The American Journal ofPATHOLOGY

APRIL 1974 * VOLUME 75, NUMBER 1

Aging in Hiroshima and Nagasaki AtomicBomb Survivors

Speculations Based upon the Age-Specific .Miortality ofPersons with Malignant Neoplasms

Robert E. Anderson, MD, Charles R. Key, MD, PhD,Tsutomu Yamamoto, MD and Todd Thorslund, BS

Evaluation of 1639 malignant tumors from 3067 autopsies of members of theExtended Life Span Study Sample reveals that death occurs earlier in those personsmost heavily irradiated ( 5100 rad) compared with those persons who were lessexposed. This effect is particularly pronounced in the younger age categories andamong females and is not attributable to a specific neoplasm. Assuming that apositive correlation exists between aging and the age-specific mortality of personswith neoplasms, it is concluded that this response is consistent with other observa-tions which suggest the presence of accelerated or precocious aging in the mostheavily irradiated group of survivors (Am J Pathol 75:1-12, 1974).

Two OF THE MORE CONSPICUOUS experimental consequencesof exposure to biologically significant amounts of ionizing radiationare a reduction in life span and an increased prevalence of many typesof tumors. These phenomena are interrelated experimentally in that

From the Departments of Pathology and Statistics, the Atomic Bomb Casualts Com-nission (a cooperative research agency of the US National Academy of Sciences-NationalResearch Council and the Japanese National Institute of Health and The Mlinistry ofHealth and Welfare), Hiroshima and Nagasaki, Japan.

Supported by the US Atomic Energv Commission, the Japanese National Instituteof Health, the US Public Health Service and the John and M\anr R. Mfarkle Foundation.

Accepted for publication December 19, 1973.Address reprint requests to Editorial Office, Atomic Bomb Casualt- Commission,

5 2 Hijiyama Park, Hiroshima 730, Japan.

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2 ANDERSON ET AL American Journalof Pathology

the prevalence and appearance time of neoplasms have been shownto represent excellent parameters of the accelerated or precociousaging noted postexposure.1-2 In this regard, however, it is important toemphasize that the life-shortening response to radiation is not entirelydependent upon the tumorigenic effect. Thus, in an elaborate evaluationof a large number of mice exposed to neutrons and gamma ravs froman atomic weapon exploded near Eniwetok, Upton et al 3 noted that theattendant reduction in longevitv was not attributable to an increasedmortality from one or several specific entities but rather correlated withthe premature appearance of all of the diseases associated withspontaneous senescence.An increased prevalence of several malignant tumors has been docu-

mented among the atomic bomb survivors of Hiroshima and Nagasaki.Implicated thus far are: several forms of leukemia, myelofibrosis wvithmyeloid metaplasia, malignant lymphoma including multiple mvelomain Hiroshima survivors, carcinoma of the thvroid, possiblx carcinomaof the lung, carcinoma of the major salivary glands, possibly carcinomaof the breast, and a variety of malignant tumors among individualsexposed during the initial decade of life.45 In several of the foregoinginstances, the appearance time (the period between exposure and theonset of the malignancy) has also been accelerated in proximallylocated persons in comparison with a more distal group or with indi-viduals who were awav from the involved cities at the time of theexplosions.The purpose of the present study is to extend the above observations

to include an evaluation of all neoplasms, as documented by post-mortem examination, as a function of exposure status and age at deathamong the survivors of the atomic bombs of Hiroshima and Nagasaki.As such, it represents one of a series of efforts to apply various agingparameters to the populations under surveillance at the Atomic BombCasualty- Commission (ABCC) even though the authors realize thatage-specific mortalitv associated with tumors is not universally acceptedas a measure of aging.

