Studies of the Mortality of Atomic Bomb Survivors, Report 14, : An Overview of Cancer and Noncancer Diseases

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1 RADIATION RESEARCH 177, (2012) /12 $15.00 Ó2012 by Rdition Reserch Society. All rights of reproduction in ny form reserved. DOI: /RR Studies of the Mortlity of Atomic Bomb Survivors, Report 14, : An Overview of Cncer nd Noncncer Diseses Kotro Ozs,,1 Yukiko Shimizu, Akihiko Suym, Fumiyoshi Ksgi,,b Midori Sod, Eric J. Grnt, Ritsu Skt, Hiromi Sugiym nd Kzunori Kodm c Deprtment of Epidemiology nd c Chief Scientist, Rdition Effects Reserch Foundtion, 5-2 Hijiym-koen, Minmi-ku, Hiroshim, , Jpn; nd b Institute of Rdition Epidemiology, Rdition Effects Assocition , Kji-cho, Chiyod-ku, Tokyo, , Jpn Ozs, K., Shimizu, Y., Suym, A., Ksgi, F., Sod, M., Grnt, E. J., Skt, R., Sugiym, H. nd Kodm, K. Studies of the Mortlity of Atomic Bomb Survivors, Report 14, : An Overview of Cncer nd Noncncer Diseses. Rdit. Res. 177, (2012). This is the 14th report in series of periodic generl reports on mortlity in the Life Spn Study (LSS) cohort of tomic bomb survivors followed by the Rdition Effects Reserch Foundtion to investigte the lte helth effects of the rdition from the tomic bombs. During the period , 58% of the 86,611 LSS cohort members with DS02 dose estimtes hve died. The 6 yers of dditionl follow-up since the previous report provide substntilly more informtion t longer periods fter rdition exposure (17% more cncer deths), especilly mong those under ge 10 t exposure (58% more deths). Poisson regression methods were used to investigte the mgnitude of the rdition-ssocited risks, the shpe of the dose response, nd effect modifiction by gender, ge t exposure, nd ttined ge. The risk of ll cuses of deth ws positively ssocited with rdition dose. Importntly, for solid cncers the dditive rdition risk (i.e., excess cncer cses per 10 4 person-yers per Gy) continues to increse throughout life with liner dose response reltionship. The sex-verged excess reltive risk per Gy ws 0.42 [95% confidence intervl (CI): 0.32, 0.53] for ll solid cncer t ge 70 yers fter exposure t ge 30 bsed on liner model. The risk incresed by bout 29% per decde decrese in ge t exposure (95% CI: 17%, 41%). The estimted lowest dose rnge with significnt ERR for ll solid cncer ws 0 to 0.20 Gy, nd forml dose-threshold nlysis indicted no threshold; i.e., zero dose ws the best estimte of the threshold. The risk of cncer mortlity incresed significntly for most mjor sites, including stomch, lung, liver, colon, brest, gllbldder, esophgus, bldder nd ovry, wheres rectum, pncres, uterus, prostte nd kidney prenchym did not hve significntly incresed risks. An incresed risk of non-neoplstic diseses including the circultory, respirtory nd digestive systems ws observed, but whether these re cusl reltionships requires further investigtion. There ws 1 Address for correspondence: Deprtment of Epidemiology, Rdition Effects Reserch Foundtion, 5-2 Hijiym-prk, Minmi-ku, Hiroshim, , Jpn; e-mil: ozs@rerf.or.jp. no evidence of rdition effect for infectious or externl cuses of deth. Ó 2012 by Rdition Reserch Society INTRODUCTION The Rdition Effects Reserch Foundtion (RERF), nd its predecessor the Atomic Bomb Csulty Commission (ABCC), hs conducted mortlity study since 1950 on fixed popultion [Life Spn Study (LSS) cohort] of bout 120,000 subjects including tomic bomb survivors nd residents of Hiroshim nd Ngski who were not in either city t the time of the bombing to determine the lte helth effects of ionizing rdition derived from the tomic bombs in Hiroshim nd Ngski. Periodic nlyses of the LSS mortlity dt hve resulted in series of LSS Reports (1, 2). This is the 14th report in the series, which covers the period , including n dditionl 6 yers of follow-up since the lst comprehensive report (2). The impct of chnging to the DS02 dosimetry system (3) from the erlier DS86 system on rdition risk estimtes hs been reported for mortlity from ll solid cncer nd leukemi through 2000 (4). The risk of rdition for solid cncer incidence through 1998 ws lso reported (5). However, this is the first time the DS02 dosimetry system hs been used while exmining mortlity from wide rnge of cuses of deth. The most importnt finding regrding the lte effects of A-bomb rdition exposure on mortlity is n incresed risk of cncer mortlity throughout life (2). The rtes of excess solid cncer deths hve continued to increse in pproximte proportion to rdition dose s the cohort ges. Significnt rdition-ssocited increses in risk hve been seen for most sites of solid cncer. The dose response reltionship for these sites hs tended to show n pproximtely liner increse with rdition dose. The reltive risks for mny cncer sites were higher in those exposed s children. The reltive risks declined with incresing ttined ge of the subjects s well s the number of yers fter the bombing, lthough the excess bsolute rtes continued to increse with ttined ge. In 229

2 230 OZASA ET AL. TABLE 1 LSS Cohort Members by DS02 Dose, City nd Sex Subjects with known DS02 dose [weighted colon dose (Gy)] Totl, þ Unknown b NIC c Totl Totl 86,611 38,509 29,961 5,974 6,356 3,424 1, ,058 26, ,321 Hiroshim 58,494 21,697 22,733 5,037 5,067 2,373 1, ,442 20,179 82,214 Ngski 28,117 16,812 7, ,289 1, ,616 6,350 38,107 Mle 35,687 15,951 12,342 2,382 2,482 1, ,287 11,143 50,175 Femle 50,924 22,558 17,619 3,592 3,874 2, ,771 15,386 70,146 Note. Among the totl of 120,321subjects, 123 were unvilble for the study becuse of misidentifiction or insufficient informtion. These numbers exclude the NIC nd unknown-dose groups. This group ws used for estimting rdition effects. b Those with unknown doses hd insufficient loction informtion or were in complex shielding situtions where dose could not be estimted relibly. c NIC: Not in the cities of Hiroshim or Ngski t the time of bombing. contrst, the risk of leukemi incresed in the erly period fter the bombing nd then decresed, nd the dose response reltionship for leukemi showed linerqudrtic ssocition (6, 7). Those different onset nd dose response ptterns imply different pthogenesis between leukemi nd solid cncer. This report provides n overview of the updted results nd chrcterizes the risk of rdition bsed on the DS02 dosimetry system for totl deths nd mjor cuses of deth including solid cncer, leukemi nd vrious types of noncncer disese. Due to the elongtion of the follow-up period compred to the previous reports nd the consequent incresed number of outcomes, new findings hve emerged for the risks of rdition for cncer nd noncncer disese mortlity. The purpose of this report is to (1) compre the mortlity from wide rnge of cuses of deth using common model s n overview, (2) conduct more detiled nlyses on dose response reltionships nd effect modifiction by ge t exposure nd ttined ge, nd (3) describe chnges in the shpe of the dose response for solid cncer nd noncncer diseses over the long observtion period. A discussion on the effects t low exposure levels such s dose nd dose-rte effectiveness fctor (DDREF) ws lso included. For leukemi, since detiled nlyses hve recently been reported for mortlity over the period bsed on the DS02 dosimetry system (7), further detiled nlyses were not conducted. MATERIALS AND METHODS Study Popultion nd Follow-Up The LSS cohort includes lrge portion of the tomic bomb survivors who were within 2.5 km of the hypocenters t the time of the bombings, together with n ge- nd sex-mtched smple of people who were between 2.5 nd 10 km from the hypocenters. The cohort lso includes smple of bout 26,000 persons who were registered s residents of either Hiroshim or Ngski in 1950 but were not in the cities (NIC) t the time of the bombings. LSS Report 8 nd the lter LSS reports hve excluded the NIC group from nlyses of rdition risk becuse of concerns bout the comprbility of their mortlity rtes to those for other zero-dose cohort members, likely due to sociodemogrphic or other differences (1, 8, 9). The subjects were recruited from the 1950 Jpnese Ntionl Census, which hd supplementry questionnire bout A-bomb exposures, plus two surveys conducted by the Atomic Bomb Csulty Commission (ABCC) in 1950 nd 1951, nd the resident surveys by Hiroshim nd Ngski cities in 1953 nd 1950, respectively (1). Comprehensive mortlity follow-up begn on October 1, 1950 (1). The finl number of subjects ws 120,321 members (82,214 in Hiroshim nd 38,107 in Ngski) (10). Among them, 123 subjects were unvilble for the study nd were excluded from the nlyses becuse of misidentifiction or insufficient informtion. Individul DS02 dose estimtes re vilble for 86,611 survivors. Another 7,058 survivors do not hve dose estimtes, minly due to insufficient or uncertin informtion on loction nd shielding t the time of the bombing, nd were excluded from these nlyses (11). The totl number of subjects nd the distribution of DS02 dose ctegories by city nd sex re shown in Tble 1. Mortlity follow-up ws fcilitted by the fmily registry system (koseki), which covers the whole of Jpn nd is.99% complete. A smll number were lost to follow-up due to migrtion out of the country nd were censored t the time of emigrtion. In this report, follow-up dt until December 31, 2003 were nlyzed. We found 19 individuls who were born before 1900 nd presumed to be live by the koseki s of Jnury 1, 2004 (104 yers of ge or older). They were checked t municipl office registries: five were documented s live, six migrted to other countries, seven were deleted from the residence registries becuse the municiplity offices could not confirm their residence sttus, nd no informtion ws obtined for one person. The six individuls who migrted overses were treted s censored t the time of migrtion. The seven individuls who were deleted from residence registries were treted s decesed t the time of deletion due to unknown cuses. The one with no informtion ws treted s censored t the end of the follow-up. Cuse of deth for the subjects ws clssified by trined stff in the ABCC/RERF ccording to the Interntionl Clssifiction of Diseses (ICD), 7th to 10th editions (12 15). The list of disese ctegories, corresponding ICD numbers, nd pplicble yers re shown in the Appendix found on pge 243. We nlyzed ll solid cncer, cncer of mjor sites, hemto-lymphoid mlignncies, nd brod clssifictions of noncncer diseses including diseses of the blood nd bloodforming orgns, circultory system, respirtory system, digestive system, nd genitourinry system, infectious nd prsitic diseses, nd externl cuses. Dosimetry This report is the first to pply DS02, which includes number of improvements over the previous system (3, 11), to the mortlity experience from wide rnge of cuses of deth in the LSS Report series. The primry systemtic chnge effected by DS02 ws n increse of bout 10% in c-ry estimtes for both Hiroshim nd

3 MORTALITY OF ATOMIC BOMB SURVIVORS, Ngski, consequently cusing the estimted risks from rdition exposure to be slightly lower thn before (4). Weighted dose, which is the sum of the c-ry dose plus 10 times the neutron dose, ws used to llow for the greter biologicl effectiveness of neutron doses nd is expressed in units of gry (Gy). Although the reltive biologicl effectiveness (RBE) of neutrons is thought to be decresing function of dose, with vlues possibly higher thn 10 t low doses, we could not precisely estimte the neutron RBE for the tomic bombs of Hiroshim nd Ngski. Therefore, we used constnt RBE of 10, which hs been used previously (6, 27). DS02 includes clculted doses for 15 orgn sites. In keeping with pst reports, nlyses of ll solid cncer used colon dose s representtive for ll orgns, while those of hemto-lymphoid mlignncies used the dose to bone mrrow. Anlyses for site-specific cncers nd noncncer diseses of mjor orgns used corresponding specific orgn doses. For individul dose estimtes, shielded kerm estimtes bove 4 Gy (317 members) were truncted to 4 Gy becuse they re likely to represent misinformtion on exposure fctors such s shielding or exct loction. To correct for dose uncertinties due to rndom mesurement error, undjusted