NCRP report no 121 principles and application of collective dose in radiation protection

NCRP REPORT No. 121

PRINCIPLES AND APPLICATION
OF COLLECTIVE DOSE IN
RADIATION PROTECTION
Reconimendations of the
NATIONAL COUNCIL O N RADIATION
PROTECTION AND MEASUREMENTS

Issued November 30, 1995

National Council on Radiation Protection and Measurements
/
Bethesda, MD 20814-3095
791 0 Woodmont Avenue


LEG& 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
persons contributing to or assisting in the preparation of this Report, nor any person
acting on the behalf of any of these parties: (a) makes any warranty or representation,
express or implied, with-resped to the accuracy, completeness or usefulness of the
information contained in this Report, or that the use of any information, method or
process disclosed i n this Report may not infringe on privately owned rights; or
(b) assumes any liability with respect to the use of, or for damages resulting from
the use of any information, method or process disclosed in this Report, under the
Civil Rights Act of 1964, Section 701 et seq, as amended 42 U.S.C. Section 2000e et
seq. (Title VZZ) or any other statutory or common law theory governing liability.

Library of Congress Cataloging-in-PublicationData
Principles and application of collective dose in radiation protection.
p. cm.-(NCRP report ; no. 121)
Includes bibliographical references and index.
ISBN 0-929600-46-0
1. Radiation-Dosage.
2. Radiation-Safety measures.
I. National Council on Radiation Protection and Measurements.
11. Series.
RA569.P6713
1995
616.9'897-dc20

95-26030
CIP

Copyright Q National Council on Radiation
Protection and Measurements 1995
All rights reserved. This publication is protected by copyright. No part 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 from the copyright owner, except for brief quotation in critical
articles or reviews


Preface
The Committee on Interagency Radiation Research and Policy
Coordination asked the National Council on Radiation Protection
and Measurements (NCRP) to provide advice on the use of collective
dose in radiation protection, particularly as it should pertain to

radiation exposures of the United States public.
In response to this request, NCRP Scientific Committee 1-3,Collective Dose, was established. Serving on Scientific Committee 1-3 were:

Ronald L. Kathren, Chairman
Washington State University
Richland, Washington
Members

John R. Johnson
Battelle, Pacific Northwest
Laboratories
Richland, Washington

Barbara J. McNeil
Harvard Medical School
Boston, Massachusetts

Dade W. Moeller
Dade Moeller & Associates, Inc.
New Bern, North Carolina

Keith J. Schiager
University of Utah
Salt Lake City, Utah

Roy E. Shore
New York University Medical
Center
New York, New York

Robert Ullrich
University of Texas
Galveston, Texas

David A. Waite
Ebasco Environmental
Bellevue,Washington
Scientific Committee 1 Liaison

Eric J. Hall
Columbia University
New York, New York


iv

1

PREFACE

NCRP Secretariat
William M. Beckner, Senior Staff Scientist
Cindy L. O'Brien, Editorial Assistant
The Council wishes t o express its appreciation to the Committee
members for the time and effort devoted to the preparation of this
Report.
Charles B. Meinhold
President

Contents
Preface ........................................................................................
1 Introduction .........................................................................
2 Historical Development ........................,... .......................
2.1 Introduction .....................................................................
2.2 Applications .....................................................................
2.3 Concept Evaluations .......................................................
3 Scientific Bases for Collective Dose .............................
3.1 Introduction .....................................................................
3.2 Mutagenesis .....................................................................
3.2.1 Cellular Studies ....................................................
3.2.1.1 Cytogenetics ..........................................
3.2.1.2 Somatic Cell Mutations ..........................
3.2.2 Animal Studies ......................................................
3.2.2.1 Chromosome Aberrations ........................
3.2.2.2 Germ Cell Mutations ...............................
3.3 Transformation and Carcinogenesis ..............................
3.3.1 Tumor Induction ...................................................
3.3.1.1 Leukemia ..................................................
3.3.1.2 Solid Tumors ............................................
3.3.2 Life Shortening ...................................................
3.3.3 I n Vitro Transformation .......................................
3.4 Human Studies ...............................................................
3.4.1 Human Studies of Cancer Risks from Low
Radiation Doses .................................................
3.4.1.1 Thyroid Cancer ........................................
3.4.1.2 Breast Cancer ..........................................
3.4.1.3 Leukemia ..................................................
3.4.1.4 Multiple Myeloma ...................................
3.4.1.5 In Utero Irradiation .................................

3.4.1.6 Lung Cancer ............................................
3.4.1.7 Other Cancers ..........................................
3.4.2 Genetic Risks .........................................................
3.5 Summary ..........................................................................
4 Limitations ...........................................................................
4.1 Conceptual Limitations .................................................
4.2 Practical Limitations ......................................................

.
.
.

.


vi

/

CONTENTS

4.2.1 Tissue Weighting Factors ....................................
4.2.2 Population Characteristics ..................................
4.2.2.1 Uncertainties in Future Population

.................................
.................................................

