Radiation and congenital malformations

Radiation and congenital malformations

Radiation and congenital malformations* A. B. Nashville, E. H. BRILL, M.D., PH.D.** Tennessee FORGOTSON, Washington, D. M.D., LL.B., C. T...

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Radiation and congenital malformations* A.

B.

Nashville, E.

H.

BRILL,

M.D.,

PH.D.**

Tennessee FORGOTSON,

Washington,

D.

M.D.,

LL.B.,

C.

THRO u G H 0 u T his history, man has been exposed to a wide variety of environmental hazards, with which, through the process of evolution, he has ‘been able to achieve equilibrium, and to survive. The increasing exposure of people to various manmade sources of ionizing radiation, along with the rapidly growing list of new potentially toxic compounds in our environment have been the subject of study and concern in lay and scientific quarters in recent years. Current knowledge of ionizing radiation and its effects is far advanced compared with our understanding of numerous other hazards now deservedly receiving increasing attention. On both empirical and a priori grounds, it was realized at an early date that during early development the blastocyst and, after implantation, the embryo are very sensitive to a variety of insults which might adversely affect its proper development. The nature

and effect of the radiation insult have been investigated extensively. Adverse development is known to depend upon the quality and quantity of the radiation, the developmental time at which it is experienced, and the biological species. The recent experiences with thalidomide received wide publicity and refocused official and scientific attention on the general problem of sensitivity of the embryo to various agents which may be potential teratogens. In many respects, our knowledge of radiation effects can serve as a prototype for studying and developing guidelines for work on other potential teratogens. Generally speaking, most of the agents in question, including radiation, have social and economic benefits as well as liabilities. Medically, the use of radiation can be life-saving. Consistent with current knowledge, the concept of balancing the benefits against the risks has been developed and standards or radiation exposure guides established for the general public and radiation workers.” 2 These exposure guides are not applicable to ionizing radiation given to patients for medical diagnosis and therapy. Medical determinations are left to the prudent informed judgment of the individual physician whose actions are based upon knowledge of the patient and his health. The indications for dose-delivering procedures are radiation weighed against the potential hazards be they ever so slight and possibly not even measurabIe. Among these potentiai hazards must

*The views expressed herein are those oj the authors and do not necessarily of reflect the views of the Department Health, Education and Welfare, the Atomic Energy Commission, or the Public Health Service. **Division of Radiological Health United States Public Health Se&ice, Current address: Department of Medicine and Radiology, Vanderbilt University School of Medicine, Nashville, Tennessee. ***Special Secretary Education

Assistant to the the Department and Welfare, for

of

LL.M.***

Assistant of Health Legislation.

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he included possible harm to the unborn fetus. Such harm can be encountered even when the physician is unable to determine whether the patient is pregnant. Radiation effect studies are useful as prototypes for work on other potentially hazardous or teratogenic agents because ionizing radiations (1) can result in many different types of anomalies singly or in combination; (2) can penetrate various barriers including the placenta at random; and (3) can provide an opportunity for the formulation and testing of the significance of doseeffect relations. The timeliness and appropriateness of a discussion of the effects of radiation on human, postzygotic prenatal development is underlined by (1) the recommendations of the 1961-1962 Presidential Panel that a comprehensive attack on mental retardation be developed”; (2) the authorization for and subsequent creation of the National Institute of Child Health and Human Development by the United States Public Health Service to study such problems ; and (3 ) the medicolegal decisions that have been reached and which have broad implications with regard to factors with potential adverse effects on human prenatal development. We will discuss the effects of radiation on prenatal (postzygotic) development and will consider some of the medicolegal questions which might arise or already have done so. The potentially long latency of genetic and somatic effects on adults (including among others, neoplastic and degenerative changes) in the current generation or its progeny makes it difficult to document medical causality in the usual sense (as exemplified by Koch’s postulates regarding infectious diseases ) , and to quantitate the role of radiation in the presence of other etiologically significant agents. In the case of medical diagnostic and therapeutic exposures, the benefit-risk balance concept for ionizing radiation has been relatively well pointed out and acceptec12 Of greater potential importance but much less well understood are the hazards of the various drugs, chemicals, infectious, and other agents, singly and in the

combinations in which they are commonly encountered by constitutionally and genctitally diverse persons. The restriction of our discussion to the postzygotic effects allows us to focus on potential effects in the progeny of a particular exposed individual and to inform the physician for counseling in this area. The problems in genetic counseling involve many more factors such as regulatory genes, dominance, recessivity, lethality, and linkage. A brief consideration of the complexities involved in both pre- and postzygotic exposure would cause confusion and consequently we will focus on prenatal postzygotic effects. We do not mean to de-emphasize the importance of prezygotic effects on the germ plasm which are of obvious importance to this and subsequent generations. Confusion sometimes arises when we use the terms genetic and somatic in describing radiation effects as if they were mutually exclusive. They need not be. Effects may involve the hereditary materials of germinal tissue of the mother and/or the fetus, in which case we refer to these as genetic or prezygotic changes, whereas effects on the somatic cells of the mother or the fetus regardless of whether they affect its nuclear or cytoplasmic machinery are called somatic or postzygotic effects. A discussion which considers the hazards of ionizing radiation alone is likely to be misleading if not placed in the proper perspective. The benefits of the prudent, productive medical use of radiation in diagnosis and therapy are clear-cut and can far outweigh the potential hazards. One can define a productive exposure as one which delivers the minimal dose consistent with obtaining the necessary diagnostic information or the best therapeutic result. This is determined by medical judgment based upon knowledge of the patient from history, physical examination, and necessary laboratory studies. A recent publication by the World Health Organization entitled, “Radiation Hazards in Perspective,“-’ presents a very clear succinct discussion of both genetic and somatic radiation effects and succeeds in establishing a

Radiation

well-considered forthright perspective which we shall not repeat. In addition there have been several excellent recent reviews of the subject of the prezygotic effects of radiation, to which the interested reader is referred.+* The comprehensive monograph by Neel, entitled “Changing Perspectives of the Genetic Effects of Radiation,“g presents a well-balanced, easily read review. In addition, a comprehensive discussion of genetic injury to man by Estep and Forgotson entitled, “Legal Liability for Radiation Induced Genetic Injuries,” was recently published in the Louisiana Law Review.‘” Some of the major notions from the legal liability paper will be restated below and are extended primarily to cover the postzygotic effects of radiation on the developing embryo and fetus. The current emphasis on human genetics is a natural consequence of ( 1) an interest in radiation and other potentially toxic agents; (2) the growing awareness on the part of scientists of the importance of host factors in disease susceptibility; and (3) emergence of appropriate tools which permit human developmental systems to be investigated in depth. In this regard, radiation itself has been a most useful tool in advancing our understanding of mammalian genetics and factors influencing development. Because of the extensiveness with which radiation has been used in the laboratory as a biological probe, much information is available which will be summarized in our discussion, emphasizing data from human studies. The recent emergence of human cytogenetic technology has given medicine another very useful tool which already has provided valuable insight into a variety of pathological conditions. It is expected that in vitro studies, used markers of significant injury such as chromosome aberrations, will permit investigations of the potential terato,genic activity of various extrinsic agents. The developments in computer technology have made it possible to collect and consider the biologic implications of large amounts of data derived from man himself, used appro-

