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Executive Summary
INTRODUCTION
This report, prepared by the National Research Council's Committee
on the Biological Effects of Ionizing Radiations (BEIR), is the fifth in a
series that addresses the health effects of exposure of human populations
to low-dose radiation. Ionizing radiations arise from both natural and man-
made sources and can affect the various organs and tissues of the body. Late
health effects depend on the physical characteristics of the radiation as well
as biological factors. Well demonstrated late effects include the induction of
cancer, genetically determined ill-health, developmental abnormalities, and
some degenerative diseases (e.g., cataracts). Recent concern has centered
on the risks of these eRects following low-dose exposure, in part because
of the presence of elevated levels of radon progeny at certain geographical
sites and fallout from the nuclear reactor accidents at Three Mile Island
in Pennsylvania in 1979 and Chernobyl in the USSR in 1986. In addition,
there is concern about radioactivity in the environment around nuclear
facilities and a need to set standards for cleanup and disposal of nuclear
waste materials.
Since the completion of the 1980 BEIR III report, there have been
significant developments in our knowledge of the extent of radiation expo-
sures from natural sources and medical uses as well as new data on the
late health effects of radiation in humans, primarily the induction of cancer
and developmental abnormalities. Furthermore, advanced computational
techniques and models for analysis have become available for radiation risk
assessment. The largest part of the committee's report deals with radiation
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2 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
carcinogenesis in humans, primarily because: (1) there is extended follow-
up in major epidemiological studies, particularly those of the Japanese
A-bomb survivors and radiotherapy patients treated for benign and malig-
nant conditions, and (2) the revision by a binational group of experts of
the dosimetric system for A-bomb survivors in Hiroshima and Nagasaki
allows improved analyses of the Japanese data. The report also addresses
radiation-induced genetic injury and health effects associated with prenatal
irradiation. While only limited application of the advances in our under-
standing of the molecular mechanisms of cancer induction and genetic
disease is possible, these have been examined with the aim of narrowing
the range of uncertainties and assumptions inherent in the risk estimation
process.
RISK ASSESSMENT
The 1988 BEIR IV report addressed the health effects of exposure to
internally-deposited, alpha-emitting radionuclides: radon and its progeny,
polonium, radium, thorium, uranium and the transuranic elements. The
current BEIR V Committee report includes information and analyses from
the BEIR IV report that are appropriate for cancer and genetic risk
assessment. In addition, this report addresses the delayed health effects that
are induced by low linear energy transfer (LET) radiations such as x rays
and gamma radiation and, where possible, makes quantitative risk estimates
based on statistical analyses of the results of human epidemiological studies
and laboratory animal experiments.
The human data on cancer induction by radiation are extensive; the
most comprehensive studies are of the survivors of the atomic bombings
of Hiroshima and Nagasaki, x-rayed tuberculosis patients, and persons
exposed during treatment for ankylosing spondylitis, cervical cancer, and
tinea capitis. Radiation associated cancer risk estimates have been calcu-
lated for a number of different organs and tissues, including bone marrow
(leukemia), breast, thyroid, lung, and the gastrointestinal organs. 1b the
extent possible, the biological differences among human beings that may
modify susceptibility to radiation-induced cancer have been taken into
account.
Considerable progress has been made in our understanding of the
mutation process on genes and chromosomes and its expression as genetic
disorders. Due to a lack of direct evidence of any increase in human
heritable effects resulting from radiation exposure, the estimates of genetic
risks in humans are based, primarily, on experimental data obtained with
laboratory animals. As in all experimental animal studies, the extent to
which the results can be extrapolated to humans and the confidence that
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EXECUTIVE SUMMARY
3
can be placed on such extrapolation remain uncertain. At present, no data
are available to provide reliable estimates of the risks of most complex,
multifactorial hereditary disorders. Such risks were not evaluated by the
committee.
During the past decade, extensive data have become available on the
developmental anatomy of the mammalian brain, and this information
has aided the interpretation of effects observed among Japanese survivors
irradiated in utero during the atomic bombings. New analyses of the data
on A-bomb survivors exposed in utero, together with the reassessment
of the A-bomb dosimetry, have permitted delineation of the time-specific
susceptibility to radiation-induced mental retardation, the most prevalent
developmental abnormality to appear in humans exposed prenatally, and
has allowed the risk of these effects to be estimated.
