Click for next page ( 185


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 184
Chapter XIII THE AUTOPSY FINDINGS ONE facet of the attempt to characterize the kinds and frequencies of abnormal terminations occurring to exposed and non-exposed persons in Hiroshima and Nagasaki was as ambitious an infant necropsy program as space and per- sonnel would permit. The performance of infant autopsies began in Hiroshima in 1948 although it was not until May, 1949 that a con- centrated effort was made to obtain the bodies of as many stillborn registered infants or regis- tered infants dying during the first six days of life as was possible. Autopsies were not per- formed in Nagasaki until somewhat later (Octo- ber, 1949), due to lack of personnel. The pro- gram in Nagasaki never attained the standard of exhaustiveness which we felt necessary to permit valid inferences. The reasons for this are somewhat complex but revolve largely around the fact that both the ABCC and Dr. I. Hayashi of the Nagasaki University Medical School were attempting to conduct an infant autopsy pro- gram. The efforts of Dr. Hayashi were moti- vated both by the requirements of an active teaching program in anatomy and an interest in a possible relationship between irradiation and malformation. Under the circumstances ob- taining in Nagasaki, we could not assure our- selves that the infants whom we obtained for necropsy represented a random sample. Ac- cordingly, the data obtained in Nagasaki will be presented later only with a view towards supplementing the data of Dr. Hayashi (see Hayashi, 1955; Sevitt, 1955 ~ . The genetic argument which would lead us to expect differences between exposure cells in the frequency with which major congenital anomalies would be detected at autopsy is the same, in all major particulars, as the argument advanced in Section 8.3. 13.! The randomness of the Hiroshima an- topsies.- In the interval 1948-1953 approxi- mately 750 infant cadavers were collected for i84 autopsy in Hiroshima. Of this number, 717 were actually autopsied and the remainder were rejected because of advanced autolysis. Among the 717 infants autopsied only 431 represented registered pregnancies. The 286 unregistered infants who were autopsied have been excluded from the data to be presented in this chapter because they are known to be a non-random sample of all unregistered pregnancies. During the interval, March, 1948-May, 1949, only a few autopsies were performed on registered in- fants, the majority of these involving "special interest" material, and certainly non-random. In May of 1949, the autopsy program was greatly expanded. We have felt it wise to ex- clude from consideration all autopsy results obtained prior to this expansion of the program, as well as autopsy material not meeting the restrictions placed on all data and described in Section 6.4. The actual analysis is thus confined to 406 autopsies conducted on registered in- fants between May, 1949, and December, 1953. Tables 13.1 through 13.4 present an analysis of the randomness of this autopsy sample. From Table 13.1 we note that: (1) the in- fants coming to autopsy were distributed by exposure in the same fashion as those registered infants not coming to autopsy; (2) a signifi- cantly higher proportion of males than females was obtained; and (3) in all, some 62 per cent of the infants who were stillborn or who died in the first six days of life were examined at necropsy. In view of the absence of an interac- tion between sex and exposure and also the absence of a significant difference in the ex- posure distribution of autopsied and non-autop- sied infants, it would appear that valid infer- ences could be drawn from these data. However, this body of data is no less affected by con- comitant variation than those portions of the total data presented in preceding chapters. Ac- cordingly, it is of some interest to determine

OCR for page 184
