Tài liệu Ncrp report no 126 uncertainties in fatal cancer risk estimates used in radiation protection

NCRP REPORT No. 126 UNCERTAINTIES IN FATAL CANCER RISK ESTIMATES USED IN RADIATION PROTECTION Recommendations of the NATIONAL COUNCIL ON RADIATION PROTECTIONANDMEASUREMENTS Issued October 17, 1997 National Council on Radiation Protection and Measurement 7910 Woodmont Avenue / Bethesda, Maryland 20814-3095 LEGAL NOTICE This Report was prepared by the National Council on Radiation Protection and Measurements (NCRP). The Council strives to provide accurate, complete and useful information in its documents. However, neither the NCRP, the members of NCRP, other persons contributing to or assisting in the preparation of this Report, nor any person acting on the behalf of any of these parties: (a) makes any warranty or representation, express or implied, with respect to the accuracy, completeness or usefulness of the information contained in this Report, or that the use of any information, method or process disclosed in this Report may not infringe on privately owned rights; or (b) assumes any liability with respect to the use of, or for damages resulting from the use of any information, method or process disclosed in this C Report, under the Civil Rights Act of 1964, Section.701 et seq. a s amended 42 US.. Section 2000e et seq. (Title VZZ) or any other statutory or common law theorygoverning liability. Library of Congress Cataloging-in-PublicationData National Council on Radiation Protection and Measurements. Uncertainties in fatal cancer risk estimates used in radiation protection :recommendations of the National Council on Radiation Protection and Measurements. p. cm. -- (NCRP report ; no. 126) "Issued October 1997." Includes bibliographical references and index. ISBN 0-929600-57-6 1. Radiation carcinogenesis. 2. Cancer--Mortality 3. Cancer--Risk factors. 4. Health risk assessment. 5. Radiation--Dosimetry. I. Title. 11. Series. [DNLM: 1.Neoplasms, Radiation-Induced--etiology. 2. Neoplasms, Radiation -Induced--mortality. 3. Radiation Protection. 4. Risk Factors. 5. Radiation Dosage. QZ 200 N2745c 19971 RC269.55.N36 1997 616.99'4071--dc21 97-41391 CIP Copyright O National Council on Radiation Protection and Measurements 1997 All rights reserved. This publication is protected by copyright. No part of this publication may be reproduced in any fonn or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyrightowner,except for brief quotation in critical articles or reviews. Preface In recent years, the practice of providing uncertainties when formulating estimates of dose and risk in human and environmental exposure circumstances has become recognized as an important step in expressing the degree of confidence appropriate to stated values. Knowledge of the magnitude of uncertainties in the nominal values of the coefficient for risk of fatal cancer per unit dose can be very helpful in providing perspective to those involved in radiation protection practice. In human cancer risk estimation, however, only rather tentative approaches to the evaluation of these uncertainties have been made, starting with the report of the NIH Ad Hoc Working Group on Radioepidemiological Tables in 1985 and with relatively brief attempts by the United Nations Scientific Committee on the Effects of Atomic Radiation and the National Academy of Sciences/National Research Council's Committee on the Biological Effects of Ionizing Radiation. The data on mortality from the Lifespan Study of the Japanese atomic-bomb survivors up to 1985 are virtually the sole numerical source used for risk estimates for low-LET radiation exposure today. (Later evaluations of the LSS data to 1987 and to 1990 are of wide interest in epidemiology but have not so far modified the risks recommended for use in radiation protection.) Other sources of risk information are used mainly to support and complement the data from the LSS. In the NCRP Taylor Lecture in 1993, it was pointed out that the singularity of the LSS as a source of low-LET risk information simplifies the assessment of uncertainties in the risk estimates. Because the LSS risk estimates depend on five distinct components, uncertainties overall can be evaluated by examining the uncertainties in each of these components. In the 1993 Taylor Lecture, the evaluation (and discussion) of the five components was quite limited, although an overall picture was outlined. The NCRP decided recently to build on that Taylor Lecture by looking at each of the five components in more detail and attempting to be more quantitative about their uncertainties. This Report is the result. It makes clear that the fundamental basis on which the