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OCR for page 65
Genetic Effects of Radiation
INTRODUCI ION
Ionizing radiation damages the genetic material in reproductive cells
and results in mutations that are transmitted from generation to generation.
The mutagenic effects of radiation were first recognized in the 1920s,
and since that time radiation has been used in genetic research as an
important means of obtaining new mutations in experimental organisms.
Although occupational exposure to high levels of radiation has always been
of concern, not until during and after World War II was there a concerted
effort to evaluate the genetic effects of radiation on entire populations.
These efforts were motivated by concern over the effects of extremely large
sources of radiation that were being developed in the nuclear industry, of
radioactive fallout from the atmospheric testing of atomic weapons and of
the rapidly increasing use of radiation in medical diagnosis and therapy. In
1956 the National Academy of Sciences-National Research Council (NAS-
NRC) established the Committee on the Biological Effects of Atomic
Radiation (denoted the BEAR Committee), which was the forerunner of
the subsequent NAS-NRC committees on the Biological Effects of Ionizing
Radiation (BEIR committees; of which this BEIR V report is one). A
series of reports from the U.N. Scientific Committee on the Effects of
Atomic Radiation (UNSCEAR) has also addressed the genetic effects of
radiation exposure on populations.
Although there is a continuing need to assess the genetic effects
of radiation exposure, for several reasons the perspective has changed
somewhat from that in the 1950s. First, it is now clear that the risk of cancer
65
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66 EFFECTS OF EXPOSURE TO LOW DEALS OF IONIZING MOTION
in individuals exposed to radiation is significant and that limiting exposure
to radiation to reduce the risk of cancer also limits the genetically significant
exposure. Second, the instruments and techniques used in medical radiation
have improved significantly, so that the overall doses used in medical
diagnoses are reduced and patient exposure in all but the targeted organs
is lessened. Third, in regard to the induction of mutations, the greater
current risk seems to result from exposure to chemical mutagens in the
environment rather than from the exposure of populations to radiation.
Despite changed conditions, estimating the genetic effects of radiation
remains important for setting exposure standards, both for the general
population and for those exposed in their occupations.
There are many difficulties in measuring the genetic effects of exposure
of the human population to radiation and other mutagens. This is why,
more than 20 years after the BEAR Committee first addressed the issues of
radiation exposure, there is still uncertainty and controversy. The following
are some of the difficulties and considerations that must be kept in mind.
The genetic effects of radiation are expressed, not in irradiated indi-
viduals, but in their immediate or remote offspring. The time lag is great
because of the duration of the human life cycle, and massive epidemiologic
studies with long-term follow-up are needed to accumulate sufficient data
for statistical analysis. Moreover, for risk estimation of exposures that are
not uniformly or randomly delivered to the entire population, the age and
sex distribution of the exposed population and the different probabilities of
having children for members of the population of each age and sex must
be taken into account.
The mutations induced by radiation can also occur spontaneously.
When humans are exposed to low doses of radiation, it is difficult to
estimate what small increment of mutations is induced by radiation above
that from spontaneous background radiation. However, radiation has been
found to be mutagenic in all organisms studied so far, and there is no reason
to suppose that humans are exempt from radiation's mutagenic effects.
These mutagenic effects are expected to be harmful to future generations
because, in experimental organisms, the majority of new mutations with
detectable effects are harmful, and it is assumed that humans are affected
similarly. Indeed, the harmful effects of mutations that occur spontaneously
in humans are well documented, because many of them result in genetic
disease.
The genetic effects of radiation must be detected through the study of
certain endpoints, for example, visible chromosome abnormalities, proteins
with altered conformations or charges, spontaneous abortions, congenital
malformations, or premature death. In addition, radiation induced muta-
tions may affect different endpoints to different degrees. For example, the
dose of radiation required to double the incidence of one endpoint need
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GENETIC EFFECTS OF RADL4TION
67
not be the same as that required to double the incidence of a different
endpoint.
