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Chapter V TII E COMPARABILITY OF IRRADIATION SUBCLASSES ~ 1 of the radiation exposure categories of their fathers and mothers, as these categories were defined in the preceding chapter. The crux of our problem is a comparison of the characteris- tics of the infants comprising these subclasses. As has been emphasized several times already, all of the indicators of possible genetic damage utilized in this investigation may also be in- fluenced by a variety of other factors. It will be the purpose of this chapter to undertake a detailed comparison of the parents of the in- fants comprising these subclasses with respect to certain possible differences which might in- fluence the outcome of pregnancy. Of the many possible differences which could be explored, we shall restrict ourselves to those which in our opinion are most pertinent to the problem at hand and for which we have more nearly satis- factory data. In the comparisons which will be presented, usually no allowance has been made for the fact that because of repeated pregnancies the same couple may be represented more than once among the parentage of a subclass. The tests of significance that follow assume no duplicate registration and thus yield underestimates of the errors of differences. It might be pointed out that, in the main, we should underestimate variances in the parental population more than in the offspring population. 5.1 Cor7sa'Jg~inity. It is generally recog- nized that the offspring of consanguineous marriages more often exhibit the consequences of genetic homozygosity than do the offspring of non-consanguineous unions. To the extent that there is a recessive, incompletely recessive, or semi-dominant genetic component in the cow THE infants examined in Hiroshima and Naga- etiology of congenital defect, stillbirth, or neo- saki during the course of this study may be natal death, such homozygosity might be ex- annortioned among 25 subclasses on the basis pected to alter the frequency of these events sufficiently to obscure real irradiation differ- ences or to create spurious ones. The occurrence within the populations under study of a non- random distribution of consanguineous mar- riages thus might introduce a source of bias into the findings. This, then, was the theoretical consideration which led to the inclusion of an item in the Genetics Short Form regarding parental consanguinity. The problem seemed of special importance because of the relatively high frequency of consanguineous unions in Japan (Neel, Kodani, Brewer, and Anderson, 1949~. In Tables 5.1 and 5.2 the present data are examined as regards a relationship between ex- posure subclass and the frequency of consan- guinity.~ Although all known degrees of con- sanguinity were recorded by the clerks, in the analysis attention has been restricted to mar- riages of first cousins, first cousins once re- moved, and second cousins. A few uncle-niece unions, and some involving more remote de- grees of consanguinity than second cousin marriages, have been recorded during the study; all such unions have been excluded from these considerations because of the uncertainty regard- ing the exhaustiveness of the ascertainment. There is significantly more consanguineous marriage in Nagasaki than in Hiroshima, this presumably a reflection of social and cultural differences between the two localities. Moreover, within the cities there is heterogeneity among exposure subclasses. In general this consists in less consanguineous marriage among the "ex- posed" (categories 2, 3, 4, 5) than among the The differing forms utilized in the presentation of the results of the analysis of the various tables will be evident following the reading of Chapter VI. 53

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54 Genetic Ejects of Atomic Bombs Chapter V TABLE 5.1 CONSANGUINITY ( FIRST COUSIN, FIRST COUSIN ONCE REMOVED, SECOND COUSIN ~ BY CITY AND PARENTAL EXPOSURE Hiroshima Fathers n 1 2 3 4-5 Total Jrn18,7231,61164842221,404 1 r1,2429742231,404 p.0663.0602.0648.0545.0656 ~ n5,7211,9934162648,394 24 r3111172716471 ~ p.0544.0587.0649.0606.0561 v, In2,3204515451613,477 3g r9723164140 up.0418.0510.0294.0248.0403 In1,2082171161271,668 4-54 r7796698 l P.0637.0415.0517.0472.0588 ~ n 27,972 4,2721,725974 34,943 Totals r 1,727 2469149 2,113 tp .0617 .0576.0528.0503 .0605 Nagasaki Fathers A 1 234-5 Total cS In16,3382,42025814919,165 14 r1,5412111381,773 up.0943.0872.0504.0537.0925 f n10,1414,48330118815,113 2\ r68329322101,008 up.0674.0654.0731.0532.0667 ~ n823298109391,269 3g r69147494 up.0838.0470.0642.1026.0741 ~ n5961293530790 =54 r3310 245 up.0554.0775 .0667.0570 ~ n 27,898 7,330 703 406 36,337 Total$ r 2,326 528 42 24 2,920 l P .0834 .0720 .0597 .0591 .0804 a In this and subsequent tables, the term "Fathers ' will be used as an abbreviation for Father's Exposure Category, and the term "Mothers" similarly.