evaluation of some of the components rests is, itself, uncertain and difficult to quantify. Nevertheless, the Report seeks not only to clarify the foundation of estimates of iv / PREFACE uncertainty, but also to make a reasonable overall appraisal of the uncertainties in the average risk estimates presently used in low-LET radiation protection. Risk estimates for individual organs involve greater uncertainties than for total cancer and are not dealt with specifically in this Report. This Report was prepared by Scientific Committee 1-5 on Uncertainty in Risk Estimates. Serving on Scientific Committee 1-5 were: Warren K. Sinclair, Chairman National Council on Radiation Protection and Measurements Bethesda, Maryland Members And& Bouville National Cancer Institute Bethesda, Maryland Charles E. Land National Cancer Institute Bethesda, Maryland NCRP Secretariat William M. Beckner, Senior StaffScientist Cindy L. O'Brien, Editorial Assistant The Council wishes to express its appreciation to the Committee members for the time and effort devoted to the preparation of this Report. Charles B. Meinhold President Contents ... Preface ............................................. 111 1 Intmdudion ....................................... 1 11 Risk Estimates for Radiation Protection .............. 1 . 12 Past Risk Estimates .............................. 2 . 13 Present Risk Estimates ...........................3 . 131 Age and Sex Dependence .....................3 .. 132 Lifetime Risk ............................... 3 .. 133 Risk Estimates for Low Dose and Dose Rate ..... 4 .. 1.4 Uncertainties in Risk Estimates .................... 5 141 Past Uncertainty Evaluations ................. 5 .. 1 4 2 NCRP Approach to Uncertainty in Risk .. Estimates for Radiation Protection ............. 6 143 City Differences ............................ 8 .. 15 Dose Response ................................... 8 . 2 Epidemiological Uncertainties ..................... 10 21 Introduction .................................... 10 . 22 Specific Epidemiological Uncertainties .............. 13 . 23 Bias i Risk Estimates Due to Errors of Detection . n and Confirmation ............................... 16 24 Biases Affecting Risk Estimates of Cancer . Morbidity ...................................... 18 25 Unrepresentative Population ...................... 20 . 26 Bias Deriving from City Differences ................ 21 . 2 7 Summary of Epidemiological Uncertainty ........... - 2 2 . 3 Dosimetrical Uncertainty .......................... 23 31 Random Errors and Biases ........................ 23 . 3 2 Bias Resulting from Random Errors in Dose ......... 24 . 3 3 Bias in Gamma-Ray Measurements Versus DS86 ..... 30 . 3 4 Uncertainty Due to Survivor Shielding . Characterization in DS86 ......................... 32 35 Uncertainty Due to Neutron Weight (Relative . Biological Effectiveness).......................... 32 36 Bias and Uncertainties Due to the Presence of . Thermal Neutrons a t Hiroshima in Excess of Those Predicted by DS86 ............................... 34 3.7 Combination of Uncertainties and Bias for Dosimetry. . 37 . . . vi / CONTENTS . 4 Transfer of Risk Between Populations.............. 40 4.1 General Considerations .......................... 40 4.2 Factors Modifying Risk in Relation to Transfer Between Populations ............................ 42 4.3 Site-Specific Evidence for Selecting the Transfer Model ........................................-47 4.4 Uncertainty Due to Method of Transfer ............. 49 5 Projection to Lifetime Risk ........................ 51 5.1 Constant Relative Risk Projection Model 51 5.2 Considerations Regarding the Projection to Lifetime . . 5.3 5.4 5.5 ............ Risks in the Lifespan Study ...................... 51 Attained Age Model ............................. 53 Lifetime Risk of Those Exposed a t Young Ages ....... 55 Uncertainty in Lifetime Risk ..................... 57 6 Extrapolation to Low Dose or Dose Rate ............ 6.1 Effect of Dose Rate and Dose in Radiobiology ......... 6.1.1 The Effect of Dose Rate 6.1.2 The Effect of Dose ......................... 6.2 Human Data and Dose-Rate Effects................ 6.3 The ICRP Choice of a Dose and Dose-Rate 60 60 ..................... 60 60 61 Effectiveness Factor ............................ 63 6.4 The NCRP Position on the Application of a Dose and Dose-Rate Effectiveness Factor ................ 64 6.5 UNSCEAR Evaluation of a Dose and Dose-Rate Effectiveness Factor and Recent Studies ............ 64 6.6 Uncertainties in the Application of a Dose and . Dose-Rate Effectiveness Fador ................... 65 7 Combination of Uncertainties ..................... 