Effects of low doses of radiation

New epidemiological data

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 high doses to low doses high dose-rates to low dose-rates over time, across countries, ....
Radiation Protection Conference, Berlin, June 2007

Extrapolation models:

Possible extrapolations of radiation-induced cancer risk to low doses

Radiation-related cancer risk

Dose Protection Conference, Berlin, June 2007 Radiation

Based on a comprehensive review of the literature, the committee concluded that the risk would continue in a linear fashion at lower doses without a threshold and that the smallest dose has the potential to cause a small increase in risk to humans.

Radiation Protection Conference, Berlin, June 2007

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 incidence data:

Well described by linear model Compatible with small amount of curvature

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Atomic bomb survivors - LSS solid cancer incidence: Excess relative risk
1.5 Low Dose Range
6 3 4 Leukemia (for comparison) 5 0 0.0 1 2

Excess Relative Risk of Solid Cancer

1.0

0.5

1.0

1.5

2.0

0.5

BEIR VII, Fig. ES-1

Linear fit, 0 - 1.5 Sv Linear-quadratic fit, 0 - 1.5 Sv 0.0 0.0

0.5

1.0

1.5

2.0

Radiation Dose (Sv) Radiation Protection Conference, Berlin, June 2007

Use of model to estimate risk at low doses and dose rates

If true response is linear-quadratic, linear estimates need to be reduced
1.2 1.0 0.8 ERR 0.6 0.4 0.2 0.0 0 1 Gy 2 Gy 3 Gy
True response Linear approximation Low-dose response

Factor used for this is the Dose and Dose Rate Effectiveness Factor (DDREF) Many past risk assessment - DDREF = 2
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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 Radiation Protection Conference, Berlin, June 2007

Direct epidemiological evidence - Requirements Study population

Very large Well-defined No selection bias

Follow-up / Case & control ascertainment

Complete, non-differential Accurate diagnosis Individual Accurate and precise

Dose-estimates

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Nuclear industry workers

Characteristics

Very large, stable populations Well characterized exposures

Generally low doses, protracted

Detailed individual annual dose estimates measured in real time with personal dosimeters

Mainly external radiation

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, protracted

exposures to external-photon radiation

Approach

International Collaborative study Retrospective cohort study Much effort to assess and ensure comparability
Common core protocol Studies of errors in doses
IRE, Japan

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Radiation Protection Conference, Berlin, June 2007

Radiation Protection Conference, Berlin, June 2007

Participating cohorts
Main study population Person years Australia Belgium Canada Finland France CEA-COGEMA France EDF Hungary Japan Korea (south) Lithuania Slovak Republic Spain Sweden Switzerland UK US Hanford US NPP US INEEL US ORNL TOTAL 877 12,110 5,037 77,246 38,736 473,880 6,782 90,517 14,796 224,370 21,510 241,391 3,322 40,557 83,740 385,521 7,892 36,227 4,429 38,458 1,590 15,997 3,633 46,358 16,347 220,501 1,785 22,051 87,322 1,370,101 29,332 678,833 49,346 576,682 25,570 505,236 5,345 136,673 407,391 5,192,710 Number of Average deaths individual All All cumulative causes cancer dose (mSv) 56 20 6.1 322 90 26.6 1,204 417 19.5 317 34 7.9 645 229 3.8 371 119 15.8 104 40 5.1 1,091 432 18.2 58 21 15.5 102 25 40.7 35 10 18.8 68 25 25.5 669 194 17.9 66 24 62.3 7,983 2,273 20.7 5,564 1,331 23.7 983 340 27.1 3,491 924 10.0 1,029 246 15.2 24,158 6,794 19.4 Collective cumulative dose (Sv) 5.4 134.2 754.3 53.2 55.6 340.2 17.0 1526.7 122.3 180.2 29.9 92.7 291.8 111.2 1810.1 695.4 1336.0 254.6 81.1 7891.9

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Distribution of cumulative doses

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Results comparison with study of atomic bomb survivors

15-Country Study N All cancers excluding leukemia Solid cancers Leukemia excluding CLL Linear model Linear quadratic model ERR/Sv (95% CI) Atomic bomb survivors men exposed 20-60 N ERR/Sv (95% CI)

5 024 0.97 (0.14-1.97) 4 770 0.87 (0.03-1.88) 196 1.93 (<0b, 8.47) 3 259 0.32a (0.01, 0.50) 83 3.15c (1.58, 5.67) 1.54d (-1.14, 5.33)

[a] Analyses carried-out at IARC using an excess relative risk model that allows for age at exposure modification, adjusting for attained age, calendar period, and city. Estimate for men exposed at age 35. [b] Estimate on boundary of parameter space [c] Analyses carried-out at IARC using a constant excess relative risk model, adjusting for attained age, calendar period, and city. [d] Analyses carried out at IARC - linear term of the linear-quadratic model preferred model for describing leukemia mortality in analyses of A-bomb survivor data

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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

All doses Cumulative Cumulative Cumulative Cumulative

doses doses doses doses

<400 <200 <150 <100

mSv mSv mSv mSv

N 5,024 5,012 4,937 4,863 4,772

ERR/ Sv 0.97 1.18 2.52 1.39 1.51

90% CI 0.27 1.80 0.37 2.11 1.31 3.87 0.02 2.92 -0.29 3.51

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ERR by dose category

All c a nc er s exc lud ing leu kemia All c a nc er s exc lud ing leu kemia, lung and pleur a Leuke mia 4 ERR/S v ERR/S v ERR/S v

