pts 3 pts Ly - - 1 pts 6 pts Mo - - 6 pts - 1 pt. only 8 pts. only RBC - - - 1 pt 30 days after HGB - - - 1 pt conclusion WBC - - - 4 pt of treatment PMN - - - 5 pt Ly - - - 3 pt Mo - - 4 pts - 7 pts. only RBC - - - 1 pt 60 days after HGB - - - 1 pt conclusion WBC - 1 pt 2 pts - of treatment PMN - 1 pt 1 pt 3 pts Ly - 1 pt 1 pt 1 pt Mo - - 5 pts 1 pt 3. 4. 1000 & 200 Kv 1000 Kv 300r 100r 2 pts. 6 pts. sig + sig - sig + sig - RBC - 1 pt - 1 pt Conclusion HGB - - - - of treatment WBC - 1 pt - 1 pt course PMN - 2 pts - 1 pt Ly - 2 pts 1 pt 4 pts Mo - - 2 pts - RBC - 1 pt - 1 pt 30 days after HGB - 1 pt - - conclusion WBC - 1 pt 1 pt 2 pts of treatment PMN - 1 pt 1 pt 1 pt Ly - 2 pts 1 pt 4 pts Mo - - - - 4 pts. only RBC - 1 pt - 1 pt 60 days after HGB - - - 1 pt conclusion WBC - - - - of treatment PMN - - - 1 pt Ly - 1 pt 1 pt 1 pt Mo - - - - 27 5. 18 Patients 1000 Kv Total 300r of numbers 7 pts. 2, 3, & 5 sig + sig - sig + sig - RBC - - - 2 pts Conclusion HGB - - - - of treatment WBC 1 pt 1 pt 2 pts 2 pts course PMN 1 pt 1 pt 2 pts 2 pts Ly - 6 pts 1 pt 14 pts Mo 1 pt - 7 pts - 6 pts only 16 Patients RBC 2 pts 1 pt 2 pts 3 pts 30 days after HGB - - - 2 pts conclusion WBC - 4 pts - 9 pts of treatment PMN - 3 pts - 9 pts Ly - 5 pts - 10 pts Mo - - 4 pts - 15 Patients RBC - - - 2 pts 60 days after HGB - - - 1 pt conclusion WBC 1 pt 3 pts 2 pts 5 pts of treatment PMN 1 pt 1 pt 2 pts 4 pts Ly - 5 pts 1 pt 7 pts Mo 1 pt - 6 pts 1 pt Summary of results on 26 of the patients treated to total of 100 r (6 pts.); 300 r (20 pts.), with daily doses of 5 r, 10 r, 15 r, and 20 r. 28 Table X-C Submitted by R. S. Stone TECHNIQUES EMPLOYED FOR TOTAL IRRADIATION (J. J. Nickson) cm Name and Year K.V.P. M.A. Filtration t.s.d. 1923 Chaoul & Lange 1 mm Cu 40-45 1927 180 0.5 mm Zn Teschendorf 2.0 mm Al 150 1931 Teschendorf 170 6 180-200 1931 Groedel & Lossen 1931 Sluys 200 150 1932 548 & Heublein 185 3 2 mm Cu 732 1932 .5 mm Cu Ardent & Gloor 170 3 .5 mm Zn 1936 0.5 mm Zn Squalitzer 170 3 1.0 mm Al 150 1936 1.0 mm Cu O'Brien 200 5 1.0 mm Al 300 Field No. of Location Size Field of Field rRX Min/RX 1/4 of Upper & Lower torso 4 torso - A. & P. ~ 60 1/2 of body 2 A. & P. ~ 10 30-45 1/2 of body 2 A. & P. 12 6-10 Small 28 Covered body 84-360 1/4 of Upper & Lower torso 4 torso - A. & P. 25-50 Body 1 Body 1.26 t/h 20 hrs. out of 24 Body 60-120 Body 2 A. & P. ~ 25 ~ 20 Body 1 Body ~ 10 40 Frequency of Rx Remarks About every 60-70% S.E.D. to 2 days each field in 8 weeks About two times a week Usually 5-8 day interval 4-5 fields Not body irradiation, a day really Daily Total -- 200-2400 r 1 field Up to 187 hours 1 r a day 6 Usually 2 courses of days - rest irradiation. Shields 6 days eyes, genitalia 29 Table X-C continued TECHNIQUES EMPLOYED FOR TOTAL IRRADIATION - continued cm Name and Year K.V.P. M.A. Filtration t.s.d. 1936 0.5 mm Cu Hunter 200 4 4.0 mm Cal- 215 luloid 1936 Hunter 200 6 same 215 1936 Sanderson 200 4,6 0.5 mm Cu 225 1939 Mallet 340 1942 Craver & Medubger 185 1 5.5 mm Cu 300 1931 0.5 mm Zn Dale 2.0 mm Al 100 1946 0.5 mm Cu Mallet 200 2.0 mm Al 150-300 Field No. of Location Size Field of Field rRX Min/RX Body 1 Body 20 60 Body 1 Body 54 60 Body 2 A. & P. 24, 60 42 Body 1 Body 5-20 Body 1 Body 0.86 t/hour Body 2 A. & P. 12-18 12-18 20x10 to Vary Body 25 30 Body Frequency of Rx Remarks Daily (Polycythemia vera) 600 r in 35 days Daily (Polycythemia vera) 1192 r ub 30 days Daily (Polycythemia vera) 70-600 r given Continuous 100 r- 300 r usually Daily - 5 d to Head, neck, & genitalia 5 weeks shielded. 1/10 - 3/5 S.E.D. total per series. 4-5 Rx/week Stop if WBC below 2500, HBC below 2.5. 