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OCR for page 29
6
Current Knowledge and
Estimation of Genetic Risk
The estimation of the genetic effect of ionizing radiation on human popula-
tions has been a matter of concern since World War II. The two main bodies
involved are the United Nations' Scientific Committee on the Effects of Atomic
Radiation (UNSCEAR) and the U.S. National Academy of Sciences' Committee
on the Biological Effects of Ionizing Radiations (BEIR). In addition, the Inter-
national Commission on Radiological Protection (ICRP, Oftedal and Searle,
1 980J as well as the Nuclear Regulatory Commission (Nuclear Regulatory
Commission, 1985) have published documents in which genetic risk estimates
are included. All tend to give similar estimates because they all use basically the
same set of data.
In what follows it is important to understand three points:
1. The health effects resulting from mutations induced by ionizing radiation
are indistinguishable from those resulting from other agents or that arise sponta-
neously.
2. Even if a significant increase in some endpoint is shown statistically to
be due to additional radiation exposure, no specific case can be proved to be
ascribable to that exposure.
3. Finally, even high doses of radiation (greater than 2,000 mSv t200 rem])
will add only a small number of additional cases of genetic disorders to the rela-
tively large number that are expected to occur as a result of spontaneous muta-
tions, most of which have existed in the population for many generations.
29
OCR for page 30
30
AD VERSE REP ROD UCTI HE OUTCOMES
BASIC ESTIMATION EQUATION
Many of the estimates of the genetic impact of ionizing radiation on human
populations have made use, in one form or another, of the following formula:
I=Sx 1/DDxMCxD,
where:
(Equation 1)
I is the increased number of cases (per generation) of genetic effects due to
radiation, often called the induced burden,
S is the number of cases (per generation) normally present in a population
not exposed to additional radiation, the spontaneous burden,
DD is the doubling dose (see below),
MC is the mutation component (see below), and,
D is the dose of additional radiation to which the population is exposed.
The use of Equation 1, especially when applied as in the case of the Atomic
Veterans, requires some explanation. Let B = the total burden to the population
of some genetic disease or class of diseases, e.g. the total number of cases arising
per generation; and let m = mutation rate. Now consider the equality:
/\B/B = Am/m x (/\B/B) I (/\m/m). (Equation la)
that is, the relative change in B equals the relative change in m times the
relative change in B to the relative change in m.
Suppose that in the dose range being considered, we may assume that muta-
tion rate is a linear function of dose, for example, m = mO + bD, where mO is the
spontaneous mutation rate. Then
/\mlm= (m-mO)/mO=bD/mO.
But, m0/b is the doubling dose exactly that dose that induces mO mutations.
So we see that /\m/m = D/DD. Furthermore, (/\B/B) I (/\mlm) is the mutation
component (Crow and Denniston, 1981), the relative change in the burden to the
relative change in the mutation rate. Hence, we see that Equation la can be
written /\B/B = (D/DD) x MC or since /\ B = I and B = S. we have I = S x
(D/DD) x MC, which is Equation 1.
Now, in the usual application of Equation 1, I ~ = /\B) applies to the change
in the burden from just before a permanent change in the dose to the time the
population reaches the new equilibrium between mutation and selection. But, in
fact, the relevant time period is determined by how the mutation component
(MC) is defined. The MC may be defined to apply to any number of generations
after the change in radiation exposure. In particular, it may be defined to apply
to the first generation after the increase in dose. If the increase in dose is perma
OCR for page 31
GENETIC PRINCIPLES
31
nent, I (= /\B) slowly increases from generation one to equilibrium; if the dose
increase is temporary (e.g., a burst, as in the case of the atomic veterans), then I
(= AB) increases in the first generation but then slowly decreases until the old
equilibrium is reestablished.
The simplest example is that of an autosomal dominant gene. At equilib-
rium between mutation and selection, the frequency of the trait is 2m/s, where m
is the mutation rate and s is the selection coefficient. If the mutation rate in-
creases permanently from m to m(1 + k) then in generation n after the increase
the frequency is:
2tm/s+km(1 -~1 -s)"/s)~.