67 7.1 Sources of Uncertainty .......................... 67 7.2 Method to Propagate Uncertainties ................ 69 7.3 Results ....................................... 71 7.3.1 Population of A11 Ages ...................... 71 7.3.2 Adult Worker Population ................... 73 7.4 Conclusions ................................... 74 Glossary............................................ 77 References ......................................... 83 TheNCRP .......................................... 92 NCRPPublications ................................. 100 Index ............................................. 109 1. Introduction 1.1 Risk Estimates for Radiation Protection This Report is concerned with the evaluation of uncertainties in the risk estimates of fatal cancer induced by low-LET radiation (see Glossary) as presently used in radiation protection, i.e., in estimates of the risk of fatal cancer following exposure of individuals or populations in occupational, environmental or domestic circumstances. These cancers are the main component of the health detriment following radiation exposure identified by the International Commission on Radiological Protection [ICRP (1991)l and the National Council on Radiation Protection and Measurements [NCRP (1993a)l as pertinent in low-LET radiation protection. Recent evaluations of the risk of fatal cancer induced by low-LET radiation are numerically based on the 1950 to 1985 mortality experience of the survivors of the atomic bombs dropped in Japan, as ascertained by the Lifespan Study (LSS) (EPA, 1994; ICRP, 1991; NASLNRC, 1990; NCRP, 1993a; NRPB, 1993; UNSCEAR, 1988). Other epidemiological studies, although they can be highly informative with regard to particular cancer sites, have served mainly to support the results from the LSS, and to show that the LSS results are not isolated, but are generally and broadly supported by these other sources of data. Later evaluations of induced fatal cancer risk in the LSS include the mortality and incidence data up to 1987 reviewed by the United Nations Scientific Committee on the Effects of Atomic Radiation [UNSCEAR (199411 and the more recent mortality evaluations up to 1990 (Pierce et al., 1996a). These new studies provide additional information, especially on cancer incidence, but they do not alter substantially the risk estimates derived in the 1988 to 1990 reports and, more especially, the derivation procedure, which is the source of the uncertainty considerations, remains the same. Not all aspects of radiation protection (notably those involving high-LET exposures)use risk estimates based on the LSS of the atomic-bomb survivors. For example, any consideration of radon exposure to workers or to the public uses risk estimates based on radon 2 1 1. INTRODUCTION exposures to miners. However, many radiation protection situations in which risk is at issue will use the results of the LSS. The results of the.LSS indicate that lifetime risk coefficients for fatal cancer derived from the high-dose rate exposures of the SV-' for a population of atomic-bomb survivors are about 10 x all ages and about 8 x S V - ~ for an adult (worker) population. 1.2 Past Risk Estimates It is worth noting, [see Table 1.1,taken from ICRP (1991), Table B-101 that lifetime risk estimates for an acute exposure [i.e., no dose and dose-rate effectiveness factor (DDREF) applied1] have ranged over t,he period 1972 to 1990 from about 1 to about Table 1.1-Excess lifetime mortality from all cancer, attributable to 1Gy (or 1Sv)acute uniform whole-body low-LET irradiation of the general population (ICRP, 1991). Probability of Death Source of Estimate NASNRC, 1972 UNSCEAR, 1977 NASNRC, 1980 Evans et al., 1985 UNSCEAR, 1988* NASNRC, 1990d Gilbert, 1991d Additive Risk Projection Model Multiplicative Risk Projection Model 6.2 - 2.3 to 5.0 5.2 7.0' to 11.0~ 8.gdP.f 7.1d a Population of Japan. Estimate based on age-specific coefficients of probability. 'Estimate based on constant (age-averaged) coefficient of probability. United States population. Modified multiplicative model. "LOW-dose" leukemia component multiplied by two. or low-LET radiation, the ratio between the biological effect of high-dose rate radiation to that of the effect of low-dose rate radiation a t the same dose is known as the dose and dose-rate effectiveness factor, DDREF. 