NCRP REPORT No. 104
THE RELATIVE BIOLOGICAL EFFECTIVENESS OF RADIATIONS OF DIFFERENT QUALITY Recorr~niendationsof the N...
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NCRP REPORT No. 104
THE RELATIVE BIOLOGICAL EFFECTIVENESS OF RADIATIONS OF DIFFERENT QUALITY Recorr~niendationsof the NATIONAL COUNCIL O N RADIATION PROTECTION AND MEASUREMENTS
Issued December 15, 1990 National Council on Radiation Protection and Measurements 7910 WOODMONT AVENUE 1 Bethesda, MD 20814
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 reports. However, neither the NCRP, the members of NCRP, other persona contributing to or misting in the preparation of this report, nor any person actingon 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 pmceas diacloaed in this report may not infringe on privately owned rights; or (b) assume8 any liability with respect to the use of, or for damages resulting from the use of any information, method or process disclosed in this report, under the Civil Rights Act of 1964, Section 701 et seq. as amended 42 U.S.C. Section 2 W e et seq. (Title VII) or any o t k r statutory or common law theory governing liability.
Library of Con-
Cataloging-in-PublicatianDate
National Council on Radiation Protection and Measurements. The relative biological effectiveness of radiations of different quality : recommendations of the National Council on Radiation Protection and Managementa. p. cm.-(NCRP report : no. 104) "Ieeued December 15, 1990." Includes bibliographical references. ISBN 0-929600-12-6 :$22.00 (eat.) 1. Radiation-Physiological effect. 2. Relative biological effectiveness (Radiobiology) I. Title. II. Series. IDNLM: 1. Dose-Response Relationship, Radiation. 2. Radiation Effects. 3. Radiation Protection-standards. 4. Relative Biological Effectiveness. WN 650 N279rbl QP82.2.R3N35 1990 59Y.01915--&20 DNLMIDLC for Library of Congress
Copyright O National Council on Radiation Protection and Measurements 1990 All rights reserved. This publication ie proteded by copyright. NOpart of this publication may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission h m the copyright owner, except for brief quotation in critical articles or reviews.
Preface The relative biological effectiveness of radiations of different quality is examined in detail in this report. The analyses were performed by Scientific Committee 40 of the NCRP which is charged with the responsibility for analysis and evaluation of radiobiological data relevant to radiation protection recommendations. This report is a follow-on to the previous report of Scientific Committee 40 on its evaluation of the effects of dose rate which was published in 1980 a s NCRP Report No. 64 entitled Influence ofDose And Its Distribution In Time On Dose-Response Relationships For Low LET Radiations. Initially, it had been planned that the effects of dose and dose rate and relative biological effectiveness of radiations of different quality would be addressed in the same report. However, later, the Committee recommended publishing two separate reports which resulted in the publication of NCRP Report No. 64 and this report in succession. The Committee intentionally has not made recommendations on how to use the available RBE data in defining a quality factor (Q) for any of the radiations studied. Rather, the Committee performed a comprehensive compilation of RBE data across many different biological systems for numerous radiations of different quality. The evaluation of this data with regard to recommendations for Q will be performed by or under the umbrella of Scientific Committee 1on Basic Protection Criteria. The International System of Units (SO is used in the report in accordance with the procedures set forth in NCRP Report No. 82 entitled, SZ Units In Radiation Protection And Measurements. Serving on Scientific Committee 40 during the prepartion of this report were:
Victor P. Bond, Chairman Brookhaven National Laboratory Upton, New York Seymour Abrahamson University of Wisconsin Madison, Wisconsin
Eric J. Hall Columbia University New York, New York
iv
1
PREFACE
John D. Boice, Jr. National Cancer Institute Bethesda, Maryland
George Hutchisona Harvard School of Public Health Boston, Massachusetts
R.J. Michael Fry Oak Ridge National Laboratory Oak Ridge, Tennessee Douglas Grahn Argonne National Laboratory Argonne, Illinois
Gayle Littlefield Oak Ridge National Laboratory Oak Ridge, Tennessee Charles W. Mays (deceased) National Cancer Institute Bethesda, Maryland
Peter Groer" Harold Smitha Oak Ridge National Laboratory Brookhaven National Laboratory Oak Ridge, Tennessee Upton, New York Robert Ullrich University of Texas Gaveston, Texas Consultant John F. Thomson Argonne National Laboratory Argonne, Illinois NCRP Secretariat-William M . Beckner 1982-1990 E. Ivan White 19NL1982 Thomas Fearon 1978-1980 The Council wishes to express its appreciation to the members of the committee and consultant to the Committee for their time and effort devoted to the preparation of this report.
Warren K. Sinclair President Bethesda, Maryland September 26, 1989
.The Committee was reconstituted in 1984. Completing their service at that time were P. Gmer, G. Hutchieon and H. Smith.
Contents Preface ........................................................................................ iii 1 Introduction .......................................................................... 1 1 1.1 Summary .......................................................................... 2 1.2 Scope of the Endeavor ..................................................... 1.3 Definitions of FU3E and Radiation Quality ................... 3 1.4 Background Information ................................................. 5 1.5 Alternatives to the RBE Concept .................................. 13 2 Cytogenetic Effects in Plant, Animal. and Human Cells ........................................................................................ 2.1 Introduction ..................................................................... 2.2 Cytogenetic Effects in Plants ......................................... 2.2.1 Environmental Effects .......................................... 2.2.2 RBE Versus Dose and Dose Rate ......................... 2.2.3 RBE Versus LET ................................................... 2.2.4 Tradescantia Studies ............................................. 2.2.5 Summary of Cytogenetic Effects in Plants ......... 2.3 Cytogenetic Effects in Human and Other Mammalian Cells .................................................................................. 2.3.1 DoseResponse Relationships for Low-LET Radiation ................................................................ 2.3.2 DoseResponse Relationships for High-LET Radiation ................................................................ 2.3.3 FU3E Values for Cytogenetic Effects in Mammalian Cells .................................................. 2.3.3.1 Variation of RBE with Radiation Dose ... 2.3.3.2 RBE, for Cytogenetic Aberrations in Human Cells After In Vitro Exposures to Radiations of Differing LET ............... 2.3.3.3 RBE Values for Chromosome Aberrations in Human Cells After I n Vim Exposure to High-LET Radiations ... 2.4 Summary .......................................................................... 3 Transformation and Mutation in Mammalian Cells h Vitro ....................................................................................... 3.1 Introduction ..................................................................... 3.2 Radiation Induced Oncogenic Transformation Assayed In Vitro ............................................................................. 3.2.1 Basic Techniques ..................................................
.
.
.
vi
I
CONTENTS
3.2.2 Data for Neutrons: Fresh Explants of Cells from
................................................. and Fission Neutrons ............................................
Hamster Embryos
3.2.3 Data for C, W1OT 4fr Cells with High Energy
3.2.4 RBE Data for Incorporated Radionuclides and
Alpha Particles in 3T3 Cells
................................
3.3 Radiation-Enhanced Viral Transformation .................. 3.3.1 Basic Technique .................................................... 3.3.2 Data ........................................................................ 3.4 Mutation Studies with Mammalian Cells in Culture .. 3.4.1 Basic Technique .................................................... 3.4.2 The Mechanism of the Hypoxanthine-Guanine
Phosphoribosyltramferase (HGPRT) System ......
3.4.3 Radiation-Induced Mutation Studies ................... 3.4.3.1 Chinese Hamster V79 Cells ..................... 3.4.3.2 Human Fibroblasts .................................... 3.4.4 Conclusions From the Mammalian Cell
Mutation Data
.......................................................
3.4.5 The Pros and Com of the HGPRT System and
New Developments
.
................................................
3.4.6 Other Mdel Systems for Mutation Studies ........ 3.4.7 Mutation and The Dose Rate Effect ....................
4 Hereditary Eff-I ......................................................... 4.1 Dominant Lethal Mutations ........................................... 4.1.1 Neutron Irradiation .............................................. 4.1.1.1 Effects on Male Mice ................................ 4.1.1.2 Effects on Female Mice ............................ 4.1.2 Alpha Particle Irradiation .................................... 4.1.2.1 EGcts on Male Mice' ................................ 4.1.2.2 Effects on Female Mice ............................ 4.2 Chromosome Aberrations and Reciprocal
Translocations Induced in Spermatogonia .................... 4.21 Neutron Irradiation .............................................. 4.2.2 Alpha Particle Irradiation .................................... 4.3 Effects on Cells in Meiosis ...................... . . . ............. 4.4 Abnormal Sperm Morphology ........................................ 4.5 Summary .......................................................................... 5 Hereditary Eff&II ........................................................ 5.1 Mammalian Germ Cell Mutagenesis ............................. 5.1.1 Specific Locus Mutations-Spermatogonia ......... 5.1.2 Specific Locus Mutations in Oocytes ................... 5.1.3 Mammalian Germ Cell Summary and Conclusions ............................................................ 5.2 Non-Mammalian Germ Cell Studies .............................
.
5.2.1 Drosophila ............................................................ 95 5.2.2 Silkworm Studies ................................................. 101 5.2.3 RBE Values For Interspecies Genetic-
.
Cytogenetic Endpoints
..........................................
6 Experimental Carcinogenesi~ExtemdHigh-LET
105
Radiation .............................................................................. 106 106 107 107 110 113 6.2.4 Dose-Rate Effects .................................................. 113 6.3 Epithelial Cell Tumors ................................................. 114 6.3.1 Ovarian Tumors ................................................... 114 6.3.2 Dose-Rate Effects .................................................. 115 6.4 LungTumors ................................................................... 117 6.4.1 Types of Lung Tumors .......................................... 117 6.4.2 Lung Adenoma ...................................................... 118 6.4.3 Lung Adenocarcinoma .......................................... 119 6.4.4 Fractionation and Dose-Rate Effects on Lung Tumors ................................................................... 122 6.6 Mammary Tumors ........................................................... 123 6.5.1 Mammary Adenocarcinomas ................................ 123 6.5.2 Dose-Rate and Fractionation Effeds on Mammary Tumors ................................................. 126 6.6 Harderian Gland ............................................................. 126 6.7 Tumorigenesis in Rats .................................................... 127 6.7.1 Mammary Tumors ................................................ 127 6.7.2 Fractionation and Protraction .............................. 133 6.7.3 Skin ........................................................................ 133 6.8 Studies in Other Species ................................................. 133 6.9 Dose Rate and Fractionation .......................................... 134 6.10 The Relationship of LET and RBE .............................. 135 6.11 Conclusions Concerning the Influence of Radiation Quality on Carcinogenesis ............................................ 139 7 Internal Emitters ................................................................. 142 7.1 RBE of Alpha-Particles Versus Beta Particles for Inducing Bone Sarcoma .................................................. 142 7.2 RBE of Fission Fragments Versus Alpha Particles for Inducing Bone Sarcoma ................................................. 148 7.3 RBE of Alpha Particles Versus Beta Particles or Gamma Rays for Inducing Liver Chromosome Aberrations ...................................................................... 149 7.4 Lung Cancer Toxicity Ratio from Alpha Versus Beta Particles ........................................................................... 149 6.1 Introduction ................................................................. 6.2 Leukemia in Mice ......................................................... 6.2.1 Myeloid Leukemia ................................................. 6.2.2 Thymic Lymphoma ............................................... 6.2.3 Other Lymphomas .................................................
.
viii
1
CONTENTS
7.5 Toxicity of Selected Radionuclides Relative to 226Ra ... 150 7.6 Summary of Internal Emitters ...................................... 151
. Life Shortening in Mice..
RBE ......................................... 152 Introduction ..................................................................... 152 Single Exposures ............................................................. 155 Short-Term Fractionated and Protracted Exposures ... 157 Duration-of-Life and Other Long-Term Fractionated or Protracted Exposures ................................................. 161 8.5 Discussion of Life Shortening in Mice ........................... 163 9 Discussion and Conclusions ............................................. 167 References .................................................................................. 171 The NCRP ................................................................................ 198 NCRP Publications ................................................................ 205 Index ........................................................................................... 215
8
8.1 8.2 8.3 8.4
.
1. Introduction 1.1 Summary
This report is a review of the literature relevant to the selection of relative biological effectiveness (RBE) values for use in arriving at values of the quality factor (Q). Emphasis is placed on responses to small (
Z 10"
3 V) \
V)
I-
5
z a
0
tiz a a
95 % confidence limits
I-
10-~
lo-*
lo-'
lo0
10'
DOSE (Gy) Fig. 3.1 Pooled data,for the hamster embryo cells, of the number of transformanta per surviving cell following irradiation with 250 kVp x-rays (full symbols) or 430 keV monoenergetic neutrons (open symbols) produced at the Radiological Research Accelerator Facility. The e m r bars indicate 95 percent confidence intervals for the estimated value. The e w e s ahould be regarded only as a m t h repre~ntationof the shape of the data with a minimum of parametric-related bias.(From Hall et al., 1982).
at higher doses. Neutrons are clearly more effective than x rays in both cell killing and the induction of transformations. When the RBE of neutrons as compared to x rays was calculated as a function of dose for both oncogenic transformation and cell sunrival, it indicated clearly that the RBE value changed with dose for both endpoints examined (Figure 3.2).
52
/
3. TRANSFORMATION AND MUTATION
-
1
7
HAMSTER EMBRYO CELLS' 4 3 0 keV neutrons vs. 7 250 kVp x rays
lo2,
.
W
m
E-
_
d
-
= 10' --
O 0
--
loo-.
1
*...**.
1
10-~
..II... lo-'
-
Q'o
....#.*I
lo0
.*.**,.I
10'
NEUTRON DOSE (Gy) Fig.3.2 The RBE of neutrons versua x rays for hamster embryo cells plotted as a function of neutmn dose. The vertical bare correspond to oncogenic transformation as an endpoint, and indicate RBE values excluded with 80 percent confidence. RBE values for cell survival (open circles) are alao ehown. (FromHall et al., 1982).