Materials and MethodsThree thousand sixty-seven (3067) members of the Life Span Studv' Sample

autopsied prior to 1968 form the basis of this studv. The composition of the totalLife Span Studv Sample by exposure status, age at the time of exposure and sex issummarized in Table 1 and Text-figure 1. Other demographic characteristics of thiscarefully constructed population are detailed elsewhere.6f7 In recent years, ABCCautopsy contractors have achieved a 47% autopsy rate among hospital deaths and a32% rate among persons who died at home. In this connection, several areas of possi-

Vol. 75. No. 1 AGE-SPECIFIC MORTALITY AND NEOPLASMS 3April 1974

Table 1-Approximate Composition of Life Span Study Sample

Persons in categoryDistance from

Exposure category hypocenter (m) Hiroshima Nagasaki Total

Inner proximal 0-1,999 21,200 6,600 27,800Outer proximal 2,000-2,499 11,500 5,100 16,600Distal 2,500-10,000 21,200 6,600 27,800Not in city 21,200 6,600 27,800Total persons 75,100 24,900 100,000

ble bias deserve emphasis: persons with death certificate diagnoses of malignantdisease are more likelv to come to autopsy than individuals w%ith other diagnoses,particularly persons with diagnoses suggestive of mechanical trauma; verv voungand very old people are underrepresented in the autopsy population.s For thesereasons, it should be borne in mind that the data presented herein apply only to thesegment of the Life Span Study Sample which was autopsied at ABCC and mayor may not apply to the entire Study Population. The demographic composition ofthe autopsy subsample is shown in Table 2.

Autopsies are performed in meticulous fashion and are generallv reviewed by twoor more pathologists. Disease entities are coded in standard fashion. Instances wherea malignant neoplasm is included as the primary or contributorv cause of death areincluded herein. Also included are cases in which a malignant tumor, with the celltype documented histologicallv, was removed surgicallv prior to death with thelatter attributable to a nonneoplastic etiology.

Exposure categories are based upon Tentative 1965 Dose (T65D) Estimates pro-vided bv Oak Ridge and are thought to be reasonablv accurate. These estimates arebased upon the air dose curves shown in Text-figure 2 with appropriate correctionsfor man-made and natural objects. On the basis of the foregoing, individuals aregrouped into the following exposure categories by total dose estimate with gammarays and neutrons combined on a 1:1 basis: 1) 100 or more rad; 2) 1 to 99 rad;3) Less than 1 rad. The latter category includes persons who were away from the

O Nogasakia Hiroshima

TEXrr-FiG 1-Survivors byage, 1950 census, Hiroshima v-s.

Nagasaki.

85+80-84

fAtes 75-79 Fmf70-74

C65-6960-6455-5950-5445-49

35-3930-3425-2920-2415-1910-145 -90-4

10 8 6 4 Age 4 6 8 g0Survivs Surviws(th ) (thousarcW

4 ANDERSON ET AL American Journalof Pathology

Table 2-Demographic Composition of Autopsy Sample*

Estimated dose (rad)

Age at <1 1-99 100 Unknowndeath(yrs) Female Male Female Male Female Male Female Male Total

0-9 0 0 0 0 0 1 0 0 110-19 4 5 2 4 0 2 1 1 1920-29 9 23 7 13 4 5 0 1 6230-39 26 32 20 23 10 6 4 4 12540-49 42 24 39 32 10 10 2 7 16650-59 111 101 74 56 13 16 2 8 38160-69 179 303 145 165 16 34 4 20 86670-79 220 237 191 211 22 36 6 10 93380-89 141 101 115 72 10 8 3 2 45290-99 22 12 10 13 1 2 0 2 62Total 754 838 603 589 86 120 22 55 3067

* Figures indicate actual number of persons in group; individuals away from cities attime of bombings included in <1 rad group.

two cities at the time of the explosions. Parenthetically, it should be noted thatapproximately 5OX of the Life Span Study Sample (Table 1) was exposed to lessthan 1 rad at the time of the bombings.

ResultsThe autopsy prevalence of malignant tumors as a function of exposure

category is shown in Text-figure 3. A few specific entities of generalinterest are included separately as well as the totals for all neoplasms.

Hiroshima N

S0E-

8i

6

E

ILI

8is

DisWnc From Hypocenter(meters)

TExr-FiG 2-Tentative 1965 air

Disarce From Hypocter(meters)

dose estimates by city, gamma rays vs. neutrons.

oo_w_

Vol. 75, No. 1 AGE-SPECIFIC MORTALITY AND NEOPLASMS 5April 1974

70r-

600_

*4 5007-04-m

'< 400000

1300c

0~> 00

10

* 5100 rod

I-99rod

D1 < rod

Total Leukemia Carcinoma CarcinomaTumors of Thyroid of Stomoch

TEXT-FIG 3-Distribution of malignant tumors in autopsy population by exposurecategory. For individuals with more than one primary neoplasm, each malignancy is in-chlded separately.

