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·GENETICS, RADIOBIOLOGY AND RADIOLOGY

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·Genetics, Radiobiology
And Radiology Proceedings,
Mid-Western Conference
By
WENDELL G. SCOTT, M.D., CHLAIRJIAN
Chairman, Committee on Radiology
Marional Research Council
and
TITUS EVANS, Ph.D., CO-CHAIRMAN
Member, Committee on Radiology
National Research Council
BLACKWELL

·This book is copyright. It may not be reproduced by any means in whole er in part without permission. Application with regard to copyright stould be addressed to the publishers Published and copyrightdal 1959 In the United States of America by CHARLIS C THOM IS I'UBLISITER, 301-327 East Lawrence Avenue, Springfield, Illinois Published simultaneously in Canada by THE RYTRSON PRFSS, Queen Street It'est Toronto ? Printed in the United States of America ·PREFACE The simultanenus release in June, 1956, of repxiis lop the United States Sational Academy of Sciences. Vational Researa li Council on "The Biological Effects of Atomic Radiation" and the British Medical Research Council on "The Hazards to fan of Nuclear and Allied Radiations" produced an intense interest in the use of ionizing radiations in medicine. These reports 1100 only focused the attention of the public on this subject, but also pulili. erred the genetic hazard that can accrlie frojn small amounts of radiation and intensified the cellorts of the medical profession 10 minimie radiation done from the use of ways, In the assessment of possibile deleterious effects arising from the medical and dental use of x rays, it must be clearly inderstood that (1) only small amounts of radiation are used in clinical exam. Inations, and (2) the exposures are limited to local or segmental areas of the loods as opposed to local los irradiation As will be brought out in these proceedings, the deleterious effects of rada. con of this order are largels the genetic effects which depend om exposure to the gonadal tissues and which are of long range concern to the human race It should be pointed out that the informatiou contained in these two reports was based largely on the work of the Varinnal Committee on Radiation Protection and the Committee on Radio local Unns and Measurements Since 1931 Mese bodies baie formulated the scandards for the safeguarding of patients, the ox cupational personnel and the public Their work provided the foundations for the Handhools of radiation of the National Bureau of Standards The recommendations of these Committees and those contained as the handbooks have proven to be practical m application and to have provided eifective proxection. What has not been widely appreciated, is that small amounts of radiation can be a genetic hazard when delnered to the reproductive glands, and that the sidespread use of radiation in medicine has expanded V ·Genetics, Radiobiology and Radiology enough to yield a significant average gonadal dose to the popu. lation. The Committee on Radiobiology of the Academy Research Council felt that measures should be instituted to call attention to thesc problems and that one of the best means would lic to set up three regional conferences, one for the eastern states, one for the states in the middle west, and one for the western states. Those invited to the Conference would be the professors of genetics, radiobiology and radiology. In this way a fosum would be set up for a ficc and informal interchange of hnowledge in these fields. The geneticists and the radiobiologists could teach the radiologists about the genetic hazards and the radiologists in turn could show what was licing done to minimize sadiation dosage to the gonads and something of the practical aspects incumied in solving these problems. Participants would in turn disseminate the information through their tcaching programs to the residents, interns and medi. cal students attending their classes. The Midwestern Conference, held on May 2, 1958, was eminently successful in that there wcic four professors of genetics, four professors of radiobiology, and twenty-one professors of radiology who participatcel. Considerable interest was expressed in the possible somatic ellects following radiation exposure of the body tissues and these were thoroughly discussed during the Conference. It was cuisent that the prossilsilaey of shortening the life span from the small amounts of radiation delivcied during diagnostic examinations is cxtremely remote. Likewise, the possibility of inducing Iculemia by radiation from diagnostic examinations is also very remote Ilowever, it is a less remote possibility in the radiograplıic exam. ination of pregnant women who require special care when under: going these procedues. The use of ionwing radiation in the treatment of licnign conclitions requires re-evaluation in ile light of deletcrious effects of both the genetic and somatic types. This is especially true in radiation of a persistent thymus gland and in the irradiation of the ovaries in infertility, both of which are procedures that have already becn largely abandoned and shouki be donc away with completely. Similaris, licavy irradiation of the entire spine ſos degenerative ·Genetics, Radiobiology and Radiology arthritis is also open to question, although these cases must ise cire. fully esaluated on an individual basis. The development of the sulla drugs and the antibiotics have made it possible to do away with the superficial radiation (reatment of many benign shin con. dicions Here the dermi.tologists have had to reevaluate many conditions that they formerly treated by radiation. These and similar problems were brought up for discussion at the Conference and it was surprising to see the uniformity of opinion that existech in the management of these conditions. In discussing the deleterious effects of radiation, one mist 1100 lose sight of the tremendous benefits that have archied from diag. nostic radiology in the practice of medicine, nor of the great contributions it has brought and is still bringing to the health and well-being of mankind The rapid and widespread use of diagnos. WA MBELARY trum medical diagnosis It is indispensable. In any situation, we must always weigh the benefit to be gamed against the possible hazard. This decision must always remain with the accending pliysician for it is he who must decide what is best for the patient. The health and welfare of future generations must depend on the health and welfare of the generation before us. An indirect benefit of the Conference will lie the dissemi. nation of accurate informauion on these problems to the public, many indivduals of which have developed an almost psychiatrical fear of radiation. They do not know what they fear. They are just afraid. The time has come when we must help them realire that this is the nuclear age and that they must learn that they can Ine in a safely, both physically and emotionally. Our goal is to heep all sums of controllable ionizing radiation to a minimum so that we may enjoy the benelis and the developments afforded by the harnessing of nuclear energy. This applies to ionizing radiation for medical use as well as for other purposes. As a guide, 1c might keep in mind that no matter what the gonadal dose is from diagnostic examinations, it is too high if it can be reduced. By the same token, let us realize that the gonadal dose from a radiographic txamination of the chest is comparable to about one-fourth the

·viii
Genetics, Radiobiology and Radiology
amount of natural radiation that onc receives on an airplane flight
from St. Louis to Denver. In the discussion of these problems, let
us always try to keep them in the proper perspective,
WENDELI. G. Scorr, M.D.,
Editor

·ACKNOWLEDGMENTS In the publication of the proceedings of the Conference, I am much indebted to my associate, Dr. Bernard Loitman, who ably assisted me in the proofreading, and to my secretary, Miss Barbara Sampley, for her splendid transcribing of the recordings of the Conference and efficient handling of the correspondence. We thank our publisher, Mr. Charles C Thomas and staff, for gerung the material promptly published and for their willingness to accept the contractual provisions suggested try the National Academy of Sciences To Dr Tins Evans and Dr. Hymer Friedell I am indebteri for their suggestions in de eloping the prestam. Above all, I want to thank those geneticists, radiobiologists, and radiologists who made the formal presentations at the Conference and who suissequently were obliged to check their transcrip cron. It was their work that made this volume possible. It has been a pleasure to plan the Conference and to arrange for the proceedings, for throughout we have received the full support and cooperacion of the officers of the National Academy of Sciences National Research Council as well as their Committees on Radiobiology and Genetics WENDELL G. SCOTT, V.D.

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·INTRODUCTION AND PLAN OF CONFERENCE WENDELL G Scott, M.D., Chairman Dr. Scott: It is a pleasure to welcome you on behalf of the National Academy of Sciences-National Research Council and its Committee on the Biological Effects of Atomic Radiation. This Conference is one of three authorized by the Academy Research Council under the guidance of Dr. Hymer Friedell of the Commit. tee on Radiobiology. These conferences are designed to desclop a better understanding of the generic problems arising from the medical use of ionizing radiation among the geneticists, radiobiol. ogists, and radiologists. They are to be informal forums for the exchange of ideas and Inowledge between these groups about pos. sible radiation hazards and their control in the practice of medicine. The program for the Conference is divided into two sections. The morning will be taken up with a discussion of the fundamentals of radiobiology and genetics. This is designed primarily for the edification of the radiologists They are deeply interestcul in the newer concepts of the effects of radiation on biologic proc. esses in general and in particular the effects on the genetic mechan. ism They are interested in the practical applications of them in the medical use of ionizing radiation and will want to discuss them and to ask questions This is to be an informal conference for an exchange of knowledge that can be of mutual help The afternoon session will be detased to the climcal problems of hoy to minimize the radiation genetic effects in the daily work of the radiologist The program will be opened by Dr. Titus Evans, Head, Radiation Research Laboratory, College of Medicine, State University of lona He is a member of the Committee on Radiology of the Academy Research Council and will serve as Moderator for the moming session

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·CONTENTS MORYIXG SESSION Moderator: 1 ITU's EVANS, PhD. FUNDAMENTALS OF RADIATIOX GENETICS 1. INTRODLCTION AND PLAN OF CONFERENCE Wendell G. Scott, MD Professor of Clinical Radiology Washington Unnersits School of Medicine St Louis, Missouri 3 2 SIT AND MECHANISM OF Radiatio Action (CEILI LAR, HISTOLOGIC AND SYSTEMIC). Titus Evans, PhD Head, Radiation Research Laboratory College of Medicine, Scale I'Rioruyol lona lona City, lona 17 3 MECHANISM OF RADIATION DAVACE TO LIVING TISSUE. George H Mickey, PhD Chairman. Dept. of Zoology, Physiology and Entomology Louisiana State Inversity, Baton Rouge, Louisiana Discussion 25 28 4 FACTORS AFFECTING RADIATION-INDUCED MUTATION RATES Irwin Herskoniu, PhD Associate Professor of Biology, St Louis L'niversits St Louis, MISSOUTI Discussion 38 5 RADIATION INDLCED GENETIC DAMAGE IN MAVVALS. 1 L Russell, PhD I'rincipal Geneticist Blogs Devision Oak Ridge Wational Laboratory Oak Ridge Tennessee Discussion 15, 49, 52, 51 . XII

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·Genetics, Radiobiology and Radiology 91 2. A TRIAL, BALANCE OF THE RESLLTS OF CLINICAL. EXPOSURE TO JOVIZING RADIATION Theodore P Fberhard, VID Member, Xational Commision on Radiation Protection Department of Radiologs, St Joseph Vlerc, Ilopital Inn Arlont, lichigan 101 3 APPLIED RESEARCH TO DIVJIVISH MEDICAL-DXTA1 RADIATION HAZARD Daud Couid. 11 Professor and Head, Department of Radiology Cpiversity of Arkansas Viedical Cenuti Little Rock, Ashanay 106 4 GONADAL RADIATION RESULTING FROU VARIOUS DIAGNOSTIC RADIOLOGICAL PROCEDURES Fred Jenner Hodges, VID Professor and Chairman, Department of Radiology University flospital, Ungversity of Michigan inn Arbor, Michigan 5 RADIATION REDUCTIONS OBSTETRICAL RADIOGRAPJIY. Sobn A Campbell, >> Professor and Chairman, Department of Radiology Indiana Chersite Vedical Ceniti, Indianapolis, Indrana 6 SUMMARY OF CONFERENCE W REVARAS ON THE GENETIC FLAZARD OF DCVOSTIC RADIOLOGY AV MEANS FOR REDUCING IT Paul C Jodges, D Professor and Chairman, Department of Radiolog C'nisersity of Chicago, Chicago, Illinois 127 GENERAL DISCLSSION 132 INDEX 113 ·xiv Genetics, Radiobiology and Radiology 56 6. ICCUMULATIVE DOSE CONCEPT Arthur B. Smith,..D Radiologist, Department of Radiology Research lfospital, Kansas City, Missouri Discussion 58 59 7. SomF GENLRAL ASPECTS OF THE Dose RFsl'OX42 CURVE AND Iis SIGNIFICANCE Ilymer Friedell, M.D. Director, Department of Radiology University Hospitals of Clevcland. Clevclan, Olie Discussion 69 71 8. POPULATION ASI'I CTS: HOW TO ASSESS THE IMPACT ON FUTURE GENERATIONS or AN INCRFASED MUTATION RaTF; How DAVAGE MIGIT BE DISTRIBUTED IN TIME; EXTLNT or UNCERTAINT) or PROMLUV James F. Crow, l').D Professor, Department of Genetics University of Wisconsin College of Agriculture Madison, Wisconsin Discussion 79 81 9. DiscusSION OF LEUXFMIA AND RADIATION Austin M. Brucs, V 1. Senior Biologist and Director, Biological and Meclical Rescuch Argonne National Laboratouies, Lcmont, Illinox GENERAL DISCUSSION 81 AFTERNOON SESSION Moderator: WENDOLI G. SCOTT, M.D 11. THE PROBLEM OF REDUCING RADIATION GENETIC EFFECTS IN THE MEDICAL USE OF X-RAYS 91 GROWTII or DIAGNOSTIC Rapiot OGY AND MAGNITURI OF PROBLLM. Wendell G Scott, A.D. Professor of Clinical Radiology Washington University School of Vedicine St. Lous, Missouri ·Genetics, Radiobiology and Radiology 91 2 TRIAL BALANCE OF THE RESULTS OF CLINICAL EXPOSLRE TO LOVIZING RADIATION Thcodore Eberhard, VID Member, National Commission on Radiuina Protection Department of Radiology, St Joseph Mercy Hlapital Ann Irbor, Vichigan 101 3 APPLIED RESEARCH TO DIMINISH MEDICAL-DENTAL RADIATION HAZARD David Gould, VID Professor and Head, Department of Radiology L'anverity of Arlansas Kledical Center Liste Roch, Arkansas 106 4 GONADAL RADIATION RESILTING FROY VARIOL DIAGNOSTIC RADIOLOGICAL PROCEDURES Fred Jenner Hodges, MD Professor and Chairman, Department of Radiology l'outcrsity Ifoxpucal, Chiserssts of Vichigan Ann Iror, Vlichugan 111 5. RADIATION REDUCTION OBSTETRICAL RADIOGRAPELY John A Campbell, VD Professor and Chairman, Department of Radiology Indiana University Vedical Center, Indianapolis, Indiana 6 SUVVARY OF COVFERENCE IT REVARAS ON THE GENETIC HAZARD OF DIAGNOSTIC RADIOLOGY AN MEANS FOR REDLCING IT Paul Hodges, in Professor and Chaitan Department of Radınlom L'nnessics of Chicagn, Chicago, Illinois 127 GENERAL DISCUSSION 132 INDEX

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·GENETICS, RADIOBIOLOGY AND RADIOLOGY

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·MORNING SESSION
FUNDAMENTALS OF RADIATION GENETICS
Moderator: Titus Erans, Ph.D.

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·SITE AND MECHANISM OF RADIATION ACTION (CELLULAR, HISTOLOGIC AND SYSTEMIC) Ву TTUS EVANS, PhD. Hrad Radiation Research Laboratory College of Medicine State Untersihi of toda lou a Lily, lova I. ain between the pure scientist on the one hand and the man on the other. My tall will be introductory, chrecreto the genetic ists to show them that the radiologists Inow somethmg about radiation effects, and to the radiologists so that they can sce the background for what the geneticists biase in mind. I would hle ro remind the geneticists and radiobiologists that our radiologists are busy clinical physicians. They are worried about patients, budgets, personnel, gastro-intestinal examinations, etc. We have taken them away from this enyronment for a betle br. We will leact them into the scienufie discussions slowly ans is wmething as ex clear, we wish to have them ash questions. I will resten briefly some of the basic principles o radio boly The radiologists have the responsibility 10 explain to pxeple s lo acome to them and say, for example, "Yie had trouble burung technicrans They're scared no death of radianon" What Alus be tell thema A fes days ago in the bus, 1 heard a man say. te. I real in the paper this morning that the sun is gong to trracliate us all so death" With so many lay people being concerraedd alssat radiation, we have in be alle o explain its effects in getieral terus Three or four years ago, I attempted to meet this gira ileti by making some simplified charts. If someone says, "I'm afraid to oth with ridation," you can put out to him that he uses in a radiation endronment, It'e frase radioactile materials in our bodies $0, it isn't a question of 3

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·Genelis, Radwbrology and Radiology avoiding radiation. It's a question of avoiding excess amounts of more than acceptable levels (Fig. 1). The second slide tahes up the questions of amount of boly exposed to radiation (Fig 2). Even today, some people in adding up the exposures to a person will include the exposure from a dental a-ray, covering one square inch of the body, to whole body cxposures and try to coine up with a figure for the total accumu. lative exposure. In one sense, this is entirely wrong inasmuch as exposure to the whole body is more serious than exposure to various parts alone As long as an organ is protected with lead, It will not suffer a direct effect from the radiation. On the other hand, we have to realize that something more is involved than the Volume dose We must try to avoid, as much as possible, excessive whole body irradiation because it affects all of the bone marrow and other regenerative organs (Fig 3) The severity of rachation damage is related to the milensely of the exposure lu the investigations of McComb and 1000) AN EXPOSURE WHICH WOULD BE LETHAL IF RECEIVED WITHIN A FEW MINUTES SOO WOULD RESULT IN ONLY GRADUAL INCREASE IN OLD AGE SYMPTOMS HF RECEIVED OVER A YEAR OF EXPOSURE 0 Doroge required to product skin naction of expotur Received during short treatment Total damage quired to produce tone erfect pot faceived doily for the works th, demonstrates that some covery from irradiation effect may take place in time T! - Serenity or damage is related to be becalit of be exposure Figure 3 ·4 Genetics, Radiobiology and Radiology BIOLOGICALLY EF- 1000.00 >Exposure of small areas for treatment FECTIVE EVEN IN SINGLE EXPOSURES 100.0 10.0r >Exposure of parts of body during fluoroscopy and photofluoros- Copy NOT HARMFUL IN SINGLE OR IN- 1.0r FREQUENT EXPOSURES 0.1 >Exposure of parts of body during chest X-ray, etc. >Possible exposure of X-ray and radium workers ACCEPTABLE DAILY EXPOSURE 0.01 r 0.0011 NATURAL LEVELS OF >Radium in body >10 and C in body DAILY EXPOSURE 0.0001 >Cosmic radiation Figure ! LOSS OF HAIR EYE DAMAGE SORE THROAT SKIN DAMAGE CHEST PAIN LOSS OF APPETITE - NAUSEA BLOOD DAMAGE DIARRHEA STERILITY DEATH Fig. 2-Severkty of damage is related to the region and amount of the body ensed rigure 2 ·Genetics, Radiotrology and Radiology avoiding radiation. It's a question of avoiding excess amounts or more than acceptable levels (Tig. 1). The second slide tahes up the question of amount of body exposed to radiation (I'ig. 2). Even today, some people in adding up the exposures to a person will include the exposure from a dental x-ray, covering one square inch of the boxy, 10 whole body cxposures and try to come up with a figure for the total accumt:- laine exposure in one sense, thus is entirely wrong inasmuch as exposure to the whole body is more scrious tlian exposuic to sarious parts alone As long as an organ is protected with lead, It will not suffer a direct effect from the radiation. On the other hand, no have to rcalize that sometlung more is involved than the volume close We must try to assil, as much as puissibile, excessive whole body irradiation because it affects all of the bone marrow and other regeneratie organs (Fig 3) The severity of radiation damage is related to sho intensity of the exposure In the estigations of McComb and 1000 11 AN EXPOSURE WHICH WOULD BE LETRAL IF RECENYED WITHIN A FEW MINUTES 300 WOULD RESULT IN ONLY GRADUAL NCREASE IN OLD AGE SYMPTOMS IF RECEIVED OVER A YEAR OF EXPOSURE O Dosage tequired to produce thin TESC tion if epofure received during short treatment 1 Tovel dorazer Qurred to produce some effect. pour und deity for three weeks Shit de montates that some recovery from irradiation effach may the place in the Flc *-Sestiny of usage is related 10 the intentity of the expORUT Figure $ ·6 Genetics, Radiobiology and Radiology Quimby on shin erythema, they found that by fractionating the dose, they could prolong the latent period for the appearance of radiation effects and that more radiation could be given in these fractionated exposures to produce the same effect. It is known from animal experimentation that the effect of dividing the exposure into a number of small ones greatly decreases the acute and also the sub-acute reactions. It may not decrease the delayed effects so much, but it certainly does reduce the more acute reactions, THE MOST SENSITIVE CELLS ARE LYMPHOCYTES OF THE BLOOD AND OTHER CELLS WHICH ARE SIMPLE IN STRUCTURE AND HAVE A SHORT NATURAL LIFE SPAN INTERMEDIATE IN RADIO- SENSITIVITY ARE CELLS WHICH ARE NOT USUALLY WORN OUT SO RAPIDLY AND ARE MORE STRUC- TURALLY COMPLEX MORE STRUCTURALLY DIF- FERENTIATED AND LONG LIVED CELLS APPEAR TO BE RESISTANT BUT WHEN DAMAGED ARE NOT EASILY REPLACED White blood cells Calls of blood vessel wall Bone calls Rad blood cells Nerve cells desse Cells tha line the Intestine Connective besue calls Ropidly dividing Iperm forming cells Figure ! (Fig. 1) This slide denionstrates the response in the diffcrent tissues If we are interested in carly reactions, we will see these in tissues that are rapidly growing, such as the cpithelial cells and the blood cells. Those intermediate in response are the ones that are intermediate in reactivity to things in general, the ones whose life span is longer and so on The ones that are very slou to show any effect are the bonc cells, the nerve cells, etc, as they arc alrcady mature and do not undergo much differentiation or cell division following irradiation. We could spend several hours discussing the law of Bergoni and Tribondean, but in general, I think you would find the statement to hold that those tissues and cells which are going to show a radiation reaction first, are those more often involved with cell division at the time of irradiation.

·Genetics, Radiobiology and Radiology 7 One has to distinguish between ionizing irradiation and ultra-s10let which is not sonizing. Among the various types of ionizing radiation, one has to distinguish betucen low voltage X-rays, high voltage x-rays, beta rays, gamma rays, Isetatron rays, and others that lay people and even the medical students lave heard of, but are not sure as to what they mean. In general, ne have to consider two different effects of quality (Fig. 5). If the 7 Energy absorbed only of face Energy obrorbed over larger volume body of tissue LOV ENERGY X-RAYS ARE LESS PENETRATING MEGR EKERGT X.RAYS AAE MORE PENETRATING «F THE SOURCES ARE WITHIN THE BODY THEN A MAZARD ETISTS AS KOST OF THE ENERGY IS ASSORDED WITHIN THE TISSUE THE RELATIVE BIOLOGIC EFFECTNE NESS OF DIFFERENT RADIATIONS VARIES A650 BECAUSE THEIR ABSORPTION MAY PRODUCE QUITE DISTERENT INTENSITIES OF 109ZATION ALONG THEIR PATNS T. LESS PENETRATING Energy is obsorbed RADIATION REPRESENTS outside living tissue LITTLE MAZARD 1P THE SOURCES ARE EXTERKAL Diplogic Bende forzation mon affective for certain effects Figure 5 energy of the radiation is different, there is a different distribution of the energy in the body. It is pretty difficult to have the same distribution in the boxly wuh low energy x-rays that you have with high energy radiation Los energy X-ray effect is shown, in the upper left, as far as depth dose is concerned You can see that Very little of it gets to the deeper part of the body, ushereas in the case of high energy radiation, the energy is distributed over a larger volume. Thus, you have a different volume dose and a different geometry situation It is only where you have the same ·6 Genetics, Radiobiology and Radiology Quimby on skin erythema, they found that by fractionating the dose, they could prolong the latent period for the appearance of radiation cffects and that more radiation could be given in these fractionated expostres to produce the same cffect. It is known from animal experimentation that the effect of dividing the cxposure into a number of small oncs greatly decreases the acute and also the sub-acute reactions. It may not decrease the delayed effects so much, but it certainly clocs reduce the morc acute reactions. THE MOST SENSITIVE CELLS ARE LYMPHOCYTES OF THE BLOOD AND OTHER CELLS WHICH ARE SIMPLE IN STRUCTURE AND HAVE A SHORT NATURAL LIFE SPAN INTERMEDIATE IN RADIO- SENSITIVITY ARE CELLS WHICH ARE NOT USUALLY WORN OUT SO RAPIDLY AND ARE MORE STRUC- TURALLY COMPLEX MORE STRUCTURALLY DIF- FERENTIATED AND LONG LIVED CELLS APPEAR TO BE RESISTANT BUT WHEN DAMAGED ARE NOT EASILY REPLACEO White blood celli Call of blood vessel wall Bons cofts Red blood cells Nerve cells potente Calls tha ling the Inteihina Connective tissue colls Rapidly dividing sperm forming colts Figure 1 tissues (Fig. 4) This slide clemonstrates the response in the different If we are interested in early reactions, we will see these in tissues that are rapidly growing, such as the cpithelial cells and the blood cells. Those intermcliate in response are the ones that are intermediate in reactivity to thumgs m general, the ones whose life span is longer and so on The ones that are i cry slow to show any cffect are the bone cells, the nerve cells, etc, as they are already mature and do not undergo much differentiation or cell division following irradiation We could spend several liours discussing the law of Bergoni and Tribondeau, but in general, I think you would find the statement to hold that those tissues and cells which are going to show a radiation reaction first, are those more often involved with cell division at the time of irradiation.

