|
Items in cart [0] |
Questions? Call 888-624-8373 |
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 42
7
Adverse Reproductive Outcomes
The term "adverse reproductive outcome" includes such diverse endpoints
as the inability to conceive (sterility or infertility), the premature spontaneous
termination of a pregnancy (abortion), the birth of an infant with a congenital
malformation or with mental or physical retardation, and the premature death of
an offspring (stillbirth, neonatal, or infant death). Many host and environmental
factors contribute to the origins of such outcomes. They may be caused by ma-
ternally or paternally derived inherited defects, exposure to noxious environ-
mental agents, including ionizing radiation, smoking, or the consumption of al-
cohol, preexisting maternal illness (such as diabetes) or illness during pregnancy,
and malnutrition (Bracken, 19841. This diversity of possible origins makes diffi-
cult the assignment of causation in any specific instance.
Of primary interest here are those adverse reproductive outcomes that may
have arisen through the induction of a deleterious mutation in the paternal germ
cells as a consequence of exposure to ionizing radiation. As noted in Chapter 6,
this contribution to the totality of adverse reproductive outcomes is called the
mutation component, and it varies substantially from one endpoint to another.
Unfortunately, in most instances the precise size of this mutation component is
either unknown or poorly estimated, but sufficient information is available to
estimate its probable magnitude.
42
OCR for page 43
AD VERSE REPRODUCTI VE OUTCOMES
43
GENERAL REMARKS
In the paragraphs that follow, the committee examines separately each of 11
adverse reproductive outcomes. This examination will include a definition of the
endpoint, current estimates of its frequency, its causers), possible sources of ex-
traneous variability (confounders) that may contribute to its prevalence or inci-
dence, the interaction of various contributors to the occurrence of the endpoint,
and the difficulties inherent in obtaining reliable estimates of prevalence or inci-
dence and paternal exposure. The risk factors described primarily relate to the
mother's preconceptional or gestational exposure. Although much of what Is
known about the causes of these endpoints relates to maternal exposure, specific
reference will be made to the status of evidence for male-mediated effects. In
addition, these maternal risk factors are discussed because they are potentially
strong confounders that would have to be taken into account in any study of pa-
ternal radiation exposure. A confounder in this context is a variable that is
causally related to the disease under study and that is associated with exposure in
the study population, but that is not a consequence of this exposure (Kelsey et
al., 19861.
Current research on adverse reproductive outcomes has been expanded to
include effects on the reproductive systems of both men and women as well as
effects on the offspring. This expanded list of effects is shown in Table 4 and
includes menstrual cycle changes; semen characteristics; fecundability and fer-
tility; embryonic and fetal loss; any complication affecting the embryo, fetus, or
mother; infant morbidity and mortality; and childhood malignancies. For ex-
ample, preconceptional exposure may lead to spermatic or ovarian toxicity and
germ cell mutations in either sex. These latter effects may in turn lead to infer-
tili~y, spontaneous abortions, or abnormalities in the offspring. Prenatal expo-
sures could lead to functional deficiencies and illnesses in the offspring that may
not become apparent until childhood or even adulthood, such as developmental
disorders and malignancies. In summary, the reproductive and developmental
effects of environmental agents may operate through a variety of mechanisms
including toxic, mutagenic, teratogenic, and carcinogenic effects.
TABLE 4. Possible Reproductive Effects of Environmental Exposures
. .
1. Menstrual cycle disorders
2. Hormonal changes
3. Sperm or semen abnormalities
4. Infertility
5. Single gene defects
6. Chromosomal aberrations
7. Fetal loss
8. Altered sex ratio
SOURCE: Adapted from Berkowitz (1985).
9. Intrauterine growth retardation
10. Preterm birth
11. Maternal complications
12. Birth defects
13. Neonatal and infant deaths
14. Developmental deficits
15. Childhood malignancies
1 6. Other childhood diseases
.
This multiplicity of possible adverse reproductive effects and etiologies
makes difficult the design and implementation of epidemiologic studies seeking
to establish the association of a specific effect(s) with a given exposure, as well
as the meaningful interpretation of a suspected association.
-
OCR for page 44
44
ADVERSEREPRODUCTIVE OUTCOMES
MALE-MEDIATED REPRODUCTIVE AND
DEVELOPMENTAL OUTCOMES
The feasibility of studying adverse reproductive outcomes among Atomic
Veterans and their families hinges in large measure on the likelihood that genetic
effects may be seen following exposure of the male to ionizing radiation. To
assess this likelihood the committee summarized the evidence on paternal expo-
sures and adverse reproduction and disease in offspring found in studies of ani-
mals and humans.
The role of paternal exposure in the origin of many adverse reproductive
and developmental outcomes has not been investigated extensively in humans
(Olshan and Faustman, 1993~. The effects of chemicals or ionizing radiation on
the sperm, chromosome, and fertility have been demonstrated (Wyrobek et al.,
1983; Martin et al., 1986; Geneseca et al., 1990~. The prevailing view is that
exposure of the human male to chemicals and ionizing radiation is generally un-
related to the occurrence of developmental endpoints such as miscarriage, birth
defects, growth retardation, and cancer (Brown, 1985~. Animal studies, some
repeatedly confirmed, demonstrate that paternal exposure can lead to a variety of
effects, including skeletal malformations and cataracts, in the offspring. A
causal connection has been established with radiation-induced mutations. There
is a paucity of human data on this subject.