DS02 estimtes were replced by expected survivor dose estimtes using the method developed by Pierce et l. (16) nd ssuming 35% mesurement error in individul doses. Sttisticl Methods nd Orgniztion of Dt for Anlysis Poisson regression methods for grouped survivl dt were used to describe the dependence of risk on rdition dose nd to evlute the vrition of the dose response with respect to city, sex, ge t exposure, nd ttined ge (17). Significnce tests nd confidence intervls (CI) were bsed on likelihood rtio sttistics. The results were considered sttisticlly significnt when the two-sided P, The models used here, which were lso used in previous reports (2, 5), re s follows. Excess Reltive Risk (ERR) model: k 0 ðc; s; b; Þ½1 þ ERRðd; s; e; ÞŠ; Excess Absolute Risk (EAR) model: k 0 ðc; s; b; ÞþEARðd; s; e; Þ; where k 0 is the bseline or bckground mortlity rte t zero dose, depending on city (c), sex (s), birth yer (b), nd ttined ge (). k 0 ws modeled by strtifiction for the ERR model nd by prmetric function involving relevnt fctors for the EAR model. ERR or EAR depends on rdition dose (d) nd, if necessry, effect modifiction by sex, ge t exposure (e), nd ttined ge. In effect, the ERR nd EAR functions re described s prmetric functions of the form q(d)e(e,s,), in which q(d) describes the shpe of the dose response function nd e(s,e,) describes the effect modifiction. First, we estimted ERR for mjor cuses of deth using liner dose response model (L) (q(d) ¼ b 1 d) without effect modifiction becuse this simple model cn be pplied to most cncer sites to compre them in common wy. The ERR model is s follows: k 0 ðc; s; b; Þ½1 þ b 1 dš: For leukemi, liner-qudrtic model (LQ) (q(d) ¼ b 1 d þ b 2 d 2 ) ws used since previous LSS reports hve indicted tht it hd the best dose response for leukemi mong the LSS (4, 7). Next, we took ccount of effect modifiction by sex, ge t exposure, nd ttined ge in the liner dose model for ERR nd EAR, respectively, for ll solid cncer nd cncer of selected sites becuse the model cn estimte the rdition risks more ccurtely nd lso cn be pplied to selected mjor sites with sufficient numbers of excess cses. Effect modifiction ws described using multiplictive-function models s follows: eðe; s; Þ ¼expðse þ t lnðþþð1 þ rsþ; where s, t nd r were the coefficients for effect modifiction by ge t exposure, ttined ge, nd sex, respectively. The term tht includes sex (s ¼ 1 for men nd s ¼ 1 for women) s modifier llows the b 1 prmeter to represent sex-verged risk estimtes. Therefore, ERR nd EAR models were, respectively, k 0 ðc; s; b; Þ½1 þ b 1 d expðse þ t lnðþþ ð1 þ rsþš; k 0 ðc; s; b; Þ½b 1 d expðse þ t lnðþþ ð1 þ rsþš: In ddition to the simple L model, we hve considered LQ nd pure qudrtic (Q) (q(d) ¼ b 2 d 2 ) models with effect modifiction (by sex, ge t exposure, nd ttined ge) for ll solid cncers. The curvture of the dose response ws exmined using the rtio of the qudrtic nd liner coefficients (h ¼ b 2 /b 1 ) in the LQ model. h cn rnge from zero for pure liner model to infinity for pure qudrtic model. To evlute the rdition effects in limited dose rnges, the ERRs for ll solid cncer for selected dose rnges were estimted bsed on the liner model with effect modifiction by sex, ge nd ge t exposure [ERR ¼ (b l d þ b h d) exp(s e þ t ln() (1 þ r s))], where b l d is the coefficient for the lower dose rnge nd b h d for the higher dose rnge. Coefficients for the effect modifiction terms were common to the two prts of the dose rnge. The lowest dose rnge with sttisticlly significnt ERR dose response for ll solid cncer ws estimted by testing the null hypothesis tht the low-dose slope ws zero by stepping up the cut point by 0.01 Gy. Threshold doses for ll solid cncer were lso estimted using the liner model s q(d) ¼ b 1 (d d 0 ) for d. d 0 or q(d) ¼ 0 for d d 0, where d 0 ws the threshold, nd djusted for sex, ge nd ge t exposure with modifiction by sex, ge nd ge t exposure. A wide rnge of possible vlues for d 0 were exmined by stepping up by 0.01 Gy, nd the point with the gretest mximum likelihood vlue ws determined. The minimum devince ws used to determine the dose threshold nd the dose yielding devince of the minimum plus 3.84 (which corresponds to v 2 1 degree of freedom cutoff point) determined its upper nd lower 95% CI. If the lower limit of the 95% CI of the threshold exceeded 0 Gy, we would conclude tht threshold exists, while the upper limit indictes the mximum threshold vlue tht is comptible with the dt. It hs been suggested tht the LSS cohort constructed in 1950 suffers from selection bis in tht members of the cohort who survived from the time of bombings to 1950 my hve been helthier nd hence more resistnt to the rdition effects (2, 18). To investigte this effect, the dose response reltionships of noncncer diseses were evluted using n LQ model without effect modifiction for both the erly period of follow-up ( ) nd the lter period ( ) using n ERR model. For reference, the sme nlysis ws lso conducted for ll solid cncer using the liner-qudrtic model with effect modifiction by sex, ge t exposure, nd ttined ge. Attributble frctions were estimted from the numbers of rditionssocited excess deths nd the corresponding totl numbers of deths from solid cncer nd noncncer diseses except for nonneoplstic blood diseses bsed on the liner ERR model with effect modifiction by sex, ge t exposure, nd ttined ge to llow comprisons between the two clsses of outcomes. CIs for estimting excess deths were estimted by the multivrite delt method. Anlyses re bsed on detiled tbultions of the dt crossclssified by city, sex, ge t exposure, ttined ge, follow-up period, nd rdition dose. The ctegories of ge t exposure were 5-yer ctegories for ges 0 through 69 nd 70 or more. Attined ge ws ctegorized by 5-yer intervls for ges 5 though 99 plus 100 or more. The dose ctegory cut points were 0.005, 0.02, 0.04, 0.06, 0.08, 0.1, 0.125, 0.15, 0.175, 0.2, 0.25, 0.3, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5 nd 3 Gy. The follow-up period ws divided into 5-yer intervls.

