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Effects of low doses of radiation
New epidem iolog ic a l dat a
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Radiation Protection Conference, Berlin, J une 2007
Radiation Protection Today
Bases of radiation protection
Estimates of radiation induced cancer risk from:atomic bomb survivors
patients irradiated for therapeutic purposes
populations with occupational exposures (miners)animal experiments
mechanistic studies
Extrapolation models:high doses to low doseshigh dose-rates to low dose-rates
over time, across countries, ....
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Possible extrapolations of radiation-induced cancer risk to low doses
Dose
Radiatio
n-relatedcancer
risk
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Based on a comprehensive review of theliterature, the committee concluded that the riskwould continue in a linear fashion at lower doseswithout a threshold and that the smallest dosehas the potential to cause a small increase in riskto humans.
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BEIR VII reviewed dose responses
for low doses and dose-rates
Radiobiological data:Linear-quadratic dose-response over the range
0-2 Gy with upward curvature
A-bomb survivor solid cancer incidencedata:Well described by linear modelCompatible with small amount of curvature
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Atomic bomb survivors - LSS solidcancer incidence: Excess relative risk
BEIR VII,
Fig. ES-1
Radiation Dose (Sv)
ExcessRelativeRis
kofSolidCancer
0.0 0.5 1.0 1.5 2.0
0.0
0.5
1.0
1.5
LowD
oseRange
Linear fit, 0 - 1.5 SvLinear-quadratic fit, 0 - 1.5 Sv
0.0 0.5 1.0 1.5 2.0
0
1
2
3
4
5
6
Leukemia
(for comparison)
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Use of model to estimate risk atlow doses and dose rates
If true response is linear-quadratic, linear estimatesneed to be reduced
Factor used for this is theDose and Dose Rate Effectiveness Factor (DDREF)
Many past risk assessment - DDREF = 2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
0 1 Gy 2 Gy 3 Gy
E
RR
True respon se
Linear approximation
Low-dose response
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BEIR VII DDREF
Derived from Bayesian analyses of
Data from relevant studies in mice
A-bomb survivor solid cancer incidence data
in range 0-1.5 Gy
Estimate with 95% interval: 1.5 (1.1 2.3)
Referred to as LSS DDREF not a universal low-dose correction factor
LSS = Life Span Study of A-bomb survivors
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Direct epidemiological evidence
- Requirements -
Study population
Very large Well-defined No selection bias
Follow-up / Case &control ascertainment Complete, non-differentialAccurate diagnosis
Dose-estimates Individual
Accurate and precise
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Nuclear industry workers
Characteristics
Very large, stable populationsWell characterized exposuresGenerally low doses, protracted
Mainly external radiation
Detailed individual annual dose estimates -measured in real time with personal dosimeters
Relevant population for radiation protection
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15-Country study of cancer risk among
radiation workers in the nuclear industry
Objective
direct estimation of the effect of low dose, protractedexposures to external-photon radiation
Approach International Collaborative study Retrospective cohort study
Much effort to assess and ensure comparabilityCommon core protocolStudies of errors in doses
IRE, Japan
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Participating cohorts
All
causes
All
cancer
Australia 877 12,110 56 20 6.1 5.4
Belgium 5,037 77,246 322 90 26.6 134.2Canada 38,736 473,880 1,204 417 19.5 754.3
Finland 6,782 90,517 317 34 7.9 53.2
France CEA-COGEMA 14,796 224,370 645 229 3.8 55.6
France EDF 21,510 241,391 371 119 15.8 340.2
Hungary 3,322 40,557 104 40 5.1 17.0
J apan 83,740 385,521 1,091 432 18.2 1526.7Korea (south) 7,892 36,227 58 21 15.5 122.3
Lithuania 4,429 38,458 102 25 40.7 180.2
Slovak Republic 1,590 15,997 35 10 18.8 29.9
Spain 3,633 46,358 68 25 25.5 92.7
Sweden 16,347 220,501 669 194 17.9 291.8Switzerland 1,785 22,051 66 24 62.3 111.2
UK 87,322 1,370,101 7,983 2,273 20.7 1810.1
US Hanford 29,332 678,833 5,564 1,331 23.7 695.4
US NPP 49,346 576,682 983 340 27.1 1336.0
US INEEL 25,570 505,236 3,491 924 10.0 254.6
US ORNL 5,345 136,673 1,029 246 15.2 81.1TOTAL 407,391 5,192,710 24,158 6,794 19.4 7891.9
Main studypopulation
Collectivecumulative
dose (Sv)
Averageindividual
cumulative
dose (mSv)
Number ofdeaths
Personyears
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Distribution of cumulative doses
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Results comparison with study
of atomic bomb survivors
15-Country Study Atomic bomb survivors
men exposed 20-60
N ERR/Sv (95% CI) N ERR/Sv (95% CI)
All cancers excluding
leukemia
5 024 0.97 (0.14-1.97)
Solid cancers 4 770 0.87 (0.03-1.88) 3 259 0.32a (0.01, 0.50)