If the increase in mutation is only a burst, the frequency in generation n is:
2tm/s+km(1 -s)"-".
The first frequency eventually rises to 2m (1 + k)/s while the second returns
to 2m/s. In generation one, the two are identical. Using the definition of muta-
tion component given above, the mutation component in generation n can be
defined as MC,, = 1 - (1 - s)" in the case of a permanent change and as MCn =
s(1 - s)"~ ~ in the case of the burst. The term "mutation component," without
specification of the generation, conventionally refers to MC~.
For more complicated traits, no simple formulas exist, but for threshold
traits, such as congenital abnormalities, the mutation component in the first gen-
eration is generally less than one or two percent. Equation 1 thus can be applied
to the case of the Atomic Veterans by using the value of mutation component
that applied to the first-generation effect. Subsequent generations (e.g., grand-
children) would show even smaller effects.
If the dose-response curve is not linear but concave upward, this use of the
doubling dose in Equation 1 will tend to overestimate risk if the data from which
doubling dose is estimated are obtained from high doses. The doubling dose has
traditionally been estimated from experimental animal data, mostly the mouse,
although an estimate is also provided by the extensive studies of the children of
atomic bomb survivors from Hiroshima and Nagasaki.
In summary, the Beir V report (NRC, 1990) states
"Although the doubling dose method is based on equilibrium considerations,
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 dam-
age. For example, for a permanent increase in the mutation rate the effect of a
dominant mutation in the nth generation is 1 - (1 - s)" of the equilibrium dam-
age, where (1 - s) is the fitness of carriers of the dominant gene."
An alternative method of estimating genetic risk in the first generation is
provided by the so-called "direct method" pioneered by Ehling and Selby (see
Ehling, 1991~. A detailed description of this method is given in UNSCEAR
1993, Appendix G. Briefly, the method is based on the equation:
lo, a,
OCR for page 32
32
where:
ADVERSE REPRODUCTIVE OUTCOMES
Risk per unit dose = Fit x M x N.
Fat is the frequency of radiation-induced dominant mutations per unit dose,
M is the reciprocal of the fraction of total mutations thought to affect the
body systems under study, e.g., skeletal, cataracts, and
N is the number of children born in the population under consideration.
For example, the dominant cataract mutation frequency in the mouse was
estimated to be 0.15-0.18 x 10-6 mutations per 0.01 Gy per gamete for low dose
rate data. It was also estimated that approximately 2.7% of all serious dominant
mutations are cataract causing mutations, i.e., M = 36.8. This gives a risk of 6-7
serious dominant disorders per 0.01 Gy of paternal exposure per 106 offspring.
The estimate based on skeletal mutations in the mouse is similar.
Returning to the discussion of the doubling dose method, the spontaneous
burden S is estimated from human epidemiologic data. The mutation compo-
nent, MC, is roughly that portion of the spontaneous burden expected to increase
in proportion to the mutation rate (Crow and Denniston, 19811. Dose as used in
Equation l usually refers to the average or common dose to the gonads of both
sexes, unless a sex-specific effect is being estimated.
As an example, the BEIR ~ committee (1990) estimated the induced burden
of congenital abnormalities caused by radiation to be, after a new equilibrium is
attained, 10 to 100 additional cases per million liveborn offspring per 10 mSv (1
rem) per generation (NRC, 19901. The calculations were as follows:
S = 20,000-30,000 spontaneous cases of congenital abnormalities per mil-
lion liveborn offspring.
DD = 1 Sv (100 rem) for low dose or low dose rate estimated from a con-
sideration of data from studies in mice and humans.
MC = 0.05-0.35, at the new equilibrium.
D = 0.01 Sv (1 rem) to each of the parents.
Therefore, I = (20,000-30,000 cases) x (1/1 Sv) x (0.05 - 0.35) = 10-105
per million liveborn, at the new equilibrium. In the report this estimate was
rounded to 10-100 per million liveborn, to avoid the appearance of false accu-
racy. As a worst case, it was assumed that as much as 10% of this effect might
manifest itself in the first generation after the increase in exposure.