For persons with more than one primarv neoplasm, each malignancvis included separately. This point deserves emphasis since such anappoach appears to exaggerate the prevalence of malignant tumors(ie, it is not the case that 66% of persons autopsied at ABCC die withmalignant neoplasms). As might be expected, an excess number ofmalignancies is noted in the 5100 rad group. The most pronouncedrelative increase is noted with leukemia.Age at death for autopsied persons with malignant neoplasms as a

function of exposure category is shown in Text-figure 4. The age-specific mortality, is displaced to the left (ie, younger age at death)for both sexes in the 5 100 exposure category. This effect is particularlvevident in the younger age groups and is more pronounced in femalesthan in males.Carcinoma of the stomach is the most frequentlv encountered

malignant neoplasm among the general Japanese population; Japanranks second onlv to Finland with respect to the number of deathsattributable to this entity. Although the incidence of this neoplasmdoes not appear to be increased postexposure in the surviving popu-lation (Text-figure 3), the relative frequency of carcinoma of thestomach is so pronounced in most age increments that a positiverelationship between the age at death and exposure status could beresponsible for the discrepancies noted in Text-figure 4. Therefore, the

I

6 ANDERSON ET AL

I

00

S0

E0

American Journalof Pathology

MALE

0-9 2K-29 40-49 D-69 -89 0-9 2D-29 40-49 GD-9 8-99

Age at death (yrs)TEXT-FIG 4-Cumulative mortality of persons with malignant neoplasms bv exposure

category as a function of decade of death.

attendant data are replotted in Text-figure 5 excluding the 359 examplesof this disease. It is evident that this maneuver does not abolish theeffect noted in Text-figure 4.Carcinoma of the thyroid is also relativelv frequent in Japan, particu-

larly among autopsy populations when specific surveillance mechanismsare instituted to document occult tumors as is the case at ABCC.

1I

4-

0

0b-

0E0

'AL,

rod

&---& <1 rod

0-9 2-29 4049 6D-69 60-0 0-9 2D-29 40-9 60-

Age at death (yrs)TEXT-FIG 5-Cumulative mortality of persons with malignant neoplasms excluding carci-

noma of stomach by exposure category as a function of decade of death.

| AA

A

d

I/S// fI

I-W--410.-'

Vol. 75, No. 1 AGE-SPECIFIC MORTALITY AND NEOPLASMS 7March 1974

.ff%,\ _ _ _

I-' 80

._

- 600

2 400

E= 20C,

FEMALE r

I7~~~~~~~~~~~~~~~~~~,1/0A

-/I I/

_X ''s 09 2-2 40-49 60_ s0-9

Age at death (yrs)TEXT-FIG 6-Cumulative mortalitv of persons with malignant neoplasms excluding car-

einoma of thyroid by exposure category as a function of decade of death.

Text-figure 6 depicts the data excluding the 536 examples of this entity.Again, the displacement under consideration persists.

Since the discrepancies in appearance time are most pronouncedin the vounger age categories, tumors peculiar to this period mightbe expected to be of particular importance in the genesis of thesedifferences. As shown in Text-figures 7 and 8, such is partially the case.Exclusion of leukemia markedly mutes the effect in autopsied males,although not in females, and exclusion of both leukemia and carcinoma

0-

4-

020

75EC-ca

0- @-01

A- - A

V- i-c "L-q t_vl 0L U-9 WZ9 'w_9 1s9 u-

Age atdeath(yrs)TEXT-FIG 7-Cumulative mortalitv of persons with malignant neoplasms excluding leu-

kemia bv exposure categorv as a function of decade of death.

MG %%-Om Aw%-Am Aw%Am M%.Mo

8 ANDERSON ET AL American Journalof Pathology

I f%eIvy

4-so

tb--600

p 40a

=f 200 2Ol

FEMA L

/.0o9 2 494 D-69 0-89 o_ _Ds 40 49 ao-"

Age at death (yrs)TEXT-FIG 8-Cumulative mortality of persons with malignant neoplasms excluding

leukemia and carcinoma of thyroid by exposure category as a function of decade of death.

of the thvroid virtually abolishes this response among the autopsiedmale although it persists in the female component.