4 232 OZASA ET AL. TABLE 2 Observed Person-Yers nd Deths in the LSS Cohort Members with Known DS02 Doses, s of Jnury 1, 2004, by Age t Exposure Age t exposure (yers) subjects Observed person-yers deths , ,347 2,200 88% , ,826 4,887 72% , ,021 5,178 52% , ,694 10,410 15% , ,240 13,397 1% 50þ 14, ,079 14,548 0% Totl 86,611 3,294,210 50,620 42% These numbers do not include the subjects who were NIC, unknown dose, or censored becuse of deletion from koseki by municiplity offices nd other resons. Alive The bsic dt for ech cell in the tbultions were the number of deths for specific cuses nd time t risk in terms of person-yers. The cell-specific men vlues were included for c-ry nd neutron dose nd ech ge/time vrible. Prmeter estimtion nd tests were bsed on likelihood using Epicure softwre (19). When the lower limit ws not estimble, n implicit lower bound on the ERR ws thought to be 1/d_mx, where d_mx ws the mximum individul dose. RESULTS Among the 86,611 subjects with estimted DS02 doses, 50,620 subjects (58%) died in the follow-up period (Tble 2). While 99.6% of those who were exposed to A-bomb rdition t ge of 40 yers or older hd died, fully 80% of those under ge 20 t tht time were still live. The numbers of subjects who died of specific cuses of deth is shown in Tble 3. Twenty-two percent of deths were due to solid cncer, 1.4% to lymphoid nd hemtopoietic mlignncies, 71% to non-neoplstic diseses, nd 5% to externl cuses. Site-Specific Cncer Excess Risks Rdition risks for mjor cuses of deth, including mjor cncer sites, re shown in Fig. 1 (ERRs in the simple L model). The ERR per Gy (ERR/Gy) for totl deths ws sttisticlly significnt, 0.22 (95% CI: 0.18, 0.26). Also the risk estimte for ll solid cncer ws 0.47 (95% CI: 0.38, 0.56). The highest ERR ws observed for cncer of the renl pelvis nd ureter, then cncers of the brest (femle only), other digestive system, bldder, ovry (femle only), lung, colon, esophgus, gll bldder, liver nd stomch in descending order, lthough the CIs for these estimtes overlpped considerbly. The ERR estimte for renl pelvis nd ureter ws notbly unstble becuse of the smll number of cses. Other cncers such s rectum, pncres, uterus (femle only), prostte (mle only), or kidney prenchym did not hve significntly incresed risks. Sex-specific ERRs long with 95% CIs re shown in Tble 3. The sex-specific ERR/Gy in femles ws round twice s high s tht in mles for both totl deths nd ll solid cncer. The ERRs for cncers of most sites were lso higher in femles. There were some notble differences in the mgnitude of rdition effects between sexes. Cncer of the gllbldder nd renl pelvis nd ureter hd incresed risks in mles but not in femles, wheres cncers of the stomch, rectum nd other digestive diseses showed incresed rdition risk in femles but not in mles; however, the CIs for mles nd femles overlpped in ll cses. The sex-verged ERR of leukemi ws 3.1 (95% CI: 1.8, 4.3) t 1 Gy nd 0.15 ( 0.01, 0.31) t 0.1 Gy in the LQ model. However, the ERR ws not significnt for mlignnt lymphom or multiple myelom (Fig. 1). There were some pprent sex differences; nmely, there were significnt increses for mlignnt lymphom in mles only nd for multiple myelom in femles only (Tble 3). The estimtes of effect modifiction of the ERR by sex, ge t exposure, nd ttined ge re shown in Tble 4 for ll solid cncer nd cncer of the selected mjor sites. The left column shows the sex-verged ERR/Gy for the subjects t n ttined ge of 70 yers fter exposure t the ge of 30. The right columns show the prmeter estimtes of the effect modifiers. The ERR/Gy for femles ws round two times higher thn mles nd the rtios were significntly greter thn unity for ll solid cncer nd cncers of the stomch nd lung. The ERR/Gy for solid cncer declined 29% per 10-yer increse of ge t exposure nd lso declined in proportion to the 0.86 power of ttined ge, nd both effect modifiers were significnt, s illustrted in Fig. 2. The ge effects for cncers of specific sites were similr to those for ll solid cncer, but most were not sttisticlly significnt. The estimtes for the sme cncers using the EAR model re shown in Tble 5 (three sites were omitted becuse of nonsignificnt results in the ERR or effect modifiction terms in Tble 4). The left column shows the sex-verged EAR/10 4 person-yers/gy. The right columns show the prmeter estimtes of effect modifiers. There were no sex differences in EAR for ll solid cncer or for mjor individul types of cncer. The EAR significntly declined 19% per 10-yer increse in ge t exposure for ll solid cncer, s illustrted in Fig. 3. Estimtes for specific cncer

5 MORTALITY OF ATOMIC BOMB SURVIVORS, FIG. 1. Estimtes of excess reltive risk (ERR) per Gy nd 95% CI for mjor cuses of deth. ERR ws estimted using the liner dose model, in which city, sex, ge t exposure, nd ttined ge were included in the bckground rtes, but not llowing rdition effect modifiction by those fctors. b Confidence intervl. Horizontl brs show 95% confidence intervls. c The size of plots for site-specific cncers ws proportionl to the number of cses. d ERR (95% CI) of leukemi ws 3.1 (1.8, 4.3) t 1 Gy nd 0.15 ( 0.01, 0.31) t 0.1 Gy bsed on liner-qudrtic model with 318 cses (not displyed in the figure). e The lower limit of 95% CI ws lower thn zero, but not specified by clcultion.

6 234 OZASA ET AL. Cuse of deth TABLE 3 Deths, Excess Reltive Risk (ERR) Estimtes per Gy for Specific Cuses of Deth by Sex Bsed on rdition dose to: deths Mles ERR/ Gy (95% CI b ) P deths Femles ERR/ Gy (95% CI b ) P All cuses Colon (0.10, 0.20), (0.24, 0.35),0.001 Cncer All solid cncer Colon (0.21, 0.42), (0.52, 0.80),0.001 Esophgus Stomch ( 0.006, 0.97) (0.04, 3.0) 0.04 Stomch Stomch ( 0.02, 0.30) (0.28, 0.78),0.001 Colon Colon (0.09, 1.09) (0.16, 1.1) Rectum Bldder (NA c, 0.19) (0.06, 1.5) 0.03 Liver Liver (0.08, 0.58) (0.15, 0.85) Gllbldder Liver (0.19, 1.9) ( 0.12, 0.76) 0.24 Pncres Pncres ( 0.17, 0.83) (NA c, 0.43).0.5 Other digestive (NA c, 2.33) system Colon (0.51, 6.6) Lung Lung (0.17, 0.67), (0.68, 1.6),0.001 Brest Brest (0.52, 128) (0.93, 2.3),0.001 Uterus Uterus ( 0.09, 0.64) 0.19 Ovry Ovry (0.07, 1.9) 0.03 Prostte Bldder (NA c, 1.2) 0.30 Bldder Bldder (0.02, 2.3) (0.21, 3.8) 0.02 Kidney prenchym Colon (NA c, 1.4) (0.01, 4.9) Renl pelvis nd ureter Colon (0.25, 14) (NA c, 8.0) 0.13 Other Colon (0.02, 0.83) (0.14, 1.0) Lymphoid nd hemtopoietic mlignncies Leukemi Bone mrrow (3.0, 6.9), (2.5, 6.1),0.001 Mlignnt lymphom Bone mrrow (0.08, 1.7) ( 0.21, 0.24) 0.33 Multiple myelom Bone mrrow (NA c, 1.6) (0.02, 2.5) 0.04 Other neoplsms Colon ( 0.10, 0.88) (0.44, 2.0),0.001 Non-neoplstic diseses Blood diseses Bone mrrow (0.68, 3.8), (0.76, 2.8),0.001 Circultory disese Colon ( 0.001, 0.16) (0.06, 0.23),0.001 Respirtory disese Colon (0.02, 0.31) (0.11, 0.47),0.001 Digestive disese Colon ( 0.09, 0.23) ( 0.01, 0.40) 0.07 Genitourinry disese Colon (NA c, 0.28) (0.01, 0.62) 0.04 Infectious disese Colon ( 0.16, 0.22) (NA c, 0.18).0.5 Other disese Colon ( 0.12, 0.21) ( 0.15, 0.15).0.5 Externl cuses Colon (NA c, 0.11) ( 0.07, 0.41) 0.21 ERR ws estimted using the liner dose model, in which city, ge t bombing, nd ttined ge were included in the bckground rtes, but not s rdition effect modifiers. b The lower limit ws not estimble, but n implicit lower bound (1/d_mx) ws 0.28 for mles nd 0.27 for femles (see text). sites tended to be similr, but most were not significnt. The EAR significntly incresed s the 3.4 power of ttined ge s n effect modifier for ll solid cncer nd lso significntly incresed for cncer of mjor sites (Tble 5). The fits of the L, LQ nd Q models were compred for ll solid cncer in the full dose rnge (left columns of Tble 6). They did not show significnt difference of devinces between the L nd LQ models (P ¼ 0.36), indicting tht qudrtic term ws unnecessry. The Q model hd significntly worse model fit thn the L or LQ models. Furthermore, the L model showed the smllest Akike Informtion Criterion (AIC) (20), the LQ model hd 1.2- point lrger vlue thn the L model, nd the Q model ws 23.7 points lrger, gin indicting tht it provided the poorest fit. Those differences were clculted from the devinces in Tble 6. Consequently, the L model ws selected s the best model in the full dose rnge. Figure 4 shows the estimted plots of dose dependence ccording to the L nd LQ functions. Although the liner model provided the best fit in the full dose rnge, sttisticlly significnt upwrd curvture ws observed when the dose rnge ws limited to 0 2 Gy (h ¼ 0.81, P ¼ 0.02) (Tbles 6 nd 7). The curvture over the 0 2-Gy rnge hs become stronger over time, going from h ¼ 0.20 for the period to 0.81 for , nd hs become significnt with longer observtion (Tble 7).

