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OCR for page 367
8
Genetic, Teratogenic, and Fetal Effects
GENETIC EFFECTS
INTRODUCTION
The health consequences of genetic damage that results from
human exposure to low levels of ionizing radiation have been con-
sidered in the reports of the Committee on the Biological Effects
of Ionizing Radiations (BEIR) 25926 and in the reports of other na-
tional and international groups, such as the United Nations Scientific
Committee on the Effects of Atomic Radiation (UNSCEAR).4i The
BEIR }~6 committees estimates of the risks due to genetic damage
were recently updated in a study for the U.S. Nuclear Regulatory
Comrnission.6 That study incorporated several modifications to the
BEIR ITI estimates, including the adoption of equivalent induced mu-
tation rates for the two sexes, the development of an X-linked muta-
tion rate for humans, and the development of an estimate for induced
numerical chromosomal abnormalities of nondisjunctional origin. In
addition, rather than simply tabulating estimated increases in ge-
netic effects of various categories, as in the 1980 BEIR Ill report,26
the authors developed a computerized health-effects mode! (HEM)
that used existing demographic data to predict health outcomes of
radiation accidents through approximately the next five generations.
They also incorporated the health impairment concept, developed
in the 1982 UNSCEAR report,4t to estimate the societal impact of
radiation-induced genetic effects, as well as their numbers.
367
OCR for page 368
368 HEALTH RISKS OF RADON' AND OTHER ALPHA-EMITTERS
A task of the present BEIR committee (BEIR IV) is to estimate
the genetic health consequences of human population exposures to
alpha-emitting radionuclides. In the absence of any positive empirical
human data, or even animal data on many of these radionuclides,
estimates of genetic ejects due to alpha-emitters must be based
largely on estimates of the genetic health consequences of exposure to
low linear energy transfer (LET) radiation. Estimates of the genetic
consequences of low-LET radiation are based on experimental data
(mostly on mice) and must be related to the few animal data on
genetic effects due to high-LET alpha-particle radiation.
After some deliberation, the committee decided that attempting
to derive new low-LET genetic-effect estimates or to update earlier
estimates would be unwarranted. The BEIR [~26 estimates were
thought to constitute a logical foundation on which to base the
required genetic-efFects estimates for alpha-emitting radionuclides.
As noted in the BEIR IT] report, those estimates are numerically
not very different from estimates that have appeared elsewhere, for
example, in UNSCEAR reports. While the committee believes that
updating of the BEIR Ill genetic-e~ects risk estimates for low-level
human exposure to low-I.ET radiation might be desirable, the current
committee was not constituted with the broad expertise required for
such a revision. In addition, some of the issues that would have to
be considered are controversial (e.g., the relative sensitivity of males
and females to mutation induction and whether low to moderate
doses of ionizing radiation induce nondisjunctional events).
Therefore, the committee bases its genetic-effects risks estimates
for alpha-ern~tting radionuclides on the low-LET estimates provided
in the BEIR IT] report.26 We have, however, noted the influence that
the adoption of the HEM6 would have on the estimates of genetic
risk in the BEIR IlI report. We have also adopted the demographic
projection techniques developed for the HEM as a logical extension
of the tabulations in the BEIR ITI report, so that we could project
genetic effects into future generations. Because the demographic
projections require numerical inputs, whereas the BEIR Ill estimate
for chromosomal abnormalities was stated as "fewer than 10/million
liveborn offspring at 1 rem/generation," we have arbitrarily used 9
as the upper limit and 1 as the lower limit for this endpoint.
OCR for page 369
GENETIC, TERJ4TOGENIC, AND FETAL EFFECTS
TYPES OF GENETIC EFFECTS
369
The term genetic effects of radiation, as used here, means sta-
ble, heritable changes in the DNA of germ cells or their precursors.
(Similar changes that occur in the DNA of somatic cells can be
called genetic effects in a broad sense, but they cannot be passed
on to future generations and thus do not constitute genetic effects
in the sense of our concern.) Genetic effects can be grouped into
two broad categories: (1) mutations and (2) chromosomal anoma-
lies. These were once treated as separate classes, but recent work
has demonstrated that so-called point mutations and chromosomal
aberrations are the extremes of a continuous distribution of changes
involving increasingly large portions of the genome. Chromosomal
aberrations, usually defined as visible changes in the structure or
number of chromosomes, have counterparts that constitute, for ex-
ample, deletions and exchanges of segments of DNA; these segments
are so small that they must be demonstrated by methods other than
direct visualization.