The Autopsy Findings TAl3LE 13.1 A. The randomness of the distribution of autopsied infants by sex of infant and parental exposure Mother Father Neither ex- ex parent ex ~^x posed Male{xb 1 90 Female Total: Ox 156 98 91 60 334 201 211 127 posed; posed; father mother not not 103 23 67 18 24 13 47 31 26 304 10 174 65 647 37 406 a Total number of infants stillborn or dying during the first 6 days of life. b Number of infants stillborn or dying during the first 6 days of life who were autopsied. B. Chi-square analysis of the frequency of autopsy by sex of infant and parental exposure Source%2 Total 13.6767 Sex-exposure interaction. 6.2765 Sex (unadjusted) 7.4599 Exposure (adjusted for sex) 6.1008 50.OI 40.0 MALf OR'vlAT ION (PER CENT) 30.0 20.01 10.0| 185 DF P 7 .05-.10 3 .05-.10 1 .01-.001 6 .30-.50 1 whether the autopsied infants differ from the non-autopsied infants in such sources of ex traneous variation Al, the age of the mother at the birth of the infant, the economic status of Both the parents, and the presence of a positive parents serology on the part of the mother at the time posed Total of delivery. 39 343 Let us consider first the evidence with regard 27 232 to maternal age. In Figure 13.1, the frequency of malformation among autopsied infants is distributed by maternal age. Mother's age is, we see, a rather important factor in the fre quency of malformation among infants coming to autopsy. Krooth's (1955) index of absolute difference which may be used to evaluate the significance of these data is, in this instance, 10.61 per cent (variance 1.1770). Maternal age differences could, then, be an important source of bias if maternal ages are dissimilarly distributed among exposure cells. From Table 13.2, we note (a) no evidence of interaction between the sex, autopsy, or exposure categories, (b) no effect of sex of infant nor the occurrence of an autopsy on the age of the mother, but / / / / / / ~0 ~ 1 1 . 1 1 -A 1 45 20 25 30 35 no 45 MOTHER S AGE FIGURE 13.1 The distribution of the frequency of autopsied infants with major malformation, relative to all autopsied infants, by age of mother with parity ignored.

OCR for page 184
86 Genetic Efects of (c) a significant difference in mothers' ages between exposure cells. This latter effect is principally characterized by a pronounced in- crease in mean maternal age when both parents were exposed as opposed to those cases where only one or neither parent was exposed. The Atomic Bombs Chapter XIII is not significant. The apparent trend is not unexpected in view of the fact that the ABCC assumed all expenses in the cremation, etc. of the infant cadaver. It seems quite probable that this would be a consideration of some moment to parents in the lower economic strata. The TABLE 13.2 MEAN MATERNAT AGE OF INFANTS STILLBORN OR DYING DURING THE FIRST 6 DAYS OF LIFE BY SEX OF INFANT, PARENTAL EXPOSURE, AND THE OCCURRENCE OF AUTOPSY Class of Neither parent Mother exposed; Father exposed, Both parents infant exposed father not mother not exposed Total Autopsied r 27.16 26.91 26.39 28.96 27.24 Males ~ (120) (67) (18) (27) (232) r 26.70 26.90 27.54 31.70 27.12 Females ~ (91) (60) (13) (10) (174) Not autopsied Total r 26.02 26.08 25.60 28.42 26.28 Males ~ (58) (36) (5) (12) (111) ~ 27.26 27.84 28.18 28.44 27.65 Females ~ (65) (38) (11) (16) (~30) r 26.79 26.62 26.22 28.79 26.93 Males ~ (178) (103) (23) (39) (343) r 26.94 27.27 27.83 29.69 27.35 Females ~ (156) (98) (24) (26) (304) Analysis of variance SourceSSDF MS F Sex 41.872 1 41.872 1.68 Autopsy 11.715 1 11.715 2.12 Exposures 312.946 3 104.315 4.20* * Interactions 188.875 10 18.888 1.32 Between 537.415 15 35.828 1.44 Within 15,707.445 631 24.893 Total 16,244.860 646 TABLE 13.3 THE DISTRIBUTION OF ECONOMIC STATUS AMONG A{rrOPSIED AND NON-AUTOPSTED INFANTS - Infant Very poor Autopsied 5 Not autopsied 2 Total 7 Poor 56 18 74 Economic status A_ ~ Average Well-to-do RichUnclassifiable Total 325 20 406 210 11 241 535 31 647 %2 = 6.474 DF = 3 P = .05-.10 difference in maternal age distributions will lead chiefly to a bias which results in an increase in the frequency of congenital malformations when both parents are exposed relative to the case when neither or only one parent is exposed. With respect to the distribution of economic status we note that the autopsied infants appear more frequently to represent the lower economic groups (see Table 13.3) although this trend rise in frequency among the well-to-do parents, if real, is quite possibly correlated with higher levels of education and an appreciation of the information to be gained from a postmortem examination. In view of the absence of a signifi- cant difference in economic classes it seems un- likely that the autopsy data with regard to mal- formation are grossly biased by parental eco- nomic status.