1.3 PRESENT RISK ESTIMATES / 3 1 x 1 SV-l with the type of projection model used being one of the largest contributorsto the variation of risk estimates. Risk estimates have been more consistent over time when the multiplicative risk projection model is used. UNSCEAR, BEIR I11 [Committee on the Biological Effects of Ionizing Radiation of the National Academy of ScienceslNational Research Council (NASINRC)],ICRP and NCRP, in the period 1977 to 1980, were all in substantial agreement about estimates of lifetime risk coefficients for fatal cancer that were several times lower SV-l, compared with 4 to than those in use now (about 1to 2 x 5x SV-~). Evident1y;risk values agreed upon today must still be considered subject to future change as different information comes forward on any of those aspects on which the estimates are based. 13 Present Risk Estimates . The ICRP (1991) and the NCRP (1993b) have further derived the nominal values of risk to be used for (low-dose rate) radiation protection as 5 x SV-l for a population of all ages and 4 x ~o-~sv-' for adult workers, after dividing the average high-dose rate estimate by a DDREF of two. It is uncertainties in these estimates of risk, now widely used in radiation protection, with which this Report is concerned. 131 Age and Sex Dependence .. These risk estimates apply to the populations specified. If the age and sex of the population group is known in more detail, tables such as Table 1.2 can be used to apply risk estimates more accurately. More detail on age and sex dependencies is provided in references such as Land and Sinclair (1991) and Pierce et al. (1996a). 1 3 2 Lifetime R s .. ik The term "lifetime risk estimate" is not a unique description of the risk resulting from exposure to a tumor inducing agent. For a detailed discussion of some of the issues relating to lifetime risk see Thomas et al. (1992) and UNSCEAR (1994). One point only with reference to lifetime risk estimates will be cited here. It concerns the choice of "risk of exposure-induced death* (REID) or the choice of "excess lifetime riskn (ELR) as a measure of radiation-related 4 / 1.INTRODUCTION Table 1.2-Fatal cancer risk for different ages and sex after low SU-l) (Sinclair, 1992).a dose or low-dose rate exposure (x Age (Y) Male Female Average 'United States population, average of multiplicative and NIH transfer models (Land and Sinclair, 1991). population detriment. REID represents the probability of an "untimely" death due to exposure. ELR is the difference between the probability of a cancer death given a specific exposure history and the probability of a cancer death in the absence of the specific exposure history. Consequently, the REID includes the exposure-induced earlier deaths of those who would have later died of cancer without the exposure. Because about 20 percent of the population would be expected to die of cancer in the absence of radiation exposure, the REID is about 20 percent higher than the ELR for all cancer sites combined for uniform whole-body exposure. For exposure limited to a single organ (e.g.,salivary gland, for which lifetime mortality rates are considerably below one percent) the REID and the ELR are more closely comparable. It should also be pointed out that single values (point estimates) of lifetime risk coefficients do not convey the wealth of information already known about sex and age variations in risk, which should usually be accounted for when dealing with specific practical situations. Consequently, uncertainties in past estimates are only a beginning to the consideration of uncertainties in many risk circumstances. Furthermore, uncertainties in risk estimates for individual organ and tissue sites are also of practical importance and probably differ among themselves; but these will not be addressed in this Report. 1.3.3 Risk Estimates for Low Dose and Dose Rate The lifetime risk coefficients presently recommended by ICRP and NCRP were derived from the LSS data of the atomic-bomb survivors taking into account the following evaluations: (1)the REID values given by UNSCEAR (1988)for the multiplicative projection model for the period of observation to the end of life and a Japanese 1.4 UNCERTAINTIES IN RISK ESTIMATES / 5 population2 (11x SV-'1, (2) the ELR values given by BEIR V (NAS/NRC, 1990) for a United States population3 (about 9x SV-'1, and (3) REID values derived by the ICRP for a n SV-l (ICRP, 1991). These valaverage of five populations, 9.5 x ues for high-dose rate exposures were averaged and rounded to 10 x 10" SV-l and divided by a DDREF of two to obtain 5 x SV-' for a population of all ages and for the low-dose rate conditions of normal radiation protection (ICRP, 1991; NCRP, 1993b). The nominal lifetime risk value for workers was derived simiSV-' CUNSCEAR, 1988) larly from a high-dose rate value of 8 x SV-' for divided by a DDREF of two for a nominal value of 4 x adult workers (ICRP, 1991; NCRP, 1993b). Lifetime risk coefficients for individual organs were also derived by ICRP and NCRP for use in radiation protection (ICRP, 