1. Donald A. Pierce Radiation 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/

2. 2

3. 3 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)

4. 4 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

5. 5 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

6. 6 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)

7. 7 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.

8. 8 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

9. 9 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

10. 10 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

11. 11 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

12. 12 General Summary (CA incidence) Dose GyMean Distance Persons Followed CA Cases 1958-98 Est Excess Cases < 0.005368060,8009,6003.005 – 0.1199027,8004,40080 0.1 – 0.216305,50097075 0.2 – 0.515005,9001,100180 0.5 – 112803,170690210 1 – 211101,650460200 >2900564185110 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)

13. 13 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

14. 14 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

15. 15 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

16. 16 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

17. 17 This is excess RR, averaged over sex and at attained age 70

18. 18 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

19. 19 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

20. 20 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

21. 21 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

22. 22 Noncancer disease mortality dose response ERR about 10% of that for cancer Could be no effect for about < 0.30 Gy

23. 23 For major disease types

24. 24 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

25. 25 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, 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.