Size and Location

4.2.2.2 Uncertainties in Future Population

Fertility

4.2.2.3 Uncertainties in Future Medical

Technology

.

............................................

4.2.3 Environmental Exposure Pathways ....................
4.2.3.1 Agriculture ...............................................
4.2.3.2 Resource Conservation ............................

5 Risk Assessment and Management ................................
5.1 Collective Dose as a Surrogate for Societal Risk ..........
5.2 Collective Dose Distributions .........................................
5.3 Risk Assessment in Specific Applications .....................
5.3.1 Medical Procedures ...............................................
5.3.2 Radiation Workers ...............................................
5.3.3 Special Occupational Groups ...............................
5.3.4 Current Exposures to Members of the Public

from Localized Environmental Sources

...........

5.3.5 Indoor Radon .........................................................

5.3.6 Consumer Products and Other Miscellaneous

Sources

...............................................................

5.3.7 Future Exposures from Long-Lived

Environmental Contaminants

.

..........................

5.4 Risk Management ...........................................................
5.4.1 Acceptability of Risk .............................................
5.4.2 Categorizing Levels of Risk ..................................
5.4.3 Optimization of Protection (ALARA) ...................
5.4.4 Valuation of Collective Dose Avoided ..................

6 Conclusions and Recommendations ..............................
Glossary ......................................................................................
References .................................................................................
The NCRP ..................................................................................
NCRP Publications ..................................................................
Index ...........................................................................................


1. Introduction
Conceptually, collective dose is the summation of all doses received

by all members of a population a t risk, and may thus be expressed
mathematically as:
where S refers to the collective dose to the population a t risk, and

Hiis the per capita dose in subgroup i, and Pi is a subgroup i of
population P (ICRP, 1977). Any dose quantity can be used, provided
usage is consistent. Collective dose is expressed in units of persondose, using the appropriate dose units for the quantity selected.
Typically, collective dose to a population is expressed in units of
person-sievert.
Collective dose is applicable only to stochastic risks. Implicit in
the concept of collective dose is the assumption that the effect or
risk of a given dose is identical whether the collectivedose is administered to a single individual or distributed over a population of individuals. Application of collective dose in this manner assumes linearity
of dose response, and lack of any dose-rate effect. While these
assumptions may or may not be valid, they are considered to be
conservative and have been generally accepted by the scientific community concerned with radiation protection (ICRP, 1977; 1991; NASI
NRC, 1990; NCRP, 1987a; 1993).
In recent years, collective dose has been applied ever increasingly
to prospective radiation protection problems, particularly relating
to long-term effects of environmental radiation. Such applications
lead to questions regarding the applicability of the collective dose
concept to large populations with very small individual doses and
to populations that will exist several generations hence. This Report
seeks to address these and other questions regarding collective dose
and its applicability for radiation protection purposes, and to provide
practical guidance for the employment of this potentially useful concept in consonance with current National Council on Radiation Protection and Measurements (NCRP) philosophy and recommendations
on exposure limitation a s described i n NCRP Report No. 116
(NCRP, 1993).
This Report provides a review of the historical development and
current applications of the collective dose concept, and attempts to

2

/

1. INTRODUCTION

identify and examine the scientific and other bases that underlie it.
It examines the meaning and utility of the concept ofcollective dose in
radiation protection and risk assessment for workers and members of
the general public. Finally, it provides recommendations for applying
collective dose based on current scientific knowledge of the health
effects and potential risks of radiation.
Underlying the consideration of the collective dose concept and
the recorrfmendations provided herein is the continuous evolution of
radiation protection standards towards a system based on risk. For
such a risk based system to be practical, it must take account of the
uncertainties in the risk estimates which form its basis. Additionally,
consideration should be given to societal factors, including the willingness of society to incur certain risks in view of the perceived
overall benefit to be derived.


2. Historical Development
2.1 Introduction
The collective dose concept is widely used within the radiological
protection community in the estimation of radiological risk, in the
optimization or decision making processes, and in the development
of regulations. Some authors trace the origin of the concept back to
the term "genetically significant dose," or "population dose" which
was proposed to limit radiation induced genetic risk of populations