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priate epidemiological and ecological trchniques. ReaIisticaIIy speaking, this increased ability to look at a large catalogue of human data does not necessarily insure that answers will be forthcoming from this inquiry to any or all significant questions in radiation hiology or elsewhere, especially if the catulogrle is imperfect, and we may continue to depend upon the results of in vitro and experimental animal studies for the answers to many of the key questions. This is especially true where the experience of many generations is required for the formulation of meaning:ful analyses. Clues from laboratory studA arc needed to furnish leads for epidemiological studies, and vice versa. Ultimately many of the definitive answers will come from the emerging field of m~tl~ular biology. From these fundamental inquiries wt hope to learn the cytoclItmical determinants of biological effects for \.;iriouq specific agents (including ionizing radiation ) and how the resulting ultrastructural (left’cts develop into clinical anomalies. Mechanisms, of

radiation

markers, effect

and on

the

Preliminaries. It is generally

modifiers embryo

accepted that the processes specifically affected at an) given developmental stage are those which are undergoing the greatest rate of growth or differentiation. Sensitivity need not be greatest in those primordia with the fastest visible rates of proliferation, in which circumstance some biochemical process related to, or responsible for, orderly ct-II gro\vth and differentiation, i.e.. organizers, enerk. tsansport systems, etc., may be most sensitive to and affected by radiation. Of presumed importance is morphological damage, an example of which may IX* radiation-induced chromosome anomalicxs. Although the primary distribution of ionirativn may be random. the aberrations W~III‘ with uneven distribution. This irrrgularit!, in the cellular reflection of primaly damage presumably reflects the frequency of cells under.goin,g rapid mitosis in various regions of the developing embryo. In addition to this differential distribution of immediate &ect, it

is also probable that different regions of the embryo have different capacities for repair, processes which themselves may have varying radiosensitivities and affect the probability of expression of damage. The fact that radiation exposure at a particular stage of development apparently leads to specific and consistent types of abnormalities in sensitive primordia implies that damaged cells react to severe injury in relatively few ways.** Furthermore, it suggests that the effect does not cause the cell to act in a specific aberrant fashion, the variety of which would be manifold, but subtracts the contribution of this cell from the developmental community, presumably by cell death or retarded growth potentiaLI In general it is noted that at a given gestational stage on increasing the dose one finds: ( 1) an increase in incidence of abnormalities; (2) an increase in the severity of the lesions produced; and (3) effects seemingly identical to those produced at more sensitive stages by lower doses.ll These findings can be attributed to the increased probability of inducing critical physical-chemical changes in the involved cells, which in part may reflect a diminution in the effectiveness of repair processes.13 Changes in chromosome structure. It is known that a variety of agents can cause chromosome anomalies both in vivo and in vitro. The list still incomplete but growing, includes : radiation,l* various alkylating agents,15-17 certain of the antibiotics including Streptonigrin,18 and Mitomycin,19 colchicine,l? and various viruses.‘O The chromosome-damaging effects of these agents are believed to be most marked on dividing cells. Hence, the known somatic effect on adult tissues provide valid evidence that qualitatively similar fetal effects can occur. The evidence for damage by radiation in vitro to cells from various species including man is extensive. In addition, information on in vivo effects has been derived from studies on several human populations exposed to high radiation doses. The studies by Bender and associates of otherwise normal persons exposed to relatively large doses of

radiation in industrial accidents have demonstrated that the type and frequency of radiation-induced chromosome anomalies observed in man follows the same pattern as in animals and in vitro cell systems and that the frequency of anomalies increases with dose.‘ll O2 Similar studies on patients with ankylosing spondylities treated with x-ray+ 24 demonstrate on a larger scale the dose-response curve, types of anomalies, and their persistence in circulating leukocytes taken and cultured as late as 20 years following these exposures. These studies show that radiation induces persistent chromosome aberrations in man and that these may be useful as biological dosimeters as well as of potential prognostic significance. Preliminary reports have suggested that relatively high dose diagnostic x-ray examinations in children may result in an increased frequency of cytogenetic damage in cultured circulating leukocytes.25j 26 The significance of these preliminary findings, however, is not yet established. Changes in chromosome number (including translocations) . Autosomes. One of the ways in which radiation is known to be capable of inducing chromosome anomalies is by nondisjunction. This is evidenced by an abnormal number of chromosomesin the cell, due to the failure of the members of a pair of chromosomes to proceed to separate daughter cells at the time of the cell division. The resulting cell either lacks a chromosome or possesses one more than the normal complement. The gestational stage at which the process occurs defines the extent of the anomaly. As early as 1921,27it was suggestedthat nondisjunction of the sex chromosomes couId be induced by radiation in Drosophila, and subsequent work has verified these findings.28-“1 The recent finding that in Mongolism, there is, in effect, an extra chromosome in the 21, 22 group32 (presumably No. 21) is of interest. It is not known whether or not radiation plays a quantitatively significant role in the etiology of trisomy 21 in man, but if it does, its role may differ in the various types of Mongolism discussed.

Volume Number

90 f, part 2

Uchida and Curtiss33 recently reported the results of a small retrospective study designed to determine whether or not mothers of Mongoloids had received a greater amount of diagnostic abdominal x-ray during the index pregnancy than they observed in controls. Their findings are subject to the same reservations as will be expressed for the relation between prenatal irradiation and leukemia. Nonetheless, an increased frequency of prezygotic medical radiation exposure was found. Schull and Nee134 noted the discrepancy between the above findings and their observations in the progeny of the Japanese (who did not show an A-bomb survivorP increased incidence of Mongolism) and supported the cautious attitude which Uchida and Curtiss also expressed. In addition, Neel has suggested that by the time the second meiotic division goes to completion at ovulation, disturbances in cell function resulting from exposures to radiation over the preceding years, which might result in an increased tendency to nondisjunction, would have completely abated. He suggests that only the most recent exposures may be of importance.g Since the temporal accumulation of injuries by the ova could explain the observation that mothers of Mongoloids tend to he in the older age ranges, a quantitation of the rate of abatement will be of importance. A further possible mechanism has been proposed which, if valid, may explain several unusual patterns of inheritance in Mongolism. Dekabon et a1.36 and others,37 have presented suggestive evidence that various nonspecific chromosomal alterations which may be present in a small percentage of apparently normal persons may increase the probability of meiotic irregularity and nondisjunction in the germ line (in either the male or the female parents). If this is true, radiation of people could by this indirect mechanism induce nondisjunction much later, and in fact, can go on for many generations.“* It is now known that prezygotic Mongolism involves all the cells in the individual, either as regular Mongolism (trisomy 21)

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in which the zygote receives the extra autosome from either the mother or the father (whose body cells do not show the defect , or translocation Mongolism, in which thp patient and either the mother or the father has a chromosome 21 (or a piece thereof) attached to the end of one of the other chromosomes. In addition to prezygotic mongols there are well-documented cases of postzygotic Mongoloids (mosaics). In these persons cells in some organs have the characteristic trisomy 21 while cells in other organs ae normal.3s It is presumed that whenever tri3omy 21 involves the central nervous system including its precursors, the characteristic mental retardation seen in mongoIs is prt:sent. The distribution of the various stigmas in a given patient then reflect the organs involved, and possibly the quantitative significance of the aberrant clone therein. Thus, the type and extent of the defect may bc useful in determining the stage at which it occurred. Sex chromosomes. An ever increasing variety of partial (mosaic) and complete sex chromosome anomalies are being found in which the chromosomes individually appear normal, but are numerically abnormal. As in the case of autosomal anomalies prczygotic errors result in abnormalities in all cells, whereas postzygotic involvement most likely resuhs in mosaics. No information in man on the significant exogenous factors Wsponsible for these defects is availablt,. ‘I’he finding that with increasing age there is a linear increment in the frequency of nonmodal leukocytes, presumably caused by nondisjunction of the X chromosome, may be an important clue.“o In certain instances, when suitable markers are present, the particular cell division can be detected at which sex chromosome anomalies arise, and the parent donating the> extra chromosome can be identified.” Evidence has been presented recently which strongly suggests that chromosome anomalies may be important in determining pregnancy outcome.4*~ 42 In Carr’s recent reporP one third of the material from un-