Mutations can be grouped according to the mode of their phe-
notypic expression. If they are recessive, the alleles inherited from
both parents must be mutant for them to be expressed. If they are
dominant, only one copy of the mutant gene is required for pheno-
typic expression. Recessive mutations of genes on the X chromosome
constitute a special case. Such mutant alleles are expressed in the
male, in whom there is only one X chromosome (the hemizygous
state), but not in the (heterozygous) female. Such a pattern of in-
heritance is termed sex-linked. Examples of human mutations with
these three patterns of inheritance are albinism, inherited as a simple
autosomal recessive; achondroplasia, inherited as a simple dominant;
and hemophilia, which displays typical X-linked inheritance, being
expressed in males but (usually) not in females. In practice, the
three categories are not completely distinct. Some recessives have
definite, although often different, effects in the heterozygote. Many
dominants may have more severe phenotypic effects, or even differ-
ent ones, in the homozygote than in the heterozygote. And many
mutations classified as dorn~nant might fad! to be expressed at all in
some heterozygous individuals a phenomenon known as incomplete
penetrance.
Many mutations induced by ionizing radiation, in both man
and experimental animals (such as the laboratory mouse), are now
recognized as chromosomal aberrations. In particular, many, perhaps
most, apparent point mutations, when examined on the DNA level
OCR for page 370
370 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
with the powerful new techniques of molecular biology, are now seen
to be deletions of tens, hundreds, or even thousands of base pairs.
Gross chromosomal aberrations are in two distinct categories:
chromosomal breaks and rearrangements, which are termed struc-
tural aberrations; and variations in the number of chromosomes char-
acteristic of the species, a phenomenon resulting from chromosomal
nondisjunction during meiosis and termed aneuploidy. Structural
aberrations include simple deletions, inversions, transiocations, and
occasional, more bizarre types. In humans, a deletion of a specific
segment of one chromosome produces the congenital abnormality
known as cri-du-chat syndrome, and a specific transiocation between
two chromosomes is responsible for a form of renal cancer. Aneu-
ploidy can consist of the absence of a chromosome or the presence
of an extra copy of a chromosome. Aneuploidy involving the sex
chromosomes is much more easily tolerated than aneuploidy of auto-
somes, which either are lethal or produce massive congenital defects
if they involve any but the smallest autosomes. Down syndrome
is a well-known example of the presence of an extra chromosome
(trisomy); those affecter! have 47 chromosomes, including 3 of the
small chromosome 21. Examples of sex-chromosome aneuploidy in
humans include Turner syndrome, in which those affected have only
45 chromosomes (only 1 X chromosome), and Kleinfelter syndrome,
in which those affected have at least 47 chromosomes (including 2 X
chromosomes and 1 Y chromosome).
It is important to recognize that mutations of all types—point
mutations as well as chromosomal abnormalities occur sponta-
neously in humans without any radiation exposure other than the
unavoidable ubiquitous background radiation. The most recent edi-
tion of McKusick's catalog of human mutations 23 lists 588 definite
plus 710 probable recessives, 934 definite plus 893 probable dom-
inants, and 115 definite plus 128 probable X-linked mutations, as
wed as many chromosomal abnormalities. In addition to these rela-
tively simply inherited conditions, however, much human ill health
has some heritable component, even though such conditions are not
inherited in any clear-cut simple pattern. Such conditions are said
to be irregularly or complexly inherited. Such inherited predisposi-
tions to many major human diseases (e.g., diabetes, schizophrenia,
and cancer) are well known. Estimation of the numbers of added
cases of such diseases that would be caused by irradiation of a hu-
man population constitutes one of the most complex and uncertain
elements in the consideration of human genetic effects of radiation;
OCR for page 371
GENETIC, TEIR~ATOGENIC, AND FETAL EFFECTS
371
it involves highly subjective approaches to the genetic component of
the diseases.
BEIR III ESTIMATES
The BEIR Ill Subcommittee on Genetic Effects used two some-
what independent methods for estimating human genetic risk: the
so-called indirect and direct methods. These methods adhered to
the following five principles. which were originally enumerated in the
BEIR ~ report.25
~ , , ,
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
reliable data exist as being more relevant to the usual conditions of
human exposure.
3. Use simple linear interpolation 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 are 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.
S. If the sexes differ in sensitivity, use the unweighted average
of data for the two sexes.
Because there are no positive human data, principle 1 meant that
the bulk of the data used for the low-LET genetic effect estimates
were on the laboratory mouse, the organism closest to man on which
it was deemed practical to accumulate experimental data. Principle 3
provided a reasonable basis for conservative extrapolation, although
many geneticists would argue that the mutation-induction curves for
acute doses of low-LET radiation might best be fitted with a linear-
dose square quadratic mode! (linear-quadratic), as was in fact done
in the 1985 HEM.6 In mammals, the longest-lasting cell stages during
which the largest portion of received radiation would be absorbed are
the immature resting oocyte in females and the spermatogonium in
males. Many mouse mutation-rate data have been obtained on these
stages and applied virtually directly to the derivation of human
genetic-effect estimates. This makes principle 4 unnecessary. The
degree, if any, of mutational sensitivity difference between males and
females has been controversial. The authors of the 1985 HEM6 de-
cided to adopt equal mutation rates, although the BEIR ITI report26
OCR for page 372
372 HEALTH RISKS OF RADON AND OTHER ALPNA-EMITTERS
had adopted a female mutation rate (i.e., oocyte sensitivity) that
was no more than 0.44 times the male (spermatogonial sensitivity),
so application of principle 5 is not straightforward.