Several potential mechanisms have been proposed to explain possible male-
mediated effects on offspring. A direct effect of an agent on male germ cell
DNA is the traditional explanation for the induction of some abnormalities and is
of major relevance for considering the potential effects of ionizing radiation.
Since the time span for male germ cells to mature into spermatozoa is only about
8-9 weeks (compared to the longevity of a lifetime for resting oocytes), the ef-
fect of environmental agents must be on the spermatogonia for possible effects to
be long lasting. The majority of the available data from tests in animals suggest
that this mechanism is involved.
More indirect mechanisms involving the transfer of toxic agents in seminal
fluid and maternal exposure to agents brought home by the father have been sug-
gested. Some toxicants, such as PCBs and lead, have been found in seminal
fluid, and vaginal absorption of substances in semen can occur. Nevertheless, it
is unclear whether the concentrations of these toxicants obtained through this
mechanism would be sufficiently great to have an effect on the fetus (Hatch and
Marcus, 1991~. There are some data from studies in animals linking seminal
transfer of chemicals to preimplantation loss (Robaire and Hales, 1994~. There
is no evidence of seminal fluid toxicants being produced as a result of radiation
exposure.
As noted above, evidence for the direct effects of exposure on male germ
cell DNA (germ cell mutagenicity assays) from studies in experimental animals
has been available for several decades. In fact, an important test in animals for
germ cell mutagenicity, the specific locus test, was developed in 1951 and has
been extensively used in tests involving ionizing radiation (Russell, 1951~. The
OCR for page 45
AD VERSE REPRODUCTI HE OUTCOMES
45
majority of the data from tests in animals were obtained in the evaluations of
radiation and chemicals in relation to the expression of defined visible pheno-
types caused by mutations at recessive loci (specific locus test), fetal loss
(dominant lethal test), inherited chromosomal aberrations (heritable translocation
test), and congenital anomalies (dominant skeletal and dominant cataract tests).
Ionizing radiation and a small number of chemicals (compared to animal car-
cinogenicity assays) have yielded positive results in these test systems. Data
from tests in animals also show that exposure of males to ionizing radiation and
some chemicals can produce other outcomes in the offspring such as tumors,
growth retardation, and neurobehavioral effects (Olshan and Faustman, 19931.
Detailed data from studies in experimental animals exposed to ionizing radiation
can be found in Chapter 6.
Epidemiologic associations between paternal exposure and reproductive and
developmental abnormalities in offspring have been reported, although further
verification is needed. Most of the studies have focused on occupational expo-
sures. A brief summary of the findings from epidemiologic studies is provided
here. The major epidemiologic studies relating to ionizing radiation and devel-
opmental outcomes, such as the studies of the atomic bomb survivors, can be
found in Chapter 6. There is evidence that a small number of agents such as
ionizing radiation and dibromochloropropane (DBCP) may affect semen quality
and result in reduced fertility or sterility when individuals are exposed to high
doses. An increased risk of fetal loss (spontaneous abortion) has been linked
with paternal occupational exposure to vinyl chloride, anesthetic gases, dibro-
mochloropropane, mercury, lead, other metals, and various solvents (Savitz et
al., 19941. A number of epidemiologic studies have examined the relationship
between paternal occupation and birth defects (Olshan and Schnitzer, 1994~.
Positive associations have been found for individuals with a variety of occupa-
tions, including painters, welders, firemen, forestry and logging workers, motor
vehicle operators, wood workers, farm workers, and metal workers. Individuals
in these occupations have a variety of exposures, often mixed, to metals, sol-
vents, pesticides, and paints.
Several recent large case-control studies have reported some paternal occu-
pations and exposures that may be associated with childhood cancer in the off-
spring (Savitz, 1986; Savitz and Chen, 1990; O'Leary et al., 1991~. These asso-
ciations include leukemia in the offspring of painters, mechanics, and machinists;
childhood brain tumors in the offspring of painters, metal workers, those in elec-
tronics-related occupations, and those with motor vehicle-related jobs; Wilms'
tumor (childhood kidney tumors in the offspring of auto mechanics and machin-
ists, welders, and painters; and neuroblastoma in the offspring of those in elec
tronics-related occupations.
To summarize briefly, some male-mediated environmental exposures may
affect pregnancy outcome through fertilization by mutation-bearing sperm,
which could lead to pregnancy loss or possibly congenital malformations or
childhood cancer (Berkowitz and Marcus, 1993~. It is also possible that male-
mediated effects could occur because male workers bring toxicants into the
OCR for page 46
46
ADVERSE REPRODUCTIVE OUTCOMES
home environment or because toxicants are absorbed into the female genital tract
via sperm or seminal fluid. The experimental animal and epidemiologic data
indicate that the exposure of the male to various toxic agents may increase the
risk of the full spectrum of adverse developmental endpoints from fetal loss to
cancer. However, the evidence is not firm and clearly requires more study and
confirmation in both laboratory and epidemiologic settings.