DiscussionWhole body exposure of several types of rodents to moderate

amounts of ionizing radiation occasions a shortened survival in com-parison with their nonirradiated contemporaries. This response is dose-dependent and cannot be attributed to a specific cause. The exposedanimals appear to die at an earlier age from most of the same diseaseentities which affict their nonexposed counterparts. Such acceleratedor precocious aging, although generally accepted with respect toexperimental animals, has yet to be documented conclusivelv in man.Thus, to date, the only positive evidence relates to the radium dialpainters, the early American radiologists and possibly the exposedpopulations of Hiroshima and Nagasaki. The attendant data are dis-cussed in detail elsewhere.9 Two important studies relevant to theABCC experience may be summarized as follows:

1) NMortality ratios for survivors located within 1400 meters of thehypocenter at the time of the explosions were higher during 1950-60than the comparable figures for more distally located persons.10The excess in mortality was attributable to a variety of causes, wasparticularly pronounced during 1950 to 1952 and gradually becameless marked subsequent to that time. In addition, the average radia-tion dose estimates were significantly larger for those individuals

V-

Vol. 75, No. 1 AGE-SPECIFIC MORTALITY AND NEOPLASMS 9April 1974

who died of natural causes during this decade than for those whosurvived the interval.2) In a somewhat similar approach, Ciocco 11 subsequently focusedattention upon those individuals who were 45 years of age or olderat the time of the explosions as that portion of the Life Span StudySample subject to the greatest mortality risk as well as a groupwhich, at the time of the evaluation (1965), was rapidly approachingthe modal age of death. Ciocco documented similar differences inmortality which were particularly pronounced during 1950 to 1955and in the female segment of the population where they were sig-nificant at the 2% level.

The present study documents a displacement in the age-specificmortality curve to a younger age at death from malignant neoplasmsfor autopsied survivors exposed to an estimated dose in excess of99 rad. As in the two related ABCC studies summarized above, thiseffect is more pronounced among females. Of interest in this regard,female mice have been shown by several investigators to be moresusceptible than males to the life-shortening effects of radiation.'2 Inthis connection, however, it should be reemphasized that not all ob-servers accept age-specific mortality associated with neoplasia as aparameter of aging. Assuming for the moment, however, that a positivecorrelation does indeed exist, it is tempting to postulate that thesegment of the exposed population susceptible to the tumorigeniceffects of radiation is also particularly sensitive to the life-shorteningeffects. A possible common denominator between these two responsescould involve the defined mutagenic effect of ionizing radiation.Somatic mutation has been implicated in several of the currentlypopular theories of aging.2The mortality data of Jablon et al and Ciocco suggest an effect

which was most pronounced in the early 1950's. In contrast, the vastmajority of autopsies on members of the Life Span Study Samplehave been performed since the inauguration of the current PathologyStudy Program in 1961. Therefore, assuming a positive correlationbetween aging and the age-specific mortality of individuals with neo-plasms, and neglecting for the moment the observation that the autopsyseries does not identically reflect events which encompass the entireLife Span Study Sample (see below), accelerated or precocious agingamong individuals receiving the heaviest radiation would appear tocontinue through the 1960's and probably to date. In fact, the unusualprevalence of a variety of neoplasms among children who were less

10 ANDERSON ET AL American Journalof Pathology

than 10 years of age when thev wvere exposed to 100 rad or more, aphenomenon which has vet to reach a peak,4 suggests that an accentua-tion of the accelerated aging demonstrated herein will become evidentduring the next several years.As emphasized previously, several important discrepancies distinguish

members of the Life Span Study Sample who are autopsied vs. thosewho are not: the very young and the xery old are underrepresentedin the postmortem group as are individuals who succumb attendantto trauma; on the other hand, persons with suspected malignancies,particularly leukemia and related disorders, appear to be overrepre-sented. Presumably such bias dces not influence the differences betweenexposure groups described herein but still should serve to exert ameasure of caution when extrapolating from the autopsy segment ofthe Life Span Studv Sample to all deceased members of this popu-lation. WN'hy not employ the latter group for the present studv? Herethe problem of bias is more marked in that the degree of correlationbetween the death certificate diagnosis and the postmortem findingsvaries considerably according to the malignancy in question.