as early as the late 1950s and early 1960s [see NCRP (1957); ICRPI
ICRU (1957) and ICRPACRU (1961)l. An early usage was the 1965
annual collective dose limitation of 100 person-Sv y-' for each nuclear
power station imposed by the Canadian Atomic Energy Control
Board (Hurst and Boyd, 1972). The concept does appear in the International Commission on Radiological Protection's (ICRP) Publication
22 (ICRP, 1973), where it was first called "population dose," and
evolved to "collective dose" by the time of ICRP Publication 26
(ICRP, 1977).
Modern usage of the collective dose concept originated in the early
1970s within the United Nations Scientific Committee on the Effects
ofAtomic Radiation (UNSCEAR)and the ICRP. The 1969 UNSCEAR
report did not mention collective dose, but by 1977, the use of collective dose by UNSCEAR was prevalent (LTNSCEAR, 1977). The transition seems t o have occurred i n the 1972 UNSCEAR report
(UNSCEAR, 1972), in which the unit man-rad was introduced. Population doses in units of person-rem were also used in the initial
report of the Committee on the Biological Effects of Ionizing Radiation [BEIR (NASINRC, 1972)l.
A discussion of topics similar to collective dose in NCRP Report
No. 39 (NCRP, 1971) did not mention the conceptper se. But, NCRP
(1957) talked of "The maximum permissible dose to the gonads for
the population of the United States as a whole from all sources
of radiation, including medical and other manmade sources, and
background, shall not exceed 14 million rems per million of population over the period from conception up to age 30, and one-third of
that amount in each decade thereafter." The first specific reference
to the collective dose concept in an NCRP report occurred in NCRP
Report No. 43, entitled Review of the Current State of Radiation


4

/

2. HISTORICAL DEVELOPMENT

Protection Philosophy (NCRP, 1975), and the concept has been discussed, refined and applied in subsequent NCRP reports and
recommendations.
2.2

Applications

The use of the collective dose concept has permeated into many
aspects of radiation protection policy making and program implementation worldwide. The scientific and technical literature contains
numerous examples of collective dose-based estimates of the collective risk for a wide variety of radiation-related activities. In its series
of reports assessing the ionizing radiation exposure to the population
of the United States (NCRP, 1987b; 1987c; 1987d; 1987e), the NCRP
has made extensive use of the collective dose concept. NCRP Report
No. 93 (NCRP, 1987b) summarizes radiation exposures from all
sources that were individually reviewed in the other assessment
reports, and includes collective dose estimates. Other NCRP reports,
notably Reports No. 105, 107 and 116 (NCRP, 1989; 1990a; 1993)
consider collective dose in their discussion of radiation protection
recommendations.
Other examples of considerations of collective dose for radiation
protection purposes in other countries include a study by Iyengar
and Soman (1987) which examines in detail the collective occupational and public doses from all components of the Indian nuclear
fuel cycle. Similarly, Hyvonen (1990) evaluates the effectiveness of
the Finnish radiation protection programs vis-a-vis exposures in
medicine, industry, research and nuclear power. Early United States
examples include the final environmental statements for Pilgrim
Nuclear Power Station (AEC, 1972) and for Hanford Waste Management Operations (ERDA, 1975), both of which discuss impacts and
comparative population or overall risks in terms of collective doses,
and a more generic study of light-water reactor effluents (AEC, 1973).
Relevant guidance documents incorporating collective dose have

been prepared by others including the ICRP (19731, and the Organization for Economic Cooperation and Development/Nuclear Energy
Agency (OECDLVEA, 1988). In the mid-1950s the principle of maintainingradiation exposures to the lowest practicable limit was introduced into its recommendations by the NCRP (1954) and the concept
of optimization, also known as ALARA (as low as reasonably achievable), began to evolve (ICRP, 1955; 1959). This concept is now central
to radiation protection practice and is based on a balancing of risks
and benefits. The ALARA concept was formally introduced as a recommendation for radiation protection by the ICRP in 1977 (ICRP,


2.3 CONCEPTEVALUATIONS

1

5

1977), although its origins in radiation protection practice go back
a t least to the early 1950s (Kathren et al.,1980).
Regulatory bodies have integrated the collective dose concept into
United States radiation protection regulations in various ways. In
the mid-1970s, the Nuclear Regulatory Commission (NRC) adopted
the use of the collective dose concept with a spatial cutoff of 50 miles,
see Appendix I to 10 CFR 50 (NRC, 1975). Amplification of the
regulation was provided two years later in NRC Regulatory Guide
1.109, Appendix D, which stated that "These doses should be evaluated for the population within a 50-mile radius of the site.. . For
the purpose of calculating the annual population-integrated dose,
the 50-mile region should be subdivided into a number of subregions
consistent with the nature of the region" (NRC, 1977). This type of
spatial truncation has been widely accepted and utilized in the past,
particularly in documents such as environmental impact statements
prepared for regulatory purposes.
Such acceptance has not been the case when dose-related and
other truncation rationales have been attempted in other aspects of

the regulatory framework such as the NRC proposed adoption of
"below regulatory concern" for determining when individual radiation exposures are or will be so low that they do not warrant further
regulatory control (NRC, 1988). In addition to an individual dose
criterion, the NRC proposed a collective dose limit as well, stating
in its 1988 policy statement that "The Commission specifically seeks
comments on the need for establishing a collective dose limit in
addition to a n individual dose criterion" (NRC, 1988). These proposals have not been adopted.