·Genetics, Radiobiology and Radiology such as "dominant" and "recessise," etc. Ble inherit from both parents. We inherit to possibilities you might say tsxo comparable genes-one of which you use. The other you simply carry along It is very endent livat some inherited characteristics will show up more often than others In other words, they are the dominant ones. In this diagram, the dominants are capital and the recessite are small letters. Consider t10 individuals, both heterozygous (in other words, there is one dominant and one recessive in each paren) each produce two different kinds of gerni cells one with a dominant, the other with a recessise gene. When typ two dominants come together, of course, the individual is going to have a dominant character It will be homozygous for dominant. There will be no others that are heterozygous. They will appear to be black haired or brown eyed or latever the dominant clar. acter is Que out of the four, if you have enough children (in frui Thes, this holds more definitely) would have the double recessive showing up in the case of radiation effects, you simply are increasing ke races of mutation. You are increasing the frequency with whuc abnormalities or unusual characteristics are produced LIAC radiation itself being in our environment and being in all of us, the occurrence of mutations is a natural one There is a natural mutacron rate for lumans and radiation exposure increases this frequencs So far as I know, and I hase read this in many genetic papers there is no way to determine whether a particular mutation luas been the result of ionizing radiation of the result of some other All sou can tell beseen two experimental groups is that one has a higher frequency than the other. Nor sometimes the dommant character is lethal and will dill hue ollspring either in the Teri earls stages or in later stages of development On the other hand many mor10715 are recessive as shown in the lower right. and such a mutation will not die out right 23:25 In fact, st will not shows up right away and miglit neser show up at all, but continue to be carried unul eventually at occurs in a doulile number or unless 11 cxculls in the alysence of a dominant gene u luck situation would llon it to express itself I believe that these are the important points to know in tall. ing to nurses to techniciatis, or to the public. We do not like the factor ·8 Genetics, Radiobiology and Radiology geometry and the same dose distribution that you can discuss the relative biologic effects of these two different radiations in a strict sense. In a gross way, you can compare them. You can even compare the effects of x-rays with the effects of some internal cmitter like inhalcd radon or some other radioactive material that gets inside the body. If it is an alpha emitter, although the alpha particles would not penetrate the skin, once they're inside and in thic mucosal lining of the lungs, for example, or in the bone mar. row, all of their cnergy is going to be absorbed right in living tissue and is very effective. In the lower right (Fig. 5) is a diagram of a chromosome. Photo-elections possessing cnough energy can plow through tissue or cells to produce ion pairs that are far apart as shown in the uppei onc and in the one just below it, 100 Down at the bottom of the chromosome, arc trachs produced by slowly moving particles which are giving up their energy in a very dense pattern so that several ion pairs may take place in a very small part of the chromosome This makes it morc cffective in some cases, but in other cases, where only one ion is necessary, then the others would be wasted. This is the basis for the relative biological effectiveness of lifler. ent radiations in the strict sense On the other hand, there is the gencral or practical sense of the term in ubul you can compare the relative effectiveness of any type of radiation Thicc is a tendency to differentiate these tho by speaking of the strict deſımtion as relative efficiency and the gross as relative effectiveness I am not sure whether these terms will continue to be used. (Aa) (Aa) TISSUE CELLS A d - GERM CELLS (AA)-Taa)-Ta A) Ta a) POSSIBLE OFFSPRING Tigure 6 Just in case the geneticists do not talk in simple terms, Fig. 6 is to remind the radiologists that we are talking in genetic terms, ·Genetics, Radiobiology and Radiology rather than the genetic or gene mutation probability thenry for the induction of cancer. The genetic tlieory that tumors are the result of somatic mutations, (mutarrons in tissile other than geri tissue) is very popular at the present time. (Fig. 7) Thus demonstrates the effect of licas y irradiation on the epiphysis of a bone As a (inid, this patient was irradiatel for a lesion of the hnee 11 sas known at the time that it would Figure 7 affect the growth of the bone, but in medual practice, one always has to balance the gooxt against the bad That is our problem today--to discuss ways whereby we can reduce the exposure as much as possible to use the radiation in the most efficient way, and, 10 continue 10 tale the great advantages it offers in diagnosis of treatment of human ills ·10 Genetics, Radiobiology and Radiology' idea of trying to settle the scientific facts by public opinion, but scientists as well as politicians have thrown us into this and we have to face it now. We have the problem of trying to talk about technical problems to lay people and it's not casy l»ut we have to do it ourselves or get sonicone else to do it. Now, I would like to discuss briefly the luistoucal develop ment of rachation protection procedures and some of the clinical terms which will be helpful to the geneticists. By an "acute acaction" we mean one that appears rapidly, is very harmful and comes on very soon after a large exposure to radiation. There is colema or snelling which is followel l»y niccrosis or formation of large aicas of dead tissuc. "Erythema" is a reddening of the skin. This biologia i caction was noted in the carly clays cven lclore we lack x-ray closimeters and certainly long before we liad pochet chambers and film badges that nould measure exposures quantitatively. Some of you might be surprised to know how long we have had regulations for (012- trolling radiation exposure. They were started even beloic wc had the plıysical cxposure unit, the "roentgen." Exposures were iegulated in tcums of milliampere-minutes at accutain voltage and with a ccitain filtration. These cxposure times were based on their ability to produce an erythema and so the first espone icgulations ncre in fractions or multiples of crythema units. As the methods of measuring radiation exposure improved the maxi mum acceptable levels of radiation exposure were lowered. Not all of the credit for the lowering of acceptable levels of exposure can be attributed to pressinics from various scienuſte groups or committees. I think that quite a bit of 10 lias licen a logical clevelopment paralleling improvements in the methods of measure. ment. Whenevci it has been found that it would be practical to lower the acceptable immuts, it has been donc. Histologically, when the sun is irradiated with a cuy hcany close, wc sce (1) cpilation, or a loss of the hair follicles, (2) an increase in fibrous tissue and (3) what appears to be a compensalory hyperplasia of tlic epidermis. In many cases we sees, huisto. logically, compensations or overgrowthis resulting from insults The histopathologist kould prolably favor tlic ploysiological ·13 Genetics, Radiobiology and Radiology effect? The interesting thing is that there does seem to be an almost proportional relation between the daily dose and the reduction in surunval time. Fig. 15-Collection of alpha emitters in the lungs. 60 A 4 50 A 401 REDUCTION IN SURVIVAL TIME, % 301 D A 10 جينيفيلبينطيليل 5 20 25 10 15 R PER DAY Fig 16 Effect on lonkesity of the amount of daily irradiation. Figure 9 When a biologist talks about timor production, it has to be understood that usually he is working with a imals of a particular strain Perhaps it is one that has a high frequency of tumor incidence already. It is much easier to produce more leukemia in a strain that already has leukemia than it is in one that is resistent. We are not always very clear to point this out, but it must be lepi in sund. For example, in one expeţiment at 0 dose (these animals ·1 Genelics, Radiobiology and Radiology (Fig. 8) This is an example of a clironic effect resulting from many repeated small exposures. This dentist used his thumb and forefinger to hold dental film for his patients. Today, the well informed dentist does not do this, but years ago protective measures were not taught in the dental schools. We have known about radiation effects since the very early days, yet, somehow, it has not been kept as a consistent subject in the teaching of dental and incdical students We seem to forget about it ruil sonic damage appears, then it is emphasized again. It needs to be given if definite place in the curriculum so it can't be leſt ont. JI Tigure 8 (Fig. 9) Tere is another effect, the delayed effect on trac. tionated exposures of so many roentgenis per day I compleal these figures from my own data and from that of the others on the life span in muce who received different amounts of radiation exposure per day One does not know just where to dratt tfic line, Does it go to zero or is there a threshold above tuch you get an ·15 Genetics, Radiobiology and Radiology STEPS IN ABSORPTION OF RADIATION 0 kation* ALTYD OLUNEECTEO IONIZATION ACTIVATION CHEMICAL CHANGES MONOK M40*7**0 OH-ON-M202 H.0, MO Figure 10 absorption per unit as does the primary events. This carries on to chemical changes in which the processes are spread over a large volume and results in recombinations to produce such toxic materials as hydrogen peroxide and others when a radiation change is not affected very much by protraction or fractionation, we think that this must be related to an early step, such as ionization, or the primary process. One of the biologic effects that seems to fit this condition is the increased frequency of gene mutations. These are inherited changes and you cannot see any chromosome abbera. tions to account for it so we think that it is due to a point mutation On the other land, chromosome aberrations might be due to this primary process or they imight be due to this second one. perhap, a little farther along because the dose effect curve show's a little bit of a threshold Its more S-shaped There is a little more of a change if you fractionate or protract and it is a little more affected by temperature oxygen and other ens ironmental factors ·11 Genetics, Radiomology and Radiology micaris It happened to be exposed to neutrons) there were 37 out of 100 that had one tumor, four that had two. Thus a sinall increase in number of tumors per animal following irradiation was not very significant. This strain was susceptible to lung tumors If you considered lung tumors alone and if you considered only those that appeared early in the life of the animal, there appeared to be a great increase in the incidence of lung cumors in the irra. diated animals But when you consider the data foi the entire life span of the animal, there were actually no more tumors in the irradiated group than in the controls. The tumors came on earlier and had I stopped the experiment in three months, I would have concluded that the induction of tumors was much greater, when actually it was an acceleration. Also you will hear statements that the production of tumors is directly proportional to dose and this again is all right in the sense in which the biologist However, if you carry it to the extiemc, it doesn't hold because at the high close of 1.4 r. per clay, only fifteen of these animals had tumors where as the controls had 37. Just to look at the data like that you would say, "Well, radiation wouli icduce the number of tumors." It didn't. What it did was to kill them before they had time to develop a tumor, so these things can't be carried to an extreme when they talk about pioportionality The last diagram (Fig. 10) is designed to demonstrate the mechanisms of how I think radiant energy produces Inologic effects Starting at the left, I have three ordinants One, tlie amount of energy absorbed per unit volume (energy-ergs per cubic mm); the next ordinant is duration of time and the hori zontal one, the relative volume effect. The first thing that happens is that a ploton knocks out an election and this photocie tron then produces ionization This initial event is one whuch repre. sents the alısorption of a lot of energy in a very short period of time but doesn't alfd, c a very large volume The next step is that each of these sons has the ability to mteract with other atoms, perhaps to activate them to cause the clections to move with a little lugher velocity so that iadkals may be produced this acti. vation or excitation process lasts longer and spreads over a larger volume of protoplasm although it doesn't represent as much energy ·MECHANISM OF RADIATION DANIAGE TO LIVING TISSUE Лу CEORGE H. MICKEY, Ph.D. Charlian, Department of 7onleg. Physiology and Fotowoln Sana Sialen TSITY Baton Rouge, Louisiana I should should like to preface my remarks by stating that although I am a geneucist, I think that radiology has been a great boon 10 mankind The judicial, proper, and careful use of x-rays are highly desirable. lly own interest in the effects of radiation go back for many years - sume thirty years now. I was associated with Muller and Patterson and some of the others who were working at the Unisersity of Texas in the early days. In lack, 1 used the same x-ray machine that Dr Muller did when he irradiated the flies in 1937 and came up with his famous paper. Genella cists have not always been as cognizant of the dangers of radiasion as they appear to be at the present time I remember back in the early 1930s, one of the graduate students at the Univer. sity of Texas went into the attic where this x-ray machine was located It was not shelted by lead or anything I was sitting out in the middle of the attic room where 1 nas operated. There was a little lead booth over 181 the corner where the operator sat and watched the instruments Ds. Patterson had some flies unler the x-ray beam that he was busily irradiating This graduate student happened to come up and found him sitting there is the tinprotected x ray tube, and he said, "Why, Dr. Pat, don't you 1110w what this will do to you" And he said. "Why, sure, but Im all through anyway" Irradiation damage is always a ualculated rish. As Dr Evans said, you always have to compare the expected damage 10 the expected good which will result from it My interest, of ·16 Genelics, Radiolrology and Radiology This brings us to those effects which are definitely altered by the environment, such as the amount of oxygen, the temperature, ctc. They probably act in a later process more like the chemical changes produced by other toxic agents in the body. I could go on and on, but I think I've clone enough to intro. duce Dr Michey's talk on "The Mechanism of Radiation Damage to Living Tissite." FIGURE REFERENCES Figures 1. 2. 3. 1 5.6 and 9 arc from a paper entitled Effect of lonizing Radiation on Mammals and its imphcations for facelerator Sheldmy bs I ( Frans. at Conference on Shieldmg of High-Energy Accelerators, Neu York City, April 11 to 13, 1957 Figure 7 1x from an article bs Frantz, C H, entitled, "Extreme Retardation of Fpt. physcal Grouth fruin Roentgen Irradiation," from Radiology. 55 720-721, 1950 Figure 8 is from an article by Hultberg, Sven, Larrson, L I. and i hund, I. cntitled Some cases of Radiation Injamin Radiology Il'ork, from fata Radiologica, 33 376. 1950 ·19 Genetics, Radiobiology and Nadinlagy speak of as somasic pr pathologic damage. Accoring to this classification, she genetic damage may be defined as changes wtonght in the gerni cells either in the mature sperms from the male or the mature engs from the female or in the earlier germ cells in the ponads which grie rise to these delinitive günetes. Even here, sensitivity varies according to the stage of deiclop ment of the germ cells. For example, the sperinatiils, that is, those male germ cells which have undergone the several mitotic divisions and the two meiotic or maturation divisions and are undergoing the metamorphosis into the mature sperm, are considerably more sensitive than some of the other stages Tliese alterations in the germ cells, whether they are gene mutations or chromosomal aberrations (that is, the chromosomes are brukcii and reumted in various ways), can be transmitted to the progeny and thus are inherited or passed on to future generatim. Many different kinds of muations are known from experi: ments with a great variety of plants and animals. For example. we may speak of dormant and recessive mutations, as has already been pointed out to you, affecting visible characters or traits in the individuals. These are commonly referred to in genetics as isibles in other words, a kind of a mutant that slim's up as a morphological or a physiological change in the organisin, we call aussble They may be further characterized as either sewlinked or autosomal The sex-anled mutations are the result of changes in genes carried on the X chromosoincy or the sex chromosome, whereas, the autosomal mutations ate in genes which are located on any of the other chroniosomes besides the sex cliremnosumes Then, of course, there are the mutations which liave been referred to as lethal mutations That is, those which interfere so drastically with the normal development or functioning of the (ells that they result in the death of the organism. Most of these lethal mutations have their effect early in the life cycle. That is, in mammals it might occur in the egg or in the emiryo or in the fetus, or if we're talking about some other organism, an insece Int example, it might excur in the larvae or in the pupae or esen 13 the adult Most of them have early effects These, too. we may ·18 Genetics, Radrobiology and Radiology course, has been in the basic, or fundamental lviological aspects of the problem tlle way in which these comizing radiations will affect the cells. As Dr. Evans lias already cxplained, ionizing radiations damage liying tissue regarlless of the someo, wiretirer it be external or internal, and regardless of the specific kind, whether A-rays, gamma rays, alplia or beta particles, protrons, Deutions or cosmic rays. Even ultra-violet is damaging to living tissue if it eaches that living tissue. As you know, the ultraviolet is not ionizing radiation, but it does excite material, and it has low energy. It has a long wave length and it doesn't pene. trate very far. Therefore, it affects only tlie surface tissue of the skin. But if one gets the ultra-violet to living cells, say for example in tissue culture, and irradiates them, one can see the effect of it. It is very powerful in fractionating or fragmenting the cliromosomes of the cells Ultra-violet can do this if it reaches these chromosomes. There are many factors, some of which will be discussed by Dr Herskuwitz, that control the degree of damage. Among them, of course, are innate or genetic differences in the biological organ. isms themselves. In other words, even among luman beings you will find some people that are far more susceptible to the effects of x-rays than others; 600 r of whole body irradiation delivered in a single dosc will result in the death of practically all the invididuals that icccive such a dose, whereas, 150 r. of whole body irradiation is considered to be the LD 50 That is, it will kill approximately 50% of the individuals that receive such a whole body irradiation at a single close Furthermore, various tissuics, again as Dr Evans pointed out, will exhibit different sensuivities to the same amolint of irradiation The blood fornung elements are perhaps the most sensitive with as little as 25 r of whole body irradiation resulting in a cletectable change in the blood picture. Whereas other tissues can withstand a great deal more with no apparent damage, for example, brain, liver, bone cells, cic. - not the red bone marrow but the bone cells themselves Radiation clamage has been classified in two general rate. One of these we call genetic damage and the other we gories ·19 Genetics, Radiobiology and Radiology speak of as somatic or pathologic damage faciling to this classification, the genetic damage may be defined as changes wrought in the germ cells either in the mature sperus froin the male or the mature eggs from the female or in the earlier germ cells in the gonads which give rise to these definitive gametes Even here, sensitivity varies according to the stage of driclop ment of the gern cells. For example, the spermatids, that is, those male germ cells which have undergone the ses cral mitotic divisions and the two meiotic or manration divisions and are undergoing the metamorphosis into the mature sperm, are considerably more sensitive than some of the other stages. These alterations in the germ cells, ai liether they are gene mutations or chromosomal aberrations (that is, the chromosomes are broken and reunited in various ways), can be transmmucl to the progeny and thus are inherited or passed on to furture generations. Many different kinds of mutations are down fron experi. ments with a great variety of plants and animals For example, we may speah of clnminant and recessie mutations, as has already been pointed out to you, aſſecting usible characters or trans in the inducials These are commonly referred 11) in geneins as visibles In other words, a kind of a mutant that shows was a morphological or a physiological change in the organıyın, we call a visible They may be further characterized as either sex-Imhed Or autosomai The sex.linked mutations are the result of changes genes carried on the X chromosomes or the sex chrom. osome, whereas, the autosomal mutations are in genes which are located on any of the nther chromosomes besides the sex cliromo. Sesties Then, of course, there are the mutations which hase licen referred to as lethal mutations Tliat is, those which meriere so drastically with the normal kleselopment or functioning of the cells that they result in the death of the organism Most of these lethal mutations have their effert early in the life cycle Thas is, in mammals it might occur in the egg or in the embryo or in the letus, or if we're talking about some other organism, an insect for example, it might occur in the lars de or in the pupac or even in dhe adni Vinst of them hase carly effects These, too, we may ·20 Genetics, Radiobiology and Radiology designate as sex-linked or autoscual, depending upon the chrom. osomes which are involved. Since by far the great majority of mutations are recessive, they may be transmitted to the progeny of the individual in whose germ cells they occurred and may be carried in the licterozygous state. That is to say, these so-callel recessive genes are covered up or hideen or obscured by the fact that there is a normal gene, an allelic gene which is normal and this normal gene can perform the function satisfactorily so that the recessive genc does not express itself phenotypically. They may be carried for many generations before they make them. selves known or become expresse«l since these genes must be disseminated in a population sufficiently to have two such hetero. zygous individuals mating before the genes become homozygous and chus, show tip This is why the germnal changes resulting from radiation may exist in the human population for as long as 500 to 1,000 years before cropping out. This is one reason why it is ridiculous to looh at the progeny of irradiated people such as those of Hiroshima and Nagasaki and conclude that because few mutations appear in the first or second generation, that little or no damage has been done. Likewise, it is folly to conclude that since no monsters are observed in one or two children of a woman who has been irradiated with X-rays to induce ovulation, that 10 mutations have resulted from the treatment. This is a false as. stumption. In the first place, certainly you do not expect a mon. ster in all genes of all cells and therefore, in order to detect them, you require a large number of progeny Furthermore, it is possible that a few of these mutations that may have resulted will be letlials which will eliminate the individuals before birth, and you are simply not aware of it. Tlus point would bear fur. ther cliscussion, but that is all the time I can spend with it at this moment We have mentioned the chromosomal abnormalities By these we mcan that the chromosomes within the nucleus are broken and they may reunite in the original way without any genetic effect or they may reumte in many different ways, producing abnormalities or aberrations When they fuse together in ·21 Genefies, Radiobiology and Radiology certain fashions, they produce the line of aberrations that we refer to as translocations – that is, the part of one chromosome broken off and tied onto another; or interious, which means that a portion of the chromosome is broken out and tumed end for end and tied back into the chromosome again; deletions or deficiencies, wluch mean that parts of the chromosomes are broken out and lost; or duplications wherein portions of the chromosomes are found more than the number of times expected Tlus constitutes a whole area of study in itself; that is, chrom. some breakage and reunion and so on, and the facis imolsel here are quite intricate It might be that a linie later (>, shall hare the opportunity to mention some of these factors, fut at this stage 1 shall pass over them quickly. I should mention that the word "lilation" is used in a rather loose sense by the geneticists. We use the word line as a verb and as a tour fl'e also use it in the sense to inean a point mutation or gene mutation, in which there is a change in the molecules that constitute a gene – that is, a point nntation Or We also itse it in a broad sense to include the chromosomal aber rationis, because the expressed effects in an individual sometimies cannot be distinguished between a poine mutation and a chromosomal aberration Oftentimes when the chromosomes are rearranged, we have what is known as a positive effect and this effect resembles that of a gene mutation Many of the so-called dominant mutations and also many of the lethal mutations are the result of chromosome breaks Those are less likely to sunne, that is, they are apt to be eliminarea from the population more rapidly than the gene mutations are For instance, a sex linked lethal mlitation, even if recessive, will be eliminated in a male that recerles such a geste since the male has only one X chromosome and has no normal counterpart in carry the indivuluaj through Thus, sexual reproxiuction series in part to prune mu such lethals Let tis consider neu the somatic or pathological changes, those alterations Oxcurring 183 cells of the body outside of the gonads in any of the tissues other than she gonadal tissue, As ·22 Genetics, Hadiobiology and Radiology pointed out by Dr. Evans, these are most likely to be expressed in tissues that are growing rapidly in which the cells are undergoing rapid cell division. This is clue in part at least to the fact that the broken chromosomes in sex cells causc irregularitics in the distribution of the genes and chromosomes to their daughter cells, thus creating the c!uplications and deficiencies which wc mentioned earlier, resulting in the loss of some vital functions. Tlıcy can no longer carry on normal metabolism. It is true that chromosomes can be broken and chromosomal abnormalitics can occur in so-called resting cells; that is, cells which are not rapidly dividing. It is true that these breahages can oxcur in such radio. resistant cells as nerve cells or bone cells or any other non-clividing cells in the body, but as long as these cells do not divile, all of their genes, or cssentially all of them are retained in the same cell and can continue to funktion properly even if a necessive point mutation or gene mutation is produced. This mutation is likely to be obscurcal or hidden lyy its normal allele in that same cell smce these cells are diploid, that is, they have two representatives of cach chromosome and the probability of producing identical mutations in both homologous chromosomes simultaneously is practically nil. However, if such a cell subsequently divides, even weeks or montlis or years later, the damage can become evident. This explains, in part at least, one of the most insidious fcatures of radiation damage, that is, the delayed effects, the latent period The delaycl cffects of irracliation have been known for a long time. Often it may be two to twenty years after treatment that cancer or leukcinia results from evessiic treatment. A feu cases have been recorded in wuch a delay of as much as forty years has been observed. As to the mechanism by which living cells are damaged, we may classify it in the categories first, the direct effect, and secondly, what we ca}l the indirect effect The direct effect means that an ionization has occurred within the molecule of the gene or <hromosome and results in a chemical change. These clirect luts are more likely to result from heavy particles suicio as alpha rays and neunions and so on.

·23 Genetics, Radiobiology and Radiology The indirect effect results when ionization occuits in the immediate vicinity of the cliromosome or gene, resulting in the formation of charged particles or free radicals and these in turn set up a chain of reactions which eventually in olie the genes or chrom. osomes within the nucleus of the cell. Such changes must be considered genetic, too, although not in the same sense that we mentioned earlier, since they are not in the germ cells and cannot be transmitted to offspring, at least in organisms which reproduce sexually; although it is possible, of course, for somatic mutations to be transmitted in such organisms as plants where the germ cells are produced on any branch of the plant. They are genetic in the sense that the hereditary units of the cell (that is to say the chromosomes and the genes within the nucleus) are invold Exposure of the body to the maximum permissible dose of radia. tion, which is.3 r. per cel, clirectly disrupts about three hundred molecules in each of the one hundred forty trillion cells in the human body. A dose of 1,000 r., which would kill a human being, duectly disturbs only about one molecule in ten million, Obviously, the changes inducedi among these relatively few mole. cules must become enormously amplified. How does thus come about? Well, se do not know the precise answer to this ques. tion, but we do Inon the general pattern of radiation damage in cells The cells in the body are mainly water, and it is in the water that the primary effects of radiation take place. It is largely concerned with the production of free radicals. When water in the cell is acted on by radiation, a small fraction is decomposed! mto extremely reactic fragments called free radlıcals which read. sly interact to form peroxidles and other celt poisons. These peroxides as well as many other decomposition peroxides can move around for a short while tintil they alter a receptive molecule. Among the most sensitise substances in the cell are enzymes which are essentially large protein molecules, and one enzyme molecule modified may transform a 100,000 or wore molecules wluch are necded for the continuation of the metabolic activi. ties of the cell Consequently, we have here one of the necessary multiplication mechanisms for transforming a relatively small radiation effect into an eventual observable injury in the ·22 Genetics, Radionology and Radiology pointed out by Dr. Evans, these are most likely to be expressed in tissues that are growing rapielly in which the cells are imdergoing rapid cell division. This is due in part at least to the fact that the broken chromosomes in sex cells cause irregularities in the distribution of the genes and chromosomes to their daughter cells, thus creating the cuplications and deficiencies which we mentioned carlier, resulting in the loss of some vital functions They can no longer carry on normal metabolism. It is true that chromosomes can be broken and chuomosomal abnormalities can occur in so-called resting cells; that is, cells which are not rapidly dividing. It is true that these brcalages can occur in such radio. iesistant cells as nerve cells or bone cells or any other non-clividing cells in the body, but as long as these cells do not divide, all of their genes, on essentially all of them are retained in the same cell and can continue to function properly even if a recessive point mutation or gene mutation is produced This mutation is likely to be obscured or hidden by its normal allele in that same cell since these cells are diploid, that is, they have two representatives of each chromosome and the probability of producing identical mutations in both homologous chromosomes simultaneously is practically nil However, if such a cell subsequently divides, even wechs or months or years later, the damage can become evident. This explains, in part at least, one of the most insidious features of radiation damage, that is, the delayed clfccts, the latent peuocl The delayed elfects of irradiation have been known for a long Often it may be two to twenty years after ticatment that cancer ou leukemia iesults from excessiic cica ment. feu cases have been recorded in wluch a delay of as much as forty years bas been observed. As to the mechanism ly nhuch living cells are damaged, we may classify it in two categories: first, the direct effect, and secondly, what we call the indirect effect. The direct effect means that an ionization las occurred within the molecule of the gene or cliromosome and results in a chemical change. These (lirect hits are more likely to result from heavy particles such as alpha rays and neutjons and so on. time.

·Genetics, Radiobiology and Radiology also been studied) it it indicated that there is no threshold level helos which mutations cannot ikcur. The print mirations are directly proportional to the dose recented, whetlier it is in (rac. tronated doses or whether it is in a single rose, Recent studies suggest, although conclusive evidence is 1900 yet available, that perhaps the same us true even for somatic tis. sues. If this is true, it means that no cell truly rechters from a dose of radiation, somatic or germinal. While a cell may seem to recover, there is an irreversible elfect on the cliromosomes and genes As in the case of hereditary traits, these somatir mua. nions may tile many cell generations of a given ce}} rype ro mani. jest themseh es. Sometimes the mutations may conſer in the affected cell and its descendants the property of more rapul grossth than their neighboring cells Such cells may multiply rapidly, apparently not restrained by influences which inhibit the gronth of normal cells As a resule, the continuing growth becomes abnormal and is classed as (arceraus. Wlicte white blood cells are inoked, of course, we speak of it as leukemia. In many cases the effects of radiation are produced in top eraton ish dastulerances in braly funct in general One of these disturbances, the hormonal inbalance, can in itsell aid and abet the cancer producing elfects of radiation. This of conirse is an udirect effect It does not appear to be the direct result of irradiation but it is tied in u2th it For example, in mice as locale as 50 r to the gonads depresses the proxiuction of the sex hormone This in w stimulates the patuitary to form excessive amounts of the gonal stimulacing harmone and in such mice the incidence of tumor is raised considerably There are many other p93145 which I should like to touch upon, but I am sure that I have used all the time allotreci to me Dr Paul Hodges I hase one question I would like to ask Jou mašle the sialement, I beliese, that it is possible for tumors to be produced as long as forty years after irradiation that are traceable to that ittadiation What proof is there for thai? How (an one trace an induidual tunor back that fat? Dr Slicker The case that I'm thinking about is reported Ixx the doctors. Koman who was irradiated on the ship for a ·24 Genetics, Radiobiology and Radiology cell. Sunilar analyses can be applied to single genes since these hereditary units presumably function through the production or elaboration of enzymes. Thus, radiation can harm cells by pro. ducing changes in the cellular environment. The cells are bathed by solutions from which radiation produced activated products reach and damage them. The poisonous product re. leased by radiation-killed cells can circulate in the blood to other tissues; so, although we do ordmarily invision the damage to be directly on that tissue which has been irradiatod, nevertheless this radiation damage can spread to a certain extent through the transportation of these poisonous toxic substances from the point of damage to other portions of the body The response of tissues depends very much on the rate of delivery of radiation. The short range effects of radiation from sources as gamma rays, x-rays or beta rays are dependent upon the intensity of irradiation and the duration of exposure. Somatic damage to cells other than the germ cells may be repaired in part of broken doses or fractionated doses are given, but this does not apply to mutationis produced in the germ cells Tliesc inutations are not repaired. Once they are produced, they remain and they can multiply or reproduce themselves in the altered states must as well or essentially as well as they did in the original state. For here the mutation rate is essentially directly proportional to the dose regardless of the rate or intensity. The dosage is cumulative This is why it is so inportant to slueld or protect the gonads from radiation Furthermore, experimental studies with many different organisms indicates that there is no threshold level with respect to these mutations That is, there is no level byclon which danı. age is not induced. Now I realize of course that chars statement cannot be absolutely and unequr ocably established, but particu. larly in those organisins where we can carry on extensive experiments, and working with low levels of radiation you have to have a very extensive experiment in order to detect the difference between that and the controlled rate, These have been carried out primarily in Drosophila In these organistis (incidentally, in rather rapidly producing organisms such as bacteria they have ·Genetics, Radiobiology and Radiology 27 through about ten years of study at the University of Indiana with him We will now hear from Dr. Irwin Hershoritz on "The Biological Factors Affecting Radiation-Induced Mutation Frequencies" ·26 Genetics, Radiobiology and Radiology lesion that showed immediate effects of over-irradiation. This appeared to heal but at that same site (and of course this is argui. able whether it was actually the result of it) a tumor did occur ſorty-nine years later. This is one case. Dr. Paul Hodges: This is a shin tumor related to a shin damage. Dr. Afickey: That is right. Dr. Hymer Friedell: I'd like to point out that aquestion. ably a tumor appeared, and I don't think there is any reason to challenge this, but to interpret that tlus necessarily is due to somatic or genetic changes in the cell is very difficult because you can injure the cells in other ways and produce tuniors There- Core, all that one could really say is that injury occurred and a tumor resulted. Whether this is due to the specific effect on the genes, the somatic genes, or some somatic effect of some other hand, I think would be very difficult to establish Dr. Mickey. I readily admit this There is no question but what there are many factors which enter into the picture, but I think that the so-called mutation theory of cancer explains only one type of «lamage which may result in cancer. 1). Evans In case you've been wondering why I speak to George (Dr. Michey) so familiarly, he and I were studients bach in Baylor University many years ago, and I also becanic acquaine. ed with Dr. Muller, although I didn't work with him Ilnet of his work and I think this influenc el any interest in radiation biol. ngy a great deal in fact, I was myitel as a student by a friend of imine who w.35 a doctor to attend a meeting of McClemnan County Medical Society at one time at which Dr Muller talked about his experiments. This, I think was in 1927, or 1926, and he told the racliologists at that ume that racliation would affect the genes and rould increase the mutation frcquena y and that racliologists should be very careful about it Of course, there was a trench)- cous discussion thereafter Points were lyrought out that there was quite a difference in fruit flies and humans and so on. But it was very interesting that many of the points that might arc sulj being discussed today Some with more assurance and some with less assurance. Dr. Muller has also influenced our next speaker, ·29 Genetics, Radiobiology and Radiology single file. like the lieads on a string. There are probably als many as 2,000 genes along the length of an aicrage luuman chromosome Since the chtomosomes iv all cells but the inature egg and spesin occur in paits, so do the genes they carry. Typical chromosomes hase three parts the ends, two arms and a specialized region that is needed for transporting the chromosome into a daughter cell after division. Iny permanent loss or change of these parts ssill woke the genes located therein and is called a mulation Usually only one chromosome tahes pant in a mutation lule the others present are unaffected. So, in a cell with paired chromosomes an unchangeel chromosome with its unchanged genes is usually present when the other member of the pair lias inutated Permanent changes that involve whole sections of genes can result after the chromosomes are broken in one or more places These broken ends can join in other brokes ends un paits, each anios being permanent once it occurs 1f the broken ends from the same break rejoin, there will be no change in the number or position of the chromosome pieces. But if the preces comlyıne se the genes are arranged in a new order, the result is called a gross chromosomal reariangement So long as a rell containing a grens chromosomal rearrangement does not diside rolar els Putte damage results If however, this cell divides, then, depend 103 pou the type of searrangemeni, »e of the ino daughter cells may have a whole section of rearranged genes missing while the other daugliter cell has this sect 1 exress As a result the nely balanced gene content of the normal cell as upset and the daughter cells cannot function properly, or die Tot only are there mutations involving whole sections of genes as just desertbed, but there are those ssisch roke a tery to alized region of the chromosemie, convaiming perliaps only (itic or a few genes These minute changes 113 chromosomes are called pomi 11 fat1015 Is already mentioned his Dr Michey, there is no good evidence that a minimum dose of radiation is Tequired to procure a point mutation When people talk about the amouni of natural radiation being acceptable, they do not mean that such radiation fails to produre its share of mutations ·FACTORS AFFECTING RADIATION-INDUCED MUTATION RATES By IRWIN II, HERSKOWITZ* Associate Professor of Biology Saint Louis University, St Louis, Missouri Before discussing some of the factors which influence the production of mutations by radiation, it may be profitable to review briefly the basis and nature of human inheritance. This is casily done at the cellular level. Each cell, as you know, normally, contains a mucleus which is in turn filled with bodics called chromosomes. While viruses and other materials outside the nucleus may be transmitted from a parent cell to its two daughter cells after a cell division, it is primarily the chromosomes which transmit the hereditary material from one cell to another In thuis way heredity produces two human cells from the division of one hunan cell. The great majority of people probally have 16 cromosomes in each tissue cell of their boly, these chromosomes being composed actually of 23 pairs. One set of 23 unpaired chromosomes was contributed by our mother and the other set of 23 by our father when we started life as a fertilized egg Subsequent cell divisions produced a baby and later an adult, each of whose loudly cells carries 23 pairs of chromosomes. In each mature sex cell of the adult, however, as a result of special series of (ell divisions, there is only one set of 23 chromosomes. Moreover, each of the 23 inpand chromosomes carried by a mature egg or speim has an equal chance of being one that came originally from the mother on from the father of the individual forming the sex cell Along the length of each chromosome are the smallest parti. cles of inheritance, the genes, lined up onc lielund the other in Time for preparing this report was made aslable in part bos Atonur fuergs Contract .IT (11-1) 639 nin ·S1 Genetics, Radrounology and Radiology between ion pairs and clusters of thein, on the one hand, and mutations on the other Unfortunately, we do not have any radiation that produces clusters composed of a single ion pair 11th a big space in the tissue before another ion pais is produced, and so on. Had we such a ray ne could determine whether only a single on pair is needed to produce a polne station. Ioniz ng radiation like 1-ray's produces clusters which prols. ably range in size from those with only one son pris in others containmg a hundred. A typical vsay cluster is compared of more than one ronization pair with a given quality of iomring radiation one obtains a range of cluster sizes and up lowering the dose this range does 130t change Suppose with a low dose 11 more than one cluster oct uits in a nucleus. This probably is true when 20 r of x-rays are dels cred to Drosophila (fruit fly) sperin Assume in this case 20% of the sperin have one cluster in them, and that each cluster has, on the average, 12 ion pairs in it. 11 the dose is reduced 10 5 r one will not get 20% of cells having a cluster containing only 4 ion pairs. One would get 5% of the cells haung a cluster of 12 con pairs. Dosage experiments down fo about 50 r hase shown in Drosophula that the point mutatiou race is proportional to (le dose It the doses were further reduced so only one cluster occurred in a nucleus at the higher one (and hence az ilte lower close, 100) one would almost surely find that the point mutation rate was linear to dore That is, ont ilfation has ng threshold, or sale, dove Should dewage experiments down in 5 r be periormed, they would involve considerable techmical difficulty because the radiation-induced effect would be small and very careful large-scale controls would have to be run Most geneticists feel that all the way down lo zero-r point mutatuon rate will be proportional to the amount of x-radiation re- Lented, lying at these low doses proponuional to the tumber of nuclei containing a cluster Not only do ye not inox lots many ton pairs are required to produce a point mutation, but he do not know exactly lion many are required to break a chromosome is stinbutable to the aunion of a single cluster of jonizations poliit mutation and the cluster which produces it may or may not have also ·30 Genetics, Radiobiology and Radiology They understand that this amount is unavoidable and since onc cannot do anything about it, the consequent damage is accepted Any additional radiation, this may be more or less than the natural amount, will also cause cellular damage and produce mutations. This is the part society may be able to avoid by hccping the added radiation exposure to a minimum. And one of the main purposes of this symposium is to discuss this problem. If one considers the nature of the energy that stays in tissue after treatment with ionizing radiation it is found that the energy left is not entirely in the form of ionization. (We measure the amount of tissue dose only in terms of ionization when we use the roentgen as the unit) The rocntgen is not the best measure of the relation between absorbed energy and mutation production. This is so because mutations are procluced not only by the ionizations (which act on the genes directly, or indirectly via some nearby nuclear material like water) but they are produced also by energy left in the nucleus in the form of excitations on activa tions which make compounds more reactive chemically and, therefore, more likely to interact with gencs. In the case of x-ray's or gamma rays, however, probably only about one-sixth of the energy is left in tissue as activations, the rest as ionizations. Genc. ticists are interested in the answer to the question, “How much of the energy of other hinds of radiation is left in tissue in the form of ionization and how much as activation?" We need to know more about the ability of non-ionizing energy to produce mutations With ultra-violet radiation all of the mutations are produced through activations Accordingly, more basic icsearch on the study of ultra stolet-induced muta. tions will be fruitful. We also need to have more plıyakal studies on the distribution and the form of ionizing energies left by different wave and particulate radiations As already indicated by the two previous speakers, we simply do not know enough For instance, what is the spread of the ionization 11 tissue for different kinds of radiat'on? More specifically, what are the sizes of tlic clusters of ion pairs produced and how are these clusters distributed relative to cach other? One se bave accur rate data on these matters, we can study better the relationship ·39 Genetics, Radrobiology and Radiology Niere produced. This would leave the pieces from the second break no alternative to join other than in the original arrangeess. 5. under these conditions, lower way intensity would proluce fener gross rearrangements. This illustrates why the dose and the intensity of x-rays play an important role in the prexluction of tho-breah 16 chromosomal rearrangements. gross X-ray Issue damage is dose or intensity depenıleni and has a ge new baxis, it is almost certainly due to gross rearrangement This dine intensity dependence for x-rays does not obtain, however, for mature sperm of animals, and probably of humans, also for in these cells the broken pieces cannot join to cach other and are therefore accumulated for thus reason, it makes no difference hos fast or slow a dlose is given in the lirunisomes in a spermt hiead The breals remain unjoined until fertiliza- 1104, when the sperin head swells and the bornes enils are permitted to join in pairs So much for the discussion of certain physical aspects of penetrating radiation and their tearing on muratton proxluction In disctlyg the fological factors which alles the frequency of radiation-induced mutations several questions must aliass be kept ni mmnd. Hou dla these agents act in the chromo. some breakage proxcess, and how so they affect the ability of the broken pieces to join to others? It is usually difficult, unless carefully designed experiments are performed, 10 se)) whether an agent : affecting the breakage or the rejoining phenomenon, or toch It should be mentioned that no agent is known whichi can local cromosome vet not produce point mutations on the Tenerse of this There are severa) ways that the gene content of the rell itsel! intenc radiation-induced mutation sale We know that there are gene klase presence increases x-ray susceptibility of the cell Hernatxe qenes san decrease this cell sensuvity. perhaps operating by decreasing the likeli}xxl of breakage and or by increasing ihe likelihood of burolen pieces sejoining in 10 mutati the old position Insther genetic factor is involied when an organism or cell fias extra chromonies. In one case, there might be one extra ·32 Genetics, Radiobiology and Radiology produced a break in the chromosome in the same or a nearby region. Therefore, point mutations sometimes are and some times are not located at a point of exchange of a gross chromo. somal rearrangenient. We do huow, however, that some radiations which produce large clusters are in some ways relatively inefficient and wasteful of ionizations. These densely ionizing rays produce a sinaller percentage of cells with gross chromo. somal rearrangements than is produced by the same dose of a radiation having smaller cluster sizes, that is, where the ionizations are spread out more. Here then is one measure of relative cfficiency of different radiations for the production of mutations, Certain types of gross chromosomal rear rangement, already described by Dr. Mickey, require two breaks for their produce tion. When a neutron enters a nucleus it produces ronizations in clusters which are large and close together. Because of this concentration the ionizations can pass through one chromosome at two different places or through two different chromosomes, so that a gross carrangement, even though it equired two separate breaks, can be produced by the passage of one particle through the nucleus Thus, the frequency of two-break gross rearrangements following netition radiation increases linearly with dose and is independent of tle rate with which the dose is clelis. ered. If a less densely ionizing type of racliation is uscal, like X-rays, the clusters are smaller and spaced farther apart. Here, two breaks in the same nucleus are usually produced by two sep arate clusters, one having no dependence upon the othei for its origination For this reason many vay-induced gross rear. rangements are dose and mtensity (lependent For wien a low dose is given, a nucleus could contain only one cluster and could produce only one break. The close would have to be raised high enough to get cases of two or more borcals per nuclers For these rearrangements, then, there is a threshhold, or safe, close for x-rays. If a larger x-ray dose is gren in a short interval, tuo breals could be produced in the same nucleus simultaneously and could result in rearrangenient But if the same dose is given more slowly, then the pieces of the first break could join w form the original gene arrangement before those from the second break ·5 Genelors, Radiobiology and Radiology ent mutation rates for genetic reasons Thus, for example, a species with more genes will have more point mutations prexluceri in it for a given dose, and one with inore chromosomes will have more gross chromosomal mutatious of certain typees. This may be part of the reason why an organism like thie fruit fly, which has only four pairs of chromosomes, and perhaps 10,000 genes, is relatively less mutable than a species like man, with 23 poits and maylie 50,000 genes Other biological factors which can influence mutation rate are known which are not based so directly on the lind of number of genes or chromosomes, although these may be influenced lsy genes One of these concerns the spatial arrangement of the chruitwysomes relative to each other. When the clironimomies are packed into a tight ball of threads like they are the tiny head of the tperm, a different picture is presented for breakage and fater rejoining than when the chromosomes are spread throughout a large nucleus For Yf they are spread us the ionizations of a small cluster or froin a penetrating particle are unlilely to Isreak chromosomes twice Even in those cases where two breaks do Oscar in a large nucleus, the pieces will be frequently fru) far apart tu intercange, and the result will be thai those which you will 1111ally form she isriginal gene order Even within the same sized cell there are a number of other brological factors which can influence breakage or rejoining These include the presence of a restrictive and insulation nuclear membrane, the degree of spiralization of the chromeximes, the stress of tension under which the parts of a chromosome are hell, the degree of hydration and the amount of chromosome matrix 111 ufich the genie string is embedded, protoplasmic viscosity and the amount of movement around the chromosomes orzyno ar farts - ILI Were the members of each chromo. come pair come to lie clone to each other, as they do at a certain stage in sex cell formation For under these conditions the forces whxh Leep lile parts of one chromosome apposest to the like parts of the other member of the pair may prevent the pieces ·3.1 Genetics, Radiobiology and Radiology set of chromosomes present, so instead of two sets three are pres. ent. The number of point mutations per cell caused by a given radiation dose will be proportionately increased (tyy 50%) by the presence of the extra set. While more point mutations would be produced the damage caused to the cell carrying these would probably be less per mutation than to n normal two-sct cell because there would be present two sets of normal genes and chromosomes to counteract the effect of the mutation in the third set. On the other hand, it can be shown that gross chromosomal rearrangements, and much of the damage they procluce, would lic increased by more than the proportional amount expected due to the addition of an extra set of chromosomes. These expectations neel to be taken into account also in cases where certain cells or individuals have one or two chromosomes more than otheis, a situation known to exist among humans. Within the same individual, one can find autous cells with different chromosome numbers. For instance, human matic sperm and eggs have only one set of chromosomes, that is, 23, while the normal cell has twice thus number, or 23 pairs typl. cal cell which is just about to divide will have its 23 pairs of chiromosomes exactly doubled and so it will be expected to be especially radio-sensitive This is true also during contain stages in the maturation of sperın and ess cells In adation, one can find, within the liver, cells which have more than two sets of Chiromosomes. Differences within and between individual chromosomes also can modify the type or rate of radiation-induced mutation. It is known that some parts of a chroin some are more likely to undergo breakage and rearrangement than others. Certain point mutations are induced more frequently than others by radiation. This docs not mean that one can selectively produce a specific type of mutation by radiation, but that amongst a large number of induced mutations certain oncs crop up more frequently than others. This demonstrates, another way, that the genetic content of the individual modifies mutability, Not only can there be genetic differences in mutability withm an individual or a species, but different species can have differ.