The BEIR I Committee (NRC72) espoused five general principles
of risk estimation. Subsequent committees have generally followed these
strictures whenever possible, as has the present committee. They are as
follows:
1. Use relevant data from all sources, but emphasize human data
when feasible. In general, when data of comparable accuracy exist, place
greater emphasis on organisms closest to man.
2. Use data from the lowest doses and dose rates for which reli-
able data exist, as being more relevant to the usual conditions of human
exposure.
3. Use simple linear extrapolation between the lowest reliable dose
data and the spontaneous or zero dose rate. In order to get any kind
of precision from experiments of manageable size, it is necessary to use
dosages much higher than those expected for the human population. Some
mathematical assumption is necessary, and the linear model, if not always
correct, is likely to err on the safe side.
4. If cell stages differ in sensitivity, weight the data in accordance with
the duration of the stage.
5. If the sexes differ in sensitivity, use the unweighted average of data
for the two sexes.
Deliberate exposure of humans to radiation without diagnostic or
therapeutic justification is unacceptable, and therefore, most genetic stud-
ies have had to be carried out in experimental organisms, particularly mice.
Such studies raise numerous additional problems of their own, including
extrapolation of results obtained under experimental conditions to the con-
ditions relevant to population exposure, such as dose rates, fractionation,
and other variables; and extrapolation from an experimental organism
such as the mouse, in which radiation effects may be estimated with some
confidence, to humans, because organisms differ in radiation sensitivity.
UNSCEAR (UN86) has summarized three principal assumptions that
are necessary for extrapolating data from mice and other suitable mammals
to humans:
1. The amount of genetic damage induced by a given type of radiation
under a given set of conditions is the same in human germ cells and in
those of the test species used as a model.
2. The various biological (e.g., sex, germ cell stage, age, etc.) and
physical (e.g., quality of radiation, dose rate, etc.) factors affect the magni-
tude of the damage in similar ways and to similar extents in the experimental
species from which extrapolations are made and in humans.
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68 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION
3. At low doses and at low dose rates of low-LET (linear energy
transfer) irradiation there is a linear relationship between dose and the
frequency of genetic effects studied.
Direct studies of the genetic effects of radiation exposure to human
populations have been carried out on the children of the Japanese pop-
ulations in Hiroshima and Nagasaki who were irradiated in the atomic
bombings in August 1945. Results of these careful and very extensive stud-
ies, when taken at face value, suggest that humans may be somewhat less
sensitive to radiation than mice.
The BEIR I Committee (NRC72) used two methods of estimating ge-
netic effects. One method relied on direct estimates. This method was used
whenever possible, for example with reciprocal translocations. The other
method was indirect and was used for such endpoints as gene mutation.
The indirect method required estimates of the mutation rates, the incidence
of genetic disease in the human population, and the extent to which the
incidence depends on recurrent mutation, to infer the increased incidence
of genetic disease resulting from radiation exposure. Both immediate, first-
generation effects and long-term, equilibrium effects were estimated from
either the direct or indirect estimates of induced mutation by taking into
account the presumed rates of mutant elimination to project the ratio of
newly induced genetic damage to that transmitted from previous genera-
tions. The BEIR III Committee (NRC80) reviewed and updated the BEIR
I report (NRC72~. New estimates caused some changes in the previous
estimates, and some new methods of estimation were added.
The BEIR V Committee has reviewed and reevaluated the data that
are pertinent to the estimation of genetic risks in humans. The present
report summarizes the methods and conclusions of previous committees.
In deriving new risk figures, it places rather more emphasis on the results
of the studies of Japanese atomic-bomb survivors than have previous BEIR
reports. However, the committee has also made use of the extensive
radiation studies carried out with mice, which are briefly reviewed.
SUMMARY OF CONCLUSIONS
Based on our review of relevant data from humans, other mammals,
and mice, the BEIR V Committee believes that the values in Able 2-1 give
the current best estimates of risk based on the conclusion that the doubling
dose in humans is not likely to be smaller than the approximate 1 Sv (100
rem) obtained from studies in mice. Ibble 2-1 gives the estimated genetic
effects of an average population exposure of 1 rem/30-year generation.
