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Radiation-related cancer incidence and non-cancer mortality among A-bomb survivors Donald A. Pierce Radiation Effects Research Foundation, Hiroshima (retired) These slides, other things, at: http://www.science.oregonstate.edu/~piercedo/ 2 • 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) 3 • 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 4 • 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 5 • 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) 6 • 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. 7 • 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 8 • 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 9 • 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 10 • 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 11 General Summary (CA incidence) Dose Gy Mean Distance Persons Followed CA Cases 1958-98 Est Excess Cases < 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 44,584 7,805 855 Tot excl < .0005 row 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) 12 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 13 • 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 14 • 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 15 • 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 16 This is excess RR, averaged over sex and at attained age 70 17 • 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 18 • 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 ERR / 100mSv (Sex avg) ERR / 100 mSv (Sex avg) Agex 5 30% Agex 15 Agex 5 30% Agex 15 Agex 30 20% Agex 55 Agex 30 20% Agex 55 10% 10% 0% 0% 35 45 55 65 Age (at risk) 75 85 35 45 55 65 75 85 Age (at risk) 19 • 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 20 • 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 21 Noncancer disease mortality dose response ERR about 10% of that for cancer Could be no effect for about < 0.30 Gy 22 For major disease types 23 • 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 24 SOME REFERENCES Preston, 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, 231248. 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 25 survivors: 1958 – 1998.