INFERTILITY
Approximately 15% of all couples of reproductive age cannot achieve a de-
sired pregnancy (McClure, 1986~. The large majority of previous research has
concentrated on the female component; however, half of all fertility problems
may be due to male reproductive dysfunction (Swerdloff, 1985~. The role of
extrinsic environmental factors on male reproduction has suggested that chemi-
cal and physical exposures have an effect (Biava et al., 1978; Steeno and Pang-
kahila, 1984; Bonde, 1990~. In a recent study, occupationally related exposure
to electromagnetic fields was unrelated to morphology, motility, or concentration
of semen (Lundsberg et al., 19951. Ionizing radiation at high enough doses can
lead to temporary or permanent sterility. The doses and time course of the proc-
ess in humans have been studied extensively. In general, the human data related
to testicular effects are reported from accidental exposures or from males irradi-
ated for therapeutic reasons, for example, as a treatment for testicular cancer.
Following the administration of doses as low as 80 mGy (8 reds), a reduction in
the number of spermatogonia occurs. At these low doses, the more resistant and
more differentiated cells in the line may continue normal maturation. A reduc-
tion in the sperm count may not be evident until 30 to 60 days have passed. The
ultimate degree and duration of depletion of the sperm depend on the magnitude
of the dose received.
Sterility following irradiation is often a loosely applied term; it may repre-
sent complete sterility, temporary subfertility, or in fact, fertility with a reduced
number of sperm. Investigation of human volunteers indicates that administra-
tion of 25 fractions of 150-200 mGy (15-20 red) daily may cause a decrease in
the sperm count. It is of interest that in the few patients treated with radiother-
apy to one testicle or to the inguinal nodes at doses of 600-2,500 mGy (60-250
red), a significant percentage were subsequently able to father children. Lush-
baugh and Casarett (1976) have reviewed the literature and have found no case
reports of malformed infants from parents who had received radiotherapy before
the conception of the child.
Five to six Gy (500 to 600 red) in a given dose will cause permanent steril-
ity in most men; however, in some cases, that dose has been exceeded without
causing permanent sterility. A dose of 2.5 Gy (250 red) may cause transient
sterility for about 12 months. UNSCEAR (1982) has reviewed the available lit-
erature and concludes that
OCR for page 47
AD VERSE REPRODUCTI HE OUTCOMES
(1) temporary sterility is reported to occur with single doses to the testes
ranging from 1.5 to 4 Gy (150 to 400 red) and with fractionated doses of 0.1-2
Gy (10 to 200 red), and (2) permanent sterility occurs with single doses rang-
ing from 5 to 9.5 Gy (500 to 950 red) and with fractionated doses of 2-6 Gy
(200-600 red).
47
A person may have transient sterility for a matter of years before fertility
returns. Five individuals who received doses of 2.3-3.7 Gy (230-370 red) in the
Oak Ridge criticality accident were aspermic for 4 months and hypospermic for
21 months; at least one individual experienced "sterility" for several years, but
the individual subsequently had a normal offspring (Andrews et al., 1980~.
Ortin et al. (1990) have reviewed data on 148 boys treated for Hodgkin's
disease and followed for a median of 9 years. Sexual maturation was achieved in
all boys without the need for androgen replacement. Of eight boys who were
treated with radiation alone, three who received a pelvic dose of 40-45 Gy
(4,000~,500 red) were able to father children. Three others who received 30-
44 Gy (3,000 - ,400 red) of pelvic radiation were oligospermic. This was in
contrast to an 83% incidence of absolute azospermia in boys treated with chemo-
therapy and no pelvic radiation. Patients who have received whole body irradia-
tion before bone marrow transplantation have been studied by Sanders et al.
(1986) and Deeg et al. (1984), who report that gonadal failure occurred in almost
all boys who were postpubertal at the time of irradiation.
Radionuclide Irradiation
Irradiation of the testes by radionuclides may result from internal or external
exposure. In the case of energetic beta radiation, the germ cells may be irradi-
ated by external radionuclides. Although there may be internal deposition of
radionuclides such as cesium, few data on the human sperm count or sterility are
available. Although some radionuclides are known to be preferentially deposited
in specific organs or tissues, such as radioiodine in the thyroid or strontium in
bone, no radionuclide is known that is preferentially deposited in the testes.
SPONTANEOUS ABORTIONS
The World Health Organization (1970) has defined spontaneous abortion as
"the non-deliberate interruption of intra-uterine pregnancy before 28 weeks
(LMP) in which the embryo or fetus is dead when delivered." However, in many
technically developed countries 22 weeks of gestational age separates spontane-
ous abortion from stillbirth (Bracken, 19841.
Spontaneous abortions occur much more frequently in early pregnancy, with
most thought to occur before pregnancy is recognized. Spontaneous abortion
rates as high as 80% of all conceptions have been suggested, but the most widely
cited rates are 30-35% (Wilcox et al., 19881. Of clinically recognized pregnan-
cies, approximately 15% will spontaneously abort. Second-trimester spontane-
ous abortion occurs in 1-3% of all pregnancies.
OCR for page 48
48
AD VERSE REPRODUCTI HE OUTCOMES
There is considerable heterogeneity of spontaneous abortion that varies by
the gestational age of pregnancy. As many as 95% of very early abortions are of
congenitally malformed embryos and a large proportion of these have chromo-
somal abnormalities. Of the clinically recognized pregnancies that spontane-
ously abort, 65% are chromosomally abnormal and include fetuses with devel-
opmental anomalies.
The risk of spontaneous abortion is higher with increased gravidity, and this
may relate to such maternal factors as retroversion of the uterus, fibroids, pro-
lapsed uterus, cervical erosion, and uterine incompetence. A septate or bicornate
uterus will also increase the risk of spontaneous abortion. There is a reoccur-
rence rate of about 1.6% which is found for abortions of both euploid and ane-
uploid fetuses. Repeat spontaneous abortion (sometimes called habitual abor-
tion) has also been shown to relate to both very early or very late age of first
menstrual cycle.