OCR for page 184
The Autopsy Findings In Table 13.4 is given the distribution of positive serologies by parental exposure and the occurrence of an autopsy. It is apparent from the analysis of these data that the autopsied infants differ somewhat from those not autop- sied in the frequency with which the mother of the infant has a positive postpartum serology. The reason for this is not apparent. However, there is no evidence of an exposure effect with respect to serology, nor is the autopsy-exposure interaction significant. Accordingly, we condude that there is no evidence of significant ex 187 exposure than in Nagasaki, and as a conse- quence, an irradiation effect should be more pronounced in Hiroshima than in Nagasaki (other factors being equal, of course). 2. The sampling scheme underlying those in- fants coming to autopsy in Hiroshima is reason- ably well known. 3. The data from Hiroshima are confined to infants where the age range is known; the in- fants were all of no less than 21 weeks' gesta- tion and were either stillborn or died in the first six days following birth. TABLE 13.4 THE DISTRIBUTION OF POSITIVE SEROLOGIES BY PARENTAL EXPOSURE AMONG AUTOPSIED AND NON-AUTOPSIED INFANTS (Serology is scored as the number of infants whose mother's serology was positive or negative.) NeitherMother Father Both parentexposed; exposed; parents Infant exposedfather not mother not exposed Total Autopsied Positive 11 6 0 2 19 Negative 200 121 31 35 387 Total 211 127 31 37 406 Not autopsied Positive 15 4 2 1 22 Negative 108 70 14 27 219 Total 123 74 16 28 241 Total Positive 26 10 2 3 41 Negative 308 191 45 62 606 Total 334 201 47 65 647 Chi-square analysis a ^ ~ Source %8 DF P Total 9.5635 5 .05-.10 Autopsy-exposure interaction 3.8209 2 .10-.20 Autopsy 5.0427 1 .02-.05 Exposure (unadjusted) 2.4682 2 .20-.30 a Father exposed and both parents exposed pooled. traneous variation with respect to the frequency of possibly syphilitic mothers among the mothers of autopsied infants. 13.2 The data. Two bodies of data exist pertinent to the occurrence of major malforma- tions among infants born to exposed and non- exposed parents and coming to autopsy in Hiro- shima and Nagasaki. The first body of data to be presented here is the data obtained in Hiro- shima under the auspices of the Atomic Bomb Casualty Commission. We present these data first for the following reasons: 1. Proportionately more "exposed" individuals in Hiroshima received significant amounts of In Table 13.5 are presented the data with regard to the frequency of congenital malforma- tions among infants autopsied in Hiroshima, distributed by parental exposure without ad- justment for differences in maternal age. Four comparisons have been made, namely, the equality of the frequency of congenital mal- formations (a) among all four exposure cells, (b) between infants born to non-exposed par- ents and those born to parents one or both of whom were exposed, (c) between infants born to non-exposed parents and to exposed parents one or both of whom were exposed and in ex- posure classes 4 or 5, and (d) between infants

OCR for page 184
