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NCRP REPORT No. 171
Uncertainties in the
Estimation of Radiation
Risks and Probability of
Disease Causation
Recommendations of the
NATIONAL COUNCIL ON RADIATION
PROTECTION AND MEASUREMENTS
July 20, 2012
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Library of Congress Cataloging-in-Publication Data
National Council on Radiation Protection and Measurements.
Uncertainties in the estimation of radiation risks and probability of disease
causation:recommendations of the National Council on Radiation Protection and
Measurements.
p; cm. -- (NCRP report;no. 171)
"March 28, 2012."
Includes bibliographical references.
ISBN 978-0-9835450-1-9
I. Title. II. Series: NCRP report;no. 171.
[DNLM: 1. Disease--etiology. 2. Radiation Effects. 3. Epidemiologic Studies. 4.
Risk Assessment. WN 600]
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2012015276
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Preface
High-quality exposure data are essential in accurately estimating
the association between ionizing radiation and adverse health effects.
Measured or estimated doses from such exposures, however, are sub-
ject to uncertainties. Further, estimates of radiation risk can be influ-
enced by the dose rate (acute or chronic), the type of exposure (external
or internal), the quality of the radiation (low or high linear energy
transfer), the organ or tissue exposed, population characteristics (such
as age-at-exposure, time-since-exposure, sex, genetic predisposition,
and period of observation), the presence of co-factors or lifestyle factors
(such as tobacco use and viral infections) and study biases. The goal of
this National Council on Radiation Protection and Measurements
(NCRP) Report is to appraise the major aspects of uncertainty in relat-
ing absorbed doses in specific organs and tissues to the risk of disease,
including cancer, noncancer and heritable effects. The Report builds
upon the analyses in NCRP Report No. 158, Uncertainties in the Mea-
surement and Dosimetry of External Radiation (2007) and NCRP
Report No. 164, Uncertainties in Internal Radiation Dose Assessment
(2009) of sources and magnitude of uncertainties in the estimation of
doses from external and internal sources of radiation.
At the present time, estimates of the risk of radiation-induced
health effects are primarily based on long-term studies of atomic-
bomb survivors in Japan, with supportive or complementary data from
observations of patients given radiation for medical purposes, workers
exposed to radiation in the course of their occupation, survivors of radi-
ation accidents, and populations exposed to elevated levels of natural
background radiation. This Report describes uncertainties associated
with making conversions from absorbed doses in organs and tissues to
estimates of health risks, and considers how these uncertainties are
incorporated into calculation of the probability of disease causation
used in evaluating claims for compensation of workers who developed
cancer after being exposed to radiation. Risk assessments and their
uncertainties in radiation protection are also discussed.
Topics addressed in the Report include:
• uncertainties in epidemiological methods;
(cid:129) dosimetric uncertainties;
(cid:129) uncertainties in selected radioepidemiological studies: atomic-
bomb survivors, Mayak workers, breast cancer cohorts, under-
ground miners, populations exposed to indoor radon, and sev-
eral other occupationally- and medically-exposed groups);
iii
iv / PREFACE
(cid:129) uncertainties in noncancer health effects;
(cid:129) uncertainties in heritable effects;
(cid:129) how animal and cellular data can be used in support of epide-
miological studies;
(cid:129) uncertainty and excess lifetime risk projection and probability
of causation of a specific disease; and
(cid:129) risk assessments and their uncertainty in radiation protection.
This Report evaluates the magnitude of the various uncertainties
underlying the estimation of risks and their subsequent use in
theestablishment of dose limits for radiation protection purposes. The
Report also describes the handling of uncertainties in the Interactive
Radio-Epidemiological Program used to estimate the probability of
causation (assigned share) as a basis for compensation for an individ-
ual with a history of prior exposure. The use of radiation risk estimates
and their uncertainties in radiation protection is summarized, includ-
ing an historical review and perspective. Types of ongoing or proposed
epidemiological studies that could reduce some of the uncertainties in
current risk estimates are discussed. Recommendations for future ave-
nues to pursue in reducing uncertainties are made.
This Report was prepared by Scientific Committee 1-16. Serving on
the Committee were:
R. Julian Preston, Chairman
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
Members
John D. Boice, Jr. Richard W. Hornung
Vanderbilt University Cincinnati Children’s Hospital
Nashville, Tennessee Medical Center
Loveland, Ohio
A. Bertrand Brill Dale Preston (2009–2010)
Vanderbilt University Hirosoft International
Nashville, Tennessee Corporation
Eureka, California
Ranajit Chakraborty Roy E. Shore
University of North Texas Radiation Effects Research
Health Science Center Foundation
Fort Worth, Texas Hiroshima, Japan
Rory Conolly Gayle E. Woloschak
U.S. Environmental Protection Northwestern University
Agency Northwestern, Illinois
Research Triangle Park, North
Carolina
PREFACE / v
Consultant
David C. Kocher
SENES Oak Ridge, Inc.