·97 Genetics, Hadiobiology and Radiology of broken ends, thereby decreasing the opportunity for chromosomal rearrangeinent The action of many physical, clemnical, and biochemical agents in modifying the musasion rate can be partly understoxxl in terms of an effect on oxygen concentration during or after X-radiation This includes the elfect of respiratory enzymes which mcrease or decrease ou gen concentration and of agents which poison these chemically (including metals which are in solled in enzyme construction or inactivation), chemical sub stances which release oxygen (such as inorganic or organic perov. nies). pff, and temperature (at lower ones more oxygen is dis. soh ed) Certain normal biological phenomena may themselves produce or involve changes in oxygen concentration, such as the b10xhemical events which accompany cell differentiation, the presence or dissolution of the nuclear membrane, and the location of tissue relatise to inter-cellular oxygen supply It should not be thought, lionever, that the entire effect of aligen is explicable in terms of a single patch of action enler for breakage or for jum, suve a number of the lyolewscal factors mentioned must be also dependent upon oxygen and the mulation effekt must in some cases result from modifying these. One should also realize that although much of the modifying effect of biological factors can be attributed to elfects on oxygen certain of these agents influence mutation rate by other means For example, temperature is known to modify mutation rate apart from its relation to the solubility of oxygen X-rays produce more gross chromosomal rearrangements when treated oocytes are previously dehydrated This may be so because the rocyte nucleus is shrunken, causing the pieces from different breaks to de loxated closer together, proximity of brolen ends favoring interchange, and acting contrary to the radiaproxecise acrion which removal of water frequently provides In summary an attempt tas been made to describe briefly certain intrinsic characteristics of penetrating radiation «hich cause differentces in mutation rates, as well as to indicate some of the hological and non-biological factors which can influence the ability of Dmizations and actuations to produce mutation, ·36 Genetics, Radiobusology and Radiology newly produced by brcalage froin moving apart freely, the unbroken chromosome strand serving as a splint for the broken one. This would serve to reduce the opportunities for cross union between ends from different breaks. All these factors determine to what degree the pieces produced by a brcalage may move or spring apart. Those which change the distances between different chromosomes or the parts within a chromosome will also affect chronosomc brcalability, On the biochemical level there is a very simple system which greatly influences the number of point mutations or the number of breaks and their joinatılity. This involves water and the oxygen dissolved in it. X-rays produce very reactic (hence shortlived) chemical ions from both, as already described in some cletail loy both Drs Evans and Michey. Not all radiation-induced mutations have their lasis in ions from oxygenated water, lowcver, although a good many of them clo. Those with this orig 11 have a pathway from the radiation to the gene that is indirect, Consiler next the specific role of oxygen in radiacion muita. tion. If a normally oxygenated cell is x-rayed a certain number of chromosomes will be broken. When the amount of oxygen is reduced the same dose procluces fewer breakages, and when the amount of oxygen available is incrcased alrove the normal amount somewhat more mutations are obtained than under normal con clitions. The presence of oxygen curing irradiation, therefore, promotes cliromosome breahage It also increases the frequency of point mutations It is also known that once a break is procluced the presence of oxygen permits or promotes the joining between broken cncs If oxygen is absent or reduced after a break is produced the pieces are not able to join togethier luder tlus condition brohen ends are saved up, unulovygen is restoel, at which time the cell may contain pieces from many different breals. These can then jou in rearrangements that would not liave been possible had the close been given slowly in the pres. ence of oxygen when a given piece would liave had fewer oppor. tunities for cross tihion. From the standpoint of gross chromo. soinal mutation, therefore, oxygen las two opposite effects; it increases the number of breaks but promotes the carly rejoining ·30 Genetics, Radiobiology and Radiology Dr. Crou: Dr Herskowitz has been talking about radliation. mduced mutations, which because of the oxygen effect may have a segarise temperature coefficient, wliereas mutations from other causes seem to have a positive coefficient. If thus is true in man, then the testes will have a lower mutation rate tfian if they were internal and at a higher teniperature. Dr. Gould: One may cancel the other thesi. Dr Grou: Possibly. However, it is probable that the majority of mutations are not due to rad arion. Thus, the nunst lihely effect of a decreased temperature woull lie a decreased mutation rate Dr Scott is there any bask difference in normal cells and maligrant cells in these tlungs you'le been talking about? Dr Herskouit: There is probably a genetic difference I always amuses me to hear someone say: "See, there's a nalig. fant cells You can tell its malignant because it has a nurlar spindle, or because you see a chromosome bagging, or because you see broken ends" "That's not the malignant cell Thac's a dead cell or it's going to be a dead cell The real malignant cell, the one that is going to divide and produce more cancer cells, is the one ufrich is apparently not very much abnormal cromosomally: Many people think that cancer cells differ froin nonnal cells, horsever, by a number of point mutations Surcly. It's ursie in some cases that pm mutations are responsible for initiating tumors The major difference, I think, betrieen the malignant and the normal cell sould be in the rate of cell div. sion, and the more rapidly these cells are dividing, the more 5135c epuble they are to irradiation damage Dr Bruts: May ) ja question the statement that the ma. lignant cell divides more often than the normal cell There are vers fex film-.' Dr Mickey as cells in Dr A wilt gaat statement would apply to such cells 35 well as to the malignant tissue, sharis ) say, these embryonic (issues are just abon as susceptible to irradiation damage as are the malignant cells.

·38 Genetics, Rodionology and Radiology Dr. Evans: Is there any question you want to ask before Dr. Hershowitz leaves? Di. Gould: I was wondering how much of a difference in thie mutation rate there would be with a cell in a resting phase when the chromatin is spread around the nucleus and differences between prophase, telephase or the various phases. Dr. Herskowitz: I'll take a guess Fourſold. Dr. Gould: It could be fourfold. Dr. Heiskowitz: Yes. Dr. Gould: And it's most sensitive in which plase would you say? 1). Herskoniz: The metapliase is supposed to be most sensitive. Say, for instance, you irradiace oogonia which are in all stages of nucleai division and obtain a certain intitation rate. If a colchicine treatment piecdles the radiation many of these (cils will be hept in metaphase and the mutation at would be increased several-fold Modifying factors produce an effect on mutation rate which is of a d fferent order of magnitude than is the cffect of radiation itsell For while radiation can produce a thousandloid increase over the normal mutation rate, some mocl. ifying factors described may exit the rate down to only a five hum. dredtok increase. Thus, wlule the effect of molilying factors may loc vcry appreciable, the protection they may afford may be only a relatively sınall percentage of the total damage by radliation. Dr. Gould. One other question you said that when the temperature is clecreasca, moc oxygen brconies available to the cell. Dr. Heiskowiz: It is not dissolved Dr Gould: More is dissolved, and therefore, the mutation rate will be increased. Di Ilerskowitz: Right. Dr. Gould: How does that jube with the Swedislı pont of view that the reprodlucuve cells «f the testes are at a lower body teinperature than the reproducic cells of the ovaries> Dr. Herskowitz: You would expect a slightly ligher muta. tion rate per cell, at the lower temperature.

·39 Genetics, Radiobiology and Radiology Dr. Crou: Dr Hershowitz has been talking about radiationinduced minations, which because of the oxygen effect may lase a negative temperature coefficient, is hereas mutations froin other causes seems to have a positive coefficient. If this is true in man, then the testes will base a lower mutation rate than if they were internal and at a higher temperature. Dr. Gould: One may cancel the other then. Dr. Crou. Possibly. However, it is probable that the majority of mutacions are not due to rail'3101. Thus, the most likely effect of a decreased temperature would be a decreased mitation te. Dr. Sroll Is there any basic difference in normal cells and miligrant cells in these things you've been calling alont? Dr Herskowitz: There is probably a genetic difference. I always amuses me to hear someone say. "See, there's a sualig. 1316 cell l'ou can tell it's inalignant because it has a 112pxlar spindle, or because you see a chromosome lagging, or because you see broken ends" That's not the malignant cell That's a dead cell or it's going to be a dead cell. The real malignant cell, she one that is going to diside and produce more cancer cells, is the one which is apparently not very much abnormal chromosomally Many people think that cancer cells differ froin normal cells, however, by a number of point mutations Surely, it's true in some cases that point mutations are responsible for initiating tumors Dr Mickey. The major difference, I think, between the malignant and the normal cell would be in tlie rate of cell disision, and the more rapidly these cells are dividing, the more susceptible they are to irradiation damage. Dr Brues. May I just question the statement that the ma. lignant cell divides more often than the nominal ceil. There are Very fen tumors whose cells grow as rapidly as embryonic cells or as cells in segenerating tissues or in intestinal epithelium Dr Mickey: Bart that statement would apply to such cells as kell as to the malignane tissue, that is to say, these embryonic tissues are just about as suscepuble to irradiation damage as are the malignant cells.

·40 Genetics, Radiobiology and Radiology Titus Evans: Well, I hate to stop this, but we must go on with our talks now and withliolel our discussion until cach spcaker lias had a chance to get over his main points. Now our next one is Dr. William Russell and I am sure that most of you know that Dr. Russell lias been engaged in a tremendous project with enormous numbers of mice, and he is going to tell us about the radiation induced genetic damage in mammals.

·RADIATION-INDUCED GENETIC DAMAGE IN MAMMALS RY W, L, RUSSELL, Ph.D. Principal Geneticesi Biology DireStort (Jak Rudge Sational laboratories Oak Rux, Tennessee 1 De Exans mentioned the large nuuse colony we have might point out that if these mice were Drosophulae, you could contain them all in half pint milk bottles occupying probably about half of one table top here. So don't expect nonilers from Montse genetics because of large numbers They take up a lot mure space than Drosophilae, and our mouse laboratory could compare to a very small Drosophila laboratory. I thought I might briefly discuss 18 points that I prepared for a recent summary of mammalian radiation genetics. I few of these are basic things that were discovered in mammalian periclics some time ago and which our mosh lias confirmed! We have found others that I think have a very direct practual application to the question of genetic hazards of radiation in man And still others undoubtelly will have a practical application, sooner or later, but, at the present time, they are fundamentally of pure biological interest (1) The first point deal, not with a genetic effect, but actually with damage obsersed in the testis following irradiation The findings in this field have important implications for inter pretation of the genetic damage Dr. Oalberg in our group has found, by careful quantitate estimates of the amount and type of damage in the testis, that one-half of the spermatogonia are aktually killed by a dose of 22 r of gamma rays, and he can meas- Alre the amounts of killing, with statistical significance, down to (111h the size 3mples which he used, which are not enormous) ·40 Genetics, Radiobiology and Radiology Titus Evans: Well, I hate to stop this, but we must go on with our talks now and withhold our discussion until cach speaker las had a chance to get over his main points. Now our next one is Dr. William Russell and I am sure that most of you know that Dr. Russell has been engaged in a tremendous project with enormous numbers of mice, and he is going to tell us about the radiation induced genetic damage in mammals.

·13 Genetics, Radiobiology and Radiology The builh of the dose will hase been received in the spermatogonial stage. Similarly, if you are exposed to an acme close at one time from an accident or inedical treatment, it is likely that you will actually have a ſenile mating within the file or sit Neels immediately following irradiation. ln such cases, you usually know that you lase ticen e posed anyway and can refrain Thus, from procreation for these fen seeks after irracliation here is the one place in mammalian radiation geneties where some of the risk can be controlled, at least with regard to chroinosomal aberrations. However, even if we don't try to control these, they inay still not be a very important bazarı (3) The preceding point fras concerned chromosomal aberrations induced in males. We turn now to females Oogona are not present m the aduit mammai, certainly not in the mouse and probably not in the adult human femalc. All germ cells in the flouse are in the primary oxyte stage, i.c.. they have already passed out of the cogonial stage. And fiere, chromosomal abertations could conceivably have turned out to be a hazard because the gonial stage, from which radiation-induced derrations are not recovered in the male, has been irrevoxally pasved 111 the adult female However, it was shown in our work (This Virs Russell's noth) that with females, as had been found with males, dominant lethals cause death extremely carly in deselopment Abom 60% of them are detectable in the tocell stage of the einbrya, and practically all of the sleallis slye sa dominant lethals tx{uir fefore implantacion, est at the situe al implantation, or very shortly alternards. Thus, although comnant lethals are induced in females, they would not cause mucha griet in a buban situation (The same consideration apples. of course also to downınant lethals juduced in males) 1) lile dominant letals, translocations are not sceles! out early in dezelpment and are passed on to descendant gen. ctations, causing particularly senli-sterility in the olispring These translocations as already mentioned, are inclucral in prisi-spremna. togonal stages but are tiot induced in the spermatogonia siulies still existed that they might be induced in the oocytes of the female bout here ne found an extremely low rate. Only one ·12 Genetics, Rodrobnology and Radiology speras low as 5 r ol gamma rays and even with 2 1ер of ncutions. Now, these are the cells in which we are primauly interested from the point of view of genetic effects. From these measurements, which are made in vivo and not in tissuic culture, 11c fund tlıcse cells to be extiemely sensitive. In contrast to this, the testis does recover from tremendous closes of irradiation in mice. We can give 1000 r of acute .-ray exposure to the testis and the males will cturn to fertility. In fact, with a good lybrid stock to start with, there is no difference in the percentage of animals that is finally fertile: less than 1% are sterile, both in the control and exposed groups. Thus, some of the spermatogonia are apparently extremely resistent to hillmg. We have, then, these (wo very clearly defined <ifferent types of cells among the matogonia: and this, as I will mention later, clocs have a licaring on our wterpretation of the genetic effects observed. (2) As earlier work has shown, and our work has conta firmed, most chromosomal aberrations, induce in males, are found only in the offspring conceived in what we call the pics sterile period, which in our experimental work means shortly after irradiation That is, the cliromosomal aberrations accom cred in the offspring are those that liave been induced 111 postspermatogonal stages (the spermatocytes possibly, spermatics clefinitely and sperm definitely), which occupy only about five wechs in the clevelopment of mature sperm from spermatogenia. In this short interval after irradiation, one docs find a lugh inci. cience of chromosomal aberrations - clominant lethals, trauslocations, and so on - in the offspring But, so far. a staustically cletectable mcrease in these aberrations caused by irradiation of spermatogonia has not been really firmly established! The actual Inward from tlus type of genetic effect is, therefore, I thinh. wall in man where the radiation close received by a male gem cell in its post-spermatogonal stages will usually be negligible com. pared to that received in the spermatogonal stage For example, if you are exposed to chroun irradiation over a long period of time, since it takes only five or six necks for the spermatogona to mature, then only the small close rerenied in Inter sages will be important for the production of chromosomal aberrations ·15 Genetics, Radiobiology and Radiology CISES, is that mutation rate is linearly relate to dose. On the other hand, some pathologists would tend to think that the intitation rate is not linearly related to dose and that there inay Ise stille threshold mechanism involved, or that the two-hit processes may be more important than is thought and that the mutation rate would not be as high at the lower doses as you would expect on the basis of simple linearity Our results have actually revealed the possibility that the mutation rate might be higher at lower doses To explore this third possibility, le performed a mintation rate experiment with 300 r and, so far, the results are not out of line with the rates obtained at 0 and 600 T The actual 300 rate is, it turns out, a little bit lugher than the value derned by mterpolating between 0 and 600 r, but not significantly se The fact that the 300 r rate is a little higher than expectation again raises the question of whether, at sull Bower duses, ile rare might not be higher still Los dose experiments of course take an enormous amount of work, but we have approximate data for an 8G r dose as the present time This dose consisted of gamma rays guien chronically, whule the radiation in the 300, 600 and 1000 r experiments I mentioned consisted of acute x-rays. Thus, the experiments are soc esauily comparable, and ihis may (173) out to be important As it stands, the rate at 86 r from chronic gamma rays is actually below the 300-400 interpolation "This, course, fras only limited mearung because, lue to the small yield of mulations at this low dose, the confidence limits are still What we can definitely conclude, houeset, is that the upper 90%, limit is less than twice the valuedlerseer! by interpolation betiseen the land the 300 1 al lite X-ray rates This is reassurance that, at lou doses, we are not going to have a fantastically bugher mucation rate than that estimated lyy interpolation Question What is the rate at which thus 86 is deluered wide at the present time hid you say Dr Russell About 10 r per weel for a period of between eight and nine weels () We come nok to possible differences betreen chronic and acute irradiation With 516 1 of chronic gamma radiation, ·Genetics, Radiobiology and Radiology translocation was picked up in over 300 offspring examined for this particular anomaly, which is a very much loner rate than occurs in postgonial stages of the male. The conclusions from Drosophila worh apparently apply directly to the mammal in this case: a very low translocation rate has been reported for Droso. phila females. (5) We now turn from major chromosome aberrations to so-called point mutations. Here I might mention some rather recent work which may not even be known to many gencricists: the x-ray induced mutation rate in spermatogonia of mice show's a departure from the Imear relation with close at lugher doses At 1000 r, the mutation rate actually drops down Now, this departure from linearity is the reverse direction from that which would be expected if two-hit processes were imolcd. i.e., chromosomal aberrations involving tuo separate bucahages, that situation would tend to make the line curve upward as the close increased. The departure actually observed is in the other duection. A plausibic hypothesis is that this may be due to differential sensitivity among the spermatogona Thus, at the higher doses, we may be killing a high proportion of more sensitive spermatogonia, and, if there is a correlation beineen their sensitivity to Killing and their mutation rate, then at the very high doses we may have just the mutation rate that is left in the more resistant spermatogonia As I say, this is just a plausible hyppothesis at the present time. At least it is boine out by the his. tologically observed differential sensitivity among the spermatogonia (6) As a sort of corollary of point (5). I thank the possibility is not yet excluded that the mutation rate pei rochtgen at lower doses and intensities may actually be lughei than that so far estimated from the doses nie have used If differental sensitivity of the spermatogomia is the explanation for the drop in mutation rate between 600 and 1000 r, then possibly at doses below 600 r, where perlaps we liave all the sensitive cells left, 11c nught have a mutation rate higher than the 600 r rate. I should like to emphasize this a little bit because it is contrary to illo common notions about genetic damage One, held by geneti.

·-15 Genetics, Radiobiology and Radiology cists. is that mutation rate is linearly related to dose. On the other hand, some pathologists would tend to think that the muintion rate is not linearly related to duse and that there may be some threshold mechanism involved, or that the two hit processes may be more important than is thought and that the mutation rate would not be as high at the lower doses as you would expert on the basis of simple linearity Our results hasc actually revealed the possibility that the mutation rate might be higher at lower doses To explore this third possibility, we performed a mutation rate experiment with 300 r and, so far, tlie results are not out of line with the rates obrained at 0 and 600 r. The actual 300 r rate is, it turns out, a lutle bit liigher than the value derived by interpolating between 0 and 600 r, but not significantly so. The fact that the 300 r rate is a little higher than expectation again raises the question of whether, at still lower closes, the rate might not be higher still Low dose experiments of course take an enormous amount of sork, but we have approximate data for an 86 r dose at the present time This close consisted of gamma rays gnen chronically, while the radiation in the 300, 600 and 1000 r experiments I mentioned consisted of acute a-says. Thus, the experiments are not exactly comparable, and this may turn Ollt to le important Is it stands, the rate at 86 r from chronic gamma rays is actually below the 300-100 interpolation This, of course, has only limited meaning because, due to the small Jield of mutations at this low dose, the confulente lunits are sull wide at the present time What we can definitely conclude, howfier, is that the upper 30% limit is less thin twice the value derivedi by interpolation betwech the 0 and the 300 r acuite x-ray rates This is reassurance that, at low doses, we are not going to liale a fantastically lugher mutation rate than that estimated by interpolation Question What is the rate at which thus 86 t is delivered did you say? cight and nine neeks Dr Russell. About 10 r per week for a period of between We come nok to possible differences between chronic and acute irradiation. With 516 r of chronic gamma radiation, ·16 Genetics, Radiobiology and Radiology given at the rate of 90 r per week, the mutation rate is unexpect. edly low when compared with the results of 600 r of x-rays given at 80 r a minute. The intensities of radiation in the two expcii. ments differ by 4 orders of magnitude. The results at 516 1, in conjunction with the limited data at 86 : total dose, raise the question of whethier chronic irradiation might give a lower muta. tion rate than does acute in the spermatogomia of the mammal. Question: Excuse me. What kinds of changes are you refer. ring to: D. Russell: I shoukl have mentioned these. Wc mcasure what we call specific locus mutations. We have icason to think that major chromosomal aberrations are not mvolved when we irradliare spermatogonia - and all dara I am talking about now concern spermatogonia. In ut radiation of mature germ cells, on the other hand, results arc complicated ly the production of chromosomal alerratiens, some of which appear like specific locus mutations. Question: What do you mean by specific locus mutations? Dr. Russell. Just a mutation restricted to the place (locus) occupied on the chromosome by a parucular gene. Question: Give an example of what you see – is it a hail color? D. Russell: Yes. Five of the seven we look for arc hair color changes, one is winte-spotting, and the scienth one is a short-car mutation, Mutations at these seien loci that have och cured spontancously m the laboratory in the past were built into a specific "test" stock We u radiate the stock not caraying their mutationus, mate to the "test" stoch, and look for repeats of these particular hins of muations n the fore general offspring As far as we can tell, these repeats are gene mutations, or, strictly speaking, "point" mutatious, since it is impossible, at the present time, to prove that ke are not alcaling with very muunte clefic 101. cics, 1.c, losses of chromatun matcual ruvolving the locals or its imnicchiate adjacent region. However, there is very good evidence that sucli deficiencies, if they occur at all in spermatogona, must be exticmely small To return to pomt (7) The idea that wonic uraduation ·Genetirs, Radiobiology and Radiology might be genetically less effective than actite, is of course, litresy among geneticists, so one looks for vier possible explanations of the results. Well, one possible explanation is that we are caus. ing more damage to the testis with citronic irradiation than 10 were with acute and that, following only 516 r chronic gamma, we may have a situation similar to that postulated for 1000 r acute x-rays, ie, a mutation rate that characterizes resistant cells. In any case, until we have more evidence on this point, I think it would be risky 10 jump to the conclusion that chronic gaisa irradiation to spermatogonia in matmals will give less mutation than acute x-rays However, this possibility is nou, I think, torth exploring considerably. I have a private vier on this, but I won't state it at the present time (8) The three preceding points have, I am sure, indicated the complexities in the relation between mutation rate, dose, and dose rate. You see, we have found in departures from the gen. erally accepted genetic concept, ie, (a) <trop in the station rate at 1000 r of acute x irradiation, and (b) the loner mutation rate following chronic exposure than following 600 r acute A-rays. In tien of these observed complexities and other complications that excur when we are dealing - not with a uniform population of sperm - but with the spermatozonia, that are going through cell division all the tune, and are known to have differential sensi- Ulity to killing, I think the best thing "e can do at the present ume is to take the highest mutation rate so far obtained in the ineuse, namely, that in the 300 r experiment with acute irradianon, and use this for estimates of damage in man. The induced rate in the 300 r experiment, if you want an actu figure is 28 10-* per r, per locus Thrs rate is many times higher than that found in comparable experiments with Drosophila. There have been a number of statements that man is not a Drosophila and that his mutation rate may be much Joner than the Drosoplusla sate But non an organism nhich is a good deal closer to meni, the mouse, actually goes in the other direction: the mammalian mutation rate seems to be considerably higher than the Drosophula rate Points 5-8 have concerned specific locus mutations illu ·18 Genetics, Radiobiology and Radiology' duced in males. We have a little data also on the mutation rate in offspring of irradiated female mice. It is difficult to do acute experiments in ſemnale mice because they become permanently sterilc with cven a low acute closc. Thus, even 50 stcuilizes after four litters and one neeels, in general, higher closes than this to make an easy experiment. Howcver, we have some work in progress in which females were given 258 r clironic gamma irra. diation at the rate of about 86 r per wech, and here fortility persists almost as long as in controls, at least long enough to get a large number of offspring And again the mutation rate is low. Now in the female gonad we are not dealing with a population of rapidly divuling cells: oogonia are not present in adults, and oocytes remain in a constant condition apparently throughout life until just before ovulation. Consequently, the lon mutation rate cannot be explained on the same hypothesis as that suggested to cxplain the crop-off found in males at high acute doscs, or fol. lowing chronic application of the dose Thus, it appears that the mutation rate in females may be really low and 100 spuriously low, if you want to use this tcrm This raises, I thuh, considerable liope that thus fındmg may also apply to the human ovan el posed to chon c gamma inadinuon. We can't speak of acute ways because we don't know the results, and this leaves considerable lincertainty as far as meelical exposures are concerned, because fractionated acute doses may gue a genetic effect more like that of the single acute dose than that of chronic gamma irradiation given continuously. (10) There is no cilence of significant reuincy from genetic damage with time after irradiation, I think Dr. Mickey mentioned this for Drosophia, but, for various seasons, this point necded to be established alresh ma mammal The carlier ell. dence for lack of recovery came primarily from close Tract10nation studies in Drosophila, but this work was all on mature sperm Now there were (or so it seemed to us at least), voy deſmite possibilities for recovery. when one was dealing with spermato). gonia instead. Supposing the induced mutation itself actually affected the rate of cell dilyision of a spermatogomum Then it would lose out in competition with other spermatogonia and, i.

·19 Genetics, Radiobiology and Radiology long time after irradiation, the gation rate miglit drop, as the probability of recovering a mutant sperm derived from this par. Irular spermatogonium would decrease. We felt thai, in sieks of this possibility, it required sery definite experimental work on spermatogonia, and also in a longer-lised organisin than Drosesphila, and also, I think. In a testis that is luistologically similar to mm (rather than being quite different in anatomy and physiology as in the Drosoplıila testis) to re-establish the principle of lack of recovery. Well, we have looked at this carefully enough. I think, to say that there is no significant difference in the spermatogenial mucation rate a short time after irradiation and a long time after irradiation. So there is no endence that would allow us to count on recovery from genetic damage with time. (11) The mutation rates of the ses en luci in muy sample sary markedly from each other. This, there is a factor of over 30 between the lowest rate and the highest rate in spermatogonia. These differences tend to disappear when you deal with the radation of mature spens, and I think this is probally clue primarily to the contribution 1 other thromosomal aberrations wluch gne ellects simulating the specific locus mutations Dr Alickey: l'on sytty missed a point there. Do you rican the differences of the different Inxci Is that what you were referring to Ir Russell. Yes, the ad-fokus, fost example, has a very low Tate and the clockus has a very lugh rate and the difference is more than thirty-fold in a sample of only 7 loxi Ds Jackey. Excuse me. You're spcaling of the radiation. induced mutation rate? Dr. Russell. Yes, l'in speaking of radiation-induced mua. Tot rates Di Michey It Ocents spontaneously, 100 Di Russell Well, it's well known, of course, with 4px93- tanetsiis rates, cg in masse ihan the lactation among Ini 15 vemendous Much bigger differences than this occur. Hr Mickey Are these in the same order when you looh at the spontaneous sales Ir Russell The number of spontaneous mutations, un.

·50 Genetics, Nadrobnology and Radiology fortunately, is not extensive enough yet to answci this. There is such a low spontaneous ratc, when you deal with specific loci, that we can't conclude anything definite, so tai. Di. llickey: May I inject the studies of Staviler on maire? He has shown this particularly with specific loci spontaneous rates in corn. D. Brnes: What is the correlation between radiation-inducer mutation rates and spontaneous rates? Dr. Russell: As I have mentioned, we have just a handful of spontaneous mutations so nothing <lcfinite can be decided at this time. (12) point that I've already touched on lightly is that deſı ieircies commonly found among mutations induced in postspermatogonal stages have not been found, so far, in the cases recovered from irradiated spermatogowa. In specific locus inutation experiments on irradiated sperm, further analysis of certam of the specific locus mutatious rescals that they are not point mutations or genc mutations, but are caused by a small pieces al the cromosome having been knocked out of this particular region The same criteria applied to mutations indurcil by the 11 radiation of spermatogonia reveal no such sign of deficien. cies. This is part of the supporting evidence that most mutations induced in spermatogonia are pont mutations, and that they may cven be gene mutations (13) There are also significant clifferences, among the scien Hoci cxplamed, m the proportion of the mutations that turn out to be recessive lethals It two of the seven loxi, for example, will of the mutations that were detected by their visible eflect on coll color tuned out to be lethal in liomozygous conuon, that is. when the mutation is brought in from both the mother and the fathci, in a descendant generation, those offspring Techning it in clouble-close fail to survile Lethals have been induced in all lout, and the total proport2011 is quite substantial 11 least hall of all the mutations recovered are completely lethal This is. thuh, an unbiased result because, when we started the experiment 110t a single lethal inutation was nown at any of the seven loci that we pichael for a study 1 ·51 Genetics, Radiohnology and Radiology (14) In contrast to what Dr. Michey reportel, cist of the recessile lethals tested in our experituents do not fall into the category in which death (xcurs so early in the cmlıryos as lo pass kinnoticed in human experience. On the contrary, they will at cimes that I think would be tragedies in luman experience. 11 the lethals at one locus kill a alimut seasing age, which is alt three weeks of age in the tyouse. Not a single mutation at this Ixus Lill, earlier than this At the other of the 1110) toxi that have given nothing but lethals, most of the mutations (in homozygous condition) apparently hill at about the line of birthi. Thus, these recessive lethals induced in the mouse are quite dif. ferent from many recessive Jethals known in Drosophila and also quite different from the dominant lethals induced in the mouse whech kill in the early stages of development. (15) Some of the lesbials induced in the rive base streng a dominant deleterious effect that it is actually apparent in the individuals carrying them in heterozygous condition. That Is, the lethal, wlen homozygous (inherited from both parents). will all the indissdual; iſ inherited from poly one parens. it has an effect on body size so marked that you can actually see it with Crete scighing the individual, These heterozygous individuals may be allected in other ways as well: en it is probable that thesr life as shortenedl. (16) Other mutations in heterozygous condition, ic. interited froth only one parent, have effects which are not apparent in the indus 101a) Isuz which are discernille statistically. Thus, the trailey of offspring of trathated animals is recluced, as como pared with the controls I think it is quite inxirtant that the find out more about these statistically detectable heterozygous effects, because, if the mutations which are completely lethal in the homarygate lase a slight delelerious effect cx the heieron. gore in the human situation, then the heterozygous effect will probably be far more important, from the point of view of haz. Stih, than the cumplete lethality of the homozygote. The reason for this will, 1 expect, be discussed by Dr. Cras, s 1 » }} leave it to him. (17) One way in which we have measured the heterozy.