7 MORTALITY OF ATOMIC BOMB SURVIVORS, TABLE 4 Effect Modifiction of the Excess Reltive Risk (ERR) Model for Mjor Cncers Sex (r) (ERR rtio: femle/mle) Age t exposure (s) (Percentge chnge per 10-yer increment) Sex-verged ERR/Gy b Attined ge (t) (power) (95% CI c ) (95% CI) (95% CI) (95% CI) All solid cncer 0.42 (0.32, 0.53) 2.1 (1.4, 3.1) 29% ( 41%, 17%) 0.86 ( 1.60, 0.06) Esophgus cncer 0.60 (NA, 1.64) 4.3 (0.54,.100) 35% ( 28%, 184%) 3.7 ( 9.6, 1.0) Stomch cncer 0.33 (0.17, 0.52) 3.7 (1.3,.100) 18% ( 47%, 20%) 0.74 ( 2.5, 1.2) Colon cncer 0.34 (0.05, 0.74) 1.4 (0.39, 6.6) 3% ( 51%, 63%) 5.8 ( 10.4, 2.2) Liver cncer 0.38 (0.11, 0.62) 1.6 (0.43, 7.9) 8% ( 62%, 42%) 0.02 ( 2.8, 4.2) Gllbldder cncer 0.48 (0.12, 1.02) 0.42 (,0.001, 2.4) 27% ( 76%, 40%) 1.9 ( 6.6, 7.8) Lung cncer 0.75 (0.51, 1.03) 2.7 (1.3, 6.8) 7% ( 35%, 29%) 0.04 ( 2.2, 2.6) Brest cncer d 0.90 (0.30, 1.78) 45% ( 67%, 17%) 0.17 ( 2.7, 2.3) Bldder cncer 1.19 (0.27, 2.65) 1.7 (0.2, 9.0) 2% ( 62%, 92%) 0.49 ( 3.6, 6.1) Ovry cncer 0.20 (NA, 1.30) 22% ( 96%, 218%) 4.1 ( 33, 1.9) The ERR model ws defined s k 0 (c,s,b,) [1þ b 1 d exp(s e þ t ln()) (1 þ r s)], where d is dose, s is sex, b is birth yer, e is ge t exposure, nd is ttined ge. s, t nd r re coefficients for effect modifiction. b The sex-verged ERR/Gy is shown for subjects t the ttined ge of 70 yers fter exposure t ge 30. c 95% confidence intervl. d Femle only. However, the estimted ERRs under 0.3 Gy were nominlly higher thn the best-fitting liner slope or the LQ function for either 0 2 Gy or the full dose rnge in Fig. 4. A qudrtic-spline function with knot t 0.2 Gy tht llowed higher estimtes t the low-dose level did not provide significntly better fit thn the LQ function (P ¼ 0.16). It ws prticulrly notble tht the ERR/Gy estimtes for liner functions clculted for vrious low-dose rnges showed higher vlues for rnges less thn 0.1 Gy compred to estimtes obtined from higher dose rnges (Fig. 5), i.e., FIG. 2. Modifiction of the excess reltive risk (ERR) for ll solid cncer by ge t exposure nd ttined ge. the slope ws not shllower in the low-dose rnge thn t high dose levels. The lowest dose rnge with significnt ERR for ll solid cncer ws 0 to 0.20 Gy with n estimted ERR/Gy of 0.56 (95% CI: 0.15, 1.04, P ¼ 0.01) nd included 74,444 persons with 9,063 solid cncer deths. For the rnge of 0 to 0.18, the ERR/Gy ws 0.43 (95% CI: , 0.91, P ¼ 0.052) nd included 8,920 deths (Fig. 5). The mximum likelihood estimte of dose threshold ws 0.0 Gy (i.e., no threshold) with n estimted upper bound of 0.15 Gy for 95% CI s determined by minimizing the devince. Noncncer Disese Excess Risks The risks were significntly elevted for non-neoplstic diseses of the blood (ERR/Gy ¼ 1.7, 95% CI: 0.96, 2.7), circultory system (0.11, 95% CI: 0.05, 0.17), nd respirtory system (0.21, 95% CI: 0.10, 0.33). Among the nonmlignnt respirtory diseses, the risk of pneumoni nd influenz ws significntly elevted (ERR/Gy ¼ 0.24, 95% CI: 0.10, 0.40, with 3,244 deths). Other nonneoplstic diseses including infectious diseses did not show ny incresed rdition risk in either sex except for genitourinry diseses in femles. There were no doserelted excess mortlity risks from externl cuses (Fig. 1, Tble 3). As for the chnges in dose response over the long followup period, the risks of circultory, respirtory nd digestive diseses were ll significntly elevted during the period fter 1965 (Tble 8). The risk of pneumoni nd influenz ws lso higher in the ltter period (ERR/Gy ¼ 0.25, 95% CI: 0.10, 0.43), but liver cirrhosis, mjor digestive disese, did not show ny incresed rdition risk during the whole period or for the period fter 1965 (ERR/Gy ¼ 0.11, 95% CI: 0.07, 0.34 nd 0.17, 95% CI: 0.04, 0.42, respectively).