It should be noted a t this point that the same authors, using the same transformation assay system, showed an RBE of two for x rays versus gamma rays at doses of a few tens of mGy (Borek, et al. 1983). Therefore, in considering RBE values for higher-LET radiations at low doses, it is necessary to take into account whether the reference radiation is x or gamma radiation. 3.2.3 Data for C$UIOTII, Cells with High Energy and Fission Neutrons Using C3H/10T1/, cells, Han and Elkind (1979) investigated the effect of single and fractionated doses of both x rays and a hardened beam of fission spectrum neutrons (average energy & = 0.85 MeV, 200 keV pm-' the picture is different; with increasing atomic number the inactivation cross section increases. Although there is a saturation effect, as indicated by the earlier work, the saturation cross section does not correspond to the geometrical cross section of the cell nucleus as implied by the suggested overkill effect. The rate of induction of chromosome aberrations is greater with the greater track diameters and not the higher LET values when different energies of the same heavy ion are compared. The investigations of the relationship of track structure and energy transfer to carcinogenesis have not progressed as far as the cell survival studies. However, some studies have provided some information about the relationship of LET to RBE. A systematic investigation of the LET-RBE relationship has begun using helium, carbon, neon, argon, and iron ion beams generated by the BEVALAC and with the mouse Harderian gland as the test system (Fry et al., 1985).In the completed experiments, the effect of heavy ions, with the exception of iron, were studied with the Bragg peaks of heavy ion beams, spread by a ridge filter. The dosimetry and estimate of an average LET of such beams is complicated by fragmentation and the inherent problems of LET determinations. However, the comparative tumorigenic effect of the various heavy
1
137 ion beams is of interest. It can be seen in Figure 6.22 that the curves for prevalence as a function of dose show an increasing effect from Wo, argon and iron, respectively. The estimated effect of the heavy ions, argon and iron, appears to be comparable to h i o n neutrons. The estimates of RBE given in Table 6.3 are based on the slopes of the initial part of the dose-response curves for fission neutrons 0.25 Gy rnin-I and the slope of the dose response for lS7Csgamma radiation 0.083 Gy d - I (Ullrichet al., 1976;Ullrich and Storer, 1979; Ullrich. 1984).The error associated with the RBE values have been approximated, i.e., S.E.= RBE [ ( s ~ +~ ) ' where fn and 6.10 THE RELATIONSHIP OF LET AND RBE
'*])I-
Y
HISTOLOGICAL DATA
0
0.4
Q0
1.2
1.6
2.0
2.4
2.8
3.2
Eigure 632 Prevalence of Harderian gland tumow as a function of dose of heavy ions and 60Co Y rays: 'He, 228 MeVIamu; 12C,400 MeVIamu;T e , 425 MeVlamu;T e , 600 MeVIamu; and 'Oh,570 MeVIarnu. Irradiation of the mice was in spread Bragg peaks for all ions except q e , for which the plateau region of the beam was used. Precise LET valuee are diflicultto determine for the spread Bragg peak m u r e 8 but the doae-average LET values were estimated to be as follows: "He, 1 - 2 keV '2C, 80 keV p,m-l; mNe, 160 keV pm-I; q e , 190 keV pm-I; and *Ar, 650 keV pm-l. (Adapted from Fry et al., 1985).
TABLE 6 . 3 - ~ s t i m t e s of RBEM b m initid sbpea
Mow Strain
RFM
Sex
P
'l'ieeue-tumor
Thymic lymphoma Ovarian tumor Pituitary Harderian gland Lung tumor
BALB/c
9
of f i s s h neutron and gamma-ray response c u w r for difiervnt tissue-tumor t y p s fn 0.56 2 0.004 0.52 -C 0.04 0.41 2 0.21 0.54 + 0.03 1.7 -c 0.15
Initial elope Y
RBEM
0.021 +. 0.02 0.0 0.007 0.005 0.015 r 0.004 0.29 + 0.151
27
+
a
59 36
6
Approximate S.E.of RBEy 2
26
+-52
+
*
10 3
4
I3 L?
g
.n
Lung adenocarcinoma
0.76 2 0.19 0.041 2 0.009 2 6 19 Mammary carcinoma 1.14 0.27 0.035 2 0.01 33b 2 12 'RBE, values are not given for ovarian tumors because it is not clear that RBE, is appropriate for these tumors. For example, it can be seen that infinity is the arithmetical value for the RBE of ovarian tumors. This illuetrates the problem of the use of RBE for tumom that demonstrate a threshold responee. bHigher values (approximately 70) have been estimated for low dose rate neutron expmures.
8
6.11 CONCLUSIONS
1
139
y = the coefficients for the initial slopes for the responses to fission neutron and gamma radiation, respectively.
6.11 Conclusions Concerning the Muence of Radiation Quality on Carcinogenesis The following conclusions seem to be justified concerning the influence of radiation quality on radiation carcinogenesis. (1) The LET-dependent differences in the tumorigenic effeds of different radiation qualities are assumed to be quantitative and not qualitative. That is, there is little evidence that different radiation qualities influence the biological characteristics (such as malignancy) of the tumors induced. The RBE of a particular radiation is not only LET dependent but also dose dependent, tissue dependent, dose rate and dose fractionation dependent. In the case of mice, the risk of death from tumors in females is about twice that in males for both gamma and fission neutron radiation, and therefore, RBE values for comparable tissues should be independent of sex. The RBE value may vary with age. The excess incidence of tumors induced per unit dose of radiation varies between tissues. At low doses the tissuedependent differences are greater with low LET radiation than with neutrons. As a result of these differences the RBE values have a very wide range. (2) Dose-response curves for tumor induction by some high-LET radiations, such as fission neutrons, that include doses greater than about 0.2 Gy are not linear, although the initial part of the curve almost certainly is linear. Thus, linear interpolation cannot be used to estimate the effects of low doses from data obtained a t higher doses. The dose range over which the response appears to be linear varies with different tissues. A number of factors influence the shapes of the dose-response curves for tumor induction, and as yet no acceptable model has been derived that takes into account all the physical factors, such as the distribution of dose in the tissue and cell, and all of the biological factors that include cell killing. Doseresponse curves (tumor incidence as a function of dose) reflect the sum of the effeds of all the factors that influence the induction of the initial events and their expression. There are endogenous and exogenous factors that determine whether or not the induced tramformation in initiated cells is expressed and that cells progress to overt cancers. Therefore, the inci-
140
/
6.
EXPERIMENTAL CARCINOGENESIS
dence of tumors is a poor measure of the number of initiated cells capable of forming tumors (and vice versa). (3) The response to high-LET radiation is generally less dependent on dose rate than with low-LET radiation. However, the induction of rodent breast cancers following protracted exposure to fission neutrons has been found to be greater than single exposures at a high dose rate. (4) Although, there is limited information for tumorigenesis both in relation to total doses and tumor types, fractionation of the total doses of fast neutrons does not usually result in a reduction in the tumorigenic effeds in contrast to low-LET radiation. The results suggest that fractionation, protraction and lowering the dose rate of fission neutrons may increase the tumorigenic effect compared to single exposures in some tissues and for some fractionation regimens. However, the total dose, the dose per fraction, and in the case of split doses, the time interval between doses, all appear to be important in determining the effect of fractionation. (5) The RBE value of neutron radiation for tumorigenesis, in general, varies inversely with the neutron energy down to about 0.4 MeV. The RBE increases with LET,probably up to 100 to 200 keV pm-l, but the precise relationship of RBE to LET has not been delineated. It is of interest that other highLET radiations, such as some heavy ions, may be as effective as fission neutrons, but not more so. (6) Currently, there is an insflcient amount of suitable data for validation of possible models of the dose-response relationships for cancer induction &om external exposure to highLET radiations. The reasons for the inadequacy include: (a) a t very low doses of high-LET radiation the absorbed dose is an inadequate descriptor for energy deposition within the biologically significant target(s), (b)there are insuf%cientdata on the induction of cancer with very low neutron doses < 0.1 Gy in different tissues and in different strains and species, (c) most of the data from the mouse have been obtained from females and the high sensitivity of the ovary results in an altered hormonal balance (tumor incidences in hormonedependent tissues cannot be considered independent under such conditions), (d) some of the published conclusions about the dose-effect and dose-RBE relationships are based on data from experiments that determined changes in the times of appearance of tumors and not changes in tumor induction rates. Different mechanisms may be involved in the induction of a higher cumulative incidence than in the advancement of
6.11 CONCLUSIONS
1
141
time of appearance of tumors and it is not clear what generalizations can be made based on one or the other. (7) The range of values of RBEs is broad (from1to approximately 80, depending on tissue, dose rate, method of analysis, etc.), largely, but not entirely, because of marked differences in the responses to low-LET radiation. This makes RBE an unsatisfactory, but a t this time a necessary guide, in the choice of Q values for different radiation qualities. For tumors in which the dose response characteristics are sufficiently defined to derive RBE,the range in values is not as wide but substantial variability still remains (60 to 60).
Internal Emitters Extensive investigations have been made on the toxicity of internallydeposited alpha emitters in humans and laboratory animals (NAS/NRC, 1988). These studies have been very valuable in establishing the risks of cancer and other effects from radioactivity within the body. However, many of these results are of limited applicability in evaluating the RBE of alpha particles relative to low LET radiation in terms of dose to the target cells. This is because the alpha emitters usually deposit energy nonuniformly within tissue; the alpha-particle range in soft tissue is short (about 24 pm at 4 MeV for 232Thto 82 pm at 8.78 MeV for 212Po);and the precise locations of the target cells relative to the alpha emitters are often uncertain. As the distance from an alpha-particle source increases, the dose progressively decreases and is zero beyond the alpha-particle's range. The few studies in which these complications are minimal are the following: (1) Bone sarcoma RBE of alpha versus beta particles, (2) Bone sarcoma RBE of fission fragments versus alpha particles, (3) Liver chromosome aberrations of alpha particles versus beta particles or gamma rays. Discussion here of RBE values derivable from internal emitters is limited to the above three examples. In addition, the toxicity ratios (the ratio of averaged organ doses a t equal levels of effect) will be given for lung cancers produced by alpha versus beta particles and for bone sarcomas produced by selected radionuclides versus 226Ra.
7.1 RBE of Alpha-Particles Versus Beta-Particles for Inducing Bone Sarcoma
A preliminary analysis was published on the RBE of alpha-particles versus beta-particles for bone sarcoma induction in beagles and mice (Mays and Finkel, 1980).Their analysis has been updated here to reflect the following changes: (a) all of the beagles have died, (b) three additional bone cancers are included, (c)dogs dying before their minimal bone sarcoma appearance time of 500 days are excluded, (dl the assumed skeletal weight for young adult beagles is changed from
7.1 RBE OF ALPHA-PARTICLES
1
143
7.5 percent of body weight at injection to a more realistic 10 percent, (el skeletal retention equations are slightly revised (Miller and Buster, 1986) and (0the minor dose from 210Pband progeny is included in the 226Radecay series (Lloyd et a1. 1986b). No changes were required for the mice. These studies are of a particular importance because of the large amount of data on the effects of radium in man collected by Evans (Evans, 1974). 226Raand 90Srwere injeded intravenously into young adult beagles a t 17 months of age at the University of Utah (Miller and Buster 1986) and into young adult CF1 female mice at 70 days of age at Argonne National Laboratory (Finkel et al., 1959 & 1969a). Bone sarcomas, mostly osteosarcomas, were the main radiation-induced cancer in beagles (see Table 7.1 and Figure 7.1) and in mice (see Table 7.2 and Figure 7.2). 2asRais an alpha emitter and @OSris a beta emitter. Both are bone volume seekers so that the mean endosteal dose, 0-10 pm from bone surface, is roughly equal to the skeletal dose averaged over bone and marrow (Beddoe and Spiers, 1979; Mays and Lloyd, 1972). The average skeletal dose was computed at the assumed start of tumor growth, which was taken as 1 year before death in the beagles (Thurman et al., 1971), 140 days before death with bone sarcoma in the mice injected with and 100 days before first radiogmphic
AVERAGE SKELETAL DOSE IN GY AT I YEAR BEFORE DEATH F'ig. 7.1 Bone sarcoma incidence
2
1 S.D. in beagles iqjected with %or %r.
AVERAGE SKELETAL DOSE IN GY 100 DAYS BEFORE TUMOR APPEARANCE OR 140 DAYS BEFORE DEATH Fig. 7.2 Bone sarcoma incidence +- 1 S.D.in female CFI mice injeded with 226Ra or gOSr.
appearance of the tumors in the mice injected with 226Ra,to allow for the typical 40 days between first radiographic appearance and death with tumor (Mays and Finkel, 1980).Because the slopes of the retention curves for nGRa and 90Srwere similar, assumptions on the time span of the "wasted" radiation had little influence on the calculated RBE (Mays et al., 1969). The RBE of alpha particles versus beta particles in producing bone sarcomas was taken as the ratio of 90Srd ~ s e / ~ ~dose ~ Raat a given level of incidence (Table 7.3 and Figure 7.3).The RBE increased as the incidence decreased, reaching an RBE value of 25 at 7.7percent incidence in mice and a value of 26 a t 8 percent incidence in the beagles at Utah. Similar results were obtained for beagles at Davis, California, that received eight injections of 226Ra a t two week intervals beginning at 435 days of age or that received 90Srin food from mid-gestation until 540 days of age (Raabe et al., 1983).The basic tabular data for these beagles (Book et al., 1983)lists 125 dogs with bone sarcoma following 226Rainjection and 36 dogs with bone sarcoma following 90Srfeeding. When these data were analyzed in the same way as for the beagles a t Utah, the RBE of 226Rarelative to 90Srprogressively increased
hid
Nuclide
kw k p - I
TABLE7.1-Bone Time Or) From iqi. To death
sarcomus in beagles injected with 22sRaor Number of Dogs Number of Dogs With bone at 500 days Sarcoma Post injection
Incidence (percent)
Skeleton dose (Gy)one year Before death
TABLE7.2-Bone sammaa in female CFl mice iqjected with PsRa or soSr betted
=%a
%r
bBq b-' 4440 2960 1480 740 370 185 92.5 46.3 37.0 27.8 18.5 9.25 3.70 1.85 0
Number of mice at 150 days Post injection
Number of mice with Bone eareoma
Incidence or Mortality (percent)
45 44 45 44 43
14 31 33 38 34 28 45 22 56 94 80 19 5 11 6
31.1 70.5 73.3 86.4 79.1 62.2 43.3 21.2 23.4 18.7 11.7 7.7 2.0 4.3 1.2
45 104 104 239 504 683 247 252 254 521
81400 26 19 32600 45 41 16300 42 34 7400 59 8 3260 74 2 83 3 1630 329 104 0 166 119 2 48 148 2 0 149 2 Dose for 329 kBq kg-' level calculated at 460 days (600 days
-
73.1 91.1 81.0 13.6 2.7 3.6 0 1.7 1.4 1.3 140 days)
Bone sarcoma mice Av. days iqi. Skeltal dose (Gy) To appear (Ra) 100 days before appearance (Ra), Or death (Sr) Or 140 days before death (Sr)
328 359 394 428 484 544 639 657 643 686 655 580 853 710 730
289 213 118 64.2 36.4 20.4 11.9 6.14 4.80 3.83 2.44 1.09 0.62 0.26 0
z
Q)
, 9
aiz
C
%
7.1 RBE OF ALPHA-PARTICLES
TABLE7.3--Bone
I
147
samoma RBE ofaasRaversus 90Sr pe6Ra
Incidence percent
&particla (Gy)
Beagles
66.7 41.7 16.7 8.7 8.0
71.4 65.4' 59.3 23.2 21.1'
Mice
86.4 81.0 79.1 62.2 43.3 21.2 23.4 18.7 13.6 11.7 7.7
65'
Species
63 62a 55' 46' 37" 38" 35' 33 3 1. 27' 'Interpolated from curve8 on Figurea 7.1 and 7.2
a-particlea
(GY) 13.5' 8.77 3.37" 1.66 0.80
RBE
5 7 18 14 26
64.2 44.P 36.4 20.4 11.9 6.14 4.80 3.83 2.8P 2.44 1.09
1 1.4
2 3 4 6 8 9 12 13 25
AVERAGE SKELETAL DOSE IN GY FROM =RA a-PARTICLES Fig.7.3 Relativebiological effectivenessofalpha particlee from %and progeny, relative to beta particles from BOSr and progeny.