Other known or suspected maternal risk factors for spontaneous abortion are
maternal smoking, which primarily increases the risk of abortion of euploid fe-
tuses; maternal alcohol use; occupational exposure to lead, vinyl chloride, and
solvents; exposure to antineoplastic drugs; cocaine use; and heavy maternal caf-
feine use. Maternal infection with malaria, rubella, rubeola, herpes virus, cy-
tomegalovirus, and genital mycoplasmas has been associated with an increased
risk of spontaneous abortion. Recent use of oral contraceptives or a diaphragm
has been related to a decreased spontaneous abortion risk. The frequency of
spontaneous abortion was studied in atomic bomb survivors, but the data were
internally inconsistent (Neel and Schull, 1991~.
PRETER1\I DELIVERY
Preterm delivery is a major cause of neonatal morbidity and mortality.
Traditionally, prematurity was defined as birth weight of less than or equal to
2,500 g. Today, a distinction is made between low birth weight births and pre-
term births. Low birth weight characterizes an infant who weighs less than 2,500
g (5 pounds 8 ounces) at birth, and preterm refers to a birth that occurs at a ges-
tational age of less than 37 completed weeks (<259 days). The rate of preterm
delivery in the United States is approximately 10% (Berkowitz and Papiernik,
19931. The rate has varied only slightly between 9 and 10% since 1970.
Established maternal risk factors for preterm birth include African-American
race, single marital status, low socioeconomic status (SES), previous low birth
weight or preterm delivery, multiple second-trimester abortions, cigarette smok-
ing, in vitro fertilization pregnancy, and such gynecologic or obstetrical compli-
cations as in utero diethylstilbestrol exposure, cervical and uterine anomalies,
gestational bleeding, and placental abnormalities. In addition, urogenital infec-
tions, cocaine use, and no or inadequate prenatal care are probably associated
with preterm delivery. Other factors such as age, parity, and maternal weight
gain appear to be weakly associated or not associated with preterm delivery.
OCR for page 49
ADVERSE REPRODUCTIVE OUTCOMES
49
Still, the association remains inconclusive for other factors such as low prepreg-
nancy weight, physical activity, and psychological stress (Berkowitz and Pa-
piernik, 19931. The frequency of congenital malformations is higher in preterm
than in full-term pregnancies (Placek, 1977; Hartikainen-Sorri and Sorri, 1989~.
Standing for long periods of time at work (Teitelman et al., 1990) and a history
of asthma and bronchodilator use during pregnancy have also been implicated as
risk factors for preterm delivery (Doucette and Bracken, 1993~. A short interval
between pregnancies has recently been reported to be a possible risk factor for
delivery of a preterm, low birth weight infant and, potentially, as an important
explanatory factor for the racial disparity in adverse pregnancy outcomes
(Rawlings et al., 19951.
Neither paternal nor maternal exposure to low dose radiation is considered
to be a risk factor for preterm birth. There are reports that the number of pre-
term births in the seventh to eighth month were increased in contaminated areas
shortly after the Chernobyl nuclear power plant accident in 1986 (IAEA, 1991~.
However, it is not clear to what extent this may have been due to such factors as
maternal nutrition, stress, cigarette smoking, and alcohol consumption. No ef-
fect of parental irradiation on mean birth weight could be demonstrated in survi-
vors of the atomic bombs at Hiroshima and Nagasaki (Neel and Schull, 1991~.
STILLBIRTHS AND NEONATAL DEATHS
(PERINATAL DEATHS)
Stillbirth is widely accepted to be a fetal death occurring at 28 weeks of
gestation or later (from the last menstrual period ELMP]~. Because both stillbirth
and early neonatal death (under 7 days of age) share in a number of causes,
which are themselves somewhat different from causes of death in older neonates,
the term "perinatal death" is often used to refer to both of them. In 1977, the
World Health Organization recommended including all infants weighing at least
500 g or, if the birth weight is unavailable, infants delivered at 22 or more weeks
of gestation as stillbirths. Occasionally, all deaths of infants delivered at 16
weeks or more of gestation are included as stillbirths.
Perinatal (neonatal) mortality rate is typically measured as the number of
deaths occurring within the first 28 days of life per 100,000 live births. Neonatal
mortality has declined substantially in the past 50 years. In the United States in
1992, neonatal death rates were 537.5 per 100,000 live births; however this dif-
fered significantly among black and white infants (rates of 1,083.1 per 100,000 live
births and 434.6 per 100,000 live births, respectively) (DHHS, 1995~.
The higher perinatal (neonatal) mortality rate (PMR) is seen in lower socio-
economic (SES) groups, but it is difficult to disentangle the behavioral, social,
and environmental factors that correlate with socioeconomic class. PMR is
consistently higher in unmarried women and women who smoke, and PMR de-
creases with parity. PMR increases with maternal age and variety of maternal
diseases; including diabetes, blood group incompatibility, uterine infections,
renal disease, and preeclampsia. Pregnancy complications include placenta pre
OCR for page 50
so
ADVERSE REPRODUCTIVE OUTCOMES
via and abruptio, pelvic anomalies, malpresentation, prolonged duration of labor,
uterine rupture, umbilical cord complications, and fetal complications. These
maternal factors are among those that should be taken into account in evaluating
paternal influences on PMR.