1991, Table 4; NCRP, 1993b, Table 7.2). These were also used to derive tissue weighting factors (rounded fractional health detriments) for estimating effective doses used in determining compliance with radiation protection limits (ICRP, 1991, Table 2; NCRP, 1993b, Table 5.1). The values are called nominal values because they apply to averages for the whole population and a worker population. They do not apply to a specific individual unless that individual can be considered to fit the average in all characteristics. Adjustments for age and sex have already been recommended, see Table 1.2. In this Report, low doses will refer to absorbed doses in the range 0 to 0.2 Gy and to equivalent doses of 0 to 0.2 Sv. Low-dose rates are those below 0.1 Gy d-' for all radiations. 1.4 Uncertainties in Risk Estimates 1.4.1 Past Uncertainty Evaluations I t is important to address uncertainties in risk estimates for radiation induced fatal cancer in a realistic manner. The first serious attempt to do so occurred in relation to the evaluation of probabilities of causation in given exposure circumstances, i.e., the production of the "NIH (National Institutes of Health) tables" (NIH, 1985). A very useful initial appraisal of uncertainties in the relative probability that a specific cancer was due to a given 2~apanese national mortality patterns, 1980 (see UNSCEAR, 1988, Appendix F, Table 64). 3~ital statistics of the United States, 1980 (PHs, 1984). 6 1 1. INTRODUCTION radiation exposure resulted. Our currently used estimates of the risk of cancer in radiation protection start with the evaluations by UNSCEAR in 1988. The UNSCEAR (1988) treatment of uncertainties dealt with such issues as confounding (by smoking for example), the "healthy worker effect," different and changing baseline cancer rates in different countries and the dose response pattern, but in a general rather than a specifically quantitative way. In the BEIR V Committee report of 1990 (NASNRC, 1990)the uncertainties were addressed in a more quantitative manner following broadly the approach of the NIH Committee in 1985 (NIH, 1985) and concentrating on individual tumor sites rather than total cancer risk. The features considered included not only random error associated with sampling variation in the fitted coefficients of the models used but uncertainties in dose estimates, certification of cause of death, population effects, the choice of risk versus time model, sex and age differences, and the shape of the dose response curve. Some results were provided in the form of geometrical standard deviations (GSD), a number greater than one (see Glossary). The range of uncertainty, expressed as a confidence interval is computed by dividing and multiplying the point estimate by a specified power of the GSD. For example, a 90 percent confidenceinterval for estimate E with GSD G has lower limit E / G ~ and upper limit . ~ ~ ~ E ~1.645 . While some GSD's provided by the BEIR V Committee for individual tumors, age groups and time after exposure were estimated to be as low as 1.24, others ranged up to more than three. Until now, neither ICRP nor NCRP has specifically addressed the issue of uncertainties in risk estimates recommended for use in radiation protection. 1.4.2 NCRP Approach to Uncertainty in Risk Estimates for Radiation Protection The question now arises, W h a t degree of confidence (or uncertainty) can be attached to the current nominal values of lifetime risk coefficients for all cancer used for radiation protection a t low doses and dose rates as recommended by ICRP and NCRP?" This Report examines individual uncertainties in the five modular components on which the lifetime risk coefficients are based (Table 1.3). The evaluation of overall uncertainty has been accomplished in the following way. For each of the five individual modular components, a probability distribution, a likeliest value (usually the 50th percentile), and a 90 percent confidence interval (5th to 95th 1.4 UNCERTAINTIES IN RISK ESTIMATES / 7 Table 1.34omponents of risk coeficient derivation from the LSS of the atomic-bomb survivors. Componenta Epidemiological uncertainties Dosimetrical uncertainties Population transfer model Projection to lifetime Extrapolation to low dose or low-dose rate exposure (DDREF) Section 2 3 4 5 6 T h e first four of these components concerns the estimate of high dose, high-dose rate risks from the atomic-bomb survivors. The fiRh is the component for converting high dose and dose-rate risk to low dose and dose-rate risk. percentile) have been subjectively selected. Other choices of confidence interval, e.g., 95 percent, could have been made but 90 percent is commonly used and