To estimate the effect of increased radiation exposure on the children of ex-
posed parents, then, one must have estimates of the spontaneous burden of the
endpoint of interest, its doubling dose, the dose itself, the mutation component of
the endpoint, and finally, how much of the total effect is expected to appear in
the first generation after exposure.
OCR for page 33
GENETIC PRINCIPLES
33
DATA FROM WlIICII RISK ESTIMATES
HAVE BEEN MADE
Mice
Studies with the mouse have yielded two kinds of results: (1) a general
qualitative and semiquantitative understanding of the nature of genetic radiation
effects and (2) quantitative estimates of the doubling dose. Both have been
summarized in detail by the National Research Council's BEIR V committee
(NRC, 1990~.
The qualitative conclusions were as follows:
Radiation-induced mutation rates are higher in the mouse than in the fruit
fly (this original finding stimulated much of the subsequent emphasis on mice
because of its obvious greater relevance to estimating radiation risks in humans).
2. For mutations of specific loci (a locus is a point on a gene) induced in the
spermatogonial stage, there is no significant change in the mutation rate with
time after irradiation (i.e., the risk does not decrease with time after exposure).
3. Radiation-induced mutation rates differ markedly from gene to gene.
4. Mutations induced in spermatogonial and post-spermatogonial stages dif-
fer with respect to absolute and relative frequencies among loci and by radiation
quality.
5. A significant proportion of the mutations detected in the specific locus
test have proved to be recessive lethals.
6. Some of the recessive lethal mutations have had a heterozygote effect
dramatic enough to be identified in specific individuals.
7. Dominant effects on viability are demonstrable in the first-generation
progeny of irradiated males.
8. Chronic irradiation is considerably less effective than acute radiation in
inducing mutations in both spermatogonia and oocytes. This dose rate effect
appears to be less in males than in females.
9. A significant proportion of radiation-induced mutations in the specific
locus test are small deletions.
10. The immature mouse oocyte is highly sensitive to cell killing.
Extensive literature on the mouse provides multiple endpoints from which to
estimate genetic doubling doses. A detailed summary of the data can be found in
Chapter 2 of the BEIR V report (NRC, 1990). The question of estimating dou-
bling dose is discussed in the next section which includes a summary table of
doubling doses for mice.
The mouse is the only mammal for which substantial data on the mutagenic
effects of ionizing radiation are available. These effects have been shown to de-
pend on dose, dose rate, fractionation pattern, LET, cell stage, sex, age at expo-
sure, and the test stock and gene loci used. Qualitatively, these conclusions
OCR for page 34
34
ADVERSE REPRODUCTIVE OUTCOMES
probably apply to humans as well, but whether the specific quantitative relations
observed in mice transfer to humans is much less certain
Humans
Two sets of human data have played the predominant role in estimating the
risks of ionizing radiation to human populations: (1) data pertaining to the esti-
mation of the spontaneous burden, S. in Equation 1 (Stevenson, 1959; Trimble
and Doughty, 1974; Jacobs, 1975; Carr and Gedeon, 1977; Carter, 1977; Hook
and Hamerton, 1977; Childs, 1981; Czeizel and Sankaranarayanan, 1984; Baird
et al., 1988) and (2) data on the Hiroshima-Nagasaki atomic bomb survivors and
their children used to estimate the doubling dose (Neel et al., 1953, 1974, 1990;
Neel and Schull, 1956b, 1991; ABCC, 1975; Schull et al., 1981a, b; Neel and
Lewis, 1990~. A useful compendium of the major articles on the Japanese stud-
ies was provided by Neel and Schull (1991~. Summaries and discussions of
these data may also be found in reports by Denniston (1982) and UNSCEAR
(1986 and 1993) and in the BEIR V report (NRC, 1990~.
Estimating the Spontaneous Burden
The doubling dose approach uses the existing "normal" incidence of genetic
disease as a yardstick against which to measure the effect of radiation. To do
this one must know the approximate natural incidence of the endpoints under
study. For example, in a sample of random births, approximately 3 percent are
expected to have some kind of major congenital abnormality. Presumably, ex-
posing the parents to additional radiation will produce additional cases over and
above this spontaneous incidence.