Also of importance in the present context is the study of Johnsonet al 13 which included an evaluation of skin tumors among a sub-population of the Life Span Studv Sample. This subpopulation isknown as the Adult Health Study Sample and is examined at 2-yearintervals for clinical abnormalities. In an evaluation of 12,007 persons,Johnson et al documented an increased prevalence of select benignskin tumors among proximally exposed persons in comparison with theirmore distally located counterparts and also noted an earlier averageappearance time of such lesions in the former group.'3 This studv,among a more representative subset of the Life Span Study Sample,thus appears to support the observations reported herein.

As implied above, vounger individuals have been noted to be par-ticularly sensitive to the tumorigenic effects of radiation in severalABCC studies. In this connection, displacement of life span followinga constant amount of radiation in the experimental situlation is gen-erally inversely proportional to the age at exposure.'2 Therefore, it isof interest in the present study to note that the most marked changesin the mortality% data are associated with the younger age groups.

References1. Jones HB: Handbook of Aging and the Individual. Edited by- JE Birren.

Chicago, University of Chicago Press, 1959, p. 3362. Walford RL: The Immunologic Theory of Aging. Baltimore, WVilliams and

*Wilkins Company, 1969, pp 198-204

Vol. 75, No. 1 AGE-SPECIFIC MORTALITY AND NEOPLASMS 11April 1974

3. Upton AC, Kimball AV, Furth J, Chrinstenberrv KW, Benedict WVA: Somedelaved effects of atom-bomb radiations in mice. Cancer Res 20:1-60, 1960

4. Jablon S, Belsk-y JL, Tachikawa K, Steer A: Cancer in Japanese exposed aschildren to atomic bombs. Lancet 1:927-932, 1971

5. Jablon S, Kato H: Studies of the mortality of atomic bomb survivors. V.Radiation dose and mortality, 1950-1970, Atomic Bomb Casualty CommissionTechnical Report. Radiat Res 50:649-698, 1972

6. Beebe GWX, Ishida M, Jablon S: Studies of the mortality of A-bomb survivors.I. Plan of study and mortalitv in the medical subsample (selection I), 1950-1958. Radiat Res 16:253-280, 1962

7. Beebe GXV, Kato H, Land CE: Studies of the mortality of A-bomb survivors.IV. Mortality and radiation dose, 1950-1966. Radiat Res 48:613-649, 1971

8. Beebe GCV, Yamamoto T, Miatsumoto YS, Gould SE: AACC-JNIH pathologystudies, Hiroshima-Nagasaki. Report 2, October 1950-December 1965. AtomicBomb Casualty Commission Technical Report 8-65, Hiroshima, AtomicBomb Casualty Commission, 1965

9. Anderson RE: Longevity in irradiated human populations with particularreference to the atomic bomb survivors. Am J Med 55:643-656, 1973

10. Jablon S, Ishida MI, Yamasaki 'M: JNIH-ABCC life span studv, Hiroshimaand Nagasaki, Report 3. Mortality, October 1950-September 1960. AtomicBomb Casualty Commission Technical Report 15-63, Hiroshima, AtomicBomb Casualtv Commission, 1963

11. Ciocco A: Mortality 1950-64 and disease and survivorship 1958-64 amongsample members aged 50 years or older 1 October, 1950. Atomic Bomb Casu-altv Commission Technical Report 18-65, Hiroshima, Atomic Bomb CasualtyCommission, 1965

12. Van Cleave CD: Late somatic effects of ionizing radiation, USAEC Divisionof Technical Information Report TID-24310, Oak Ridge, Tenn, US AtomicEnergy Commission, 1968, pp 29-57

13. Johnson MILT, Gregory PB, Taura T, Milton RC, Land CE: Effects of ioniz-ing radiation on the sin. Atomic Bomb Casualty Commission Technical Re-port 20-69, Hiroshima Bomb Casualty Commisssion, 1969

12 ANDERSON ET AL American Journalof Pathology

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