Results from the atomic bomb survivors show that high doses had no effects
on PMR (Neel and Schull, 1991), so no effect would be expected at the much
lower doses received by Atomic Veterans.
BIRTH DEFECTS
Conventionally, a birth defect (a congenital malformation) implies a failure
of proper or normal morphologic development. Such failures can vary greatly in
the threat that they pose to an individual's physical and mental integrity and
survival. As a result, it is common to divide malformations into major and minor
malformations although there is no absolute dividing line between these two
classes of defects. Major birth defects include those failures of normal devel-
opment that are incompatible with life (anencephaly, for example), that are seri-
ously life-threatening (such as many congenital heart defects), or that materially
compromise the individual's ability to function effectively in the society of
which he or she is a member (cleft palate). All other birth defects are construed
as minor.
Birth defects, whether major or minor, are often further classified in two
ways: (1) malformations arising from anomalies of a gene or a chromosome and
(2) developmental disorganization occurring in an embryo or fetus with a nor-
mal genotype.
Human Chromosome Abnormalities
Four subtypes of chromosomal abnormalities can be considered on the basis
of whether the affected cell is somatic or germinal and whether the anomaly is
structural or numeric. Many chromosomal abnormalities are incompatible with
embryonic or fetal survival and are never expressed in the human phenotype at
delivery, although some (e.g., trisomy 16) may be relatively common in early
spontaneous abortion.
Table 5 shows the prevalence of the more frequently seen chromoso-
mal abnormalities in individuals born to parents exposed to ionizing radiation at
Hiroshima and Nagasaki and to controls. The data were tabulated by Hook
(1984) and were collected by Awa (for a recent summary of the findings see
Awa et al., 1987, 19889.
The offspring of exposed parents (in = 8,322) and control parents (in =
7,976) who were delivered between May 1946 and December 1984, are being
studied at about age 13 years. This late age at examination screens out many of
the chromosomal anomalies that might incur early mortality, and thus, the data
provide reliable estimates on only two types of chromosomal abnormalities,
OCR for page 51
ADVERSEREPRODUCTIVE OUTCOMES
51
namely, sex chromosome aneuploids and balanced structural rearrangements,
which confer relatively little threat to survival among liveborn infants. The data
presented do not suggest any major differences according to exposure. How-
ever, when the frequency of sex chromosome aneuploidy is examined in the
context of the combined parental gonadal dose, there is a small but statistically
nonsignificant increase in these anomalies with increasing parental dose (Neel et
al., 1990~.
Developmental Abnormalities
Developmental abnormalities can affect any organ, and as a result, there are
several hundred potential diagnostic categories. Early fetal lethality reduces the
number of malformations seen at birth. The most frequent developmental mal-
formations and their prevalence in those under age 1 year are given in Table 6
(Bracken, 1983~. The most commonly observed malformations at birth are of
the ventricular septum of the heart; the majority of malformations occur at rates
of <2 per 1,000 live births (Merlin, 19639. Overall, in some 3% of newborns a
major congenital anomaly will be diagnosed at birth, and an additional 3-5%
will be diagnosed with a major congenital anomaly in the first 10 years of life.
If the Atomic Veterans each fathered an average of two or three children, the
total would be about 500,000 offspring. The rates for birth defects given in Ta-
ble 6 can be used to estimate the numbers of birth defects that would be seen
among these children of Atomic Veterans in the absence of any radiation ef-
fects. For example, spine bifida is routinely observed in 1.4 in 1,000 babies,
which would be 700 among the infants in 500,000 offspring of Atomic Veter-
ans. Among the offspring of Atomic Veterans there would be 5,000 infants with
heart defects, and nearly 600 would be diagnosed with cancer during childhood.
In total, one would expect to find 15,000 infants with major malformations
among the children of Atomic Veterans if the rates among those children were
the same as those in the general population.
A subcategory of malformation, sometimes called Reformational, are those
in organ systems that developed normally but that incurred a secondary deform-
ity. Usually, this is due to intrauterine molding because of oligohydramnios and
physical constraint (examples of these are some types of talipes, congenital hip
dislocation, and midline cleft palate).
OCR for page 52
cd
o
· -
cd
~ -
ce
o
a)
o
x
c~
a'
s~
ct
o
4~
o
m
U:
-
Ct
· _
. _
~_
._
a'
C~
C~
P~
t,V
- o
,~ ~
~0
O ~
~ O
_
Ct ~
c: ·_
O Ce
O
O ~
Z
O
C~
m O
~ .-
V)
e
~o
"S ~
=i=
~ O
C~
._
_
Ct
£
¢
~ ~r~ ~ ~
. .. . . .
_ C~ oo o o ~o°
~ . -, ~-, ~ oo
. . .. . . .
_ C~ o- o o ~o°
.. . .
o ~ oC~ o CM ~
o o
. . . . . . .
o ~ o o o o ~o o
o ~ ~
. . . .