Leukemia excluding CLLLinear model 196 1.93 (
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Discussion - all cancers
excluding leukemia
Analyses of smoking and non-smoking causes of
death indicate Significant association with lung cancer Non-significant increased risks for non-malignant respiratory
diseases
Smoking likely to be a confounder
Smoking related cancers other than lung: lower risks Risk estimates for different groupings 2-3 time higher than
A-bomb estimates
Smoking unlikely to explain all of the risk
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ERR per Sv for all cancers excluding leukemia
analyses restricted to different dose levels
N ERR/ Sv 90% CI
All doses 5,024 0.97 0.27 1.80
Cumulative doses
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ERR by dose category
-1
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
0 100 200 300 400 500 600
Rad ia tion Do se (m Sv)
ER
R(
baseline: 50 years
Protracted exposureExternal and internal radiation
Populations with different ethnicbackgrounds
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Extended Techa River Cohort
TRDS-2000 Dose Estimates
0
500
1000
1500
2000
min median mean max
Dose,m
Gy
stomach low large intestine red bone marrow
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Extended Techa River Cohort
Solid Cancer Risk Estimates
Observed 1,842
Expected 1,796Excess 46 (2.5%)
Effect modification
Attained age P=0.03Ethnicity P=0.052Age at entry P=0.08
0.0 0.2 0.4
0.0
0.2
0.4
0.6
ETRC Solid Cancer Dose Response
Linear-Quadratic
Linear
ERR
Stomach Dose (Gy)
ERR/Gy 0.92 (95% CI 0.2; 1.7)
Techa River Dosimetry System 2000
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Leukemia Risk Estimates
excluding CLL
0.0 0.5 1.0
0
2
4
6
8
10
ETRC Leukemia Dose Response
Linear-Quadratic
Linear
ERR
Marrow Dose (Gy)
ERR/Gy 4.6 (95% CI 1.7, 12.3)
Techa River Dosimetry System 1996
Nested case-control study 60 cases, 300 controls
Evaluation of role of potentialconfounding factors
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Concerns with
Techa river dosimetry
Are estimated doses too low?Sr-90, Cs-137 okRole of short lived isotopes in internal and
external dose under reviewNo systematic monitoring before J uly 1951
Uncertainties in amount of activity released and
radionuclide composition
Balonov et al, 2005
Degteva et al, 2006
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Conclusion low dose
protracted exposure studies
Both studies however suggest existence of asmall risk at low doses
Risk estimates higher than linear extrapolations froma-bomb survivors
Both studies have limitations15-country study: exact magnitude of smoking
confounding not clear
Techa river: uncertainties/errors in dose estimates
Risk estimates statistically compatible withextrapolations from a-bomb survivors
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Effects of age and gender
Difficult to evaluate from these studies
Nuclear workers mainly men, exposed as adults Techa river no clear evidence of age at exposureeffect
But evidence from other populations thatchildren are more susceptibleAtomic bomb survivors
Thyroid cancer after exposure to I-131 from Chernobyl Medically irradiated populations In utero exposure at 6-10 mGy increased childhood
cancer risk
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Gene-radiationinteractions ?
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Gene-radiationinteractions ?
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Gene-radiationinteractions ?
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Gene-radiationinteractions ?
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Gene-radiationinteractions ?
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Conclusions
Careful studies of populations withlow-dose protracted exposuresSuggest that such exposures cause a small
increase in the risk of cancer Increase is statistically compatible with
extrapolations from a-bomb data
Exact magnitude of ERR/Gy cannot bedetermined at present
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Conclusions
DDREF
Premature to estimate it based on lowdose protracted exposure studies
BEIR VII Based on a-bomb data below 1.5 Gy, inconjunction with animal data
1.5, uncertainty interval 1.1-2.3
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Conclusions
But what about even lower doses ?
Arguments suggesting risk even at very low doses Increased risk of childhood cancer following in utero
exposures to 6-10 mGy (1 photon/cell on average)
Biophysical argument:9 If dose is decreased, this will result in fewer electron
tracks and proportionately fewer hit cells.
9 Those cells that are hit will be subject to the same
types of electron damage, and will be subject to thesame radiobiological processes
magnitude of risk uncertain, but even the smallest
dose has potential to increase the risk
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Nuclear workers - heterogeneitybetween countries
p for heterogeneity = 0.18
Cardis E, Vrijheid M, Blettner M et al. BMJ 2005;331:77-83