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selected spontaneous abortions (8 to 16 weeks) successfully cultured for chromosome analysis, was found to contain cytogenetic anomalies* along with embryonic evidence of retarded development. Thus differential viability of cells bearing various anomalies is of importance in ascertaining their longrange import. It is of interest that though there should be an equal frequency of XXY and X0 types in the general population, all surveys reported reveal a marked relative deficiency of X0 individuals.Q The survey by Harnden and associates in Scotland revealed in newborn babies 12 XXY individuals as compared with 3 X0 individuals.43 This shows that the deficit in X0 individuals is not due to differential mortality in postnatal life and suggests that the individuals with the X0 pattern have a low probability of surviving fetal life. Indeed the types of anomalous aborted fetuses reported by Carr” reinforces this suggestion. Thus, it is clear that radiation can cause chromosome anomalies. Chromosome anomalies have a counterpart in human disease, and the presence of these anomalies may influence the outcome of pregnancy. These anomalies may not have pathogenetic significance but may be the first of many potentially useful markers of cell injury. Iris heterochromia. In 1960, Lejeune and co-workers reported a disproportionately high incidence of the iris anomaly, segmentary heterochromia, in children who had been in utero at the time their mothers had examinations.41 received diagnostic x-ray This rare anomaly is a condition in which a segment of the iris of one nonbrown colored eye is of a different shade than the remainder of the iris. Among children who, while in utero, had received an average of 3 to 5 rads, during diagnostic medical x-ray procedures, 15 of 1,101 were noted to have segmentary heterochromia. The incidence was only 11 in approximately 7,092 nonirradiated control siblings and parents. The

*The different anomalies fetuses involved (as shown) E trisomy(l) C trisomy(1)

noted and included: X0 triploid (1).

the number (2) D trisomy(3)

of

difference is highly significant statistically. This somatic effect was seen only in children of women irradiated at 6 to Sj/, months‘ gestation. The etiology of this defect, be it a point mutation, a chromosomal aberration, or other cellular change, or a reflection of maternal disease which led to the irradiation! is not yet known. On the other hand, a recent preliminary survey conducted in this country suggested that the natural frequency of this condition in a suburban community in Maryland is not greatly different from that seen in Lejeune’s irradiated group.‘” The in utero irradiation experience of this group was not such as to account for this discrepancy, and thus the value of this index or marker of in utero radiation exposure is somewhat in doubt. Teratogenesis and carcinogenesis. Some agents which are oncogenic are aIso teratogenie. Our knowledge of the possible relationship between these processes has recently been extended significantly. Good and co-workers at the University of Minnesota have furnished two major cIues: (1) knowledge of the relation between immunologic competence and the role of the thymus has grown out of their early studies of children with agammaglobulinemia. In this developmental anomaly an unusual frequency of malignancies, including leukemia, has been noted.lG The enhanced incidence is clearly of significance but the mechanism involved is not yet understood. The earlier observation of the high incidence of leukemia in mongols by Krivit and Good”’ has been amply verifiedi4 and extended, most recently by Miller.‘8 Based on findings from the National Cooperative Leukemia Survey [Childhood Leukemia), Miller has noted a tendency for children with leukemia to have an increased incidence of various anomalies, not limited to Mongolism.‘x An excess of Mongolism was noted in the siblings of the leukemic children, in addition to an increased incidence of malignant disease, 5 out of 8 of which were leukemia (1 malignancy expected). Whether this reflects preor postzygotic injury is not certain,

Rodiotion

More recently Miller, Fraumeni, and Manning have reported the results of a survey of children with Wilms’s tumor.@ Out of a total of 440 cases, they found a highly significant increase in certain congenital anomalies. These included aniridia (6 cases) and congenital hemihypertrophy (3 cases), the combined expectancy of which was less than 0.1. In addition, an increased frequency of hypospadias, cryptorchidism, horseshoe kidneys, and other anomalies of the genitourinary tract were noted. The similarities which have been noted between oncogenesis and teratogenesis suggest that clues derived from the study of developmental anomalies may be extended to and tested in, the childhood malignancies, and vice versa. Speculations. The suggestion that malformations and neoplasms may be end results of similar processes is not new. Ionizing radiation and, possibly, alkylating agentsg6, @j possess, in common, mutagenic, teratogenic, and carcinogenic properties. We know relatively little about prenatal development, but it is expected that prenatal stages should be most sensitive to these agents. Since we know more about these insults in later life one is tempted to extrapolate from these and related observations to the prenatal period. It is known that certain types of leukemia are associated with chromosome anomalies. Almost without exception, untreated patients with chronic granulocytic leukemia have an anomaly of chromosome 21 (Ph “‘, ‘I which apparently reflects an altera1’1J 2 tion in the stem cells. Chromosome anomalies in the acute leukemias are less frequent and apparently random.“O In recent experiments in mice, radiation induced leukemia has been reported to have a characteristic chromosome anomaly. This ‘Lmyelogenous leukemia” has been transmitted through numerous mouse passages by cell free filtrates,“” which leads one to think of lysogenic virus, “infectious DNA,” or some similar agent, accounting for transmissability, absent chromosomal material, and the “disease” itself. Viruslike particles have

ond

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been seen in mouse leukemias for many years. The recent reports of similar particles in human leukemia”:’ have not yet hren evaluated but may be of considerable iniportance. In mice given 6-amino nicotinamidt: during pregnancy (day 11% ), a high frequency of cleft palate has been found associated with cytogenetic anomalies.“* Additional studies with other agents are necessar) to determine how commonly and in what way different developmental and cvtogenetic anomalies are related. Agents which can cause leukemia, such as benzol, ionizing radiation and, possibly, alkylating agents as well as several additional suspect compounds also can cause bone marrow depression. The sensitivity of the fetus has been related to the amplitication attendant to the geometrical progression of cell replication. Exposure in later life to agents which are mutagenic and which cause cell depression, singly or in combinations followed by rapid repopulation, simulate a feature of the fetal system. ‘This may explain in part their mode of action, and if so serves as a clue as to which agents sbould be looked at most carefully as their toxicity is being evaluated. In addition, research (such as carried out on radiation protection agents), may be extended with profit to attempt to protect against various potcntially injurious exposures. certain diseases in which In summary, chromosome anomalies are present and following exposure to agents which produce similar anomalies an increased risk of leukemia has been noted. Immunologic maldevelopment may be important, as may the role of viruses, which themselvch?; are associated with chromosomal instability.‘” The importance of these findings alone and in combination is obvious, and r&ects merging lines of results from different disciplines. This successful beginning has involved clinical, experimental, and epidemiological approaches, phrasing the questions ir, quite different terms. It can be concluded that the actions of radiation and other damaging ionizing

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agents on the developing embryo and fetus are probably similar at the molecular and cellular levels. In addition to effects on DNA replication and chromosomes, developmental effects may reflect more subtle intracellular metabolic alterations possibly involving energy transfer mechanisms. The markers of postzygotic prenatal effects are not amenable to clear distinction yet and cannot be quantified. However, they are probably qualitatively similar to the markers for adult preor postzygotic damage. Effects of radiation on mammalian prenatal development

Background. Ionizing radiations can interfere profoundly with the normal development of mammalian and other embryos. The high susceptibility of actively dividing embryonic tissue in contrast to adult tissues reflects both the radiation sensitivity of cells undergoing rapid mitosis and the intense amplification of induced defects during fetal development. Several inherent difficulties have hindered our understanding of the somatic (postzygotic) effects of radiation on mammalian prenatal development. How much of the effect of radiation is due to direct effects on the fetus in contrast to effects mediated through the fetal environment including the placenta, especially with large doses, is not known with certainty. The evidence strongly suggests that direct effects are most significant,55 but maternal factors cannot be eliminated.56 In mammals, genetic variables, small litter size, and competition between embryos add to the complexity of the of the problem. A precise determination time of conception and the radiation dose received by the fetus is difficult to reconstruct from the early studies in which the factors used usually were not so specified as to permit reliable quantitative estimates. In addition, the detection of different kinds of damage at the phenotypic level requires a systematic adherence to extensive autopsy and biochemical protocols. Furthermore, the detection of functional abnormalities in lower species is necessarily incomplete.

