Transcript A-Bomb Survivors Talk: OHSU Anesthesiology 2011

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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• 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
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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
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
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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)
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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
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
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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
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
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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
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)
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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
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
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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, 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
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survivors: 1958 – 1998.