Donald A. PierceRadiation Effects Research Foundation,

Hiroshima (retired)

Radiation-related cancer incidence and non-cancer mortality among

A-bomb survivors

These slides, other things, at: http://www.science.oregonstate.edu/~piercedo/

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• Virtually all quantitative information about effect on humans of modest radiation exposure comes from this study

• Most other information from high-dose radiotherapy, or low-dose exposures where dose is much more uncertain

• Due to nature of study, possible to estimate (excess) relative risks as small as 10%. (i.e. relative risks 1.1)

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• There was negligible fallout or creation of long-lived radioisotopes in soil, food, water, etc.

• Radiation dose was mainly that directly and immediately emanating from the bombs

• The primary limitation of the study is that it pertains directly only to such “acute” radiation exposures

• Prolonged low-dose exposures may have different (lesser) effects

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• Bombs August 1945, “Joint Commission” of Occupation, October 1945

• Pres. Truman directive to National Acad. Sciences 1946, Atomic Bomb Casualty Commission (ABCC)

• Motivations: leukemia, cancer, acute effects, inherited effects, others

• By 1950 Depts of Genetics, OBGYN, PEDS, Internal Med, Radiology, Pathology, Biochem/Micro, Biometrics

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• Large-scale clinical and pathology programs: examinations and autopsies

• Enormous efforts interviewing survivors within 2 km for “shielding histories”

• More than 1500 employees at peak, now about 250 with 40 scientists

• Became bi-national Radiation Effects Research Foundation (RERF) 1975

• Americans: Around 10-15 recently, with far more at peak (largely physicians – military and jointly with Yale)

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• External advisory committee 1955 had profound effect establishing sound epidemiological study

• Fixed study cohort of around 100,000 survivors with no later addition of “cases only”, etc.

• Includes most survivors within 2 km that were “followable” (perhaps about half)

• About half of cohort unexposed (sample from 3-10 km). Comparisons are all within cohort.

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• This refers to the “survivor” cohort considered in this talk

• Also F1 (75,000) and In-utero (3,500) cohorts

• Virtually no demonstrable effects in the F1 cohort (birth defects, later ailments) – major finding in some respects

• In-utero study shows cancer effects similar to survivors, and also special effects such as mental retardation and small stature

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• Individual survivor dose estimates for those within 2 km

• Based on detailed interview information regarding location and shielding, along with elaborate radiation ‘transport’ calculations by physicists

• Considerable “random” estimation errors, and possibly a few more systematic ones

• Most recent large-scale efforts on the dosimetry calculations in 1998-2003

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• Possibilities richer than most epi studies, due to size of study and small chance of confounding (can estimate RR’s of 1.1)

• Largely because the dose-distance gradient was very steep, so those with large and small doses differ little otherwise

• Also, the participation and follow-up rates were essentially 100%

• Though there is clinical follow-up, that for results here is from death certificates and tumor registries

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• To proceed, we need some perspective on radiation dose Gray (about 100 roentgen)

• 1 Gy to major organs causes serious illness, although seldom fatal

• A CT scan, although usually localized, is about 0.01 Gy

• Occupational limits are about 0.02 Gy/yr, although cumulatively further limited

• Thus 0.10 Gy is a fairly large dose of considerable interest

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General Summary (CA incidence)Dose Gy Mean

DistancePersonsFollowed

CA Cases1958-98

Est ExcessCases

< 0.005 3680 60,800 9,600 3

.005 – 0.1 1990 27,800 4,400 80

0.1 – 0.2 1630 5,500 970 75

0.2 – 0.5 1500 5,900 1,100 180

0.5 – 1 1280 3,170 690 210

1 – 2 1110 1,650 460 200

>2 900 564 185 110

Tot excl < .0005 row 44,584 7,805 855

Estimated excess through 1994 was 723, so the excess in recent years for this cohort appears to be about 35 cases/year (I would roughly estimate less than 100/year for all survivors)

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Solid Cancer Excess: Sex Averaged (1.5:1)