In preparing risk estimates, the committee has relied chiefly on its
own evaluations, using recently developed methods for the analysis of
population cohort data, rather than relying solely on information in the
scientific literature. The Committee recognizes that the application of more
sophisticated statistical methods for estimating risks reduces, but does not
eliminate, the uncertainties inherent in risk estimation. Throughout the
Committee's deliberations consideration was given to both the sources of
uncertainty in the data and the potential effect of the assumptions on which
the risk estimates are based. The degree of uncertainty in the Committee's
risk estimates is presented as an integral part of the risk estimates in this
report.
STRUCTURE OF THE REPORT
The report consists of seven chapters. The first chapter reviews the sci-
entific principles, epidemiological methods and the experimental evidence
for the biological and health effects in populations exposed to low levels
of ionizing radiation. Chapter 2 summarizes the scientific evidence for
heritable effects. Chapter 3 includes a discussion of mechanisms involved
in the initiation, promotion and progression of cancer induction. Chapter 4
describes the Committee's radiation risk models and the total risk of cancer
following whole body exposure. Chapter 5 addresses site-specific cancer
risks in the various organs and tissues of the body. Chapter 6 reviews
the evidence for fetal and other radiation-induced somatic effects, and the
concluding chapter reviews low dose epidemiological studies.
As in previous reports, the Committee on the Biological Effects of
Ionizing Radiation cautions that the risk estimates derived from epidemio-
logical and animal data should not be considered precise. Information on
the lifetime cancer experience is not available for any of the human studies.
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4 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION
Therefore, the overall risk of cancer can only be estimated by means of
models which extrapolate over time. Likewise, estimates on the induction
of human genetic disorders by radiation are based on limited data from
studies of human populations and therefore rely largely on studies with
laboratory animals. It is expected that the risk estimates derived by the
Committee will be modified as new scientific data and improved methods
for analysis become available.
SUMMARY AND CONCLUSIONS
Of the various types of biomedical effects that may result from irradia-
tion at low doses and low dose rates, alterations of genes and chromosomes
remain the best documented. Recent studies of these alterations in cells of
various types, including human lymphocytes, have extended our knowledge
of the relevant mechanisms and dose-response relationships. In spite of
evidence that the molecular lesions which give rise to somatic and genetic
damage can be repaired to a considerable degree, the new data do not
contradict the hypothesis, at least with respect to cancer induction and
hereditary genetic effects, that the frequency of such effects increases with
low-level radiation as a linear, nonthreshold function of the dose.
Heritable Effects
The effects of radiation on the genes and chromosomes of reproductive
cells are well characterized in the mouse. By extrapolation from mouse to
man, it is estimated that at least 1 Gray (100 red) of low dose-rate, low LET
radiation is required to double the mutation rape in man. Heritable effects
of radiation have yet to be clearly demonstrated in man, but the absence
of a statistically significant increase in genetically related disease in the
children of atomic bomb survivors, the largest group of irradiated humans
followed in a systematic way, is not inconsistent with the animal data, given
the low mean dose level, < 0.5 gray (Gy), and the limited sample size.
The Committee's estimates of total genetic damage are highly uncertain,
however, as they include no allowance for diseases of complex genetic
origin, which are thought to comprise the largest category of genetically-
related diseases. ~ enable estimates to be made for the latter category,
further research on the genetic contribution to such diseases is required.
Carcinogenic Effects
Knowledge of the carcinogenic effects of radiation has been signifi-
cantly enhanced by further study of such effects in atomic bomb survivors.
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EXECUTIVE SUMMARY
5
Reassessment of A-bomb dosimetry at Hiroshima and Nagasaki has dis-
closed the average dose equivalent in each city to be smaller than estimated
heretofore; furthermore, the neutron component of the dose no longer ap-
pears to be of major importance in either city. As a result, lifetime risk
of cancer attributable to a given dose of gamma radiation now appears
somewhat larger than formerly estimated.
Continued follow-up of the A-bomb survivors also has disclosed that
the number of excess cancers per unit dose Induced by radiation is in-
creased with attained age, while the risk of radiogenic cancer relative to
the spontaneous incidence remains comparatively constant. As a result, the
dose-dependent excess of cancers is now more compatible with previous
"relative" risk estimates than with previous `'absolute" risk estimates; the
Committee believes that the constant absolute or additive risk model is no
longer tenable.