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r6~ cam of ~ i~6r7~I ~55 unexposed (category I i, aRbough the tendency is statlstlcally sl~nlEcant only filth respect to the mothers. fibers is also ~ significant clty- m~ber interaction. Category 1 contains ~ hub proportion of persons Hobo did not legaDy re- ~de in thy of the No Titles ~ Me time of the bo~lngs. It may be surmised that ~ s~- stantla1 pt~orbon of these persons bee rural antecedents; the freguen~ of consangulnl~ Kahn to be blabber in rural communizes (NeeI et at., 1949~. hem par~ta1 We ~ an] pad~,3 and ~ of the lndlcators of possible genetic dodge herein studied is attested to ~ ~ volumloous literature Be. Clocco, 1938; Yerusbal~, 1938; Pen- ros~ 1939; Mushy, 1947; Lanitman, 1948; Record and Eon, 1949; Suthedand, 1949; Cagey 1950; Lee and ~^e~ 19 go; Worcester, Stevenson, and Rice, 1950; H~- naue~ 1951; Earn an] Penrose, 1951; Novel, 195 3; Salber and Bradsha~, 195 3; Con and Gordon, 1953; Eyed, 1954). Our own TABLE ~2 CHI~^RB ANALYSIS OF THE DEFOE NCY OF CONSANGOINEOOS ABRIDGES BY Cal AND PARENTAL EXPOSURE Source DE X ~P Tota1 51 26I~53 <(.OOI Interactions, first order Chi ~- 16.913 CE ~L610 B4F 9 6317 Chin Endue City Bloth~\ exposure 1 B{otbe~ exposure 2 Blotber~ exposure brothers exposure Blothert Hlroshlma (~) I ~ probable or cer- taln relationship between the correlated verb analysis of these relatlonshlps in the present data ~111 be Toolshed elsewhere. Suffice it to say at Oils point that sl~nlEcant ass~latlons can be readily demonstrated. Abe On~lngs in these d~a Lab respect to mean maternal age and party diRerences Cony the mothers of the children falLng loto the various subclasses are swan in Tales 5.3 2~ ~ ' an' 'I ~~ ~ "paternal age" as here used refer simply to age of parent(s) at birth of child. 3 The term "parity" refers slimly to total number of conc~Hons, lncludlng the posed.

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56 Genetic Effects of Atomic Bombs Chapter V TABLE 5.3 MEAN MATERNAL AGE BY CITY AND PARENTAL EXPOSURE (Based on unrelated parents orally) Hiroshima Fathers , ~ 1 2 3 4 5 v' ; - ~: o Total rtin17,4811,51460613626320,000 lx27.046927.325027.516527.485328.270027.1013 2;n5,4101,8763891081407,923 six26.836630.131129.295628.092628.750027.7883 r n2,22342852981763,337 31x26.952329.140230.998130.012329.039527.9961 4 in38888452419564 mix27.786128.363629.666731.166729.684228.2340 in7431206526521,006 5lx-27.125229.366729.338528.538531.480827.7972 Total in26,2454,0261,63437555032,830 l--27.008728.909129.198928.514728.850927.3988 Nagasaki Fathers , ~ 1 2 3 4 5 Total ~ c o X fin14,7972,2092454110017,392 (x28.542729.142129.526528.487830.280028.6425 din9,4584,1902795112714,105 l-x27.608730.847730.311830.117629.897628.6540 in75428410212231,175 Six-27.657829.841531.529431.583330.652228.6204 4 in105351443161 (x29.933330.485734.642932.000034.666730.6025 i n4588421120584 5)x26.744528.476229.190513.000029.400027.1490 1 T t lrn25,5726,80266110927333,417 ~ 0 a Ax28.144730.220730.264829.578030.117228.6299

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The Comparability of Irradiation; Subclasses 57 through 5.8. It will be noted that the compari- son is restricted to unrelated parents. In the fol- lowing chapter we shall advance reasons for excluding children born to related parents from the analysis. Because of the potential great im- portance of age-parity differences in this analy 2, 3, 4, or 5) than when non-exposed (cate- gory 1) . This appears to be true with reference to fathers' but not mothers' exposure in Naga- saki. An obvious explanation of the findings with regard to the relation between paternal ex- posure and mean maternal age is the fact that TABLE 5.4 ANALYSIS OF VARIANCE: MOTHER'S AGE BY CITY AND PARENTAL EXPOSURE (Unrelated parents) (In this and subsequent tables, one asterisk will be used to denote a value significant at the 5 per cent level, and two asterisks, a value significant at the 1 per cent level.) Sums of squares Sourceof deviationsDFMean squareF Main effects City (C) 21,983.321551 1 21,983.3216 830.86** Father (F) 43,401.030323 4 10,850.2576 410.08** Mother (M) 947.687594 4 236.9219 8.95** Interactions First order CF 74.432938 4 18.6082 1.42 CM 3,107.667017 4 776.9168 29.36** M F 18,682.813301 16 1,167.6758 44.13** Higher orders 871.870114 16 54.4919 2.06** Between classes 94,513.849388 49 1,928.8541 72.90** Within classes 1,751,484.087605 66,197 26.4587 Total ; . 1,845,997.936993 66,246 TABLE 5.5 THE DISTRIBUTION OF MEAN SQuAREs FOR MATERNAL AGE BY CITY, SEX OF INFANT, AND PARENTAL EXPOSURE ~ Unrelated parents ) (The sample numbers are the same as in Table 5.3. The form of the analysis will be discussed in Chapter VI.) v, o Hiroshima Fathers A Sex 1 2 3 4-5 1 i: 22.160 27.336 29.653 25.529 l: 21.628 24.205 29.271 23.310 2~3 'it 3{d 5{: 21.999 28.964 22.327 29.351 24.216 29.592 23.381 29.429 26.112 28.495 24.226 36.713 33.690 28.247 40.519 34.122 32.618 25.009 31.245 36.640 47.317 35.253 27.148 36.738 Nagasaki - - ~ o Sex 1 (d' 25.376 1~: 25.822 2l,: rep 3~:S: 4-5{: Fathers 28.335 37.926 26.361 38.289 30.266 49.061 29.384 39.629 27.956 28.292 27.720 48.456 2 3 36.213 40.472 33.257 32.491 43.489 42.377 Xc: = 121.021** DF = 15 Xc: = 222.236** DF = 15 XS? = 144.251~* DF= 15 X:- = 192.154** DF= 15 sis, it has seemed wise to anticipate this decision with respect to this tabulation. Not only do the cities differ but there is also significant heterogeneity within cities among exposure subclasses as regards both mean ma- ternal age and mean parity. In Hiroshima there is a clear tendency for maternal age to be greater when the mother or father is exposed (category 4-5 38.920 32.455 31.397 40.381 42.831 18.423 37.398 31.729 32.515 28.743 39.000 55.269 the younger males tended to be in military service while the older males remained at home (and so were exposed), and mother's age is correlated with father's. Heterogeneity between the subclasses is also indicated by the fact that most of the interaction terms are also significant. No less variable than the mean maternal ages and parities are the mean squares (variance esti