The major studies that have provided estimates of the spontaneous burden
for a number of genetic categories are provided elsewhere (Stevenson, 1959;
Trimble and Doughty, 1974; Jacobs, 1975; Carr and Gedeon, 1977; Carter,
1977; Hook and Hamerton, 1977; Childs, 1981; Czeizel and Sankaranarayanan,
1984~. A summary of findings is provided in Table 1 (Table 2-5 of BEIR
[NRC, 1990]).
OCR for page 35
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OCR for page 36
36
ADVERSE REPRODUCTIVE OUTCOMES
Again, it is important to stress that a host of genetic defects and heritable
disorders will appear in any population in each generation whether or not the
parents have been exposed to ionizing radiation. Radiation will tend to increase
this number, but as will be seen below, the increased incidence ascribable to
exposure to ionizing radiation is likely to be a very small proportion of the natu-
rally occurring incidence.
Estimating the Effect of Ionizing Radiation
The cohort of atomic bomb survivors and their children from Hiroshima and
Nagasaki is the main body of humans capable of providing estimates of the ef-
fects of ionizing radiation on the incidence of genetic disorders.
In November 1946, a presidential directive was issued at the request of the
Secretary of the Navy, James T. Forrestal, giving authority to establish a Com-
mittee on Atomic Bomb Casualties. The committee was formed in January 1947
(ABCC, 1975) and was the forerunner of the Atomic Bomb Casualty Commis-
sion (ABCC), which was later transformed into the Radiation Effects Research
Foundation (RERF). Its mission was "to undertake long range investigations of
the effects on survivors of the bombs in Hiroshima and Nagasaki" (NRC, 1947~.
The data structures and experimental designs used since the initiation of the
genetic program of ABCC and RERF are described by Neel and Schull (1956a,
b), Kato et al. (1966), Schull et al. (1981a), and Awa (1987~. The studies were
divided into four substudies:
_ \ 7 ~
1. The clinical program, 1948-1954. This was a prospective study of the
children of atomic bomb survivors and controls involving both questionnaires
and physical examinations. Five endpoints were measured: sex ratio, congenital
abnormalities, viability at birth, birth weight, and survival during the neonatal
period. About 92% of the children were examined as neonates and 30% were
reexamined at about 9 months of age. In addition, some 717 infants who were
stillborn or died in the neonatal period were autopsied. The sample included
69,706 births, of which 12,401 were from parents who were proximally exposed
(i.e., were within 2,000 m of the hypocenter at the time of the bombing tATB]~.
2. Fi mortality cohort, 1946-1985. In 1959, to increase the efficiency of
the survival study, three cohorts were created from among the children born in
the two cities since the bombings. The first cohort comprised all children born
in the city where one or both of the parents were less than 2,000 m from the hy-
pocenter ATB (proximally exposed). The second cohort comprised age-, sex-,
and city-matched control births to parents who were more than 2,500 m from the
hypocenter ATB (distally exposed). The third cohort comprised age-, sex-, and
city-matched control births to parents who were not in the bombed cities ATB
(not in city NICK. The proximal cohort contained 31,150 children, and the
distal and the NIC groups numbered 41,066 children. These cohorts have been
OCR for page 37
GENETIC PRINCIPLES
37
followed through the years and form the basis not only of the Fat mortality study
but the following studies as well.
3. Cytogenetic study, 1968-present. In a subset of the Fat cohort samples,
X-chromosome anomalies and balanced structural rearrangements were looked
for in the blood of the children of proximally exposed, distally exposed, and NIC
parents. All children were at least 13 years of age when the samples were ob-
tained.
4. Biochemical studies, 1975-1992. In a subset of the Fat mortality cohort,
a direct search was made for new mutations by using a battery of 30 serum and
erythrocyte proteins.
Overall, eight health outcomes have been investigated:
1. Untoward pregnancy outcomes: congenital malformations, infant still-
birth or death within the first 2 weeks after birth.
2. Fit mortality: death in children of exposed parents after 2 weeks, exclu-
sive of cancer.