500-1200 4/field series 30 POLYCYTHEMIC AND LEUKEMIC PATIENTS LIVING 1 YEAR OR MORE Submitted by Dr. Shields Warren New England Deaconess Hospital, Boston SUMMARY Table X-D In One Year In One Year In One Year 10,000 u.c. 10,000-20,000 20,000 u.c. p32 u. c. p32 p32 TOTAL + hurt by 0 2 1 3 radiation - not hurt by 18 12 5 35 radiation TOTAL 18 14 6 38 10,000 U.C. p32 Case No. 1. -4,750 u. c. 6 Hodgkin's Disease 2. -4,645 u. c. 10 Monocytic Leukemia 3. -4,680 u. c. 16 Hodgkin's Disease 4. -8,385 u. c. 27 Terminal Lymphatic Leukemia 5. -8,663 u. c. 30 Myeloma 6. -5,130 u. c. 37 Acute Lymphatic Leukemia 7. -5,982 u. c. 38 Hodgkin's Disease 8. -6,140 u. c. 45 Polycythemia 9. -2,280 u. c. 57 Polycythemia 10. -7,800 u. c. 64 Terminal Chronic Myelogenous Leukemia 11. -7,720 u. c. 77 Lymphosarcoma 12. -7,800 u. c. 79 Polycythemia Vera 13. -9,000 u. c. 83 Leukemia 14. -7,000 u. c. 88 Polycythemia Vera 15. -8,000 u. c. 89 Polycythemia 16. -5,500 u. c. 92 Myelogenous Leukemia 31 Table X-D 10,000 U.C. p32 Case No. continued (continued) 17. -4,000u. c. 98 Polycythemia 18. -6,700 u. c. 99 Multiple Myeloma 10,000 - 20,000 U.C. p32 (continued) 1. -10,038 u. c. 3 Subacute Lymphatic Leukemia 2. -16,955 u. c. 7 Chronic Myelogenous Leukemia 3. +15,700 u. c. 26 Terminal Chronic Lymphatic Leukemia 4. +13,100 u. c. 28 Subacute Chronic Lymphatic Leukemia 5. -12,528 u. c. 31 Chronic Lymphatic Leukemia 6. -18,615 u. c. 33 Myelogenous Leukemia 7. -19,664 u. c. 34 Chronic Myelogenous Leukemia 8. -12,857 u. c. 39 9. -13,680 u. c. 47 Multiple Myeloma - Group A 10. -15,615 u. c. 65 Chronic Lymphatic Leukemia 11. -15,700 u. c. 86 Lymphoid Leukemia 12. -12,300 u. c. 87 Polycythemia Vera 13. -16,000 u. c. 95 Myelogenous Leukemia 14. -14,500 u. c. 96 Myelogenous Leukemia 20, 000 U.C. p32 1. -25,440 u. c. 60 Chronic Myelogenous Leukemia 2. -20,080 u. c. 63 Chronic Lymphatic Leukemia 3. -27,872 u. c. 66 Chronic Myelogenous Leukemia 4. +24m159 u. c. 72 Chronic Myelogenous Leukemia 5. -21,100 u. c. 74 Chronic Myelogenous Leukemia 6. -25,900 u. c. 93 Myelogenous Leukemia 32 Table XI CHEMICAL ASPECTS (1) Type Species Reference Irradiation Enzymes & other Many Authors naturally occurring organic compounds Barren MDDC-484 X-rays Rat Barron et al " MDDC - 1221 Dog Processor et al " Radiology 49, 299, (1947) Dog Allen et al " J. Exp. Med. 87, 71 (1948) Rat Kohn & Robinett " ORNL 116 Rat Processor et al " ibid Dob " " Observed Application Dose r (2) Results See Footnote (3) Produce chemical change Acute 100 r Inhibited respiration in spleen slices 10%; testes 31% " 50-500 r Inhibited uptake of glucose by intestine over 2-4 hours " 200 r Blood clotting increased 2-4 times " 450 r Heparin - like substance found in blood " Heparin not found " 200 & 100 r SCN space increased by 2% for a few days " 100 r Increased sedimentation rate of erythrocytes Remarks Biological significance unknown apart from possible genetic effects. Later similar observations have been made in rabbits at 800 r and apparently in man By administering Heparin the LD 50 was reduced from 550 r to 350 r Dogs required 400 r. Water intake and urine output distributed with mid-lethal doses (1) The examples given illustrate various types of chemical approach to the radiation problem. Many of the observations still require confirmation. (2) The doses given are not usually minimum doses. (3) The dose to produce effects depends on the purity of the compound, its dilution, and the number of molecules changed per ion pair. 33 Table XI continued CHEMICAL ASPECTS (1) - continued Type Species Reference Irradiation Mouse? Dougherty & White X-rays End. 39, 370 (1946) Rat Patt et al CH-3830 " P59 (1948) " Patt et al ANL-4163 " P 86 (1948) Mouse Dougherty & White " Rabbit Craddock & Lawrence " Lawrence MDDC-1698 Fern Spores Zirkle R. E. " Yeast Anderson R. S. " Rat 1 day old Evans T. C. " Dog Rekers & Field " Science 107, 16, 1948 Male Mouse Gardner et al End. " 32, 116, (1943) Observed Application Dose r (2) Results Acute 200 r Adrenal cholesterol dropped from 60-65 mg.