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58 Genetic Ejects of Atomic Bombs Chapter TABLE 5.6 MEAN PARITY BY Corm AND PARENTAL EXPOSURE (Based on unrelated parents only) Hiroshima Fathers 1 2 3 4 5 Total v, sit o By J n17,4811,51460613626320,000 1 ~2.42282.41082.37622.36762.46772.4207 2 r n5,4101,8763891081407,923 ~ x2.42223.61513.23392.79632.94292.7588 3 ~ n2,22342852981763,337 ~ a;2.43683.28973.91873.91363.31582.8370 4 r n38888452419564 x2.60313.22733.48893.87503.36842.8511 r n7431206526521,006 5 six2.40783.53333.06153.42313.51922.6680 T talon 26,245 4,026 1,634 375 550 32,830 l ~2.4261 3.1167 3.1377 2.9947 2.8364 2.5596 Nagasaki Fathers 1 2 3 4 5 : - o Total 1 r n14,7972,2092454110017,392 ~ x2.90083.09463.15512.48783.15002.9295 2 J n9,4584,1902795112714,105 six2.72943.97543.68103.29413.64573.1287 r n75428410212231,175 3 six2.85943.72544.00005.00003.69573.2060 4 r n105351443161 x3.47623.80005.35714.75006.33333.7950 J n4588421120584 six2.62013.16673.61901.00003.75002.7705 T t ltn 25,572 6,802 661 109 273 33,417 0 a ~2~8335 3.6680 3.5688 3.2110 3.5055 3.0247

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The Comparability of Irradiation Subclasses 59 mates) for these two variables.4 From Tames 5.5 and 5.8 we note a significant heterogeneity among exposure classes, within each sex and city, in the variance estimates. It can also be shown that the variance estimates differ signifi- cantly between cities. In general, the variance in post-war Japan, those persons closer in having suffered in material ways to a greater extent than those farther out. Economic status appears to be related to some of the indicators of radiation effect here under consideration, notably still- birth frequency, birthweight, and neonatal TABLE 5.7 ANALYSIS OF VARIANCE: PARITY BY CITY AND PARENTAL EXPOSURE (Unrelated parents) Sums of squares Sourceof deviationsDFMean squareF Main effects city (C) 1,663.729494 1 1,663.7295 531.52** Father (F) 6,053.779421 4 1,513.4449 483.51** Mother (M) 852.862735 4 213.2157 68.12** Interactions First order CF 181.504471 4 45.3761 14.50* * CM 62.510339 4 15.6276 4.99** MF 2,637.923744 16 164.8702 52.67* * Higher orders 77.508327 16 4.8443 1.55 Between classes 13,593.325165 49 2,774.1480 886.27** Within classes 207,206.531342 66,197 3.1302 Total 220,799.856507 66,246 TABLE 5.8 THE DISTRIBUTION OF MEAN SQuAREs FOR PARITY BY CITY, SEX OF INFANT, AND PARENTAL EXPOSURE ~ Unrelated parents ~ (The sample numbers are the same as in Table 5.6.) . . Hlroshlma Fathers Sex 1 2 3 4-5 1J'd 2.255 2.156 2.360 2.067 :: 2.076 2.311 1.691 2.217 2 ;: 0.242 3.438 4.023 2.286 :: 2.232 3.840 3.659 2.729 3 2.361 3.610 4.460 4.286 :: 2.134 3.274 3.785 4.251 4_5;c; 2.239 4.171 4.999 5.328 i: 2.206 4.526 3.884 3.441 Nagasaki , ~ Fathers , ^- ~ Sex 1 2 3 4-5 1 J'3 2 867 ~ ~ 2.899 2<(s? 3{? 4-5~: 3.022 4.933 2.795 5.183 3.059 4.849 3.624 4.647 3.258 2.967 3.434 4.878 4.111 4.717 4.036 3.297 4.652 4.284 4.306 3.350 4.434 4.529 X~ = 281.717*4 DF = 15 Xcp = 337.847* ~DF = 15 X~?2-324.417** DF= 15 X; =397.544*4 DF= 15 estimates increase with increasing conjoint death (e.g., Ebbs et parental exposure. 1944; 5.3 Economic stains. On a priori grounds et al., it seemed quite possible that there might be a correlation between distance from the hypocenter at the time of the explosion and economic status 4 The effect of heterogeneity of the variances on the tests given in Tables 5.5 and 5.7 will be discussed in Section 6.6. 3.266 2.328 3.984 3.992 4.474 5.862 6.495 5.359 al., 1942a, b; Balfour, Antonov, 1947; Smith, 1947; Burke 1949; Dean, 1950; Nixon, 1950). It therefore seemed advisable to make some at- tempt to evaluate this possibility. The economic status of the home into which the child was born was estimated for all preg- nancies terminating abnormally, as well as every pregnancy whose registration number ended in