from an RBE value of nine a t 56 percent bone sarcoma incidence, to an RBE value of 20 at 12 percent incidence and RBE value of 35 at three percent incidence. Below three percent incidence, it is unknown whether the RBE of alpha particles, relative to beta particles, continues to increase or reaches some constant value. The high RBE at low incidence is due mainly to the low effediveness per Gy of beta particles for bone sarcoma induction at low doses and low dose rates. If the target cells for bone sarcoma production were deeper than the assumed 0 to 10 pm from bone surfaces (ICRP, 19771, then the doses to the target cells would be decreased proportionally more for the short-range alpha particles than for the long-range beta particles. This would increase the RBE values shown in Figure 7.3 by a constant multiplication factor, but the shape of the curves would remain unchanged. 7.2 RBE of Fission Fragments Versus Alpha-Particles for Inducing Bone Sarcoma When a heavy atom fissions, the two fission fragments recoil in opposite directions, producing tracks of ultra dense ionization averaging about 4,800 keV pm-' in soft tissue. To evaluate the effectiveness of fission fragments in bone sarcoma induction, beagles and mice were injected with 252Cfor 249Cf(Tayloret al., 1983).The skeletal dose from 252Cfis about one-half from fission fragments and one-half from alpha particles. The comparison isotope was 2*Cf, which emits alpha particles in 100 percent of its disintegrations and is identical chemically and metabolically to 252Cf.From combined results in beagles and mice, the average RBE ? S.D.for bone sarcoma induction by fission fragments relative to alpha particles was 0.1 2 0.1 (Mays et al. 1989). The low RBE of fission fragments for cancer induction agrees with the findings of Brooks et al. (1972), that fission fragments from 262Cf were very much less effective per Gy than alpha particles from "'Am in the induction of chromosome aberrations in the livers of Chinese hamsters. For equal doses, from %*Cffission fragments and alpha particles, the summed length of all the alpha tracks in tissue is about 34 times longer than that of all the fission tracks, as can be seen from the ratio of their average LETS in water (about 4,800 keV pm-' for fission fragments to 140 keV pm-I for alpha particles). Thus, about 34 times more cells were traversed by alpha particles than by h i o n fragments.
7.3 RBE OF ALPHA PARTICLES
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149
7.3 RBE of Alpha Particles Versus Beta Particles or Gamma Rays for Inducing Liver Chromosome Aberrations
Injected monomeric 239Pu,241Amand lUCe, in citrate solution, deposit uniformly throughout the livers of Chinese hamsters. Brooks et al. (1972)and Brooks (1975)found that low LET radiation from the beta particles of internallydeposited lUCe and protracted external gamma rays from 60Cowere equally effective per Gy in producing chromosome aberrations in the liver. However, the alpha particles from 239Puand 241Amwere about 15 to 20 times as effective as the protracted low LET radiation, Their results are plotted in Figure 2.9.
7.4 Lung Cancer Toxicity Ratio from Alpha Versus Beta
Particles A detailed analysis of world-wide data on radionuclide-induced lung cancer concluded that, in terms of the calculated dose averaged over the entire lung, the alpha radiation from inhaled radionuclides such as 239Puwas roughly 30 times as effective as the beta radiation from intratracheal intubation of radionuclides such as 14Ce in producing a given incidence of lung cancer (ICRP, 1980). Throughout the lungs of these laboratory animals, mainly rats, the local distribution of dose was nonuniform, especially for the alpha emitters. Results from inhaled =Rn progeny were not included in the analysis. Preliminary results have recently appeared from the Inhalation Toxicology Research Institute at Albuquerque on beagles that inhaled the beta emitters OOY,91Y,'We, or 90Srin fused aluminosiliin monodisperse parcate particulates, or the alpha emitter 239h02 ticulates. Within the lung, these particulates are retained mainly within the alveolar region. In terms of the averaged lung dose, the alpha dose from 239Puappeared to be about 10to 18 times as effective as the beta dose from 9'Y in producing a given risk from lung cancer (Boecker et d.,1988).However, many of the beagles exposed to received high dose rates exceeding 1 Gy d-l. Using the same data base, Griffith et al. (1987)found that the lung cancer risk per Gy from the beta emitters decreased with decreasing dose rate, and below 1 Gy per day appeared to be a constant one-third of that for the combined 91Yexposures. Thus, Griffith et al. (1987)suggest that it might require 33 to 58 times the average lung dose from a beta emitter, at low dose rate, to produce the same lung cancer risk as
the alpha dose from 239Pu. These conclusions are preliminary because about 30 percent of the lowdose 239pUdogs were still alive in 1987.
7.5 Toxicity of Selected Radionuclides Relative to aaeRa Bone-seeking radionuclides are classified as either bone-surface seekers or bone-volume seekers, depending on the skeletal location of their early deposition. Complications to this simple classification are that some of the volume seekers have a transient deposition on bone surfaces, whereas long-lived surface seekers become partially buried under the apposition of newly formed bone. A further complication is that a single intake of either a surface seeker or a volume seeker usually deposits nonuniformly. For example, radium concentrates in regions of bone accretion, whereas plutonium concentrates on endosteal surfaces. While attempts have been made to predict the toxicity of internallydeposited emitters by simplified mathematical models (ICRP, 1979), it may be more reliable to determine relative toxicities by direct experimental observation in laboratory animals. Radium-226 is often used as the comparison radionuclide, based on extensive knowledge of radiation effects in the U.S.radium dial workers (Aub et al., 1952; Evans, 1974;Finkel et al., 196913, Rowland et al., 1978 and 1983; Mays et al., 1985 and 1986). Table 7.4 shows the relative toxicity of selected bone-seeking radionuclides compared to 22% in terms of the average skeletal dose in GY. The alpha emitting surface seekers (%%f, wpWm, "'Am, =Pu, and 228Th)were all more toxic per unit of average skeletal dose than the bone volume seekers (n8Ra and 226Ra,both of which have alpha emitters in their decay series). Plutonium-239 was about 16 times TABLE7.4-Taxicity of selected bone-seekingmdionlrclides relative to =Ra in bone-samma induction in beagles and C57BLIDo mice (Mayset al., 1986, Taylor et al.. 1983 and Jones d al.. 1985) Toxieitv ratio
Radionuclide
mCf
a*zwcm %'Am
Beaglea
-
5.4 2 1.6 =TJll 16.6 2 4.5 % 8.5 2 2.3 228Re 2.0 0.5 ZL8Ra 1 .Based on average akelatal dose (in Gy)
.o
2
S.D..
Mice 5.0 4.4 4.9 15.3
2 1.4 2
1.8
2 1.4
2 3.9
-
1.0
7.6 SUMMARY OF INTERNAL E m R S
1
151
more toxic than 226Ra,both in beagles and in mice. Furthermore, 239PUwas about three times more toxic than the trivalent transplutonium radionuclides P41Am, 2430244Cm, and 249CfJ,suggesting that 239Pupreferentially deposits in high concentration in regions that are richly populated with cells that can be transformed into bone sarcomas. Among the bone volume seekers, the higher toxicity of relative to 226Ra, may result from, (a) the longer average range of the alpha particles in the 22sRadecay series (50 pm in soft tissue) compared to 40 pm for 226Raand its retained progeny, (b) the tendency of 22Thformed from the decay of 22eRain bone volume to redeposit on bone surfaces when the bone volume is resorbed, and (c) the redeposition on bone surfaces of some of the short-lived 3.62-day 2uRa produced by the decay of nsTh. In human radium dial workers, the effectivenessfor bone sarcoma induction, per Gy of average skeletal dose, for 228Rawas about 1.5 times that for (Rowland et al., 19781, in good agreement with the relative effectiveness of 2.0 & 0.5 derived for beagles (Mays et d., 1986).
7.6 Summary of Internal Emittera
The effectiveness of alpha emitters is high, relative to beta emitters,being in the range of 15to 50 times as effectivefor the induction of bone sarcomas, liver chromosome aberrations, and lung cancers. The RBE of alpha emitters tends to increase as the dose decreases, probably mainly due to the decreased effectiveness per Gy of low LET radiation a t low doses and low dose rates. Alpha emitters, like 2SgpUthat deposit on bone surfaces, are more toxic than alpha emitters like 226Rathat deposit within bone volume, and thus irradiate fewer target cells. The low RBE of fission fragments, relative to alpha particles, may be because mainly, at equal doses, many more cells are traversed by alpha particles than by fission fragments.
8. Life Shortening in Mice-
RBE 8.1 Introduction
Many end points of radiation injury that have been established quantitatively with low-LET (x or y) irradiation have been also measured with high-LET radiations, particularly neutrons, yielding RBE estimates that may vary over two orders of magnitude, depending on the biological system under study and the radiation doses and dose-rates employed. This section is a review of most of the large-scale rodent studies carried out during the past 30 years in which life shortening from all causes of death was the end point of radiation iqjury. In practically all of these studies, the experimental animals were well-characterized strains (or hybrids) of the house mouse (Mus musculus), and the high-LET radiations were neutrons. However, it needs to be recognized that one of the major differences among mouse strains is their different susceptibilities, both spontaneous and radiationinduced; and, furthermore, within a given strain, there are frequently sex differences in the incidence and time of onset of specific tumor types. Nevertheless, in all mouse strains examined, regardless of the spontaneous incidence of various tumor types, the radiation-specific excess mortality is almost entirely attributable to tumors, regardless of radiation quality, total dose, or dose rate (Grahn et al., 1978).This statement holds true for other species that have been examined, including the white-footed mouse (Peromyscus leucopus), a rodent that is taxonomically closer to the hamster than to the house mouse (Thomson et al., 1985a)],the beagle (T. E. Fritz, personal communication), and man (Beebe et al., 1978). Section 6 of this Report shows that each tumor type has an essentially unique RBE value, and that the extremes of these values may vary by a fador of five or more. This range is considerably greater than that observed for the RBE values for life shortening from all causes in different mouse strains, where the extremes differ by a factor of no more than two (Storer and Mitchell, 1984).
8.1 INTRODUCTION
I
153
Therefore, the use of life shortening from all causes, including deaths from infectious and degenerative diseases as well as tumors, has certain advantages, not the least of which is the objective and unequivocal nature of the end point. (There is often a degree of subjectivity in the assignment of a specific cause of death.) Of equal importance is the modulatory effect of this end point; the effect of an unusually high or low RBE value of a specific tumor type, particularly one of low incidence, will be diminished, and a more realistic RBE value for the high-LET radiation may be obtained. Earlier attempts to measure the RBE of neutrons for life shortening aRer single exposures at relatively high instantaneous dose rates and total doses gave estimates of about three, roughly the same as In these the RBE value for acute radiation toxicity (30day LD50). experiments, the investigators generally concluded that the doseresponse curves for both neutrons and gamma rays, at least over the appropriate dose ranges, were linear, so that the RBE value was essentially the ratio of the slopes of the two curves. Under some conditions, straightforward relationships between neutron RBE values and neutron dose can be derived; under other conditions, particularly in the lowdose range, the relationship may not be at all simple. The problem is that the establishment of reliable RBE estimates requires the establishment of dose-response curves for two radiations, the shapes of which may be difficult to determine satisfactorily (Land, 1980). More recent data, however, have shown that after small single doses of neutrons, the dose-effect curve for life shortening rises rapidly, then tends toward a plateau at higher doses. The proper description of the curve thus becomes the matter of primary concern, i.e., whether or not there is a linear initial segment, and which of a variety of curvilinear functions best describes the nonlinear portions of the curve. There are several problems associated with the measurement of RBE values for small doses of radiation. One of these relates to the fact that the effects of the low LET radiation-generally 60Coor 13'Cs gamma rays-are markedly dependent on dose rate: the more a given total dose is protracted or fractionated, the less effective it becomes, and, consequently the higher the RBE value for the highLET radiation becomes. In the case of high-LET radiation, however, there is strong evidence that a t least under some circumstances, fractionation of a given total dose may be more damaging than the same dose given in one exposure. In the case of life shortening in BGCF, mice (Thomsond al., 1981a),this augmentation phenomenon L dose), is most pronounced a t high doses (- 75 percent of the,D but there is no evidence of augmentation at a total dose of 0.2 Gy of
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8. LIFE SHORTENING LN MICE-RBE
0.8 MeV fission neutrons (Ainsworth et al., 1974, 1976; Thomson et al., 1981a). It follows then that any estimate of the RBE value must precisely specify the exposure conditions. The extreme values would be represented by: (1)a comparison of the effects of single doses of neutrons and gamma rays delivered a t instantaneous dose rates that are sufficiently high to obviate problems of dose-rate dependence (low RBE); and (2)a comparison of the effects of fractionated or protracted neutron doses with those of continuous low dose rate gamma radiation, where the differences in magnitude and direction of dose-rate dependence would be maximal (high RBE). Intercomparison of results from different laboratories is often difficult for several reasons: radiation sources, dosimetric procedures, and experimental animal strains are generally different. Although the differences in physical parameters can often be adjusted, the biological variables-genetic makeup, age at exposure, diet, housing conditions, bacterial and viral disease incidence, etc.-are not easily reconciled. There are, however, some radiation responses that seem to be essentially strain-independent (Grahn et al., 1978). A more important problem, however, is the difficulty in establishing the shape of the dose effect curves for both high and low-LET radiations in the low dose range, i.e., doses one to two orders of magnitude or so above background. Thus, the approach customarily employed is to use data obtained a t high doses as the basis of a model for extrapolation to low doses. As will be pointed out, however, the mathematical function that best describes the neutron dose-response curve for single doses above 0.1 to 0.2 Gy does not satisfactorily predict the observed results for life shortening after lower doses. A survey of data published before 1981suggests that the relationship between neutron dose (D)and the RBE value for life shortening, regardless of the mode of neutron exposure (single, fractionated, or continuous) could be expressed as: RBE value
=
ADB
(8.1)
where the value of B was approximately a negative 0.5 and that of A (the RBE value a t 0.01 Gy) ranged from 10 to 80, depending on a number of factors, the most important of which was the instantaneous dose rate of the reference low-LET radiations (Thomson et al., 1981a, 1981b). This analysis employed the radiation-specific excess mortality rate [approximated by the method of Sacher (1976); see Thomson et al. (1981a) for the complete derivation], and led to a conclusion compatible with that advanced by Rossi (1977a1, i.e., that the neutron RBE value varied inversely with the square root of the neutron dose
8.2 SINGLEEXPOSURES
1
155
However, almost all of the data then available on life shortening after neutron exposures involved total doses greater than 0.2 Gy the exception being the experiments of Storer et al. (1979). More recent data from the Argonne and the Oak Ridge National Laboratories on both single and fractionated neutron exposures at doses as low as 0.01 Gy have cast doubt on the usefulness of Equation 8.1, and suggest that: (1)the initial segment of the neutron dose-response curve, like that of the gamma-ray curve, is indistinguishable from linear, and (2) there may be a limiting value for the RBE (Storer and Mitchell, 1984; Thomson et al., 1985a). Dennis (1987)has suggested that Equation 8.1 is a special form of a complex equation, and is not valid at low neutron doses. The more general form of his equation is: RBE value
=
A (K + D)B
(8.2)
The constant K is about 0.04 Gy for single exposures, and about 0.2 Gy for fractionated exposures. Clearly, when D is large relative to K, Equation 8.2 approaches Equation 8.1. Conversely, when D is small relative to K, the RBE reduces to a constant value.