8 236 OZASA ET AL. TABLE 5 Effect Modifiction of the Excess Absolute Risk (EAR) Model for Mjor Cncers Sex-verged EAR/ Sex (r) (EAR rtio: 10 4 PY/Gy b femle/mle) Age t exposure (s) (Percentge chnge per 10-yer increment) Attined ge (t) (power) (95% CI) c (95% CI) (95% CI) (95% CI) All solid cncer 26.4 (20.3, 32.8) 1.1 (0.80, 1.74) 19% ( 31%, 7%) 3.4 (2.7, 4.1) Stomch cncer 4.1 (2.1, 6.7) 1.8 (0.66, 32) 18% ( 18%, 62%) 2.0 (1.0, 3.6) Colon cncer 1.6 (0.5, 3.0) 0.98 (0.34, 4.5) 30% ( 58%, 2%) 3.2 (1.3, 5.3) Liver cncer 3.4 (0.7, 5.9) 0.69 (0.19, NA) 25% ( 66%, 15%) 6.0 (3.2, 12) Lung cncer 6.5 (4.3, 9.0) 0.78 (0.40, 1.8) 16% ( 37%, 6%) 6.2 (4.5, 8.2) Brest cncer d 2.3 (1.0, 3.8) 51% ( 68%, 30%) 3.0 (1.7, 4.7) Bldder cncer 1.2 (0.3, 2.4) 0.40 (0.0, 5.3) 1% ( 65%, 80%) 7.5 (3.1, 15) The EAR model ws defined s k 0 (c,s,b,) þ b 1 d exp(s e þ t ln()) (1 þ r s), nd prmeters re indicted in Tble 4. b The sex-verged EAR/10 4 person-yers/gy is shown for subjects t the ttined ge of 70 yers fter exposure t ge 30. c 95% confidence intervl. d Femle only. The dose response reltionships of noncncer disese mortlity for the erly period ( ) nd lte period ( ) of follow-up re shown in Fig. 6. The reltionship for the erly period (dotted line) showed essentilly no rdition effect below bout 1.5 Gy while tht for the lte period showed n pproximtely liner dose response reltionship for noncncer diseses s whole, nd the difference in shpes ws significnt between the periods (pnel A, P ¼ 0.02). Among noncncer diseses, circultory diseses did not show difference between the periods (pnel B, P, 0.05), but both respirtory nd digestive diseses showed mrginl differences between periods (pnel C, P ¼ 0.07 nd pnel D, P ¼ 0.06, respectively), nd the temporl difference for ll solid cncers ws not significnt (Pnel E, P ¼ 0.18). A comprison between L nd LQ fit for ech period showed tht the LQ function fit significntly better in the erly period for totl noncncer diseses (P ¼ 0.04) but not for the lte period (P ¼ 0.29). A similr pttern ws found for respirtory diseses (P ¼ 0.01 nd P ¼ 0.35, respectively). There were no differences between the L nd LQ fits in either period for circultory diseses (P ¼ 0.23 for the erly nd P. 0.5 for the lter), digestive diseses (P, 0.5 nd P ¼ 0.22, respectively), or solid cncer (P, 0.5 nd P ¼ 0.39, respectively). Estimtes of the numbers of rdition-ssocited excess deths in the LSS between 1950 nd 2003 re shown in Tble 9. The excess deths of solid cncer were estimted s 527 (95% CI: 157, 899). About 8.3% (¼525/6308) (95% CI: 2.6%, 14%) of the deths mong cohort members with colon dose of Gy or higher (men dose of 0.2 Gy) ppered to be ssocited with rdition. The percentges ttributble to rdition were 5.8%, 13%, 25%, 35% nd 57% t dose rnges of , , 0.5 1, 1 2 nd 2 Gy nd higher (the person-yer-weighted men doses were 0.14, 0.31, 0.72, 1.4 nd 2.5 Gy), respectively. The excess deths for noncncer diseses were estimted s 353 (95% CI: 252, 958) using the ERR model with effect modifiers. About 1.8% (95% CI, 1.2%, 4.8%) mong those with colon dose of Gy or higher ppered to be ssocited with rdition. The vlue ws 1.9% (95% CI, 1.2%, 2.7%) when the ERR model without effect modifiers ws used becuse those effect modifiers were estimted less precisely due to smll ERRs nd high bckground rte. FIG. 3. Modifiction of the excess bsolute risk (EAR) for ll solid cncer by ge t exposure nd ttined ge. DISCUSSION The most importnt finding regrding the lte effects of A-bomb rdition exposure on mortlity is n incresed risk of cncer mortlity throughout life (2). The current dt showed tht the risk for ll solid cncer deths hs continued to increse throughout the survivors lifetimes in pproximte proportion to rdition dose. The sexverged reltive excess of solid cncer deths ws 42% per Gy t ge 70 yers fter exposure t ge 30 bsed on liner

9 MORTALITY OF ATOMIC BOMB SURVIVORS, Dose rnge model TABLE 6 Prmeter Estimtes of the Dose Response Models for Excess Reltive Risk (ERR) for ll Solid Cncer in the Full Dose Rnge nd for the Rnge of 0 2 Gy L b LQ Q L LQ Q Full,2 Gy b 1 : liner b 2 : qudrtic Effect modifiction r: sex (femle ¼ 1; mle ¼ 1) s: ge t exposure (yer) t: ttined ge (log(ge/70)) Devince df Test (vs. LQ model ) P ¼ 0.36 P, P ¼ 0.02 P ¼ 0.02 Note. Bolded columns re the selected models. The ERR model ws defined s k 0 (c,s,b,)[1þ q(d) exp(s e þ t ln()) (1 þ r s)], where d is colon dose, s is sex, b is birth yer, e is ge t exposure, nd is ttined ge. q(d) ws b 1 d for the liner model, b 1 d þ b 2 d 2 for the liner-qudrtic model, nd cd 2 for the qudrtic model. s, t nd r re coefficients for effect modifiction. b L: liner, LQ: liner-qudrtic, Q: qudrtic. model with effect modifiction by ge t exposure nd ttined ge. The sex-verged excess deth rte of ll solid cncer ws 26/10,000 person-yers per Gy under the sme conditions. The second importnt finding is tht those who were exposed t younger ges hd higher reltive risk for cncer deth; e.g., the sex-verged ERR of solid cncer deths ws 0.83 t ge 70 in those who were exposed t 10 yers of ge compred with 0.30 in those exposed t ge 40. For solid cncers the reltive risk declined with incresing ttined ge of the subjects s well s yers fter the bombing, lthough, importntly, the excess bsolute rtes continued to increse with ttined ge nd the rtes were higher in those exposed t younger ges mong those with the sme ttined ge. These findings suggest tht young people re more sensitive to rdition thn older people, possibly t the initition stge in crcinogenesis t the time of exposure, nd imply n overll increse in lifetime risk for those exposed t younger ges. To provide continuity, the methods of nlysis nd risk indictors re the sme s those in previous reports since 1987 (2, 10). In previous report, mortlity dt up to 2000 were exmined for chnges in the estimted risk of rdition due to chnges in dosimetry between DS86 nd DS02 (4). In tht report the estimtes of solid cncer risk per unit rdition dose decresed bout 8% due to the upwrd revision in the c-ry dose estimtes (4). The ERR/Gy for ll solid cncer decresed from 0.45 bsed on DS86 to 0.42 bsed on DS02 for (4). The estimtes of ERR/ Gy nd modifiers for solid cncer in this study (Tble 4) were similr to those in the ltter report (4). The effectmodifiction results showed substntilly similr tendencies to previous estimtes using DS86 nd less follow-up time (2,5). Effect modifiction ws evluted for the ERR (Tble 4) nd EAR (Tble 5) models. The ERR estimtes were FIG. 4. Excess reltive risk (ERR) for ll solid cncer in reltion to rdition exposure. The blck circles represent ERR nd 95% CI for the dose ctegories, together with trend estimtes bsed on liner (L) with 95% CI (dotted lines) nd liner-qudrtic (LQ) models using the full dose rnge, nd LQ model for the dt restricted to dose,2 Gy. TABLE 7 Chnge in Dose Response Curvture For Excess Reltive Risk (ERR) of Solid Cncer in The rnge of Gy by Observtion Period Curvture (h) % CI b ( 0.23, 3.2) ( 0.09, 3.2) (0.08, 8.6) Significnce (P) c The ERR model ws defined s k 0 (c,s,b,) [1þ b 1 (d þ hd 2 ) exp(s e þ t ln()) (1 þ r s)] seprtely for ech period of nlysis, where d is colon dose, s is sex, b is birth yer, e is ge t exposure, nd is ttined ge. s, t nd r re coefficients for effect modifiction. b Confidence intervl. c Likelihood test.