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60 Genetic Effects of Atomic Bombs Chapter V TABLE 5.9 ECONOMIC STATUS BY CITY AND PARENTAL EXPOSURE (The figure given for economic status is proportion of homes falling into the "poor" and "very poor" categories.) Hiroshima Fathers 4-5Total f~ n1,77014365462,024 1jr14446 154 P.0814.0280.0923 .0761 ~ n5691714728815 2: r49244279 P.0861.1404.0851.0714.0969 n218265619319 ~s 35 r1456126 ~p.0642.1923.1071.0526.0815 ~ n103211011145 4-54 r911112 lP.0874.0476.~ 000.0909.0828 J n2,6603611781043,303 Total~ r21634174271 I~P.0812.0942.0955.0385.OS20 Nagasaki Fathers _~ 1234-5 Jn1,45922727141,727 1- r226338 267 l n.1549.1454.2963 .1546 Jn89438733141,328 12> r1257451205 ~p.1398.1912.1515.0714.1544 11 n6129106106 3j r752216 IP.1148.1724.2000.3333.1509 ~ n56124375 4-5 J r921-12 IP.1607.1667.2500-.1600 1 ~ n2,47065574373,236 Total: r367114163500 :~p.1486.1740.2162.0811.1545

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The Com parability 0 zero, in connection with the use of the Genetics Long Form (Sees. 2.2 and 2.3~. This evalua- tion was made according to a very rough scoring system admitting of five economic classifica- tions: very poor, poor, average, well-to-do, and rich. The evaluation was carried out by the Japanese physician at the time of the home visit. The physicians were instructed that it was ex- pected that most homes would be graded as average, i.e., that existing rather than pre-bomb- ing standards should serve as the yardstick of comparison. Inasmuch as in the course of time a physician employed in the program found himself in all sections of the city, it was felt that this crude system of rating would pick up any marked differences between exposure cate- gories. The findings are given in Tables 5.9 and 5.10. The data are presented in simplified form, in terms of proportion of all homes graded as "poor" or "very poor." In view of the subjective nature of the ratings, it is difficult to attach sig- nificance to the apparent difference between the two cities. There is no apparent relation between economic status and mother's exposure category, nor is there a relation between father's category and economic status. At first glance this observa- tion would seem to be counter to common sense, since it would seem obvious that persons close to the hypocenter would have suffered greater material losses than those more distant, losses which would reflect themselves in economic level. However, the effect of the atomic bomb was but one of a number of sources of severe economic dislocation in post-war Hiroshima and Nagasaki. The obvious conclusion from the findings summarized in this section would be that these other causes of economic readjustment tended to complicate and even to nullify the effects of the bombs. 5.4 Frequency of positive serological te it f or syphilis. In view of the well-known relation- ship between syphilis and stillbirth and neonatal death, a serological test for syphilis was carried out in the ABCC laboratories on each woman whose registration number terminated in "0," as well as for any woman whose pregnancy terminated abnormally. In about 3 per cent of the terminations no test was performed, usually because of the disinclination of the mother to submit to venipuncture. The tests used were the cardiolipin microflocculation and the Kline. Tables 5.11 and 5.12 present the findings. f Irradiation Subclasses 61 There is a significant difference between cities, but no indication of heterogeneity between parental exposure classes. 5.5 Frequency of induced abortions Ovid of dilatation Arid curettage of the Sterns fD and C7. During the post-war years, in an effort to control birth rates, the Japanese government relaxed the indications for legal "therapeutic" abortion. Exact figures on the frequency with which abortions were performed are impossible to obtain for a variety of reasons. However, be- cause of the possibility that the late complica- tions of uterine infection following an induced TABLE 5.10 CHI-SQUARE ANALYSIS OF THE DISTRIBUTION OF ECONOMIC STATUSES BY CITY AND PARENTAL EXPOSURE (Unrelated parents) DF Total 31 Interactions, first order CM CF ME Main effects Cities ( C ) Fathers (Fir Hiroshima 3 Nagasaki 3 Sum .......... Mothers (M) ~ Hiroshima ....... Nagasaki ........ a Adjusted for cities. X 120.378 3 2.268 3 0.365 9 17.683 1 S2.529 3.782 6.262 6 10.044 3 3.354 3 0.028 6 3.382 p < 0.001 .50-.70 .90-.95 .02-.05 < 0.001 .20-.30 .05-.10 .10-.20 .30-.50 > .99 .70-.80 abortion might influence pregnancy termination, an attempt was made to obtain some informa- tion on this point through the use of the Genet- ics Short Form. Each registrant was questioned concerning the occurrence of abortions. The abortions which were reported were divided into two categories, depending on occurrence before or after the date of the atomic bombing, and further subdivided as to whether they were spontaneous or induced. The findings concern- ing induced abortions are shown in Tables 5.13 and 5.14. The figures refer to the proportion of women reporting one or more induced abor- tions. Each mother is scored only once, on the basis of the first registered pregnancy. Induced abortions are reported with a significantly greater frequency in Hiroshima than in Naga- saki and, in both cities, appear to be more