188 Genetic Effects of Atomic Bombs Chapter XIII born to exposed parents with exposures less cent of the parents received inappreciable than 4 with infants born to parents in exposure amounts of irradiation (exposure class 2~. It classes 4 or 5. In no one of these instances does seems doubtful, therefore, that the autopsy data there emerge a significant difference. In view are sufficiently extensive to detect small irradia- of the effect of maternal age, adjustment for the lion effects such as a priori considerations would age differences among exposure groups would lead us to expect. TABLE 13.5 THE DISTRIBUTION BY PARENTAL EXPOSURE OF INFANTS BORN IN HIROSHIMA AND FOUND TO BE GROSSLY ABNORMAL AT AUTOPSY (a) Distribution of abnormal infants by parental exposure when exposure is defined as "present in city at the time of the bombing" Neither parent Mother only Father only Both parents Class of infant exposed exposed exposed exposed Total Normal 174 107 24 28 333 Abnormal 37 20 7 9 73 (17.5~) (15.8%) (22.6~o) (24.3~7o) Total 211 127 31 37 406 (b)Distribution of abnormal infants by parental exposure when exposure is defined in terms of the categories given in Chapter IV Both parents One or both exposed but parents in ex- neither in ex Class of posure categories posure categories Infant 4 or 5 4 or 5 Normal 33 25 Abnormal 5 (13.2%) 8 (24.2%) Total 38 33 (c) Analysis of data in Tables 13.5a and 13.5b Contrast %2 All exposure cells in 13.5a 1.912 Neither parent vs. one or both parents exposed in 13.5a 0.059 Neither parent (13.5a) vs. One or both parents ex posed as 4 or 5 (l3.5b) . 0.440 All exposure cells in 13.5b 1.451 DF P 3 .50-.70 1 .80-.90 1 .50-.70 1 .10-.20 TABLE 13.6 THE DISTRIBUTION BY EXPOSURE CLASS OF THE EXPOSED PARENTS GIVEN IN TABLE 13.5 Father not Mother not more heavily exposed; exposed; Exposed mother in father In parent In class shown class shown class shown Exposure in first in first in first class column column column Total 2 72 (56.7%) a 14 (45.2~o) 18 (48.6%`J 104 (53.3%) 3 38 13 7 58 4 4 1 4 9 5 13 3 8 24 Total 127 31 37 195 a Percentage of total. lead to differences between exposure categories deviating in a greater fashion from what is to be expected under an hypothesis of radiation- induced genetic changes. Obviously the sensi- tivity, as it were, of the comparisons given in Table 13.5 is a function of the number of parents who received significant amounts of irradiation. The distribution of the exposed parents by exposure category is given in Table 13.6, from which we note that about 53.6 per A second body of autopsy data bearing on the problem of radiation-induced genetic changes in the malformation rate is the data collected by Professor Ichiro Hayashi of the Nagasaki Uni- versity Medical School. We feel compelled to present and discuss these data in some detail because of the recent grossly over-simplified, biased presentation of these data by Sevitt (1955) . Professor Hayashi has kindly furnished us with a copy of a preliminary report on these

OCR for page 184
The Autopsy Fir~dir~gs data given as an address at a meeting of the Japanese Atomic Bomb Investigation Group and members of the Japan Science Council, held at the Nagasaki Medical School on 3 October 1955. At the outset of a discussion of Hayashi's data, it should be pointed out that his data differ in two important respects from the data we have presented from Hiroshima, namely, (1) the fact that the age range among the infants coming to autopsy is not clearly defined (they are described as fetuses or newborn infants), and (2) the definition of exposure. Hayashi's exposed cases are defined as those infants who were born to parents one or both of whom lived Wilshire 10 kilometers of ground zero at the time of the bombing (August 9, 1945~. It should be noted that the definition specifies lived within, which does not necessarily imply present within. Hayashi asserts that the location of these parents with regard to the hypocenter