2.3 Concept Evaluations
In recent years at least two studies have examined the fundamental validity and utility of the collective dose concept. The first was
a study by Lindell(1984) who was commissioned by the OECDINEA
to prepare a report describing the various situations in which ICRP
recommendations would require a n assessment of collective dose,
the objectives of such assessments, the related methods, and the
limits and difficulties of these collective dose assessments. Regulatory aspects were not addressed in this study.
In the Lindell report (Lindell, 1984), the following applications of
the collective dose concept are identified as the most commonly used
in radiation protection:


1. in the assessment of the highest per capita dose in the future
from a continued practice which exposes some members of the
population to radiation,
2. in the limitation of present use of radioactive material, if it is
believed that additional sources in the future may add to the per
capita dose in a population so that it might reach unacceptable
levels unless all sources are controlled a t a n early stage,
3. as a n input to justification assessments, indicating the total
detriment from a certain practice, and
4. as an input to optimization assessments as the basis for costing

detriment in differential cost-benefit analysis of protection
arrangements.
His primary conclusion is that while it is often said that for the
collective dose to be useful, an assumption of a nonthreshold, linear
dose-response relation is needed, in truth, this assumption is not
always necessary. Applications (1)and (2) are possible without any
assumptions on the dose-response relationship at low doses. Only
applications (3) and (4) require a strictly defined dose-response
relationship.
Lindell also acknowledges that there is some hesitation in using
the collective dose, not only due to distrust of the biological assumptions implied by uses (3) and (4), but also in lack of confidence in the
predictiveness of collective doses that have been derived by adding
contributions over very long time periods. However, none of the four
applications is by necessity related to extreme time scales.
The second was a study commissioned by the German Radiological
Protection Commission in 1985 (SSK, 1985). The objective of this
investigation was to determine whether collective dose is suitable
as (1)a measure of the radiation-related detriment and (2) a tool
for the optimization of radiological protection and for the comparison
of safeguards, and thus a meaningful measure of radiation exposures. The study considered both the scientific state-of-the-art and
the legal situation that existed in Germany in 1985, and reached
the following conclusions relative to detriment, optimization and
regulation:
"1. The collective dose is only suited to be a measure of detriment
if there i s a sufficient knowledge of t h e risk coefficients
required for the calculation of detriment in the dose range
of interest. As far as the relevant dose ranges in practical
radiological protection are concerned, it must be recognized
that the required risk coefficients are derived from estimates
and not from quantitative determinations. This applies in

particular to dose ranges t h a t a r e of importance for t h e
populations.


2.3 CONCEPTEVALUATIONS

/

7

"2. With respect to protection implementation, the Radiological

Protection Commission considers the optimization of the radiological protection of personnel by means of a minimization of
the collective dose and the comparison of safeguards suitable,
using the collective dose a s a measure of comparison.
"3. Although there is a binding obligation for the optimization of
radiological protection, there is no obligation to consider the
collective dose as a suitable tool for reaching this objective.
The Radiological Protection Commission recommends that collective dose not be included in legal regulations."
The following sections of this Report extend the considerations
made in these earlier studies and reviews these issues in the context
of present circumstances in the United States.


3. Scientific Bases for
Collective Dose
3.1 Introduction
The utility of collective dose rests on the assumption that the
biological response at low dose and dose rates is both linear and
time independent, and that the response of any individual to a given

dose is more or less uniform. This logically leads to the prediction
that at low doses the response will be the same whether the dose is
delivered as a single acute exposure, as multiple small fractions, or
as a protracted low-dose rate exposure. The assumption of time
independence also implies that the time between each fraction and
the time over which the total dose is delivered are not important.
Whether these assumptions are appropriate have not been determined from human epidemiologic data. Some animal studies have
shown that both the time between fractions and the time over which
the total dose is delivered are important. The following sections will
review cellular, animal and human studies on the mutagenic and
carcinogenic effects of radiation which have bearing on these
assumptions of linearity and time independence a t low doses.

3.2 Mutagenesis
3.2.1

Cellular Studies

3.2.1.1 Cytogenetics. The effects of dose, radiation quality, and
dose rate or fractionation on the yield of chromosome aberrations
have been extensively studied using cultured lymphocytes from a
variety of species including humans. Data indicate that similar
results are obtained whether cells are irradiated in vivo or in vitro
(Brewen and Gengozian, 1971; Schmid et al., 1974). Pertinent
reviews can be found in NCRP (1980; 1990b) and UNSCEAR (1988;
1993). A large body of data examining the induction of chromosome


3.2 MUTAGENESIS

9

aberrations following in vitro exposure of human lymphocytes has
shown, for low-LET radiation, that over a 0.05 to 8 Gy dose range,
two-break chromosome aberrations, such as dicentric aberrations,
increase with dose according to the linear quadratic function:

where I is the incidence of radiation induced chromosome aberrations, D is the dose and a and p are numerical constants with the
linear term
predominating a t low doses. A reduction in the doserate results in a reduction in the PD2 term with no apparent effect
on the aD term of the response equation (NASNRC, 1990).The data
imply that the response a t low doses is linear and time independent.
At very low doses induced by internally deposited radioactive materials, the yield of aberrations was found to be described by the function
(I = d).
A linear dose-response function was found regardless of
the LET of the radiation (NCRP, 19870. The a coefficient is similar
a t low radiation doses whether protracted or delivered as an acute
exposure. For high-LET radiation, the yield of aberrations increases
as a linear function of dose over a wide range and is dose-rate independent. This point is discussed in greater detail below.