- , _ o ~ o o C~
C)
C~
C)
._
.- C~
_ _
e ~_
~C
C)
s~
o _ ~
~Ct Ct
,= _ -
~ ~ ~ ~ ~
o
£ x ° ~ ~
vo' v, ~ ~ 50
- Ct c~s tC P~ -
a' ~ X X ~ ~ ° V' s: C
~ ~ ~ x ~ e X '~ ~ ° e e ~
OCR for page 53
~ - oo
~ ~ ~ ~ cr~ ~ 0
o o - o o ~o o c~ ~ ~ ~
~ o ~
~ o ~
~ ~ c~ ~c~ ~ ~ ~ - ~
o o o o o -o o ~ ~c~ ~ ~
c~ - )~ ~- ~ ~
o o c~ o o ~o o cN u~ ~ oo
~ - ~
oC ~ ~
=} -} ~ -~ ~ o'^ =~-^
o o o o o c~o o ~ ~- - (~]
~ ~ - ~
. .. . .-
O O O O O -O 0 ~ ~r,_
e
c)
- ~
V
-~
c)
)
, ct
- ~
~oo
`~ n c~
; ~, ~ O D ~ ~ =~ ~- E c: E
7
r_
:^
O
cn
Ct
._
Ct
X
O
V:
C~
C)
._
X
V'
C~
V,
.
:~
C~ _
~ C~
._ rl
~ O ,L,
~ 5 c'
· ~ (~ u
_^ 0 5
$~ O
O _
-S O
ct _
X 5:
cs
~ v' v'
cn O
~ v,
c ~c~
- ~
oo
cr~
-
o
o
o
. -
o
~i
o
OCR for page 54
54
AD VERSE REPRODUCTIVE OUTCOMES
The range of risk factors studied for their effects on developmental malfor-
mations is too large to summarize in any detail here. Several maternal infections
(e.g., rubella, cytomegalovirus, toxoplasma, and herpes virus) have been associ-
ated with an increased risk of malformations and may account for 2% of all mal-
formations. Maternal diabetes is linked to a range of malformations. Numerous
environmental substances have been studied (usually, inadequately) but with
inconclusive results. Lead at relatively high doses is a behavioral teratogen, but
it is not related to physical malformations. Mercury, especially in organic forms
(methyl mercury), has some physical teratogenic properties, but it is primarily a
neurobehavioral teratogen. Maternal alcohol and cocaine use are related to a
range of malformations at moderate levels of exposure. Cigarettes and caffeine
do not appear to be teratogenic at their usual levels of intake. Only a few phar-
maceutical agents have clearly been shown to be teratogenic, including diethyl-
stilbestrol, thalidomide, phenytoin, and some other antiepileptic drugs. Warfarin
and some cytotoxic drugs have also been linked to developmental anomalies.
Nutritional deficiency, particularly folate deficiencies, increases the frequency of
developmental anomalies. These maternal exposures should be excluded in
considering the birth defects attributable to paternal exposures. There was no
evidence of an increased risk of congenital malformations following paternal
exposure to ionizing radiation or in children of atomic bomb survivors (Neel and
Schull, 19911.
MATERNAL ILLNESSES
The committee has interpreted periparturient diseases of the mother as dis-
orders that can cause maternal and neonatal morbidity. Numerous chronic and
pregnancy-related disorders in the mother may affect the mother's and neonate's
health and well-being. These include infections such as cytomegalovirus, herpes
simplex virus, and hepatitis; maternal cardiovascular disease including congeni-
tal and rheumatic heart diseases; hypertensive disorders; pulmonary disorders
such as pneumonia and asthma; diabetes mellitus, including gestational diabetes;
hyper- and hypothyroidism; maternal adrenal gland disorders such as Cushing
syndrome and Addison disease; collagen vascular disease such as systemic lupus
erythematosus; renal diseases such as glomerulonephritis and nephritis; placenta
previa, abruptio placenta, and retained placenta; hematologic disease including
idiopathic thromobocytopenic purpura and Rh incompatibility; myasthenia gra-
vis; and epilepsy and other necrologic diseases. None of these diagnoses, how-
ever, are known to be related to irradiation of either parent.
OCR for page 55
AD VERSE REPRODUCTI HE OUTCOMES
Table 6. Prevalence per 1,000 Live Births of Congenital Malfonnations by
Diagnostic Group from Five Major Hospitals in Connecticut, 1974-1976 and
Expected Prevalence at Birth for a Population of 500,000 NewbomsU
Diagnostic Group
Number per 1,000 Expected Number
(All Diagnosed) Among 500,000 Births
All malformations 57.0128,505
All neoplasms 1.16580
Hemangiomas and lymphangioma 2.061,030
Strabismus 0.87435
Heart block fibrillation, tachycardia 0.33165
Inguinal hernia plus obstruction 7.683,840
Anencephaly 0.41205
Spina bifida 1.40700
Hydrocephaly 1.40700
Eye anomalies 0.54270
Common truncus 0.21105
Transposition of great vessels 0.99495
Tetralogy of Fallot 0.70350
Ventricular septal defect 6.073,035
Atrial septal defect 0.50250
Heart valve 1.73865
Other heart anomalies 0.87435
Total heart anomalies 11.075,535
Patent ductus arteriosus 2.191,095
Coarctation of aorta 0.62310
Single umbilical artery 0.78390
Cleft lip palate 1.86930
Pyloric stenosis 8.014,005
Tracheal-esophageal fistula 0.45225
Other digestive system anomalies 1.69845
Undescended testicles 0.62310
Hypospadias 1.40700
Congenital hydrocele 1.57785
Other genital organ anomalies 1.03515
All talipes 3.301,650
Polysyndactyly 2.191,095
Limb reduction 0.66330
Congenital dislocation of hip 0.99495
Lower limb anomalies 0.21105
Skull and face anomalies 0.62310
Other muscular-skeletal anomalies 1.16580
Skin anomalies 2.621,310
Down syndrome 1.36680
Other autosome anomalies 0.58290
Other unspecified multiple anomalies 1.28640
55
" Data are based on malformations found among 24,224 live births in five Connecticut Hospitals
over a 24-month period.