3. Malignancies in the Fat cohort: cancer arising in the children of survi-
vors. Some cancers are the result of a combination of germinal and somatic
mutations. Mutations induced by radiation might be detected by observing an
increase in the incidence of such cancers.
4. Balanced structural rearrangements of chromosomes in children over age
13 years: because the children from whom samples were obtained had all
reached at least the age of 13 years, only balanced rearrangements would be ex-
pected.
5. Sex chromosome aneuploids in children over age 13 years: Individuals
with the sex chromosome anomalies XXY, XYY, XO, and XXX are all viable,
although some would not be expected to survive to age 13 years.
6. Mutations altering protein charge or function: this program centered on
the detection of rare protein variants, in which case studies involving the family
were carried out to determine whether the variant had been inherited or was the
result of a mutation in the preceding generation. Collectively, 1,256,555 locus
tests were done, and among these, seven apparent mutations were detected. Four
of these occurred among the children of exposed parents and three occurred
among the children of the controls.
7. Sex ratio in children of survivors: the proportion of male births among
parents exposed to different amounts of ionizing radiation.
8. Growth and development of children of survivors: birth weight and
weight, body length, head circumference, and chest circumference at 8-10
months of age.
Overall, the studies of health outcomes in the Hiroshima-Nagasaki atomic
bomb survivors and their children have revealed a small but statistically nonsig-
nificant difference in health outcomes between the children of the atomic bomb
survivors conceived subsequent to the bombing and the children of nonexposed
OCR for page 38
38
ADVERSE REPRODUCTIVE OUTCOMES
parents. This increase, albeit small, is qualitatively and quantitatively consistent
with the known mutagenicity of ionizing radiation in experimental animals and
provides the best currently available basis for estimating the doubling dose from
human data (Neel and Schull, 1991~.
ESTIMATING TlIE DOUBLING DOSE
To make use of Equation 1, it is necessary to estimate a genetic doubling
dose. This has been done in a number of original studies and also by the various
committees assigned the task of evaluating the genetic risks of radiation. The
idea is straightforward. If one assumes that the relation between mutation rate
and dose is linear, at least at low doses the model may be written as
M = ml + m2 + bide + b2D2, (Equation 2)
where 1 refers to males and 2 refers to females. Here me and m2 are the sponta-
neous mutation rates in males and females, be and b2 are the induction rates in
males and females, and Do and D2 are the doses applied to the two sexes. If
applied to both sexes, the common dose would be M = 2(m~ + m2), therefore, the
doubling dose (D), is ems + m2~/(b~ + b21. This is estimated by the regressing
effect on the average dose to the two sexes, M = or + ED, and obtaining the
doubling dose from the estimation equation DD = or / 0, where a is the intercept
and ~ is regression.
Mice
Table 2 (Table 2-11 of BEIR V tNRC, 1990~) contains estimates of the
doubling doses for chronic (low dose rate) ionizing radiation for a number of
different endpoints. The ranges in parentheses were obtained by the BEIR V
committee by multiplying acute doubling dose estimates by a correction factor
range of 5-10. The figures in this table are based on a large number of studies
of different sizes and reliabilities. The reader should refer to the original studies
(references given in BEIR V) before making use of individual estimates.
The overall median estimate is in the range of 1.0-1.14 Sv (100-114 rem)
for chronic exposure. The median acute doubling dose estimate is about 0.30 Sv
(30 rem).
Humans
The Japanese data have been used to estimate minimum and probable ge-
netic doubling doses in humans (Neel et al., 1974, 1990; Neel and Lewis, 19901.
Table 3, modified from Table 5 of Neel et al. (1990), contains the most re-
cent estimates of minimum acute doubling dose on the basis of data from Hi
OCR for page 39
GENETIC PRINCIPLES
39
roshima-Nagasaki atomic bomb survivors. The numbers in the last three col-
umns are the lower 99, 95, and 90 percent confidence limits of the doubling dose
for five endpoints: untoward pregnancy outcome (UPO), Fat mortality, Fat cancer,
sex chromosome aneuploids, and loci-encoding proteins. These lower 95 per-
cent confidence limits range from 50 mSv (5 rem) to 2,270 mSv (227 rem). In
addition, Neel et al. (1990) suggest a range of point estimates for acute doubling
doses of from 1,690 mSv (169 rem) to 2,230 mSv (223 rem) and for chronic
(low-dose-rate) ionizing radiation exposure of 3,380 mSv (338 rem) and 4,660
mSv (466 rem).
