Radiation effects on cancer risks in atomic bomb survivors

Chelyabinsk October 2, 2012

Dale L. PrestonHirosoft International

Eureka, CA

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OutlineOutline

• Historical background of atomic bomb survivor studies background

• Outline of major survivor cohorts• Dosimetry• Solid cancer risk estimates• Leukemia risk estimates• (Informal) comparison of survivor and Techa River cohort

risks

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A-bomb Survivor StudiesA-bomb Survivor StudiesAtomicAtomicbombingsbombings

NationalNationalCensusCensus

CohortsCohortsEstablishedEstablished

TumorTumor RegistriesRegistries

1945 1947 1950 1955 1958 1968 1975 1987 1995 20041945 1947 1950 1955 1958 1968 1975 1987 1995 2004

ABCCABCC StudiesStudies

Cancer Incidence Study (LSS)Cancer Incidence Study (LSS)

Clinical Study (AHS)Clinical Study (AHS)

MortalityMortality StudyStudy (LSS)(LSS)

FrancisFrancisComm.Comm.

T65DT65D

RERFRERFcreatedcreated

DS86DS86

BlueBlue RibbonRibbon CommComm..

F1 Mortality StudyF1 Mortality Study

DS02DS02

F1 ClinicalF1 ClinicalStudy (FOCS)Study (FOCS)

JointJointCommComm.

4

Early StudiesEarly Studies

• Genetic effects (malformations, premature birth, sex-ratio)

– 72,000 registered pregnancies 1948 -1953

– No apparent radiation effects

• Leukemia– Initial reports from Japanese physicians in late 1940’s

– First published report in 1952

– Initial crude risk estimates in 1956 (not from ABCC)

• Solid Cancer– First studies in late 1950’s and early 1960’s– Some indication of effects

• Hampered by crude dose estimates and limitations of statistical methods

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Saving the Survivor StudiesSaving the Survivor Studies

• Calls for end to ABCC studies in early 1950’s– Major genetic studies were completed with

no compelling evidence of hereditary effects– Leukemia excess risk appeared to be declining– Studies being carried out in ad-hoc manner– Costs for program rising– Staff morale low

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Saving the Survivor StudiesSaving the Survivor Studies

• US National Academies of Science organized committee to assess what should be done about ABCC research

• Recommendations– Reorganized program should continue– Unified study plan

• Focus on fixed cohorts of survivors and their children with internalcomparison groups

• Mortality follow-up

• Pathology (autopsy) program

• Clinical studies

• Highlighted need for dose estimates

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ABCC/RERF CohortsABCC/RERF CohortsLife Span Study (LSS)Life Span Study (LSS)

A-bomb SurvivorsA-bomb Survivors284,000284,000

Master SampleMaster Sample195195,,000000

Life Span StudyLife Span Study121,320121,320

19501950CensusCensus

1958-1958-

1958-1958-Adult Health StudyAdult Health Study22,00022,000

Original LSS includes groups of non-military Japanese for whom follow-up data could readily be obtained:

1) All survivors' < 2 km with acute effects

2) Matched group of other survivors < 2 km

3) Matched group of people who were 2.5-10km

4) Matched group of unexposed (not-in-city) individuals

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ABCC/RERF - F1 study cohortsABCC/RERF - F1 study cohorts

F1 MortalityF1 Mortality80,00080,000

Untoward pregnancy Untoward pregnancy outcomesoutcomes

77,00077,000

Biochemical Biochemical Genetic studiesGenetic studies

28,00028,000

FOCSFOCS25,000 selected,25,000 selected, 12,000 examined12,000 examined

Born between Born between May 1946 and May 1946 and December 1984December 1984

BornBorn between between 1947 and 19531947 and 1953

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ABCC-RERF cohortsABCC-RERF cohortsIn-utero cohortIn-utero cohort

Pooled IU cohort3,638 people

• Pooled cohort combines overlapping clinical (1,606 members) and mortality (2,802 members) cohorts.

• Mortality and cancer incidence data are available for all members of the cohort.

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ABCC/RERF Follow-up ProgramsABCC/RERF Follow-up Programs

• Mortality– Based on mandatory nation-wide family registration – Updated on a three-year cycle

• Cancer incidence – Hiroshima & Nagasaki tumor registries (1958 – present)– ABCC pathology program 1958 – 1972– Hiroshima & Nagasaki tissue registries 1973 - present

• Leukemia and related disorders– Leukemia registry 1950 – 1987– Hiroshima & Nagasaki Tumor Registries 1958 – present

• Clinical Examinations– Biennial exams– 70-80% participation through 25 AHS exam cycles– Adapted for use in F1 clinical study (FOCS)

• Mail Surveys– 1965 (Ni-hon-san study men), 1968 (women), 1978, 1991, 201?