ERR/Gy is factor increasing baseline rates:

e.g. at 0.1 Gy and age 65, rates are increased by about 5%

EAR/Gy is excess absolute rate

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• I suggest it is best not think of some specific cancer cases as “caused” by the radiation exposure

• Fairly well-accepted model: A cancer arises when enough somatic mutations accumulate in a stem cell (and its descendants)

• Effect of a specific radiation exposure is to cause one (or more) of these mutations

• The data strongly support such a model

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• An affected cell is “a step ahead” of where it would have been --- for all of life

• Effect of A-bomb radiation is essentially to “increase one’s cancer age”, by about 5 yrs/Gy --- causing about as many mutations as would otherwise occur in that time

• But as life goes on, a single “extra” mutation becomes a smaller portion of the somatic ones --- thus the RR decreases with age

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• Note that variations with exposure age are far more important on the EAR scale, than on the ERR

• Surely has something to do with birth cohort increases in most cancer rates

• Although complicated, this suggests that most of any “exposure-age effect” is not really a “radiation” one, but reflects variation of baseline rates with birth cohort

• Same issue arises, more simply, regarding sex effects

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This is excess RR, averaged over sex and at attained age 70

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• Why such long follow-up, and such penetrating analysis, is needed

• Lifelong effect for cancer was (in my view) not expected

• Effect of exposure age is important, those exposed as children are alive and entering ‘cancer age’

• Statistical methods considerably developed in past 15 years

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ERR / 100 mSv (Sex avg)

0%

10%

20%

30%

35 45 55 65 75 85

Age (at risk)

Agex 5

Agex 15

Agex 30

Agex 55

ERR / 100mSv (Sex avg)

0%

10%

20%

30%

35 45 55 65 75 85

Age (at risk)

Agex 5

Agex 15

Agex 30

Agex 55

• The left panel here shows the view of things until the late 1990s (still widely held) and the right panel shows our current understanding of the same data

• What was thought an effect of exposure age was largely the decline in RR with attained age

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• On another issue, some would like to believe that for small radiation doses, e.g. 0.05 Gy, there is no cancer risk at all

• But careful analysis based on the 30,000 survivors in the low-dose range shows that this is implausible

• Major statistical efforts also have clarified the (modest) effect of random errors in dose estimates

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• Less explicable effect on non-cancer mortality, much smaller ERR

• Seen for most of the major causes of death

• That is grounds for suspicion, but effects seem unlikely to be due to confounding

• Possible that this is only for large doses, due to killing large proportions of marrow cells, with permanent immunological effects

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Noncancer disease mortality dose responseERR about 10% of that for cancerCould be no effect for about < 0.30 Gy

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For major disease types

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• Much attention has been given to whether this might be some kind of confounding

• Seems unlikely

• Smoking, Soc-Econ information available from mail surveys --- adjusting for these has little effect

• There is a statistically significant effect when restricting to 900 – 1200 m from bombs

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SOME REFERENCESPreston, D.L., Shimizu, Y., Pierce, D.A., Suyama, A. and Mabuchi, K. (2003b). Studies of mortality of atomic bomb survivors, Report 13: Solid cancer and noncancer mortality 1950 –1997. Radiation Research 160, 381-407.Pierce, D.A. and Vaeth, M (2003e). Age-time patterns of cancer to be anticipated from exposure to general mutagens. Biostatistics 4, 231-248.Pierce, D.A. (2002). Age-time patterns of radiogenic cancer risk: their nature and likely explanations. Journal of Radiological Protection 22, A147-A154.Pierce, D.A., Stram, D.O., Vaeth, M., and Schafer, D.W. (1992b). The errors-in-variables problem: considerations provided by radiation dose-response analyses of the A-bomb survivor data. J. Amer. Statist. Assn. 87, 351-359.Pierce, D.A. and Preston, D.L. (2000a). Radiation-related cancer risks at low doses among atomic bomb survivors. Radiation Research 154, 178-186. Preston, D.L. et al (2007). Solid cancer incidence in Atomic bomb survivors: 1958 – 1998.