Admittedly there are uncertainties, but the calculated risks are based on
an impressive body of data and knowledge of radiobiological principles.
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GENETIC EFFECTS OF RADIATION
69
As will be reviewed below, attempts to estimate doubling doses from
data on Japanese atomic-bomb survivors have consistently led to values
larger than those derived from the animal data, and consequently they
imply lower risks. Although risks calculated from animal data have large
confidence intervals, estimates from those exposed to radiation in Hi-
roshima and Nagasaki are known with even less precision. In spite of these
uncertainties, the data suggest a real difference, with the estimated lower
95% confidence limit of the human data approximating the median of a
large number of values obtained in mice. If it is assumed that the apparent
difference is real, humans would be less sensitive to radiation induction
of mutations in germ cells than mice, and the risks in Able 2-1 should
be considered conservative. On the other hand, the human data might be
biased too low for reasons that are not presently understood, in spite of
all the careful work that has gone into their collection and analysis. The
BEIR V Committee is in no better position to decide the issue than were
the previous groups and individuals who have grappled with it. Considering
the uncertainty, the BEIR V Committee has adopted what it considers a
prudent position in basing its risk estimates on the approximate lower 95%
confidence limit for humans. This approach, while admittedly conservative,
has the advantage of leading to risk estimates that, if anything, are too high
rather than estimates that subsequent data may prove to be too low.
The background and methodology for the estimates given in Table 2-1
are provided in the following sections. The material not only provides the
background for Able 2-1 but also summarizes the methods and conclusions
of previous BEIR, UNSCEAR, and other reports.
It must be emphasized again that virtually all mutations have harmful
effects. Some mutations have drastic effects that are expressed immedi-
ately, and these are eliminated from the population quite rapidly. Other
mutations have milder effects and persist for many generations, spread-
ing their harm among many individuals in the distant future. However,
many of the long-term effects are impossible to estimate given present data
and understanding, and for this reason the present committee emphasizes
the effects of mutations that manifest themselves in the first generation,
since these are of immediate concern and can be estimated with some
confidence. The effects in the first generation are primarily those caused
by simple Mendelian dominant and X chromosome-linked recessive traits
because of their high heritabilities. Other kinds of mutations may be more
important in the long run and constitute a significant burden for future
generations.
Much of the uncertainty in estimating the risks of radiation-induced
mutations centers on traits with complex patterns of inheritance that result
from the combination of multiple genetic and environmental factors. Risk
estimates are determined in part by the degree to which these traits are
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70 EFFECTS OF EXPOSURE TO LOW AILS OF IONIZING MOTION
TABLE 2-1 Estimated Genetic Effects of 1 rem per Generationa
Additional Cases/106 Liveborn
Current Incidence
. . . Offspr~ng/rem/Generat~on
per Million Lovelorn
Offspring
Type of Disorder
Autosomal dominant
Clinically severer
Clinically mildf
X-linked
Recessive
Chromosomal
Unbalanced
2,sooc
7,500g
400
2,500
<1
<1
First Generation
5 - 20d
1 - 15d
E.... .
qulllorlum
25e
75e
<5
Very slow increase
translocations600h<5 Very little increase
Trisomies3,800'< 1 < 1
Congenital
abnormalities20,000-30,00010' 10-100k
Other disorders of
complex etiology
Heart diseased600,000
Cancer300,000Not estimated Not estimated
Selected others300,000
-
a Risks pertain to average population exposure of 1 rem per generation to a population with
the spontaneous genetic burden of humans and a doubling dose for chronic exposure of 100
rem (1 Sv).
b Assumes that survival and reproduction are reduced by 20-80% relative to normal (s =
0.2- 0.8), which is consistent with the range of values in Table 2-2.
c Approximates incidence of severe dominant traits in Table 2-2.
d Calculated using Equations (2-7), with s = 0.2- 0.8 for clinically severe and s = 0.01- 0.2
for clinically mild.