TABLE 2. Estimated Doubling Doses for Chronic Radiation
Exposure (primarily mouse)
Genetic Endpoint and Sex Doubling Dose (rads)a
Dominant lethal mutations,
Both sexes
Recessive lethal mutations,
Both sexes
Dominant visible mutations
Male
Skeletal
Cataract
Other
Female
Recessive visible mutations
Postgonial, male
Postgonial, female
Gonial, male
Reciprocal translocations
Male
Mouse
Rhesus monkey
Heritable translocations
Male
Female
Congenital malformations
Female, postgonial
Male, postgonial
Male, genial
Aneuploidy (hyperhaploids)
Female
Preovulatory oocyte
Less mature oocyte
Median (mouse, all endpoints, both c
Direct estimates
Indirect estimates
Overall
40-1 00
(150-300)
(75-1 00)
(200~00)
80
(40-1 60)
70-600
1 14
10-50
(20~0)
(12-250)
(50-1 on)
(25-250)
( 125-1,250)
(80-2,500)
(15-250)
(250-1,300)
70-80
(150)
100-1 14
" Values not in parentheses are based on the spontaneous rate
divided by the induced rate/reds for the low dose rate; values
in parentheses are based on the spontaneous rate divided by
the induced rate/red at the high dose rate, multiplied by a
factor of 5-10 to correct for the dose rate effect.
It is important to note that these doubling dose estimates for humans and
their lower limits refer to "conjoint" doubling doses, that is, the sum of the pa
OCR for page 40
40
AD VERSE REPRODUCTIVE OUTCOMES
rental doses that is expected to double the genetic burden. The doubling dose
estimate for the mouse given in Table 2 and the doubling dose calculated from
Equation 1, as customarily used, refer to the common or average dose exposure
to each of the two parents that is expected to double the genetic burden. For
example, a common exposure of 10 mSv (1 rem) to each of the two parents cor-
responds to a conjoint dose of 20 mSv (2 rem). Consequently, to compare the
doubling doses for mice with the lower bounds and point estimates of doubling
doses for humans, either divide the figures for human by 2 or multiply the fig-
ures for mouse by 2. Both are perfectly valid doubling doses; they are simply
scaled differently. Either can be used in Equation 1, so long as DD and D are
used consistently.
It appears that humans may be less sensitive to the mutagenic effects of
ionizing radiation than mice. Neel and Lewis (1990) have recently attempted to
resolve this difference by suggesting that, overall, the mouse estimates of dou-
bling doses are actually higher than those suggested in Table 2.
In sum, the general scientific consensus is that the overall doubling dose of
mutation induction for low-LET, low-dose ionizing radiation is on the order of
100 rem, and it may, in fact, be larger.
OCR for page 41
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. . . . .
000 ~0
_ ~ ~_
~ 00 - ] ~' O
0~gg g
oOOo O
O . . .
+1 +1 +1 +1 +1
~-
= - o' o
oo co - ~o
co ~ o o o
oooo o
. . .
~ ~ oo c ~-
~o
~ - oo o
oooo o
oooo o
. . . . .
+1 +1 +1 +1 +1
~ ~ oo ~-
~o ~ o ~o
mooo o
oooo o
oooo o
1 1
~ ~ o
. . ~
~ l oo g
. .
~-
~ oo ~ o o
o ~ - ~o
'=oo o
oooo o
oooo o
04
;^ ~.=
. -
o E ~ X ° . ~ o
o
C)
3
s~
=:
Ct
C)
o
~C
.=
-
._
C,2
=^
o
~,o
Ct
Ct
. -
c:
o
..
C)
o
_ ~
o ~
~ .°
O~ ~
P~
3^
o
s
=,
~ s~
o ~
~ o
~o
Representative terms from entire chapter:
ionizing radiation