% to 10 mg.% " 200-650 r Drop in adrenal cholesterol 2- 6 hours " 650 r Total cholesterol in gland doubled 5 days after irr. Weight of gland also increased at that time. " 10 r Decrease in plasma gamma globulin " 250 r Antibody production markedly decreased if antigen injection start after irr., not if started 4 days previously " Ammonia or carbon dioxide modified the sensitivity " The sensitivity varied depending on the presence or absence of oxygen " Less damage at low temperatures or with respiration or circulation stopped " 350 r Fewer dogs treated with rutin died from this dose than in an untreated series " 550 r Prior injection of estradiol benzoate decreased the radiosensitivity Remarks Such a change in cholesterol is interpreted as paralleling an increase hormone secretion. Fall prevented by prior adrenal cortical extract injections. 3 hours after irradiation Rats are reported to be unaffected 34 APPENDIX GENERAL BACKGROUND Submitted by Dr. Donald Charles 1. A human sperm contains 24 chromosomes. Each chromosome contains a "string" of some hundreds of genes. 2. A human egg contains a similar set of chromosomes and genes. 3. So in the nucleus of a fertilized egg there are 48 chromosomes altogether - 24 kinds, each in duplicate - and perhaps 10,000 kinds of genes also each in duplicate. 4. Each gene has two main types of action: a. Each catalyses some particular chemical process, given the proper materials; b. Each reduplicated itself at, or some time before, each cell division. (In this latter action the bonds between genes in the same chromosome also reduplicate.) 5. So each new cell of a developing embryo is equipped with 24 pairs of chromosomes with their associated genes. 6. Some genes come into action at or shortly after fertilization. They operate in a "field" of limited complexity, i.e., the cytoplasmic differences already existing in the fertilized egg. Their activity probably increases the regional differences and permits other genes in turns to come into play. 7. In general different batteries of genes come into action at different times, in different cells or tissues, and for varying intervals - determined by when and where the materials for their operation become available. Some genes perhaps remain inactive until long after birth. 8. Most, if not all, genes were very slightly unstable. among the example of million descendants by reduplication from a single original gene perhaps one or a few will have a somewhat different structure. 9. Once a gene has undergone such a change (mutation) it reduplicated the changed structure thereafter, except for the occurrence of further mutations. 10. Mutation probably decreases the catalytic activity of genes. So a mutant gene M acts in the same process as the normal gene M from which it arose, but less effectively. 11. A child who inherits a mutant M from one parent and the normal gene M from the other parent may or may not show effects of the mutuant. a. If MM cells are able to do no more of the specific M- catalysis than in necessary, MM cells may be able to do enough so that the presence of M is not indicated by any deviation from normal structure of function. The mutant M is said to be recessive. b. If MM cells do just enough of the M-catalysis, MM' will not. Some embryonic process will deviate from its normal course and some detail of structure func- 35 tion will become abnormal, through not necessarily harmful. A mutuant of this sort is said to be dominant. 12. Radiation-induced mutants, like the spontaneous, may be either recessive or dominant. 13. In man the potentially dangerous mutants are the dominant, and the recessive in that one pair of chromosomes which determines sex. 14. A third class of potentially dangerous inheritable changes can be induced by radiation: chromosome mutations. A piece may be broken off one chromosome and attached to another. A section may be inverted in situ. Chromosomes may exchange sections. 