Thus, studies on experimental organisms do not and cannot by themselves answer man)of the questions in which there is preat interest. We shall first consider the data iron1 experimental animal studies and then the It is more limited human information. easier to quantitate radiation dose from external sources of ionizing radiation than from internally administered radiation sources. For this reason our knowledge of the radiological hazards to the fetus is derived largely from studies using external sources of radiation. In this circumstance, the dose distribution is relatively uniform and calculable. When evaluating chemical hazards, the quantitative assessment of “dose” at the subcellular level is much more difficult than for radiation because of differential solubility and transport of various materials across selective barriers, and competitive interactions within the cell. The sensitivity of the fetal system can be investigated at relatively sharply defined points in time using the rapid pulses in which external radiation can be administered. The ease with which radiation parameters can be modified provides an opportunity to investigate mechanisms by which effects are induced. For these reasons radiation has been a most useful tool in establishing the chronology of mammalian embryology and delineating at the same time the hazards attendant to these types of exposures. During the first 3 months of human fetal life, organogenesis takes place. However, the primordial germ cell line is established within the first 2 weeks after conception and the actual germinal ridge forms approximately during the fifth week. The migration of early germ cells into the gonadal areas and their rapid multiplication occupies a brief period between the sixth and eighth week of fetal life.“8 In the female mouse, further differentiation to oocytes proceeds, so that at birth no germ line stem cells remain, and all oogonia have completed their first meiotic division. This is presumably true in man. The female

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Fertiiliz ation Abnormalities

100 Prenatal

80 60 Percentage

40 20 0 I L 2

Fig. 1. Incidence irradiation chronology

of mice for man

of pre- and neonatal at various is shown.

intervals

germ cells remain as secondary oocytes in a state of dormancy throughout childhood and thereafter, until the final meiotic division is completed, one ovum at a time during reproductive life. Thus, there are no cell or chromosome divisions of any kind in the oocytes throughout the largest part of the life of the mouse. Despite the fact that the cell is not dividing, mutations can be induced by radiation during this time.57 Conversely, the risk of mutation from agents other than radiation that act only during replication itself, is maximal in the female mouse during the earlier stages of oogenesis.57 In the mouse and, presumably, in man, spermatozoa enter the ovum when the ovum is in metaphase of the second meiotic division”’ which may be of general importance. In the male it is believed the stem cell divisions occur regularly throughout childhood with degeneration of postspermatogonial cells before they form mature spermatozoa.57 At puberty the regular maturation and shedding of sperm begins and continues through reproductive Iife, during which asymmetric stem cell divisions continue to take place and this mechanism, it is conthereby preserves the germinal jectured, which act stem cell line.Z7 For mutagens

I 1

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by

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Man (weeks)

of abnormal individuals at term after 24 hours. The corresponding estimated

upon the replication or division process, a strong age effect in the male but not in the female would be expected.J7 It is estimated that during the average human life span only 400 to 450 ova mature. The remainder regress at different stages in their development. Any ovum that is fertilized at say age 30, may summate the effects of the various kinds of exposures to which it was heir in utero during rapid division, and thereafter for 30 years from those agents, such as ionizing radiation,“; which are effective in the absence of cell replication. This potential genetic burden may be reflected by an increased frequency of point mutations, chromosome alterations, or segregation anomalies, as expressed in their offspring. Experimental findings. We shall slunrnarize the highlights of the major experimental rodent data as a framework for our subsequent discussions. A comprehensive review of the effects of radiation on prenatal development in mammals was presented by Russell in 1954” and recently summarized and brought up to date in the 1962 report of the United Nations Scientific Committee Effects of Atomic Energy on the (UNSCEAR) .6 An interesting symposium

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on congenital malformations in a recent issue of Practitioner contains an excellent succinct review article on radiation and congenital malformations covering both preand postzygotic effects.“’ The prenatal period is divisible into three phases for the purpose of the discussion at hand. These include : ( 1) the preimplantation period, during which early deaths are induced but the survivors appear mostly normal; (2) the period of major organogenesis, in which neonatal deaths and abnormalities occur; and (3) the fetal period during which growth and minor organogenesis takes place and during which the sensitivity to death and gross malformations decreases. The preimplantation period. When female mice are irradiated after fertilization but before implantation, the zygote mortality is high and rapid. Studies by Russell indicate that deaths are maximal following radiation given during the first two postcopulation days in mice, and that approximately 80 per cent of the prenatal mortality risk is experienced during the first 5 days after fertilization, i.e., the preimplantation period for the mouse.5 Fig. 1 shows the major events noted following irradiation of mice at varying gestational ages.5 The estimated human time scale placed next to the mouse chronology is derived from the graph correlating development of mouse and human embryos constructed by Otis and Brent59 and included in the UNSCEAR report.5 Radiation delivered preimplantation, in general, is not followed by morphological abnormalities, alterations in birth or postweaning weights, fertility or life-span.ll This all-or-none response to radiation, with either an apparently normal offspring or a dead fetus, led Russell to suggest that mammalian blastomeres are totipotent, and that loss of a cell at this stage can be compensated for, at least in part, by remaining cells. One possible exception, the significance of which is unclear, has been noted. Rugh and Grupp in one experiment on a small number of animals noted that following 15r delivered preimplantation to mouse embryos,

3 of the embryos developed cerebral anomalies.“” Further confirmation of their findings on a larger scale would be desirable. It is possible that anomalies induced by higher doses are masked by the associated high prenatal mortality. A general variability in response between species is seen following radiation during the preimplantation stage, with the rat showing a greatly diminished radiosensitivity during the early cleavage stages.5 Since information on radiation sensitivity from human studies will be most difficult to obtain at these very early stages, we will have to be content with imprecise knowledge concerning potential radiation hazards at these times. The period of major organogenesis. At doses above 100r prenatal mortality is generally increased in the earliest part of the period of organogenesis but less so than is noted when the radiation is given in the earlier stages of embryogenesis. A striking increase in neonatal mortality is seen following radiation doses in excess of IOOr during days 7vz through 11 f/2 with a sharp peak at days 9f/2 and 10!4z.11 Higher doses only increase the frequency of neonatal deaths observed and do not shift the peak or alter the shape of the curve of mortality. Whether the pregnancy goes to term, or is artificially interrupted and the effect quantitated shortly following radiation, retardation of growth (as expressed by organ and body weight) of the irradiated embryos has been consistently noted. The mean birth weight is related clearly to both the time post conception at which radiation is delivered and the size of the dose. Investigations of the magnitude of the effect of radiation on birth weight have been carried out at several dose levels in mice llf/, days post conception, at which time radiation effect is maximum, and a linear relation between decrement in birth weight and increasing dose has been found.” No information is generally available on postnatal growth and maturation over the life span, following irradiation during this stage. Relatively few systematic studies have been carried out to determine the quantita-