3.2.1.2 Somatic Cell Mutations. The induction of gene mutations
in cultured cells by irradiation has been studied by a number of
investigators using several different cell lines including those
derived from mice, hamsters and humans. In addition, specially
engineered hybrid hamster cells containing the bacterial gene gpt
or containing human chromosome number 11have also been used
to study radiation mutagenesis (Evans et al., 1990; NCRP, 1990b).
Because of the limited sensitivity of these model systems, most studies have not directly examined the dose response at doses below
about 0.5 Gy. Although data a t low doses are limited, inferences can
be drawn about the shape of the dose-response curve in the low-dose

range based on the effects of dose rate on the response and based
on molecular analyses of the induced lesions. The data indicate that
the dose-rate dependence of radiation induced mutations depends
upon the type of mutation induced (NASNRC, 1990). In general,
lesions that can be hypothesized to involve the interaction of damaged DNA, such as intragenic deletions, rearrangements and other
multilocus mutations, have been found to be dose-rate dependent.
Because of the apparent involvement of the interaction of sublesions,
the prediction of a linear-quadratic dose-response function and doserate dependence for such lesions seems reasonable over the range
of doses used. In other instances, such as point mutations (i.e., base
substitutions), the data suggest no dose-rate effect and also strongly


10

/

3. SCIENTIFIC BASES FOR COLLECTIVE DOSE

suggest a more linear dose-response relationship over a wide range
of doses. In either case, the response a t low doses is expected to
be linear and independent of the time course over which the dose
is delivered:
For high-LET radiation, the association is somewhat less certain
although the data indicate an approximately linear dose response
following acute exposures. Studies examining effects of dose rate and
fractionation, however, suggest that reducing the dose-rate results in
an increase in the induced mutation frequency over the 0.10 to 1Gy
dose range (NCRP, 1990b).

3.2.2

Animal Studies

The principal focus when considering genetic effects in animals
is on the germ cells, for which information comes primarily from
experiments examining chromosome aberrations in these cells and
from studies of specific locus mutations in the mouse. These studies
have been reviewed extensively and most recently in ICRP (19911,
NAS/NRC (1990) and UNSCEAR (1988). With respect to low-LET
effects at low doses and dose rates, the most comprehensive reviews
can be found in NCRP (1980) and Searle (1974). A comprehensive
review of high-LET effects from external exposure is presented in
NCRP Report No. 104 (NCRP, 1990b) and for internally deposited
radionuclides in NCRP Report No. 89 (NCRP, 1987~).
3.2.2.1 Chromosome Aberrations. The induction of reciprocal
translocations in spermatogonia has been studied over the dose
range 0.5 to 12 Gy of low-LET radiation and can be described by a
linear-quadratic equation followed by a downturn a t higher doses
(UNSCEAR, 1986). Reducing the dose rate or the size of the dose
fractions reduces the response principally by reducing the beta term
(see Equation 3.1). This suggests a more nearly linear response at
dose rates below about 0.1 mGy min-l. Further reduction in the dose
rate below 0.1 mGy min-I does not significantly affect the slope of
this response.
Information on chromosomal changes in oocytes is available from
studies of Brewen and coworkers (Brewen and Payne, 1977; 1979;
Brewen et al., 1976). In these studies, the yield of chromosome aberrations following acute exposures increased as a linear quadratic
function of dose. Chronic gamma irradiation resulted in a linear
response function with a slope similar to the linear portion of
the linear quadratic responses obtained following high-dose rate

exposures.


3.2 MUTAGENESIS

1

11

3.2.2.2 Germ Cell Mutations. Evaluations of specific locus mutations in mice have emphasized the studies of spermatogonia and the
resting oocyte. Because of the extreme sensitivity of the oocyte, which
results in killing and early onset of sterility a t intermediate to high
doses of low-LET radiation, studies first concentrated on responses
in spermatogonia. While dose-response data for spermatogonia are
limited, i t is clear that lowering the dose-rate results in a progressive
decrease in mutation incidence down to a dose rate of approximately
10 mGy min-' (UNSCEAR, 1986). Importantly, lowering the dose
rate below 10 mGy min-l results in no additional decrease in mutation incidence.
Although fractionation studies are more difficult to interpret, it
is important to point out the studies of Lyon et al. (1972) that compared the effects of a single 6 Gy dose with fractions divided into 60
daily doses delivered as acute fractions or split into weekly doses of
0.5 Gy delivered as acute fractions. The daily fractionation regimen
resulted in mutation frequencies similar to those obtained at lowdose rates while the higher weekly fractions resulted in mutation
frequencies similar to those after acute exposures. These results,
as well as the dose-rate data described above, are consistent with
additivity of effects a t low doses and dose rates.
In the female mouse, few if any mutations are observed a t doses
up to several Gy when delivered at low-dose rates (NCRP, 1980;
1990b;Searle, 1974). Because of the extreme sensitivity of the mouse
oocyte to killing by x rays, this test system has been called into