15. Thus in a sperm which has been exposed to radiation any one or more of many thousands of genetic changes may occur; any of the thousands of genes may mutate and chromosomes may break and re-attach at any of the thousands of bonds between genes. 16. Since any one of these changes has a very low probability at moderate exposure, the majority of exposed sperm will not undergo any mutation. In the minority which are affected one gene will mutate in one sperm, a different gene in another sperm, in still a third cell there will be a chromosome mutation, and so on. GENETIC CHANGES INHUMAN SPERM AND EGGS, CAUSED BY A SINGLE EXPOSURE OF 300r OR LESS Submitted by Dr. Donald Charles Until data from Hiroshima and Nagasaki are studied, we can only assume that radiation would affect reproduction and heredity in humans as much as it does in other animals. Unfortunately it is just the range from 50 to 300 r about which we know least, evening mice and rats, so far as genetic effects are concerned. Pre-war experiments were done chiefly at 400 r and above; Manhattan work has been mainly on chronic exposures of 10 r and less. So the following statements rest on a double extrapolation: from low or high exposures of 10 r and less. So the following statements rest on a double extrapolation: from low or high exposure to intermediate, and from other mammals to man. 1. In exposed males, the amount of sperm available for ejaculation would vary with time after exposure roughly as follows: FOR REFERENCE SEE (10bb01.gif) 36 How far the count drops and when the recovery begins both depend on the number of roentgens received. The sterile period might last 1-2 weeks at 200 r and 3 weeks at 300 r. 2. Eggs fertilized by sperm released in the initial period have poor prospects. (a) About 10% would die for each 100 r the father had received. Most of these eggs would die before implantation, and so cause the mother little trouble. But perhaps one-third of them would implant, die later and be resorbed as embryos or be still-born. (B) Among the live=born children there would be roughly 0.5% with detectible structural abnormalities for each 100 r the father had received. (c) Among these children there would also be some who, as adults, would themselves be permanently semi-sterile: half of their children (grandchildren of the exposed male) would die in utero. The proportion so affected varies with roughly the square of the dose and is represented in the following graph. FOR REFERENCE SEE (10bb02.gif) 3. Eggs fertilized by sperm released in the recovery period have fair prospects. Of the three effects shown in the previous graph: deaths in utero (top curve) would be reduced by perhaps half; semi-sterility in children would be nearly absent; structural changes would persist in the same frequency. thus at 300 r only about 6-7% of recovery-period pregnancies would be affected, in contrast to 16-17% of initial period pregnancies. And for the 6-7% affected, perhaps 3% would be early resorptions, so that the over-all genetic hazard after the initial period might be about 1% per 100 r. 4. The reason for the difference between initial and recovery periods is as follows. (a) The initial period sperm were in the testis ducts at the time of exposure. The recovery period sperm were formed, after the exposure, from "sperm cells" in the testis. (b) Radiation produces chromosome breaks in both mature sperm and stem cells. The broken ends may stay so, or may recombine in various ways. (c) The affected sperm are able to fertilize eggs but, in the divisions which follow fertilization, the rearranged chromosomes are not distributed normally so that some cells get too much or too little chromosome material and the embryo dies. (d) The affected stem cells go through a cell division in forming sperm. Only those cells without major chromosome change give rise to sperm which are viable. This division then acts to filter out many of the chromosome abnormalities from recovery period sperm. 