Effects of Low Dose Radiation

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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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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

Effects of Low Dose Radiation

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