8 2 Single Exposures
The results of studies of the effects of single exposures to 0.85 MeV fission neutrons (from the JANUS reactor) and 60Cogamma rays on life shortening in BGCF, mice (C57BLI6 x BALBIc hybrids) have been published by Thomson et ul. (1981a, 1983,1985a, 1985b).In the experiments reported in the first two papers, the dose ranges were 0.05 to 2.4 Gy for neutrons, and 0.9 to 7.88 Gy for gamma rays. In general, exposure times were 20 minutes, and the instantaneous dose rates were varied from 0.0025 to 0.12 Gy min-I for neutrons and 0.045 to 0.39 Gy min-I for gamma rays. It was clear that the life shortening per Gy of gamma radiation was relatively constant over the entire dose range studied, so that the data could be fitted with a single linear equation with a slope of about 40 days of life lost per Gy. However, for neutron exposures the life shortening per Gy varied inversely with neutron dose, and the data could be best fitted by a power function [see Thornson et ul. (1983) for the parameters]. If one examines the lowest end of the dose range (0.05 to 0.2 Gy) it is evident that a linear dose-response curve cannot be rejected (Thomson et al., 19831, and, therefore, a limiting value for the neutron RBE is possible, about 12 for males and 18 for females. An
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8. LIFE SHORTENJNG M MICE-RBE
independent analysis by Storer and Mitchell (1984) of these data as well as those from Oak Ridge National Laboratory (Storer et al., 1979; Storer and Ullrich, 1983) suggested a range of RBE values from 13 to 23, depending on sex and strain (and possibly, differences between the laboratories in physical factors, such as neutron energies and dosimetry). An experiment a t Argonne National Laboratory (Thornson et d., 198%) was specifically designed to examine directly the shape of the dose-response curves for female mice at low doses of neutrons (0.01, 0.025,0.05,0.1,0.2 and 0.4 Gy) and gamma rays (0.225,0.45 and 0.9 Gy). The results show that the prediction equations presented by Thomson et al. (1983) seriously overestimate the life shortening a t the lowest doses, although the agreement between observed and predicted values is reasonably good at doses above 0.05 Gy. Over the range of 0.01 to 0.1 Gy a linear dose response is satisfactory; inclusion of the data at 0.2 Gy and above cause the linear fit to be rejected. The slopes of the neutron (0 to 0.1 Gy) and gamma ray dose-response curves are 561. and 38. days of life lost per Gy, respectively, and the RBE value, given by the ratio of the slopes, is 15.0 + 5.1. The entire range of neutron doses 0.01 to 0.4 Gy can also be fitted reasonably well by a linear-quadratic equation of the form: Y = a + b,x + b2x2,where x is the dose and Y is the mean after survival. The limiting RBE value will then be the ratio of the fist power coefficient, b,, to the slope for the gamma dose-responsecurve, or 14. In 1979,Storer et al. published considerabledata on life shortening in female RFM and BALBIc mice after gamma (13'Cs) or neutron radiation from either the HPRR reactor or a 252Cfsource, depending on the dose rate desired. In a subsequent publication, Storer and Ullrich (1983) presented additional data on the BALBIc strain. The radiation responses of the two strains were appreciably different. Over the dose ranges of 0.048 to 0.47 Gy for neutrons and 0.1 to 0.5 Gy for gamma rays, Storer et al. (1979) concluded that the neutron dose-response curve for the RFM strain was linear, whereas that for gamma rays was parabolic (i.e., life shortening was a function of the square of the dose). Their estimate of the RBE was: RBE = 0.95 D,-0.5
(8.3)
where D, is the dose in Gy i.e., the same form as Equation 8.1. In the case of the BALBIc mice, the picture more closely resembles that seen with the BGCF, mice. The most recent analysis ofthese data (Storer and Mitchell, 1984)suggested linear dose-responsecurves for both neutrons and gamma rays, with a limiting RBE value of 13.3, similar to the value of 15.0 derived for BGCF, females.
8.3 FRACTIONED AND PROTRACTED EXPOSURES
TABLE8.1-Summary Neutron Doee Range
157
of projected RBE values at 0.05 Gy
Projected
Mouse
(Gy) Strain 0.28-2.5 C57L x M e male C57L x M e female CP-5 reador 0.36-2.75 CF No. 1 female Cyclotron, 1 MeV 1.3 -3.32 RF male Neutron Source
Weapons
1
B E value at 0.05 Gy
Reference
16
Upton et al. (1960)
12 10
Vogel et al. (1961) Upton et al. (1967)
Other large scale studies include those of Upton et al., (19601, Vogel et al. (1961), and Upton et al. (1967). In each case, the range of neutron doses was well above the level (0.1 or 0.2 Gy) where departure from linearity becomes obvious. The data conformed reasonably well to Equation 8.1; the parameters are given by Thomson et al. (1981a). From this equation, we have estimated the RBE value at 0.05 Gy of fission neutrons assuming that below this dose the RBE value will be constant, with the summary given in Table 8.1. This analysis is by no means precise, but it at least provides answers that are consistent with the results obtained by Storer and Mitchell (1984) and Thomson et al. (1985a) in the low-dose range. 8.3 Short-Term Fractionated and Protracted Exposures
This section examines some of the experiments in which mice were given either periodic exposures to radiation up to a predetermined total dose, or continuous exposure over an extended period of time ranging from a few days up to a few months (20 to 25 percent of the life span of the animal). In general, only those protraction or fractionation protocols in which fewer than 10 to 20 percent of the animals died during the exposure period have been considered. Concurrent with the single exposure series (see Section 8.2) using 0.85 MeV neutrons at Argonne, animals were exposed to similar total doses given in 24 weekly fractions (Ainsworth et al., 1974, 1976). From a comparison of the results of single and fractionated exposures (Thomson et al., 1981a), it is clear that the effectiveness of neutron radiation is greater (augmentation) when a given total dose is divided into 24 fractions. In the case of male mice, the life shortening per Gy is consistently 50 to 60 percent higher at all fractionated dose levels over the range of 0.2 to 2.4 Gy. In the case of females, however, the augmentation is less pronounced at low doses and is not obsewed a t 0.1 Gy total dose (Thomson et al., 1983). Thomson et al. (1981a) used the same analytical approach to these data on fractionated neutron exposures as they had used with single
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exposures, and concluded that the coefficient of Equation 8.1 (i.e., the RBE a t 0.01 Gy) was 60 to 80, three-fold greater than seen for single exposures. Much of this difference could be attributed to the decreased effectiveness of the total gamma dose when divided into 24 weekly fractions; the days of life lost per Gy dropped from about 40 for single exposures to about 20 for fractionated exposures. A reevaluation of these data (Thomson et al., 1983)showed that if linearity is assumed in the lowdose range for neutrons, the RBE value approaches a limiting value of 20 for males and 25 for females. Storer and Mitchell (1984) have reached essentially the same conclusions. The conditions under which the augmentation phenomenon occurs for neutrons have not been fully defined. There were no significant differences in life shortening following 2.4 Gy of fission neutrons given: (1)in 24 weekly fractions of 0.1 Gy; (2) 6 fractions of 0.4 Gy per fraction given at 4-week intervals; or (3) 72 fractions of 33.3 mGy given three times per week for 24 weeks (Ainsworth et al., 1974, 1976). However, an exposure series completed a t Argonne in which mice received neutron doses of 2.4 Gy in 1,2, 4, or 6 fractions with a one week interval between fractions did show a difference (Thomson et al., 1985a). Splitting the dose into two fractions of 1.2 Gy resulted in significantly greater life shortening than a single exposure; division into four fractions of 0.6 Gy each was even more effective. Six fractions of 0.4 Gy produced no greater effect than four fractions of 0.6 Gy; both regimens were as effective aa those employed earlier involving 24 weekly fractions. The augmentation of neutron-induced life shortening by fractionation or protraction of a given total dose is not universally observed. Storer et al. (1988) studied it in BALB/c mice exposed to 1.88 Gy delivered both continuously (0.01 Gy per day for 188 days) and in eight fractions (0.235 Gy per fraction) given seven weeks apart in RFM mice: the augmentation was observed only after continuous exposure. No differences in life shortening were seen in either strain following exposure to a total dose of 0.47 Gy, regardless of the mode of exposure. Considering all the data now available, it seemsunlikely that the neutron RBE a t total neutron doses below about 0.4 Gy will be significantly augmented by fractionation. In an experiment involving the white footed mouse (Peromyscus leucopus),the animals received total doses of 0.4 and 1.6 Gy delivered in either 24 weekly fractions or as single doses. The augmentation of life shortening was only 10 percent, rather than the 60 percent seen with the BGCF, Mus musculus (Thomson et al., 1986). Storer et al. (1979) exposed RFM and BALBIc female mice to 262Cf neutrons a t a dose rate of 0.01 Gy d-I for 24,47,94, and 188 days,
8.3 FRACTIONED AND PROTRACTED EXPOSURES
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159
and to gamma rays at a dose rate of 6.9 x Gy min- I, 0.083 Gy per 20 hour exposure dayfor6,12,24,and48 days(0.5,1,2 and4 Gy). At high total neutron doses, as mentioned above, the augmentation effect was clearly discernible in the BALBIc strains; at low doses, the dose-response curves tended to merge. Supplementary data on fractionated and protracted neutron exposures to BALB/c mice at lower total doses were presented by Storer and Ullrich (1983). From all these data, Storer and Mitchell (1984) concluded that the RBE value is about 13. As was the case for exposures to single doses of neutrons, the response of the RFM mice was different from that of the BALBIc strain. As mentioned above, the augmentation phenomenon was observed only a t the highest total dose (1.88 Gy). At the lowest dose (0.24 Gy), the life shortening following lowdose-rate exposure was only half of that observed after exposure at a rate of 0.25 Gy min-'. Another complication is that the effectiveness of both neutrons and gamma rays, as measured by days of life lost per Gy, diminished with increasing doses. for BALBIc mice, it can be estimated that the limiting value for days of life lost per Gy of protracted neutron exposure will be about 260 (not significantly different from the value of 290 for single exposures), while that for protracted gamma radiation will be about 35, significantly less than 105 observed for single exposures. Thus,for continuous short-term neutron exposures (24 to 188days, 3 to 20 percent of the life span) in BALBIc mice, the limiting value for the RBE is eight. In addition to the studies on the effects of single exposures, Upton et al. (1967) studied the effects (for the most part in RF female mice) of different rates, ranging from 0.003 to 8.3 x Gy rnin-' of neutrons, with total doses ranging from 0.016 to 9.3 Gy; and from 0.4 to 49.3 x lop6Gy min-I of gamma rays, with total doses from 1.01 to 98.75 Gy. Exposure times varied between 3 and 560 days. Unfortunately, no one dose rate was employed at a sufficient number of data points, spread over a broad enough dose range, to warrant a detailed examination of the dose-response curves for different dose rates. Therefore, the results obtained were pooled a t the same total accumulated dose, regardless of instantaneous dose rate, omitting from the analysis those data points at which more than 20 percent of the animals died during exposure. The data show that the life shortening per unit dose of neutron irradiation did not vary inversely with the dose but rather (within limits of error) remained constant, whereas the life shortening per unit dose of gamma ray irradiation increased rather markedly with increasing dose, at least between 0 and 6.1 Gy. Inspection of the data suggested that polynomial fits might be attempted; for days of life shortening (LS) the most satisfac-
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LIFE SHORTENING IN MICE-RBE
tory fits were a linear equation for the neutron data and a quadratic with a zero coefficient for the first-power dose for the gamma-ray data: LS (n) = 86.1 ( 2 12.1) D, (8.4) where D, is the dose of neutrons in Gy and Dy is the gamma dose in GY. The RBE equation derived from these equations becomes: (8.6) RBE = 6.63 D;0.5 Although the dose-response curves for RF female mice exposed to protracted gamma and neutron radiation do not resemble those seen with other strains, the relationship between RBE and neutron dose seems to be consistent. The coefficient of 6.63 may be compared with the value of 0.95 reported by Storer et al. (1979)(Equation 8.2),using the same analytical approach, for RFM female mice exposed to single doses of gamma rays and neutrons of high dose rates. The difference is largely attributable to the greatly reduced effectiveness of gamma radiation delivered to RFM or RF mice at low instantaneous rates. Neary et al. (1957) and Mole and Thomas (1961)presented results of experiments in which female CBA mice received either continuous or once-a-week exposures to neutrons at weekly dose rates of 0.022, 0.064,0.15, or 0.17 Gy (air doses) for varying periods of time. All of these data have been combined here because there were too few doses a t any given dose rate to treat separately. Further, the doses have been multiplied by the fador of 0.75 given by Neary et al. (1957) to convert air doses to absorbed doses. Over the range of 0.5 to 1.12 Gy, the dose-response curve is indistinguishable from linear, and the days of life lost per Gy of neutron exposure is given by: LS(n) = 278 ( + 50) (8.7) The RBE value will then be given by 278 b,-l, where b, is the days of life lost per Gy of gamma irradiation. Mole and Thomas (1961) provided data for continuous gamma irradiation at three weekly dose rates, 1 , 2 and 3.25 Gy, for which values of b, can be determined over a total dose range of 0 to 30 Gy. These are, respectively, 14.2, 16.6, and 28.3, and the RBE values become, respectively, 20,17, and 10. Although the absolute accuracy of these numbers is questionable, their relative values are less open to question, and emphasize the point made earlier that the neutron RBE values will depend on the conditions under which the dose-response curve for gamma radiation is established.
8.4 DURATION-OF-LIFE & OTHER LONGTERM EXPOSURES
1
161
It is instructive to compare these dose rates with those used by Sacher and Grahn (1964) in their duration-of-life gamma-ray studies. The lowest daily dose rate used by Mole and Thomas (1961)falls in the range of doses (below approximately 0.2 Gy d-'1 where the survival of the animal is dependent only on total dose, and is doserate independent (Sacher, 1976).The highest dose rate used by Mole and Thomas (1961) is in the dose-rate dependent portion of the response, and their intermediate rate is near the transition point. By analogy, it is possible that the RBE value of 20 will, in fad, be the limiting value, and would not be increased if still lower gamma rates had been studied.