The indirect method for estimating genetic risk used by the BEIR
i}~26 Subcommittee on Genetic Effects was a mutation relative-risk
method, as had been used in the BEIR ~ report.25 The newer direct
method was based on directly observed phenotypic damage induced
in a single generation. The relative-risk method is based on the
idea that, whatever the contribution of the current incidence to the
fraction of genetically related ill health in the population caused by
mutation, doubling that incidence ultimately doubles the incidence
of genetically related ill health, if the increased mutation rate is
maintained over enough generations to reach genetic equilibrium. If
the amount of radiation required to double the mutation frequency is
known (i.e., the doubling dose), the fractional increase in frequency at
equilibrium due to any added radiation exposure can be calculated by
using the reciprocal of the doubling dose, the relative risk of mutation
per unit exposure. If the current incidence of genetically related ill
health is known, the increase in incidence at equilibrium can easily
be calculated. From several assumptions (hence, the term indirect),
it is possible to extrapolate from the incidence at equilibrium to
the incidence anticipated in the first generation after an increase in
exposure. The BEIR lll26 Subcommittee on Genetic Effects adopted
a range for doubling dose of 50-250 rem (relative risk of mutation,
0.004-0.02/rem) and a current incidence of 107,100/million liveborn
offspring, of which 10,000 are thought to be expressions of autosomal
dominant and X-linked genes, 1,100 expressions of recessive genes,
6,000 expressions of chromosomal aberrations, and the remaining
90,000 irregularly inherited.
The doubling-dose estimate of 50-250 rem translates into esti-
mates, at genetic equilibrium, of 40-200 autosomal dominant and
X-~mked effects and 2~900 irregularly inherited effectsmnillion live-
born offspring for a dose of 1 rem/generation unfit equilibrium is
reached. For recessively inherited effects, the BEIR Ill Subcommit-
tee on Genetic Effects made no numerical estimate, noting only that
there would be a very slow increase in such effects. Nor did the sum
committee make a numerical estimate for chromosomal aberrations,
noting that the numbers of effects would increase only slightly.
The direct method used by the BEIR Ill subcommittee depends
on observations of phenotypic skeletal anomalies in first-generation
offspring of irradiated mice. The subcommittee used estimates of the
OCR for page 373
GENETIC, TE~TOGENIC, AND FETAL EFFECTS
373
fraction of all phenotypically expressed anomalies affecting health
that might be represented by the skeletal effects and some assump-
tions, for example, that dose-rate effects and male-female mutation
rate differences would apply to this category of mutations, even
though it had been measured only for recessive mutation induction.
It concluded that between 5 and 65 effects might be expected/mullion
liveborn offspring/rem. No separate estimate was made for irregu-
larly inherited or recessive effects, as the effects in heterozygotes
were expected to be included in the 5~5 autosomal dominant and
X-linked effects. The numerical estimate for first-generation chro-
mosomal aberrations, also a direct estimate, was based on direct
cytogenetic observation of aberrations; fewer than 10 were estimated
to result from a 1-rem parental exposure among a million liveborn
offspring. As noted by the Subcommittee on Genetic Effects,26 the
estimate of 5-65 added genetic effects/million liveborn offspring/rem
of parental radiation is in reasonable agreement with the estimate
that would be derived by extrapolation from the equilibrium estimate
based on the doubling-dose, or relative-risk, method with the same
assumptions as were used by the BEIR ~ Subcommittee on Genetic
Effects in 1972.25
It is important to recognize that the BEIR II! genetic-effects
risk estimates were derived from experiments with laboratory mice
in which specific-Iocus mutations or first-generation skeletal anoma-
lies were determined after exposure of the parental generation to
relatively high doses of low-LET radiation, often at high dose rates.
The doubling-dose estimates have been corrected for low-dose and
low-dose-rate effects, essentially by reducing the slope of the linear
downward extrapolation by a factor of 3; that factor was determined
experimentally from observations that the spermatogonial specific-
locus mutation rate decreased as a function of decreasing dose rate
until a plateau was reached at about one-third of the high-dose-rate
mutation rate (at about OeO1 rem/min). However, no such obser-
vations have been made for the oocyte or for the dominant skeletal
mutations that provide the basis for the direct estimates. Whether
this dose-rate effect results from the simple loss of a dose-squared
component in a quadratic dose-effect curve has been much discussed;
the dose-rate factor of 3, however, reflects the empirical observation
and is thus independent of the debate over curve shape.