·50 Genetics, Radiobiology and Radiology fortunately, is not extensive enough yet to answer this. There is such a low spontaneous rate, when you deal with specific loci, that we can't conclule anything definite, so far. Dr. Mickey: May I inject the studies of Stadlei on maize? He has shown this particularly with specific loci spontancous rates in coin, 1)), Bres: What is the correlation between radiation-induced mutation rates and spontaneous rates? Di. Russell: As I lave mentioned, we have just a handful of spontaneous mutations so nothing lefinite can be clecided at this time. (12) point that I've already touched on lightly is that deficiencies commonly found among smutations induceri in postspermatogonial stages have not been found, so fai, in the cases recovered from irradiated spermatogona In specific locus zun. tation experiments on irradiated sperm, further analysis of certain of the specific locus mutations ieveals that they do not point mutations or gene mutations, but are caused by a small piece of the chromosome having been knocked out of this particular region The same criteria applied to mutattonis induced by the rrracliation of spermatogoua rescal no such sign of defce 2011- cies. This is pait of the supporting evidence that most mitations induced in spermatogona are pomt mutations, and that they may even be gene mutations (13) There are also significant differences, among the scien loci explained, in the proportion of the mutations that turn out to be recessive lethals, Ai tuo of the seven lou, foi example, all of the mutations that were detected by clicir visible efect on con color turned out to be lethal in homozygous condition, that 15. when the mutation is brought in from both the mother and the father, in a descendant generation, those offspring rocering it 111 double-close fail to surulle. Lethals have been induced in all loci, and the total proportion is que substantial .It least half of all the mutations recovered are completely lethal "This is, thinh, an unbiased result becarise, when we started the experiment, not a single lethal inuitation was known at any of the seven les that he picked for a study ·55 Genetics, Radialioing and Radiology Question: llouldn't this be an important dllererce ubesher the lutter size was ihminished or khether they actually were born liable and then diecta Dr Russell. Yes. We liave tried to determine this but it would take a tremendously targe-scale experiment to break dow Inrther something that is only 3-4, to begin with. We have some Indication from what we have done that at least some of the deaths occur after birth Thus, here again it is not all death before Birth My guess would be thai, since we are presumably dealing with a point mutation type of effect here, we probably have to look for slight shifts in statistical distributions. ic. if an animal carries a certain mutation, it will increase liis proba bly of dying before a certain age Vot cicry animual tliat (ar. ries this mutation will die, of course. Question By litter size here, do you mean the number of olfspring or the coul weight? Dr Russell The number of animals per liter, (18) Perhaps our most definite direct measure of damage 113 the descendant generations was established atrout a year ago from an experiment that was set up primarily to maximize the eflect We found a very strihing shortening « life in the oll. spring of the exposed individuals. This includes the whole life. span - not just that up to three weeks ol age in fact, deaths be. fare three weeks of age i ere excluded from the analyses In this experiment, in which irradiation was done with reutrons, se found 0 6 days stortening of lıfe per rep of neutron irradiation given to the father Translated in man by simply assuming that life slioneming would be the same proportion of the toual 1113 pan. sluch probably is not justifiable, but gres a rough klea> this means about twenty days sluortening of life per rep. ol neutrons retened by the father. Nou I mest emphasize that the effect was maximized in this experiment, on several counts First of all the relatne biological effectiveness of neutrons may be greater than unity for this effect. Secondly, this was not a spermatogomia experiment irradiation was gren (o mate mature gametogenic stages, probably sperinatids, which, as Dr Hers. louisz has already menimmel, are very sensitive genetically. It ·Genetics, Radiobiology and Radiology пр gous effect is by relative survival to three weeks of age in the large specific locus experiments. I use this particular age because it is then that we kill all the animals if they don't show specific locus mutations, and we, therefore, have large numbers of animals saised to three weeks of age. Survival to this age in the first generation descendants of the irradiated animals is lower than in the controls. The difference is not big with 300 r we get about 3 or 4% reduction in survival to this age - but it has turned in every single experiment that we have done, and if you break down the 300 r experiment, for example, muito ten successive groups, you will find about the same clifference in cach of the ten successive groups There is, I think, no doubt that we are clealing with a real reduction Question: Are these thic cluldren of parents that have been i radiated or are the children themselves irradiated also? Di. Russell: These are the offspring of males that were irradiated. You simply observe the litter size at three weeks of age and you find that it is reduced in the group where the male has been irradiated, as compared to the control group where the male has not been irradiated Question The children themselves were not irradiated in thus three-week period? Di. Russell. No, they were not irradiatool The same, of course, is true of the other heterozygous cffects mentioned, reduir. tion in size and so on. Question Does the litter size (liminish, too? Di Russell Well, survival to three weeks is actually mcas. ured by litter size I call it survival to three wechs of age because when you talk about litter size, people usually assume thus mcams at birth Actually, these animals are not looked at anul they are three weeks of age, the reason for that being we have to go through such tremendous nunlvers that if we looked at them twice, we would have to double the work and wouldn't recover many more illitations - only those that have died in the merval between birth and three weeks. So we have these large-scale c\periments m which the animals are looked at at three wechs of age.

·53 Genetics, Radiobiology and Radiology here. That is, in this experiment alone we have over the years, looked at 100,000 mice to recover 100 or so mutations. Of course we have several other acute x-ray cyperiments in addi. tion The mutation rate in the chronic e periment of 516 r is, so far, based on one mutation. You may recall that I spole about a 600 r acute and also about a chronic esperiment in which the rate was much louer. The 600 r acule rate is based on our 100 mutations. In the chronic gamma experiment, our estimate is based on one mutation in over 10,000 offspring at the present time, but, nevertheless, this is statistically a significant difference. That is, even the upper confidence limit of the mutation rate from chronic irradiation doesn't approach the higher rate. Thus. We have one mutation, where on the basis of the 600 r acute, we would expect about 12. This is a highly significant difference. Question: One locus maybe that would clarify is a bit. That is a specific type of mutation at this locus. Dr. Russell: No, this is just one mutation in all seven loci Queston: And that was in how many mice: Dr. Russell That was in about 11,000 Question How many mice did you irradiate with 600 actite Dr. Russell Well, the number of offspring was about 120,- 000. Question And the number of mice irradiated? Dr Russell I guess it must have been between 1500 and 2500 1r Evans. I know you hase a lot of questions, but we have some more talks and discussion belore the moon recess We have ashed to radiologi ho hale ghien this some thought to come in at this point The first one is Dr. Arthur Smith from the Research Hospital in Kansas Cray He is going to talk on the . fecumulative Dose Concept."

·54 Genetics, Radiobiology and Radiology is, I think, clesirable to maximize an effect in tlic early phases of experiments when one is trying to uncover whether something exists or not. We now have other experiments going along these lines. They are not complete yet, but two of them (employing X-radiation) are far enough along to show that the effect is in the same direction. As expected, it looks as though the effect will not be as big as in the neutron study, but it will probably add up to a significant shortening of life. SUMMARY One type, Let me give you a quick summary to help organize the seemingly disconnected points I have discussed. Most of our cu. periments (points 5-18) would ſit into two categories the specific locus experiments, have been conducted primarily to male comparisons: to compare mouse with fruit fly. to compare low doses with hugh closcs, to compare intensities, to compare males with females, to compare mutation rate a short time after irradiation and a long time after irradiation Let me stress that all of these are comparisons They are not direct measures of the amount of damage expected, but thcy explore the factors which will affect the damage So little was known about the genetic cffects of radiation in mammals that we felt these basic things hacl to be looked into first In the second category of cyperi. ments, which were not begun unul recently, are those concerned with empirical measures of the actual damage Among these are studies of the effects of particular mutants that we have found, and, more important, population studies, such as the ones in which we found reduction in survival to three wechs of age or sliortenmg of the whole life-span. All of these studies fall into the category of direct measures of damage. Dr. Scott: Dr Russell, what kind of numbers are you talk. ing about in your experiments, 10,000 mice or 100,000? D. Russell: Well, in the 600 r x-ray experiment, the 100- ber of mutations, I think, was Ill in over 100,000 offspring c\. amined. We got about one mutation per thousand offspring ·Genetics, Radintology and Radiology and need only to discoser ways in which to measure them pre. cisely Radiation can ghe rise in mutations in the genes. The inajority of radiation induced mutations are harmful. The genetic damage done is roughly proportional to the total mutation rate. .Iny radiation dose, hogever small, can induce some mutations. Idditional radiation, over and above the irrcducible minimum due to natural calises, produces additional mutations mer ani abse the spontaneous mnarions The probable immer i allditional inance Mtations excurring in an indi dual over a period of time is by and large proportional to the total dose of extra radiation recented over that perial by the reproductie organs where the germ cells are formed and stored To the best of our present hnowledge, if we increased the radiation la Xa. the gene mutations caused by radiation will also be increased lys The total dose of radiatim is what counts, 1135ecl <> alve fats that the genette damage done by radiation is cumulatıc larger amount of radiation produces a larger number of mutanons within the limits of radiation doses being considered in this report, molerarely larger doses of radiation would proxluce more but not worse mutants The concept of a safe rate ml radiation does not make sense of one is tonernes with genetik damage lo future generations What counts from the point of trex of genetic damage is not the rate It is the total accumulateel dose to the reproductive cells of the individual from the begin ming of his life up to the time the child is conceived What is geneixally important to a child is the total radiation dose shar child's parents hale recented from their inception to the conception of the child The significant total close period shouk le approximately the number of years that normally elapsed front the conception of a person to the average time at which offspring are conceived in the t'nited States, this is thirty years, and this is also the figure usually chosen to measure a generation tising this 30 year figure for characterizing the "ipiat reprochtic. tite life radiation close," we have the result what about half the total olfspring would recene the possible effects of a smaller and about half the possible radiation effects of a larger radiation ·ACCUMULATIVE DOSE CONCEPT ARTHUR B. SMITH, M.D. Harltologist, Department of Radiology Research Hostal Kansas City. Vissouri I am going back a bit to the beginning to revien some fundamentals on the accumulative dose concept. I am not sure it is coni. pletely accurate yet, but based on the NAS report. “Biological Effects of Atomic Radiation" and a little from Lee's book on the actual radiation on living cells, I am going to present this outline and hope that it is in agreement with the general teuns that we have heard. The science of human genetics has not yet advanced far enough to be able to give precise answers regarding the dangers of various levels of radiation. Naturally, there are some differences in opinion among geneticists themselves as to exact ownerical values, althoughi no disagreement as to fundamental condu. sions. Single celled organisms, as well as fruit flies and corn plants have been especially rewarding objects to genetic studies. 111 evolutionary terms, however, insects and plants are clearly a long way from man and we are just beginning to get genetic informa. tion about the effects of radiation on some of the lonei mammals such as mice Even so, certain important matters have become clear. Bacteria or fruit fly, mouse or man, the chemical nature of the hereditary material is universally the same, the mam pattern of the hereditary transmission of traits is the same for all forms of life reproducing sexually, and the nature of effects of high energy radiation upon the genetic material is likewise mi versally the same in principal Hence, in human genetics wliere the impossibilities of ordinary scientific experimentation are dicar, we can at least feel certain of the general nature of the effects, 56 ·SOME GENERAL ASPECTS OF TUE DOSE RESPONSE CURVE AND ITS SIGNIFICANCE 81 ITYJER L FRIEDELL. 1.D. Director, Department of Radiology I'mirersity Itopuitals of Ciarland Clarland, Ohrn There isn't any question that radiation prixlones e estan delayed effects There are fairly well knoun and can be classi. fied essentially into three broad categories. (1) mutations as a result of changes in the genes: (?) the pruxluction of cenam spxcial diseases. generally of a neoplastic nature, such as leukemin. and perhaps certain types of tumors, and (3) a general loss of viulis, one of the measures of which is decrease in longevity. The first of these - mutations - proxluces effects in the ollspring, the last two produce effects in the individuals. It has been suggested thar the first is thought to be an effect on the geses, fout it has been postulated that it is conceivable that the latter tua may also be due to genetic changes, but these are genetic changes up the somatic cells rather than in the reproduc- Il cells These changes liave been shown to be present at hugh levels «f radiation. The question that must be ansyerel is, clothese same effects cxcur at lower levels of radiation, and if these «Keitt ar mier levels of radiation, what is the character of the dine response curve, and can one determine whether these effects are cumulative and non-threshold By nox-threshol ne mean that any level of radiauon, honeser small, produces some effect The best evidence that one could possibly obtain would lze 11) establish the mechanism by which biological effects are produred by radiation, and until we knok this mechanism clearly, there is not likely to be any complete understanding of the lyri- 59 ·58 Genetics, Radiomology and Radiology dose. In summary, it is not the radiation pei se which accumu. lates, but the mutations produced by tacliation contme on through one generation after another, and it is these mutations and thicis harmful genetic effects which are cumulative At present, 2% of the total live births in the United States have genetic defects. If mauhind were subjected to a doubling dosc, say 30 to 80 r of radiation, this figure would probably increase by 10% in the first generation. On the above basis, at jadiation dose ol 10 r would give rise to 50,000 new instances of tangible inherited defects in the first generation. The effect of il given close of radiation m produong mutations is independent wliether it is concentrated into a short exposuic at high intensity or is spread over a long time by fractionation or by the use of lou mtensity and I woukl say, of course, after listening to Dr. Russell, that that last statement probably is not truc – that these things cien as written are not as true as when they were written. Dr. Evans: Thank you, Dr Smith. That was a very 120, concise presentation, Di Prokegiu l'el like to bring up a pomt apropos of what Dı. Smith sad I'm just wondering if we should always sudy als he did in his talk, that all mutations are harmful because as I understand it, without mutations, we would still be amochas. That is, iſ life began as a one cell organism in the sca, wouldn't We still be amocbas? 1). Ivans We're getting into the realm of discussion, but we'll allow one answer here 1). Croce You are precisely correct Ir all mutations were harmful, we would still be viritses or whatever he originally It would be much more correct to say almost all Evolutionary progress depends on that small minority of mutationis that are favorable. Di. Sroll Before Dr. Friciell begins his talk, you should hrow that it was bis suggestion that led to the authorizatiou for these Conferences. His advice and suggestions were most lielpful in getting this meeting organized. were ·Genetics, Radiobiology and Radialogy tracis X. fram . and the equation becomes X-V. (i -- ~*D). As noted above, this is not matfiematically a linear cutse and is strictly semi-logarithm. However, when the number of csenis that are excutting are very small compared to the pxxssible total number of eients, or the numlier of targets that are alicred compared to the total puniber of targets is very small, this is essentially linear and it is permissible in plexi she smilies of Clents directly against doxe. (See Fig 1-2 and 3-b.) FG Ja T*$ KOMEXT OF DUIVE ESSENTILLA LLAR (WERT VERY SMALL 1 KB CONSTANT 0.003 NUMIECTED SUMivor1 MAPPLETED, FORRATION BOIL laching specific information as to the mechanism of the air - mes su exist of fat, and therefore whether the dose 3 cumulanse or not. It stirsenal be portal out that this is not umque fos tailarion effects alone. frut applies in all fological studies where the dose i plotted against respxinse i automaci. Gally means that if the cure i semi-Jogarithmic, it is, therefore, a single event function and it is very difficult to avoid the conclu. Ston that there is no threshold and that the closes must be culinitlatine ·60 Genetics, Radiobiology and Radiology" - I will logical effects of radiation, and at best will be presumptive and cien conjectual. For the present discussion, the points that are cuitical are whether the effects are cumulative and whether or not a tlueshold exists. From my olreivations, the basis for making such decisions has rested primarily upon the close response curve and certain tests that can be made of this cute. I huve, therefore, chosen to examme the character of the dose response curve and see what possible interpretations may exist Broadly speaking, the close iesponse curves may be looked at two ways – is it lmcar, or non. linear? The icason for making such a separation is that the linear carve (truly not linear and really semi-logarithme touch про this later) indicates that the events that are o curring with respect to dose are independent of one another This may be termed a single event function, and variously referred to as the direct effect, the target effect, or single hit mechanism. The multiple esent function means that a number of events must occm 11 order to produce a biological effect. This fits primarily with the concept of an indirect effect and is by far the most com. Mon process which is found in physiological data. The reason for stressing these two types of curves are essentially these. If the dose response curve is linear, there is a very strong possibility that the eftects are non-thresholl and cumulative. If the close response curve is non-linear and appears to be a multiple event function, there is almost certamly a threshold and the effects with respect to additive doses cannot be completely cumulative As I moted above, generally a single event function is referred to as a mear curve Actually this as a sem-logarithm (tive IN which the logarithm of the response is plotted along the axis and the close is plotted along the axis. The equation for thus is N.C-KD (N are the events being observed, K is the constant, and D is the dose). This is a simple semi-logauthimic espression. It mclicates that the number of unaltered units are clecreasing If you are measuring mutations, it would indicate cliat the number of unaltered genes are decreasing In most instances, the dose response curves are plotted so that the effect is plotted against the dose and in this instance one simply suls. simply N ·Genetics, Radiobiology and Radiology range. Secondly, it is interesting to note that a wesent une fits these data essentially as well as a single event curie, suggesting that other types of curies could be used quite satisfactorily. You will note that if a threient cuine can be fitted, it means that there must be some type of threshold and a change in the rate of accumulation throughout the dose range ought be present. Thirdly, note that the lowest dose is 23 roentgens Although lower doses have been studied in bacteria, plants, and unicellular organisms, this is the lowest desse that is available on complex organisms and, of course, is very far from the extremely sinall doses which are sometimes delivered to the gonals and are meas, ured in a few niilliroentgens. Fourth, it is important to note that all of these studies are dependent upon establishing the natural mutation rate, which appears quite variable, and is the sarinus sudies show quite a wide range. Failure to properly establish this interferes seriously with establishing the exact character of the close response curve Fifth, it should be noted also in one experiment that cas pari and Stern found very little difference in the mmation rate of flies irradiated at 50 roentgens as compared with normal unirradiated flies The difference was considered ly them to be not significant. This has been attached by geneticists on the basis that these data were not satisfactory because of the unusually high natural mutation rate in their particular control flies. Sixth, Bonnier and Luning have perforined experiments on Drosophila and found that the mutation rate at low les cls 135 tunnderably lugher than that which might be expected on the basis of a linear cuirse proceedling (lirectly to the vrigin. Seventh, it should be noted also that the mutations which are studieil in these experiments are generally krtown as pont mutations – that is, there is no anatomical chromisonil altera. tion It lias been established that the prociuction of mutations by chromosomal abertations is some type of multiple dem inncton and is hnuten to be clearly non-linear and may be represented buy some vype of power curie It is mteresting that in evainining the lata on mutations, these mutants which appear to be the Tesult of chromosomal effects need to le elinunated and there.

·62 Genetics, Radrobiology and Radiology FIG 1b No No -M-KO No N, Cr-KD) AFFECTED POPULATION TMS SEGMENT OF CURYE IS ESSENTIALLY LINEAR N. ( WHERE IS VERY SMALL ) Na DOSE Having discussed the dose response curve in this way, I woull like to proceed to the direct cxamination of some of the data whuch is available First, let us consider mutations in wluch there are enten. sive quantitative data. The data wuch are available on a rela. tively complicated organism is that of Drosophila figures are available at several levels and clown in relatnely low doses Typical material is that published by Curt Stern and lus co-workers. In an analysis of these data it has been postulated that the curie appears to be lincar through a fairly large range and appears to proceed directly to the origin It has been proposed, therefore. chat this is evidence in favor of lmcarity and therefore is a single cient function, and therefore indicates that the doses are cumulative and non-threshold. It should be powted out, towelcr, that there are sei cral points which deserie serious discussion First of all, if one plots Curt Stern's data so that the curve assumes N-N.C-KD form, only 8% of the total range is presented Iງ. other words, 92% of the organisins were unaffected for the lethal mitations which were observed This appears to be a narrow ·63 lienetics, Radiobiology and Radiology very significant test and supports the concept of a (timulative non-threshold type of cune. Howeser, I am sery mucli intrigued by what Dr. Russell has reported today. lle inlicates that lien 600 roentgests are celuered at once and then 600 roentgens delis. ered by fractionation or recluced intensity that the mutations are statistically fener. This, to me, is a very important item, and in effect means that the rest of linearity was $3* Iseen 132ct in mice. This could uucan eliat there might be some threshold, or dif. fering rates of acetimulation with differing doses. I am sure that geneticists will wish to examine this clonely. (Incidentally. I would like it) pant out here that I am 3036 a genetic ist and have camined this type of inforination as a radiologist and radiacion brokgist primarily to become mformed on this important aspekt of radiobiological effects ) Stall another test of linearity of the close respeirise curve can be made when varying types of ionization are sisexl, so that the density of the sonizing events per unit soltume is wiclely duver. gem It has been postulated on a theoretual basis that appears quite sound that the more densely ionizing the radiation, the smaller the effect per unit of jonization When the lonizations are densely pacheci, a single structure such as a gene or other target may be traversed by an jonization there than one. The sulse sequent comzations only contribute to the close but produce 10 added effect of only one jonization is necessary derical that Muller quvies work in Ives et nl. and by Vlickey anul Muller, in which radiation known to have a lugli ensity of tonization seems more effectne in producing point mutations consider that there needs to be further resolution of this in order to satisfy the single hit concept Some other points of conflict liave to do with the fact that when biological material is irradiated at various temperatures and varying oxygen pressure, the number of mutations vary 11 has been reported variously that increase in temperature increases the number of mutants, and other data haie indicated no differ. ences in tenperature Temperature effects and oxygen effects miglit be important since there might be sene indication as to whether a direct or indirect effect ix curs It seems para - ·61 Genetics, Radiobiology and Radiology fore the data for point mutations has actually been modified by the deletion of that number of mutants which have been esti. mated to be due to chromosomal aberrations. One of the questions that is important to ask is whether there is any biological material that appears to respond in 11011 linear fashion to ionizing radiation. In scaicing through the litcrature, it appears that the spores of Actinomyces worked on by Kellner and by Newcome indicate that there is non-linearity with response to the radiation. Although these are presumably point mutations, it has been suggested that these may actually be chromosomal breaks, thus accounting for the 10n-linear character of the close response curve. It is also interesting to note that mutations as a result of ultra. violet radiation are uniformly non-lmcar. The exact signifi cance of this is not clear, but in the radiation of biological tissuc. some of the energy transfer should concenvably be in the form of excitation Since ultraviolet radiation may only excite, it appears that excitation produces some type of non-linear curve, and it is conceivable, therefore, that some fraction of the energy transfer of ionizing radiation may be a non-linear function. It is also of interest to examine possible tests of the linear that is, testing of the cuve by various manipulations may indicate whether this is indeed a single cvent function and therefore linear, or semi-logarithmic and therefore likely to be non-threshold and cumulative. A semi-logarithmic curve has in it some inherent built-in statements. In a single event function in which one event is independent of tive other, tractionation of the dose should make no difference The density of the ionizing radiation should have certain types of effects and the character of the response should not be altered by extraneous occurreures One of the pieces of information uluch is strongly in favor of 1 single event or semi-logaritlumic function is the fact that radiation has been given over a wide range of mtensities and in widely fractionated doses. It appears that in the older literature, primarily on Drosoplula, and partially accumulated by Lea in "The Action of Radiation on Living Cells" that fractionation and wide ranges of intensity give essentially the same response. This is a Curve ·67 lienelis, Hadiomology and Radiology level of leukemia must be known in order to estalslish thic base ime. The data that are used indicare luat a loner naturalli (xul FOR AT ring ucidence of leulema vas present for the Japmese than is generally attributed to Imerican and European p>pula. tions It has been suggested that incomplete dugnasi mutheds mas contribute to this. If the incidence of leukemia in the 14px? nese should actually prole to be lugher than the level userl tliese studies, the character of the cure would be cleraly) alierer? and would tend to be m fav197 of the concept that a tresloki might exist Additional information which is interesting in tlus respect is that in animals, fractionation of the dese appears to pro duce a lower incidence of lenienia If this were izarly a single event function the incidence should be the same whether the classe is given at once or by fractionation. Additional studies abuch most appear to supjxır the thesis that leulenza is produced by lon levels of radiatum re illae reşkire. ed by Stewart in the Lancet Tlus is a study which is retrosper live in character and is designed to determine whether loukeni children terened more radiation 111 utero than non-leukemit chil dren The radiarion was delivered to the mother and the fetus This is a preliminary study - m my opinion 22 best provocare and not conclusie The objections to the study are these (1) it is in the most part in the form of a ques. connaire, and (2) it is not a blud study since the examwer 171015 słuch are the inothers of leukemic chuldren and which are the mothers of non-leukeini chulren. The effects altyabutable lo radiation must necessarily be very small from examination of the data. I do not recall the figures exactly. Iulit about 500 mothers of leukemic and 11-leukemi shildien were compared (111 a contemplared study of 1300} In the mothers of leukelti (luildren about 80 recensed alxdominal 1-rays of me type or another in the non leulemu group, about 40 mothers recensed V-rays It must be clear that 120 mnothers did that recente radiation and the leukemia in these children must be attributes to some other cause Collsersely. 10 of the non-leukem cikiren recensed radiation, such is not an inconsiderable peti entage. and yet these produced no leukemia Although the differences during pregnancy ·66 Genelirs, Rodiolwolngy and Nadrology Because of the proposals in the case of mutations that this might be a single cvent function, certain somatic changes lave been investigated from the post of view of the possibility of establishing these as single event functions as well. You are all familiar, I am sure, with the work by E. B. Lewis which was pul). lished in SCIENCE in which he tries to establish that the inct. dence of leukemia in Hiroshima and Nagasaki was essentially 3 linear sort of curve, proceeding to rero, and therefore postulating that there is no threshold for the production of leukemia and that the closes are cumulative no matter how they are fractionated or no matter how low the itensity It is difficult with the limi tation of ume to go muito tlus completcly, but may I report simply that the data as taken from his publication and handled by the method of lcast squares intere cpts the axis at a consulerabile dis- FIG 2 INCIDENCE OF LEUKEMIA IN MIROSHIMA AND NAGASOKI SURVIVORS (FROM EB LEWIS 1500 CURVE FITTED BY LEAST SQUARE YM. INTERCEPT I AXIS 49, ON INCIDENCE OF LEUKEMIA PER MILLION PER YEAR 1000 COMPILED BY WJ MCINTYRE WESTEAN RESERVE UNIVERSITY 300 SVOGESTS THAT THRESHOLO MAY BE PRESENT 500 2000 1000 1300 AVERAGE DOSE {RCENTGENS) tance from the origin. (See Figure 2). This suggests that some type of on-linear curve would fit the data betici. Ju is also inteiesting to note that in order to establish such a (llsc, the natual ·Geneles, Radobiology and Radiology ably this will not be possible until the exact mechanism of the production of biological effects by radiation is known. It will eventually be necessary to teigh the benefits of radiation against its risks To do this effectively, frotli will have to be assesseal very carefully Dr. Russell Jlay I ask a question? When you were dis. (Ussing this 115 and 075, are these two garnına ray experimens: Dr Friedell. Yes, there are the gamma ray experimcils. Dy Rucell. X-ray experment is, I think, ingher. Or Fredell lll get your the slope, but we may have been gamma and one inay baie lieen x-ray, I am not sure. Dr. Russell. You did tno gamma experiments, 1,011ar 50 r and then compared these with an acilte experineni? In Friedelt les 1r. Russell The first gamma experiment was ly Caspar and Stern. whu showed 10 significant <li{ference betkeen the irradiared and the controls Imever, the control rate was usually lugh Dr Friedell That s right Dr Russell And they invoke this as a possible esplanavon for the alysence ol a chillerence And the second one gasp a sig. ficant difference at the 34t, level as I remember D. Friedeli That's right That was lplroll and Stern.) 29 sang exactly the same data to shost that a imple of things $121 they didn't compare really showed a difference in other tuds. 1 houts exposure at 50 r ? days expxsure at 32,5 r \x{}} having in essence age sperm, the them these results which are Matistically different Dr Russell les So these were both gamma ray then That's what I wanted to kncil Di Crow The questtons Dr Friesiell mentioners are this. cussed regularly buy generxisis, and nobody regards them as finally and conclusiels sertle! Almost all studies have shown a strict proputihinality lietneen increased mutation production and Jose, though there are some exceptions The initisual rate in the controls mas explain the Steril and Caspari results. The problem in man is what happens at very low doses, and ·68 Genetics, Radioinology and Radiology in the two groups ale statistically significant, the interpictation will, in my opinion, be clusive itil much futher work is donc. It is clear that iſ radiation contributes to thic incicased incidence of leithemia in the fetus, it is m combination with some other causes and these are far greater than the contribution by the radi. ation itsell. The question of reduced longevity lalls into exactly the same category. The data on humans ale essentially nonexistent and practically all data are based on animals. It should be emphasized again that in order to conclude that small closes of radiation are cumulative, that a definite single event type of curve must be established. I bclicic that the evilence here is at best presumptive in animals, and certamly not conclusive. The only data that comes at once to min ou humans was published by Shield Warren in the Journal of the AM A. Thus purported to show that there was a decrease in longevity of radiologists as compared 10 other comparable specialists. It is cry interesting to note that E. B. Lewis in his article w SCIENCE used another type of sta. tistical analysis on these same data and concluded that the clifferences were not significant and might be expecteel statistically. Before I conclude, I wish not to leave any improper impies. I am certainly in favor of using radiation in the most (a1cful and sanitary fashion. I believe ici tainly that piccautions against the crcessive use of radiation are necessary, and I am not in any way opposing the idea that radiation produces scrious biological effects. However, a very important aspect of the prob. lem is determining whether the biological effects are nonthreshold and completely cumulative. I am amg the question that the data for the cumulatie non-ineshold xxn cpt us cutt clusive, that many aspects are equal, and there is a strong possibility that a non-lmear dose response (tri e might cientually be established, particularly for somatic effects .is I have repeat edly stated, a non-linear dose response curse would almost cer. tamly mean that there would be some type of threshold and incom. plete accumulation of the effects In the final analysis it will be essential to fully establish the Prob. dose respoise curve for various types of biological effects sion ·POPULATION ASPECTS: Aversing the Impact on Future Generations of an Increased Mutation Role; Jon Damage Might Be Distributed in Time: and the Extent of L'ncertainty of the l'roblem* Hs JAMES F. CROW, Ph.D), Professor of Cornelies (Mersity of Il 140 Vadison Il consta Irund a radiologist ought be tempteci to ask a geneve ist wly. In stets of the fact that the production of mutations by rays has been known for three clecades, many genetuists have only recently begun to express their concern about **»»le har. anels froin radiation in medu al practice I think the 21241 er is more than 31s2 the gresks the of public interest in radiaton Cullou. ing the deseenery of socieat tilesy and fallout For one tang, some genetic 13ts nutally 11 | Muller bare 10 uaited unul recently It the time of his great discovery in $427 Vuller (alter attention 10 this possible ampluation of luis findings However there are (10) kienui ( results that have caused genetiches to yourse apkard their previous quantitatile 1000)) alust possible hazards One of these has alrcarly seen print- Posted - Dr Russells findmy hai lhe intralien rate in the ilumuse is sme 15 tmies as fuigh as that in Drosophila, which pre. lisly had been the sole Basis for quantitaine extrapulation to man The second funding is that most recesse" mutations that fase been studied carefully turn out not to be compluiely reces **t, latt 117 have appreciable elles is on a single close It wo closes of a mutant gene are required to predice the effect, any bariful affect will be delayed anul luy coin adente or (artisanguineous ·70 Genetics, Radiobiology and Radiology I have one reservation about Dr. Friedell's emphasis on studies of intensity variation and fractionation at high doses. I suspect that in many circumstances we are dealing with a mixture of single and multiple lit cffects. Il only high doses are studied, multi ple hit effects may predominate and intensity and fractionation cffects will be observeel, wheicas at sufficiently low cleses single hit effects would become pieclominant I think that lincarity at high closes generally implios linearity at low closes as well, but curvilincarity at high doses does not preclude linearity at low doses I think that low dose studies of somatic effects, despite their great expense, are very much an order.