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62 Genetic EJects of Atomic Bombs Chapter V TABLE 5.11 FREQUENCY OF POSITIVE SEROLOGY BY PARENTAL EXPOSURE, CITY, AND GROUP (Unrelated "zero" parents only) Hiroshima 2 {r |:n 33 r ~tP rn , 4-5 ~ r UP En1,610131 14 r613 I P.0379.0229 \ Fathers ~_ . - 123 4-5 41 145 10 .0690 2551 11 .0400.0196 18 197 5 0254 84 .0595 43 4 .0930 9 .1111 Total 1,842 71 .0488.0385 26723 28 .0387 291 8 .0275 122 7 .0574 2 .0769 118 .0556 11 1 .0909 En2,400319163962,978 Total: r8314116114 tp.0346.0439.0675.0625.0383 Nagasaki Fathers - - 1234-5Total ~ n1,40121426141,655 14 r70114-85 lip.0500.0514.1538 .0514 ~ n85336332111,259 2g r42232 67 l p.0492.0634.0625-.0532 in6225106103 34 r11 - 11 p.1774 -.1068 Cn 4-5: r UP 55 12 4 1 72 .0545 .0417 Jn2,37161472 323,089 Total r126346 166 l P.0531.0554.0833 .0537

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The Comparability of Irradiation Subclasses common following the bombing than before. However, there is no apparent, consistent rela- tion to exposure history. Three of the interac- tion terms are significant. In view of the possibility that it might be easier to obtain a history of a "therapeutic" D and C than of an induced abortion, a question concerning D and C was included in the Ge- netics Long Form. The Endings in those termi- nations where the registration number ended in "O" are shown in Tames 5.15 and 5.16. The figures refer to the proportion of women report- ing one or more D and C's, with no reference TABLE 5.12 CHI-SQUARE ANALYSIS OF THE FREQUENCY OF POSITIVE SEROLOGIES BY CITY AND PARENTAL EXPOSURE (Unrelated parents) Source DF X 2 Total 31 60.330 Interactions, first order CM ............... CF ........... ME ........... Main effects Cities (C) ........ Fathers (F) a Hiroshima ....... Nagasaki ........ 3 .... 3 9 . . ~ .. 1 3 3 Sum 6 Mothers (M) a Hiroshima Nagasaki Sum a Adjusted for cities. 3 2.136 3 6.099 . 6 8.235 63 nancies in Nagasaki than in Hiroshima. Fur- thermore, particularly with respect to mothers' exposure in Nagasaki, there is apparent a tend- ency for the more heavily irradiated mothers to have borne more children. 5.7 Porrer~tal coopero~tiorz. If for any reason one group of parents was more cooperative than another in permitting an examination of their p 6.645 3.522 2.876 .001-.01 6.469 .05-.10 3.106 .30-.50 9.575 newborn child, herein lies a source of bias. Fortunately, parental cooperation was excellent throughout the course of this study. Refusals to permit the ABCC physician to examine a child were infrequent, so infrequent that no analysis of the phenomenon has been carried out. It should in this connection be pointed out that such refusals could influence only the data on malformation, since sex, birthweight, and the occurrence of stillbirth were reported by the midwife, and since, further, it would be im ~~ pi practical to attempt to conceal a neonatal death. In Japan as in the United States, the birth of a malformed child tends to stigmatize the par ents in the lay mind. In a country where mar riages are still often arranged to a large extent by the families concerned, and where the koseki (census register) is freely consulted when a marriage is under consideration, there are at work social factors encouraging the concealment .~0-.20 of congenital abnormality. In this connection, the possibility has to be recognized of subtle influences tending to make one of the groups under study more cooperative than another group. More specifically, one had to recognize the possibility that some of the "exposed" group, learning from the newspapers that con- genital abnormalities were a possible aftermath of exposure to an atomic bomb, would cooperate more completely than the controls, and thus introduce a bias. The chief opportunity for concealing major congenital defect lay in children who were still- born or died shortly following birth, and whose bodies were disposed of without being seen by an ABCC physician. As mentioned earlier (Sec. 2.5), an attempt was made to obtain autopsies on as many children who were stillborn or died during the neonatal period as possible. In 1950 and 1951, when the autopsy program was in full stride in Hiroshima, autopsies were obtained on approximately 50 per cent of all children who were stillborn or died during the neonatal period. Another 15 per cent of all children who were stillborn or died during the neonatal .50-.70 .~0-.20 .20-.30 as to whether the event preceded or followed the bombings. There is a striking difference be- tween the cities, similar in direction to that re- ported with respect to induced abortions, but much greater in magnitude. However, no differ- ence with respect to exposure groups is apparent, nor are any of the interaction terms significant. 5.6 The frequency of repeat registrations. Depending upon the number of pregnancies which she experienced during the period cov- ered by this study, a woman residing in Hiro- shima or Nagasaki could bear one, two, three, four or even more infants whose examination fell within the scope of the program. Table 5.17 summarizes the mean number of infants per mother in relation to the exposure categories of mother and father, by city. There is a tend- ency towards a higher average number of preg