A-bomb survivors who were irradiated early in life are just now reach-
ing the age at which cancer begins to become prevalent in the general
population. It remains to be determined whether cancer rates in this group
of survivors will continue to be comparable to the increased cancer risk
that has been observed among survivors who were adults at the time of
exposure. For this reason, estimation of the ultimate magnitude of the risk
for the total population is uncertain and calls for further study.
The quantitative relationship between cancer incidence and dose in
A-bomb survivors, as in other irradiated populations, appears to vary,
depending on the type of cancer in question. The dose-dependent excess
of mortality from all cancer other than leukemia, shows no departure from
linearity in the range below 4 sievert (Sv), whereas the mortality data for
leukemia are compatible with a linear-quadratic dose response relationship.
In general, the dose-response relationship for carcinogenesis in labo-
ratory animals also appears to vary with the quality (LET) and dose rate of
radiation, as well as sex, age at exposure and other variables. The influence
of age at exposure and sex on the carcinogenic response to radiation by
humans has been characterized to a limited degree, but changes in response
due to dose rate and LET have not been quantified.
Carcinogenic effects of radiation on the bone marrow, breast, thyroid
gland, lung, stomach, colon, ovary, and other organs reported for A-
bomb survivors are similar to findings reported for other irradiated human
populations. With few exceptions, however, the effects have been observed
only at relatively high doses and high dose rates. Studies of populations
chronically exposed to low-level radiation, such as those residing in regions
of elevated natural background radiation, have not shown consistent or
conclusive evidence of an associated increase in the risk of cancer.
For the purposes of risk assessment, the Committee summarized the
epidemiological data for each tissue and organ of interest in the form
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6 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
of an exposure-time-response model for relative risk. These models were
fitted to the data on numbers of cases and person-years in relation to dose
equivalent, sex, age at exposure, time after exposure, and attained age.
Standard lifetable techniques were used to estimate the lifetime risk for
each type of cancer based on these fitted models.
On the basis of the available evidence, the population-weighted average
lifetime excess risk of death from cancer following an acute dose equivalent
to all body organs of 0.1 Sv (0.1 Gy of low-LET radiation) is estimated
to be 0.8%, although the lifetime risk varies considerably with age at the
time of exposure. For low LET radiation, accumulation of the same dose
over weeks or months, however, is expected to reduce the lifetime risk
appreciably, possibly by a factor of 2 or more. The Committee's estimated
risks for males and females are similar. The risk from exposure during
childhood is estimated to be about twice as large as the risk for adults, but
such estimates of lifetime risk are still highly uncertain due to the limited
follow-up of this age group.
The cancer risk estimates derived with the preferred models used
in this report are about 3 times larger for solid cancers (relative risk
projection) and about 4 times larger for leukemia than the risk estimates
presented in the BEIR III report. These differences result from a number
of factors, including new risk models, revised A-bomb dosimetry, and more
extended follow-up of A-bomb survivors. The BEIR III Committee's linear-
quadratic dose-response model for solid cancers, unlike this Committee's
linear model, contained an implicit dose rate factor of nearly 2.5; if this
factor is taken into account, the relative risk projections for cancers other
than leukemia by the two committees differ only by a factor of about 2.
The Committee examined in some detail the sources of uncertainty
in its risk estimates and concluded that uncertainties due to chance sam-
pling variation in the available epidemiological data are large and more
important than potential biases such as those due to differences between
various exposed ethnic groups. Due to sampling variation alone, the 90~o
confidence limits for the Committee's preferred risk models, of increased
cancer mortality due to an acute whole body dose of 0.1 Sv to 100,000
males of all ages range from about 500 to 1,200 (mean 760~; for 100,000
females of all ages, from about 600 to 1,200 (mean 810~. This increase in
lifetime risk is about 455 of the current baseline risk of death due to cancer
in the United States. The Committee also estimated lifetime risks with a
number of other plausible linear models which were consistent with the
mortality data. The estimated lifetime risks projected by these models were
within the range of uncertainty given above. The committee recognizes
that its risk estimates become more uncertain when applied to very low
doses. Departures from a linear model at low doses, however, could either
increase or decrease the risk per unit dose.