·POPULATION ASPECTS: Assessing the Impact on Future Generations of an Increasca Mutation Rate; Ilow Damaçe Might Be Distributed in Time: and the Extent of Uncertainly of Ilie Problem* JAMES F, CROW. Ph.D. Professor of Genetics nerirty olonsan Vadison Course I think a radiologist miglu be sempted 10 ask a genetist why, in vient of the fact that the production of mutations by rays has been known for three decades, many geneticists have outs recently begun to express their concern about pxins lile bas. ards from radiation in medical practice I think the answer is more than just the grouth of public interest in rashanion (olloru. ing the discovery of nuclear energy and fallout For one thing, some generte ists, notably fl I Muller. have not waited until recently At the time of his great dexovery in 1927 Vuller called attention to this possible implication of his findings Horseser there are the scientific results that have caused geneticists to revise upuard their previous quantitatile 1100TS abmus possible hazards One of these has already been men. nimned – Dr Russells finding that the mutation rate m the mouse is some 15 times as high as that in Drosophula, wbuch pre- Hesusis had been the sole basis for quantitative extrapolation to תונח The second finding is that most "recessite" mutations that hase been studied carefully with out 1101 to be completely recessise, but to har e appreciable effects in a single dose 1f t1so closes of a mulant gene are required to proluce the effect. any harmful effect will be delayed until by concidence or consanguineous ·72 Genetics, Radrobnology and Radiology' marriage two corresponding mitmt genes occur in the same person. The average delay might be hundreds or thousands of gen. erations. However, if there are appreciable effects in single dose those would begin in the immed ate progeny and the total effect would be spread over dozens rather than huireds or thousands of generations. These two fundings suggest that human effects are likely to be greater and to occur sooner than previous estimates had indicateci. Finally there is a somewhat changed opinion about somatic effects. There is now much wider acceptance of the possibility that lcuhemia and other malignancies at least in some cases may be due to somatic mutation or some other process that is linel. ically equivalent. The heritabılity and transmissibility by $11. gle cells of experimental tumors suggests the possibility of ctiol. ogy by way of some event in a single cell The analyses by Court-Brown and Doll (I) and by Lewis (2) of leukemia in irradiated populations suggest the possibility that there may be no threshold and that low doses of radiation may produce malig. nancies For all these reasons I believe that the current concern is justified and that it is quite proper that a new look be given to possible radiation hazards in medical practice I am therefore appreciative of the interest in the question that this symposium indicates. A SHORT SUMMARY OF THE ACCEPTED PRICIPLES OF RADIATION MUTAGENESIS During the past three years the genetic effects of radiations have been reviewed in so many papers and committee reports that only a heavily shiekled person could avoid encountering at least one of these missives (3-5) I'll confine nyself to a quick (onri-Brown, 11' 11 and R Doll 1977 leukemia of plastic anaemia !!! patients irradiated for anks lexing spondylitis Wrderal Pesearch Council Special Report X 295, pp 1 131 Her Vajests Stations Office LEWIS, E. 8 1957 Leukemia and conding radiation Science, 124 761 972 The Biological 1 flects of tomu Ratllations Summary Reports 1956 National Academy of Sciences-Vational Research Council, Washingten pp 131 ·Genelirs, Radionology and Radiology summary of current genetic opinions. The main points are these: 1. Jutain genes, whether spontaneous or radiation in. duced, are generally just as stable as the original genes from which they were derived: tllat is, there is ordinarily no "repair" of a want gene. Therefore, we conclule shat a mutant genre petsiats in the population until it is eliminated iss the preniature death or failure to reproclure of an arudin idual carrying Hl. Mutant genes, may, of course, be eliminated by chance, but they are exactly balanced by those that inultiply by chaine. Also there may be reverse mutarion, but this is len rare to require comm. sideration here ? The reglu of evidence indicates that the number of mutations produesi is largely independent of the intensity or spacing of the radiation, as long as the total dine delivered to the pre-reproduciile gonadis is constant For example, 100 r given in one minute, er 1 to widels separated doses, or at a scry slou rate over a long perxxl of me hare the same effect. The interence drawn from this is that lonizations frwn inlepyenilent imie. ang parrucles da not ordinarily interact Stext of the evidence comes from irradiared Drosophila sperm, and were clara from other organists and other stages are needed. 3 The number of mutations is linearly proportional in the chise in roentgens for better, rads). This has been demonstrated in Drosophila fr» disses as lon a's 25 r and to a lesser extent in many other experimental animals and plants. Unforemately, the data don't entend up as los doses as these likely to be encoun. leteci by the human population, and it is an important question whether extrapolation 10 lowes doses is justified Genericists are convinced that the lineanty persists doun to zero dose with no threshold, for Yestral reasons the line correctly preditts the tanruus mutarion rate when extrapolated lack ta zero dose; the sprontask of intensity or spacing effects mentioned above argues for the independence of each ronining panicle as a muragenic agent, 7 Be Hazards ? VAR O SITI AI and tiled Rattintsons 1974 Heincal Research ( NUZLU Her via's Stationen Office Report of the nicesi Saluopis Spumalac (oimmillee in the Fffetti sur Atom Rusytarat 45% (renal fiseve swel Hecords Thirteenth Session, Supplertiene No 11 l/5935) ·Genetics, Radiobiology and Radiology at very low doses spread over a long time there are hardly cier two or more ionizing particles simultaneously near together se there is no obvious physical basis for a non-linear effort. For these and other reasons, geneticists are convinced of the lincarity at low closes (5) I should mention that I have ignored numerous complicato ing factors. For example, spermatixls in Drosophila are more mutable than spermatogonial cells, but spermatid radiation is a very small and often preventable) pait of human poste Also those liereditary changes that depend on gloss chuomate changes do not follow the lincanty vule given here, but these are rare at the low closes being considered. I thinh none of the var. Jous complications are such as to altei appreciably the general conclusion of lincauty of genetic effects at low doses NATURE OF MUTATIONAL EFFECTS We are all familiar with vallons inherited diseases that occur by mutation - eg, aclırondioplasia, hemoplulta, neumoblastoma. agammaglobulmema Undoubtedly part of the effect olan increased mutation rate would be a somewhat increased fiequency of such conditious But there is gool reason to the shirt most of the geneth harm horn an increaseil muation rate would be of a los obvious sort Evidence for this comes pulmonly from (Ho somos. One is Drosophila studies These basc bow that mutations that cause cleath (lethal mutations) are much more (requent than those causing an obvious visible elicit But still more frequent than those that, while not causing certain deatii. incicase the probability of death by a statistically cletectable amount Such mutations appeal to cause minor impartments in the body function, such that the fly is more likely to succumb 10 the usual vicissitudes of life than if it duel tot carry thic mirant gene (7) "fuller, HJ 1917 Ilon untion changes the gentre constitution Ilom Ir, 1/ 929 939 Vuller, 11 ) 1950 Our load of mutat Im Inn (.cnet 21|| 170 ·73 Genetics, Radrobnology and Hadiology There is also indirect evidence from human sources. There is good reason to think that genetic weaknesses that are their ongin to mutation are uniquely resealed by inbreeling. Tlus He can get an idea of the nature of mutational eller es by examin. ing the children of cousin marriages and other consanguincous unions (8) There is so far a dearth of really satisfactory quan citatnie data on this subjet, but from what data are available the conclusion is quite clear: children of cosangumeonis mar. riages have an appreciably lugher death and morirulity rate than their outbred comemporaries The causes of learh are the 1931 ones eti(cutitered in children of non-consanguineous marriages; relaunely rarely are they due to recognized genetic diseases From this evidence from Dropinia anıt man, and from inte belief that most genes evert their major effect on the popularum in suugle dose (7). I would follos flat a large share of the genieuse damage in the population would be a general weakeung clue to various kinds of minor impairments, leading 11) increased! death and morbidity rates rather than to specific recognizalile genetic diseases The fact that much of the genetic damage is of this form. where it would not ordinarily be recognized as such, mahes k particularly difficult to asses Some geneticists have preferrut to ignore tlus as hemg toks intangible to deal sph, and have contenirared on specific genetic diseases where there are more pre (ise preluat ons of the sexial and medical consequences I must sly that to me this seems somewhat like measuring only tliat pari of an icelierg that appears above the surface of the water lle cannot tahe the angıne i tek that if most ulitations are mikl, they are therefore less important If a mutant gene (auses Its bearer a great deal of kannst 13 blely to merfere with his sufinal artd reproduction If lie doesn't surine or quesi)'t repro tlike she muntant gene is elimmated In general the less liarm a mutant lauses. the longer it persists as the xxpulauum There- Jesse if Ify effect on each individual is less it will affect a corre "Morton E.} } Croke and H | Suflet 1976 An estimate of the mutational dainage fratri data on constiguneous mariages proc Vat frad v 42 404 ·76 Genetics, Radiobrology and Radiology spondingly larger number and the overall effect on the population may be just as great or greater. There is considerable uncertainty about the effect of an increased mutation rate on genes of small effect, genes whose individual effects cannot be noted but which are thought col. lectively to influence quantitative craits still as licight and weight. To the extent (now unhnown) that the present frequencies of such factors are determined by balance between selective forces rather than by mutation, an increased mutation rate will not cause a proportional change in their effect on the population Hows. ever, the genes studied in Drosoplula and in the mouse, and on which all the quantitative extrapolations to man have been made are not of Uus kind DISTRIBUTION OF MUTATIONAL EFFECTS IN TIME As mentioned before, it itsed to be thought that most mutant genes were completely recessive In this case a mitant gene would remain in the population causing no effect mul. because of a consanguincolis marriage oily meeting a similai mutant of independent origin, two mutants occurred in the same indivudual. On the average this would require hundreds or thousands of generations with present levels of inbeed ng However, there is now abundant euidence that mutant genes that have a lethal effect when in a double dose cause appreciable damage in sigle close. In Drosophila a "recessive lethal causes a five percent or greater decrease in the surswal rate (7. 9. Presumably there is the same absence of complete recessivenless in genes whose homozygous effects are less than lethal, but this pomt has not been explicitly tested However there is indirect supporting evidencc for this conclusion If a number of new mutations were to occur non, the mutant genes would persist in future generations in inverse ratio to the extent to which they affected survival and fertility I find it con- Stern, C. G Carson, V Kinst. I Nositshi and D ''phoff 1952 Ilir sults of heterozigotes for lethals Genetics, 37 113 119 ·Genetics, Radrobiology and Radiology Tenient to express the time over which the population is affected in terms of the half damage time". This is the time by which half the mutants have been eliminated and therefore half the damage has been clone One can only guess at what this time is in man, from Drosophila data one would estimate it as from 10 to 50 generations (10. 11). So an increased mutation rate non would have effects spreading over thousands of years, diminishing gradually over this time QUANTITATIVE ESTIMATES If the muration rate were to be permanently increased luy a certain fraction, say 10 percent, es entually the inculence of inu. tationally caused disease and death would increase by this same fraction If we assume for convenience that the populatiem started at an equihbrum where nen mutants were being elim. nated at the same rate that they were arising by mutation, then It would require many generatus for the new mutation rate in be fully manifested in an increase in morbidity and death. The approach is ass mptotic so it is com enient to speak of the time » u Perch the population moves 50 percent of the way to the nex cquilibrium As before, this is protsably 10 to 50 generations The general result then, of a pernianent increase in the muta. {inn rate is a slow rise m the frequency of all inuitationally causeit conditions entil they have increasedi buy the same fraction as the 11utation rate ff we wish to say anything quantitative we have to rely on data from mie, there being no quantainely reliable data on man l{ ne compare the rate of occurrence of x-ray induced muta finns it me with spontaneous mutation rates in man, ne fun! that some 30 50 rad are required to cause in mice a rare equal lu etie spomaneciis rate in mau (3. 4, 5, 10). Thus a 30-50 rad (tox } 19% ihe estimation of spontaneous and radiation induced mula ton fa' 0 14t Lucents Quqrt 201 20k "Crow 1911 Possible consequence of an increaseul mutation rate Lugen Is Quart 467 ) ·76 Genetics, Radiobiology and Radiology spondingly larger number and the overall effect on the population may be just as great or greater. There is considerable uncertainty about the effect of an increased inutation rate on genes of small elfcut, genes whose individual effects cannot be noted but which are thought collectively to mfluence quantitative natts such as lieight and weight. To the extent (now unknown) that the present frequencies of such factors are determmed by balance between selective forces rather than by mutation, an incieascal mutation rate will not cause a proportional change in their effect on the population. How ever, the genes studied in Drosophula and in the mouse, and en which all the quantitative extrapolations to man have been made are not of this kind. DISTRIBUTION OF MUTATIONAL EFFECTS IN TIME As mentioned before, it used to be thought that most mutant genes were completely recessive In tiuis case a mutant gene would remain in the population causing 110 cliece until, berause of a consanguincous marriage or by meeting a similai mutant of independent origin, two mutants occurred in the same individual. On the average this would require hundreds on thousands of generations with present levels of mbreed ng However, there is now abundant evidence that mutant genes that have a lethal cffect when in a double dose cause approtiable damage in single dose In Drosopluia a "recessne" Jethal causes a five percent or greater decrease in the surual rate (7.)). Presumably there is the same absence of complete recessiveness in genes whose homozygous cffects are less than lethal, but this point has not been explicitly tested However there is indirect supporting evidence for this conclusion If a number of new mutations 1ere to occur non, the mutant genes would persist in future generations in inverse ratio to the extent to which they affected survival and fertility I find it con. Stern, C. 6. Carson, M hins, I lovitski, and D iphofi 1952 1hr walutors of heterozigotes for lethals Genetics, 37 113 119.

·79 Genetics, Radiobiology and Radiology a later age is a major tragedy. How do we compare physical with mental disease? Hon many persons whose health is mildly im. paired equals one seriously diseased? Furthermore, how do uc compare disease this generation with genetic impairment la cr shen medical progress in care and alles iation will have changed the nature of the disease? Yet it is only by attempting such measurements that any rational procedure for decision making can be evohed. For in principle each decision involving radiation must be made by bal. ancing the risk to the patient of not carrying out the radiation against the risk to his descendants (or to his later health from somatic effects) if the radiation is given. The problem of measuring future damage is complicated by the fact that our environment is changing so rapidly. In general these changes are such as to mitigate the effects of the mutations. But since reducing the ainount of suffering and death due to a disease usually causes an increase in the chance of reproduction, correspondingly more persons will be affected by the mutation. An environmental improvement is thus more like a postpone. ment than an obliteration of genetic damage. From this stand. point the most useful medical or ensironmental advance is onc that reduces suffering and unhappiness more than it increases festility Thus the problem of an increased mutation rate becomes a part of an overall problem of the relation between genes and a rapidly changing environment. Dr. Evans. Is there any specific question on interpretation or understanding that you would like to ask? Dr Pukey I would like to have some idea from the geneti. cists on the effect on the population of the deaths from amomo. bile accidents as compared to this overall radiation effect Dr Crow I don't have the figures in mind, but certainly al you consiler only gross abnormality the number of deaths from automobiles is considerably larger. Dr Friedell I made a calculation that if you ride in an amtomobile the same amount from now unt 1 you die naturally, the chance will be one in a hundred. It's casy to malc the cal.

·78 Genetics, Rodrobiology and Radiology close per gencration might Ive expected 10 double the human mn. tation rate If the amount of radiation froin meclical treatment is of the same order as background radiation (say, 3 rad) it may be estimated to be responsible for inci casing the mutation rate by about 10 percent, and thus to cause, if continued, an eventual 10 percent increase in genetic impairment. It is casier to say that the inci case is a certain percent of something than it is to say what that something is Accorcling to the National Academy of Sciences Report (3, sce also 5). about 2 percent of children born have or will have a scrious generic impairment. A 10 percent increase would add 0.2 per. cent to this. Relative to other hazarıls in life, this is small. At the same time in a large population the absolute increase would be grcat. Furthermore, I have included only the simply inherited tangible cflects. If what I have been saying is correct, the overall impact of individually small mutants would be much larger 1 have gncn somnc rather tunccrtali estimates of this elsewhere (u). UNCERTAINTIES One of the most serious defects in our present knowledge is the absence of quantitative human clata One couli extrapolate from clata on mice with more couligence of other mammals had also been studied. The only information to be siawn from the Hiroshima and Nagasaki populations is that human mutation rates are not grossly higher than those of me If, for example, man were as much more mutable than mice as mice are than Drosoplula, the effect should have shown up as sigmficant (lilfer. cnces in the data Even if we hiew the radiation meu el mutation rate with precision, the assessment of the impact of an increased rate on the population poses almost insuperable problems What le need is some overall measıne ol the wonial bilrsion - the clfect on health and liappiness - of mutation I mutant that causes and carly embryonic sleasli say be of little consequence, 1 deals at ·79 Genetics, Radiobiology and Radiology a later age is a major tragedy. How do se compare physical with mental disease? How many persons whose hicalth is mildly im. paired equals one seriously discased: Furthermore, how do no compare disease this generation with genetic imprirment laser when medical progress in care and alleviation will have changed the nature of the disease? Yet it is only by attempting such measurements that any rational procedure for decision making can lie colic. For in principle each decision involving radiation must be made by bal. ancing the risk to the patient of not carrying out ilic radation against the risk to his descendants (or to lus later health from somatic effects) if the radiation is filen. The probleni of measuring future damage is complicates Iyy the face that our environment is changing so rapidly In general these changes are such as 10 mitigate the effects of the inutations But since reducing the amount of suffering and dcaur dhuc in a disease usually causes an increase in the chance of repr««luction, correspondingly more persons will be affected by the mutation An ennronmental improvement is thus more like a postponement than an olliteration of genetic damage from this stand point the most tiselul medical or environmental advance is one that reduces suffering and unhappiness more than it increases fer- Thus the problem of an increased mutation rate becomes a part of an overall problem of the relation between genes and a rapidly changing environment. Dr Evans. Is there any specific question on interpretation or understanding that you would like to ash? Dr Purkey I would like to have sitne idea from the cists on the effect on the population of the deaths from automo bile accidents as compared to this userall radiation effect Dr. Crow I don't have the figures in mind, but certainly konsider only gross abnormality the number of deathis from automobiles is considerably larger Dr Fredell I made a calculation that if you ride in an automobile the same amount from dess unt 1 dic naturally, the chance will it on genet you you ·80 Genetics, Radiobiology and Radiology culation. There are 40,000 deaths from automobile accidents a year, out of 160 million people, multiplied by the number of years you are likely to drive, this will tell you the chance. It's pretty high – 1 in 100 of being killed in your lifetime by an automobile. Dr. Pirkey: One can express that another way that the average life shortening by automobiles is of the order of one year, Dr. Crow: Such comparisons are useful in giving is per. spective. However, I think cach health hazard ought to be regarded not so much as to whether it is bigger or smaller than something else but as to whether it is preventable or not. The main reason for really discussing radiation damage here is the hope or the possibility that whatever this amount is, even though small, it might possibly be reduced. And I would say the same thing about automobile accidents; they can and should be reduced Dr. Brues: This las perhaps an historical basis. Sometime ago all of these things were judged on the basis of how much was permissible. Then when it became clear that we didn't have the data to determine what was permissible un soine cases, we found that it was necessary to look at what people were willing to put up with for certain gams. The philosophy is a questionable one, but this is one way at least of seeing what people are willing to put up with when they have a choice Dr. Crow: If you take the best guess I can make from mouse data, you might say that a person who receives 20 r to the gonads would have about one chance in 20 of transmitting muita. tions that would cause a substantial effect in some descendant. As a very crude test, you might ask yourself, before giving such a dose, whether the good that you're doing for this person will more than compensate for a risk of 1 in 20. I want to emphasize that my estimate of 1 in 20 may be grossly wrong, but it serves as an illustration of the kind of approach one could consider.

·DISCUSSION OF LEVKEMIA AND RADIATION B1 AUSTIN M. BRUES, M.D. Sentor Biologist and Director Biological and Medical Research Atgofie Jatianal Laboratories Irmont, Illinois I regard to the patient who objected to having his chest film, it is possible to point out certain things The best guess is that under usual conditions, the gonadal dose is about .5 mr. from a routine chest film This is about the additional dose which you would get on an airplane trip overniglit to the West Coast or to Europe at 21.000 feet altitude Since this was an X-ray machine, the man was disturbed because he had not considered it Tal in such a context The dose to his chest is perhaps 100 mr ing the worst possible assumption as to the hazard of leukemia or cancer with this dose being about 10 per year or so, it > pxxssible to point out to him that at his age there is about a 10- chance of his developing lung cancer. We may assume that surgery offers about a 20% chance of curing one discovered early by tou. tine radiograplıy so there is a factor of something more than 100 becseen any concenable risk for the man, and what benefit would possibly be gained, leaving out the question of tuberculo. sis and other lesions which may vary from place to place. We have to look at these things intelligently The whole question has eleveloped certain psychiarrc aspects which should concerts all of us We should think carefully about these things. We can perhaps legitimately assume that radiation us in the main a harmful thing much of the additional concern is due to the fact thar many persons who are tertified by the holocaust that might occur if we have nuclear or thermonuclear war, will not admit this to themselses They transfer their anxiety to simpler things and, I thiah, particularly to leulemia. We have been 1 1 ·82 Genetics, Radiobiology and Radiology told, on inadequate evidence, that the hazard of leukemia following radiation is a straight-line function of radiation close. This is based on a simple somatic mutation thcory, assuming that a simple point mutation in a cell causes a cumor. We may recall, however, that in the human bone marrow, there are about 10:11 proliferating myloid cells. Assume that most of those might be cells in which a leukemia could originate. If the leukemia rate per r per year is estimated at about 10-", or one in a million, and if this is spread over ten years, which is based on the best evi. dence, we come out with a cell mutation rate producing leukemia around 10-14. This is an extremely low value and it forces one to conclude that there must be something besides one mutation in one cell that causes leukemia. Maybe it is cwo or three inutations in the same or adjacent cells, in which case, you would not get a linear relation It might possibly be a combination of things that radiation has nothing to do with; we don't know. Now, if we consider the mouse (who has a comparable leukemia rate) he does not live as long and does not have as many cells. His mutation rate has to be different from that of man by a factor of 10,000 or 100,000 If there is that much difference between the mutation rate of the somatic cells of a mouse and of a human being, somebody should look into this rather basic question If this is not the case, then this means that the situation is a little more complicated than that of a single point mutation. Court Brown and Doll have made a careful study of persons who received spinal irradiation for spondylitis, and infer that there is a linear relationship between the amount of radiation in the spinal marrow and the number of leukemias The lincar curve was obtained only by the device of cutting out a certains category of cases wluch happened to inclucle about 80% of the cases which were in the highest dosage category Laching thus (I think) illegitimate selection of cases, we find that the leukemia incidence departs from a straight line and suggests a very small, or no response, at low doses We have also examined the number of leuhemias wluch were observed in the various zones at Hiroshima At the time these furt nublisher It seems as though they made 1 ·83 Genetics, Radiobiology and Radiology straight line with dose, but they no longer do with further data now available. All that we can say at present is that doses above 100 r are leulemogenic. About a year ago, the geneticise, Dr. E. B. Lewis, furtherer? the straight-line theory by using the data discussed above. If we repeat his data on a logarithmic graph, we find that a better fit is obtained if we assume that the leulemia hazard follows the square of the dose, or if there is a true threshold, at around 70 r. Probably the most striking data are those on the incidence of mouse leukemia folloning various doses of gamma rays and neu. trons The Ilio behare rather similarly, judged by Upton and Furth's study. What one sees here essentially is an increase, palta ticularly when one gets up to about 120 r exposure, and some of. fect has been suggested as low as 12 r. 'The data not suffi. cient in scope. This. I think, is trule of all data on animals that have been obtained so far to demonstrate whether or not there is a linear relation between myloid leukemia and radiation expers. use it is very definite that there is not such a relation scisces lymphatic tumors and irradiation, as I think is well kurus Perhaps the most disturbing data are based on a suncy by Alice Stewart. Similar findings have been obtained in a louisi. ana study These are studies of childhood leukemics thosc histories have been riaced. They found that if a child has leukemia. there was a greater probability that he was x-rasel in nero. While the excess s about (110 times, the actual increase in Stewart's series amounts to about 18 cases There is also a similar excess in the case of cancers occurring below the age of 10 This could be a serious matie This has been criticised in various respects One objection is to the effect that peliituery is sumc. umes done on the basis of some medical indication and that this indication might in sume way represent a particular state of heath The other thing to mention is that one ought to look at as many possible potential causes of childhood leukemia as posschie and not limit consideration to radiation study done by the Pubs. lic flealth Service, using Dr. Sitiney Farber's clinic seems to show that chikiren of allergic mothers, who incidentally had been on ·81 Genetics, Radiobiology and Radiology antihistiminic drugs, showed a similar relationship. They turned up more frequently in the motherhood of the leuheinic children than in the motherhood of the controls. I would only mention for the benefit to the radiologists who are here that studies of this general nature are treniendously important. They must bc done quite judiciously, because it is very casy to embark upon a followup of a series of cases where it can be demonstrated that a positive answer cannot be obtained. So far, the retrospective studies have been very difficult to cvaluate. For instance, when one looks at a clinic full of children and attempts to trace these things back and tries to draw a correlation between them, a very small population of leukemics will represent a very large total population Certainly there are other lulemogenic agents than radiation. The inculence of leukemia when corrected for proba. ble improvements in diagnosis has certainly more than doubled in the last twenty years in this country durmg a period when I 301 sure that the total radiological exposure of individuals has gone up somewhat less than that. Besides, we know of other leuke mogenic factors Dr. Evans: The discussion on the morning session is now open to the floor Dr. Lodwick: Just one question. What gencs are alscnt on the Y chromosome of the male? Dr. Herskowitz: On the fruit fly, they are all absent cxccpt for a few fertility genes, and in humans there is a section of genes on the X chromosome not present on the Y Di Crow: In the human you realize we don't know (00 much There are hrown to be several on the X, but we don't know whethcr there are any on the Y or not Di Friedell I would like in ask Dr Cron a question X-ray's produce «leleterious mutants which are introduced into the entire gene pool One of the ways of adding to the <lelctcrious genie's is by changing the rigors of selection It is conceivable that mci. ical science is adding to our cleleterions genes without completely Would you elaborate on some aspect of this a bit? Dr. Crow: I have one thing I want to say before I start 01 compensating for them ·85 Genetics, Radiobiology and Radiology this discussion if we were treating the question of the origin of leukemia strictly as a scientific question, even boxly would say that the evidence isn't in yet. We don't knows whether there is a linear cffect (in low doses, so therefore, le don't say anything about it. There is no evidence that is crucial either way. We have the kind of evidence that Dr. Brues has reviewed, most of hxh is relevant for high doses, but less certain for low. We have the kind of evidence which Lenis has put together, which is inconclusive though strongly suggestive. Under those ciruum. stances, I think an agnostic attitude is all that sic can take. Until the evidence is clear, I think there is merit in basing our calcu. lavons and practical decisions on the more pessimistic assumption of no threshold! I have the same remath about Alice Stewari's dara. It is strongly suggestive, but I would certainly agree with Dr. Friedell that retrospective studies can never conclusively ansuer cause and effect relations and that we must try so get information from other sources Regarding this other question, 1 grossly ojcrsimplified this problem, though I herpe next to the extent of lyeing misleading But I think froin the standpoint of the medical man and the eugenecist that the way to look at it is this. I suppose we have a mutation that occurs at a rate X and it causes death. That means in every generation there are X dcaths due to this cause. Nou suppose that medical advance tales place in such a way that this particular mutation has only a 50% probability of causing death That means that this population is going to approach a state in which there are 2X of these genes in the population ciery generation Since each of them nos causes only half a death, on the average, there will still be X deaths. Now I think the impxır. jant question to ask is whether the amount of suffering to the human population (ram 2X mutations in the new ens ironment is less or more than it was from X mutations in the olal environment To restate this in other words, I think that a medical advance that decreases suffering more than it increases fertility is a good medical advance A medical advance thai increases fertility more ilian desseases suffering is, eugenically speaking. a bad medical adiance ·86 Genetics, Radiobiology and Radiology D}, Friedell: I don't want to prolong this conversation. The only reason I brought it up is that it is conceivable that some day you might want to measure the introduction of new genies that are deleterious. Let iis assume essentially they are all deleterious, by x-rays as compared to the kind of suffering, if this condition occurs, by ameliorating the rigois of selection, which is what you are really doing with medical advance. I would like to liave the geneticists do that rather than me do it. Di. Croue: Well, the geneticists ought to be doing it. I for one have spent a lot of time thuhing about it. I don't think it is very apparent from what I have said now, but the time was spent. The other thing I want to say is that I have more or less assumed in what I have said thus far that the cconomic status is well enough that we can afford 10 contribue in every generation a larger fraction of our time to taking care of genetic weaknesses in the other person. That is, of we should ever icach a state where we can't affoud to have as many doctors as we used 10) lave or we can't afford to have as many blood banks or whatever cise it takes, then one has to consider the genetic problem ser agun. I alunk that inter-relates economics, medicine, eugenics and everything into one lopelessly complex problem. Di Paul Hodges In discases where the incidence is as low as a leukemia, it is easy to be trapped into a statistical error. Some years ago we did pelvimetries on a thousand consecutive pregnant women at the Chicago 1.ying-In Hospital and I, like many of my students and colleagues, made the statistically foolish mistake of assuming that it would be profitable to examine these mothers and their babies for leukemia and neoplasm One of my extremely capable statistician friends saved me from thuis eno by pointing out that even if our pelvimetries hacl «loubled the normal incidence of leukemia (normal, a per hundred thou sand) we couli not hope to get statistically valid information from an examination of a thousand patients In situations such as thus, mestigations have to be based on statistical analyses of sliole populations Di. Cron": I want to make two other remarks enactly con. firming wliat Dr Friedell has said Maybe everyone here is ·87 Genetirs, Radiobiology and Radining familiar with Dr. Shields Warren's study in which lic suggester! klat radiologists lived five years shorter on the average than other inedical specialists. This is a retrospective sfasily, it's clanc by gathering death rates from the obituaries published in repitta. ble journals But it has a very olssions statistical fallacy, the fal. lacy simply being that radiology is a comparatively young profes. sion and that there aren't as many radiologists to examine. It is almost as if you measure the age of leaths of all Princeton students you would conclude that l'rinceton studemis dical at an extremely young age because those who die while they are stil. dents are young. There are other things alxu questionnaires. Mock and Lawrence ran a study of radiologists and I ran one at the same time Our the questionnaires dillered in one con spichleus respect, and inaybe some of you were among the guinea pirms that answered one or both of these, Jack and Laurouce's cre done by taking the respondent into his confidence and tell. mg him the purpose of the questionnaire and then getting the Mine was done by sntentionally concealing the purp KC of the questionnaire, at least intil that person started 10 ansuer 11 There is a very conspicuous diung in Dr. Mock's daia That is that the persons that he had to write back to the second ume and no (anted to answer at the first time have a higlier miscarriage Frequency than the persons who answered the first time. We neser del get as many responses from the pathologist group as he did from the rachologist group It seems quite reasonable that had he been able to get as many pathologists to respe, and setnizing the bias in fasor of those not responding if you had bad some defect in the family, perhaps this difference soukl fase sdisappeared 1r Boites Sight I add for the benelit of those who may sull be sorried about their life spans, that the British have now clone a study on all British radiologists going back to 1898 or whenever they started. They find, having done the eight corrections siluch Warren apparently did not do, that radiologists Bronn, Land Hall, R. Expectasso al Life and Vonalits from Cancer Antong British Radiologists British Medical Journal, Vol 2 (July 26. 1958), PP answers IAL 1R7 ·88 Genetics, Radiobiology and Radiology ! had a better survival than in some controlled series of doctors Dr. Scoit: In the February 8, 1958 issue of the J A.M.A. is an article by Seltser and Sartwell on "Ionizing Radiation and Longevity of Physicians," which concludes, "that the average age of radiologists at death is younger than that of other physicians cannot be ascribe to their exposure to ionizing radiation since differences in age composition alone can account for the finding" Dr. Fredell: I think Lewis pointed this out very well. In his one article, he made this particular analysis showing that statistically the difference that was found was to be expected. Dr. Evans: I think everybody will agree that regardless of the amount of the problem, we certainly want to reduce raclia. tion exposure to the gonads insofar as is feasıble and thus is going to be taken up by the clinicians as to how they can best do it

·AFTERNOON SESSION
THE PROBLEM OF REDUCING RADIATION CENETIC
EFFECTS IN THE MEDICAL USE OF .X-ITYS
Moderator: Pendell G. Scoll, J.D.

·88 Genetics, Radiobiology and Radiology 19 had a better survival than in somnc controlled series of doctors. Dr. Scoll: In the February 8, 1958 issue of the J.A.MA. Is an article by Seltser and Sartwell on "Ionizing Radiation and Longevity of Physicians," which concludes, "that the average age of radiologists at death is younger than that of other physicians cannot be ascribed to their exposure to ionizing radiation since differences in age composition alone can account for the finding" Dr. Friedell: I thinh Lewis pointed this out very well. In his one article, he macle this particular analysis showing that statistically the difference that was found was to be expected. Dr. Evans: I think everybody will agree that regardless of the amount the problem, we certainly want to reduce radia. tion exposure to the gonads insofar as is feasible and this is going to be taken up by the clinicians as to how they can best do it.