is quite appropriate for our purposes. There is usually little or no information on the shapes of the probability distributions and therefore the choice has been largely subjective. A triangular distribution (such as shown later in Figure 3.2 for example) has been chosen when a degree of subjective confidence can only be attached to the likeliest value and to the possible range of values. Normal or lognormal distributions have been preferred for smooth, symmetric or right-skewed distributions. These two distributions are appropriate theoretically when there is no reason to believe that random error represents the sum or product of independent incremental components. However, the overall results for the combined uncertainties are not sensitive to the particular shapes of the probability distributions selected for each component provided the likeliest values and the 90 percent confidence intervals remain the same (IAEA, 1989; NCRP, 1996). Finally, the overall uncertainty in the risk estimate and its central value have been estimated using Monte Carlo methods which take into account all the uncertainty estimates for the individual modular components (Section 7). The text of this Report will rely on customary methods of uncertainty analysis as applied to uncertainty in environmental data and other circumstances. A useful source of information which includes many of the references to relevant principles and methods is NCRP Commentary No. 14 (NCRP, 1996). The uncertainty evaluations addressed in this Report relate to the methods of derivation 8 / 1. INTRODUCTION of risk estimates and concern average or nominal values. They do not consider variability in the characteristics of individuals in the population which influences their risk and contributes to individual uncertainty. 1.4.3 City Differences In some ways, it might have been useful to examine the uncertainties in the risk of cancer derived from the exposures at Nagasaki separately from those derived from the exposures at Hiroshima. One reason for this is that the estimates of the dose according to the present DS86 system, may be relatively sound for Nagasaki (although this is not certain and there are some unique dosimetry problems with some specific groups from Nagasaki included in the analysis also), whereas more questions have continued to arise about Hiroshima, especially about the magnitude of the neutron component. This and other factors concerning city differences are discussed later (see Section 2.6). The sample of attributable cancers is small, 339 solid cancers and leukemia, in 5,936 cancer deaths altogether in the LSS up to 1985; consequently, subdividing the sample into Hiroshima (about two thirds of the sample) and Nagasaki (one third of the sample) is not considered desirable at this time. In this Report, uncertainties are considered collectively in the entire LSS sample. 1.5 Dose Response The evaluation of each of the five components (and in some cases subcomponents as well) of the uncertainty in risk estimates for radiation protection is described in Sections 2 through 6. Section 6 is of special impo~~tance because it discusses and accounts for the effects of dose and dose rate by using the DDREF. Inevitably, the choice of DDREF involves a choice in the shape of the dose response curve starting with a simple linear response (DDREF = 1)and proceeding to linear quadratic responses with initial linear portions of lower and lower slope as the DDREF increases. Values of DDREF from one up to five are considered in the distribution for the DDREF. Only if the DDREF went to infinity would the response be initially independent of dose, i.e., a threshold. Those responsible for the analysis of risks in the LSS state firmly "... the data for solid cancer, including tumor registry incidence data as well as cancer mortality data, are inconsistent with the notion of a threshold for 1 5 DOSERESPONSE / . 9 radiation effects" (Pierce and Preston, 1996). Consequently, for the purposes of this Report, viz the evaluation of uncertainties in the risk coefficients derived from the LSS, the choices of DDREF will include all the reasonable linear and sublinear dose response models for the atomic-bomb survivor data. For the more general issue of linearity versus threshold for radiation effects, the NCRP has a committee addressing this question. It is noted that values of DDREF less than one, i.e., a supralinear response, have not been considered here either. If they had been, only a small value for the frequency could be assigned to a DDREF of say 0.5 or 0.3, and this would have only a very minor impact on the overall uncertainty. 