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66r Ger~etic Effects of Atomic Bombs Chapter V TABLE 5.13 FREQUENCY OF MOTHERS REPORTING ONE OR MORE INDUCED ABORTIONS BY PARENTAL EXPOSURE, CITY, AND TIME (Unrelated parents) Hiroshima before AUg. 6, 1945 , ^ ~ Fathers - Total rrn4,738310115795,242 14 r2071644231 (p.0437.0516.0348.0506.0441 pn1,037902137782,154 2g r42286177 (p.0405.0310.0438.0128.0357 rn43716528183966 3gr1936129 tp.0435.0182.0214.0120.0300 v, o - Jn1867362 66387 4-5> r274 13 I~P.0108.0959.0645 ~.0336 l n6,3981,450 5953068,749 Total] r27054 206350 (p.0422.0372 .0336.0196.0400 Hiroshima after Aug. 6, 1945 Fathers 1 2 3 4-5 Tc~tal ~n 10,599 799 426 223 12,047 I1 ) r 581 50 20 19 670 p .0548 .0696 .0469 .0852 .0556 rn 2,860 402 128 85 3,475 2g r 187 18 9 4 218 p .0654 .0448 .0703 .0471 .0627 n 1,185 127 99 42 1,453 J 3~` r 77 8 7 - 92 tp .0650 .0630 .0707 .0633 rn 599 51 39 19 708 4-5 g r 45 4 7 56 (p .0751 .0784 .1795 .0791 __ ~n 15,243 1,379 692 369 17,683 Total: r 890 80 43 23 1,036 I

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The Comparability of Irradiations Subclauses TABLE 5.13 Continued Nagasaki before Aug. 9, 194S , ~ Fathers 1 2 3 4-5 - Total rrn5,61670665346,421 1j r12117 138 (p.0215.0241- .0215 En1,9182,322128804,448 2/ r27273158 (p.0141.0116.0234.0125.0130 En1711205829378 34 r 1 12 lip .0083 .0345.0053 En87482110166 4-5gr --11 (p -.1000.0060 On7,7923,19627215311,413 Total] r1484533199 tp.0190.0141.0110.0196.0174 Nagasaki after Aug. 9, 1945 Fathers ^ - ~n 7,953 1: r IMP v, : - a~ o 1 2 182 .0229 4,692 98 .0209 Jn 2~ r UP En 33 r UP rn 4-5 ~ r UP 361 .0111 291 5 .0172 1,073 23 .0214 1,028 20 .0195 120 4 .0333 56 1 .0179 Total 129 859,240 2 207 .0155 .0224 90 555,865 3 -121 .0333 -.0206 25 13 8 509 8 .0157 368 6 .0163 En13,2972,277257 15115,982 Totals r289485 -342 (p.0217.0211.0195 -.0214 65

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66 Genetic Efects of Atomic Bombs Chapter V TABLE 5.14 CHI-SQUARE ANALYSIS OF THE FRE QUENCY OF MOTHERS REPORTING ONE OR MORE INDUCED ABORTIONS BY PARENTAL EXPO SURE, CITY, AND TIME (Unrelated parents ~ Source DF X 2 p Total 63 574.384 <.001 Interactions, first order CT ..... TM .... TF .... CM .... CF .... MF . . . . . .. 1 3.057 3 16.265 3.725 3 3 9 .05 -.10 .00 i-.01 .20 -.30 0.087 .01 -.02 2.616 .30 -.50 30.308 <.001 Main effects Cities (C) Before bombing . . . 1 95.230 < .001 After bombing 1 270.261 <.OO1 Sum 2 365.491 <.001 Time (T) Hiroshima (H) 1 40.677 <.OO1 Nagasaki (N) 1 5.401 .02 -.05 Sum 2 46.078 < .001 Mothers (M) (H) Before bomb ing 3 6.191 .10-.20 After bomb ing 3 9.001 .02 -.05 (N) Before bomb ing 3 15.700 .001-.01 After bomb ing 3 0.459 .90 -.95 Fathers (F) H ) Before bomb ing 3 5.039 .10-.20 After bomb ing 3 3.127 .30-.50 (N) Before bomb ing 3 3.898 .20-.30 After bomb ~ng Sum .80 -.90 ... 3 ... 12 12.915 30.-.50 0.851

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The Comparability of Irradiation Subclasses TABLE 5.15 FREQUENCY OF DILATATION AND CURETTAGE BY PARENTAL EXPOSURE AND CITY: ZERO TERMINATIONS Hiroshima us Fathers ~- ~ 1 2 3 4-5Total (n1,77014365462,024 1\ r26619105300 up.1503.1329.1538.1087.1482 rn5691714728815 24 r751656102 up.1318.0936.1064.2143.1252 rn218265619319 3/ r34111147 up.1560.0385.1964.0526.1473 En103211011145 4-S] r1742124 up.1650.1905.2000.0909.1655 fn2,660 3611781043,303 Totals r392 402813473 l p.1474 .1108.1573.1250.1432 Nagasaki Fathers 1 2 3 4-5 Total 1<, 2 <, con 3: UP 1 n1,45922727141,727 I r2531 29 p.0171.0132.0370 .0168 in89438733141,328 r12121126 p.0134.0310.0303.0714.0196 1 n6129106106 ;r-11 2 up .0345.1000-.0189 En56124375 ~53 r En2,47065574373,236 Total] r37163157 up.0150.0244.0405.0270.0176 67