·- GROWTH OF DIAGNOSTIC RADIOLOGY AND MAGNITUDE OF PROBLEMI WENDELL G. SCOTT, 1.D). Professor of Clinical Radiology as angion ('#nesity Sclient afterlicone Stams, facsauri Dr Srott. The afternoon session is devoted to the problem of reducing radiation genetic effects from the meclical use of x rays By way of introducing this subject, 1 3ould like to shov a fex slides to indicate the magnitude of our problem Diagrxiu radiolag, has had a tremendous month because of the scat contributions it has brought to the health and well l>eing of man. Lind This was not due to accidental or formous circumstances It came about because it was and sell is the means for lifting the cloak of uncertainty from diamosi merkene Nearly every practicing pryscian cither directly or indirectly utilizes the indispensable advantages offered by diagnostic radiology for the benefit of his patients The total number of radiologic exanına. tions and the films consumed per year are in the millious (Table 1) IV EFI I VI VIBERS OF RIDIOGR Irill III ITIOS FII COSI VED HD MIC\OSTIS 1.81 PXES I 1953 . wlogues - Tpment 1 1973 knit Laughlin Pullman (1) "Laughlin ] S. and Pullman I The Biological Effects of Atomic Radiauon (Gonaill (Xoxe From tbe llela!!* of Rass-reliminary Report) National Acaulem of Sciences Washington, 11, Varch, 1997 91

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·Genetics, Radiobiology and Radiology literature and estimated it to be 4 6 roentgens 3 in a prelimin. ary Report that has not been officially released in the National Academy of Sciences. This figure is not a fact. It is a rough estimate based on data of varying reliability. The report in Octoler, ,1957 by the International Commission on Radiological Protec. tion and on Units and Measurements (3) states that. "Enquiries up to the present kase siot revealed any records detajlet enough to use for the proper assessment of the gonadal doses les the popu. Jation." In a subsequent paper, Laughlin and associates (1) discuss the studies and surveys that are required for ohraining the necessary information to develop this figure. Until this can be done and an accurate estimate of the genetically significant gonad dose determined, we must be extremely cautious about acrepe. ing or formulating quantitative inferences from diagnostic vray prodecures In the assessment of the possible delcterious effects arising from the medical and dental use of x-rays, it must be clearly understood that: (1) Only small doses of radiation are used in clinical examinations, and (2) the exposures are limited to local or segmental areas of the body as opposed to total bowly irradia. tion Many of those who emphasize the bad effects of diagnostic expastires do not distinguish between local and inial body rachation The "roentgen" is the measure of exposure to each gram of tissue, and as Stone (2) points out, "1 roentgen to a ine is vastly different than 1 roentgen of total body exposuire", With these introductory remarks, we are ready in proxeed! with the problem of reducing radiation expostures in our clinical examinations The first paper 5 "A Tra? Balance of the Resulis of Clinical Exposure to Jonizing Radiations," by Dr Theo dore Eberhard Stone 5 Conson Sense in Radiation Protection Ipplied to Chical Prac. We Smert journal of Rnentgenology Radautt Therapy and Vauclear Medicine. iR 993 99. Decemtxt, 1937 "Expmure of an tolonizing Radjalin Irising from Vedical procedures - 19 Enquiry into Methods of Fialuation Report of the Internalona! Commiseen Radiological Protection and Internationair- Measurements Physics in "Laughlin J S Veuth (unadal Dorts in Routine.

·Genetics, Radiobiology and Radiology' Add to these figures the 5,000,000 radiographis and the 1,900,000 fluoroscopic examinations that are performed annually by thc osteopaths, the chiropractors and the chiropodists and it becomes readily apparent that we are dealing with a big and an important problem The observation that the number of plıysicians owning radiographic equipment has increased 50% from 1919 to 1955 is elisturbing and probably reflects the introduction of health plans that permit the subscriber to have "fice x-rays," a temptation that can be corrected by instituting a deductible type of health insurance. To keep these figures in the proper perspective, remember that the great bulk of these procedures are made on sich people, on those seriously ill with an obvious short liſc expectancy, and on those over 30 years of age. Only a small percent of the total could be considered as unnecessary or needless exposure. Most physicians are careful abont ordering radiograpluc examinations and do so only when the benefits will outweigh the possible larm. ful effects. Similarly, we should not overlook that during the past 50 ycars simultaneously with the expansion of diagnostic radiology, the life cxpectancy increased from 49 2 to 68.07 years, the death ratio from tuberculosis dropped from 194 to 9.1 per 100,000; infant mortality fell from 99 9 to 264 per 1,000 live births; fetal (leaths dropped from 23.9 to 17.1 per 1,000 live births, and, that American children toclay are said to be taller, healthier and have a lower death rate than before Stove (2), who assembled these statistics, points out that while radiology cannot lay claim to being the major reason for these great medical achievements, it played a very conspicuous pait. His inference is that if radiations of this order contribute to the shortening of the life span and produce genetic damage, they are not yet evident. It would be of great help in determining the extent of the genetic problem if we knew the average gonadal dose the popu. lation was now receiving from medical and dental sources and how it compares to natural background radiation. Laughlin and Pullinan (1), March, 1957, attempted to do this by a survey of the ·97 Genetics, Radiobiology and Radiology of x-rays and radium. Radiation induced carcinoma and aneinia were recognized within a few years The leukemogenic effect and the genetic effects have been known for over a quarter of a century. The so-called law of Bergonic and Tribondcau that sensitivity to radiation is insersely proportional to the degree of differentiation was formulated over 50 years ago, largely on the basis of observations of the elſect of radiation on embryos Tliese truths we also hold to be self evident What is not self-evident is the magnitude of the factors imolied How much radiation is necessary to prxluce a guen effect? What is the relation of the age of the individual to the dose necessary for any given effect? Are all end-results without threshold in their inception? To what extent are various somatic responses linear in relation to dose? What is the eflect of the rate of administration upon the ultimate response? What is the range of the variability of response in any given group of luumans? To what excent are radiation responses dependent pour co-far. cors in the genetic, hormonal, and environmental profile? To all of these questions and many more we must have lactual answers, reliable within limited ranges or small orders of magnitude. before we can truly assess the individual and the aggregate haz. ards This does not mean that we have no gude lines for that our lack of precise knowledge justifies the indiscriminate and careless use of sonizing radiation We have impressive evidence of a lon car relation of dose to genetic respxinse from 15 up, regardless of the rate of administration, and strongly suggestive esidence of linearity at much louer levels If our analysis of the mechanism of genetic elfecus is correct, there is no logical reason to expect anything but complete linearity without threshold for poine effects At the same time, we do not knox che relatise probabili. ties of lethal mutations and merely damaging changes, nor what constitue signifiant genetic injuries as opposed to those of no Colisequence How fast ran the human race breed out unclesira. ble traits and liat burden of these can the face tolerate What is the relatie impostance of radiation induced multations and these resulting from other sgrious factors? Dr Datid Barr has ·96 Genetics, Radiobiology and Radiology able that with prolongecl non-radiologic studies, the anatomic and dynamic aspects of congenital cardiovascular malformations would have become sufficiently well known to establish an ade. quate base for the accurate diagnoses and intricate surgical repairs so common today, but it is certain that this development would have been delayed many years while many hundreds of children paid the supreme price for our ignorance. Only those of us who lived and worked on neurosurgical services before the full development of pneumoencephalography, ventriculog. raphy, and cerebral angiography know the heartaches and trage. dies that went along with attempts at the clinical localization of brain tumors followed by futile inauling and probing of the bram in vain search for the lesion. Only too often we found at autopsy that we had been at the opposite end of the head from the tumor or, even more tragic, had failed to identify the lesion because its consistency offered no clue to clic explorng reelle. Luckily, lung cancer was not common in those days, for it never occurred to us to get a film of the chest first in every case of suspected brain tumor. Prior to the advent of x-ray control, orthopedics consisted of bone setting Unfortunately, there are no figures to tell us how many mothers have died bccause no one knew that some abnormality of the fero-pelvic size or position made delivery impossible, or how many kinnecessary Caesarian sections have been done because soincone could not resort to roentgen means to prove that such an impediment diel Through fustory much genetic material must have been lost and much personal tragedy inflicted through lack of ability to gain information There is no point in belabouing the issue further In the words of the Declaration of Independence, “We told these truths to be self evident Equally self-evident is the fact that konzing radiation is claumaging. My first lesson in radiology as a student of the art and my first dictum to my own students was and is. “The only safe X-ray machine is one that is turned off, and the only safe racu is that which is inside an arlequate lead block The first she damiage was noted and reported within months after the discovery - 10 more not exist.

·97 Genetics, Radiobiology and Radiology of x rays and radium. Radiation induced carcinoma and anemia nere recognized tithin a few years The leukemogenic effect and the genetic effects have been lnown for over a quarter of a century The so-called las of Bergonie and Tribondeau that sensitisity to radiation is inversely proportional to the degree of differentiation was formulated over 50 years ago, largely on the basis of observations of the effect of radiation on embryo. Tiese truths we also hold to be sell evident. What is not self-eudent is the magnitude of the factors insohed How much radiation is necessary to prxluce a given effect? What is the relation of the age of the individual to the dose necessary for any ghen effect? Are all end-results without threshold in their inception? To what extent are sarious somatic responses linear in relation to dose? What is the effect of the rate of administration upon the ultimate response? What is the range of the variability of response in any given group of humans? To what extent are radiation responses dependent upon co-fac tors in the genetic, hormonal, and environmental profile? To all of these questions and many sore we must fiave (actual answers. reliable within limited ranges or small orders of magnitudc. before we can ruly assess the individual and the aggregate har. ards This does not mean that we have 110 gunde lines nor shar nur lack of precise knowledge justifies the indiscriminate and careless use of ionizing radiation We have impressive evidence of a lin. car relation of dose to genetic response from 25 T up, regardless of the race of administration, and strongly suggestive evulence of linearity at much loner lesels Jf our analysis of the mechanism el genetic effects is correct, there is no logical reason to expect anything but complete linearity without threshold for point effects. At the same time, we do not know the relatise prolvaliili. tres of leihal mutations and merely damaging changes, nor liat constitute significant genetic injuries as oppxxed to those of no swysequence How fast can the human race loreeil out undesirable traits and what burden of these can the race tolerate? What is the relatie importance of radiation induced mutations and those resulting from other norious factors: Dr David Bars has ·98 Genelis, Radrobiology and Radiology pointed out, no agent that can modify the internal environment or organic integrity of the body can be used without hazard." We inust admit that we know precious little about the genetic effect of many of these agents, especially as they may ari in concert with ionizing radiation. It is with regard to the genctic damage to the race that we come straight atlnvartshups of the most serious moral and philosophical problems is the well-being of the mdividual para. mount or sulodunate to that of the race or group? Granting that this is not an all-or-none proposition, then what degree of risk may I take with one for the benefit of the other? What profits it the unborn children if I destroy the parent? Or one 333ay even argue thus. The individuals most likely to require extensive medical exposure are those who already possess weak nesses rendering them Jess fit to meet the exigencies of the presche world. Reducing the vrability or fertility of these indivi. duals will tend to lielp the race while at the same time alleviat. ing their personal suffering Accmare knowledge of the average number of ronizations in the gonads nccessary to produce 1 or 2 or 10 331(acous would help m assessment of the risk but would not resolve the inoral issues at stake. And these issues we must continue to face as we liave always faced them The problem is uot new It is simply bigger. Sumarit damage in the lisuual proses slightly different problems The evidence for a no-threshold, strictly Imear re. sponse relationship is less convincing than in the case of the genetic damage. It appears that there is great variation in age response or organ response as well as considerable deperience tipon the rate of acmimstration Tere, deme data is of lic utmost practical importance l'nfortunately, all we have is sug. gestive data, and all ac can say is that the available data scem to fit a pattern This pattern appears to have somethmg like ilic following form For genetic effects there is no threshold and no reenery The problem aftecis persons only from the time of their conception to the time when they have conceived their last chuld In the aggregate, thus means potentially fertile men and women up ·99 Genetics, Radiobiology and Radiology to the age of 33 or 10 years The magnitude of the risk is Sur in sed only in terms of a duilling dose thought to be in the neighborhood of 50-80 roentgens Carcinogenesis, including leuleniogenesis, while having some sort of linear relation to dose, appears to be also snfluenced by age and rate of administration Alice Stewari's figures suggest be pro. that at sonte time during embryonal life a slight effect may duced hy as little as to fr Simpson and llempleman's studies of infants indicates a similar effect from doses of 50 to 200 r. Data gnien by Court Brown. It'arren, Louis and others suggests that to get the same incidence of peoplasia in adults, it may be necessary to give 200 to 500 r or more, clepcuding upon the organ being studied, the dose rate, and other factors. In this regaril, It shouid be pointed out that the relaine volume close has received comparatsely bule astention, and it is possible liat the wate spread between Stewart's embryo figures and Court Brown's adult doses is wholly explainalle on this basis In any cuent, It is eudent that again and regardless of exact quantitatiic do. smerry, the criocal segment of the population is the young group They may be more sensitive and certainly have longer to accumlate a damaging close and a longer time in which to suffer from the effects Hence, we retum once again to the moral and plulosophical or ethical aspects of radiation exposure lonizing radiation may be looked upon as just another dangerous weapon. L'sed wisely. ir prouides safety and wellbeing for the individual and the community Abused, it can destroy both. As with a gun, one must not hesitate to use it when the need arises, but one must always tale precautions to make sure that one is shoots a burglar and pot one of the children Fortunately, this is much easier to do today than 50 years ago The 2:atšability of good training. greater knowledge of dosimetry, the development of better recording media, and increased realization of the hazards of the Heapons have greatly enlianced our ability to skox, metaphor. cally speaking, faster, more accurately, and with greater economy of ammunition In many fields, the use of ionizing radiation was of necessity somewhat profligate during the developmental stages, ·98 Genelias, Radiobiology and Radiology pointed out, no agent that can modify the internal environment or organie integrity of the body can be used without Irazard." We must admit that we know precious little about the genetic effect of many of these agents, especially as they may act in concert with ionizing radiation. It is with regard to the genetic damage to the race that we come straight athwartships of the snost serious moral and philosophical problems. Is the well-being of the melividual paramount or subordmate to that of the race or group? Granting that this is not an all-or-none proposition, then what (legree of risk may I talc with one for the benefit of the other? What profits it the unborn children if I destroy the paient? Or one inay even argue thuis: The individuals most likely to require extensive medical exposure are those who already possess wealnesses rendering them less fit to meet the exigencies of the presont world Reducing the viability or fertility of these individuals will tend to help the race wlule at the same time alleviating their personal suffering Accurate knowledge of the average number of ionizations in the gonadls necessary to produce 1 or 2 or 10 mutations would help i assessment of the risk but would not resolve the moral issues at stake And these issues we must continue to face as we have always faced them. The problem is not news It is simply bigger Somatic damage to the mdividual poses slightly diferent problems. The evidence for a 10-threshold, rictly Imear response relationslup is less copyrnung than in the case of the genetic damage It appears that there is great variation in age response or organ response as well as considerable dependence upon the rate of administration Here, definite data is of the litmost practical importance Unfortunately, all we have is suga gestive data, and all we can say is that the available data seem to fit a pattern. This pattern appears to have something like the following form. For genetic cffects thcie is no tlireshold and no recovery The problem affects persons only from the time of their conception to the time when tliey have concented their last child. In the aggregate, this means potentially fertile men and women up ·APPLIEP RESEARCH TO DIMINISH MEDICAL DENTAL RADIATION HAZARD By DAVID GOULD, .1.D. Professor and Ifead, Department of Radiology Untersity of Don Medical Cetyler Little Rock Arkansas Several monilis ago I wrote a paper on the frazards of radlia. tion, and judging from the reaction many people read it There is much talk abom the hazards of radiation. I am tempted to wsite a paper on the hazard of radiation hysteria." I think this is a very definite hazard. As an example of what is going on. I started a mass x-ray survey m the early 40's, anı ixer a period of 12 or 13 years, there were only two cases that came to my arten- Lion of people who were ress:bly worries alsu rachation. One mas a girl in the Veterans Administration and as slie was stand. ing in line for the photofluorographic examination, she said, "I can do ic. im not going to go aheaci and get that chest film because I'm allergic to radiation." I tried to convince her and finally succeded, that radiation does not cause any allergic rear- She had her chest film and we did not find any tuberculo $15 2n that particular girl Nothing happened for a period of about ten years, and when I was torking in Baltimore, a lady called me and that she wanted to borrow a geiger counter because some people in a hospital wluch was luse miles away from her home. pointed an x-ray machine at her and she was telen ing "harmful effects from these rays' This unfortunate woman was obviously mentally ill Pothing really perturbed me very much until the last fers years I could mention a dozen examples of people who have gone a bunt too far in the direction of what may be called 'radia- 11013 hysteri3" For instance, as soon as we opened our new tions 101 ·100 Genclics, Rodrobiology and Radiology but as Sosnian lias said, "... the ultimate objective ol all of these very complicated and sometimes dangerous procedures is to learn enough about these conditions so that we can go back and refer our knowledge to the original, simple, uncomplicated exami. nation and know more about what we are seeing and finding.' It has been suggested that there should be legislation limiting the amount of ionizing radiation to which a plıysician may expose a patient. I can think of no more unwise legislacion that could possible be conceivel. Had such laws been in existence for the past 25 years, for example, some of the most valuablc knowledge cvei gained from the use of ionizing radiation would never lave licen obtained, and none of the real damage would have been prevented. The real solution to our problem lies in continued research into the detailed nature and magnitude of these hazards, con. tinued education of the medical profession, scientists, and the laity, and calm, dispassionate consideration of all of the scientific, moral and ethical factors involveri Di Scott. Dr. Eberhard, you understand the art of meclical practice Thank you for a splendul presentation Would any one like to ask Dr. Eberhard a question? The general discussion will be deferred as was done this morming, but feel fiec to ask questions.

·If onc IOS Genetics, Radiobiology and Radiology On the one hand, the radiologist says radliation is gooul and on the enher hand, the geneticist says radiation is bad. They probably are both right. Raslation, in common wuh any other form of eitergy, is both geol and bad. It depenis nixon for it is useil. In my npuis, is the hands of a well-traince radiologist, radiation is at least 939 beneficial and less than 50 barnful. This figure is arlsterary. It inay kell lie 990, on the plus siile and only on the mus sode The sum total of an innfort. happiness, longevity and benefit derived from arbologi diagnos. txt and therapem proncedures can never le measureil compare the mortal.ly statistics of 1900 with the mortality 64.a. now, you will find that at lcast 20 years have been added to the lumman spans of life Idvances in Tolern meclicine have been an impartant factor 111 this improvement Many of us here are Tyg 11guantitate llie baul effects of radiation Studies shemale certainly go (orward to find out exactly hou much larm is done Since there is a fusard in the use of radiation). Aven though it has now been quantitated, ut lschronies ile ralliesterise to do every: flux jelle is made this haraul. lxl 13333.28% and genetic What can be done {rtu a practical point of vien 10 reduce this Bazard w 3 minumum Without an apprecialile (utlas of money a crainiesl railways can reduce the lazard 509,by Snjloning thi<5€ simple rules l'se the more efficient lugher Llosoliage and lover tuillampeic teslimques Test equipruent periodically for leahage anul cupit (1) 'se al lca 11 militrieters of aluminun filtration 14 I've field timang cones and draplırams as much as Kasuhile. Chxe che fastest, practicable screen, film and chem. cal combuiation (0) I'rikes films full time using 201ve chemicals 300 furopei teinperature l'rufect the gonals in patients below the age of 40 ist yourself, 'Is this examination portant to the liealthi and uel leing of the patient and what is the iztost effisient was to carry it out?"

·102 Genetics, Radiobiology and Radiology Meclical Center in 1956, an engincci was one of the many visitors in the Radiology Department. Ile told me, "you should Set rid of all thus cquipment. It is a big investment, I know, but you ought to get rid of it because you are doing so much damage to the future generations with radiation." Italheel to liim for about an hour and fmally he was comforted Yet, another instance: There was a chumcian in our de partment who wanted to take some films on a pregnant dogs Tlic particulai person who owned the dog said she would not allow these films to be taken because a friend told her that "pregnancy and radiation are a bad combination Just a wech ago, a lady called ine on Satuday night and said, "I ould like to move to Arizona bexause I have hay feier and asthma. But, if I move to Arizona, it will be close to New Mexico and close to the atomic bomb tests Woull it be harmful to my childien?" This kind of fear and confused mung is frequent The questions from the lay public don't bothei me que as much as the “radiation lysteria" exhubuted by medical people. In obstetrician told one of my secretaries who was pregnant aliat it was dangerous to work in a Department of Radiology because of pesa sible injury to her upbom chuld I shon cd hoi the measurements that we made on our various radiologists and technicians Three-fouths of our staff lave receivel only 1/20th of the manamum permissible dose, and that measurements on every one of our technical staff, with one possible exception, lave been below the maximum permissible close These are people who are nothing with the cquipment and using radiation all the time l'he scretaries are so far removed from the diagnostic rooms that it wouldlu't pay to try to measure tlie untestinal amount of raciation to which they are exposed pathologist once asked me if it would be safe to autopsy 11 patient wlio liad received telecobalt treatments lle thought that inaybe this patient would, in some way, be radioactive and the autopsy might over-expose hun There is considerable mastonary tork to be done to allay people's hysterical ſcar of radiation hazards ·Genetics, Rodrobiology and Rndiology 103 must be done on a voluntary basis. I do not believe it can be legislated Dr. Scoli: Thank you, Dr. Gould. Any questions anyone would like to ask Dr. Gould? If not, then we will proxeed to our next subject, "Gonadal Racliation Resulting Froin Various Diagnostic Radiological Procedures." by Dr. Freil lexlges.

·101 Genetics, Radiobiology and Radiology (9) Rules to follow during fluoroscopy: a. Adapt your eyes for 20 minutes before fluor b. Always wear protective gloves and apron. c. The fluoroscopic tube table distance shoul or greater. d. Keep the shutters down to the smallest practi c. Use the fluoroscope quickly and efficiently to motion and function and not as a sareen p Do not day.dreain with foot on the switch. In my own department I cannot do the best possib duninishing the radiation hazard because of the lach 1 am quite certain with unlimited funds the radiation can be diminished to 25% of what it is today. For exam are rather sensitive and expensive film emulsions availal which allow the radiation exposure to be ulit anywheic fr 16 50%. There are available mirror optic photo-fluor equipment which exposes the chest with 60% less radiar conventional cquipment Body section books which ir ple layers of screens and film can reduce the exposure of what is used with conventional apparatus. With th the new 6 minute X-Omat developing apparatus, whi $32,750 at the present time, the service work and organi the department can be so arranged that the number of films can be cut to a minimum Technical quality car proved so that repeat filmning is a rarity Nort, how badly does society want to diminish the r lazard and how much are they willing to pay to obtain mate safety? Most hospital administrators nothing budgetary limitations cannot give us a free reign I have talked to people in state and federal gove about this problem of radiation hazard Bricfly, the ai was put forth in this manner in order to reduce the ri hazard to a mininuun, let us Clevelop as nearly a perfect ment of Radiology as possible. Let us train physicists, gists and technical people to check up on every radiation tor in the state. Let us aclvise doctors, dentists and ch Such a 11 fost to rise their penintetit ·107 Genetics, Radiobiology and Radiolny closely simulating the characteristics of human tissues, in whiclı ionization chambers can be located in positions comparablc to the oraries and the testies, to the insertion of measuring desices into body cavities or into positions bearing standard relationships in ovaries and testes and held there during standard exainination procedures, as well as the use of film ballges som by patients throughout the course of various types of examinations. Many of the recorded ganadal measurements have tseen standarilized to single radiographie exposuites. in some instances assoxiateci fluoroscopic procedures have been treated separately: in others buthed vith radiographıc dosage. It liar been uinxossible, obs. sinusly, (in all instances) to redline to a single common value factors of distance between the tube target and the gonad. the factors of tube (hten. Islosaliage. me, speed ol lalu aud Screens employed, and the circumstances of film development .:ll of these factors are enorintusiy variable physically and less to this is added the habits of individual examiners, particularly in the matter of fluoroscopic procedure, the likelihovxl of achiesmg exactitude in the matter of establishing a firm value of gonadal absorption under all circumstances of diagnosti radiographic exposure seems remote indeed Some of the accumu. lated figures are further complicated by the use of specific gonadal shielding desices and it is obvious that of these devices are sufficiently massue, and extensive, gonadal absorption can be reduced to a very considerable extent The variabiluy of figures ahul are available in printer! form is great indeed Even in the matter of radiation which Teaches and is alsorbest by reproducirse cells in the course of chest examination, the values which have been reported vary widely. Some reporteis indicate that gonada! absorption is greater under various conditions of chest examination for males than for females, although the reverse is ordinarily quoted Because so much has been written and said about genetic effects may follou radiologic examination of the chest, it may be kell to point out at this time that values in the neighborhorxd of one-tenth militroentgen for males and approximately ten fitues that annount, of one milliroentgen for females comes close which ·GONADAL RADIATION RESULTING FROM VARIOUS DIAGNOSTIC RADIOLOGICAL PROCEDURES By DR. FRED JENNER HODGES Professm and (han man Depoitment of Radiolon l'ersity Hospital MIKSI) of Michigan on Irbor. Whichigan I had hopce to bring something in the way of exact figures that have been laching up to date I am sure now that that was wishful thinking of the worst soit Om physicist and the younger men in the department who tried to help me in this matter late assured me that we simply are not able to present accurate figures for the actual cosage absorbed in regenerative cells The exact magnitule of the radiation absorbed by human gonads during various diagnostic procedures which employ the use of x-radiation would seem to be essential to a meaningful in. vestigation of associated genetic effects A great many attempts to provide factual data of this very soit hasc resulted in the accumulation of values wluch cover a wide range for supposedly comparable diagnostic procedures because of the very many variabics related to the technical procedures themselves and to the methods of measuring absorbed radiation, which likewise are anything but uniformi, Gratifymg as it would be to have stand. ardized gonadal absorption close values for every conceivable type of examination, there is little likelihood that the degrec of regimentation required to regulate such exposure with exact:- tude would be acceptable to practicing radiologists. Attempts have been made to measure gonadal radiation under experimental and standard (inical conditions in a variety of These Tange from the careful construction of phantoms ways. 100 ·Genetics, Radiobiology and Hindiology 103 commonly employeel, in uluch largely inescapable gonadal radlia. lion is delisered in sizalyle amounts, involies patients who fall within the 0 to 30 year age group. By actual count i standard procedures which as clone at our institution exposc gonadal cis sue to radiation in excess of 1 roentgen per examination consti. uute only 20% of the annual total number of examinations con. ducted, 12.908 in a total of 61,076. In the order of magnitude of I (BIT) SET Tirsaf FTASTJOV 151DING SURFACE MOST IS EOS OF 11 ON THE GOLD 11 Ingrocardiogram Escreens Pyclogram 2235 Pelstein 491 Lumwacral Spine 5.4 per (astro Intestinal Examination (fluorii cup plus films) Routinc Spine Rin Petrus HNT (Doses are given as surface values and olx lousls grnadal lines are tricamıralıls les actuallı in the female) skin dose over the gonads these 7 procedures are (Table 1) agrocardiogram (15), excretory pyelogram (2 255), Jelsmetry (4.9 r). lumbar spilte (5 ft), upper gastrointestinal examination (57 1). routine spune (587), lup and pelvis (8 8 T), 11 is obvious that the actual value of radiation alsorbed by the gonads will be measus. ably less ellan the surface values listed. Taken as a group those patients subjected to these types of examinations, who at de uime Here 30 years of age or younger, numbered 3215, Os 25% ol the people so examined, Arranged in the order of increasing numbers of those who fall below the age of 10), Tahle II, che 7 examinations are listed as upper gastro-intestinal traci (12.5% age 30 and below), routine spine (29%), lumbar spine (255o), excretory pielgram (2970%), lup. pelvis (955".), peluimetry (70%), and angiocardio. gtam (78) Fortunately for all concerned the fox.using of atten tion on methods and the use of desices to slueld gonadal tissues during those examinatim prxcedures most likely to result in hears gemacht absorption involies a relatnely small number of patients ·108 Genclics, Radiobiology and Radiology to represencing an avcrage figure from a large number of sources for the expected gonadal radiation absorbed during thic roentgen examination of the chest nising standard direct filming tcchinic. These values will be increased by a factor of 5 or thercalout when the photofluorograpliic method employing refractor optics is used. It is convenient to use the rounded (igure of 5 milliroentgens of radiation absorbed by thic ovary in the coursc of a single photofluorographic exposure of the chest as the high value for gonadal radiation from chest examinations of all sorts Using this convenient figure as the divisor, and 10,000 milliroentgens or the 10 roentgens of life-time radiation absorbed by gonadis considered currently to be a tolcrable burden from the genetic vicwpoint, it will be seen that in the course of 30 years this type of chest cxamination could be repeated 2000 times before the agreed upon maximum allowable dose would be reached When cypes of examination imole bodily parts which are in close relationship to the gonasis the magnitude of gonadal absorption is very much greater. Unfortunately, the comical and experimental computations of gonadal absorption are even less uniform under these circumstances than are those for procedures which are directed toward the chiese, but one can say in complete fairness that whenever the primary x-ray beam used for diagnos. lic purposes of necessity funds gonadal tissue in its circut path the values for gonadal absorptiou will be measurable in hundreds rather than in single milliroentgens For example, pelvimetric examinations utilizing two exposures, one in anteropostcrior, one in direct lateral projectiou, may be expected to result in the absorption of something in the neighborhood of 24 10 36 frustrel milliroentgens, clepending of course upon a variety of variables including prominently the lxcxlily dimensions of the patient as well as the efficiency of photographic materials and streets One should not lose sight of the fact that the absorption of radiation by gonadal tissue is of importance only wlicni st occurs in individuals who are still withun the age group where reprodlu. tion is to be expected Before one einbarks upon any computation of the future genetic effects of gonadal radiatio, 16 15 important to take notice of the fact that only a fraction of the procedures ·Genetics, Radiobiology and Radiolog 100 commonly employed, in which largely inescapable gouadal radia. tion is delivered in sizable amounts, insolies patients who fall within the 0 to 30 year age group, By actual count 7 standard procedures which as clone at our institution expose gonadal tis. sue to radiation in excess of I roenigen per cxamination constitute only 20% of the annual total number of examinations con. duted, 12,908 in a total of 61,076 In the order of magnitude of Ses Tres Of FXAMINATION YILDIV SURFACE IS IN FXCS OF OTHEE COVADS Ingrecardurgrams 1.5T Excreion Pyelogram Pelsumeits Lumiksacral Spine 512 Ipper (astro Intestinal Examination orixxcopy plus Gims) 372 Routine Spune- 3.81 Hm. Pelvys XX (Pwy are given as surface values and olsaus, gala) <lines are miczwaratifs less eyecialls in the feinale) shin dose oser the gonads these 7 prosedures are (Table 1) angi. cardiogram (15), excretory pjelogram (2.23 r), pelumetry (1.9 T). kumbar spie (1 1r). upper gastrointestinal examination (5.7 ). routine spine (58 r), hip and pelvis (8 8 r), 31 is obuous that the actual value of radiation absorbed by the gonals will be measur. ably less than tlie surface values listed. Taken as a group those patients subjected to these types of examinations, wlw at the time were 30 years of age or younger, numbered 3215, or 250 ot the people so examined. Arranged in the order of increasing numbers of those who fall below the age of 30, Table II, the 7 examinations are listed as upper gastro-intestinal tract (125% age 30 and below), routine spine (23%), lumbar spine (23.5%). excretory pyelogram (39%), hip, pelvis (335cm. pelvetry (70%), and angiocardio Atam (78%) Fortunately for all concerned the focusing of attenztion on methods and the use of devices to stueld gonadal 115$ues during those examination proxedures most likely to result in heavy gonadal absorption insolves a relatzsely small number of patients ·110 Genclics, Radiobiology and Radiology TABLE ! FRI QIFIC} os Uſt ZATION OF EXAMINATIONS ('ARRUING 1116 GONADAL Dosar-1956-57 Tomas l'sed Pis. Under 30 ) cars I'wder 30 ) cars 12.5 (02 200 30 I 19minalion Type Upper Gastro-Intestinal Examinations Routine Spinc Immoneral Spine Excrctory lyclagram Ilips, P'c1118 l'elvinicity Angincardiogram 1801 192 21% 2795 2138 370 123 non 260 sonra 15 700 7800 in any one working day, enhancing the likelihood of achicing the inci cased degree of gonadal protection which is so highly desirable. in the interests of long range gençut experiments and observations by which man may hope to determine with reasonable accuracy the magnitude of the hazard presented by various ding. nostic procedures employing the use of radiation it is desirable that clforts stull comme on obtam values for gonadal sacuation currently being absorbed by reproductive cells from large patient populations in the course of clinical radiologue practice .ls mit tors stand presently it is unlikely that anything more than the cxtremes of gonadal racivation expressed in the broadest of scris (an be derived from accumulated and acumlaring clanical (por ience Dr Scott: Thank you, Di Tlodges That was a very helpful presentation Any specific questiou for Dr Hodges?