10 238 OZASA ET AL. TABLE 8 Excess Reltive Risk (ERR) Estimtes per Gy for Noncncer Deths, Cuse of deth deths ERR/Gy (95% CI b ) P Noncncer disese c 25, (0.08, 0.18),0.001 Circultory disese 14, (0.05, 0.18),0.001 Respirtory disese 4, (0.11, 0.36),0.001 Digestive disese 2, (0.05, 0.38) Genitourinry disese ( 0.06, 0.46) 0.15 Infectious disese ( 0.22, 0.23).0.5 Other disese 2, ( 0.11, 0.19).0.5 ERR ws estimted using the liner dose model, in which city, sex, ge t exposure, nd ttined ge were included in the bckground rtes, but not llowing rdition effect modifiction by those fctors. b Confidence intervl. c Non-neoplstic blood diseses were excluded from noncncer diseses. FIG. 5. Excess reltive risk per Gy (ERR/Gy) for ll solid cncer for selected dose rnges. The figure shows the ERR/Gy nd 95% CI for dose rnge from zero to given dose bsed on the liner model for the full dt tht llowed for different ERRs below nd bove the given dose nd tking rdition effect modifiers s common to the two dose rnges. The incresed ERR/Gy in the low-dose levels less thn 0.1 Gy corresponds to the estimtes of ERR higher thn the expected liner line in Fig. 4. substntilly higher for women thn men, but the EAR estimtes were not. This ppers to be function of the fct tht the bckground mortlity rtes of cncer were substntilly higher in men thn in women in this cohort. Similrly, it ws observed tht cncers hving low bckground mortlity rte tend to hve reltively high ERR, nd vice vers. The gender similrity in EAR estimtes suggests tht the excess of deths due to rdition is mostly constnt in rte rther thn in rtio (i.e., more dditive thn multiplictive) to the bckground cncer rtes. This interprettion is consistent with the differences in ERR between sites of cncer mentioned bove. Age t exposure is n importnt modifying fctor in rdition-induced crcinogenesis. Both the ERR nd the EAR were higher for younger ges t exposure (Tbles 4 nd 5, Figs. 2 nd 3). However, other reports [for exmple, the BEIR VII nd UNSCEAR 2006 Reports (6, 23)] hve indicted tht the ERRs for those exposed t ge 60 yers or older were similr to or higher thn risks for those exposed t ge 40 or 50 yers, especilly for cncer incidence dt (5, 21, 22). The nonprmetric ctegory-specific estimtes of ge-t-exposure effects on ll solid cncer mortlity risk in the current study were similr to the corresponding figures reported by Wlsh (22), in which n incresed risk t n old ge t exposure ws less remrkble thn in the figure reported by Preston et l. (5). The liner dose response reltionship provided the best fit to the solid cncer dt cross the entire dose rnge in this study, but significnt upwrd curvture ws observed over the truncted dose rnge of 0 2 Gy (Tble 7), which hd been hinted t in previous reports (4, 5). DDREF is defined by dividing the slope of nonliner function t lowdose levels by the slope of the extrpolted liner nonthreshold function bsed on the whole dose rnge (23), so tht this upwrd curvture my imply DDREF greter thn one. However, the dose response slope ws nominlly higher t doses below 0.1 Gy thn it ws overll or for the dose rnge 0 2 Gy (Fig. 5). The pprent upwrd curvture ppers to be relted to reltively lower thn expected risks in the dose rnge Gy (Fig. 4), finding without current explntion. A recent pper (24) compred the risk of cncer mortlity nd incidence in 12 studies of low-dose-rte, moderte-dose exposure (mostly externl) with those vlues in the LSS. The ERR per dose for ech study ws clculted using the sme gender distribution, verge ge t exposure, nd verge ttined ge s in the LSS. The expected DDREF bsed on the rtio of ERR per dose in those studies to tht in the LSS ppered to be close to 1.0, nominlly lower thn the fctors suggested by BEIR VII (1.5) (23) nd ICRP (2.0) (25). However, the number of exmined studies ws limited to the publiction period of with conditions llowing clcultion of the vlues mtching the LSS (24), so the rguments re still controversil. The high risks per unit dose observed in the low-dose rnge re difficult to interpret. One suggestion ws tht cumultive exposures to dignostic medicl rdition over the mny yers of follow-up my hve reched considerble proportion of the estimted individul A-bomb doses t the low-dose levels (26). However, to impct the ERR estimtes, medicl exposures or other sources of exposure, including fllout nd residul rdition, would hve to hve preferentilly exposed subjects with very low doses. In the LSS, zero-dose subjects were locted t round 4 km or frther from the hypocenter while the subjects with doses of up to 50 mgy were locted round the rnge of 2 to

11 MORTALITY OF ATOMIC BOMB SURVIVORS, FIG. 6. Comprison of dose response curve for erly period ( , shown with dshed line) nd for lte period ( , shown with solid line) from noncncer diseses (bsed on LQ without ny effect modifiction) nd ll solid cncer (bsed on LQ with effect modifictions). Bsed on the ERR model defined s the liner-qudrtic model without effect modifictions for noncncer diseses: k0(c,s,e,)[1 þ b 1 (d þ hd 2 )], nd the model with effect modifictions for ll solid cncer: k0(c,s,e,)[1þ b 1 (d þ hd 2 ) exp(s e þ t ln()) (1 þ s s)], where d is colon dose, s is sex, e is ge t exposure, nd is ttined ge. The figure for ll solid cncer shows the sex-verged estimtes for e ¼ 30 yers nd ¼ 70 yers. b Significnce of the difference between the two curves. Colon dose (Gy) subjects TABLE 9 Observed nd Excess Deths from Solid Cncer nd Noncncer Diseses Person-yers deths Solid cncer excess cses Attributble frction (%) deths Noncncer diseses b excess cses b Attributble frction (%), ,509 1,465,240 4, , ,961 1,143,900 3, , , , , , , , , , , ,763 66, þ , Totl 86,611 3,294,210 10, , Bsed on the ERR model ws defined s the liner model with effect modifiction: k 0 (c,s,b,)[1 þ b 1 d exp(s e þ t ln()) (1 þ r s)]. b Non-neoplstic blood diseses were excluded from noncncer diseses.