8.4 Duration-of-Lifeand Other Long-Term Fractionated or Protracted Exposures
This section considers a number of experiments in which mice were exposed continuously or in weekly fractions for the duration of their lives. Also included are some experiments in which mice were exposed continuously or repeatedly for sufllciently long periods of time so that it may be presumed that any additional exposure would not have influenced their survival. The criteria for selection were (I) irradiation over longer than half the expected mean life span of the animal; andlor (2) death of more than 50 percent of the animals during the course of exposure. The use of total or mean accumulated doses in duration-of-life experiments may be misleading. Therefore, these sets of data have been analyzed in terms of dose rate, expressed as Gy per week or Gy per weekly fraction. The experiments described in this section (Thornson et al., 1981b)involved once-weeklyexposures, so that dose rate is defined as dose per weekly fraction. In the analysis of other data in which long-term continuous exposures were involved, the given daily dose rates were converted to weekly dose rates for the sake of conformity. Experiments have been described by Thomson et al. (198:Lb) in which mice were exposed once a week to small doses of neutrons (6.7 to 26.7 mGy per weekly fraction) and gamma rays (0.07 to 0.32 Gy per weekly fraction) either for 59 weeks (60 fractions) or for the duration of their lives. In the 60-fraction series, the total neutron doses were 0.4 to 1.6 Gy, the life shortening was the same as that observed after the same doses given in 24 fractions, and about 60 percent greater than that seen after single exposures. The total garnma-ray doses were 4.17 to 19.18 Gy and the life shortening was
162
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8. LIFE SHORTENING IN MICE-FU3E
less than that produced by 24 weekly fractions, which in turn was less than that produced by single exposures. The only difference in life shortening between the two protocols was observed in male mice receiving the lowest gamma-ray dose, 0.07 Gy per weekly fraction. The difference was not statistically significant and was largely attributable to a slightly higher proportion of deaths during the first 60 weeks of exposure in the durationof-life series. Therefore it was concluded that the radiation received after the 60th exposure did not contribute measurably to life shortening (i.e., the lethal process had been unalterably established by the time that 60 exposures were completed), and accordingly the data were treated as a single experiment. As in the other Argonne experiments reported a t the same time (Thomson et al., 1981a), a n inverse relationship between neutron dose and RBE value was observed readily. However, the range of total neutron doses (in the 60-week series) did not extend into the range where linearity might be expected. It could be established, however, that the RBE value would be a t least 21. Another series employed 60 once-weekly exposures to considerably Gy per weekly fraction lower dose rates, 3.3 x to 6.7 x for neutrons, 0.016 to 0.1 Gy per week for gamma rays (Thornson and Grahn, 1988). The dose-response curves for gamma radiation (both sexes) are linear throughout the total dose range of 1to 6 Gy, with slope coefficients of 18days of life lost per Gy per weekly fraction for males and 22 for females. It is equally clear that the neutron dose-response curves are linear over a range of total doses from 0.02 to 0.3 Gy, with slopes of 330 days of life lost per Gy (males) and 388 (females). Consequently, the RBE value for life shortening from longterm fractionated radiation is about 18 for both sexes. This number is lower than the limit suggested from the earlier study (Thomson, 1981b), principally because of a much greater sensitivity to gamma radiation shown by the mice in the more recent study, 1,100 to 1,300 days lost per rad per weekly fraction versus 700 to 900 in the earlier experiments. There are relatively few other experimental data with which these can be compared. Neary et al. (1957,1962) exposed CBA mice of both sexes to 0.7 MeV neutrons on a nearly continuous basis (average 140 hours per week) for the duration of life. Neutron doses ranged from to 0.157 Gy per week (air doses), with considerable 8.5 x gamma contamination; average total accumulated neutron doses ranged h m 0.087 to 8.75 Gy. Only two gamma-ray exposures, 0.158 and 1.11Gy per week with cumulative exposures of 16.26 to 72.52 Gy were carried out. Their data have been reexamined by Thornson et ad. (1981b). As in most other experiments, the life shortening per
8.5 DISCUSSION OF LIFE SHORTENING IN MICE
1
163
unit dose for neutron exposures decreased with increasing neutron dose rates, and when the data were fitted to a power function, the parameters for the CBA animals were very close (within 5 to 20 percent) to those for the B6CF1 mice. However, the RBE values differed by a fador of over two (45 for the CBA mice, 18 for the B6CF1's at the presumed limiting value). This difference reflects the fact that weekly exposure to gamma irradiation given in a 45 minute period is twice as effective as the same total weekly dose protracted over 8 to 12 hours per day, seven days per week (Sacher and Grahn, 1964). Consequently, the RBE value for continuous exposures to a given neutron dose rate will be about twice that observed for once-a-week fractionated exposures to an equivalent weekly dose rate, provided that the reference (gamma) radiation is delivered in the same mode as the neutron radiation.
8.5 Discussion of Life Shortening in Mice
In the absence of direct observations of life shortening following low doses of radiation, one approach is to search for an adequate mathematical description of data from higher doses. In many cases, the modified power function equations (Thornsonet al., 198la, 198Ib) provide the most satisfactmy fit for high doses but are poor predictors of the results at low doses (Storer and Mitchell, 1984). It is certainly true that in the case of the gamma ray dose-response curves, equally good fits can often be obtained with linear, linear quadratic, or quadratic h c t i o n s with a zero coefficient for the linear term regression equations. In the case of the neutron data, however, there are only a few cases where a linear fit is applicable except over a rather limited dose range; and although the neutron dose-response data can sometimes be fitted with a linear-quadratic equation (LS = a D + hD2), the coefficient of the dose-squared term is invariably negative. The results of the analyses can be summarized as follows. For single exposures to neutrons at relatively high doses P 0 . 2 Gy), data from several laboratories show a rather consistent pattern of an inverse relationship between RBE and the square mot of the neutron dose over substantial dose ranges, a pattern seen with many other test ol?jecta (Rossi, 1977a, 1982). It appears, however, that the pattern breaks down in the lowdose range; below 0.1 to 0.2 Gy for single exposures, the dose-response curve for neutrons is linear, or a t least indistinguishable from linear,
164
/
8. LIFE SHOIZTENINGIN MICE-RBE
up to 0.05 to 0.1 Gy; and that the RBE value should be constant. Present estimates of the values range from 10 to 16. For short-term fractionated or protracted exposures, a similar relationship is observed. The initial slope of the neutron dose-response curve is about the same as for single exposures; the augmentation phenomenon associated with fractionation of aneutron dose is rather dramatic, a t least in some strains of mice, but it is negligible at low doses and does not appear to affect the initial slope. The slope for fractionated gamma radiation is appreciably flatter, so that the neutron RBE value is higher, lying between 11and 30 depending on sex and strain. For duration-of-lifeand other long-term protraction studies, a generally similar dose-response curve for neutrons is seen in the data from three laboratories. The dose-response curves for gamma radiation show considerable variation, depending on whether the expoures were given continuously or in weekly fractions. The RBE values consequently vary from 15 to 20 when based on weekly fractionated gamma-ray exposures to about 40 when based on continuous exposures. In conclusion, for single neutron exposures the best analyses to date suggest a limiting neutron RBE value of somewhere between 10 and 15, with a preponderance of data favoring the higher number (see Table 8.2).For continuous or long-term fractionated exposures, the answers are less definitive, but it seems probable that the RBE value will be as high as 40 to 50, when compared to a low LET radiation delivered at low dose rates and total doses. These numbers apply to RBE values for life shortening from all causes of death; RBE values for specific causes may vary by fact.org of two to four (Thomson, 1982;this report, Section 6). One final caveat: almost all of the above-mentioned data have been obtained on mice, specifically various strains of Mus musculus. The applicability of these numbers to man is, of course, uncertain, although much thought has been given to interspecies comparisons [see, e.g., Grahn et al. 1978, and NCRP, 19801.
8.5 DISCUSSION OF LIFE SHORTENING IN MICE
/
165
Neutron radiation &erange (Gy)
Low LET radiation range (Gy) Doae rate
Mouse strain and sex I. Single e q + m BALBic
W f
0.24-1.88
0.01 Gy d-I
Ia7Cey
0.54
0.083 Gy d-I
RFM
"Wf
0.24-1.88
0.01 Gy d-I
lB7Csy
0.50-4
0.083 Gy d - I
RF CF No. 1
PeBe. 5MeV CP-5 reactor
0.15-2.91 0.29-9.10
BOCo y %y
0.25-40.9 0.56-27
CBA
GLEEP reactor, 0.7 MeV
Variable 0.01-0.05 Gy min- 1 0.022-0.17 Gy wk-I
Woy
1-30
Variable 0.01-0.13 Gy min - 1 1-30 Gy wk-I
Source
0.5-3.75
Dose rate
Souree
Range of RBE values for 6nctionated and shortterm protracted expomm Ill. Duration-of-life and long-termfractionated exposurea BGCF,, d JANUS reador, 0.02-2.44 0.00033-0.0267 MCo y 0.85 MeV Gy ark-' BGCF,
P
CBA, 8 CBA, 2'
RF
JANUS reactor, 0.85 MeV
0.02-2.1 1
GLEEP reactor, 0.09-8.75 0.7 MeV GLEEP reactor, 0.09-8.76 0.7 MeV Po-Be, 5 MeV 0.016-9.3
C
Q, Q,
RBE
Reference
13b Starer et al., 1979, 1983, 1984 11-1C S-r el d.,1979, lW. 1984 3 4 Upton et d.,1967 12' Vogel el al., 1959
-
10-2P
Mole and Thomas, 1961
0.00033-0.0267 Gy wk-I
%y
1-27.50
0.000860.157 Gy wk-I 0.00085-0.157 Gy wk-I Variable
7
16.26-72.52
MCo 7
16.26-72.52
%.V
2.4-98.76
0.0167-0.319 Gy wk-I ? 3.6 0.0167-0.319 Gywk-'2 2.3 0.161.11 Gy wk-I 0.161.11 Gy wk-1 Variable
nn
thp . e m
mf
+ha u -1..me
rh-m
'
8 M
X
0
!
18.'P
E! Thomaon et al., l98lb, 1988
17Ab Thomson et al.. 1981b. 1988
- 16'
- 44.
- 2%
Neary et d., 1957, 1962 Neary et al.. 1957, 1962 Upton et a1.. 1967
Range of RBE value8 for duration of life and Long-term protracted expoeuree 17.In eases where a linear doserespome m e wuld not be established, the limiting value of the RBE was estir@d from the extrapolated neutron dose m n s e at 0.05 Gy (single and shortterm protracted exposures) or 0.005 Gy per week (duration of life exposures). bAuthors estimate. These value8 are highly dependent on the dose rate of the low-LFT radiation (see text). dPUE As-nAm
-
*
0 11-34
1-28.88
' r
i5
d
m
I
9. Discussion and Conclusions As emphasized in the introductory section 1.1, the scope of this report is limited to the influence of radiation quality on dose response functions as evidenced by experimentally determined values of RBE. Thus RBE, even though it plays a large role in determining Q, is sharply distinguished from Q. This is because several variables in addition to RBE, such as those discussed in Section 1.1, have to be taken into account in arriving a t a value for Q for a particular radiation. Accordingly, this report does not present values of Q. Any RBE value obtained experimentally is specific to the endpoint studied and to the physical factors, such as the dose, dose rate, and the protraction schedule used. It is also specific to the applicable biological and environmental conditions, and time elapsed between exposure and the observation of the endpoint concerned. For this reason, it is difficult to generalize RBE data from the various systems. In order to see if any groupings or patterns might emerge that would be useful in estimating a range of values within which those for radiation carcinogenesis in man might be expected to lie, RBE values for fisson neutrons obtained from data for low doses and dose rates6, for a number of end points including carcinogenesis in animals, are compared. This was done for the same end point across a limited number of species, and for several different end points within a species. Results from the various systems evaluated are listed in summary Table 9.1, derived from larger tables in the text. The values given are the closest available to the maximum value for the relative biological effectiveness, RBE,, taken as the ratio of the estimated slopes of the initial "linear" portions of the relevant experimentally determined dose-response curves. It has not been possible to determine by direct observation, for either the human or other mammalian species, the slopes for the 'More properly termed "temporal distributionof d m " because the effect is the result of increased time for intracellular repair with low doses spread out over time, or for restitution of cell populations in "renewal systems," and not to the physical dose rate per se.
168
/
9. DISCUSSION AND CONCLUSIONS
dose-response curves for cancer induction that have sufficiently narrow confidence limits for low doses of radiations. This is because of severe statistical limitations with small exposures. Therefore, most values for low doses must be derived either from lower systems, or by "extrapolation" (interpolation)from the higher, but still relatively low dose ranges. Statistical limitations often preclude obtaining an ;ga term when data for doses lower than 0.25 to 1Gy are available, due to the contribution of a higher order term at low dose. Such estimates of the initial slope of the linear term may systematically overestimate the slope of the linear component. If no significant higher order term is found and none can reasonably be assumed to exist, then an estimate of the initial slope derived from linear interpolation may be accepted as unbiased. An additional method, often used to estimate the slope of the initial linear term for low doses delivered a t any dose rate involves determination of the slope of the response curve following low dose rate exposures a t total doses sufficient to result in observable responses. Based on predictions of the linear quadratic model, this slope should estimate the slope of the initial linear term for low doses delivered at any dose rate. However, the "low dose rates" used experimentally, as emphasized in the earlier report on "dose rate" (NCRP, 19801, are frequently well above those commensurate with average occupational exposure limits or background radiation. The reason is that such extremely low exposure rates do not allow a total dose to be accumulated, even over most of the life span of a rodent, that is large enough to cause statistically significant or even observable increase in the mutation rate or tumor incidence. An.apparently linear initial portion of a dose-response curve does not necessarily rule out the existence of a dose rate effect. In view of the large range of RBE values obtained for different species and endpoints, three endpoints were selected for additional discussion based on relevance to radiation protection. The three selected are carcinogenesis, life shortening and chromosome abnormalities. Results for animal carcinogenesis are listed in Tables 6.1, 6.2 and 6.3, and in Table 9.1. It is seen that the dose response curves for both the low-LET and high-LET radiations differ considerably. Although the variation in the value of slope of the dose response curve may be somewhat less for the high-LET radiation, a range of 10 or more is seen for each radiation type. Accordingly, the RBE;zM values also vary widely, from close to unity to multiples of 10. For those tumors in which no excess can be found in the lower dose ranges of low LET radiation, (and where there are grounds for expecting a threshold), an RBE value cannot be determined. Life shortening in mice exposed to low doses or low dose rates is due almost exclusively to death from cancer. This end point has been
9. DISCUSSION AND CONCLUSIONS
TABLE9.1-Summary
of estimated RBEp values
1
169
for fission neutrons
versus gamma rays End point
Range of valuesa
Cytogenetic studies, human lymphocytes in culture 3 4 53 Transformation 3- 80b 5- 7W Genetic endpoints in mammalian systems 2-100 Genetic endpoints in plant system Life shortening, mouse 10- 46 Tumor induction 16- 59 a Values taken from larger tables or data given in earlier sections of this report. This value of 80 was derived h m one set of experiments only. ' The value of 70; derived h m data on specific locus mutations in mice, is not necessarily an RBE,,,.
frequently used, as the data available are more extensive than for other end points associated with carcinogenesis. Fission neutron RBE values for life shortening obtained from the low dose range lie in the range of 10 to 25 or 30 when high energy gamma radiation is used as the standard. Very low dose rates may yield somewhathigher values of RBE. The range of RBE values for cytogentic studies at low dose and dose rates is the smallest of all the end points studied. This is in contrast to RBE values for genetic end points in plant systems which have a range of 2 to 100. (Table 9.1). Results in chromosome abnormalities in human cells, some of which have been implicated in the etiology of human cancers (Rowley, 1984; Sandberg, 1980), are summarized in Section 2, see Table 2.12. The variation in RBE values for neutrons of a given energy appears to be relatively small. However, it is seen from Table 2.12 that the RBE values for neutrons, using x rays or gamma rays as the comparison radiation can differ by as much as factors of 1.5 to 3 or more. The RBE values are in the 1.1to 1.2 range for high doses delivered at low dose rates. The RBE values for induction of human chromosome aberrations for fission neutrons are in the range of 10 to 19 when 250 kVp x rays are used as the reference radiation and 34 to 53 when 60Cogamma rays (1.17 and 1.33 MeV) are used as the reference radiation. The above observations, also identified in other systems (Underbrink et al., 1976; Bond et al., 1978) suggests that a specification of the reference radiation finer than the present range that includes high energy gammas and relatively low energy x rays may be in order. The question merits attention particularly because a principal source of risk coefficients for low LET radiations is the Japanese experience, in which the radiation exposure was overwhelmingly to high-energy gamma rays. However, as noted in Section 1.2, such
170
/
9.