question as far as its applicability to humans is concerned.
The dose-response relationship for mutation induction following
exposure of spermatogonia to neutron irradiation appears to be linear over the 0.5 to 0.9 Gy dose range, but the mutation frequency
is markedly lower a t a dose of 2 Gy (NCRP, 1990b).Dose rate appears
to have little influence on the mutation yield obtained in the 0.5 to
0.9 Gy dose range. At higher dose rates and dose, a reduction in
yield is observed for many endpoints. This is most often explained
on the basis of cell killing. More significant for radiation protection
considerations is the apparent lack of any influence of dose rate a t
lower doses.
Considering the small amount of data available in the low-dose
range and the associated complicating factors, particularly with
respect to the female mouse, it appears that most of the data on
mutations a r e consistent with a linear and time-independent
response to radiation in the low-dose region following exposure to
low-LET radiation. Data for spermatogonia irradiated with highLET radiations are also consistent with a linear, dose-rate independent response.


12

1

3. SCIENTIFIC BASES FOR COLLECTIVE DOSE

3.3 Transformation and Carcinogenesis
3.3.1

Tumor Induction

Studies of dose-response, time-dose relationships and influence of

radiation quality for tumor development in laboratory studies of
animals have been reviewed extensively in NCRP (1980)and NCRP
(1990b).Despite the large body of data, there are only a few instances
in which the dose response is sufficiently well defined and for which
time-dose relationships have been studied.

3.3.1.1 Leukemia. A large body of data is available on the induction of myeloid leukemia in two strains of mice. It has generally
been concluded from these data that the dose response is linear
quadratic, although a linear response cannot be excluded (Barendsen,
1978)and the data for one of the strains has been described to fit a
quadratic with a cell killing term (Mole et al., 1983).Lowering the
dose rate has been shown to result in a reduced response per unit
dose. From analysis of data for myeloid leukemia, Barendsen (1978)
concluded that the linear component of the linear quadratic model
fitted to the high-dose rate data adequately predicted the data
obtained for continuous low-dose rate and fractionated doses. These
data support the conclusion of a linear, time independent, additive
response a t low doses. For thymic lymphoma induction, the dose
response and the effect of low-dose rate are complex and the response
a t low doses has not been sufficiently well characterized to allow
any conclusions to be reached.
3.3.1.2 Solid Tumors. Ullrich (1983)and Ullrichet al. (1987)have
reported studies on mammary and lung adenocarcinoma development as a function of dose, dose rate and fractionation. Following
high-dose rate exposures, the data indicate linear quadratic doseresponse functions for both tumor types although the dose range
over which the linear response predominated differed markedly.
For low-dose rate exposures the data were best described by linear
functions with slopes similar to the linear portions of the linear
quadratic equations obtained following high-dose rate exposures. On
the basis of these results, the effects of low-dose rate exposures and
of high-dose rate low-dose fractions were compared in a direct test

of the prediction of dose-rate independence a t low doses, i.e., doses
where the linear response predominates. The data demonstrate that
the effects of fractionation were predicted by the linear quadratic
regression equations derived from the high-dose rate data. When
the dose per fraction was on the predominantly linear portion of the


3.3 TRANSFORMATION A I D CARCINOGENESIS

1

13

dose-response relationship, the effect was similar to that after lowdose rate exposures.
These conclusions are also supported by results of studies on the
induction of pituitary and Harderian gland tumors, although the
data are not as extensive (NCRP, 1980; Ullrich and Storer, 1979).
For these tumor types in RFM mice, linear quadratic dose responses
have also been reported. Further, linear responses a t low doses with
slope coefficients similar to those derived from the high-dose rate
linear quadratic response were observed. Such results are not
obtained when ovarian tumor induction has been examined. Rather,
the reported data from several studies of ovarian tumor induction
are more consistent with a threshold model. However, the apparent
extreme sensitivity of the oocyte to killing effects, and the possible
role of indirect mechanisms in ovarian tumor development, suggest
that this may be a response unique to ovarian tumors in the mouse.
Data for induction of other tumors are not sufficient to contribute
to resolution of the question. Taken as a whole the above data are
consistent with t h e concept of a n additive, time independent

response for tumor induction a t low doses.
All available data for tumor induction following high-LET radiation support a linear dose response a t doses below 0.1 Gy (NCRP,
1990b). Further, with the exception of mammary tumor induction,
it appears that the response following fractionated or protracted
exposures to low total doses is also linear. For mammary tumors
the incidence is two- to threefold higher following low-dose rate
exposure than after high-dose rates, even after a dose as low as
0.025 Gy. The reason for this effect is not known.