3 .5

2 .5 ERR (baseline: <0.5mSv)

1 .5

0 .5

0 0 -0 .5 1 00 200 3 00 400 5 00 600

-1

R ad iatio n D o se (m S v)

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Conclusions
Largest analytical study of effects of low dose protracted exposures to date Most precise, direct estimates Estimates are statistically consistent with extrapolations from A-bomb data Confounding by smoking cannot be ruled out but unlikely to explain all increase

Results suggest that at a small cancer risk exists, even at low doses typical of workers in this study
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More detailed results

3 papers Radiation Research

Methods Study of errors in doses Detailed results cancer mortality only Non-cancer mortality
quantities

1 paper in press Int J Epi 1 paper in preparation

Effects of errors in doses and of different dosimetric

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Radiation Protection Conference, Berlin, June 2007

Exposures to Population
Mayak Industrial Association
Began operation in 1948 Production and separation of plutonium Releases of waste into the Techa River Accidental and gaseous releases external exposure internal dose from 89Sr & 90Sr, 137Cs, 103Ru & 106Ru, 95Zr & 95Nb

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The Techa River

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Exposed Populations
Extended Techa River Cohort ~ 30,000 individuals

Born before 1.1.1950 and resident

in any of the 41 exposed villages along the Techa River in 1950 1960

Techa River Offspring Cohort ~ 23,000 individuals

1st generation offspring born after 31.12.1949

whose one or both parents included in the Extended Techa River Cohort

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Extended Techa River Cohort Characteristic Features

Unselected population Long period of follow-up > 50 years Protracted exposure External and internal radiation Populations with different ethnic backgrounds
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Extended Techa River Cohort TRDS-2000 Dose Estimates

2000

1500

Dose, mGy

1000

500

min

median

mean

max

stomach

low large intestine

red bone marrow

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Radiation Protection Conference, Berlin, June 2007

Extended Techa River Cohort Solid Cancer Risk Estimates

Observed Expected Excess 1,842 1,796 46 (2.5%) P=0.03 P=0.052 P=0.08
ETRC Solid Cancer Dose Response
0.6

Effect modification
Attained age Ethnicity Age at entry

0.4

ERR

Linear-Quadratic

0.2

Linear

ERR/Gy 0.92 (95% CI 0.2; 1.7)

0.0 0.0 0.2
Stomach Dose (Gy)

0.4

Techa River Dosimetry System 2000 Protection Conference, Berlin, June 2007 Radiation

Radiation Protection Conference, Berlin, June 2007

Leukemia Risk Estimates

excluding CLL

ETRC Leukemia Dose Response

Nested case-control study 60 cases, 300 controls Evaluation of role of potential confounding factors
ERR

10

Linear

4
Linear-Quadratic

ERR/Gy 4.6 (95% CI 1.7, 12.3)

0 0.0 0.5
Marrow Dose (Gy)

1.0

Techa River Dosimetry System 1996 Protection Conference, Berlin, June 2007 Radiation

Concerns with Techa river dosimetry

Are estimated doses too low?
external dose under review

Sr-90, Cs-137 ok Role of short lived isotopes in internal and

No systematic monitoring before July 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 a small risk at low doses
a-bomb survivors Both studies have limitations

Risk estimates higher than linear extrapolations from

15-country study: exact magnitude of smoking confounding not clear Techa river: uncertainties/errors in dose estimates

Risk estimates statistically compatible with

extrapolations from a-bomb survivors

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Effects of age and gender

Difficult to evaluate from these studies
effect

Nuclear workers mainly men, exposed as adults Techa river no clear evidence of age at exposure Atomic 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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But evidence from other populations that children are more susceptible

Generadiation interactions ?

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Generadiation interactions ?

Radiation Protection Conference, Berlin, June 2007

Generadiation interactions ?

Radiation Protection Conference, Berlin, June 2007

Generadiation interactions ?

Radiation Protection Conference, Berlin, June 2007

Generadiation interactions ?

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Conclusions
Careful studies of populations with low-dose protracted exposures
increase in the risk of cancer Increase is statistically compatible with extrapolations from a-bomb data Exact magnitude of ERR/Gy cannot be determined at present

Suggest that such exposures cause a small

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Conclusions

DDREF
Premature to estimate it based on low dose protracted exposure studies BEIR VII
Based on a-bomb data below 1.5 Gy, in conjunction 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: If dose is decreased, this will result in fewer electron tracks and proportionately fewer hit cells. Those cells that are hit will be subject to the same types of electron damage, and will be subject to the same radiobiological processes

magnitude of risk uncertain, but even the smallest dose has potential to increase the risk
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Are some of us more sensitive than others ?

Age at exposure

Yes a-bomb, in-utero exposures, thyroid

cancer after Chernobyl

Gene-radiation interactions

damage recognition genes increase risk of radiation induced cancer?

Mutations and variants in DNA repair and

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Radiation Protection Conference, Berlin, June 2007

Nuclear workers - heterogeneity between countries

p for heterogeneity = 0.18

Cardis E, Vrijheid M, Blettner M et al. BMJ 2005;331:77-83

Radiation Protection Conference, Berlin, June 2007