DISCUSSION AND CONCLUSIONS
a change would interact strongly with other factors that must be considered in setting exposure limits. The substantial variation in the slope of the dose-response curves and thus RBE, noted above for both low and high-LET radiations, is for those endpoints considered most relevant to carcinogenesis and therefore to radiation protection. The higher values obtained at low doses, or higher doses a t low-dose rates, are the result largely, but not entirely, of changes in the slope of the dose response curve for the low-LET reference radiation. In addition, as noted above, the RBE value for a given high-LET radiation can differ by a factor of as much as three, depending on the reference radiation used for comparison. Average values, perhaps weighted on the basis of frequency of tumor types or other bases could be provided. However, these would be of limited use because of the larger variation in individual values. Because of the large range of RBE values for all endpoints reviewed, it must be a matter of judgement as to which values are to be used for selecting Q values for use in radiation protection.
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The NCRP The National Council on Radiation Protection and Measurements is a nonprofit corporation chartered by Congress in 1964 to: 1. Collect, analyze, develop, and disseminate in the public interest information and recommendations about (a) protection against radiation and (b) radiation measurements, quantities, and units, particularly those concerned with radiation protection; 2. Provide a means by which organizations concerned with the scientific and related aspects of radiation protection and of radiation quantities, units, and measurements may cooperate for effective utilization of their combined resources, and to stimulate the work of such organizations; 3. Develop basic concepts about radiation quantities, units, and measurements, about the application of these concepts, and about radiation protection; 4. Cooperate with the International Commission on Radiological Protection, the International Commission on Radiation Units and Measurements, and other national and international organizations, governmental and private, concerned with radiation quantities, units, and measurements and with radiation protection. The Council is the successor to the unincorporated association of scientists known as the National Committee on Radiation Protection and Measurements and was formed to carry on the work begun by the Committee. The Council is made up of the members and the participants who serve on the over sixty scientific committees of the Council. The scientific committees, composed of experts having detailed knowledge and competence in the particular area of the committee's interest draft proposed recommendations. These are then submitted to the full membership of the Council for careful review and approval before being published. The following comprise the current officers and membership of the Council: officers President WARREN K . SINCLAIR Vice President Secretary and
Treasurer Assistant Secretary Assistant Trwsurer
S. JAMES A D E ~ I N
W.ROGERNEY
CARLD. HOBELMAN
JAMESF . BERG
THENCRP Members SEYMOUR ABRAHAMSON JACOB I. FABRMANT s.JAMES ADEU~~EIN R J. MICHAELFRY PEI%XR. ALMOND THOMASF.GESELL EDWARDL. ALPEN ETHELS. GILBERT LYNNR. ANSPAUGH ROBERTA. GOEPP JOHN A. AUXIER JOEL E. GRAY WILLIAMJ. BAIB ARTHUB W. G w MICHAELA. BENDER ERICJ. HALL B GORDONBLAYLOCK NAOMIH. HARLEY BRUCEB. BOECKER WILLUM R. HENDEE JOHN D. BOICE,JR DONALDG. JACOBS ROBERTL. BRENT A EVEREITEJ m ,JR. ANTONEBROOKS BERNDKAHN KENNETHR KASE PAULL. CARSON MELVINW. CARTER HAROLD L.KUNDEL RANDALL S. C m L L CHARLESE. LAND JAMES E. CLEAVER RAYD.LLOYD FRED T. CRO89 HARRY R. WON STANLEY B. CURTIS ROGER0.MCCLELLAN GERALDD. DODD BARBARAJ. MCNEIL PATRICIAW. DURBIN CHARLESB. MEINHOLD CARLH. DURNEY L.MENDEMHN MORTIMER KEm F.ECKERMAN FRED A METIZER CHARLESEBENHAUER WILLIAM A. MILLS THOMAS S. ELY DADEW. MOELLER
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A. ALAN MOGHISSI JOHN W. P ~ N ANDREWK.POZNANSKI NORMANC. RASMUSSEN C H E R ~RICHMOND GENEVI~VE ROESSLER MARVINRO~ENSTEIN LAWRENCE N. F~YIRENBERG LEONARDA. SAGAN KEm J. SCHIAGER ROBERTA SCHLENKER ROY E. SHORE WARRENK.S ~ C L A I R PAULSLOVIC RICHARD A TELL W ~ L I AL.MTEMPLETON THOMASS. TENWRDE J. W. T H I E ~ ~ E N JoHN E. TILL ROBERTL. ULLRICH ARTHUBC. U ~ N GEORGEL. VOELZ GEORGEM. WILKENING MARVINZ w m
Honorary Members L T R I ~ ~S.~ TAYLOR, N Honorniy
ROBERT0.GORSON JOHN H. HARLEY JOHN W. HEALY L o r n H.
HEMPELMANN. JR PAULC. HODGES GEORGEV. LEROY WILFRID B. MANN KARLZ. MORGAN ROBERTJ. NELSEN
Presided
WESLEYL NWORC HARAI,DH.ROSSI WILLIAM L RUEWELL JOHN H. R u m EUGENEL. SAENGER J. S c m WILLIAM J. NEWELLSTANNARD JOHN B. S ~ O R E R ROY C. THOMPSON EDWARDW. WEBSTER HAROLD 0.WYCKOW
Currently, the following subgroups are actively engaged in formulating recommendations: SC 1
SC 16
Basic Radiation Protection Criteria SC 1-1 Probability of Causation for Genetic and Developmental Effects SC 1-2 The Aese8ament of Risk for Radiation Protection Purposes SC 1-3 Collective Dose X-Ray Protection in Dental Offices
THE NCRF' Biological Aspects of Radiation Protection Criteria SC 40-1 Atomic Bomb Survivor Dosimetry Operational Radiation Safety SC 46-2 Uranium Mining and Milling-Radiation Safety Programs SC 46-3 ALARA for Occupationally E x p d Individuals in Clinical Radiology SC 46-4 Calibration of Survey Instrumentation SC 46-5 Maintaining Radiation Protection Records SC 46-7 Emergency Planning SC 46-8 Radiation Protection Design Guidelines for Particle Accelerator Facilities SC 46-9 ALARA a t Nuclear Plants SC 46-10 ABsessment of Occupational Doee8 from Internal Emitters SC 46-11 Radiation Protection During Special Medical P d u r e e Conceptual Basis of Calculations of Dose Distributions Internal Emitter Standards SC 57-2 h p i r a t o r y Tract Model SC 57-6 Bone Problems SC 57-9 Lung Cancer Risk SC 57-10 Liver Cancer Risk SC 57-12 Strontium SC 57-14 Placental Transfer SC 57-15 Uranium Human Population Exposure Experience Radiation Exposure Control in a Nuclear Emergency SC 63-1 Public Knowledge About Radiation SC 63-2 Criteria for Radiation Instruments for the Public Environmental Radioactivity and Waste Management SC 64-6 Screening Models SC 64-7 Contaminated Soil as a Source of Radiation Exposure SC 64-8 Ocean Diaposal of Radioactive Waste SC 64-9 Effects of Radiation on Aquatic Organism SC 64-10 Xenon SC 64-11 Disposal of Low Level Waste Quality Assurance and Accuracy in Radiation Protection Measurements Biological Effects and Exposure Criteria for Ultrasound Biological Effects of Magnetic Fields Efficacy of Radiographic Procedures Radiation Exposure and Potentially Related Iqjury Guidance on Radiation Received in Space Activities Effects of Radiation on the Embryo-Fetus Guidance on Occupational and Public Exposure Resulting from Diagnostic Nuclear Medicine Procedures Practical Guidance on the Evaluation of Human Exposures to Radiohquency Radiation Extremely Low-Frequency Electric and Magnetic Fields Radiation Biology of the Skin (Beta-Ray Dosimetry) Identification of Research Needs Contamination of Materials, Objects and Soils Risk of Lung Cancer from Radon Hot Particles in Eyes, Ears and Lunge
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Ad Hoc Committee on Comparison of Radiation Exposures Ad Hoc Group on Plutonium Ad Hoc Group on Radon Ad Hoc Group on Video Display lbrminals Study Group on Comparative Risk %k Force on Occupational Exposure Levele
I n recognition of its responsibility to facilitate and stimulate cooperation among organizations concerned with the scientific and related aspects of radiation protection and measurement, the Council has created a category of NCRP Collaborating Organizations. Organizations or groups of organizations that are national or international in scope and are concerned with scientific problems involving radiation quantities, units, measurements, and effects, or radiation protection may be admitted to collaborating status by the Council. The present Collaborating Organizations with which the NCRP maintains liaison are as follows: American Academy of Dermatology American Association of Physicists in Medicine American College of ~ e d i c a Physics l American Collem of Nuclear Physicians American college of Radiology American Dental A~eociation American Industrial Hygiene Agsociation American Institute of Ultrasound in Medicine American Insurance Services Group American Medical Association American Nuclear Society American Occupational Medical Association American Pediatric Medical b c i a t i o n American Public Health Amciation American Radium Society American Roentgen Ray Society American Society of Radiologic Technologists American Society for Therapeutic Radiology and Oncology Association of University Radiologists Bioelectromagnetics Society College of American Pathologists Conference of Radiation Control Program Directors Electric Power Research h t i t u t e Federal Communicatione Cornmimion Federal Emergency Management Agency Genetics Society of America Health Effects Research Foundation (Japan) Health Physics Society Institute of Nuclear Power Operations National Electrical Manufacturers k i a t i o n National Institute of Standards and Technology Nuclear Management and Resources Council Radiation Research Society '
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Radiological Society of North America Society of Nuclear Medicine United States Air Force United States Army United States Department of Energy United States Department of Housing and Urban Development United States Department of Labor United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission United States Public Health Servica
The NCRP has found its relationship with these organizations to be extremely valuable to continued progress in its program. Another aspect of the cooperative efforts of the N O relates to the special liaison relationships established with various governmental organizations that have an interest in radiation protection and measurements. This liaison relationship provides: (1)an opportunity for participating organizations to designate an individual to provide liaison between the organization and the NCRP, (2) that the individual designated will receive copies of draft NCRP reports (at the time that these are submitted to the members of the Council) with an invitation to comment, but not vote; and (3) that new NCRP efforts might be discussed with liaison individuals as appropriate, so that they might have an opportunity to make suggestions on new studies and related matters. The following organizations participate in the special liaison program: Auetralian Radiation Laboratory Commiesariat a 1'Energie Atomique (France) Commission of the European Communities Defense Nuclear Agency Federal Emergency Management Agency Japan Radiation Council National Institute of Standards and Technology National Radiological Protection Board (UnitedKingdom) National Reeearch Council (Canada) Otlice of Science and Technology Policy Otlice of Technology Assessment Ultrasonics Institute of Australia United States Air Force united states Anmy United States Coast Guard United States Department of Energy United States Department of Health and Human Services United States Department of Labor United States Department of Tramportation United States Environmental Proteetion Agency United States Navy United States Nuclear Regulatory Commission
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The NCRP values highly the participation of these organizations in the liaison program. The Council's activities are made possible by the voluntary contribution of time and effort by its members and participants and the generous support of the following organizatiom: A h d P. Sloan Foundation Alliance of American Ineurera American Academy of Dental Radiolugy American Academy of Dermatology American Aaeociation of Physicists in Medicine American College of Medical Physics American College of Nuclear Physicians American College of Radiology American College of Radiology Foundation American Dental h i a t i o n American Hospital Radiology Administratom American Industrial Hygiene h i a t i o n American Insurance Services Group American Medical A m i a t i o n American Nuclear Society American Occu~ationalMedical Aeeociation American osteopathic College of Radiology American Pediatric Medical b i a t i o n American Public Health Amciation American Radium Society American Roentgen Ray Society American Society of Radiologic Technologiete American Society for Therapeutic Radiology and Oncology American Veterinary Medical h i a t i o n American Veterinary Radiology Society Association of University Radiologists Battelle Memorial Institute Center for Devices and Radiological Health College of American Pathologiets Committee on Radiation Research and Policy Coordination Commonwealth of Pennsylvania Defense Nuclear Agency Eastman Kodak Company Edison Electric Institute Edward M a l l i n c M t , Jr. Foundation EGLG Idaho, Inc. Electric Power Reeearch h t i t u t e Federal Emergency Management Agency Florida Institute of Phoe~hateR d Genetics Society of Amehca Health Effects Research Foundation (Japan) Health fiysics Society Institute of Nuclear Power Operatione James Picker Foundation Martin Marietta Corporation National Aeronautics and Space Administration
National Asstxiation of Photographic Manufacturers National Cancer Institute National Electrical Manufacturere Association National Institute of Standards and Technology Nuclear Management and Resources Council Radiation Research Society Radiological Society of North America Richard Lounsbery Foundation Sandia National Laboratory Society of Nuclear Medicine united States Department of Energy United States Dmartment of Labor United States ~'-nmental Protection Agency United S t a b Navy United States Nuclear Regulatory Commission Victoreen, Incorporated
To all of these organizations the Council expresses its profound appreciation for their support. Initial funds for publication of NCRP reports were provided by a grant from the James Picker Foundation and for this the Council wishes to express its deep appreciation. The NCRP seeks to promulgate information and recommendations based on leading scientific judgment on matters of radiation protection and measurement and to foster cooperation among organizations concerned with these matters. These efforts are intended to serve the public interest and the Council welcomes comments and suggestions on its reports or activities from those interested in its work.