Radiation

tive relationship between radiation dose, gestational stage, and subsequent fetal anomalies. Nonetheless numerous abnormalities of mammalian embryos following irradiation during the period of major organogenesis have been reported. Available data suggest that there is a precise timetable by which the organism develops and that injuries at specific times have predictabIe sequelae. Presumably, regions with the highest relative growth rate, DNA replication, cell division, and differentiation are maximally radiosensitive at those times when these processes are most active. The changing panorama of radiation effect, therefore, largely reflects the rapidly changing pattern of development in the mosaic represented by the maturing embryo. The systematic extensive experiments by Russell have provided us with the most detailed information on the chronology of organogenesis in the mouse and the effects of radiation thereupon. She irradiated different groups of pregnant mice at 24 hour intervals from day I/Z post fertilization to near term. It is clear from these and other studies that higher proportions of abnormalities are seen following radiation after day 5)$ than earlier. These rare occurrences at earlier times, when noted, involve slight skeletal abnormalities. The other end of the anomaly time scale is reached by day 131/p beyond which few, if any, abnormalities are noted in mice irradiated with 200r.l’ “Critical periods” for the induction of almost all a,bnormalities are relatively short, and can be extended by raising the dose.” This is taken to indicate that a certain degree of sensitivity exists at stages other than the most critical one. On the other hand, the complexity of growth and developmental processes make it very difficult, if not impossible, to assign a single precise time at \vflich radiation induces each of the major anomalies. Probably, multiple, sharply delineated times exist at which effects may occur in different sites each with its own radiation sensitivity, with outcomes which are clinically indistinguishable, although the radiation was delivered at different gesta-

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tional times. This imperfection in our current knowledge results in an apparently imprecise timetable which makes it impossible to do more than speculate on the quantitative probabilities for the induction by radiation of specific defects at precise times durReadily detectable cening organogenesis. tral nervous system and skeletal anomalies are frequently seen. In general the central are induced nervous system anomalies early, followed by effects on the eye, \,ertebra1 column and thorax, visceral skeleton, and viscera, and lastly by anomalies of the appendicular skeleton, with considerable overlap. In addition to malformations, Iocalized retardation or tardiness in normal processes, rather than aberrant growth has been noted in this as well as in the fetal period.” Embryonic neuroblasts have been iound to be particuiarly susceptible to radiation injury which presumably results in the hich incidence of central nervous system anotnalies following prenatal irradiation. Within two hours after lOOr, severe histological damage is seen, which is less marked but significant after even lower doses.s With increasing radiation dose, larger sections of developing neural tissues are affected. Since intermitotic neuroblasts are more susceptible to .radiation than those in mitosis it has been suggested that cells during active cliifrrcntiation may be more sensitive than completely differentiated cells.‘;’ l’kc> pcriorl of tlw fetus. Very little recent work has been done during the period of the fetus which in the mouse lies between day 13 and day 19J/, (term) . Prcsnata 1 mortality following fetal period irradiation is very rarely noted. When mortality OCCLLI‘S. the peak ordinarily occurs in the neonatal pcriod shortly following birth and may persist as late as two weeks following g:.rstation. The affected animals show typical signs of acute radiation sickness. Katiiation &uGng the fetal period does not lead to detrc~tablc malformations. It is probably ~~:~roneous. however. to assume that esposur~~ during the latter part of pregnancy is without morphological effect. Since a giveE. number of affected cells is a decreasing fraction of

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Table I. Major abnormalities mammals by fetal irradiation

induced

Brain Anencephaly Porencephaly Microcephaly” Encephalocele (brain hernia) Mongolism* Reduced medulla Cerebral atrophy Mental retardation* Idiocy* Neuroblastoma Deformities Narrow aqueduct Hydrocephalus” Rosettes in neural tissue Dilation of third and first ventricles Spinal cord anomalies* Reduction or absence of some cranial Skeleton General stunting Reduced skull dimensions Skull deformities* Head ossification defects’ Vaulted cranium Narrow head Cranial blisters Cleft palate* Funnel chest Congenital dislocation of hips Spina bifida Reduced and deformed tail Overgrown and deformed feet Club feet* Digital reductions Calcaneo valgus Abnormal limbs* Syndactyly” Brachydactyly’ Odontogenesis imperfecta” Exostosis on proximal tibia Metaphysis Amelogenesis* Scleratomal necrosis Eyes Anophthalmia Microphthalmia” Microcornia* Coloboma* Deformed iris Absence of lens and/or Open eyelids Strabismus* Nystagmus* Retinoblastoma Hypermetropia Congenital glaucoma Partial albinism Cataract* Blindness Chorioretinitis’ Ankvloblepharon

retina

in

Table I-Cont’d Miscellaneous Situs inversus Hydronephrosis Hydroureter Hydrocele Absence of kidney Degenerate gonad* Abnormalities in skin pigmentation Motorial disturbance of extremities Increased probability of leukemia Congenital heart disease Deformed ear* Facial deformities Pituitary disturbances Dermatomal and myotomal necrosis ‘These in utero radiation.

anomalies to radiation

have and

been found are attributed

in

~UDXUIS exposed to the action of

nerves

the developing pool at later stages of development, the probability of detecting induced defects becomes small. These defects, when present, may be reflected by functional deficits. Other effects, if present, may require a latent period for their expression later in life.*’ In laboratory animal studies genera1 growth retardatio@ along with diminished size and weight of cerebral hemispheres, corpus callosum, and gonadPI has been noted. Sterility and decreasedfertility, when observed in males following radiation during fetal stages, has been attributed to failure of sperm formation. Histological evidence of immediate effects of radiation during the fetal period have been reported in the rat and guinea pig involving the brain, retina, thymus, liver and spleen, along with the skin.‘l It is presumed that the remaining normal cells compensatefor the altered cells and prevent or forestall the appearance of gross structural anomalies, leaving the animal with potentially fewer cells in specific regions, with a possible diminution in functional reserve. Human studies. Case reports (radiation therapy). Epidemiologic studies are becoming increasingly fashionable, and emphasis and support is switching from the earlier case report orientation. In general, this is beneficial, but

Radiation

there is the danger that shrewd observations will go unreported. The earliest clues regarding the biological effects of radiation were derived from clinical observations, which led to hypotheses for investigation in the laboratory and by epidemioIogica1 studies. The extensive studies on radiation leukemogenesis, for example, started in the late 1920’s by Furth63 grew out of the case reports by Aubertin who as early as 1912 commented on the unusual frequency in his practice of leukemia in radiologists.64 Within 6 years of the discovery of x-rays by Roentgen, the first harmful effects of ionizing radiation on human embryos were recorded in the literature by physicians. The early reports have been reviewed extensivelyG5+7 and the observed malformations, as summarized in the UNSCEAR report, are shown in Table I. The most frequent abnormalities represented on this list are in the central nervous system, followed by eye defects and skeletal malformations. Goldstein and Murphy conducted a survey in 1929 to determine the outcome of 106 pregnancies during which therapeutic pelvic radium or roentgen irradiation was received.6R Of the 75 children born alive from these pregnancies, 38 were reported “unhealthy.” The condition of 10 of these (including 2 microcephalics) were not attributed to radiation exposures. Of the remaining 23 “unhealthy” children, 14 were noted to be microcephalic, 2 hydrocephalic, 1 cretin or Mongoloid, and 3 children had skeletal defects. The precise timing of the radiation was not obtained, but in 13 of the 16 microcephalics it occurred prior to the fifth month, in 2 it occurred thereafter, and in 1 the time was unknown6* The fetal doses were estimated to be 30 to 250r.5 Epidemiologic studies. In the main, our primary (other than inferential) knowledge of the various malformations in man attributable to postzygotic irradiation comes from epidemiologic studies involving high dose radiation exposures. In addition to radiation therapy, discussedabove, the other possiblesourcesof radiation to which people have been exposed, include: ( 1) natural

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: 161

background radiation plus radioactive iallout from nuclear explosions; (2) diagnostic medical studies; (3) occupational exposures of radiologists and others exposed to radioactive sources; and (4) A-bomb survi\.ors. pregnant at the time of the explosion. TERRESTRIAL

AND

COSMIC

RADIATION.