~ Calculated using Equation (2-1), with the mutational component = 1.
f Assumes that survival and reproduction are reduced by 1-20 percent relative to normal
(s = 0.01-0.2~.
g Obtained by subtracting an estimated 2,500 clinically severe dominant traits from an esti
mated total incidence of dominant traits of 10,000.
h Estimated frequency from UNSCEAR (UN82,UN86~.
i Most frequent result of chromosomal nondisjunction among liveborn children. Estimated
frequency from UNSCEAR (UN82, UNTO.
Based on worst-case assumption that mutational component results from dominant genes
with an average s of 0.1; hence, using Equation (2-3), excess cases <30,000 x 0.35 x
100-~ x 0.1 = 10.
k Calculated using Equation (2-1), with the mutational component 5-35%.
Lifetime prevalence estimates may vary according to diagnostic criteria and other factors.
The values given for heart disease and cancer are round-number approximations for all
varieties of the diseases, and the value for other selected traits approximates that for the
tabulation in Table 2-4.
mNo implication is made that any form of heart disease is caused by radiation among exposed
individuals. The effect, if any, results from mutations that may be induced by radiation and
expressed in later generations, which contribute, along with other genes, to the genetic
component of susceptibility. This is analogous to environmental risk factors that contribute
to the environmental component of susceptibility. The magnitude of the genetic component
in susceptibility to heart disease and other disorders with complex etiologies is unknown.
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GENETIC EFFECTS OF RADIATION
71
Table 2-1 Continued
Most genes affecting the traits are thought to have small effects, and new mutations would
each contribute a virtually insignificant amount to the total susceptibility of the individuals
who carry them. However, a slight increase in genetic susceptibility among many individuals
in the population may produce, in the aggregate, a significant effect overall. Because of
great uncertainties in the mutational component of these traits and other complexities, the
committee has not made quantitative risk estimates. The risks may be negligibly small, or
they may be as large or larger than the risks for all other traits combined.
determined by mutations, but the mutational component of many of the
most common traits is very uncertain. The BEIR V Committee recom-
mends that more research be carried out on such complex disorders to sort
out their genetic and environmental causes.
METHODS OF RISK CALCULATION
Table 2-1 is based on the doubling dose method, which is summarized
below, along with several other methods that have been used.
The Doubling Dose Method
The doubling dose method is based on the following equation:
induced burden = spontaneous burden x (doubling dose)~i
x mutation component x dose.
(2-1)
As a hypothetical example, if the spontaneous burden is 20,000 per
million liveborn for some class of genetic disease in the human popu-
lation, the doubling dose is estimated to be 100 rem, and the average
mutation component for these diseases is one-half, then, if the parents in
each generation are exposed to 1 rem, the induced burden is 100 cases/106
liveborn/generation. That is, after the population has reached a new equi-
librium between selection and mutation (which is inflated by the added
increment of radiation), one expects 100 additional cases of genetic disease
in each generation because of the increased radiation.
Although the doubling dose method is based on equilibrium consid-
erations, the method can be used to estimate the effects of an increase
in the mutation rate on the first few generations by taking a proportion
of the equilibrium damage. For example, for a permanent increase in the
mutation rate, the effect of a dominant mutation in the nth generation is
1 - (1-sin of the equilibrium damage, where (1-s) is the fitness of
carriers of the dominant gene.
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72 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
In previous BEIR reports the reciprocal of the doubling dose has
been called the relative mutation risk, and Equation (2-1) can be written as
follows:
induced burden = spontaneous burden x (relative mutation risk)
x mutation component x dose. (2-2)
This was done, in part, to avoid the concept of doubling dose, which
is sometimes misunderstood. By definition, the doubling dose is that
dose required to induce a number of mutations equal to the spontaneous
frequency. However, its use in this report is confined to the range of low
doses at which the dose-response curve is essentially linear. We thus have
m = mO + aD, where mO is the spontaneous frequency, D is the dose, a is
the induction rate, and m is the total mutation frequency (spontaneous plus
Induced). The doubling dose is then mO/a and its reciprocal, a/mO= (m
-mO) mOD is the relative mutation risk, that is, the number of mutations
induced as a fraction of the spontaneous number per unit dose.