is still under in- vestigation. If we assume, however, that all of the individuals who lived within were in fact present within 10 kilometers of the hypocenter at the time of the bombing, Hayashi's definition of exposure is still, in our estimation, a most unfortunate one for a variety of reasons. The most important of these reasons is that 10 km. extends some 7 km. beyond the area of signifi- cant irradiation (5r or higher) except possibly in the "fallout" sector (principally the Nishi- yama reservoir area). A definition as all en- compassing as this can only lead to a dilution of radiation effects, if such exist, because of the inclusion of large numbers of essentially unexposed persons. An additional disadvantage of Hayashi's definition which is worth men- tioning is that a radius of 10 km. extends far beyond the limits of the city of Nagasaki (par- ticularly to the north, east, and west) and hence creates difficulty in any attempt to determine the completeness and/or randomness of sam- pling. While we believe there is ample justifica- tion for a conservative definition of exposure, Hayashi's definition would appear overly con- servative. It is extremely difficult to appraise the real significance of Hayashi's data. Among the fac- tors which make it difficult is, as Professor Hayashi has pointed out, the lack of information regarding (a) the randomness of the sample, (b) the degree of exposure of the parents, and (c) other etiological agents, such as maternal age, of importance in congenital malformations. 189 Some measure of the importance and effect of these factors can be gleaned from the corpus of data collected by the Commission. With re- gard to maternal age, we have commented re- peatedly on both its importance and the fact that maternal ages are so distributed among the terminations occurring in Hiroshima and Naga- saki as to bias upwards an estimate of the effect of irradiation. With respect to the degree of exposure most probably experienced by the parents in Hayashi's series, the following observations are pertinent: 1. All dosage estimates, both Japanese and American, of the bombs detonated over Hiro TABLE 13.7 HAYASH! s DATA ON CONGENITAL AsNoRMAt~T~Es IN RELATION To EXPOSURE OF PARENTS (After Sevitt, 195 5 ~ Category One or both parents ex posed to A-bomb497 a Both parents exposed 149 Father exposed 80 Mother exposed 259 Neither parent exposed363 Both parents unknown exposure; information not available27 %2 (2 X 4~= 10.718 DF = 3 %2 (2 X 2~= 9.062 DF= 1 a Includes 9 children "mother exposed, father un- known." Number Number % of mat- mal- infants formed formed 92 18.9 27 18.1 18 22.5 47 18.1 40 1 1.0 10 P < 0.02 P < 0.01 shima and Nagasaki indicate that the instan- taneous irradiation at 3,000 meters was less than 5r and consisted of gamma irradiation alone. 2. The total irradiation received by an indi- vidual is the sum of the instantaneous irradia- tion and the residual irradiation to which he or she may have been exposed. The major com- ponent of residual irradiation arises from the so-called "fallout" following the bombing. The area of fallout in Nagasaki is reasonably well defined, and is, as has been indicated, east of ground zero in the region of the Nishiyama reservoir.] Save for a very small area immedi- ately adjacent to the reservoir, the estimated residual irradiation from one hour to infinity ~ The fallout area could be described as a band of about 3,000 meters' width (on its north-south axis) extending eastward from a point 1,500 meters from the hypocenter.