SOURCE: Modified from Bracken (1983).
OCR for page 56
56
AD VERSE REPRODUCTI VE OUTCOMES
ALTERED SEX RATIO
When studies of the Hiroshima-Nagasaki atomic bomb survivors and their
offspring began, it was believed that a person's gender was determined in a
simple way. Individuals inheriting an X chromosome from their father were
destined to be females, whereas those individuals who inherited a Y chromo-
some from their father would be males. Thus, females would have two X chro-
mosomes and males would have only one. These notions suggested, in turn, that
when mutations in genes on the X chromosome induced by ionizing radiation are
incompatible with survival (are lethal), their expression would be manifested
differently in the two genders. More specifically, since a father normally
transmits his single X chromosome to his daughters, if a lethal mutation were
present on the X chromosome in the father's sperm, it could find expression only
in his daughters. On the other hand, since mothers transmit their X chromo-
somes equally to their sons and daughters, a lethal mutation might be expressed
in either sex. If the mutation was dominant, the two sexes would be affected
equally often; however, if the mutation was recessive, since the male has only
one X chromosome, it would invariably manifest itself in males, but in females
manifestation of the new mutant would occur only if the second X chromosome
fortuitously carried a functionally similar gene.
From this rationale the likelihood of a mutation increases as the dose in-
creases. If the father were exposed, more female embryos would be lost, and the
sex ratio (males/females) at birth would rise in proportion to dose. If the mother
was exposed, more male embryos would be lost, and the sex ratio at birth would
fall in proportion to dose. If both parents were exposed? the resulting sex ratio
-or proportion of male births would be related to the individual parental doses
and the frequency of dominant versus recessive lethal mutations. As can be
seen, this theory of sex determination made fairly specific predictions that could
be compared with the actual observations that were accumulating in survivors of
the Hiroshima and Nagasaki atomic bombs.
When the data from the years 1948 through 1953 were examined, it ap-
peared that the proportion of male births, in fact, declined with dose when the
mother was exposed and increased, albeit modestly, with increasing paternal
dose (Schull and Neel, 1958~. The rate of change with dose was not, however,
statistically significant, although it was in the direction predicted by the theory
outlined above. For this reason, when the clinical phase of the studies ended,
data on the sex ratio continued to be collected on the supposition that the rate of
change might become statistically significant with further information. To this
end, observations of the frequency of male births were continued through 1966.
However, when these additional observations were analyzed, the results did not
support the earlier findings; indeed, the modest changes seen were opposite
those predicted by theory (Schull et al., 1966~.
Today, the earlier understanding of sex determination is known to have been
overly simplistic. First, it did not take into account the occurrence of X chromo
OCR for page 57
AD VERSE REPRODUCTI HE OUTCOMES
57
some aneuploids, as in the Klinefelter and Turner syndromes, which make the
predictions less precise. The first of these aneuploids was discovered in 1959 (in
unrelated studies), and soon thereafter many others were identified. As a result
of these discoveries, it is known that it is possible for some females to have only
one X chromosome (or even as many as five X chromosomes), and for some
males to have two or more X chromosomes. Moreover, these individuals with
abnormal numbers of X chromosomes are more frequent in most populations
than one would expect following exposure to ionizing radiation, at least at low
doses. Second, it is now known that in females only one of the two X chromo-
somes within a cell is functionally active. This inactivation of one of the X
chromosomes makes the prediction of the behavior of a potentially lethal gene
on the X chromosome more difficult, particularly if the inactivation is not ran-
dom (and it does not appear to be random). Given these developments, the sim-
ple, early arguments are much less compelling, and prediction of the effects of
lethal mutations on the proportion of male births more tenuous. Thus, the sex
ratio is no longer considered useful in estimating of genetic risks following ex
. . . . .
posure to Ionizing radiation.
MORTALITY AMONG THE CHILDREN OF
EXPOSED PARENTS
The largest study by far of the effects of parental exposure to ionizing ra-
diation on mortality among their children conceived subsequent to irradiation is
the study of the offspring of the atomic bomb survivors. That study involves the
surveillance of approximately 72,000 children born alive between May 1946 and
December 1984. It includes individuals whose parents were exposed at a wide
variety of ages and doses. Surveillance of a cohort of this size is possible in Ja-
pan because of the existence of a unique record resource. Since the latter part of
the 19th century, the Japanese government has maintained an obligatory system
of household censuses, known as the koseki. These censuses, which are under
the jurisdiction of the Japanese Ministry of Justice, incorporate information on
all events that affect the composition of a family, such as birth, death, adoption,
and marriage. It is thus possible to determine the life status of an individual
wherever that individual may reside in Japan if the location of the individual's
household record is known.
Customarily, on a cyclic basis, the koseki of the cohort are inspected anew
to identify deaths that may have occurred since the last review cycle. If an indi-
vidual has died, it is possible to obtain a copy of the death certificate and deter-
mine the stated primary cause of death and secondary contributors through the
regional health centers of the Ministry of Health and Welfare. Follow-up is vir-
tually complete; the vital status of more than 99% of individuals in the cohort
can be determined. On those rare occasions when vital status cannot be deter-
mined, it is usually because of the migration of the individual to another country.