‘4

1959 report suggested that in regions of New York State there was a high malformation rate in regions containing natural materials with high concentrations of radioactive materials.6sThese were assumedto be the primary etiological agent. The lack of dosimetric measurements to confirm the alleged differences in radiation exposure, the relatively small difference in malformation rates observed (19 per cent) between the contrasting regions, along with the hnown incompletenessof the reporting of congenital malformations on birth certificates, and the various factors of importance which could not be controlled in this study, make it difficult to attach much significance to the finding. Similarly, a recent report by Wes1ey’Oattempts to demonstrate a meaningful correlation between cosmic ray flux ,,as inferred from geomagnetic latitude and longitude) with the world-wide difference in congenital malformations. Unfort.rmately for his thesis, his data on radiatioa levels are apparently highly suspect,:’ wlrile the apparently low frequency of congenital malformations in tropical counttie!, upon which so much of his thesis rests, seemsvery likely to be the result of under-reporting in these countries7? Thus, to date, there is no good direct evidence that permits a quantitative assessment of the hazards of long term, low total dose, low dose rate, exposures to natural radiations as from terrestrial or cosmic 5oUrces.or from global fallout from past nuthar weapons tests. For a number of years, plans h;zve been entertained for studies of populations living in areas with high terrestrial radiation levels. The most notable of these would involve the inhabitants of certain areas of Kerala State, India, and Espirito Santo. Brazil.7s In addition, there is a coastal area

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in Ceylon, with thorium containing sands, in which the World Health Organization is conducting preliminary inquiries. Long term low dose, low-dose-rate radiation exposures? which deliver between 10 to 50 times higher doses than average terrestrial levels elsewhere are found in Kerala. The areas of Ceylon and Brazil have slightly lower doses and smaller populations at risk. If direct information is to be obtained on the effects of radiation in man from long term exposures at all times in life integrated over many generations, studies in these areas may be anticipated. The difficulties in developing effective record systems, establishing suitable sampling plans, along with the machinery with which to carry out these studies added to the uncertainties in the pertinent individual dose estimates, have so far precluded any large scale undertakings. OCCUPATIONAL EXPOSURES. Essentially no information is available specifically from this group due to the very low accident rate in the atomic energy industry, and also due to the small number of female radiologists (especially during the early years when less vigorous standards of radiological health were in force), Because of the high safety standards of the profession and the special attempt to minimize doses received by pregnant radiology technicians, we have no evidence regarding prenatal radiation effects from their experience. DIAGNOSTIC RADIATION. Much research and public attention has been directed to the possible hazards of exposures to diagnostic radiation especially during pregnancy. X-ray pelvimetry procedures during pregnancy deliver relatively large whole body radiation doses to the developing embryo estimated as 1 to 5 rads. No evidence exists at the moment which links diagnostic radiography during pregnancy with the birth of malformed children. However, as we shall next discuss, it has been reported that mothers of leukemic children had a greater frequency of abdominal x-rays during the pregnancy from which the leukemic child was born. A cautious attitude toward radiation hazards during pregnancy is proper, and attempts

should be made to eliminate unproducti\cb exposures. The study by Stewart in the United Kingdom which first suggested the possible relationship between diagnostic pelvimetry and some cases of childhood leukemia was based upon personal interviews with the mothers of all children who died of cancer in England, Scotland and Wales from 1953 through 1955, in comparison with identical data secured from matched controlsT4 Mothers whose children had leukemia or other neoplasms early in life reported almost twice as many diagnostic radiation procedures involving the abdomen during the relevant pregnancy as did mothers of control children. Persons carrying out similar studies to Stewart’s have noted that bereaved mothers of children with cancer may not respond to interviews with the same efficiency as mothers of healthy children, a factor which is difficult to quantitate.75 In addition to the possibility that the information on radiation exposures is biased there is the nagging question as to whether or not persons who seek medical attention early in pregnancy, which visit leads the physician to undertake abdominal x-ray examinations, are already experiencing complications which are themselves associated with existing maternal-fetal abnormalities, which are premonitory signs of serious disease. To control the first of these uncertainties, two large scale studies have been undertaken utilizing objective evidence of radiation procedures during pregnancy. MacMahon compared data from mothers in the Northeastern United States whose children died of cancer, 1947-1954, with the data from a one per cent systematic sample of mothers with registered births in the same time interval and locale.7c Mortality rates from leukemia and other cancers were found to be about forty per cent higher during the first eight years following births in which there had been prenatal x-ray exposures, Court Brown, Doll, and Hill, in England, failed to find evidence of an increased incidence of cancer above expectancy in their reported findings from a prospective study of

Radiation

mothers known to have received diagnostic radiation during pregnancy.?? Not enough time had elapsed and the sample size was not large enough for them to draw firm conclusions at the time of their first reports. Reports of the continuing follow-up of these individuals will be of great interest. Both the study by MacMahon and by Court Brown, Doll, and Hill are on firm grounds as far as knowledge of the fact of exposure is concerned. However, neither was able to control the maternal selection factors that go into the determination of who receives these procedures. MacMahon’s study has suggested that a history of threatened abortion is more common in the pregnancies which give rise to leukemic children than expected.“’ This may be taken as a slight suggestion that radiation in this circumstance may be “caused” by disease and not the converse. Nevertheless, it is well accepted that ionizing radiation can induce malformations as well as leukemia and other cancers in man. The question as to whether or not the doses of radiation used in diagnostic radiology are teratogenic and/or leukemogenic is still undecided. The answers will not come from statistical manipulations of existing data, but from new and different approaches. A-BOMB SURVIVORS. The studies of the Japanese A-bomb survivors provide the most valuable human data on biological effects of ionizing radiation. Since 1947, the Atomic Bomb Casualty Commission (ABCC) has conducted a broad program to detect and quantitate the genetic and somatic effects of radiation in large population samples. This includes persons who were pregnant at the time of the bomb. Early publications of the findings following prenatal irradiation showed a high frequency of prenatal mortality which continued during the first year of life.” The only other significant finding in previous reports was an increased frequency of children with microcephaly, and mental retardation, noted most commonly following significant radiation doses between the seventh and fifteenth weeks of gestation, in both Hiroshima’“, So and Nagasaki.‘”

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As the children who were in utero at the time of the bomb approached puberty, the frequency of examinations increased, and additional laboratory and clinical studies were carried out to detect possible radiation effects on endocrine maturation under the natural physiological stress of puberty.“’ No changes were noted in the urinary excrt.tion of 17-ketogenic steroids.” Estrogen excretion studies were carried out but were besc,t 1,~ technical difficulties.‘” A suggestive retardation in axe at onset of menarche was noted.” There was a statistically significant inc.reast: in minor congenital malformations. which the authors felt might reflect nothin? more than better case finding from greater ;rttt:ntion given to the heavily exposed group, especially in the earlier years. For each of the anthropometric characteristics measured, the most heavily exposed individuals in thp proximally exposed group were smaller on the average than their less heavily exposed cohorts.“A These were statistically significant in the females more often than in the males. A comparison of these indices* for closely exposedt females in the first trimcstr.1. with the remainder of the closely exposed fc,males reveals that the persons exposed in thr last 2 trimesters were smaller on every c-mint most of which were statistically significant. This finding is in line with the animal data, wherein, functional deficits, and diminution of birth weight and organ size followed irradiation in the period of the fetus in the mouse, which in man corresponds 10 the last 2 trimesters. It is not clear why this was not seen in the males. It is disqllietinq that they did not confirm the earlier well documented incidence of microcephaly. It is possible that the children who WPIP previously noted to be mentally rctardthd are living but less accessible to clinical follow-up or have had an unusual mortality esperi4 thr ence. An analysis of this portion sarnpk should be rrvealiny.