2. Epidemiological Uncertainties 2.1 Introduction "Epidemiological uncertainties" is a very genera1 term, used in this Report to refer to random error in observations, and also to systematic errors including the possibility that a model used to estimate risk may deviate from the actual (and unknown) pattern of excess risk in some important way. Confidence limits, standard errors, and p values for hypothesis tests all reflect random error in the context of a statistical model that is assumed to be true as specified. As a starting point, Table 2.1 gives the number of persons in the LSS sample as of the analysis of 1985 (Shimizu et al., 1988; 1990). Table 2.1-LSS, atomic-bomb survivors (adapted from Shimizu et al., 1988; 1990). Total sample Total sample with DS86 Exposed Control Shielded Kerma (Gy) Dose groups 91,228 75,991 41,719 34,272 Number of People 2.1 INTRODUCTION / 1 1 Then, Table 2.2 summarizes the relationship between radiationdose and cancer mortality observed in the LSS sample over the years 1950 to 1985. The tabulated estimates resulted from linear regression of mortality rates on radiation dose and the associated confidence intervals reflect statistical uncertainties. Baseline (i.e., zero-dose) risk was allowed to depend upon city (Hiroshima or Nagasaki), age at exposure (i.e., in August 1945), attained age (i.e., age at diagnosis), and calendar year, but the slope of the line expressing excess risk as a function of radiation dose (in this case, shielded kerma? rather than organ or tissue dose), was assumed to be independent of city, sex, age and year. In fact, the estimates given in Table 2.2 are only average values and for many of these sites, excess risk is known to depend on sex, age at exposure, attained age andlor time following exposure. However, the average estimates in Table 2.2 are appropriate for our specific purpose. Excess risk was expressed in two ways: first, in relative terms in which the relative risk (RR) coefficient is given as a multiplier of baseline risk, i.e., a ratio without units and second, as an average number of deaths per lo4 person-year (PY), i.e., in the same units as baseline risk over the period of observation [excess absolute risk (EAR)]. For all cancers a RR of 1.39 times (average) baseline, was found while the EAR was estimated as 10.0 deaths per lo4 PY. Excess relative risk (ERR) is the RR - 1, or 0.39 in this example. Uncertainty about these estimates was expressed by confidence limits. Briefly, a pair of 90 percent confidence limits (i.e., a 90 percent confidence interval) for an unknown parameter a includes all numerical values % for which the null hypothesis, a = a. would not be rejected at significance level p = 0.10 in favor of the two-sided alternative hypothesis, a ;t ao.In most applications, it is also the set of values ole for which the null hypothesis would not be rejected at significance level p = 0.05 in favor of either of the two one-sided . Thus, if the EAR at 1Gy alternative hypotheses, a < a or a > aO. (EARlGy)for all cancers is estimated to be 10.0 per lo4 PY Gy with 90 percent confidence limits (8.36,11.8), that means that all values between 8.36 and 11.8 per lo4 PY Gy are consistent with the data, at the 90 percent confidence level; because the lower confidence limit is greater than zero, it also implies that the null hypothesis of no radiation effect (EARlGV= 0) is rejected at significance level 4~hielded kerma is the kinetic energy released per unit mass after the incident radiation has passed through intervening shielding material, but before entering the body. 12 / 2 . EPIDEMIOLOGICAL UNCERTAINTIES Table 2.2-Summary measures of radiation dose response for cancer mortality by site:aBoth cities, both sexes (unless otherwise stated), 1950 to 1985 (shielded kerma). all ages ATB~, Site of Cancer Number Estimated Relative Excess Absolute Risk of per lo4 PYe Gy Risk a t 1Gy Deaths All malignant neoplasms Leukemia All except leukemia Digestive organs and peritoneum Esophagus Stomach Colon Rectum Liver, primary Gallbladder and bile ducts Pancreas Other, unspecified Respiratory system Lung Female breaste Cervix uteri and uteruse Cervix uterie Ovarye Prostatee Urinary tract Malignant lymphoma Multiple myeloma Other aAdopted from Table 2a of Shimizuet al. (1988). Additional detail on individual organs is given in Table 2b of Shimizu et al. (1988). b~~~ = at the time of the bomb. ' Y = person years. P d( ) Numbers i n parentheses indicate 90 percent confidence interval. Blanks in the Table indicate no lower confidence limit was provided. eRisk estimation for these sites is based on either males or females only. 2.2 SPECIFIC EPIDEMIOLOGICAL UNCERTAINTIES / 13 p = 0.05 in favor of the one-sided alternative of a