·RADIATION REDUCTION IN OBSTETRICAL RADIOGRAPHY JOHN A. CAMPBELL. M.D. Professor and Chairman, Department of Radiology Indonna ('stleri Medical Center Indianapolis, Indiana There is 110 medical field in which the reaction or limita. tion of diagnostic K-ray exposure is better justified than in clxietnics Regardles of wluich side of the lence you want to take on this point, I think you'll admit that when you are doing diagnostic work today on an obstetrical patient, it at least makes you nen ous. The potential bazard of excessiic radiation dosage is both genetic and sumatic because prenatal radiography insoles simulcancous gonadal exposure of both mother and feruis, as well as total body irradianion to the embryo at a time of major organogenesis The radiographic procedure itself imprises a maximum of undesirable factors on the radiologist The large physical dimensions of the patient necessitates a greater dose of itradiation while the use of slon screens for fetal bone detail, high density grics to absorb scattered radiation and multiple vicus significantly increase the expositre required of the geneixally significant radiation recensed by humans from medical ases, approximately 20 to 30% is said to be contributed by olistetrical radiograplıy and I am quoting figures that Dr. Fred Himiges shoned today froin Laughilm and Pullman Rathography of the pels is in women who are not aware of an (listing pregnancy ? fraught with possible bazare 10 the embryo Dr Russell las demonstrated in mice that there are crita al periods of embryogenesis, particularly between the secondt and seth neel of gestation u ben clases as low as 23 I can produce abnormal levelopments in the first offspring More alarming is 11 ·112 Genetics, Radiobiology and Radiology the report of Stewart, indicating that children born of women subjected to x-ray pelvimetry during pregnancy develop leukemlik in the first ten years of life twice as frequently as non-irrallinto offspring. It is estimated that these fetuses received almout 2500 mr. of total body irradiation. Recently a similar report has been published at Tulane University (I don't know the audio sor have I seen that report) On the other hand, no leukemia has been reported during the first decade in Japanese chileiren wlin were irradiated in utero by the Hiroshima atomic bomb. From the geneticist's stancpoint, who is concerned with the production of gene mutations, any amount in excess of natural background radiation is capable of genetic injury. The geneti. cist is, therefore, entirely consistent in recommendimg that the fetus be protected from all radiation. It is obvious that medical urgency frequently makes such a complete interdiction impractical. Nevertheless, radiography of the pregnant abdomen should be done only for compelling reasons. In such an instance, the radiation exposure must bse mimmized by cicry means at our disposal. There are several ways of aclueving thus. These may be gronped as gencral, technical and procedural considerations We were picrested in finding out where we stood on this matter for two purposes, one to study what the methods were cffective in reducing the dosage that we were using and secondly in seemg how far it coull be reduced and still get something that looked like a satisfactory diagnostic result GENERAL CONSIDERATIONS dvond routine loentgenolayıc procedures -7lus (01975ts of talking yourself out of unnecessary caminations as routine procedures as opposed to the idea of juist domg these as part of the general woriup of an olystetri al patent The routine use of chest surveys, pelumetry, pyclograms. senal films, shcleta! surveys, and fluoroscopy should be postponed during pregnancy. The yield of these procedures does not warrant such use. 2. Avoid roentgen examination of the prime aren durmg ·119 Genetics, Radiobiology and Radiology early pregnancy - Whenever possible, toenigen expussures of the pelvic arca in women of the childbearing age should be restricted to the ino needs following the last menstrual posicxi to preclude the possibility of fertilization having occurred. 3. Proper eqmpment and personel. A higli capacity (300 JIA-120 K.V.) generator and tube will permit short cxpxs. ures, longer tube film distance, efficient collimation and licas fileration Technicians must understand the advantage of csery desirable factor employed, because the greatest exposure redue. tion results from accomplishing the correct technique on the first attempt without repetition. Immobilization devices and phou. timing prevent mocion and overexposuite. Protective shielding - I lead screen of 20 am, Icad thickness may be used to cover the fetus and the maternal gonads whenever their excus on does not decrease the usefulness of the examination, re, pelvimeiry 5 Consultation, Consultation between obstetrician anel radiologist before roentgen examination nf the pregnant alda men will result in a higher yield from fener exposures Radio logic examination should be a confirmatory maneuver, 1 a means of arriving at a diagnosis by exclusion 4 TECHNICAL CONSIDERATIONS 1 I have listed the technical factors such may be utilized 10 reduue the amount of radiatio necessary for a satisfactory (13. nosti rad.ograph. (ollimation of the primary beam - The lise « cable cliaphragm rectangular aperatures will reduce scaileted radiation as much as 30% over circular fields l'se of longer target film distance Due in the niproxement in percentage depth dose, the same ainount of radiation can be delivered to she film with as litile as tho-thirds of the shin dose when longer distance is sed. Hight kilovoltage technique The use of 100 120 lilo- ·Genetics, Radiobiology and Radiology voltage techniques will reduce the cutrance dosc up to 50% with out loss of film density. 4. Added filtration of primary beam.- The addition of 2 to 6 mm, of aluminum (depending on kilovoltage level) to the primary bcam will redue the entrance doxe as much as 75% over the unfiltered bearn, Gianluca et al point out that filters are needed liccause of the shape of the curent furnished by pres. ent day valve-rectified generators They could be completely eliminated by the rise of a square wave such as given by a lysa. pulse aut. 5. Use of high speed intensifying seens.-Fast screens will reduce the necessary radiation dose at the film two to four times with negligible loss of detai). 6. Use of extra-fast film.- reduction of 20-50% in film close, depending on screen type aix! Lilovoltage range, can lic obtained by the new faster film enuulsions. The resultant toenz. genograms show less latitude and a shorter scale of contrast. We used Eastman Royal Blue anıl Ilford Red Scal film. 7. Improved film development and reductiou of caposure in the range of 20% can be accomplished by processing films in phenidone hydroquinone vlcicloper (Picker or llforrl) for 5 min. utes ac 68 alegrees Fahrenheit istead of comcntional metol lıydro. quinone developer. 8. Low absorption cassettes.-By deci casing the thickness and absorption of the cassette lised in obstetrical work, the dose may be lowered as much as 1007.10 2007 9. Lower Gud opacity_{irids of higher ratio and density, necessary to maintain contrast in high K V techniques offset 10 certain cxtent the reduction in patient dosage. The use of 6:1 10 12.1 range of grid ratios is a destable compromise according to the technique employer! Netcutheless, il gud apacity is not bal. anced against the Kl' employed, unicasonable high patient dosage or technically unsatisfactory roergonograms will result 10. Differential filter, frames and contering devices -- Wedge filters will redue regional exposure to parts of uneven thickness. Opaque frames with various-shaped apertures wil restrict the radiation to aleas of intero I reliable Summied ·115 Genetics, Radiobrology and Radiology cm beam director will aid in precise centering of the coned beam on the patient and film. It should be noted that the factors of collimation, target distance, high K.V., and added filtration chiefly reduce the entrance skin dose while maintaining relatively the same exit or film dose. While these factors cause a great reduction in shin clixse, tliis improsement in dose is steadily reduced through the clepth of the patient, becoming of little salue at and beyond depths of 20 There is, however, a definite reduction in dosage to the fetal and maternal gonadis which lie slightly interior to the midsagittal plane. One reaches an interlucible end point, however, where only a reduction in film-dose requirement will allow further reduction of the dose to the gonads Such elfece is accomplished by the factors relating to increased screen response, film speed, more radiable cassettes, and low-density grids Each of these provides a decrease in the amount of radiation required at the film which, in turn, means a reduction in shin, integral, and gonadal dosage. It is wise to investigate and adopt all possible measures which permit recording a film image of desirable quality with the least exit dose If an additional grid could be interposed above the patient and perfectly algned with the conventional grid. (the so-called sandwich grids), it would prevent the passage through the patient of primary radiation destined to be absorbed by the second grid. In the same way, a wedge filter over the thinner anterior portion of the lateral pregnant abıtlomen is a better choice than a slow steen in the cassette for equalizing the density of the image. because it prevents delivery of unneedleri radiation to the patient. PROCEDURAL CONSIDERATIONS The majority of Olssetrical radiographic procedures utilize from 2 to 4 projections of these, certain views contribute more gonadal radiation than others The lateral sies may give up in 3 times as much as the .1P, the AP tisice the PA and the pelvic ·116 Genetics, Radiobiology and Radiology 2 inlet view as much as two-thirds of the conventional three-film pelvimetry technique. There is practically no difference in the gonadal dose of AP or lateral exposures if taken only for soft tissue visualization because no attempt is made to penetrate the increased density of the pelvic bones. Elimination of non-essen. tral views reduces radiation immediately by a greater amount than would result from improvement in technical factors. Selection of a single projection which provides a broad specirum of diagnostic obstetrical information is very desirable as a pilot study I have always entertained the idea that if one could boil the procedure down to one view tlıat would do everythingsort of an all purpose technique, that perhaps this had some merit s single crect lateral view of the abdomen and pelvis provides the most useful information in this regard for the following reasons: Visualizes entire fetus and utenus Demonstrates placental location 3 Permits recognition of fetal malposition or abnormality. 4. Allows the diagnosis of fetal death. 5. Permits an estimate of fetal maturity, Furnishes pelviinetry diameters of anteroposterior bore birth canal. 7. Provides detection of extrauterine gestation and multiple pregnancy. 8. Demonstrates degree of centering, descent, and presen. tation of fetal head m pelvic inlet 4 Supplies definite indications for additional radiography Figure I shows a diagram of the positionmg technique for the lateral erect view, as well as for the AP erect view and the PA prone vien The isometric ruler is superimposed in tic mic. line plane of these projections. In order to clude the entire area of diagnostic interest in larger patients, a special 17" x 17" (assette may be employed with a standard grid tray. Figure 2 semonstrates this home made cassette. When it is determined that a frontal projection is necessary there are certain advantages in tilizing a PA view with a com- ·Genetics, Radiobiology and Radiology TABLE UPRIGRT TABLE UPRIGHT CARDBOARD TILL HOLDER (OPTIONAL) BUCKY CCKY FILM FILM DOMETRIC RULER LSOMETRIC ROLER SMALL CONE LONG TYD- BUCKY TRAY Figure ? pression band as advokated by Bewley. This redires the thich. ness of the patient up to 10 cm, over the AP supine view with a correspondingly smaller exposure requirement. The maternal gonadal dose is reduced about one-third due to shielding hy the pelvic bone, and the fetal gonad dose is up to 10 times smaller. The latter reduction is more because the fetal gonads lie on the side opposite the entrance of the primary bean when the PA projection is used The P'A view also provides an improvement ·116 Genetics, Radiobiology' nnd Radiology inlet view as much as two-thirds of the conventional threc-film pelvimetry technique. There is practically no difference in the gonadal dose of AP or latcral exposures iſ taken only for soft tissue visualization because no attempt is made to penetrate the increased density of the pelvic bones. Elimination of 101-essential view's reduces radiation immediately by a greater amount than would result from improvement in technical factors. Selection of a single projection which provides a broad spectrum of diagnostic obstetrical information is very desirable as a pilot study I have always entertained the idea that if one could boil thic procedure down to one view that would do everything, sort of an all purpose technique, that perhaps this had some merit. A single erect lateral view of the abdomen and pelvis provides the most useful information in this regard for the fol. lowing reasons: Visualizes entre ſeturs and utcany 2 Demonstrates placental location 3. Permits recognition of fetal malposition or abnormality. Allows the diagnosis of letal cleath. 5 Permits an estimate of fetal maturity. Furnishes pelvimetry diameters of anteroposterior bore birth canal Provides detection of extrauterine gestauon and mitiple pregnancy. 8. Demonstrates degree of centering, descent, and presen. tacion of fetal licad in pelvic inlet 9. Supplies defmite indications for additional radiography: Figure 1 shows a diagram of the positioning technique foi the lateral creet view, as well as for the AP creat view and the PA prone view. The isometri ruler is superimposed in the muc. line piane of these projection In order to include the entire area of diagnostic interest in larger patients, a special 17" x 17" (assente may be employed with a standard grid tray. Figure ? demonstrates this home made cassette. When it is determined that a frontal projection is necessary there are certain advantages in utilizing a PA view with a com. 7

·119
Genetics, Radiobiology and Radiology
Figure 3
Figure 1

·118 Generics, Rodrobiology and Radiology Pros Figure ? in the detail of the letal parts due to the shorter object film discance. Obviously, the PA view also may be used as a pilot study and pelvimetry of the transierse diameters obtained from it The integral racliation dose delivered is ouly 25% of the lateral vicw. Clayton et al have pomecl out that in cephalic presentations the fetal gonad lies high in the fundus anteriorly. In addition, the maternal ovaries are carried to a point about 7.0-8 0 cm. above the iliac crests in the midoronal plane by the expanding terus. Onc may take advantage of these facts to exclude the fetal and maternal gonads from the primary beam when pelviinetry alone is desired by restricting the exposure closely to the pelvic area (Figure 3). This may be nitely accomplished by placing : lead shield with a 5" 5" aperature and a !" (enter strip over the patient in the frontal and lateral projections to assure that only the bony structures of the pelvis arc exposed to the primary raulia. tion (Figure 4). Furthermore, since the semi crcct view of one pelvic inlet (Thom's projection) delivers twice as much radi. tion to the fetal and maternal gonads as the frontal or later.al ·Genelics, Hadiobiology and Radiology 121 pelvis, lumbar spine and a leather fecus and placenta were placed within the phantom. The intenening space was filled with rice (Figure 5). Holes were made in the ancerior and lateral surfaces of the piantom to pcrinit the introxluction of a 25 r Victoreen ionization chamber for obtaining jadiation doses in the midsaggital and midcoronal planes at the level of the pxels ic Figure 1 inlet Entrance and exit doses were also measured (Figure ) Because the standari wonization chambers do not accurately record the high intensity short exposites used in diagnostic proxedures, radiation of the same quality was gren with a water coolul tube using loner milluamperage and larger exposures The actual exposure doses were then calculate! frum these determi. nations. Any inherent error in these close measurements is likely to be the same for all readings.

·120 Genetics, Radiobiology and Radiology views, this technique should be avoided. As a corollary to this, when the diagnostic information desired pertains only to the con. tents of the pregnant abdomen, no attempt should be made to penetrate the density of the pelvic bones, and the exposure decreased to that amount necessary to illuminate the soft tissues. EVALUATION OF LOW DOSAGE TECHNIQUE Comparative radiographs were obtained on full-term prego nancies utilizing two techniques. Technique I consisted of the following factors: 70-90 K.V., 1 mm. Al. filter, 10" TFD, 6; I grid ratio, par speccl scieens, average speed filın (Eastman Blue Brand, Dul'ont 508) and a circular cone Technique #2 consisted of 120 K.V., 3 mm. Al, filter, 40" TFD, 16:1 grid ratio, high speed scicens, lugh speed films (Eastman Royal Blue or Ilford Red Seal) and a double-diaphragm rectangular cone Standing lateral and prone PA views were obtained in different patients with both techniques In addition, a phantom in the shape of a maternal abdomen was cast from a patient. This was made of <lressmaker's paper, which showed no significant absorption of radiation A bony Figure 5 ·123 Genetics, Radiobiology and Radiology It will be noted that the shin dose of the l'A view tising ilic los dosage technique (11) is 300-100 mr as compared to 2100. 3250 mr for the conventional Al viens (l) while the midpelvic doses are 51-73 mr as compared to 190-233 mr. The lateral view with the new technique required a skin dose ranging from 1170. 1730 mr and a midpelvic dose of 163-230 mr, while the standard technique required shin closes of 7730 8720 mr and midpelvic closes of 460-524 mr. Actually wc wcre able to obtain many I. views with the low dosage technique with as little as 10 MAS. For the average sized lateral, the exposure was reduced to as little as 50 M.IS and for the large patient about 75 MAS. We also noticed that when we stitched to the low dexage tocmquc, the exit doses were just half of the values obstainai om the standard techniques indicating that tlic recordling media was twice as sensitive to radiation The resulting roentgen image was of comparable density, but somen hat grainy and showed a shorter scale of contrast. A Figure 9 (Figure 9). This is a comparison of the AP with the old technique on the left and a PA with the new technique on the ·129 Genetics, Radiobiology and Radiology The joentgenograplu techniques used for comparable fils I INTEL (OVPARISON OF LACINIA I CIORS Technique KI rilier Ratin Tricen Speed poed Delops 80 Vice Ros Victol I lat. 90 10" Wer! Rog Wacolo II P1 120 3 11. 10" High l'hendance 11 lat 190 3.1). 10" 361 High last Pomeone hodak Rerul . Prekes Pix, Ilford POV? Figure 7 densities are given on Figue 7. Comparison of the emuan md.pelure, and exit close's measured with cache icemque are given on Figue 8. IIBLI (OMNISON OF ROX IRONAGE Lumque I pour Van llad plus in Us 150 2100 1990 11 200) 3291) 29 1 Lat 1017 7750 134) Ilar 150 87211 121 111 13 900) 11 10) II 30 11.10 50 1170) 174) 231) Il lat I igure 8 ·125 Genetics, Radiobiology and Radiology may be utilized collectively or singly. Not all of them are useful all the time 1. The potential genetic and somatic radiation hazard in obstetrical patients stems from the simultaneous gonadal expos. ure of mother and ſetus and the total holy irradiation of the feftis 2. Obstetricians and radiologists should discipline them. selves to avoid any routine or unneccessary roentgen prexcedures of the abdomen and pelvis in women of childbearing age, 10 avoid radiograplıy during early pregnancy, to use well informed rechni. cians, and to select, through consultation, the salese procedure with the highest diagnostic yield 9. Clinical experience has shown that remgen pelsimetry is infrequently necessary for obstetrical prognosis. Its use should be limited to those cases in which the exclusion of lyscocia is indeterminate by other clinical means 4. The use of high lilovoltage, heavy filtration, efficiently collimated beam, fast screens and films, full plienidone lılın devel. opment, and proper grid ratios will achieve the lowest radiation doses to the shin, gonads, and fetus. 5 The use of a single upright lateral view on a large 17" x 17" cassette covering the pelvis and abdomen will suffice as a single pilot exposure yıelding a broad diagnostic return This can be supplemented with a compressed prone PA abcomispelvic sien when indicated These two siews, providing a complete range of obstetrical roentgenologic diagnosis, may be ol). tained with as little as 250 mr. delivered to the midpelvis of an average sized patient at term This represents over 75% reduction of the radiation dosage required with standard no film techniques and esen more so over techniques which require additional films 6 For fetal survey only, a lightly exposed PA or lateral abdominal rad!ograph can be made with a total exposure of only 15-25 m to the midline. In late pregnancy, the maternal and fetal gonads are located well above the crests of the ilia in cephalic presentations. When the examination inyoles pelymetry only, restricting the ·121 Genelics, Radiobiology and Radiology right on the same patient. The right film was made with 15 MAS, the one on the left with 200. That is on Royal Blue film ou on Ilford. I am not sure which that is. We found themi not too far apart. Figure 10 Figure 10 is the comparison of two lateral views on the same patient. We weic trymg a weelge filter over the front of the abdomen. Tlus is the old technique on the left, the new technique on the right and reproduction of this is perfect, although as you notice, the pelvic area is not heavily penetrated However, we felt we could make pelvic measurements from this if necessary We could see the head. We could see placental position on the posterior wall ol the fundus and we would have been able to diagnose fetal maturity pretty well. Admittedly, we have perhaps gnen up something licre in the long run, but if you are not a pei. fectionist, I think you can still get a satisfactory diagnostic yield and a handsome reduction in radiation exposure with this low dosage technique. SUMMARY AND CONCLUSIONS Low exposure obstetrical radiography involves the applicata tion of certain general, technkal and procedural factors These ·SUMMARY OF CONFERENCE VITH REMARKS ON THE GENETIC HAZARD OF DIAGNOSTIC RADIOLOGY AND MEANS FOR REDUCING IT OR. PAUL C. TIODGES Professor and Chairman Department of Hadiology C'esy of Chirogo Chicago, Illinois I brought a set en page manuscript and six lantern slides, but I have decided to abandon them because most of the things I was going to say has been said four or five times today. 1 jotted down notes as you gentlemen talked and it seems to me that certain points frase come out that everyboxly here admits. First, radiation can cause genetic damage None of us learned that for the first time today but we learned a lot more about it. Second, inan is subjected to mucho unasoidable background radia. flon but the mere enescence of unatoidable background does not excuse the addition of avoidable radiation. These are things 110 all know but it is well to have quantitatile information alout them The sursess that have been made on estimated gonadal duscs for the entire population exaggerate the situation in diagnostic radiology They are full of errors which the people who made them must recognize Inyone who has had anything to do with radiation therapy Anons that for several decades alter it began to be important. we had only rubber yardsticks with luch to meas. uire the dose The earliest measuring devices were not ionization chambers and the first chambers that frecame available were not independent of sale length Anyone who attempts today in compare doses recorded thirty years ago another institution Isith those recorded today in his otin institution knows that this 15 # saste of time Even alter thimble chambers were imposed 191 ·126 Genetics, Radiobiology and Radiology beam to the pelvic flex and avoiding the use of the iniet view (Thou's) prevents lirect irradiation of both gonad's. Di. Sroll: Dr. Campbell, that was a fine study and clearly presented. Examinations and reports of this type are most help. ful in minimizmg radiation ellects and we need more like it. Would anyone like to ask Dr Campbell any questions about his technics? I have ashed Dr. Hodges to give as much of Iris paper as he wishes, and in adition in summarize the major points brought out during this Conference. At the conclusion of lis call, the mecting will be open for general discussion.

·SUMIARY OF CONFERENCE WITH REMARKS ON THE GENETIC HAZARD OF DIAGNOSTIC RADIOLOGY AND MEANS FOR REDUCING IT UR. PAUL C. HODGES Professor and Chairman Department of Radiology Inaersity of Chicago Chicago, Illinois brought a seven-page manuscript and six lantern slides, but I have decided to abandon them because most of the things I was going to say have been said four or five time toxlay. I jotted clown notes as you gentlemen talked and it seeins to me that certain points have come out that cserybody here adınits. First, radiation can cause genetic damage. None of us learned that for the first time today but he learned a lot more about it Second, man is subjected ro much una ouable background sadla tion but the mere existence of unavoidable background does not excuse the addition of avoidable radiation These are things uc all know but it is well to have quantitane information about them The surveys that have been made in esiimated gonadal doses for the entire population exaggerate the situation in diagnostic radiology They are full of errors which the people who made them inest recognize Anjane sho las had anything to do willı radiation therapy anons that for several decades after it began to be important weliad only rubber yardsticks with which to measure the done The earliest measusing devices were tiot ionizaton chambers and the first chambers thar berame available were 10+ independent of sase length Anyone who attempts today to compare doses recorded thirty years ago ar another institution uith those recorded today in his own institucion knows that this is a wayte of title Esen alter thimble chambers were linproved 127 ·128 Genetics, Radiobiology and Radiology it was some time before familiarity with them yeached the point where recorded dosage was dependable. We are in almost that same situation today in diagnostic radiology. Almost everybody has attempted to measure the doses in diagnostic radiology with chambers that have been developed for therapeutic radiology and these therapy chambers are almost as inaccurate in diagnosis as the carlicr measuring devk es were ! therapy. I was relieved when I leaned that the pressine loi biga ger and better surveys had cased so that public and private moncy probably now can be used to find mcans fos unaking diagnostic radiology as safe as possible rather than for additional surveys to find out how bad it can be The existence of unavoidable background radiata». I HO justification for permitting unavoidable radiation but there is considerable variation in background, about which he could do some thing if we wished to. For example, we do not aud should 1000 make it llegal to move from a hame house in San Hamuso 0.2 brick house in Denver nor do we inale it illegal in go up to Pile's Peak and sit on a rock It follows, therefore, that we should not worry about the gonadal close delivered 111 making a chiese microfiim of an adult male since that dose is identical with the additional bachground he would acquire if he had come from a frame house in San Francisco to spend 3.6 days m a brich house in Denver, (o say nothing of the close that would be incurred if hc went on up to Pile's Peak and sat on a roch Above everything else, I was impresscl with the slight divergence of opinion between the geneticists and the radiologists. It is the same okl story people misunderstand when they are quoted second or third-hand in the press and understand one another more casily when they sit down together I detected little difference lictween the extreme genetic uen and the extreme radiologic views Dr Gould and I were cliseussing at lunch a question that is frequently ashed: "If the hunian jace came out of the itecs and learned to tise its lands instead of its toes all because of mutations, then why don't we use x-rays deliberately to expedste mula tions." Of course, the answer is that whether they be natural or ·1 129 Genetics, Radmaslong and Radiology induced most mutations are deleterious and only a few advan. tageous. With irracliated seed com, one may bill off the myriads of misfits and save only the desirable mutations, but no one seriously believes that these tactics should be applied to man. Now as to precautionary measures that may lie talen to teluce the rissue dose in diagnostic radiolog). Above cierything else, there is the avoidance of unnecessary claminations. Many ray examinations being clone today in my opinion are not cu CSsary di au secucioni, we are calleci on cainstantly to repeat examinations of the stomach, colon, gall bladder, etc, not because the doctor believes they are necessary but that the patient wants them and is furious if they are not provided. Within reccill ncche one of our young men diagnosed a peptic ulcer on a patient who was sent back on the next day for repetition of the examination, When I inquired as to the cause, my colleague who had telera hmm sand, Refore I sent the patient to you I toll lis iclarines that I didn't think he liad a peptic ulcer and 50 wlien i get your report I had to call his wife and son by long distanse They reminded me that I had said that no ulcer would le forment and I said the radiologists thought they had found one but, of conte, would check their findings." Because of this commitment there seemed to be no way out and we had to go on th an unnecessary Tepeai examination Il'e should dks everything possible to avoid umecessary exam tracions but the radiologist himself can do lule - it is the reſerting physician wlio must take the responsibility of denying to lus patients examinations whuh, in his opinion, are ueressary I was interested in what Dr Campbell had to say about pelvimetry It was splendid to see what can be done to reduce the deuse when peltimetry has to be done but the importam thing 15 to recognize that not often does it have to be done Medical students have been taught manual pelumetry for a hundred years at sete an accurate means of determining the kue of the pels is, of course one should never do As a matter of fact, however, manual pelvimetry is a feeble tool X-ray peluimetry and if it is necessary to measure the pelvis accurately v-ray pelmetry is the method to be employed Fortunately, it is seldom ·necessary to have this information and the trial of labor usually is a dependable guide. In our hands, pelvimetry has been used less and less in the past decade, not because we fear to lise ic buc because we consider it necessary only in exceptional cases Dr. Campbell and others have cold you the advantages of high soltage, licavy filtration, fast screens and fast films. Dr. Friedell and I were discussing this matter of fast screens and films and we wonder whether the geneticists know what has lappened in this field. Radiologists have long known that the tissue dose could be reduced by using faster films and screens but the price we paid was cleterioration in detail and most of us were not have enough lo apologize for what we considered relatively poor qualny filmy in order to reduce tissue dose. Today we are re-educating on selves and our aim is clinically satisfactory films with minimal fiste dose rathci than films of maximum chumcal quality te. gardless of close It is strange that no one has talked of image amplification Ten years ago we would have bubulol over with cuthusiasm as to what image implifiers were going to do toward rctincong the tissue dose I wish that the predictions and some of them were minc) had come true, but they have not. Almost all of us are working with image amplifiers of one sort or arrailer They have a limited reſulness but in their present stage of de clopment have not accomplished the thing that we thought they would We would have barel work getting along without tlicw but they have not cleaned up the problem on a large scale What are ther step we can take to further redue rada. tion close? Probably the most important thing is the restra con of the size of ure incident beamn For many years we have done all of our fluoroscopy and spor filmming with a scicou that meas. ures 1-1, 1 by 7 113 lies Fuery visiting taliologut who looks at it sliahes luis head and says, "You can't do an adequate examinations with such a small screen Of course you can't until you have tried it. When we biule the instrument, le provided it with a farge screen and were going to use the little screen only for spot ·131 Genetics, Radiobiology and Radiology ilms, but after a year or so se discutered that the big screen was it gathering dust and so we never use any more. Shielding of the gonads is extremely important. I though gou imight be interested in seeing one of the devices we have leselopes (for description and illustrations, see J.A.W A., July 5, 1958, pp. 1239-1210) The shell is placed lietueen the patient's legs, the technician lexcates the pubic symphysis. places the tip of the lucile ar that level, and then joliers the shieltl mtl is is jus cumact with the sheet covering the patient The distance between the tip of the lucyte and the lead is such that in the comm. pleted pelvic film the lead, though covering the testicles, does not obsctire any of the peluc lones Phantom measurements indicate that in pelvic filming donc at 80 KV, 100 MA with ? M.M al filter, a target-film distance of 40 inches and a 16 to 1 gru the close in the testes protected lxy thic stueld is approximately 5% of what it would be without it DY \cok Thank you. Dr Hodges. I am sure you will all agree that Dr Hodges is a master at summarizing Furthermorc, jour cesticular shield is a practical and ingenious device. You always manage to produce something construemie I want to emphasize the pine brought out by Ds Eberharı iltat the decision as to what is best for the patient mmist remain the responsiiniity of the attending physician It is he who must make the decision as to what is best for the patient and what he must have in the way of examinations Any other basis destroyi the proper relationshup between the patient and the attending physician This means all physicians must be more intelligentis mformed about generics, radiobiology and the proper indicatrons and use of diagnostic radiology and the possible frazards. Furthermore, the inlormation the geneticists and radiobiologists have presented here is not the voice of gloom and doom for diag. Mentk taclulugy It is helpful Lnowledge that will enable us to do a better and more careful job It is a challenge and a stimulus lor us to improve our techniques, to develop nen protective desres, and to assist our relerting physicians to make a better election of the patients for radiographic examinations The geneticist might ash, "What is organized radiology song ·130 Genetics, Radiobiology and Hadiology necessary to have this information and thic trial of labor nisually is a dependable guide. In our lands, pelvimetry tras lscent used less and less in the past decade, not because we fear to use it but because we consider it necessary only in exceptional cases. Dr. Campbell and others have told you the advantages of high voltage, heavy filtration, fast screens and fast films. Dr. Friedell and I were discussing this matter of fast screens an! films and we wonder whether the geneticists know what lias happened in this field. Radiologists have long hnown that the tissue dose could be sexluced by using faster (ilms and screens but the price we pard was deterioration in detail and most of us were not brave enough 10 apologize for what we considered relativcly prwr-quality Salons 113 order to reduce tissue close Today we are re-eduating our. selves and our aim is clinically satisfactory films with minimal tissue close rather than (ills of maximum technical quality res gardless of dose It is strange that to one lias talked of image amplification. Ten years ago we would have bubbled over with cnthusiasm as to what mage amplifiers were going to clo coward reducing the tissue close I wish that the predictions and some of them were mine) brad come true, but they have not Almost all of us are working with image amplifiers of one sort or another Tlcy lave a limited usefulness but in their present stage of development have not accomplished the thing that we thought they would We would have hard worh getung along without them l»ut dicy have not cleaned up the problem on a large scale What are other steps we can take to further reduce radiaciou close? Probably the most important thmg is the restriction of the size of the incident heam. For many year ne hale done all of our fliktoscopy and spot filming with a screen that measines 1-1/4 by 7 iuches Every visiting radiologist who looks at it shales lus head and says, "You can't do an adequate examination with such a wall screen Of course you can't until you have cried it. When we built the instrument, we prouded it wuh a farge screen and were going to use the little screen only for spor ·138 Genetics, Radiobiology and Radiology port is decreased l'hen they are interested and crowd arouni. He hold the screen over their gonadal region. Whien the fix* stitch is actuated and the screen glons, they are astounded mose back quickly. Also, in Louistille, so far as I know, there is not a pediatrician who ouns an X-ray machine or a fluoroscope. Dr. Mickey: In respect to reaching the students carly in the stage of their training, I should like to propose that we geneti. Cists get a shot at them in pre-medical school with courses i genetics I think that it ought to be a required subject. All pre-merlıcal students should have an elementary course in genet. ics and all medical schools ought to have a required course in achanced gertetics. Dr Brues: I Would just like to pronounce a plague on both hous I don't think that medical students get ugh geneties on the slole, but a few get it very well in some places. I also thunk th D.'s in biology don't knoss enough about pathology and cancer because cancer is too often not considered as a broad binlogical problem I think we have to correct both of these deficiencies Dr. Tice, Dr Scott, I want to thank you and your Cell mittee for your excellent program I think it has been a renderful thing for its to get together and discuss these probtcons I have been thinking almout the book laminagraph Dr Gould mentioned Ile have had ours for about eight months. We take a Jot of lamagraphs, whereas previously we were taking about ses en expostres, now we male only one Inmull like to ask Iko or three questions of Dr. Paul Hodges (1) Do you think an apron type of gtrelle that goes around the patient's waist is elfetre in protecting the patient's gonads? (2) Do you think that it is prutycal (3) The premature aging process from radiation as discussed 1, the geneticists and the report of Dr Shells Warren on the shortened life span of radiologists, can we overlook these hazard, Is that nothing 10 worry about 24 far as tradisclogssts ate concerned? And last, I have heard nothing mentioned about Dr Ira haplan's work sith which you are all familiar. Dr Kaplan. for mult a period of over twenty-nine years irradiated 660 ·132 Genetics, Radiobiology and Radiology about this problem?" For over fifty years, they have been and still are very seriously concerned about it. The American College of Radiology, througin their Commission on Units, Standarels and Protection, of which Dr. Richard H. Chamberlain is Chairman, just produced a booklet, "A Practical Manual on the Medical and Dental Use of X-rays With the Control of Radiation Hazards." Miss Sampley will give a copy to each of you. This manna) is being distributed to all practicing dentists, physicians, internes and residents in the United States as an act of public service. The American Roentgen Kay Society, the Radiological Society of North America and the Section on Radiology of the American Medical Association all have symposia and Instructional Courses on this subject at their annual meetings Special bulletins and re. prmits of various articles are circulated to their members. My Commission on Public Relations of the American College of Radi. ology is not preparing an educational motion picture on railiatron hazards and their control for the medical profession These are some of the active programs that are now underway Di. Paul Hodges' discussion and summary is now open for general discussion D). Prokey: There is one point that hasn't been brought out today and that has to do with the icaching of medical sturients They are the group we as radiologists have a chance to moculate with the newer ideas and knowledge about genetics and the propei irse of diagnostic radiology In our teaching program, 1 often state that any time a physician Nuoroscopus a prtent with out having his cyes adequately dark adapted, it is malpractice It is jetst like starting to operate on a patient without boiling your ustumeurs for twenty minutes if you don't prepare your eyes for the twenty ininutes. Anothei effeuile means for impressing the importance of using limited fluoroscopo frelds on medical stil cients is to use a small fluorescent screen. Bring the students » groups of eight to ten into the fluor ose opro room and talk to them in the dark util their eyes are slark alapteri Tuis amazing how one can demonstrate scatter radiation around the side of the fluorescent sciecu with a piece of fluoi escopre screen Iliti dlje port opened, the screen is brighter and dams as the size of the ·133 Genetics, Radiobiology and Radiology port is decreased. When they are interested and crowd around, we hold the screen over their gonadal region. When the foot switch is actuated and the screen glows, they are astounderland move bach quickly. Also, in Louisville, so far as I know, there is not a pediatrician who owns an x-ray machine or a fluorescopy. Dr. Mickey. In respect to reaching the students carly in the stage of elieir training, I should like to propose that he gencti. cists get a shot at tliem in pre-medical school with courses in genetics. I think that it ought to be a required subject. All pre-medical students should hase an clementary course in genet. ics and all medical schools ought to have a rezuired course mu advanced genetics Dr Brues. I would just like to pronounce a plague on both houses. I don't think that medical students get enough genetic on the whole, but a lew get it sery well in some places ) also think Ph D's in biology don't know enough about pathology and cancer because cancer is too often not considered as a broad biological problem I think we have to correct both of these deficiencies Ir Tice Dr Scott, I want to thank you and your Com. mitee for your excellent program I think it has been a wonder. ful dumng for us to get together and discuss these problems have been thinking about the book laminagrap), Dr Gould metu. tioned We have had ours for about englit months. We tale a lot of laminagraphs, whereas previously we were saling alone seien exposures, now we make only one I would like to ask Iko or three questions of Dr. l'anHodges (1) Do you think an apron type of girdle that goes around the patient's waist is effecfile in protecting the patient's gonads(2) Do you think that it is practical (3) The premature aging process from radiation as discussed in the geneticists and tie report of Dr Shuckls Warren on the shortened life span of radiologists, can we overlook these hazard? Is thu aaching to worry about as far as we rarhologists are concerned? And last, I have heard notluing mentioned about Dr Ira Kaplan's work kriela sluch you are all familiar. Dr Kap lan, for over a period of over twenty-nine years irradiated 660 ·Genetics, Radwubiology and Radiology !! about this problem?" For over fifty years, they liave been and still are very seriously concerned about it. The American College of Radiology, through their Commission ou Units, Standards and Protection, of which Dr. Richard II. Chamberlain is Chairman, juist produced a lcxohlet, "A Practical Manual on the Medical and Dental Use of X-rays With the Control of Radiation lazarcis MıSampley will give a copy to cach of you. This mamal is Icing distributed to all practicing dentists, plıysicians, interries and 1csidents in the United States as an act of public scivicc. The American Roentgen Ray Society, the Radiological Soviety of North America and the Section on Radiology of the American Niedical Association all have symposia and Instructional Courses on this subject at their annual meetings. Specia} bullerits and 1cprists of various articles are crculated to their members. My Commission on Public Relations of the Imerican College of Racle ology is now preparing an adlık auonal motion pictuc on sadia. tion hazards and their muol for the medical profession These are some of the active programs fiat are 1x» underway. Di, Paul Hodges' clise ission and summary is now open for general discussion. Dr. Pakey. There is one point that liasn't been brought out today and that has to do with the teaching of medical students. They are the group we as radiologisu bave a chance to inoculate nith the ucncr icleas and knowledge about genetics and the proper use of diagnostic radiology. In our coaching program, 1 often state that any time a physucian fluoroscopes a prient wirlsout haung his eyes adequately dark adapted, it is malpractice It is just like starting to operate on a patient without boiling you 1184Cs assenes lut (kenty fuitutes if you don't prepare your cuyes Ion die twenty minutes. Anothei effecinc means for impressing 111" importance of using limited fumoscopi flekis on medical s11. sleuet i to me a small fluorest cut screen Bring the students in groups of cight to ten into the fluoroscopre toom and talk to then in the dark and their eyes are dark adapted luis amazing hots one can demonstrate scaner radauon around the side of the fluorescent scicon with a piece of Surenople screer. With the pris opesiel, the screen is brighter and dms as the site of the ·other group of specialists by something in the order of a year, probably not statistically significant, but the radiologists had a longer life expectancy than the non-medical specialist. So I take it if you lose anything by being a radiologist, it is (kumpensated by being a specialist To go back to the question of direct radiation of the ovaries to induce ovulation. I rough computation, using mouse data and making several assumptions, would give alsout half a percent as the member of gross abnornalities in the first generation chil. dren from a dose of 100 1. Dr Paul Hodges: Would thus be adlecl to the natural 15%? Dr, Crow': Yes. Dr. Scoll: Would lies also apply to radiation closes alcul mufated over a thirty year periaal? Dr Crow. Yes Furthermore, you would expect alsout the saine number in each of the following generations, the ember gradually diminishing over a fess dozen generations But remerber that gross abnormalities are probably a mio part of the mmal genetic effect I should think that licasy radianon 1, the olaries is about as dubious as anything a radiologist is called on to do Dr. Scoll. In the December issue of the American Journal of Roentgenology', Radium Thesagn and Vuclem Medicine you will find the reports dis Dr. Caii Braestrup, and 1r (l'ailla where both approached this problem (rom different 11e points and concluded that the shortening of the life span of radiologists was not an appreciable factor Dr. Tue: I wonder hos that figure of 15 days per roentgen ever got credence anyway Dr Scott. Well, I don't know Does anybody have thai references Di Brups, Somebody took some figures for considerable amounts of life shortening and dress the usual straight line to the x. y aves This may or may not be legitunate. This is the figure you come out with if you make the assumption that each rentgen does an equivalent thing.