3.3.2 Life Shortening
Life shortening is one of the most extensively studied late effects
of exposure to ionizing radiation. Since it has been shown that virtually all the excess life-shortening effects that occur after an exposure
a t low dose or low-dose rates is due to excess tumor mortality, this
endpoint is a useful quantitative tool for the study of the neoplastic
effects of radiation a t low doses and dose rates. The quantitative
nature of this endpoint and the ease of measurement have allowed
investigators to examine dose-response relationships and to rigorously examine effects of dose rate, protraction and radiation quality.
A review of these data is available in NCRP Reports 64 and 104
(NCRP, 1980; 1990b).
Several concepts have emerged from these studies which are of
direct relevance to this Report. Results obtained with a number of


14

/

3. SCIENTIFIC BASES FOR COLLECTIVE DOSE

different strains of mice, have led to the general conclusion that at

low doses and low-dose rates a linear relationship exists between
the degree of life shortening and the magnitude of low-LET radiation
exposure. Data from other species also tend to support these conclusions. While there is some evidence of apparent life lengthening a t
low radiation doses (Congdon, 1987; Lorenz et al., 1955; Mine et ak.,
1990), the mechanisms of this effect may be related more to the low
grade stress of the radiation exposure rather than to a true radiogenic effect that could be extrapolated to human risk estimates. A
discussion of these observations and their biologic mechanisms can be
found in NCRP (1980), Sacher and Trucco (1962) and Sagan (1989).
Investigators have concluded that the dose response for high-LET
irradiation is linear at low doses. At doses above about 0.2 to 0.4 Gy,
there is a bending or deviation from linearity in the dose-response
curve. While enhanced life shortening effects have been observed
following low-dose rate exposures a t total doses greater than 0.2 Gy,
fractionation and dose-rate studies strongly support the conclusion
that the response is in fact linear and additive a t low doses (NASI
NRC, 1990; UNSCEAR, 1986).

3.3.3 In Vitro Transformation
Since the first published report of radiation induced transformation in uitro, these model systems have served as useful tools with
which to explore many questions (Borek and Sachs, 1966). Particularly relevant to this Report are studies of dose-rate and fractionation
effects. The repairability of low-LET radiation induced transformational damage was one of the first observations made with the C3H
10T1/2 cell system. Subsequently, it has been demonstrated that
reduction of the dose rate of low-LET radiation results in a reduction
in the transformation frequency in most systems studied. Results
following fractionation are more complex and depend on total dose,
fraction size and time between fractions. The most complete data
set for studies of dose-rate and fractionation effects for low-LET
radiation for in uivo transformation studies comes from the work
of Elkind and Han (Elkind et al., 1985; Han et al., 1984). These
investigators reported a reduced transformation frequency after lowdose rate exposures. Daily fractions of high-dose rate exposures of

0.5 Gy also resulted in a lower transformation frequency than that
from a single acute dose.
In contrast to the results with photons, studies of dose-rate effects
in C3H 10T112 cells with neutron irradiation suggest an enhanced
effect a t doses above 0.1 mGy when the dose rate is less than


3.4 HUMAN STUDIES

1

15

5 mGy min-' (Elkind et al., 1985;Hill et al., 1982; 1984).While these
results were initially somewhat controversial, similar results have
now been reported by some other, but not all, investigators using
different in vitro cell systems (see Hall et al., 1991). This so called
inverse dose-rate effect appears to be a complex function of LET,
dose and dose rate. The reason for this effect is not known. Recently,
Brenner and Hall (1990)have proposed a model involving a sensitive
stage in the cell cycle for transformation which is consistent with
the experimental data.

3.4 Human Studies

Two interrelated questions pertinent to the issue of collective
dose can be examined in the human epidemiologic database. The
first is whether projections of risks from high doses to low doses are
correct using a dose-response relationship that is a linear function of
dose. Alternatively, the question may be whether a linear-quadratic

(convex upward) model, for which both components have been estimated, projects the risk with reasonable accuracy. If the doseresponse curve is truly linear quadratic, but is estimated with a
simple linear function, then low-dose effects and the estimated risk
from collective low-level doses will be overestimated. The second
question is whether the effects of many small dose fractions or highly
protracted doses are additive. If so, then the application of collective
dose is appropriate, but if not, then collective dose based on many
small doses could overestimate the risk.
The current risk estimates are largely based on epidemiologic
studies involving acute exposures up to a few Gy, such as the Japanese atomic-bomb survivors and people receiving x-ray treatments
for a variety of medical conditions. A number of studies have documented the nature of risks in these populations, and there is reasonable agreement among the studies as to the magnitude of risk per
unit dose.
There is less certainty about the magnitude of risks resulting from
exposures at low doses andlor doses at low-dose rates. It is intrinsically
difficult to assess risk accurately and precisely when doses are below
50 mSv or when they are delivered at rates of a few mSv per year.
Even among the survivors of the atomic bombings in Japan, a risk
from doses below approximately 200 mSv has not yet been precisely
demonstrated. Lowdose studies tend to be limited for at least two
reasons. First, with a lowdose study the magnitude of confounding
effects may be as large or larger than the exposure-caused effects and