OCR for page 374
374 HEALTH RISKS OF RADON AND OTHER ALPHA-I~MITTERS
ESTIMATION OF GENETIC EFFECTS OF HIGH-LET RADIATION
A simple way to derive estimates of effects of high-LET radi-
ation from estimates of effects of low-LET radiation is to multiply
the low-LET estimate by a factor analogous to relative biological
effectiveness (RBE) for the higher-LET radiation. To do this in a
valid way, however, the dose-effect curves for both radiation qualities
must be essentially linear in the dose range of interest. As detailed
in Appendix Il. such linearity is reasonable to assume in the case
of high-LET radiation. But many geneticists believe that, for mu-
tation induction and the induction of some kinds of chromosomal
aberrations, the linear assumption is not a valid interpretation of the
experimental high-dose-rate, low-LET results.
Nevertheless, if one considers how the BEIR IIT Subcommittee
on Genetics Effects obtained its low-dose, low-LET genetic-effects
estunates from data on experimental mice, it seems reasonable to
use the RBE approach in estimating the genetic effects of alpha-
emitting radionuclides. The subcommittee used the linearity as-
sumption and simply extrapolated from the lower doses on which
empirical mutation-rate data were available down to the 1-rem level.
If, as seems likely, the true form of the dose-effect curves for acute
doses of low-I`ET radiation is linear-quadratic—that is, has an im-
portant dose squared component—the error thus introduced would
leads to overestimation of the genetic effects induced by low-LET
radiation. This might raise a question about the validity of the low-
LET estimates, but not about the procedure by which high-LET
estimates are derived. The subcomm~ttee's estimates were for a very
low dose (1 rem) administered at a very tow dose rate (accumulated
over a Satyr, one-generation span), and the application of a simple
RB~like proportionality constant still seems appropriate and could
easily be used for revisions, if low-LET genetic-effects estimates are
revised.
The estimates of the BEIR III Subcommittee on Genetic Effects
were for a dose of radiation specified in rems. The rem is meant
to make just the sort of allowance for the greater effectiveness of
high-LET radiation that is outlined above. However, the factor Q.
by which the dose in reds is multiplied to arrive at a number of rems,
has two components. One is analogous to RBE; the other is meant to
take into account nonuniform distribution of dose within the target
organ and is addressed below. Instead of simply taking the BEIR
ITI subcommittee's estimates of doses specified in rems and using
them, it seems appropriate to make the adjustments for RBE and
OCR for page 375
GENETIC, TERATOGENIC, AND FETAL EFFECTS
375
dose distribution separately, where possible, for each radionuclide
of interest. Because the BEIR ITI subcommittee's estimates were
derived entirely from experiments with low-LET x and gamma rays,
we take these estimates to be valid for low-LET radiation specified
in reds.
The validity of the application of a simple proportionality con-
stant analogous to RBE to the present calculations depends entirely
on the linearity of both dose-effect curves; the proportionality con-
stant is simply the ratio of their slopes. Although, as already dis-
cussed, there is some question about the shape of the low-LET curve
for the range of low doses and dose rates of interest here, the over-
whelmingly predominant contribution to the dose curve would be
linear in any case; the dose-squared component, if any, contributes
nearly nothing at doses of only a few reds. It is clear (see Appendix
IT) that, even at much higher doses, the dose-squared component be-
comes vanishingly small if the dose rate is low enough—below about
0.01 rad/min for mutation induction in mouse spermatogonia. It is
also clear that curves for high-LET radiation are essentially linear
at least in the lower-dose range where saturation is not a factor.
RB ES FOR THE INDUCTION OF GENETIC EFFECTS
Mulations
The BEIR ITI26 and other estimates of genetic risk have been
based mainly on the mutation rates measured by the specific-Iocus
technique or the dominant skeletal-mutation technique in the mouse.
It seems appropriate to base our derivation of an appropriate RBE
factor on similar studies done with high-LET radiation. Unfortu-
nately, there is not much information on mutation induction by
internally deposited alpha-emitters measured with either system.
Russell and Lindenbaum35 used the specific-Iocus method to deter-
mine mutation rates in male mice into which 239Pu was injected.
They used what appeared to be an appropriate factor to describe the
location of the plutonium and derived an RBE for alpha particles
of only about 2.5, compared with low-dose-rate, low-LET radiation.