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New data from Hiroshima which are forthcoming will be of great interest. Since the sample size is small, we rely heavily on replication (as judged by whether or not the findings in the two cities agree). The great value of observations from the two cities is not overlooked and a final estimate of the effects of prenatal irradiation on the A-bomb survivors will await the appearance of the data from Hiroshima, and an integrated appraisal of the total experience, as seen to date, and as it continues to unfold in the future. Summary of human findings and contrast with animal studies. The observations in the Japanese A-bomb survivors have revealed a pattern we had come to expect from the earlier animal studies. Minor malformations, mental retardation, and retarded growth and development, were noted in the recent ABCC studies which add to the earlier information on microcephaly and mortality in the prenatal and neonatal periods. The stages of pregnancy at which these effects were noted are in good agreement with animal data, No striking endocrine changes have been noted as the children have progressed through puberty. The average radiation dose estimated for the prenatally irradiated Japanese A-bomb survivors whose mothers were located within 2.0 kilometers of the hypocenter at the time of the explosion is slightly less than 100 rads. Whether or not there are effects at lower doses cannot be stated from this material. The suggestion that cancers may be induced by lower doses (i.e, the 1 to 5 rads which may be received by the fetus during diagnostic pelvimetry) is less well established. No cases of leukemia to date have been seen in the offspring of pregnant women who were in Hiroshima or Nagasaki at the time of the explosion. Because of the small size of the sample, this does not discredit the alleged association derived from the other surveys, nor does it lend support. The unique value of the A-bomb survivor studies is derived from the fact that the dose of radiation is independent of other underlying diseases or conditions that

may have coexisted at the time of the lmnh. Nonetheless, a bias may exist, as coexistent constitutional defects or conditions undoubtedly influenced survivorship, but this bias should be less serious than in other radiation studies in man. Medicolegal

commentary

In all of the legal cases which might arise involving alleged postzygotic human fetal developmental defects the first issue which must be resolved is whether the fetus or embryo at the time of injurious impact, i.e., prior to its birth, has a legal existence which the law will protect by means of awarding civil damagess5 This issue is tending to be resolved in favor of allowing damages to be awarded on the grounds that: (a) Biologically from conception onward, the embryo or fetus has an independent existence, depending on the mother only for sustenance and protection; (b) The problems of proof or finding a causal relationship in these cases are not unique; and (c) The law recognizes the existence of the unborn child sufficiently to protect its other property rights such as inheritance and to grant it the protection of the rules of the criminal law.85 This trend toward granting awards is being extended on to conception itself rather than being restricted to insults occurring after fetal viability because the courts are noting that: (a) A limitation based on viability has been considered by the courts to be arbitrary and artificial ; (b) Fetal viability frequently is difficult to ascertain; (c) Many serious postzygotic prenatal injuries are more likely to be inflicted during the first trimester of pregnancy; and (d) From the time of conception onward the fetus becomes a distinct biological organism.85 With this broadening scope of potential liability and with prezygotic exposures not under consideration the basic legal problem becomes one of proof of causal relation between the exposure in question and the effect or anomaIy under consideration. Our legal system in general has delegated this

Volume Number

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2

task to a civil jury although it holds that courts (judges) must accept their responsibility for determining the sufficiency of the evidence before submitting cases to the jury and the weight and sufficiency of the evidence before allowing jury verdicts to stand.85 Courts generally hold that a plaintiff or party seeking an award must submit expert evidence that the exposure in question to the agent in question more probably than not (sometimes expressed in the language of to a reasonable medical certainty) caused the anomaly in question in order to obtain a verdict in his favor.86s 87 Legal cases involving postzygotic fetal injuries could arise in the course of medical malpractice litigation, third party negligence litigation, workmen’s compensation litigation, or employer’s liability litigation. Because of its statutory role of allowing recovery for income loss and medical and subsistence expenses to the injured worker from job incurred injuries, workmen’s compensation is an unlikely legal device through which these cases might arise. In any event, the questions of proof of causal relation will be of primary importance regardless of the means by which these cases come to the attention of judicial or quasijudicial bodies. The causal relation question itself raises two fundamental questions: ( 1) Whether the legal system and present rules of sufficiency and weight of evidence are adequate, or (2) Whether a scientifically more appropriate, juridically sound legal rule for proof of causation should be devised and instituted by our legal system. In order to resolve these two questions, the fullest information about postzygotic fetal injuries and insults must be developed and must be made available to the courts, legislatures, practicing attorneys, physicians, and those concerned with insurance coverage, adjustment, and settlement. Here and now it only can be stated that: 1. Effective means for differentiating those insults and injuries which are prezygotic from those which are postzygotic must be elucidated and clearly presented.

Radiation

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2. Much more data regarding dose-effects relations by developmental stage in the low dose ranges must be developed and articulated. (This will most probably be don<: in the cytogenetic area and in the field of molecular biology, discussed above). 3. Even in the higher dose ranges because of critical developmental time factors and “competing” or nonunique causal factors one can only state that a given exposure merely increased the risk of and altered the “risk category” of the anomalous emhyo. This last item seems to dictate that an alternative approach to liability should be considered.88 At the present time it behooves any physician, whether he is called upon (1 i to testify, (2) to evaluate a legal case, or (3 ) to give advice and counsel to his patients, to fully apprise himself of the ava.ilahle knowledge in this somewhat confusing area and to approach the medicolegal problems he might encounter with the thoroughness, prudence and judgment with which he approaches any situation in which the health and welfare of his patient is concerned. Although the available data are somewhat in a state of flux, the physician or surgeon must do his best to exercise the maximum prudence and informed expert judgment in these medicolegal situations. When called upon to testify he must learn to understand and work constructively and effectively with the legal counsel, the health physicist, the chemist, the pharmacologist, the biologists, and the industrial hygienists in ( 1) evaluating the case, (2) developing the case for settlement, dismissal, or lit&ation, and (3) educating the legal counsel in the facts and opinions and removing any misconceptions or misapprehensions held hy these counsels. There is one final area which must be considered. This involves recovery for mental distress of the exposed expectant mother because of fear of having defective children. In these cases where the exposure or insult is postzygotic, recovery has been allowed. This subject is covered in the article Liability for Genetic Tniuries on, “Legal

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from Radiation,” by Estep and Forgotson.“’ It is noteworthy that some jurisdictions have allowed recovery for this alleged item of damages even if (1) medical testimony is available to show that the feared injury would not probably follow from exposure; (2 1 a normal child was born; (3) the plaintiff had been thoroughly versed in medical sciences, she would have known that her fears were groundless.90-g2 This whole subject of recovery for fear for the “soundness” of conceived but unborn children by pregnant women with the defendant not even knowing that the would-be plaintiffs are pregnant at the time of exposure poses a very large potential problem especially in light of the famed New York Cancerophobia case. However, in any event, recovery for this mental anguish was but an item of recoverable damages to the expectant mother where the defendant was otherwise liable for injuring her.“3 It is possible that the Cancerophobia decision might expand the scope of this initial liability, however.* In any event all of the above-discussed medicolegal considerations, including the matter of fear of having defective children, highlight the importance of thorough consideration of this matter by the physician and dictate that the physician at all times exercise maximum prudence in administering diagnostic or therapeutic radiation or any other potentially teratogenic agent. All of these agents should be used productively, The writers are not trying to (a) stir up litigation, or (b) curtail the intelligent prudent-productive use of radiation or any other agents and induce potentially life

the Cancerophobia case, Ferrora u. Colluchio~ the issue under contention was whether the fear cancerophobia was a legitimate injury which was proximately caused by the defendant’s exposing the plaintiff to an allegedly excessive dose of therapeutic x-radiation for a nonmalignant condition. The primary factors involved were (1) the exposure and (2) the fear or ranrcrophobia. No cancer developed. Tbe plaintiff did have a nonmalignant dermatological condition allegedly caused by the radiation but the issue was whether the cancerophohia was a legitimate item of damages. The court concluded that it was. The other “fear” case referred to involved other personal injuries to the expectant mother, but specifically included the fear as one of the items of damage to be assessed against the defendant.wa w

