Donald A. Pierce

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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/
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(No Transcript)
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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 RRs 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 MeanDistance PersonsFollowed CA Cases1958-98 Est ExcessCases
lt 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
gt2 900 564 185 110
Tot excl lt .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 (1.51) 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 ones 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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• 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 response ERR
about 10 of that for cancer Could be no effect
for about lt 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 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.