16

/

3. SCTENTIFIC BASES FOR COLLECTIVE DOSE

hence may give "false positive" or "false negative" results. Typically,
most of the potential confounding variables are either unknown, or

data are not available to control their influence.
Second, there is a signal-to-noise ratio (SNR) problem in low-dose
studies: the smaller incidence of radiation-induced cancers may be
drowned out by the much larger spontaneous incidence. This means
that for low-dose studies, a large sample size will improve the SNR
and permit detection of smaller differences between the spontaneous
or background rate and the observed rate. In particular, the required
sample size is a nonlinear function of the expected size of the effect.
To give a hypothetical example; if there is a linear relationship
between radiation dose and lung cancer risk, and 1,000 subjects
need to be studied to detect an excess risk when the dose they receive
is 1 Sv, then over 70,000 subjects with doses of 0.1 Sv would need
to be studied to detect the same excess risk, and nearly seven million
if the dose was 0.01 Sv. In short, the necessary sample size becomes
prohibitively large when doses are small.
In the sections that follow, the available human data for several
of the most radiosensitive cancer types have been surveyed to determine whether the data support additivity of effects when the doses
are relatively low, fractionated or protracted. In particular, the data
for multiple myeloma are discussed below. This cancer, which has
been noted in a few occupational studies, is examined across the
range of doses to determine whether its induction is more likely to
appear a t low doses or dose rates. It should be noted when comparing
human studies that differences in dose and dose rate are not the
only confounders, other factors such as the "healthy-worker effect"
should also be considered.

3.4.1 Human Studies of Cancer Risks porn Low Radiation Doses
Thyroid Cancer. There are a number of epidemiologic
studies of thyroid cancer following radiation exposures. In most of
these studies, acute thyroid doses of 0.5 Gy up to 10 Gy or more were

involved. The available evidence indicates that radiation exposure a t
younger ages (less than 20 y) confers more risk than a comparable
exposure at older ages (Hanford et al., 1962; Ron et al., 1995). The
focus of this review of epidemiological studies is on populations who
received exposure before 20 y of age. These risk estimates are shown
in Table 3.1.

3.4.1.1


3.4 HUMAN STUDIES

/

17

The cohort studies provide the most reliable estimates of risk
because of their essentially complete ascertainment of thyroid cancer
over time. The screening studies should be used with some caution
because of possible subject selection biases and incomplete ascertainment over time. In addition, only two screening studies (Maxonet al.,
1980; Pottern et al., 1990)nhadscreened comparison groups for use as
a baseline. For most screening studies there is, therefore, additional
uncertainty in the expected number of cancers, since the estimates
are from populations that did not have the screening. It should be
noted that when the expected numbers are small, as in the screening
studies in Table 3.1, the uncertainty in the expected numbers makes
the estimates of excess relative risk especially unreliable, more so
than the estimates of absolute risk.
A few studies have evaluated the effect of thyroid doses on the
order of 0.1 Gy. These include two studies of children epilated with

x rays during treatment of ringworm of the scalp (Ron et al., 1989;
Shore, 1991') (see Table 3.1). The risk estimates in the larger study
were a t least three times higher than those from other cohort studies
of thyroid cancer. Whether this is due to unusual susceptibility
within this population or to other factors is unknown. The smaller
study showed a n absolute excess risk about six times lower, but
the difference in risk estimates between the two studies was only
marginally significant (p < 0.10).
The thymus irradiation study reported by Shore (1989) included
about 1,500 persons who received <0.5 Gy (mean dose of 0.18 Gy).
There was a significant dose-response relationship, although it was
based on small numbers (five irradiated cases versus five cases
among the 4,800 unirradiated subjects). When the analysis was
restricted to less than 0.3 Gy, however, the dose trend was still
positive, but no longer statistically significant.
The widespread use of 1311for diagnostic purposes has provided
several opportunities to examine thyroid cancer risk following exposure to protracted, low-dose rate radiation. In the first, Holm et al.
(1988) studied 35,000 persons to whom 13'1 was administered, of
whom about 1,800 were under the age of 20 at the time of exarnination. The average thyroid dose was 0.5 Gy among adults and 1.6 Gy
among children. Among those whose initial diagnostic examination
was not because of a suspected thyroid tumor, there was a deficit of
thyroid cancers (Table 3.1). For those under age 20 a t 1311 exposure,
two thyroid cancers were observed with 1.1expected (not statistically
lunpublished data (Shore,R.E., Department of Environmental Medicine,New York
University Medical Center, 1991).