This RBE is surprisingly low when compared with the RBE of about
17 obtained in similar experiments with neutrons2 37 or with the even
higher RBEs obtained for other endpoints. Several explanations may
be offered: the location of the plutonium might be inappropriate or
the mutations induced by the two radiation qualities might be quite
OCR for page 376
376 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
dissimilar. There is considerable support for the latter explanation,
both theoretical (see Appendix IT) and empirical. Several lines of
evidence suggest that mutations produced by 239 Pu are, on the aver-
age, qualitatively more deleterious than those induced by low-LET
radiation: Most, if not all, are lethal when homozygous; many have
marked deleterious effects in heterozygotes; and there is a greater
loss of mutants induced by 239 Pu. Nevertheless, if one reason for
the low measured RBE in the mouse specific-Iocus experiments with
239 Pu is indeed the very early loss of more serious mutations, then
these would presumably have a smaller impact on human health, as
· e
In mice.
No positive information on induction of dominant skeletal muta-
tions by alpha-emitting radionuclides is available. One small experi-
ment in which male mice were given 239Pu failed to yield mutations;
thus, it provided some assurance, at least, that the rate of induction
of such effects by an internally deposited alpha-emitter is not very
large.
Chromosomal Aberrations
Abundant evidence from experiments with alpha-emitters en c}
with neutrons indicate that RBEs for the induction of chromosomal
aberrations in plant material or in somatic cells of mammals can
be high. The ratio of linear slopes for high-I,ET radiation when
compared with chronic exposure to gamrna- or x-radiation tends to
lie in the range of 10-20, with some values approaching 100.5 27 30
Measurements made directly with the radionuclides of interest in
this report include those with 238pu, 239Pu, 24iAm, and 252Cf, in
comparison with chronic low-I`ET radiation RBEs were found to
range from 10 to 40.3~5930
Determinations of transIocation induction in the mouse have
been made both by direct observation of cytogenetically detectable
transIocations in primary spermatocytes and genetically by use of the
heritable transIocation test after exposure of spermatogonia to in-
ternally deposited 239 Pu. The results of the two tests are somewhat
conflicting. The frequency of transiocations as measured cytoge-
netically appeared to increase during the first several months after
injection of the radionuclide, but then to decrease,~° whereas no such
decline was seen in heritable transIocation tests.8 RBEs for 239Pu al-
pha particles were in the range of 10-20, compared with chronically
OCR for page 377
GENETIC, TERATOGENIC, AND FETAL EFFECTS
377
administered gamma rays, depending on the alpha dc~se-distribution
factor adopted.
Dominant Lethal
Dominant lethals are believed to result largely from chromosomal
aberrations. The efficiency of their production has been evaluated
for 239Pu.9 20 2i RBEs in the range of I(~15 were found.
Selection of RBE Values
In the absence of other information, it seems appropriate to
adopt an RBE value for mutations (dominant X-linked and reces-
sive mutations and those involved in the production of irregularly
inherited genetic effects) of 2.5, as indicated by the mouse spermato-
gonial specific-Iocus information for 239Pu. A higher value of 15
seems appropriate for the induction of chromosomal aberrations by
239 Pu in spermatogonia. The lack of any substantive information on
these effects in females is unfortunate; nevertheless, since the major
contributions to the numbers of genetic health effects estimated by
the BEIR ITI Genetic Effects Subcommittee comes from the male,
application of the male-derived plutonium-239 RBEs stated above
does not seem inappropriate.
There is no direct information on any of the other radionuclides
of interest, so there seems little choice but simply to adopt for their
alpha particles the same RBE values as those for 239Pu. Our confi-
dence in doing so ~ reinforced by the somatic-cell observations cited
above on 238pu, 24iAm and 252 Of
Distribution Factors
The fraction of alph~emitting radionuclides entering the body
that can be expected to end up in the gonads is small, and the distri-
bution within the male gonad in the laboratory mouse is nonuniform.
The concentration in the interstitial tissue around the somniferous
tubules is higher than the average testicular concentration, so a dose
to the genetically significant spermatogonia is 2-4 times larger than
that predicted on the basis of uniform 239Pu distribution in the
organ.4 ti 35 Whether this distribution factor is appropriate for the
human testis, however, is uncertain, because the primate (including
human) testis has a different geometry from the rodent testis, with a
OCR for page 386
386 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
attributable to chemical toxicity. The associated dosimetric data are
incomplete, but the action of some nuclides seems to occur via an
effect on the villose visceral splanchnopleure (yolk sac), which has a
high affinity for heavy metals and is important in absorption of nu-
trients by the early rodent embryo. The importance of this structure
is not completely parallelecl in other mammals, but similar affinities
have been demonstrated in nonhuman primates.