37 5. We have at present no basis for estimating the frequency of genetic changes in the eggs produced by exposed women. But it would probably be of the same order of magnitude as in sperm, and worse in the first egg released after exposure than in subsequent eggs. 6. All of the genetic exposure effects are, so far as we know, identical with changes that occur in the absence of radiation. The exposure simply increases the proportion of eggs of sperm in which they happen. Furthermore faulty parents nutrition, disease, etc., may produce similar end effects on embryos. Therefore, not all still-born or abnormal children of Hiroshima or Nagasaki parents after May 1946 can be blamed on radiation effects. What proportion must be so credited could only be determined if we had adequate pre-blast vital statistics. Experimental Procedure FOR REFERENCE SEE (10bb03.gif) 38 2. Gene and chromosome mutations which occurred in the sperm of exposed and control males wee detected as follows: It the sperm contained a The effect in an offspring formed from that sperm was dominant gene mutation none if F1; but half of the in the sex chromosome sons of F1 __ are affected (transmitted to F1 __, not F1 __) chromosome mutation reduced fertility (transmitted to F1 __ or __; studied only in __) 3. In brief, the procedure was to hunt among the offspring of exposed and control male mice for a. Sons and daughters with some abnormality of structure or function; b. Daughters producing definitely fewer than normal offspring in four litters; c. Daughters producing only half as many sons as daughters (i.e., daughters receiving sex-chromosome recessive mutants with lethal effects). 4. The procedure was complicated by two main factors: a. All of the effects of mutants genes or chromosomes may be duplicated by developmental and post-nasal accidents quite independent of heredity. b. The effects of mutant genes range from large and conspicuous down to very slight and difficult to detect. 5. So the procedure involved a double sifting: first, each F1 mouse had to be classified as normal or abnormal (with respect to the three criteria in item 3 above); second, those classified as abnormal had to be tested to determine whether the abnormality was hereditary or not. The latter discrimination is possible because the hereditary abnormalities are transmitted by the individual carrying them to half of its offspring. 39 GENERAL RESULTS AND DISCUSSION 1. Among male mice, the probability per roentgen that a muta- tion (of the magnitude and types studied) will occur is of the order 5.7x10-5 per r. Thus of a million sperm exposed to 30 r about 1700 undergo mutation in one or another gene or chromosome. If one of the unaffected sperm happens to be used in fertilization no hard is done; if one of the affect- ed, the result will be one of the abnormalities listed in the experimental procedure. 2. Abnormalities found in F1__ were not tested by breeding, nor were all defects in F1__ because of space and time limita- tions. Among the untested abnormalities should be some due to dominant gene mutations. Since any particular mutation is not likely to have occurred more than a few times in the experiment the missed mutants should be among those aberra- tions which were not found more than a few times altogether. Among the 11,000 F1 mice examined, the increase in some type of structural deformity with increasing dose indicates that the mean genetic effects of the radiation is at a rate of about 2.0x10-5 per roentgen. 