NCRP Publications NCRP publications are distributed by the NCRP Publications' office. Information on prices and how to order may be obtained by directing a n inquiry to: NCRP Publications 7910 Woodmont Ave., Suite 800 Bethesda, Md 20814 The currently available publications are listed below. Proceedings of the Annual Meeting No. 1
Title Perceptions of Risk, Proceedings of the Fifteenth Annual Meeting, Held on March 14-15,1979 (Including Taylor Ledure No. 3) (1980) Quantitative Risk in Standurds Setting, Proceedings of the Sixteenth Annual Meeting, Held on April 2-3, 1980 (Including Taylor Lecture No. 4) (1981) Critical Issues in Setting Radiation Dose Limits, Proceedings of the Seventeenth Annual Meeting, Held on April 8-9, 1981 (Including Taylor Lecture No. 5) (1982) Radiation Protection and New Medical Diagnostic Procedures, Proceedings of the Eighteenth Annual Meeting, Held on April 6-7,1982 (Including Taylor Lecture No. . 6) (1983) Environmental Radioactivity, Proceedings of the Nineteenth Annual Meeting, Held on April 6-7, 1983 (Including Taylor Lecture No. 7) (1984) Some Issues Important in Developing Basic Radiation Protection Recommendations, Proceedings of the Twentieth Annual Meeting, Held on April 4-45, 1984 (Including Taylor Ledure No. 8) (1985) Radioactive Waste, Proceedings of the Twenty-first Annual Meeting, Held on April 3-4, 1985 (Including Taylor Lecture No. 9) (1986)
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NCRP PUBLICATIONS
Nonionizing ElectromugneticRadiation and Ultnrsound, Proceedings of the Twenty-second Annual Meeting, Held on April 23,1986 (IncludingTaylor Lecture No. 10) (1988) New Dosimetry at Hiroshima and Nagasaki and Its Implications for Risk Estimates, Proceedings of the Twenty-third Annual Meeting, Held on April 5-6, 1987 (Including Taylor Lecture No. 11)(1988). Rcrdon, Proceedings of the Twenty-fourth Annual Meeting, Held on March 30-31,1988 (IncludingTaylor Lecture No. 12) (1989). Radiution Protection Today-The NCRP at Sixty Years, Proceedings of the Twenty-fifth Annual Meeting of the National Council on Radiation Protection and Measurements, Held on April 5-6,1989 (Including Taylor Lecture No. 13) (1990). Symposium Proceedings
The Control of Exposure of the Public to Ionizing Radidbn in the Event of Accident or Attack, Proceedings of a Symposium held April 27-29,1981 (1982) Lauriston S. Taylor Lectures No. 1 2 3 4
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6
Title and Author The Squares of the Natural Numbers in Radiation Protection by Herbert M. Parker (1977) Why be QuantitativeAbout Radiution Risk Estimates? by Sir Edward Pochin (1978) Radiation Protection-Concepts and Trade O f f . by Hymer L. Friedell (1979)[Availablea h in Perceptions of Risk, see above] From "Quantity of Radiation" and 'Dose" to "Exposure" and "AbsorbedDose''-An Historical Review by Harold 0.Wyckoff (1980)[Availablealso in QuantitcrtiveRisks in Standards Setting, see above] How Well Can We Assess Genetic R i s k Not Very by James F. Crow (1981) [Available also in Critical Issues in Setting Radiution Dose Limits,see above] Ethics, Td-off' and Medical Radicrtion by Eugene L. Saenger (1982) [Available also in Radiation Protection and New Medical Diagnostic Approaches, see abovel
NCRPPUBLICATIONS
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The Human Environment-Past, Present and Future by Merril Eisenbud (1983) [Available also in Environmental Radioactivity, see abovel Limitation and Assessment in Radiation Protection by Harald H . Rossi (1984) [Available also in Some Issues Important in Developing Basic Radiution Protection Recommendrrtions, see abovel Truth (and Beauty) in Radiation Measurement by John H. Harley (1985:)[Available also in Radioactive Waste, see above] Nonionizing Radiation Bioeffects: Cellular Properties and Intentions by Herman P. Schwan (1986) [Available also in Nonionizing Electromagnetic Radiations and Ultrasound, aee abovel How to be Quantitative about Radiation Risk Estimates by Seymour Jablon (1987) [Available also in New Dosimetry at Hiroshima and Nagasaki and its Implidations fir Risk Estimates, see abovel How Safe is Safe Enough? by Bo Lindell(1988) [Available also in Radon, see abovel Radiobiology and Radiation Protection: The Past Century and Prospects for the Future by Arthur C. Upton (1989) [Available also in Radiatwn Protection Today, see above] Radiation Protection and the Internal Emitter Saga by J . Newel1 Stannard (1990).
NCRP Commentaries No. 1
Title
Ktypton-85 in the Atmosphere-- With Specific Reference to the Public Health Significance of the Proposed Controlled Release at Three Mik Island (1980) Preliminary Evaluation of Criteria fir the Disposal of Tmnsumnic Contuminated Waste (1982) Screening Techniques for Determining Compliance with Environmental Standards (19861, Rev. (1989) Guidelines for the Release of Waste Water fiom Nuclear Facilities with Special Reference to the Public Health Signifiance of the Proposed Release of Treated Waste Waters at Three Mile Island (1987) A Review of the Publication, Living Without Landfills (1989)
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NCRP Reports
No. 8
Title Control and Removal of Radioactive Contamination i n Laboratories (1951) Maximum Permissible Body Burdens and Maximum Permissible Concentrations of Radionuclides in Air and i n Water for Occupational Exposure (1959)[Includes Addendum 1 issued in August 19631 Measurement of Neutron Flux and Spectra for Physical and Biological Applications (1960) Measurement o f A bsorbed Dose ofNeutrons and Mixtures of Neutrons and Gamma Rays (1961) Stopping Powers for Use with Cavity Chambers (1961) Safe Handling of Radioactive Materials (1964) Radiation Protection in Educational Institutions (1966) Dental X-Ray Protection (1970) Radiation Protection in Veterinary Medicine (1970) Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides (1970) Protection Against Neutron Radiation (1971) Protection Against Radiation from Brachytherapy Sources (1972) Specifications of Gamma-Ray Brachytherapy Sources (1974) Radiological Factors Affecting Decision-Making i n a Nuclear Attack (1974) Krypton-85 i n the Atmosphere-Accumulation, Biological Significance, and Control Technology (1975) Alpha-Emitting Particles in Lungs (1975) Tritium Measurement Techniques (1976) Structural Shielding Design and Evaluation for Medical Use of X Rays and Gamma Rays of Energies Up to 10 MeV (1976) Envimnmentul Radiation Mecrsurements (1976) Radiation Protection Design Guidelines for 0.1-100 MeV Particle Accelemtor Facilities (1977) Cesium-137 fi-om the Environment to Man: Metabolism and Dose (1977) Review of NCRP Radiation Dose Limit for Embryo and Fetus in Occupationally Exposed Women (1977) Medical Radiation Exposure of Pregnant and Potentially Pregnant Women (1977)
NCRP PUBLICATIONS
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Protection of the Thyroid Gland in the Event of Releases of Radioiodine (1977) Instrumentation and Monitoring Methods for Radiation Protection (1978) A Handbook of Radioactivity Measurements Procedures, 2nd ed. (1985) Operational Radiation Safety Program (1978) Physical, Chemical, and Biological Properties of Radiocerium Relevant to Radiation Protection Guidelines (1978) Radiation Safety Training Criteria for Industrial Radiography (1978) Tritium in the Environment (1979) Tritium and Other Radionuclide Labeled Organic Compounds Incorporated in Genetic Material (1979) Influence of Dose and Its Distribution in Time on DoseResponse Relationships for Low-LET Radiations (1980) Management of Persons Accidentally Contaminated with Radionuclides (1980) Mammography (1980) Radiofreqency Electromagnetic Fields-Properties, Quantities and Units, Biophysical Interaction, and ' Measurements (1981) Radiation Protection in Pediatric Radiology (1981) Dosimetry of X-Ray and Gamma-Ray Beams for Radiation Therapy in the Energy Range 10 keV to 50 MeV (1981) Nuclear Medicine-Factors Influencing the Choice and Use of Radionuclides i n Diagnosis and Therapy (1982) Operational Radiation Safety-Training (1983) Radiation Protection and Measurement for Low Voltage Neutron Generators (1983) Protection in Nuclear Medicine and Ultrasound Diagmstic Procedures in Children (1983) Biological Effects of Ultrasound: Mechanisms and Clinical Implications (1983) Iodine-129: Evaluation of Releases from Nuclear Power Generation (1983) Radiological Assessment: Predicting the ~ r a n s ' ~ o r t , Bioaccumulation, and Uptake by Man ofRadionuclides Released to the Environment (1984) Exposures from the Uranium Series with Emphasis on Radon and its Daughters (1984)
NCRP PUBLICATIONS
Evaluation of Occupational and Environmental Exposures to Radon and Radon Daughters in the United States (1984) Neutron Contamination from Medical Electron Accelerators (1984) Induction of ThyroidCancer by IonizingRadiztion (1985) Carbon-14 in the Environment (1985) SI Units i n Radiation Protection and Measurements (1985) The Experimental Basis for Absorbed-Dose CalcuLations in Medical Uses of Radionuclides (1985) General Comepk for the Dosimetry of Internally Deposited Radionlcclides (1985) Mammography-A User's Guide (1986) Biological Effects and Exposure Criteria for Radiofrequency Ebctromagnetic Fields (1986) Use of Bioassay Procedures for Assessment of Internal Radionuclide Deposition (1987) Radiation Alarms and Access Control Systems (1987) Genetic Effects of Internally Deposited Radionuclides (1987) Neptunium: Radiation Protection Guidelines (1987) Recommendations on Limits for Exposure to Ionizing Rarliation (1987) Public Radiation Exposure fkom Nuclear Power Generation in the United States (1987) Ionizing Radiation Exposure of the Population of the United States (1987) Exposure of the Population in the United States and Canadu from Natuml Background Radiation (1987) Radiation Exposure of the U.S. Population fi.om Consumer Products and Miscellaneous Sources (1987) Compamtive Caminogenesis of Ionizing Radiation and Chemicals (1989) Measurement of Radon and Radon Daughters in Air (1988) Guidance on Radiation Received i n Space Activities (1989) Quality Assumme for Diagnostic Imaging Equipment (1988) Exposure of the U.S. Population jiom Diagnostic Medical Radiation (1989) Exposure of the U.S. Population From Occupational Radiation (1989)
NCRP PUBLICATIONS
102 103 104
105
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Medical X-Ray, Electron Beam and Gamma-RayPmtactwn For Energies Up To 50 MeV (Equipment Design, Perfbrmance and Use) (1989) Control of Radon in Houses (1989) TheRelative Biological EffectivenessofRadiahnsofDifferent Quality (1990) Radiation Protection for Medical and AUied Health Personnel (1989) Limits of Exposure to "Hot Particles" on thiskin (1989)
Binders for NCRP Reports are available. Rvosizes make it possible to collect into small binders the "old series" of reports (NCRPReports Nos. 8-30) and into large binders the more recent publications (NCW Reports Nos. 32-106). Each binder will accommodate from five to seven reports. The binders cany the identification "NCRP Reports" and come with label holders which permit the user to attach labels showing the reports contained in each binder. The following bound sets of NCRP Reports are also available: Volume I. NCRP Reports Nos. 8, 22 Volume TI. NCRP Reporta Nos. 23,25,27,30 Volume III. NCRP Reports Nos. 32,35,36,37 Volume IV. NCRP Reporta Nos. 38,40,41 Volume V. NCRP Reports Nos. 42,44,46 Volume VI. NCRP Reports Nos. 47,49,50,51 Volume VII. NCRP Reports Nos. 52,53,54,55,57 Volume VIII. NCRP Reports No. 58 Volume IX. NCRP Reports Nos. 59, 60, 61, 62, 63 Volume X. NCRP Reports Nos. 64,65,66,67 Volume XI. NCRP Reports Nos. 68,69, 70, 71,72 Volume Xn. NCRP Reporta Nos. 73,74,75,76 Volume XIII. NCRP Reports Nos. 77,78,79,80 Volume XTV. NCRP Reports Nos. 81,82,83,84,85 Volume XV. N C W Reports Nos. 86,87,88,89 Volume XVI. NCRP Reports Nos. 90,91,92,93 Volume XVII. NCRP Reports Nos.94,95,96,97 Volume XVIII. NCRP Reporta Nos. 98,99,100 (Titles ofthe individual reports contained in each volume are given above). The following NCRP Reports are now superseded and/or out of print:
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Title X-Ray Protection (1931).[Superseded by NCRP Report No. 31 Radium Protection (1934).[Supersededby NCRP Report No. 41 X-Ray Protection (1936).[Superseded by NCRP Report No. 61 Radium Protection (1938).[Superseded by NCRP Report No. 131 Safe Handling of Radioactive Luminous Compounds (1941).[Out of Print] Medical X-Ray Protection Up to TwoMillion Volts (1949). [Superseded by NCRP Report No. 181 Safe Handling of Radioactive Isotopes (1949).[Superseded by NCRP Report No. 301 Recommendations for Waste Disposal of Phosphorus32 and Iodine-131 for Medical Users (1951).[Out of Printl Radiological Monitoring Methods and Instruments (1952).[Superseded by NCRP Report No. 571 Maximum Permissible Amounts of Radioisotopes in the Human Body and Maximum Permissible Concentrations in Air and Water (1953).[Superseded by NCRP Report No.221 Recommendations for the Disposal of Carbon-14 Wastes (1953).[Superseded by NCRP Report No. 811 Protection Against Radiations t o m Radium, Cobalt-60 and Cesium-137 (1954).[Supersededby NCRP Report No. 241 Protection Against Betatron-Synchrotron Radiations Up to 100 Million Electron Volts (1954).[Superseded by NCRP Report No. 53.1 Safe Handling of Cadavers Containing Radioactive Zsotopes (1953).[Superseded by NCRP Report No. 211 Radioactive Waste Disposal in the Ocean (1954).[Out of Print] Permissible Dose from External Sources oflonizing Radiation (1954)including Maximum Permissible Exposure to Man, Addendum to National Bureau of Standards Handbook 59 (1958).[Supersededby NCRP Report No. 391 X-Ray Protection (1955).[Superseded by NCRP Report No. 261 Regulation of Radiation Exposure by Legislative Means (1955).[Out o f Print]
NCRP PUBLICATIONS
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Protection Against Neutron Radiation Up to 30 Million Electron Volts (1957). [Superseded by NCRP Report No. 381 Safe Handling of Bodies Containing Radioactive Isotopes (1958). [Superseded by NCRP Report No. 371 Protection Against Radiations from Sealed Gamma Sources (1960). [Superseded by NCRP Report Nos. 33, 34, and 401 Medical X-Ray Protection Up to Three Million Volts (1961). [Superseded by NCRP Report Nos. 33, 34, 35, and 361 A Manual of Radioactivity Procedures (1961). [Superseded by NCRP Report No. 581 Exposure to Radiation in an Emergency (1962). [Superseded by NCRP Report No. 421 Shielding for High Energy Electron Accelerator Installations (1964).[Superseded by NCRP Report No. 511 Medical X-Ray and Gamma-Ray Protection for Energies up to 10 MeV-Equipment Design and Use (1968). [Superseded by NCRP Report No. 1021 Medical X-Ray and Gamma-Ray Protection for Energies Up to 10 MeV-Structural Shielding Design and Evaluation (1970). [Superseded by NCRP Report No. 491 Basic Radiation Protection Criteria (1971). [Superseded by NCRP Report No. 911 Review of the Current State of Radiation Protection Philosophy (1975). [Superseded by NCRP Report No. 911 Natural Background Radiation in the United States (1975). [Superseded by NCRP Report No. 941 Radiation Protection for Medical and Allied Health Personnel [Superseded by NCRP Report No. 1051 Radiation Exposure from ConsumerProducts and Miscellaneous Sources (1977). [Superseded by NCRP Report No. 951 A Handbook on Radioactivity Measurement Procedures. [Superseded by NCRP Report No. 58,2nd ed.] Other Documents The following documents of the NCRP were published outside of the NCRP Reports and Commentaries series:
"Blood Counts, Statement of the National Committee on Radiation Protection," Radiology 63,428 (1954)
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"Statements on Maximum Permissible Dose from Television Receivers and Maximum Permissible Dose to the Skin of the Whole Body," Am. J. Roentgenol., Radium Ther. and Nucl. Med. 84,152 (1960) and Radiology 75,122 (1960) Dose Effect Modifiing Factors In Radiation Protection, Report of Subcommittee M-4 (Relative Biological Effectiveness) of the National Council on Radiation Protection and Measurements, Report BNL 50073 (T-471) (1967) Brookhaven National Laboratory (National Technical Information Service, Springfield, Virginia). X-Ray Protection Standards for Home Television Receivers, Interim Statement of the National Council on Radiation Protection and Measurements (National Council on Radiation Protection and Measurements, Washington, 1968) Specification of Units of Natuml Umnium and Natuml Thorium (National Council on Radiation Protection and Measurements, Washington, 1973) NCRP Statement on Dose Limit for Neutrons (National Council on Radiation Protection and Measurements, Washington, 1980) Control ofAirEmissions ofRadionuclides (National Council on Radiation Protection and Measurements, Bethesda, Maryland, 1984) Copies of the statements published in journals may be consulted in libraries. A limited number of copies of the remaining documents listed above are available for distribution by NCRP Publications.