If the sexes differ in doubling dose, then the overall doubling dose is
a weighted average of the sex-specific doubling doses. Denoting the male
and female sexes as 1 and 2, respectively, and again attending only to the
linear part of the dose-response curve, the following equation is obtained:
m = ma ~ m2 + aide + a2D2
(~2-3)
where m:, al, Do and m2, as, D2 are the sex-specific spontaneous fre-
quencies (m), induction rates (a), and doses (D) for males and females,
respectively. If a population were exposed to D, = DD: = meat and D2
= DD2 = m2/a2, the mutation burden would double. DD, and DD2 are
the sex-specific doubling doses for males and females respectively. The
common dose to both sexes that will double the mutation rate is:
DD = Amp + m2~/(a~ + a2)
which is the a-weighted average of the sex-specific doubling doses.
(~2-4~)
Doubling doses from experimental mouse data are usually based on
the exposure of a single parent and are sometimes referred to as gametzc.
Doubling doses estimated from the data from Japanese atomic-bomb sur-
vivors are sometimes based on joint parental exposure and are referred to
as zygotic. For example, Neel and Schull (Ne74) have regressed various
endpoints such as early infant death and malformations on the sum of the
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GENETIC EFFECTS OF RADIATION
73
mother's and the father's doses. In this situation the linear part of the
response curse can be written as (assuming a mutation component of 1)
m = me or me + a(`D~ + D24.
(~2-5)
An estimate of the doubling dose of (m~ + m2~/a is then the summed
parental dose that would double the mutation rate. Neel and Schull and
collaborators have called this the zygotic doubling dose. 1b convert this to
an average, or gametic doubling dose for the sexes, the zygotic doubling
dose is divided by 2.
The Direct Method
The direct method of risk calculation was pioneered by Ehling
(Eh76a,b) and Selby and Selby (Se77) to estimate first-generation effects
for dominant mutations rather than relying on the assumption of the pro-
portionate effects implicit in the doubling dose method.
In the direct method, the induction rate for a specific class of defects
in mice (e.g., cataracts and skeletal anomalies) is measured directly by
using high-dose-rate radiation, and the results are corrected for dose rate.
Then, the proportion of serious dominant genetic disorders in humans that
involves similar defects is estimated, and this is used as a proportionality
factor to estimate the effect of radiation on all dominant mutations in
humans. For example, if the spermatogonial chronic induction rate for
skeletal defects in the mouse was 4 x 10-6/rad/gamete, and in humans
about one in five serious dominant disorders involved the skeleton, then
the first-generation effect of spermatogonial chronic radiation would be
estimated by this method as 20 induced cases/106 liveborn/rad.
The committee had little confidence in the reliability of the individual
assumptions required by the direct method let alone the product of a long
chain of uncertain estimates that follow from these assumptions. Therefore,
they did not place heavy reliance on the direct method in making their risk
estimates, but used it only as a test of consistency.
The Gene Number Method
In the gene number method, one attempts to estimate the total number
of mutations produced by exposure to radiation by using the equation:
No. of induced mutations = No. of genes
Reinduction rate/gene/unit dose) x dose.
(2-6)
This approach dates back to the BEAR Committee (NRC56) and
Muller's elegant concept of "genetic death." BEAR states:
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74 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION
One way of thinking about this problem of genetic damage is to assume that
all kinds of mutations on the average produce equivalent damage, whether as
a drastic effect on one individual who leaves no descendants because of this
damage, or a wider effect on many. Under this view, the total damage is
measured by the number of mutations induced by a given increase in radiation,
this number to be multiplied in one's mind by the average damage from a
typical mutation.
In other words, each harmful mutation ultimately causes one genetic
death, which is either expressed all at once in the death of a single individual
or is perhaps spread out as smaller effects over hundreds of individuals and
hundreds of generations. One difficulty with this approach is that it is
difficult to translate it usefully into societal cost and human suffering.
Another problem is that no satisfactory definition or estimate of the total
number of mutable genes is available. For these and other reasons, the
BEIR V Committee eschewed risk estimates based on gene number.