OCR for page 184
190 Genetic Effects of following the bombing is a dose probably less than 6r, and possibly less than 2r. The area encompassed by the fallout is in the main rela- tively sparsely populated, and consists princi- pally of hills and rice paddies. It is a safe con- clusion that relatively few persons residing outside 3 km. from ground zero received ex- posures of the order of magnitude of 5r from the fallout. 3. In the interval 1949-1953, some 363 regis- tered infants came to autopsy in Nagasaki under the auspices of the ABCC. The distribution by exposure of these infants is compared with those autopsied by Hayashi in Table 13.8. The two distributions are not significantly different and by inspection appear to be very nearly identical one with the other. In Table 13.9, we have given the distribution of exposed parents Atomic Bombs Chapter XIII Hiroshima data, derived from a group whose average exposure was greater, is also 18.5 per cent (36 infants out of 195~. Be that as it may, the more important consideration is that Haya- shi's control group has a frequency of con- genital malformation of only 11 per cent (40 out of 363), whereas the Hiroshima control group has a frequency of 17.5 per cent (37 out of 211~. This is a significant difference, yet the evidence from physical examinations presented in Tables 8.6 and 8.7 suggests no difference in the malformation rates between these two cities. (It need hardly be pointed out that if Hayashi's exposed group is contrasted with the control group from Hiroshima no significant difference emerges.) Further evidence which suggests that Hayashi's control is low stems from the fol- lowing considerations: (1) Among registered TABLE 13.S A COMPARISON OF THE EXPOSURE DISTRIBUTION OF HAYASH! S DATA AND THAT OF THE ATOMIC BOMB CASUALTY COMMISSION COLLECTED IN NAGASAKI Neither parent Mother exposed; Father exposed; Both parents Source exposed father not mother not exposedTotals Hayashi 363 (42.66%) 259 (30.43%) 80 (9.40%) 149 (17.51%) 851 ABCC 155 (~.70%) 115 (31.68~o) 34 (9.37%) 59 (16.25~o) 363 Total 518 374 114 208 1,214 %2 = 0.364 P _ .9-.95 8 See text for differences between Hayashi's and ABCC's exposure definitions. in our series in terms of the categories of ex posure defined in Chapter IV. We note that the large majority of exposed parents (87.5 per cent) are in exposure category 2 wherein the average exposure did not exceed 5r. Since Hayashi's definition of exposure must encom pass proportionately more individuals outside the 3 km. zone than are presently residing in Nagasaki (and hence would enter our study) we can only conclude that an even greater number of Hayashi's exposed cases are infants born to parents whose exposure was insignifi cant. In summary, then, it would appear that the great bulk of Hayashi's exposed parents must have received exposures of less than 5r. a Percentage of total. The representativeness of Hayashi's series is, as has been indicated, a matter of conjecture; however, certain observations which we shall now discuss suggest that the series may be biased. We note that Hayashi's data (see Table 13.7 ~ reveal a frequency of congenital mal- formation of 18.5 per cent among the exposed group (92 out of 497 infants) whereas the TABLE 13.9 DISTRIBUTION BY EXPOSURE CLASS OF EXPOSED PARENTS WHOSE INFANTS CAME TO AUTOPSY AT ABCC IN NAGASAKI Father Mother not not exposed; exposed; mother in father in Expo- class shown crass shown sure in first in first class column column 2 101 (87.8~%) a 33 (97.1%) ..... 12 1 2 2 Total 115 34 59 Both parents exposed; more heavily exposed parent in class shown in first column 48 (81.4~o) 9 infants who were stillborn or who died in the first six days of life and were born to non- exposed parents in Nagasaki (both parents ex posure category 1), no less than 9.4 per cent (42 out of 444) had clearly visible major mal- formations. (2) Experience in Hiroshima sug- gests that for every eight infants coming to

OCR for page 184
The Autopsy Fir~dir~gs autopsy on whom a prior clinical diagnosis of major malformation has been made (verifiable at autopsy, of course), six cases will come to autopsy and a major malformation will be found on which no prior clinical diagnosis exists. In short, among infants coming to autopsy, clinical examination will reveal only 58 per cent of the infants with major malformations. These two observations taken conjointly suggest that a more reasonable figure for Hayashi's control would be no less than 16 per cent. From the preceding considerations we are led to the conclusion that the more obvious explana- tion for Hayashi's Endings lies either in ex- traneous variation or in non-representativeness of the control, rather than in irradiation (for 191 example, a maternal age effect similar to the one noted in Figure 13.1 could easily produce a spurious radiation effect in a larger series of cases) . 13.3 Summary.- The data with regard to the frequency of congenital malformations among the pregnancy terminations to exposed and non-exposed persons in Hiroshima afford no evidence of a significant irradiation effect, although the small differences observed are in the direction of genetic expectation. Reasons are advanced for believing that the "irradiation effect" reported by Sevitt ( 195 5 ) from Haya- shi's data in Nagasaki is more likely due to extraneous variation (or sampling biases) be- tween the exposure cells than to irradiation.