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DosimetryDosimetry

• Location– Specified as coordinates on fairly crude US army maps

• Sought corroboration of location

• Recorded to nearest 10m in each coordinate if detailed shielding history obtained and nearest 100m for others

• External Shielding– Crude shielding category information available on virtually all

people of interest– Detailed shielding histories for most survivors within 1.6km in

Hiroshima and 2 km in Nagasaki

• Self shielding (organ dose)– Available for survivors with detailed shielding histories

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Evolving DosimetryEvolving Dosimetry

• Distance and occurrence of acute effects • “Air dose” curves with crude shielding

adjustments (T57D)• Gamma and neutron air kerma equations with external

shielding models (T65D)– Based on weapons tests with limited validation from

measurements (TLD and Co60 activation)

• Monte-Carlo transport codes for transport and shielding including organ doses (DS86)– More physical measurements

• Updated transport and shielding models (DS02)– Extensive validation efforts especially for neutrons

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HypocenterDose (mSv)

● 　 < 5 ● 　 5 – 100 ● 　 100 – 200 ● 　 200 - 500

● 　 500 – 1000 ● 　 1000 + ▲ 　 unknown * LSS: Life Span Study Cohort

LSS Survivors within 3 KmLSS Survivors within 3 Km

Hiroshima 　 Nagasaki

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Describing Excess RisksDescribing Excess Risks

Baseline (zero dose) risk function a age at risk; s gender; and b birth cohort

Dose-response shape , e.g. linear, linear-quadratic, threshold, …

Effect modification function e age at exposure

( )d

( , , )a s b

( , , )s e a

Excess relative risk (ERR) model

Excess absolute rate (EAR) model

( , , )[1 ( ) ( , , )]o Ra s b d s e a

( , , ) ( ) ( , , )o Aa s b d s e a

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LSS Solid Cancer IncidenceLSS Solid Cancer Incidence1958-941958-94

By age at exposure

Age at exposure

People Person years CasesEstimated

Excess AR%*

0-19 21,571 632,341 2,409 150 13%20-39 8,522 229,518 2,569 86 8%40+ 12,809 178,419 2,991 61 5%

Total 42,902 1,040,278 7,969 297 9%

0-19 24,169 755,387 2,186 240 24%20-39 21,561 679,452 4,423 233 11%40+ 16,795 289,614 2,870 83 6%

Total 62,525 1,724,453 9,479 556 13%Total 105,427 2,764,731 17,448 853 11%

By colon doseColon Dose

People Person years CasesEstimated

ExcessAR%

< 0.005 60,792 1,598,944 9,597 3 0% - 0.1 27,789 729,603 4,406 81 2% - 0.2 5,527 145,925 968 75 8% - 0.5 5,935 153,886 1,144 179 16% - 1 3,173 81,251 688 206 30% - 2 1,647 41,412 460 196 43%2+ 564 13,711 185 111 60%

Total 105,427 2,764,732 17,448 853 11%*

Male

Female

• Information on gender and age-time patterns depends (only) on radiation-associated (“excess”) cases

• Excess cases not explicitly identified

• Number of relevant cases is relatively small, especially for specific sites

* Attributable risk % for people with doses > 0.005 Gy

LSS Solid Cancer IncidenceLSS Solid Cancer IncidenceDose ResponseDose Response

• Linear ERR/Gy0 – 2 Gy 0.49

• No evidence of non-linearity (LQ model on 0 – 2 Gy) P > 0.5

• Curvature 0.12LSS-LDEF 1.14

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Using RERF public dataset lssinc07.csv (www.rerf.or.jp)

Proximal zero dose baseline (adjusted for distal and NIC)

0

.5

1

1.5

exce

ss r

ela

tive

risk

0 1 2 3weighted colon dose (Gy)

Solid Cancer Incidence Dose Response

LSS Solid Cancer IncidenceLSS Solid Cancer IncidenceDose Response 0 – 0.5 GyDose Response 0 – 0.5 Gy

• Linear ERR/Gy0 – 2 Gy 0.490 – 0.1 Gy 0.510 – 0.15 Gy 0.51

• Test for trend0 – 0.1 Gy P = 0.080 – 0.15 Gy P = 0.01

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Using RERF public dataset lssinc07.csv (www.rerf.or.jp)

Proximal zero dose baseline (adjusted for distal and NIC)

0

.05

.1

.15

.2

.25

exce

ss r

ela

tive

risk

0 .1 .2 .3 .4 .5weighted colon dose (Gy)

Solid Cancer Incidence Dose Response

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LSS Solid Cancer LSS Solid Cancer Excess Relative Risk Temporal PatternsExcess Relative Risk Temporal Patterns

Age at exposure

-29% per decade(90% CI -39%; -18%)

Attained age

Age-0.9

(90% CI -1.5; -0.2)

Gender *

M: 0.29 (90% CI 0.21; 0.39)