3. Adding the two values together gives an overall mutation hazard of 7.67x10-5 per r. This value still excludes recessive and dominant or chromosome mutations with small effects. 4. The total mutation rate is distributed roughly as follows among the several classes of mutations: dominant with structural effects 40% recessive lethals in sex chromosome 10% chromosome mutations 50% 5. Two major uncertainties remain: a. Is the x-ray mutation rate in man as high as in mice? b. What proportion of the mutants we have found would be serious if they occurred in man? Obviously neither question can be answered. With respect to the first, we might better work on the conservative assumption that the mutation rate will not be lower in man than in mouse. On the second, it might be wise to take a similar attitude. Certainly in the creature whose genetics we know best, Drosophila, nearly every mutant gene has deleterious effects. We may first notice the presence of a mutant by an alteration of some minor morpho- logical detail, like eye color, but on further study we find that superficial change to be accompanied by a greater or less reduc- tion of general vigor or of life span. 6. If we take this view we are forced to wonder whether a human exposure of 0.1 r/day is acceptable. It means an increase of 1% in the hazard of transmitting a new mutant gene for each 100 r a parent has received at time of conception. 40 INDUCED MUTATION RATE How often do genetic changes occur in x-rayed reproductive cells? Available figures are few and not very accurate, except for sex-linked lethals in Drosophila. In the following table values which are not underlined have been obtained by extrapolation from experimental results; numbers in parenthesis are note and literature references. Percent of Sperm Affected Gene Mutations Chromosome Lethal sub-lethal Marginal Mutations One 10 r dose: Drosophila 0.11 0.06 0.42 0.004 Mouse - 0.04+ - (0.01-0.07 (1) (0.1 (2) Tradescantia - - - 0.05-0.2 (3) One 600 r dose: Drodophilsa 6.6(4) 3.6(4) 25.2(4) 1.8 (5) Mouse - 2.4+(6) - 33 (7) Tradescantia - - - 90+(8) How does the induced mutation rate vary with dosage? Gene mutations seem to occur in direct proportion to total dose down at least 25 r (4,9,10) no matter how the dose is applied - continuously or intermittently, at low or high intensity (4). The evidence however is very limited: one class of mutations in one chromosome of one organism. The frequency of chromosome mutations varies not only with total dose, but also with intensity and interval between doses. Here the evidence is still more remote from man, mainly from microscopic observation of x-rayed Tradescantia pollen, plus limited mouse and fruit fly data (3,5,8). 41 NOTES AND REFERENCES 1. Obtained by extrapolation from Snell's results (7) on the assumption that chromosome mutation rate is proportional t5o the 2 and 1.5 power of dose, respectively. the former would be more probable, according to (3), for 10 r given in 17-18 minutes as in the Manhattan District work, since Snell's 600 r exposure was administered in 16.5 minutes. Extrapolation from Snell's results by Marinelli's formula (8) gives a value of about 0.02. 2. Report of Genetics Division, Mouse Section, Manhattan District, at the Industrial Tolerance Conference on 23-24 January 1945. 3. Sax, K., 1941. Cold Spring Harbor Symposia on Quantitative Biology 9: 93-101. 4. Timofeet-Ressovsky, N., 1940. Handbuch der Erbbiologie des Menschen I: 193-244. 5. Bauer, H., Demerec, M., and Kaufmann, B. P., 1938. Genetics 23: 610-630. 6. Hertwig, P., 1939. Erbarzi 6: 41-43. 7. Snell, G., 1935. Genetics 20; 545-567. 8. Marinelli, L. D., Nebel, B. R., Giles, N., and Charles, D. R., 1942. American Journal of Botany 29: 866-874. 42