PREVIOUS ESTIMATES OF HUMAN DOUBLING DOSE
BEAR (1956)
The BEAR Committee (NRC56) concluded that "the actual value of
the doubling dose is almost surely more than 5R and less than 100R. It
may very well be from 30R to 80R." The exact calculations from which
these values, in roentgens, were obtained are not included in the report,
except to say that
the calculations which lead to an estimate of this 'doubling dose' necessarily
involve the rates of both spontaneous and radiation-induced mutations in man.
Neither of these rates has been directly measured; and the best one can do is
to use the excellent information on such lower forms as fruit flies, the emerging
information for mice, the few sparse data we have for man and then use the
kind of biological judgement which has, after all, been so generally successful in
interrelating the properties of forms of life which superficially appear so unlike
but which turn out to be remarkably similar in their basic aspects.
No distinction between acute and chronic dose was made. The doubling
dose range given by the BEAR Committee would now be considered to
apply to acute radiation. It must be remembered that at the time that the
BEAR report was written, neither the dose-rate effect nor the distinction
between premeiotic and postmeiotic cell stage response to radiation were
known.
BEIR I (1972)
The BEIR I (NRC72) estimate of the doubling dose was given as a
range of 20-200 rem, which was determined as follows. A chronic radiation
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GENETIC EFFECTS OF RADL4TION
75
dose to mouse spermatogonia was said to yield about 0.5 x 10-7 recessive
mutations/rem/gene. The comparable figure for mouse oocytes was taken to
be zero, giving an average of 0.25 x 10-7. The spontaneous mutation rate
was estimated from human dominant and X chromosome-linked mutation
data to be in the range 0.5 x 10-6 to 0.5 x 10-5, giving the doubling
dose range of 20-200 rem. The figure of 20 rem was considered as being
probably too low after a rough minimum doubling dose was calculated from
the data then available from survivors in Hiroshima and Nagasaki.
BEIR III (NRC80)
Although BEIR III (NRC80) subscribed to the general principles
of BEIR I (NRC72), it disagreed with the calculation of the doubling
dose. Unlike BEIR I, which constructed a hybrid doubling dose based
on the induced mutation rate in mice and the spontaneous mutation rate
in humans, BEIR III chose to calculate a doubling dose for mice and
extrapolate it to humans. The stated objection to the BEIR I method was
that it mixed the induced rate of a set of mouse genes preselected for high
mutability with an estimate of a human spontaneous rate for more typical
genes. BEIR III took as an induced rate 6.6 x 10-8 mutations/locus/rem,
from mouse spermatogonia irradiated at 0.009 rem/minute and below. The
corresponding spontaneous rate was 7.5 x 10-6, giving a point estimate of
the doubling dose (for chronic radiation) of 114 rem. The committee then
doubled and halved this figure to arrive at a final range of 50-250 rem to
take into account uncertainties raised by the mouse oocSrre data and the
data from atomic-bomb survivors in Japan.
Other Estimates Based on Mice
Abrahamson and Wolff's (Ab76) linear-quadratic analysis of the mouse
data lead to doubling dose estimates in the range of 43-131 red. Analyses
of data from Russell (Ru77) and Russell and Kelly (Ru82a) on low-dose-
rate data in female and male mice, respectively, give a range of 99-160
red. Finally, Denniston's (De82) analysis of the mouse data using the Lea
(1947) model Y = a + bD + cD2G yielded a point estimate of 109 red.