positive effect (EAR~G!, 0). > In science, generally a bias or systematic error is something that may invalidate the results of a study, but more often can be accounted for by a modification of the results, i.e., a correction. If, for example, smoking were more prevalent among high dose than among low-dose subjects, an analysis of radiation-induced lung cancer risks that did not adjust for smoking or an adequate surrogate, would be biased. A recognized bias can be corrected by modifying the statistical algorithm for estimation or, if that is not possible, by introducing a rationale for subjective adjustment with uncertainty factors contributing to the overall random error. Uncorrected biases should be included among random errors. Statistically, a biased estimate is one whose expected value is not equal to the value of the parameter being estimated. Thus, whether the estimate is biased or not may depend upon the use to which it is put. In the example of breast cancer mortality (Table 2.2), 1.02 excess deaths per lo4 PY at 1Gy, and a RR of 2.00 (ERRlGy = 1.00) are unbiased estimates of EAR and ERR, respectively, at 1Gy as a weighted average over all ages at exposure for the period 1950 to 1985. But they are biased estimates of the EAR and ERR following exposure at age 10, because other analyses in the same study show that both absolute and RR vary by exposure aze. An example of bias resulting from statistical random error occurs with respect to individual dose estimates, and is discussed later (see Section 3.2). 2.2 Specific Epidemiological Uncertainties The statistical uncertainty in the risks derived from the 1950 to 1985 LSS mortality data (assuming the doses are known correctly) is represented by the confidence intervals in the EAR coefficients, e.g., see Table 2.2 adapted from Table 2a of Shimizu et al. (1988). For all cancer deaths, the EAR coefficient is 10.0 per lo4 PY Gy at 1 Gy with 90 percent confidence interval, 8.36 to 11.8, i.e., the 90 percent confidence limits are within about 220 percent of the nominal value. For leukemia, it is 2.29 (1.89 to 2.73) per lo4 PY Gy (also about 220 percent), and for all solid tumors, 7.41 (5.83 to 9.08) per lo4 PY Gy or about z25 percent. Further data are available for some individual tumor sites such as stomach, colon, lung, breast, etc. with somewhat larger confidence intervals, often of the order of *50 percent (see Table 2.2). 14 / 2. EPIDEMIOLOGICAL UNCERTAINTIES In this Report, the nominal value of the lifetime risk coefficient RHN(Rm = Hiroshima and Nagasaki) for all cancers for high-dose and dose rate, is taken to be 10 x SV-' (see Section 7) for a population of all ages. For the purposes of the uncertainty analysis, Rm will be assumed to have the same relative statistical uncertainty due to sampling as for the solid tumors over the period of observation, viz 225 percent. Consequently, a factor, F(RHN), which takes into account the statistical uncertainties associated with RHN,will be assumed to be normally distributed (a reasonable assumption based on a linear response model), with an average of one and a 90 percent confidence interval from 0.75 to 1.25, corresponding to a standard deviation of 0.15. The probability distribution of F(RHN) shown in Figure 2.1. is The risk coefficients in Table 2.2, which summarizes the atomic-bomb survivor experience from 1950 to 1985,were obtained with a linear model, parameterized as follows: Risk = a + PD or Risk = a (1+ yD), where a represents the baseline rate, P the EAR coefficient, y the ERR coefficient, and D is the dose. If the EAR and ERR have the same value then p = ay but, if p and y have fixed values while a does c not and instead varies with city, sex, age, etc., the absolute risk (AR) and RR models cannot predict the same risk for all combinay tions of these factors, i.e., p and a cannot always be equal. A more usual practice, not followed in the calculations leading to the results in Table 2.2, is to model RR and then convert to age-specific AR by multiplying the estimated ERR by the age-specific baseline risk. The usual practice in estimating the risk coefficient (once the choice between relative and AR has been made) is to use the simplest dose-response model consistent with the data. Linear estimates are given in Table 2.2, at least partly because, for all solid cancers combined and most single organ sites, no statistically significant improvement in fit is obtained by adding dose-squared or higher power terms to the linear dose-response model. Sometimes, this occurs because linearity fits the data very well, and the estimated dose-squared coefficient, E, in a quadratic model, e.g., in Risk = a (1 + yD + dl2), (2.3)