“In primary

endangering medical restraint. They 31.k’ merely attempting to apprise the medical profession of the medicolegal problems which have been raised already by the courts so that the medical profession might cope with them better. The physician must realize that, although the legal doctrinal scope of liability has been expanding, the ultimate public policy expressed by American Jurisprudence should not and must not force a deterioration of the quality or quantity of medical care.* Summary

and

conclusions

1. Radiation can cause prenatal postzygotic injury in man. 2. The kind and extent of the damage depends on the radiation dose, gestational stage and species irradiated. 3. Many of the findings in extensive animal studies have been confirmed in less extensive human experience. 4. Induced chromosome aberrations are suggested as one of the primary mechanisms by which radiation action is mediated. As we learn more about cytogenetics and molecular biology we may hope to understand the manner in which observable cellular damage, such as chromosomal aberrations, expresses themselves phenotypically. 5. The similarities between carcinogenesis and teratogenesis are noted. Post-zygotic irradiation can be teratogenic at certain doses and gestational stages. Epidemiology studies following x-ray pelvimetry have suggested that these may be leukemogenic for the embryo. The evidence on this final point is not well established, but is consistent with available knowledge.

*Malpractice awards involve the intervention of the courts and legal system in an effort to improve the modicum of medical care and to award monetary reparations to the injured victim who received negligent or improper treatment. The policy intended in malpractice awards is to deter negliqent practice and not to causr a deterioration in the quality and quantity of medical services. Whro thr courts have developed doctrines which might reduce thr modicum of care, legislatures have intervened and havr enacted, for example, “Good Samaritan” statutes to protect physicians against undue liability in certain cases and pmvent a potential over-restriction of available medical care. These “Good Samaritan” laws have been enacted by several state legislatures.

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6. Further investigations will be important to clarify unresolved questions concerning radiation effect and to point the way for studies on other teratogens. Special attention to mutagenic agents which transiently depress cell turnover, and which may affect other basic cellular processes is suggested. 7. In evaluating the productivity of a dose of radiation in women, the suggestion

Radiation

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of Russell should be taken into considrrntion.Q5 Unless definitely indicated by prudent medical considerations, radiation and other potentially hazardous exposures particularly to larger doses should be restricted to tht first 14 days following the beginning of a normal menstrual period to reduce the probability of damaging a potentially high]! sensitive unsuspected developing embryo.

REFERENCES

1. Federal Register, May 13, 1960. 2. Background material for the development of radiation protection standards, May 13, 1960, Staff Report of the Federal Radiation Council, Sup. of Dot., United States Government Printing Office, Washington, D. C. 3. Report of the Presidential Panel on Effective Action to Combat Mental Retardation, October 1962. 4. Radiation hazards in perspective, Third Report of the Expert Committee on Radiation, WHO Technical Report Series, No. 248, Geneva, 1962. 5. Report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), Official Records of the Seventeenth Session of the General Assembly, Suppl. 16 (A/5216), New York, 1962, United Nations. 6. Russell, W. L.: Proc. Am. Phil. Sot. 107: 11, 1963. F. H., editor: Repair from genetic 7. Sobels. radiation damage and differential radiosrnsitivity in Germ Cells. Proc. of an International Symposium, University of Leiden, The Netherlands, August 15-19, 1962, New York, 1963, The Macmillan Company. of Radiation on Human Heredity, 8. Effect World Health Organization, Geneva, 1957. 9. Ncel, J. V.: Changing perspectives on the genetic effects of radiation, Springfield, Illinois, 1963, Charles C Thomas, Publisher. 10. Estep, S. D., and Forgotson, E. H.: Louisiana Law- Rev. 24: 1, 1963. Il. Russell. L. B.: The Effects of radiation on mammalian prenatal development, In Hollaendcr, A., editor: Radiation biology, vol. I, part 2, New York, 1954, McGraw-Hill Book Co., Inc., pp. 861-918. 12. Kohn, H. I., and Fogh, J. E.: J. Nat. Cancer Inst. 23: 293, 1959. R. F.: In Sob&, F. H., editor: The 13. Kimball, relation of repair to differential radiosensitivity in the production of mutations in Proc. International Symposium, paramecium, University of Leiden, The Netherlands, August 15-19, 1962, New York, 1963, The Macmillan Company. 14,. Bender, M. A.: In Buzzati-Traverso, A. A., editor: Immediate and low level effects of

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24. 25. 26.

2 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.

41.

ionizing radiations, London, 1960, Taylor and Francis Ltd., pp. 103-118. Stevenson, K. G., and Curtis, H. J.: Radiation Res. 15: 774, 1961. Haynes, R. H., and Inch, W. R.: Proc. Nat. Acad. SC. 50: 839. 1963. Swanson, C. P.: Cytology and Cytogenetics, Chicago. 1957. Prentice-Hall. Inc. Cohen: ‘M. M., Shaw, M. ‘W., and Craig, A. P.: Proc. Nat. Acad. SC. 50: 16, 1963. Nowell, P. C.: Exper. Cell Res. 33: 445, 1962. Aula, P.: Lancet 1: 720, 1964. Bender, M. A., and Gooch, P. C.: Radiation Res. 16: 44, 1962. Bender, M. A., and Gooch, P. C.: Radiation Res. 18: 389, 1963. Tough, I. M., Buckton, K. E., Baikie, .4 G., and Court Brown, W. M.: Lancrt 2: 849, 1960. Buckton, K. E., Jacobs, P. A., Court Brown, W. M., and Doll, R.: Lancet 2: 676, 1962. Bloom, A., and Tjio, J. H.: New England J. Med. (In press.) Conen, P. E., Bell, A. G., and Aspin, N.: Pediatrics 31: 72, 1963. Mavor, J. W.: Science 54: 277, 1921. Mavor, J. W.: J. Exper. Zool. 39: 381, 1924. Demerec, M., and Farrow, J. G.: Proc. Nat. Acad. SC. 16: 707, 711: 1930. hnderson, E. G.: Genetics 16: 386, 1931. Patterson, j. T.. Brewster, W., and Winchester, A. M.: J. Hered. 23: 325, 1932. Lejeune, J., Gautier, M., and Turpin. R.: Compt. rend. Acad. SC. 248: 602, 1959 Uchida, I. .4., and Curtiss, E. J.: I,anret 2: 848, 1961. Schull, W. J., and Neel, J. V.: Lanctlt 1: 537, 1962. Neel, J. V., et al.: Science 118: 537, 1953. Dekabon, A. S., Bender, M. A., and Economos, G. E.: Cytogenetics 2: 61, 1963. Grell, R., and Valencia, Jo: Scienc-c%. (In press.) Bender, M. A.: Personal communication. Oak Ridge National Laboratory, 1964. Mauer, I., and Noe, 0.: Lancet 1: 666, 1964. Jacobs, P. A., Brunton, M., Court Brown, W. M., Doll, R., and Goldstein. II.: Nature 197: 1080, 1963. Carr. D. H.: Lancet 2: 603, 1963.

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42. 43.

44.

45.

46. 47. 48. 49. 50. 51. 52. 53.

54. 55. 56.

57.

58. 59. 60. 61. 62. 63. 64.

65. 66. 67. 68.

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