The Japanese Data
In contrast to the doubling dose estimates In mice, those derived from
the human data have tended to be larger, sometimes by a factor of 3 or
more. For example, Schull et al. (Sc81) state:
In general, human exposure to radiation will not be acute and of the magnitude
experienced by the inhabitants of Hiroshima and Nagasaki, but either interrupted
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124 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
According to Nomura's data, an increased prevalence of tumors is observed
on the basis of a one-t~me sampling of the Fat population at 8 months of
age. The increase is from about 5% in the control to 25% at a 504-rad dose
to cells in postmeiotic stages in males, spermatogonia, or oocytes. There
was no shift in the spectrum of tumor types, and 90% were pulmonary ade-
nomas, which is a common neoplasm in some strains of mice. The one-time
sample leaves unanswered the question of whether the increased frequency
is due to a shift in the time of appearance or is due to a real increase
in the total number of tumors over the mouse's lifetime. Previous studies
of this type gave negative results (Ko65), although there was evidence of
reduced life expectancy in the Fit progeny of irradiated parents in an early
study by Russell (Rump. As life expectancy in the mouse can be closely
related to age, rate, and type of tumor occurrence, Russell's results could
have indicated an induced change in death rates from tumors; however, the
results of Russell's 1957 study have not been confirmed.
Summary of Data on Mice and Other Laboratory Mammals
Tables 2-9 and 2-10 summarize the data on eight genetic endpoints that
have reasonably representative mutation rates. All these data have been
derived from studies that were specifically directed toward the particular
endpoint; thus, the rates for multilocus mutations are not included because
of their indirect derivation. Standard errors are not given because they
tend to reflect experimental factors more than they do the true level of
biological uncertainty. Most rates have been rounded so as not to imply
greater precision than that which may actually exist.
The available data are predominantly from studies in which high-
dose-rate exposures with low-LET radiations were used. This reflects the
availability or unavailability of appropriate facilities to carry out low-dose-
rate irradiations or irradiations with high-LET sources. It also probably
reflects the shifting level of interest from radiation mutagenesis to chemical
mutagenesis over the past 15-20 years. The effect of this shift has been to
leave large gaps in our matrix of information.
For the high-dose-rate, low-LET radiations, mutation rates per gamete
or per cell generally fall in the range of 10-5 to 10~4/rad, although there
are several exceptions. Higher rates are seen for dominant lethal mutations
induced in postgonial cells of male mice, for translocations induced in the
spermatogonia of one marmoset species, and for aneuploidy induced in
the preovulatory oocyte of female mice. Lower rates pertain to dominant
visible mutations; however, except for skeletal and cataract mutations, these
are recognized to be systematically underestimated. Rates per locus are in
the range of 10-8 to 10-7.
Low-dose-rate exposures cause the mutation rate to drop by a factor
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GENETIC EFFECTS OF RADL9TION
125
of 5 or greater, and a factor of 10 accommodates the range of values,
with one notable exception. The dose-rate factor for the male specific-
locus mutation rate Is only 3. This Is a firmly established value. The
reason for this rather low dose-rate factor Is not clear, although it Is not
dissimilar from some values derived from other radiobiological studies on
tumorigenesis and life shortening (NCRP Report 64, 1980~. RBE values
for fission neutron exposures are about 5 for high-dose-rate comparisons
and range from 15 to 50 for low dose rates.
Spontaneous mutation rates Table 2-9) are understandably less well
known than the induced rates; this appears to be largely a matter of
inadequate sampling statistics. The values for the specific locus test are
well defined, although even here they are not free of controversy because
of the occurrence of clusters of events. For other endpoints, such as
translocations in mice, the range of values often reflects genetic diversity
and not uncertainty per se. On this point, the committee notes that there
Is considerable diversity in the spontaneous rates among all the known
specific recessive and dominant genes in mice and humans.
The estimated doubling doses derived from Tables 2-9 and 2-10 are
summarized In Bible 2-11. Considering all endpoints together, the direct
estimates of doubling dose for low dose rate radiation have a median value
of 70-80 red, indirect estimates based on high-dose rate experiments have
a median of 150 red, and the overall median lies in the range of 100 to 114
red. These estimates support the view that the doubling dose for low-dose-
rate, low-LET radiation in mice Is approximately 100 red for venous genetic
endpoints. This contrasts with the results of the human data obtained from
the study of Japanese atomic-bomb survivors, as discussed earlier in this
chapter, which suggest that the value of 100 red represents an approximate
lower 955S confidence limit for the human doubling dose.
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Representative terms from entire chapter:
doubling dose