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68 Genetic Efects of Atomic Bombs Chapter NO TABLE 5.16 CHI-SQUARE ANALYSIS OF THE FRE QUENCY OF DILATATION AND CURETTAGE BY PARENTAL EXPOSURE AND CITY: ZERO TERMINATIONS (Unrelated parents) Source DF X 2 31 372.060 Total Interactions, first order CM 3 3.099 CF 3 7.426 MF 9 10.799 Main effects Cities (C) 1 346.140 < .001 .30-.50 .05-.10 .20-.30 < .001 Mothers (M) a Hiroshima 3 3.212 .30-.50 Nagasaki 3 1.718 .50-.70 Sum ...... Fathers (F) a Hiroshima . . . Nagasaki .... 4.930 .50-.70 3 .20-.30 .1~.20 Sum 6 9.219 .10-.20 a Adjusted for cities. TABLE 5.17 MEAN NUMBER OF REGISTERED PREGNANCIES PER MOTHER BY PARENTAL EXPOSURE AND CITY Hiroshima Fathers 1 2 us at Total :n13,5771,155490301 15,523 l x1.2881.3111.2371.326 1.288 2: n3,9641,472308189 5,933 ) ~1.3651.2741.2631.312 1.335 ~ n1,653318420121 2,512 Six1.3451.3461.2601.298 1.328 4En8211568299 1,158 -5 lx 1.378 1.333 1.341 1.2221.356 r n 20,015 3,101 1,300 71025,126 Totall 1.311 1.298 1.257 1.3031.307 Nagasaki Fathers 1 2 3 4-5 Total 1 ~ n10,5811,5821669712,426 Ax1.3981.3961.4761.4541.400 2 in6,2462,9711881229,527 lx1.5141.4101.4841.4591.481 r n4761967520767 3: x1.6321.4491.3601.7501.532 4 5 r n345812421471 lx-1.6321.4691.4581.3331.582 r n17,6484,83045326023,191 Total:.1.4491.4081.4591.4691.441

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The Comparability of Irradiation Subclasses period were seen by a physician in the employ of the ABCC but did not come to autopsy. It follows that opportunities for the concealment of defect existed with respect to only 35 per cent of all stillbirths and neonatal deaths. In 1952 and 1953 the efficiency of the autopsy program increased, to the point where some 60-70 per cent of the possible material was being autop- sied, with a corresponding decrease in onoor- tunities for concealment. Tables 13.1 through 13.4 analyze the material coming to autopsy with reference to its randomness. It can be shown that there is no detectable bias as regards the exposure history of the parents. Since this autopsy material includes the majority of the stillbirths and neonatal deaths, it seems unlikely that there exists the possibility of a serious bias as regards parental exposure among the still- births and neonatal deaths who were not seen. If, for instance, unirradiated mothers of still- born (malformed) children were especially prone to dispose of these infants without their coming to the attention of the ABCC, then, since approximately 10 per cent of stillborn children are malformed, this should depress the representation of unexposed mothers in the parents of the autopsy material; such a dispro- portion was not observed. On the other hand, the data are of course not sufficiently extensive to exclude small biases in this direction. In this connection, however, it must be borne in mind that all of the infants falling in this 25 per cent were seen by a Japanese midwife or obstetrician, which provides a partial safeguard against the concealment of defect, even though there were occasionally encountered striking shortcomings in midwife reporting. 5.S Late seq~elae of exposure to the bombs. -Reference has already been made (Sec. 4.1) to the occurrence among the parents of the in- fants under study of certain late sequelae of exposure to the atomic bombs. The best docu- mented of these late effects are cataracts (Cogan, Martin, and Kimura, 1949; Sinsky, 195S) and leukemia (Folley, gorges, and Yamawaki, 1952; Lange, Moloney, and Yamawaki, 1954; Moloney and Lange, 1954; Moloney and Kas- tenbaum, 1955 ~ . Refractory anemia may also be a delayed manifestation of radiation injury (Lange, Wright, Tomonaga, Kurasaki, Mat- suoke, and Matsunaga, 1955 ~ . These events occur with a frequency which cannot be ignored in a study of this type. Thus, the findings with respect to leukemia are given in Table 5.18. To 69 date, the over-all frequency of this disease in individuals who at one time displayed one or more of the three radiation symptoms, epilation, petechiae, or gingivitis, is 0.5 per cent. While the occurrence of cataracts would not be expected to influence pregnancy outcome, there is little doubt that a disease with the systemic manifestations of leukemia has pro- found effects. Whether in addition to leukemia there are other serious sequelae which have so far escaped detection cannot be said. Fillmore (1952) was not able to detect any significant sequelae in a general medical examination of 78 persons who had received sufficient radiation at the time of the bombings to develop, later, radiation cataracts. On the other hand, Lorenz and his collaborators (1954) have demonstrated a shortened life span in a variety of animals exposed to chronic irradiation, associated with the development of such conditions as pancyto- penia and lymphoid, pulmonary, ovarian, and mammary tumors. Whether there are compar- able effects in man is not yet known. Whereas techniques exist for coping with the age-parity and consanguinity differences be- tween the groups of parents with whom we are concerned, it is much more difficult in any plan of analysis to make allowance for the somatic effects of irradiation which might influence the outcome of a pregnancy. These somatic effects should be exerted largely through the mother. Thus, "effects" apparently consequent upon maternal radiation which are not confirmed by a corresponding analysis with regard to pa- ternal radiation history must be viewed with reservations. 5.9 The changing proportion of control arid irradiated from year to year. Table 2.1 pre- sented a summary of the number and propor- tion of registrations with at least one parent falling into categories 4 or 5 for the years 1948 through 1953. There was apparent a recent de- crease in both the absolute and the relative representation of the more heavily irradiated. If there were any marked tendency for the level of diagnostic accuracy or parental cooperation with respect to congenital malformation to change during the course of the study, or if be- cause of post-war improvements in medical and economic levels the stillbirth or the neonatal death rate fell appreciably or the birthweight increased, then here again are factors capable of introducing a source of spurious conclusions. Tables 5.19 and 5.20 summarize our annual