·131 Genetics, Radiobiology and Radiology women for sterility. As I understand, le delivered a dose of alsout 75 r to the ovaries which is a big close as compared with the closcs we have been talking about today. His last scport showed at Icast fourteen grandchildren from these women who had been irraciated. Of the 441 he followedl, 270 became preg. nant and had 247 children and 14 grandchildren. There were no al»normalities in any of these children. I would like to hear some discussion about these studics. Dr. Crow: With reference to Dr. Kaplan's stuclics, I was toki there were three with detectable abnormalities among the offspring. That's not large even for people who are not irradhatod, since the total number molved was over 100, and the normal sate is about 1% D). Tice: When you take a chest film of a patient caring a protective apron, do you think it lowers the gonadal closc? Dr. Paul Horlges: We haven't been doing that. We have been limiting the size of our port very sharply to the size of the film. We are not using the apron Dr. Tice: But the aprons are available? Dr. Paul Hodges: Yos. D. Tice They seem to create a mental hazard in the patient. We use similar size aprons for chuldiou We had a sim. lar experience to yours A porter in a hospital trad to have a chest film at ycariy intervais or not get a salary chicch bauduse it was required He refusel without having a full length lead apron from fus neck to buis ankles Of course, he cin't realize how silly the request was because under this situation no radiation could reach the film. We fmally convinced sum that he didn't necd the long apron. Dr Scott Would anybody like to talk about Shicles Warren's report for Dr. Tre? Dr Crow? Dr. Crou I don't thun I can say anymore than I said carlier. The difficulty is a the lack of the proper age corrections. In fact, Dr. Warren's was not the first study of this kind The first was done by a group from the Metropolan Life Insur ance Company. Tlicy (lici mclude the age correction They found, if I remember correctly, that radiologists differed from the ·Genetics, Radiobwlogy and Radiology' 137 means that we get a fair number of 11 and 19-year3}ls {size the 3, 4, and 3 year olds that used to give us so much trouble do slot come to lis Dr Sroll: That would apply also to the surveys made by the mobile tuberculosis units. In the statement from the national office shes recommend that the mobile units be used only in areas and among groups in uluch they expert a ligti yicid. They no longer reconinend its use for grade school and high school groups and preler to have them subjected to tuberculin insis Dr. Friedell: I want to hark back to the fact that one had better know whether there is a tlireshold or not. This, in my opinion. 1, a function of understanding the mechanisin and the dose response cuirie The decisions that one will have 10 male are going to depend on lion one interprets the dine response Curie, Let Illye this tells you whether there is a threshold and Whether the effects are cumulative I would like to reiterate that the data for muzantons look better than the data for somatic effects, but are not conclusive, if a threshold does exist, 11 ameliorates the whole problem of radiation protecting considerably. I suppose from the point of view of hon ose proceeds, it is probally 1305t autsens anel messi judicious ro aysume that perhaps none exists. But if this in any way seriously einbarrasses the use of x-ray for the diagnosis and Prearment of disease, more careful serutiny of the whole problem will be tietnam Dr Scott Dr Francis, ise hase not heard from you D. Herbert Francis: 1 tlung one of the big probleme le base at our hospital is at the polio" center I am distressed! over the large amount of X-ray diagnostic work that is necessary on these patients They have bone malformations and defortni. ties luchi require a lot of orthopedic work. They have urinary calculi commonly, lung and chest conditions, and frequently have collapses of vertebrae 1 hase med for a long time to figure out how best we can protect them during pyelograms For adults keliale ssed tho or three exposures over the lidneys with section of the lower part of the tract by lead sluelds. For the prochest films of khurse, there is always protection below their belt ·136 Genetics, Radiobiology and Radiology mate D. Sroll: Furthermore, wasn't that extrapolated from studies on mice? Di. Bruies: This was extrapolated largely from mice, with a factor – one obviously has to put a factor in encompassing thic different life spans of the species. Could I comment on one other thing? In case there has been a misunderstanding. There is no question but that radiologists have shown a very much higlier incidence of leukemia. We've been talking about life span that's another thing. Dr. Scott: You're satisfied that the statement that raciolo. gists do have a higher incidence of leukernia is a solid observa. tion? Dr. Brues: This is a solid obscu vation, yes. This represents hetween a six and tenſold increase over the general leukemia The current guess as to the dose vecerved by the average radiologise during his years of work is about 2,000 roentgens This would not be uniform total body radiation although their exposure is considerably more diffuse than that of the patients. Incidentally, a little calculation will show what ilus in itself, woull throw doubt on the figures that have been put out zegarding life shortening per pengen in man. Dr. Peleison: Do you feel we should ciminate all unnecessary examinations and does this apply to the plotofluorograms at the chest? Dr Hodges: I certainly don't tunk that chest mu rofilms are unnecessary except in the case of chukiren but for seneral reasons It is unwise to microlim chuldren On one hand, they are amcı. able to skin testing as a preliminary surcen and, on the other hand, they are poor subjects Frequently they are imwilling or unable to cooperate and hold up the live by crying, sitting down on the floor, twisting and failing to boid their breath as the exposure is being made. Even under the best of conditions it is difficult to avoid administering mee essary radiation, sometimes directly to the gonads We liate stopped erainning children and have the cooperation of our pediatricians in the decision Only when the examining physicau believes that a child las about the build of a small adult is le sent for microſt}ming This ·Genetics, Radiobiology and Radiology means thuit se get a fair number of ll ani 12-year-olds imit the 3, f, and 3-sear olds that used to give us so much trouble do not come to us Dr scon. That rould apply also xu the survey, male by the mobile iuberculosis units. In the statement froin the national office they recommend that the mobile muts he used only in areas and among groups in which they expect a lugh yield. They no longer recommend its use for grade school and high school group and prefer to have them subjected to mercalin resis. Dr Fnedelt: I want to hath back to the as that one had better know whether there is a threshold or not. This, in any opimou, is a futiction of understanding the mechanism and the dose response (lirie The decisions that one will have to wale are going to depend on hosts one triterprers de dose response Curve, because this tells you whether there is a threshold and! whether the effects are cumulative I would like to reiterate that the data for mutations look berler than the data for somatic effects, but are not conclusie If a threshold dnes exist, it ameliorates the whole problem of radiacios protection considerably I suppose from the point of view of hou mnie proceeds, it is probably most tautious and must judicious to assume that perhaps none exists. But if this in any way seriously embarrasses the use of x-ray for the diagnosis and treatment of disease, more careful scrutiny of the whole problem will be necessary. Dr Scott Dr. Francis, he hase not lieard from you. Di Herbert Francus. I think one of the big problems we have at our hospital is at the polio" center I am distressed over the large amount of x-ray diagnostic word that is necessary on these patients They hale lifte malformations and deformi. ties sinch require a lot of ortiupedic work. They have inunn cakult commonly, lung and chest conditions, and frequently have collapses of vertebrae I have tried for a long time to figure out hos best we can protect them during pyelograms for adults się lase used ino or three exposures over the kidneys "ith pretecnion of the lower part of the tract by lead shields For thie chest films, of course, there is always protection below their bele.

·138 Cienetics, Radiobiology and Radiology Many of these are very small chukiren. The doctors in attendance Iccl these are important examinations and they recd them. We have changed some of the time intervais where they did routine examinations every month or so to sec the progress of this on that - changed those to every two, three, or four months and with more clear at indications for them. Overall I'm sure that these chilren are getting a considerable amount of radiation. It will be an interesting group in the long run a study. I think this would be true in all pollo centers, 1). Wilson: No comments, except to express appreciation to these geneticists who have come here to give us a background in genetics in which some of us are seriously lacking 1 211 icly grateful for the opportunity of listening te tliei. Dr. Scoil: We certainly are grateful to the genericists and radiobiologists for coming here and giving us see much of their cinc I second everything I. Wilson said, Dr. Sante. Could I speak just a moment about something that lins always concerned me from the time I heard of 1 many years ago? With all this talent here maybe we can have some suggestions. Many years ago, it was reported from the Cook her Institute by his representative, Francis Carter WoculI think of a very interesting reaction of laboratory tlumors to the cffects of radiation. Laboratory animals injected tith a laboratony (um (Jan. sen Rat Sarcoma) (ouki le stice cssfully transplanıcd in 100% of the inoculations After growth was well establislıca, subjccc1011 to an adequate known dosage of ladiation would cause complete regression. Now, if a can croudal close or Wadution CIC given to ucll-establıshed tumor transplants and one-half of them were excised after thicco Cour days, omubied and re-injected into another group of rats, there would be about 87", tites, ind consistently the timor halves which were left in vond 113 situ went on to spontaneous destination This has a 11,11% been . 1er intriguing thing to me and I can't que figure it out! lie Uicie any thoughts? Dr. Scott: Do wc balc any help for Dr Sante D). Brues. I believe tłat experiment has beca) trufieri in ·3.39 Genetirs, Radiobalagy and Indiology one or two other laboratories since then, in other words, I think it is content to say that the state of 13scularization at least around 3 transplanted tumor is an important factor. Dr. Jante: Always favorable? Or is is 56331.cines unfavora. ble to hate vascularity? What are the factors Dr Brues; At least 101 the case of a transplanted tumor it seetly to be. Anyway, that's the way it comes out. Dr Tice I would just like to coment on the picudo. scientists I had an experience just a couple of months ago).) retenedl a telephone call from a dextur in northern Kauss. The paciente sa leung (teated by another radiologist The patient mas very disturhed because the radiologist load indicated he was going to give her 2400 roentgens She told a physicist who was a relatise about this anxi the physicist said that 1125 termble, thay 100 r as the close total a person should have and such a tlose would be entirely impossible to give and shouldn't be given This physicist is me example of the type of people who are passion out misinformation Dy kraft. There is no doubt alsout that, and the purpose of thu Conference is 117 dissemnate arcuraie infurmation in asoud slich misconceptinus 1) Crou There is some hope to learn more about the genets problem, although all of our discussions thus far may itave sounded pretty fucile from the standpoint of human beings jou expect it to be learned from direct sunly nf human padi. jyer shar pesumism is pretry mucho justified I wanted 10 point All in anster to pouts you made this moming, that tissile cul. flire closes offer some hope, at least We can study mutation of Sexsmall cells to blood grouping to compatability antigeny or in katan ristics thich influence grouth of she colony l( one were able to measlire a variety of Jumman tissuks to a sariety of munise 139€ 1f those would uurt out to be comparable, that would ne me a bit more tartli icl our present estimates based 1331 the On the other hand, of it timed out to be totally uncomp arable, then I think we are pretty much lost in any impuliate cffect Di Pani The question of liat constitutes a vieressary X-ray Irails ·138 Genetics, Radiobiology and Radiology timc Many of these are very sınall children. The doctors in attendance lecl these are important examinations and they need them. lle liaic changed some of the time intervals where they did routine examinations every month or so to see the progress of this or that - changed those to every two, three, or four months and with niore clear cut indications for them. Overall I'm sure that these children are getting a considerable amount of radiation It will be an interesting group in the long run to study. I think this would be true in all polio centers. Di. Il'ilson: No comments, except to express appreciation to these geneticists who have come liere in give us a background in genetics in which some of us are seriously lachng. I am very grateful for the opportunity of listening to them. Dr. Scolt We certainly are grateful in the generk ists audi radiobiologists for coming here and giving us so imeli of their I second everything Dr. Wilson said Dr. Sante: Coukl I speak just a moment about something that has always concerned me from the time I heard of it many years ago? With all this talent here maybe we can trave some suggestions. Many years ago, it was reported from the Crocher Institute by its representative, Franus Carter Wood. I think, of a very interesting reaction of lalwratory tumors to ilie offects of radiation. Laboratory animals injected with a laboratory niiinor (Jansen Rat Sarcoma) could be sille essfully transplanted m 100of the inoculations. After growth was well established. suljettun to an adequate known (iosage of x-radiation would cause complete regression. Now, if I can crocidal dose of radiation ucre given to well-established tumor transplants and onc-half of them were excised after three or for days, emulsified and 10-119 jected into another group of rats, there would be about 87", tales. Inc consistently the tumor halves us luch were left 1} vwo and a situ went on to spontaneous destructio} This has always been l iery intriguing thing to me and I can't une figure it out le there any thoughts? Dr. Scott: Do we liave any help for Dr Sante: Dr. Brues: I believe that experiment has been icrificd in ·Tienesus, Radunology and Radiology all the time. Dr. Hodges touched on that business of exclusion. buu I believe that are liave to lie 110t only considerare, but at the same time hamamı as regards the use of x-rays is has been stated before, we lase in inform them a litle more strongly than we have in the past. We gre attempting to do that, and that is why I use the term, "a voice in the wilderness." It is a liflicult fou, but it can be done, particularly when you insist that the chnicians consult with you a requesting shat this or that be clone on a requistion. We have got to go out and do a bule by more consulting, even if it means leaving our seat in the viesing room or fluoroscopic room, and going to the wards and talhing to them This is what we have to do, and I trunk it is gomg 11) joy oss, 13 at is going to take time. Dr. Scott. That is the vend in racltology The clay of the "ilm readers" 15 gone. Dr Esans, we are indebted to you for serving as Co-Clairman of the Conference and in helping me build this progranti. Il'ould you like to close the discussion? Dr. Erans I would just like to say that from the standpoint of the biologists and generic15ts that we don't mind associaring with you radiologists at all We would like to leave the opportunity again some time, and as Ds Bruies ticated, buslogists can learn a lot about tumors and abnormal conditions, cir. bu We cannot attempt to work with physicians about rachation. I thuni ne are going to cum more and more to the radiologists and We are going to expect the radiologists to pass the snformation on l) Other physicians llayle we are adding a little more burden i them, but now I sehele cien the diagnostic radiologist is going to have to learn something about hological effects of radiation and the geneix hazards so that he can talk abou them to other physicians as well as to students When you go lach 110 souls! Inle you to realure that you have sepresented the other radiologists in your departments So pass the word along and get them in discussions Any (ne of us would be glad to carry on the discussion los correspondence for example, as Dr. Sante mentioned, I think I can give you some references on recent papers on tumor bed. We certainly have learned a lot and have enjoyed adiation, etc ·110 Genelics, Radiobiology and Radiologi examination I think is a very difficult ouc to make. Certainly in the conduct of progress examinations, one can puce them at proper intervals and one can suggest to the patient's physicians the lycst interval. I have had the experience and am sure you frave liad the same sort of experience in cxamining a parent. This happened to be a woman in her early forties whose mother had clicc of a carcinoma of the stomach about six weeks previously. She came in and stated she lad the same symptoms as her mother. She felt she inx) was geuing carcinoma of the mach. lcr physician didn't think so, but frad her gastrointestinal tract cxamined and she had a carcinoma of the stomach It look him very badly. That is not an isolated obscivation lihim that one has to be icry cautious about ceciding that any given patient shouldn't have au X-ray ciamination mecly because the soup toms are not dcfinite. 1. Scott: 1 agree with you. I believe the decision for an examination remains the responsibility of the attendmg plıysician That is his right and his duty llle can help move by supa plying him with the necessary information and background so that he cau exercise proper judgment. Dr. Lodwick To me this has been a cty informainc and asetul conference and I appreciae very much she oppusumity co be here. Dr l'an Epps. I think that radiologists, although they may be thought of as voices crymg in the wilderness at present, must go back to the fundamental concept that they are fort of all plıysicians I feel that I liaic just as much information and know cdge regard to med cine as ouret plissimus I calue. Di. Paul, the problem that some playsicians may present I fcel very strongly that it should be up to us tot only get the students, as Dr. Pirhey mentioned, but also the residents and the staff of all our departments to go back to the old pliilosopht vi imical medicine. I don't think the philosophy of meal medsene today pervades m many departments It's a matter, m my opinion, of being an interpreter of returned requisitions and consultations Clinicians haven't gone back to the matter of trying to our a ciagriosis. They go to the point of trying to prelude something ·INDEX 1xloinen 116 195 xtrations iste Chromonomes. gross st. arrangement) (see Vutations) Asmalities (see Chromonomes Teatringement) asce Vlulations) (ctromets Spots of,61 Icvations, 50 Acute reaction, 10 Vpha particles, 18 Alpha raus, Inema radaan induce 97 Angiographs cerebral 96 Animals 67 85 B Barr, David, 965 Bergonie and Trionicau, lax of 6 97 Beta partides, 18 Belarus, 7 24 Belauan 123,7 Benle 117 Biochemisen 36 Rinch canal 116 Partiellones tells f 1% Piphus ? pelvic 113 115, 118 120 121 131 matran 5 R$9 80 Lonnier 63 Brain 18 Punte 90 Brons (nu), R299 Cara G.76 (apati 63 Cell (selka blood, 1 Ixmc. 6,182 damage, not fauli replacel alier.f.23 diterent thiomtanmt pumats $ differentiation 3 cliploid. 22 23 Non 6 22,39 citra chromonimos. 31 B777, 89 23 long inal 6 mutation rate, R? mutation raic influchcel.33 HCTIC 6,0 nticicus, 24 mums, 23 proliferating muloyd 8? rad10-sensitive 31 regenerasse 106 single. 72 site and mechanism of damage, 3 16 natic 82 <iftitralls complex 6 texts of mammals 42 191€ 28 Chemical changes 15 Chest 107 (hromosome chromosome).8.232 absentation, ahnorinalis 15.) 2), 42 hreal breakage, turolen (src Chromo some. STK's restrangement) clcfined, 28 elections, 21 duplications, 21 extra, 33 34 gras rearrangement, 21.29, 51 37 13+1,81 74 amount o mar. 35 cenuntugal lorces, 35 degree of thdration 11 Cancer taluttiots of 11 leukemia ? 25 59 06-68 72 81-89 112 tulz 81,9 Carcinogenesis leuke mogenesis 9 Catcinoma radiation induced, 97 12 ·142 Genetics, Radiobinlogy and Radiology it, and I think I speak for the otheis. Dr. Scoil: Thank you, Dr. Evans. We agree with you. Radiology has never had a hasic science group as a foundation, It is by our close association with the radiobiologises, the radio chemists, the radiophysicists and the geneticists that radiology can have a basic science group to back it up and from whuch we can make progress. By worhing together, we can go further and! faster. The Conference is adjourned.

·Genetics, Radiobiology and Radiology 117 Dogma, mice, 19 Ovary (ovaríex). 107 (1 114 Origen.36 61 intercellular suppils,37 point 21,9 31 56, 11 63 65 2,97 rufsat1011 nutical 97 recise 19 71 7b sointi Il 23 % 72.3 5JXfic Incus 17 30 uttra ulet indicat so Mines 1971 Vintation rate 21,71 cells XP imate for 1921 17 Benllic in the 1 v Increased to mail,78 length of effeut mict #1 15 18 R2 irailatson achile chrome 47 moxlifel 37 natural 63 fxonit mutations, 31 Tactualion inducal fictors affecting 24 10 is different mutation rates 31 lemy Fature moulifies. 57 Pattern, 17 relvamen, ras, *3 104, 112, 116 114. 121,1 t'elis 116, 118 120 121 131 l'erotus cuncentration 37 pl1,37 rhodom.phical presfemx 91 **** I'Ivotoelectrons, en pairs, Puutars gland, 25 L'acuinanceptualegraph, l'opulation 11 NO (M. 127 l'rogeny, 20 I'roiettan privalutes, 10 15 l'rotons, 18 Preluatre aspects of railwin, X1 Pullman 11 Prelorgrams, 112 (Juuntw. 5 Secrosss 10 Sccl Tenplasua Teutrons 18 W 30 32 RS legial electienes 19 uraduated on mice. 12 nemt 1 Lost ih Suclear teman 17 Vucleus 51 33 chris ki 1 1 1ci Italia 1,4 ilt utron enten OX 97 R Kaluation acceptabile dails <xfkisterc. I acute caction 10 biologically electic in ale cu * sures, 4 1xgy matto.3 sells bone, tloulcsscl wall 6 connet11e 1ne, fi Tere, fed blol.6 white blool, 6 that line tlic intesunc, clemical changes 15 (ancer (sterer) damage (sce Ilamago) ciental ray hazard dus 1! 101 103 0111KOR 11 OlyITi 111 12 gelierul procedures 119 113 Keshtire al procedures 113 113 (Ixstetikat Tasliographs 111 126 Cecile S7 nice 3 female 13 ·Geneties, Radrobiology and Radiology Itultherg, Sven, 16 llidrogeu ion concentration, 37 I cukemia (src Cancer) 1.CH. L. 1,06 68,72.83 90 Ilust, V.76 l.ici, 18, 31 I ongevity, 13, G1, GS, 101 Iumlar pme, 121 1 I ting mucosal loning. 8 tumor, 14 Iring, 69 1. mpirocites of the blood 6 Blia, 118.195 Incciling, 75 76 Insects, 19 Intestinc, cells the linc, G Ton paus, &. 30 31 Ionization Joming radiation, 14, 30 32. 35,61 65, 73,91 100, 107, 121, 127 cells affected, 18 arracation, 7 law to limit medical insc, 100 irradiation acute in nee, 13-16 clranic aut micc, 15 G 12.1mage (scel) image) clirect 126 close (ser Desse) embryo 11 mamma, clironic, in man, 18 gelictic in mirc 11 55 ning. 7 lougeul, 18 nionisters, 20 neutron, 53 OVC 36 pragens, 20 pn.l. 82 Itc. IR immor, 89 Wanamals (see Vice) Viacomb,5 Vodical action, damme wand. 107 105 Vetalism, 90 Ulice, 11 at 16-18 (clls 11 female, offspring of, 48 gonete damage in 19,11 % 6% genetic TECOIci alıcı artacatan. 18 gonads, 23 hetcongous genes, 57 19 length of effect of rathann 77 lethalutations 18 5013 Jeuhemaa ratc, 80-81 Inta Jol ttc 11 Ti 18 k 1 sperm spematch ymatorues 12 testis, 11 lissile 11 Yri, 13 Vishes 67 Mutatic Inc, 19 Vouster, 20 Vrtul problems 1178*** Wprton, 1.77 Vullcı 17 01 Vulc 11 ) 71 7175 Vulation (mulations) 4 15 19.1 22. 31 3 90.61 78 78 112 12x 19 autosom.l. 19 20 deincel, 29 dominant. 21 Icthal 1921 19 50 51 71 97 piec lcicrongous genry 51 Ouigen * TIC 67 K hellner 61 I. Larison, E.16 I auglılın, 111 Lall of Beryone and aboneleu 6 97 I ca, 61 Lec, 56 I ethols, 1921, 12, 62, 71, 79.97 mice, 13, 50 51 ·Genetics, Radiobiology and Radiology 1-49 U Cicer, 129 Lltra violet rays. 30.61 chromosomes, 18 fractionatsng 18 low energy, 18 surface tissue affected, 1 long wavelength, 18 not ionizing. 7, 18 t'phoff, D.76 Lpton, 83 L'terus 83,316,318 chemical son producel, Ole, 120 cassettes, 115, 116 collimälion, 113 113 doxe, 108 filtration, 113. 113 gonads 108 in utero, 83 incident Ixam, 13 isomelric Tulcr, 116 Lilovoltage, J13 113 mutation rate in mice. 15-3 mother and fecus, 192 pelvimetrs, 139 phantom, experimental, 120 121 radiation more penetrating 7 Jess penetrating, 7 sale cose, 32.9%) surves, 101 shin damage, 96 97 cesti of mice, 42 target distance, 113 115 therapy, 127 (19ue exposel, 116 120 soltage 7 V 1entriculography, 95 1111es. 19.71 Warren 99 Warren, Sheilds, 68 X ravi tavs), 10, 18, 21, 30 31 33. 36 37. 51, 77 78, 81, 83, 95 97, 99, 100 104 109 128 129 ·148 Genetics, Radiobiology and Radiology Sperm (sperms) mature, 19 mice, 42 Spermatids, 19 mice, 12 Spermatocytes, micc, 12 Spine lumbar, 121 Spinal marrow, 82 Spondy11175, 82 Stern, 62 63 Stern, Curt. 62,70 Stchart, 67, 112 Stewart, Alice, 99 Stomachi, 129 Surgery, cancer, lung. 81 T rect effect, 60 dose (see Hose) cdema, 10 erythema (see Erythema) (posure (see I'xposure) gonads (see Gonads) hysteria, 101 indircct effect, 60 ionizing (see Ionization) length of cffect on man, 77 longevity, 68, 109 man, 61 man, effects of, 72 clical, lazard listenilsed, 102-103 mother and ſettis, 67-68 moral problem. 91, 98 99 mutations (sec Mutations) mutation rate (sec.Mutation rate) olystetrics (see Obstetrics) philosoplic problem, 91, 98 99 population, 71 80.99, 127 protection of body with Icad, 5 protection procedures, 10-15 Psychiatric aspects, 87 reducing meclical and dental damage, 101 regeneratiic organs, 3 rclatiuc cfficiency, 8 safe ratc, 59 safets mcastres, 109 site and nicchanisint of damage, 3 16 som tic effects 68,73 steps in absorption, 15 tistics (sre Tissues) volume, 3 ras (see \ra}) Raihicals, 11.23 Radiology, diagnostic, 127 131 Radon, analcd. 8 Rays (secilpha rais, Beta 1315, Cosmic rays, Gamma rays, Ultra solet rats, V.1ays) Regeneratiic organs, 5 Roentgen tay free.X-ray) I cloco.elt ticaments, 1012 Temperature (temperatures). 37, 65 I estis (testes), 107, 131 Ihreshot], 60,63 66, 68 71 72 83.97.98 non, 59, 60 62, 65.68, 98 Ijsue (tissues). 22,61 207 120 cells, 28 blood, bonc, epithchal nerve, 6 damage, 33 dosion. 6 epilatron, 10 cps. to v ras 110 120 fibrous, thercascut, 10 gonadal, 10% cyposed to 104 110 hyperplasia of the epulermes 10 tradiation, 18 wir ular origen pp 97 mice, testis of, 11 rection, eitil interincinte. słox, 6 yte ani 11 13 1f slange 16 somati, 27 Iruc matcrials 15 1 ranscatofis, 31 12 mice 19 Islanku and Beryone lan of 6 97 i umor N3 brann. 96 cyperimental 7? Jumphatic, 89 S Smjsou, 99 Sosman, 100