It was first demonstrated in the early 1920s that adverse devel-
opmental effects resulted from exposure of the mammalian fetus to
radioactive materiab injected into the pregnant animal. The next re-
ported study, resulting from the efforts of the Manhattan Project, did
not appear until 25 yr later. In contrast with the extensive literature
dealing with acute exposure to external photon beams, relatively few
experiments have been performed with radionuclides, particularly
with alpha-emutters, because few laboratories have a knowledge of
developmental toxicology and the facilities and expertise to work
with alpha-emitters. Performance and interpretation of such exper-
iments is most difficult, in that establishing radiation doses requires
sacrifice of the animals and precludes determination of effect, the
radiation is not uniformly distributed throughout the fetoplacenta]
unit, and the absorbed radiation is protracted at varying dose rates.
As a result, most experiments have been directed either at measure-
ment of placental transfer and fetal content or at determination of
effect relative to administered dose, but rarely at both. Thus, the
dose-response relationships for internal alpha exposure are less well
established than those for external or for internal beta exposure.
Although our information is still limited and there are elements
on which there are no data, some progress on the developmental
toxicity of alpha-em~tters has been made during the last 40 yr. For
simplicity, an overall summary of eject patterns relative to dosimetry
in order of ascending atomic number is presented here.
Radon and Daughters
The first developmental study with an alpha-emitter apparently
wan also the first experiment with prenatal administration of an in-
ternal em~tter.~5 Radon and its daughters were dissolved in isotonic
saline and injected subcutaneously into female rats before mating or
during gestation in amounts originally equivalent to 5 mCi of radon.
Prenatal mortality was increased, and there was macroscopic hem-
orrhage in the survivors when the rats were exposed at an unstated
OCR for page 387
GENETIC, TERATOGENIC, AND FETAL EFFECTS
387
tune of gestation and even if the solution was administered as early
as 22 days before mating. Most of the offspring born on the day after
injection at 19 days of gestation (da) had similar hemorrhages, but
normal placentas.
The reports did not indicate the extent to which the several
nuclides crossed the placenta. Studies have shown that inhaled 85Kr
freely crosses the placenta and that its concentration is the same in
maternal and fetal blood; it can be inferred that radon would behave
in a similar manner. Because of the consistent involvement of the
placenta in the effect, the presence of edema and/or hemorrhage,
and the mechanical effects In malformation production, it is not
clear to what extent the effects were directly on the conceptus or
were secondary to placental and/or yolk sac changes.
Radium
Wilkinson and Hoecker44 dissolved 226 RaCI2 in saline; the so-
lution was allowed to reach equilibrium and then injected into rats
at 15 da. No radioactivity was detected in the placentas or fetuses
at 20 da, but the availability of the nuclide to the placenta after
administration is not clear.
Rajewsky et al.~i measured the 226Ra content of the bones and
soft tissue of approximately 200 human fetuses and 40 additional
placentas at various stages of gestation. The specific activity of
bone ash (10-~4 Ci/g) was independent of the stage of gestation and
was identical with that measured in adult bone. Fetal soft tissue
and placental concentrations were similar (10-~6 Ci/g) and did not
change during gestation, although the total fetal content increased
during gestation as a result of the increase in fetal mass. Martiand
and MartIand22 found less than 10-8g of radium on examination of
17 children from 10 mothers who had been employed as radium-dia]
painters. Reports regarding the developmental effects of prenatal
exposure to radium have not been found, but to the extent that
these measurements reflect the amounts transferred, demonstrated
effects might not be expected.
Polonium
Lacassagne and Lattes~9 found salts of polonium deposited in
the placental syncytium (celIs of the chorionic epithelium), but not
in the fetal connective tissue or the fetal endothelium.
OCR for page 388
388 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
Uranium
The toxicity of several uranium isotopes has been studied exten-
sively ~ adult animals of various species, but few data are available
on its placental transfer or developmental toxicity, other than those
from one experimenter that used intravenous exposure to citrated
solutions Of 233 U at 9, 15, or 19 dg at dosages of 1.8, 3.3, 5.75,
and 10 ,uCi/kg. The two highest dosages were toxic to pregnant
rats. Exposure at 9 and 15 dg produced dosage-dependent trends
toward increased prenatal mortality and decreased fetal and pla-
cental weights on evaluation at 20 da. Injection at 9 dg produced
a dosage-dependent increase in the incidence of rib malformation,
and the highest dosage resulted in cleft palate. The two highest
dosages resulted in fetal edema if injected at 15 da. Fetoplacenta]
concentrations and partition, measured in other rats, were affected
by dosage evaluated late in gestation, but not at earlier times, and
there was less selective localization in the yolk sac than was the case
with many actinides. The resulting radiation doses throughout the
fetoplacental unit were calculated from the distribution data. At the
highest dosage, the radiation doses to the conceptus, placenta, and
membranes were about I, 2, and 3 red, respectively, after injection
at 9 dg and 0.2, 1, and 7 red, respectively, after injection at 15 da.
Comparison of the doses suggests that the early maternal and devel-
opmental effects were attributable to chemical toxicity, rather than
to radiation.