12 240 OZASA ET AL. 4 km. Thus, with such lrge geogrphicl distribution, differentil exposures to dditionl rdition sources seem implusible, lthough we hve insufficient informtion bout fllout or residul rdition to completely rule out this possibility. Potentil cuses other thn rdition include selection bis due to erly mortlity prior to study initition in mnner tht correltes with dose (e.g., high doses mong urbn people nd lower doses mong rther rurl people) (1, 2, 5, 27, 28). Suggestively lower bseline mortlity hs been shown in the low-dose but reltively proximl survivors compred to the more distnt survivors, which suggests tht sociodemogrphic fctors such s urbn-rurl differences my be more importnt thn dose-bsed selection effects (1, 2, 27, 28). However, sociodemogrphic selection effects might hve wekened becuse of moderniztion of the Jpnese lifestyle over the decdes. The issues relted to the influences of dose, ltency nd sociodemogrphic-lifestyle fctors on mortlity from noncncer diseses in the LSS require further investigtion. A vriety of studies of risks for site-specific cncers from externl exposure to low-let (liner energy trnsfer) rdition re documented in the UNSCEAR 2006 Report (6). Most studies were bsed on either subjects with highdose rdition such s rdiotherpy or rdition workers with low-level exposures. Thus the LSS is often thought to provide the most relible estimtes of rdition effects becuse of its lrge size, wide rnge of reltively precise individul doses, observtion of numerous diseses, nd long follow-up period. Cncers of the esophgus, stomch, colon, lung, brest, ovry nd bldder nd trnsitionl cell crcinom of kidney, pelvis nd ureter re thought to be ssocited with low- nd high-dose rdition bsed on the LSS nd other studies (6). A strong interction between rdition nd smoking ws observed in the risk of lung cncer (29), so high ERRs of smoking-relted cncers might be prtly due to such n interction. Rectl cncer is thought to be inducible fter high-dose rdiotherpy exposures (6), but no ssocition hs been observed mong the LSS. On the other hnd, n ssocition of liver cncer with rdition exposure hs not been demonstrted in studies of medicl nd occuptionl exposure to low-let rdition, while the LSS showed significnt increse in risk (6). It is inconclusive whether there ws synergism between HCV infection nd rdition (30) or independent effects by ech of them (31). Cncers of the pncres, prostte nd uterine cervix re not thought to be ssocited with rdition (6), which is consistent with the results of this study. Uterine corpus nd kidney prenchyml cncers re possibly ssocited with high-dose rdition exposure (6), but this ssocition ws not observed in this study. Most excess cses of leukemi occurred shortly fter the tomic bombings, even before the beginning of the LSS (32), nd modestly elevted risk hs continued t low level over the lst severl decdes (1, 7). In this study, the estimted ERR t 1 Gy for totl leukemi ws 3.1 (95% CI: 1.8, 4.3) using liner-qudrtic model without effect modifiction, bsed on 313 cses, which is similr to recent, more detiled leukemi report (7). An nlysis of mlignnt lymphom mortlity in the LSS ws conducted recently bsed on the subset of mles of working ge t the time of the bombing (33). The present study similrly found n excess for mles [ERR/Gy of 0.70 (P ¼ 0.02)] but no ssocition for women [ERR/Gy ¼ 0.18 (P ¼ 0.33)]. We hve no explntion for the disprity between the mle nd femle results nd believe the rdition effect should be interpreted cutiously due to both the gender disprity nd the diversity of mlignncies under the rubric of lymphom. Erlier LSS reports of multiple myelom mortlity (34) did not show sttisticlly significnt excesses. But, bsed on hemtologiclly reviewed incident cses from leukemi registries nd tumor registries, Preston et l. (35) showed n ERR/Gy ¼ 0.25 (P. 0.5) bsed on 30 first primry cses with shielded kerm under 4 Gy nd ERR/Gy ¼ 0.9 (P ¼ 0.02) fter dding seven cses of second primries nd those with shielded kerm.4 Gy. In the present study (ll with bone mrrow doses 4 Gy), ERR/Gy of multiple myelom ws 0.11 (P. 0.5) in mles nd 0.86 (P ¼ 0.04) in femles bsed on 34 nd 59 cses, respectively. In this overview, risk of noncncer diseses ws reported using brod clssifiction of disese types. The elevted risk of diseses of the blood nd blood-forming orgns my be genuinely due to the effects of rdition or to possible misdignoses of hemtopoietic mlignncies s non-neoplstic conditions, since mny deth certifictes were completed without intensive investigtions s to the cuse of deth (8). The risk of circultory diseses ws significntly higher. This is importnt becuse circultory diseses re the leding cuse of deth in developed countries (6); detiled results for circultory disese deths mong the LSS hve been reported elsewhere (36). The risk of respirtory diseses ws lso significntly elevted due to the incresed risk of pneumoni nd influenz, which constituted 63% of the deths from respirtory diseses. However, chrcteristics of pneumoni nd influenz ppered to be different between the periods of observtion; nmely, it ws ssocited with cute epidemics in the erly period but ws more likely to be ssocited with terminl diseses mong the elderly in the more recent period. Hence problem in interpreting pneumoni nd influenz deths is tht they my be ssocited with other concurrent or underlying diseses. Although digestive diseses showed n ssocition with rdition during , liver cirrhosis, which constituted 43% of digestive disese deths during tht period, did not show ny incresed rdition risk. Therefore, further detiled nlyses of both respirtory nd digestive diseses re plnned. There ws no ssocition of rdition dose nd deth due to externl cuses or to infectious/prsitic diseses. The strengths of this LSS mortlity study re, s stted previously (2, 4, 34), (1) lrge, representtive smple cross ll ge groups of A-bomb survivors who were live