Index Alpha particles 84-87.143 Effecta on apem morphology, 86 Hereditary effects, 84 Mutagenic efficiency, 85 RBE values, 87,143 Arabidopsis (plant), 15,23,24 RBE Values, 23,24 Assay system, 4 9 , m BALBI3T3 cells, 50 C3W10T1I2cells, 50 Syrian hameter embrgos, 49 Auger electrons, 58 RBE Values, 58 Augmentation, 153, 158 Neutron irradiation, 163, 158 BALBl3T3 cells, 50 Transformation assay system, 50 Basal cell carcinomas, 134 Bone sarcoma, 142,148 RBE of h i o n fragments, 148 C3HI1(YT1/2cells, 5 0 , 5 2 4 5 Transformation assays, 60, 5 2 , M Transformation frequency, 53 Carcinogenesis, 139 Influence of radiation quality. 139 Cataract formation, 11 Cell killing, 66 Californium 252 neutrons, 119,127 Induction of harderian gland tumors, 127 Induction of lung adenomas, 119 Chromosome aberrations, 29,30, 3336,37-44,46,81, 140, 149 Alpha particle induced, 39,41 Beta particle induced, 39 Chinese hamster cells, 39 Chromitid exchanges, 38 Deletions, 29 Dicentrics, 29,33,41 Dose-response relationship, 30 Exchange type, 29 Fisaion fragment induced, 39 Gamma ray induced, 37,39,42,43 Heavy ion induced, 38 High LET radiation induced, 44 Human cells, 46 Human lymphocytes, 40.42
Internal emitter induced, 140 Lymphocytes, 30,41 Neutron induced, 35,37,42,43 Roton induced, 41 RBEy, 33 RBE valuee, 149 Single track, 40 Versue lineal energy, 34 x ray induced, 38,43 Chromoeome volume. 23 Chinese hamster V79 cells, 39,65,66 Chromosome aberrations, 39 Mutation studies, 66 RBE-LET relationship, 66 Cesium 137 gamma rays, 122,127 Induced harderian gland tumors, 127 Induced lung adenocarcinomas, 122 Cyclotron neutrons, 77 Induced dominant lethal mutations, 77 Cytogenetic effecta, 14,27,28,40 In mammalian cells, 28,40 In planta, 14.27 RBE values, 40 Dominant lethal mutations, 75 Dose equivalent, 10 Dose-rate dependencies, 55 Dose-rate effects, 72, 113, 122, 126 Lung tumors, 122 Mammary tumors, 126 Myeloid leukemia, 113 thymic lymphoma, 113 Dose-response relationehip, 29 Low-LET radiatiom, 29 Dose-response curve. 7 Linear quadratic, 7 Drosophila, 95, 96, 99 Dominant lethal mutations. 95 Neutron induced mutations, 99 RBE values ('lbble), 96 Recessive mutations, 95 location mutations, 95 x-ray induced mutations, 99 Effective doae equivalent, 10 Environmental decta. 15 Response of plants to irradiation, 15
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Epithelial cell tumors, 114 Ovarian tumors, 114 Fibrmarmmas, 134 Fieeion neutrons, 21,24,43,83,87, 88,90,93,94,116,122,124,127, 128 Dominant lethal mutations, 77 Harderian gland tumore, 128 Lung adenocarcinomas, 122 mamma^^ tumors, 127 Ovarian tumors, 116 Pulmonary tumors, 124 RBE, 21,24,83.87,94 RBEM, 43 RBE ('hble), 88 Specific locus mutations, 90,93 Fractionation, 122,126, 134 Enhancement effecte, 134 Lung tumors, 122 Mammary tumors, 126 Gamma rays, 84,86 Effects on sperm morphology, 86 Translocation frequenciee, 84 Harderian gland tumors, 126-128, 137 Cesium 137 gamma ray induction, 128 Fission neutron induction, 128 Heavy ion induction, 137 HPRR neutron induction, 127 Neutron induction, 127 RBE values, 126 Heavy ions, 24 RBE values, 24 Hereditary effects, 75,82,84,89 Alpha particles, 84 Dominant lethal mutations, 76 Mammalian germ cells, 89 Neutron induced, 82 HGPRT assay system, 64.69 HPRR neutrons, 119,127 Harderian gland tumore, 127 Lung adenomas. 119 Hodgbin like lymphoma, 113 H u m cells, 46,66 Chromosome aberrations, 46 Mutation studies, 66 Internal emitters, 142 LET, 136 Relationship to RBE,136 LET-RBE, 10 Relationship in water, 10
Leukemia, 107.108 Dose-response curve, 108 Incidence vs. type of radiation, 107 Single gamma ray expowre. 107 Life shortening, 152,155,157, 162, 165 Neutron irradiation, 155 Protracted exposures, 157 FU3E value, 152,162 FU3E values (nble), 165 Lineal energy (y),5,34 Dicentric induction, 34 Linear collision stopping power, 4.5 Restricted stopping power, 5 Lung adenocarcinorna, 117,119,122 Californium 252 neutrons, 119 Cesium 137 gamma rays, 119 Fission neutrons, 122 HPRR neutrons, 117 Lung cancer risk, 149 Lung tumors, 117, 123 RBE values, 123 Lycopersicon esculentum (tomato), 23, 24 Lymphocytes, 30 Chromosome aberrations, 30 Lymphomas, 113 Dm-rate effect, 113 Mammalian cells, 49,64,68 In vitro transformation, 49 Mutations Mammary tumors, 123,125,127,129, 131,132 Adenouminoma, 123,125 Dose-rate effecte, 125 Fractionation effects, 125 Fiesion neutron induced, 127 Neutron radiation induced, 129, 132 Neutron radiation induced 35 Mev, 127 RBE values, 129 X-ray radiation induced, 129,132 Muons, 26 RBE, 26 Mutagenesie, 49.71.72, 78-81, 85, 87,99,102 Alpha particle efficiency, 88 Mammalian germ cells, 99 I n vivo,49 Dominant lethal mutations, 78-80 Neutron radiation induced, 74,85, 87
INDEX Plutonium 239 induced, 79,81 RBE, 71.89 Mutation studies, 64,65, 70, 71 AL cell system, 70, 71 Chinese hamster V79 cells, 65 Human fibroblasts, 65 Mammalian cells, 61 Myeloid leukemia in mice, 109, 110 RBE values. 109. 110 Neutron radiation, 27.34.51.53, 78, 82,85,87, 134, 153, 155, 158 Augmentation effect. 153, 158 Hereditary effects, 82 Induced transformations, 51 Induction of dominant lethal mutations, 78 Life shortening effects, 155 Maximum effects, 34 Mutagenic efficiency, 85, 87 RBE, 27 Transformation fi-equency, 53 Tumorigenicity in mice, 134 Neoplastic transformation, 61 Nonstochastic effeda, 11 Cataract formation, 11 Sterility, 11 Nigella damascena (black caraway), 15, 23, 24 RBE values, 23,24 Ooeytee, 92 Specific loam mutations. 92 oryza sativa (rice), 15 RBE values, 15 Oncogenic transformation, 49,56,57 CgH/10TY2cells, 57 LET dependency, 56 Radiation induced, 49 ~steosarcomas,134,143 Internal emitters, 143 Ovarian tumors, 114-117 Cesium 137 gamma ray induction, 116 Fission neutron induction, 116 Incidence in mice, 115 RBE valuee, 114 Oxygen effeds in plants, 21 Partial body radiation (PBR). 9 Penetration factor (PF), 10 Proton radiation, 41 Chromosome aberration induction, 41 Plutonium 239, 79,81,85
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217
Translocation mutation induction, 85 Mutagenicity, 79 Ovarian burdens, 81 Pulmomq tumors, 124 Fission neutron induction, 124 Quality factor, 6 Definition, 6 Radiation quality. 4 Radiation toxicity, 153 RBE values, 153 Radiosenaitivity, 82 Spermatogonia, 82 Recessive lethal mutations, 95 Droeophila, 95 Reciprocal transloeations, 81,82 Neutron induced, 82 Spermatogonia, 81 Repair of potential lethal damage, 59 Restricted stopping power, 5 Reticulum cell sarcoma, 113 RBE, 1, 3,6, 13, 15, 16, 21-24, 25-28,40, 52,54, 58, 61, 63, 67, 71, 72, 77, 78,83,87-89, 94, 96, 109, 112,123,126, 129,130, 134,135, 138, 140,142, 144, 148, 152,154, 162,165,169 Alpha particles, 87, 143, 144 Alternatives, 13 Arabidopsis, 23,24 Auger electrons, 58 Bone sarcoma,142 Cell survival, 72 Chromoeome volume (plants).,23 Cytogenetic effect, 40 Definition, 3, 6 Dose and dose rate, 21 Environment effects, 15 Fission fragments, 148 Fission neutrons, 21, 24,83, 87,88, 94, 134 Heavy ions, 24,63 Hereditary effects, 83 Incorporated radionuclides, 58 LET relationship, 22, 67, 135 Life shortening, 152, 162, 165 Lung turnore, 123 Lycopersicon eeculentum (tomato), 23 Maize, 21 Mammalian cells. 40 Mammary tumom, 126,129
218
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INDEX
Moisture effect, 21 Muons, 26 Mutagenesis, 16, 71, 72, 89 Myeloid leukemia, 109 Neutrons, 27,52.54,96,134,140 Nigella damaeeena (black caraway), 23 Oxygen effects, 21 Planta, 21 Postimplantation fetal loee, 78 Postepermatogonial stages, 77 Radiation quality, 3 Thymic lymphoma, 112 Tradescantia, 21, 27 !hamformation, 61 b o r s , ('hble), 138 Versus neutron energy, 28 Variation with d m , 154 WEM, 1-3,33,4244,46,54,69,67, 84,169 Chromosome aberrations ('lhble), 44 Chromosome aberrations, 42 Fieaion neutrons. 43 LET effects, 42 Neutmm, 59 Reference radiation, 46 'hble, 169 X rays, 33 RBE-LET relationship. 66 Chinese hamster V79 cells, 66 Radium dial workers, 150 Reference radiation, 5,46 W E M ,46 Risk coeficienta, 11, 149 Lung cancer, 149 Silkworm, 103 RBE values CIgble), 103 Spermatid sensitivity, 76 Spermatogonia. 75.82.69.91 Radimnsitivity, 75-82 Specific locus mutations. 89,91 Sperm morphology. 86 RBE value for neutrons, 86 Sperm survival curve. 100 Neutron irradiation, 100 X-ray irradiation, 100 Sterility, 11 Syrian hameter cells, 50,51 Tramformation assay system, 50 Specific locus mutations, 89,90,92, 93, 102 Oocutes, 92
Spermatogonia, 89,90 'Igble, 102 Stochastic effecta, 11 Carcinogeneaie, 11 Mutagenesis. 11 Thymic lymphoma, 110-112 Incidence with neutrons. 110 Incidence with gamma rays. 111 RBE values, 112 ~ l o c a t i o n s84,8Ei, , 95,98 Droeophila, 95 Frequencies, 98 Gamma ray induced, 84 Plutonium 239 induced, 85 Triticum genus (wheat), 15 Tradeacantia, 15,23,26-28 W E , 27 WE, 28 'Ibsticular tumors, 134 'Ibxicity ratio, 149 Lung cancer, 149 Thioguanine CrCf) resistant mutante, 64 Thymidine kinase locus. 72 b o r i g e n e s i s in rate, 127 Transformation frequency, 49-61, 53-57,59,60,62 Alpha particles, 60 C,H/lOTlW cells, 55 Fieeion neutrons, 53,55 Gamma rays, 55 Gamma rays, hctionated, 56 Gamma rays, low dose, 56 In v i h , 49 Mammalian cells, 49 Neutrons, kactionated, 56 Neutron irradiation, 51,53,57 Per surviving cell, 62 X ray irradiation, 51,63,54,57,60 k f o r m a t i o n assay system, 49-64 BALBI3T3 cells. 60 C3H/1OT1/2cells, 50,52,54 RBE, 63 RBEM,54 Syrian hamster cells, 49-52 V i l transformations, 62 Radiation enhanced, 62 Weighting factors (W,), 2, 11 X rays, 51,54,77 Dominant lethal mutations, 77 Transformation frequency, 51, 54 Zen mays (maize), 15, 24 RBE, 24