Transuranic Elements
There are pronounced differences among the transuranic elm
meets relative to their metabolism in pregnant animals, placental
transfer, and fetoplacental distribution. The limited data do not
suggest marked qualitative differences in the types of responses, but
metabolic and dosimetric differences yield substantial differences in
toxicity relative to administered dosage. It should be noted that
almost Al evaluations of effects were performed with administered
dosages that were far in excess of those to which people might be
exposed. These results are of radiobiological interest, but are not
directly applicable to establishing exposure criteria.
Intravenous injection into rats of 237 Np as the oxalate at 0.3-5
psi/kg increased the incidence of preimplantation mortality. Rela-
tive to controh, offspring of litters receiving these dosages had greater
OCR for page 389
GENETIC, =~TOGENIC, AD FETAL EFFECTS
389
depression of erythrocyte production after gamma irradiation, pro-
longed narcosis after hexanol administration, and decreased sexual
function.29
Plutonium is the most thoroughly studied of the transuranic
elements, although some questions remain as to detain of its placen-
tal transfer, fetoplacental distribution, and developmental toxicity.
In the earliest reported study with 239Pu,7 it was found that mice
given plutonium at 0.016, 0.03, or 0.06 pCi/g by injection during
gestation had an increased incidence of totally stillborn litters and of
stillbirths in viable litters. If injection took place late during gesta-
tion, the newborn offspring contained about I% of the administered
radioactivity; the amounts of radioactivity decreased with increasing
dosage and with increasing time between injection and measurement.
Autoradiographic and radioanalytic studies from several laboratories
have extended and quantified those findings, but are in general ac-
cord with them. In general, it has been found that small amounts
of monomeric (citrated) plutonium cross the placenta. Intravenously
or intraperitoneally injected polymeric plutonium has been shown to
be less available to the fetoplacental unit.
Studies to examine the partition of 239 Pu at various stages of
gestation in rabbits have found a difference in distribution from that
in rats and mice. The concentrations in the placentas and fetal
membranes were not as high as those found in rodents, and the
concentration ratio in these two structures and the concentration in
the embryo-fetus were lower In the rodents.
To determine whether yolk sac deposition occurs in nonhuman
primate species, Andrew et al.t injected citrated 239Pu intravenously
into baboons at 10 ,uCi/kg at representative stages of gestation and
removed the uteri and their contents 24 h later. The uteri and feto-
placental components were dissected and subjected to radioanalysis;
concentration ratios were similar to those found in rodents. The
autoradiographic localization of activity was also similar ~ the two
species when allowance was made for morphological differences.
Kelman and Sikov~8 directly examined placental transfer using a
system in which the vesseb of the fetal side of the near-term guinea
pig placenta were cannulated and perfused to el~rninate the role of
the fetus. Graded dosages of citrated 239 Pu and a trace dose of triti-
ated water were injected into the maternal circulation, and placental
transfer was calculated in terms of clearance. Clearance was found
to be 2.3 liters/min, a value less than one-fifth of that for inorganic
mercury, which had the lowest clearance previously measured with
OCR for page 390
390 HEALTH RISKS OF RADON AND OTHER ~4LPHA-EMITTERS
this system. Moreover, on the bash of reduced clearance of tritiated
water at the highest doses of plutonium, the maternal blood supply
to the placenta was affected; the threshold for this effect was about
5 psi/kg of body weight.
Administration of 239 Pu during early organogenes~s (e.g., at 9
dg in rats) results in dose-dependent increases in prenatal mortality
and reduced weights of the fetuses, placentas, and fetal membranes.
Typically, however, the lowest administered intravenous dosage that
consistently produces statistically significant differences Tom con-
trols is about 10 psi/kg in rats. Sequential histopathological studies
at this and higher dosages demonstrated early shrinking and sup-
pressed development of the villi of the yolk sac, which suggested that
the embryotoxic effects might be mediated through changes in this
structure. The radiation doses to the embryo-fetus, placenta, and
membranes of rats under these general circumstances are approxi-
mately 0.45, 1.3, and 2.5 red, respectively, through 12 dg and about
2, 6, and 33 red, respectively, through 20 da. The dose to the yolk
sac might be 10-100 times as great as the average membrane dose
because it represents only a small portion of the total mass.
Other experiments have failed to detect prenatal mortality or
other indicators of prenatal toxicity after exposure of rats to plu-
tonium at dosages as great as 50 ,uCi (about 150 psi/kg) at 15 or
19 da. As indicated above, the pattern of fetoplacental partition is
similar to that at earlier stages.