Oak Ridge, Tennessee
Advisors
F. Owen Hoffman Charles E. Land
SENES Oak Ridge, Inc. Monte Estoril, Portugal
Oak Ridge, Tennessee
NCRP Secretariat
Morton W. Miller, Staff Consultant
Marvin Rosenstein, Staff Consultant (2012)
Cindy L. O’Brien, Managing Editor
Laura J. Atwell, Office Manager
David A. Schauer, Executive Director (2009–2012)
James R. Cassata, Executive Director (2012– )
The Council expresses its appreciation to the Committee members
for the time and effort devoted to the preparation of this Report. NCRP
would also like to thank the many colleagues not on the Committee,
and some not on the Council, who provided critical reviews and guid-
ance in a very timely manner when asked about specific areas of the
Report. NCRP also gratefully acknowledges financial support provided
by the National Institute of Occupational Health and Safety (NIOSH)
under Contract No. 211-2008-27495. The contents of this Report are
the sole responsibility of NCRP, and do not necessarily represent the
views of NIOSH.
John D. Boice, Jr.
President
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .iii
Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
2. Uncertainties in Epidemiological Studies . . . . . . . . . . . . . .21
2.1 Overview of Epidemiological Uncertainties . . . . . . . . . . . .21
2.1.1 Criteria for a Study with Relatively Low
Uncertainty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22
2.1.2 Types of Uncertainties and Examples . . . . . . . . .23
2.2 Dosimetric Uncertainties . . . . . . . . . . . . . . . . . . . . . . . . . .23
2.2.1 Uncertainties in Dose Estimates . . . . . . . . . . . . .23
2.2.1.1 Classical Random Measurement Error.23
2.2.1.2 Berkson-Type Error. . . . . . . . . . . . . . . .24
2.2.1.3 Shared or Systemic Error . . . . . . . . . . .25
2.2.1.4 Other Uncertainties. . . . . . . . . . . . . . . .26
2.2.2 Assessing and Adjusting for Dosimetric
Measurement Errors . . . . . . . . . . . . . . . . . . . . . . .26
2.3 Epidemiological and Methodological Uncertainties . . . . .28
2.3.1 Impacts of Potential Confounding Factors . . . . . .28
2.3.2 Sources of Epidemiological Uncertainties . . . . . .29
2.3.2.1 Selection Bias. . . . . . . . . . . . . . . . . . . . .30
2.3.2.2 Follow-Up Losses . . . . . . . . . . . . . . . . . .31
2.3.2.3 Personal Recall Error and Bias. . . . . . .31
2.3.2.4 Other Radiation Exposures. . . . . . . . . .32
2.3.2.5 Survivor Bias . . . . . . . . . . . . . . . . . . . . .32
2.3.2.6 Healthy Worker Effect. . . . . . . . . . . . . .33
2.3.2.7 Comorbidity Bias . . . . . . . . . . . . . . . . . .33
2.3.2.8 Diagnostic Inaccuracy . . . . . . . . . . . . . .34
2.3.2.9 Surveillance Bias . . . . . . . . . . . . . . . . . .34
2.4 Uncertainties from Low Statistical Power and Precision .35
2.4.1 Statistical Power and Precision of Risk
Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35
2.4.1.1 Sample Size, Background Rate, and
Follow-Up Length. . . . . . . . . . . . . . . . . .35
2.4.1.2 Size of Effect and Population-Mean
Dose. . . . . . . . . . . . . . . . . . . . . . . . . . . . .35
vii
viii / CONTENTS
2.4.2 Pitfalls of Underpowered Epidemiological
RadiationStudies . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.5 Uncertainties from Inadequate Modeling of Radiation
RiskData . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
2.5.1 Model Uncertainties . . . . . . . . . . . . . . . . . . . . . . . 38
2.5.2 Risk Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2.5.3 Covariates and Modifiers of Models . . . . . . . . . . 40
2.5.3.1 Temporal Pattern of Risk . . . . . . . . . . . 40
2.5.3.2 Adjusting for Covariates. . . . . . . . . . . . 41
2.5.3.3 Effect Modification by Covariates . . . . 41
2.6 Transport of Risk Estimates to Different Populations . . 42
2.7 Impact of Dose Uncertainties . . . . . . . . . . . . . . . . . . . . . . 43
3. Uncertainties in Major Radioepidemiological Studies . . 44
3.1 Atomic-Bomb Survivor Studies . . . . . . . . . . . . . . . . . . . . . 45
3.1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.1.1.1 Life Span Study. . . . . . . . . . . . . . . . . . . 45