F: 0.58 (90% CI 0.42; 0.68)

F:M: 1.9 (90% CI 1.4; 2.7)

* ERR per Sv at age 70 following exposure at age 30

0 - 9

10 - 19

20 - 39

40+0

1

2

3

4

ER

R p

er S

V

20 40 60 80Age at diagnosis

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LSS Solid Cancer LSS Solid Cancer Excess Rate Temporal PatternsExcess Rate Temporal Patterns

Age at exposure

-20% per decade(90% CI -30%; -10%)

Attained age

Age3.5

(90% CI 2.9; 4.1)

Gender *

M: 26 (90% CI 18; 34)

F: 28 (90% CI 23; 34)

F:M: 1.1 (90% CI 0.8; 1.6)

* Excess cases per 10000 PY at age 70 following exposure at age 30

0 - 9

10 - 19

20 - 39

40+

0

10

20

30

40

50

exce

ss c

ase

s pe

r 10

,00

0 P

YS

v

20 40 60 80Age at diagnosis

Leukemia Incidence Leukemia Incidence 1950-20011950-2001

• CLL is much less common in Japan than in Russia (or other countries)

• ATL cases mostly in Nagasaki with no indication of a dose response

Leukemia other than CLL or ATL 312

Acute myeloid (AML) ‡ 176

Chronic myeloid (CML) 75

Acute lymphoblastic (ALL) § 43

Other 18

Chronic lymphocytic (CLL) †† 12

Adult T-cell (ATL) 47

Any leukemia 371

Type of Leukemia Eligible

LSS Leukemia IncidenceLSS Leukemia Incidence

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• Almost half of cases among exposed associated with exposure

Person Observed

years cases Background Excess

< 0.005 2,039,093 0.0006 120 116.9 0.1

-0.1 957,889 0.03 63 60.7 3.6

-0.2 201,935 0.14 16 13.7 4.1

-0.5 206,749 0.32 25 13.6 11.1

-1 117,855 0.71 24 7.5 18.2

-2 64,122 1.37 35 4 28.4

2+ 25,761 2.68 29 1.5 28.6

Total 3,613,404 0.1 312 217.9 94.1

Dose (Gy)

Mean dose (Gy)

Fitted cases

Leukemia IncidenceLeukemia Incidence

• Significant non-linearity in dose response• Low dose risks about half of linear model estimates

22

0

2

4

6

8

10

exce

ss r

elat

ive

ris

k

0 1 2 3weighted dose (Gy)

Leukemia IncidenceLeukemia IncidenceTemporal PatternsTemporal Patterns

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10

50

30

0

2

4

6

8

exce

ss r

elat

ive

risk

20 40 60 80attained age

ERR

any age at exposure0-19 20 -39

40+

0

1

2

3

4

exce

ss c

ases

per

10,

000P

Y

20 40 60 80attained age

EAR

• ERR model with age and age at exposure dependence describes data as well as EAR model

• EAR model with only attained age effect fits better than age at exposure and time since exposure model from 1994 (gray curves)

Informal Comparison of LSS and Informal Comparison of LSS and Techa River RisksTecha River Risks

• Solid cancer– ERR risk estimates similar around age 60– Temporal patterns not significant in TRC but estimates exhibit

somewhat different patterns than in LSS (increasing with attained age or age at exposure)

– TRC has very limited power to detect effect modifications

• Leukemia– ERR risk estimates for non-CLL similar with similar temporal

patterns

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Summary and ConclusionsSummary and Conclusions

• Accumulating data and modern analytical methods make it possible to investigate radiation effect modification in some detail

• Data are limited even in the largest cohort– Especially true when examining a site-specific risks and modeling interactions

• Both ERR and EAR descriptions provide equally important and complementary information – Attained age is an important factor in both

– Generalization of age at exposure and gender effects can be difficult

• Pooled analyses may be useful in looking at effect modification– But LSS results may dominate such comparisons

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AcknowledgmentsAcknowledgments

• We stand on the shoulders of giantsGil Beebe, Seymour Jablon, Jim Neel, Jack Schull

• ABCC/RERF scientists and staff who made the ideas a realityGeorge Darling, Howard Hamilton, Tetsuo Imada, Hiroo Kato, M. Kanemitsu, Bob Miller, Kenji Omae, Itsuzo Shigematsu and hundreds more

• Collaborators Japan

Akio Awa, Harry Cullings, Saeko Fujiwara, Shochiro Fujita, Sachiyo Funamoto, Kyoji Furukawa, Kazunori Kodama, Charles Land, Kiyo Mabuchi, Nori Nakamura, Don Pierce, Elaine Ron, Yukiko Shimizu, Michiko Yamada

URCRM / NCI / JCCRER

Lyudimila Krestinina, Marina Degteva, Alexander Akleyev, Sara Schonfeld, Elaine Ron, Faye Davis