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70 Generic Effects of Atomic Bombs Chapter V TABLE 5.18 INCIDENCE OF LEUKEMIA IN THE HIROSHIMA SuRV~VORs OF THE ATOMIC BoMs~NG As RELATED TO DISTANCE FROM THE HYPOCENTER AND THE PRESENCE OF SEVERE RADIATION COMPLAINTS (After Moloney and Kastenbaum, 1955) Distance from Population a hypocenter , ^_ (meters) SRC b NRC c Total 0- 999 .......................... 750 450 1,200 1,000-1,499 .......................... 2,250 8,250 10,500 1,500-1,999 .......................... 1,750 16,950 18,700 2,000-2,499 .......................... 950 16,250 17,200 2,500 and over 850 49,650 50,500 Total 6,550 91,550 98,100 Cases of leukemia Incidence ~, ~ SRC NRC Total SRC NRC Total 14 1 15 1: 53 1: 450 1: 80 15 9 24 1:150 1: 917 1: 438 3 2 5 1:583 1: 8,475 1: 3,740 1 1 2 1:950 1: 16,250 1: 8,600 0 4 4 1: 12,412 1: 12,625 33 17 50 1:198 1: 5,385 1: 1,962 a Population estimated and rounded off to the nearest 50 persons. These population figures were based on the Commission's 1949 radiation census and the Japanese national census (1950~. Numbers of survivors with severe radia- tion complaints were estimated from an analysis of the pregnancy registration data. b SRC: severe radiation complaints (heavily irradiated). c NRC: no radiation complaints (lightly irradiated). TABLE 5.19 THE FREQUENCY OF MALFORMATIONS BY YEAR AMONG THE OFFSPRING OF PARENTS NEITHER OF WHOM WAS EXPOSED TO THE ATOMIC BOMBS Hiroshima Total births Malformations Percentage . . ....... 1,756 4,005 14 34 0.80 0.85 DF= 4 X a = 2.496 1948 1949 1950 1951 1952 Total 3,602 3,324 34 36 0.94 1.08 0.70 > P > 0.50 3,084 15,771 35 153 1.13 0.97 Nagasaki A_ ~ 1948-49 1950 1951 1952 Total Total births 3,9343,2433,1893,12313,489 Malformations 31364532144 Percentage 0.791.111.411.021.07 X2=6.584 DF=3 0.10 > P > 0.05

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The Comparability of Irradiation Subclasses TABLE 5.20 THE FREQUENCY OF STILLBIRTHS BY YEAR AMONG THE OFFSPRING OF PARENTS NEITHER OF WHOM WAS EXPOSED TO THE ATOMIC BOMBS Hiroshima Be. . 1948 1949 1950 1951 1952 Total Total births 1,742 3,971 3,564 3,287 3,037 15,601 Stillbirths 51 87 64 58 61 321 Percentage 2.93 2.19 1.80 1.76 2.01 2.06 x2=9.544 DF_4 0.05 > P> 0.02 Total births .......... Stillbirths . . . Percentage ............ % 2= 4.372 DF= 3 figures for the frequency of gross malformations and stillbirths for the first five years of the study among the offspring of parents neither of whom was exposed to the atomic bombs. The re- quency of malformations and stillbirths appears to remain sufficiently constant from year to year, that time trends should not complicate the analysis of these two indicators. On the other hand, we shall in a subsequent section (Sec. 10.4) present evidence that time trends may be of importance in the birthweight analysis. 5.10 The backgroz~r~d of group 1 individuals. -There remains one final problem for dis- cussion. There are important differences in back- ground between the parents in radiation cate- gory 1 and those in categories 2 through 5. The latter have all been urban dwellers since 1945 or before. The former parents, although in part composed of residents of Hiroshima and Naga- saki who were away at the time of the bombings, and also of urbanites who have come to Hiro- shima and Nagasaki from the other cities of Japan, in addition include a high proportion of emigrants from rural areas and repatriates from Manchuria, Korea, and Formosa. In addi- tion, among the men there are many with ex- tensive overseas military service. Although there are well-known urban-rural differences with respect to the indicators of possible genetic effect here considered, it is by no means clear to what extent these are apparent and to what 71 Nagasaki 1948-49 1950 1951 1952 Total 3,200 61 1.91 3,134 3,084 13,320 49 67 240 1.56 2.17 1.80 0.30 ~ P > 0.20 extent real, and if the latter, whether they are socio-economic or biological in origin. Finally, if biological, there are no data as to how long they persist after urbanization. In the face of this situation, one can only conclude that the significance of any finding based solely on a difference between category 1 and categories 2 through 5 collectively must be viewed with reservations. 5.~! Summary. Of the differences between the individuals in the various exposure subcate- gories which have come to light in the forego- ing analysis, some appear to be inconsequential, of such a nature that they can be ignored with safety. Others of the differences appear to repre- sent sources of potentially significant bias. These latter differences fall into a natural dichotomy, depending on whether or not allowance can be made for them in an analysis. Thus, one way or another, differences in the frequency of con- sanguinity, age, and parity can be circumvented. This is not so either with respect to the occur- rence of late sequelae of the bombing among the more heavily irradiated, the possible implica- tions of the progressive decline during the six years covered by this study in the proportion of category 4's and 5's among the registrants, or the differences in background among persons falling into category 1 as opposed to categories 2 through 5. In the following chapter, the steps taken to meet this situation will be described.