3.1.1.2 Adult Health Study. . . . . . . . . . . . . . . . 47
3.1.1.3 In Utero Cohorts . . . . . . . . . . . . . . . . . . 48
3.1.1.4 F1 Mortality Cohort . . . . . . . . . . . . . . . 49
3.1.1.5 F1 Clinical Cohort. . . . . . . . . . . . . . . . . 49
3.1.2 Uncertainties in Atomic-Bomb Survivor Studies 49
3.1.2.1 Dosimetric Uncertainties . . . . . . . . . . . 49
3.1.2.2 Classical Measurement Error . . . . . . . 50
3.1.2.3 Berkson-Type Error . . . . . . . . . . . . . . . 52
3.1.2.4 Shared Uncertainties . . . . . . . . . . . . . . 54
3.1.3 Epidemiological Uncertainties . . . . . . . . . . . . . . . 56
3.1.3.1 Ancillary Radiation Exposures. . . . . . . 56
3.1.3.2 Uncertainties in Epidemiological Data 58
3.1.4 Statistical Estimation of Atomic-Bomb Dose
Uncertainties and Related Adjustment of Risk
Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3.2 Mayak Cohort Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
3.2.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
3.2.2 Mayak Worker Cohort . . . . . . . . . . . . . . . . . . . . . 66
3.2.3 Ozyorsk Offspring Cohort . . . . . . . . . . . . . . . . . . 68
3.2.4 Summary of Uncertainties . . . . . . . . . . . . . . . . . . 68
3.3 Breast Cancer Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3.4 Occupational Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
3.4.1 Uncertainties in Occupational Studies of
Radiation-Exposed Populations . . . . . . . . . . . . . . 76
3.4.1.1 Bias from Missing Dosimetry. . . . . . . . 79
3.4.1.2 Confounding from Smoking . . . . . . . . . 80
3.4.1.3 Adjustment for Duration of
Employmentin the Analysis . . . . . . . . 80
CONTENTS / ix
3.4.1.4 Exclusion of Workers with Incomplete
Measures of Socioeconomic Status . . . .81
3.4.1.5 Exclusion of Workers with the
Potentialfor Internal Intakes of
Radionuclides or Neutron Exposure. . .82
3.4.1.6 Biological Plausibility . . . . . . . . . . . . . .83
3.4.2 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84
3.5 Medical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84
3.5.1 Example of Possible Uncertainties in a Study
ofChildren Treated with Radiation for Tinea
Capitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86
3.5.2 Example of Possible Uncertainties in a Study
ofChildren Given Diagnostic Computed
TomographyExaminations . . . . . . . . . . . . . . . . . .88
3.6 Radon Exposure Studies . . . . . . . . . . . . . . . . . . . . . . . . . . .91
3.6.1 Miners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .91
3.6.2 Residential Studies . . . . . . . . . . . . . . . . . . . . . . . .96
3.6.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98
4. Animal and Cellular Datathat Support Epidemiological
Studies: Biomarkers and Mechanisms . . . . . . . . . . . . . . . .100
4.1 Introduction to Animals Studies . . . . . . . . . . . . . . . . . . .100
4.2 Historically-Relevant Animal Studies . . . . . . . . . . . . . . .101
4.3 Recent Studies of Radiation Effects in Animals that
Relateto Human Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . .104
4.3.1 Nontransgenic Mouse Models . . . . . . . . . . . . . . .104
4.3.2 Transgenic Mouse Models . . . . . . . . . . . . . . . . . .105
4.3.3 Epigenetic Changes . . . . . . . . . . . . . . . . . . . . . . .107
4.4 Extrapolations for Estimating Human Risk from
AnimalData . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .108
4.5 Cellular Studies for Evaluating Risk . . . . . . . . . . . . . . . .110
5. Quantification of Uncertainty in Radiation Risk for
ExcessLifetime Risk Projection and Probability of
Causation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112
5.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112
5.2 Specific Components Related to Dose-Response
Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113
5.2.1 Dose Response from Primary Epidemiological
Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113
5.2.2 Adjusting the Dose Response for the Presence
ofDose Uncertainty . . . . . . . . . . . . . . . . . . . . . . .113
5.2.3 Minimum Latency Period . . . . . . . . . . . . . . . . . .114
5.2.3.1 General Considerations in Estimating
Minimum Latency Period . . . . . . . . . .114