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EXECUTIVE SUMMARY
Mental Retardation
7
The frequency of severe mental retardation in Japanese A-bomb sur-
vivors exposed at 8-15 weeks of gestational age has been found to increase
more steeply with dose than was expected at the time of the BEIR III
report. The data now reveal the magnitude of this risk to be approximately
a 4% chance of occurrence per 0.1 Sv, but with less risk occurring for expo-
sures at other gestational ages. Although the data do not suffice to define
precisely the shape of the dose-effect curve, they imply that there may be
little, if any, threshold for the effect when the brain is in its most sensitive
stage of development. Pending further information, the risk of this type of
injury to the developing embryo must not be overlooked in assessing the
health implications of low-level exposure for women of childbearing age.
RECOMMENDATIONS
There are a number of important radiobiological problems that must
be addressed if radiation risk estimates are to become more useful in
meeting societal needs. Assessment of the carcinogenic risks that may be
associated with low doses of radiation entails extrapolation from effects
observed at doses larger than 0.1 Gy and is based on assumptions about
the relevant dose-effect relationships and the underlying mechanisms of
carcinogenesis. To reduce the uncertainty in present risk estimation, better
understanding of the mechanisms of carcinogenesis is needed. This can be
obtained only through appropriate experimental research with laboratory
animals and cultured cells.
While experiments with laboratory animals indicate that the carcino-
genic effectiveness per Gy of low-LET radiation is generally reduced at low
doses and low dose rates, epidemiological data on the carcinogenic effects
of low-LET radiation are restricted largely to the effects of exposures at
high dose rates. Continued research is needed, therefore, to quantify the
extent to which the carcinogenic effectiveness of low-LET radiation may be
reduced by fractionation or protraction of exposure.
The carcinogenic and mutagenic effectiveness per Gy of neutrons
and other high-LET radiations remains constant or may even increase
with decreasing dose and dose rate. For reasons which remain to be
determined, the relative biological effectiveness (RBE) for cancer induction
by neutrons and other high-LET radiations has been observed to vary
with the type of cancer in question. Since data on the carcinogenicibr
of neutrons in human populations are lacking, further research is needed
before confident estimates can be made of the carcinogenic risks of low-
level neutron irradiation for humans. Similarly, the relative mutagenic
effectiveness of neutron and other high LET radiation varies with the
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8 EFFECTS OF EXPOSURE TO LOW AILS OF IONIZING MOTION
specific genetic end point. Therefore, additional data are also needed on
the mutagenicity of low neutron doses to permit more confident projection
of genetic risks from animal data to man.
The extrapolation of animal data to the human is necessary for genetic
risk assessment. No population appears to exist, other than the A-bomb
survivors, that could provide a substantial basis for genetic epidemiological
study. The scientific basis of the extrapolation must therefore rely upon
cellular and molecular homologies. Research needs in this area are clear.
As noted previously, the Committee's genetic risk assessment did not
attempt to project risk for the category of diseases with complex genetic
etiologies. Because genetically related disorders comparable to those in this
heterogeneous category of human disorders may have no clearly definable
counterparts in laboratory and domestic animals, the required research
should be directed towards human diseases whenever feasible.
The dose-dependent increase in the frequency of mental retardation in
prenatally irradiated A-bomb survivors implies the possibility of higher risks
to the embryo from low-level irradiation than have been suspected hereto-
fore. It is important that appropriate epidemiological and experimental
research be conducted to advance our understanding of these effects and
their dose-effect relationships.
Finally, further epidemiological studies are needed to measure the
cancer excess following low doses as well as large doses of high and low
LET radiation. Most of the A-bomb survivors are still alive, and their
mortality experience must be followed if reliable estimates of lifetime risk
are to be made. This is particularly important for those survivors irradiated
as children or in utero who are now entering the years of maximum cancer
risk. Studies on populations exposed to internally deposited radionuclides
should be continued to assess the risks of nuclear technologies and the
effects of radon progeny. Low-dose epidemiological studies may be able to
supply information on the extent to which effects observed at high doses
and high dose rates can be relied on to estimate the effects due to chronic
exposures such as occur in occupational environments. The reported follow-
up of A-bomb survivors has been essential to the preparation of this report.
Nevertheless, it is only one study with specific characteristics, and other
large studies are needed to verify current risk estimates.
Representative terms from entire chapter:
lifetime risk