The induction of developmental toxicity involves complicated in-
teractions, as indicated by differences among rat strains in sensitivity
to production of embryo lethality and fetal weight reduction. These
between-strain differences are incompletely accounted for by distri-
bution differences. Comparable quantitative differences in develop-
menta] effects and minor qualitative differences have been observed
in other species, including rabbits, but these are partially related to
the distribution differences described above.
The primitive cells that ultimately give rise to the gametes and
the hematopoietic system are formed in the early yolk sac and mi-
grate into the embryo proper. It can be hypothesized that alpha
particles emitted by radionuclides deposited in the yolk sac of the
early embryo could produce persistent adverse effects on these prim-
itive cell lines. To test this hypothesis, pregnant rats were evaluated
at 14 or 19 dg after intravenous injection with 36 psi/kg of citrated
plutonium at 9 da. Weight gains of the pregnant rats were reduced, as
were reticulocyte and leukocyte counts at both times and erythrocyte
OCR for page 391
GENETIC, TER-ATOGENIC, AND FETAL EFFECTS
391
concentrations at 19 da. Exposure increased prenatal mortality but
did not significantly affect fetal weights. Fetal hematological changes
included a transient decrease in the concentration of circulating non-
nucleated erythrocytes and altered distribution of the erythropoietic
cell types. These changes were interpreted as a disturbance of the
maturation process. The weights of the yolk sac and fetal liver were
reduced in exposed litters; their cellularity and that of the spleen
were also decreased, but the proportion of cell types was unaffected.
Detailed microdosimetry has not been performed, but the radiation
dose to the primitive hematopoietic cells might have been as high as
1,000 red.
Moskalev et al.24 injected a constant volume of solution contain-
ing 24~ Am at concentrations of 1.2-7.6~o intravenously into pregnant
rats at 1~19 da. The resulting ratio of average maternal to fetal
concentration at 24 h varied from 6:1 to 2:1 as a function of dose
and stage. Although the value is influenced by the interval between
injection and evaluation, as well as by sensitivity, they calculated
the injection dosages and radiation doses to the fetus that resulted
in death of 50~o of the fetuses as 0.003, 0.01, and 40 pCi/g and 100,
800, and 1,000 red respectively, for injection at 10, 14, and 19 da.
Weiss and Walburg42 43 reported that the effect of the mass ad-
ministered was less than they had found with plutonium, but fete]
concentration varied only by a factor of 2 between the highest and
lowest dosages. These studies and others demonstrated that, on a
percentage basis, less americium than plutonium entered the concep-
tus or fetoplacental unit. Several studies have shown that there was
proportionately less deposition of americium than of plutonium in
the placenta and membranes.
Results of a contemporaneous study with the two nuclides33
have confirmed suggestions that the prenatal effects of americium
are similar to those of plutonium and include prenatal mortality and
rib malformations, but not weight reduction. The effects are smaller
if based on intravenous dosages administered to pregnant rats, but
there is better correspondence between the effects when they are
considered relative to radiation doses to particular components of
the fetoplacental unit, especially the yolk sac.
Measurable amounts of 253 Es cross the placenta, but, according
to the limited data available, the fraction of maternal dose that is
deposited in the conceptus is low, approximating that of 24,Am.
However, einsteinium has a greater tendency than americium to be
incorporated in the yolk sac.
OCR for page 392
392 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
CONCLUSIONS
Very recently, a task group of Committee 1 of the International
Commission on Radiological Protection completed a study of the
effects of radiation on the development of the brain of the embryo and
fetus.~7 The task group reported that, within the period of maximum
vulnerability, the data it reviewed appeared to be consistent with a
linear nonthreshold response. This information was published after
this report was prepared and therefore has not been examined by
this committee, which reached no conclusions concerning the effects
of alpha dose on the developing brain.
With the exception of risks to the developing brain, no national
or international expert group has made quantitative risk estimates
of purely teratogenic effects of exposures of less than 10 red of acute
low-LET radiation, simply because of the threshold nature of most of
the dose-effect curves. For organs other than the brain, the concept
of RBE can be used to translate estimates of the effects of acute
low-I~ET exposures to the case of alpha particles. Virtually all other
teratogenic effects of radiation are believed to be due to multiple cell
killing, and one can simply translate the accepted tetrad threshold
for singI - dose low-I`ET radiation exposures by applying the RBE
commonly observed for alpha particles in in vitro cell-killing exper-
iments. RBEs for cell killing by alpha particles are around 10, but
could be higher for the very low dose rates expected from internal
emitters. Sensitive time windows have been observed, particularly
during the stage of major organogenesis, and much (if not all) of
the total dose accumulates on either side of this window, which is
apparently only a few days long even in man. Thus, most of the
total dose accumulated during the entire Midday gestation period
would not be effective. It seems reasonable to conclude that except
for brain tissues, high-LET alpha-particle doses below about 1 red
will have no teratogenic effects.
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Representative terms from entire chapter:
fetal effects