OCR for page 58
58
ADVERSE REPRODUCTIVE OUTCOMES
Insofar as malignant tumors are concerned, the mortality data are supplemented
with information in the tumor registries maintained by the Medical Associations
of Hiroshima and Nagasaki with the assistance of the Radiation Effects Research
Foundation. These registries date from 1957 (Hiroshima) and 1958 (Nagasaki).
The causes of death or incident cases are routinely coded by using the current
International Classification of Disease and the International Classification of
Cancer of 1976.
The first summarization of the mortality data occurred in 1966, and since
then other publications have appeared, the most recent being in 1991
(Yoshimoto et al., 1991~. At that time, the age of the average living member of
the cohort was 28.8 years, and some 80% had completed their nineteenth year of
life. The average dose received by the parents, father and mother combined, was
430 mSv (43 rem) on the basis of a neutron of 20 radiobiological effectiveness
(RBE). It should be noted that the assumption of an RBE of 20 is not critical to
what follows since the results described here are not materially affected by the
choice of any other RBE between 1 and 20. Deaths were divided into those at-
tributable to cancer and those attributable to other causes. Emphasis in the
analysis of these data was placed on the 67,586 liveborn children when the pa-
rental doses could be computed by using the DS86 system (Shimizu et al., 1992)
of dosimetry; however, a second analysis was based on all 72,228 children. That
analysis used imputed doses received by the parents of the 4,642 children for
whom direct calculation of the parental DS86 dose was not possible. The two
analyses did not differ appreciably in their results.
Briefly, the findings were as follows. With regard to cancer, among the
26,894 liveborn children whose parents received DS86 doses of 10 mSv (1 rem)
or more, there were 40 cases of cancer (1.5 per 1,000 births) and 14 instances of
benign or unspecified tumors (0.5 per 1,000 births), and among the 40,692 chil-
dren whose parents were not exposed or who were exposed to less than 10 mSv
Sv (1 rem), there were 75 cases of cancer (1.8 per 1,000 births) and, again, 14
cases of benign or unspecified tumors (0.3 per 1,000 births) (Yoshimoto et al.,
1991; see also Yoshimoto et al., 1990~. Statistical analyses revealed no signifi-
cant increase in the frequency of cancer deaths (cases) with increasing parental
dose either for all cancers combined or for leukemia, the most common of the
childhood cancers, which were considered separately. This was also true when
the data were restricted to those individuals whose fathers alone were exposed.
However, examination of the data suggested that only 3-5% of the tumors of
childhood that were observed are associated with an inherited genetic predispo-
sition that would be expected to exhibit an altered frequency if the parental mu-
tation rate were increased. In other words, the mutational component was small.
With regard to causes of death other than cancer, 3,709 deaths occurred
among the 67,586 individuals in the cohort with known parental DS86 doses
(54.9 per 1,000 births). Again, the frequency of such deaths did not increase in a
statistically significant manner with increasing parental dose. This was also true
OCR for page 59
AD VERSE REPRODUCTI HE OUTCOMES
59
for four major disease categories, namely, infectious and parasitic diseases, dis-
eases of the respiratory system, diseases of the digestive system, and certain
conditions originating in the perinatal period. However, if the data on all dis-
eases except neoplasms are taken at face value, there is a small but nonstatisti-
cally significant excess relative risk with increasing dose. If this excess relative
risk of 0.038 per Sv (per 100 rem) for death by age 20 is accepted as real and not
ascribable to chance, the increased risk of death per 0.01 Sv (per 1 rem) is
0.00038. To the extent that these values are applicable to the U.S. population,
they imply that in 1983 when the probability of a liveborn child dying by age 20
in the general U.S. population was 0.0200, if the father had been exposed to 100
mSv (10 rem) this probability would be about 0.0238 (National Center for
Health Statistics, 1986~. Put somewhat differently, in 1983, when two individu-
als in every 100 live births would have been expected to die by their twentieth
year of life, if the father had been exposed to 100 mSv (10 rem), the number of
expected deaths would be about 2.4. This increase is too small to be within the
resolving power of present epidemiologic studies.
CANCER AND LEUKEMIA IN PARTICULAR
U.S., Japanese, Russian, and Italian scientists have reported transgenera-
tional cancer in the mouse or rat after exposure of the parent either in utero or
before mating to carcinogenic chemicals or ionizing radiation (reviewed by To-
matis, 19941. Several years ago a report in the British media of an excess num-
ber of cases of childhood leukemia in the village of Seascale near the Sellafield
nuclear facility in West Cumbria, prompted a more careful case-control study to
ascertain whether this alleged excess could be explained. The findings of the
resulting study by Martin Gardner and colleagues supported the earlier allegation
(Gardner et al., 1990 a, b; Gardner, 1992~. These investigators suggested that the
excess was due to the relatively high doses received occupationally by the fa-
thers of the patients. More specifically, they argued that paternal preconception
exposure, in particular, exposure in the six months immediately prior to the con-
ception of a child, induced mutations in sperm that resulted in the offspring de-
veloping leukemia. Their findings stimulated a number of other studies aimed at
confirming, if possible, their findings.
Little or no support for the hypothesis that paternal exposure leads to an ex-
cess risk of childhood leukemia has been found in studies carried out in the
United States (Jablon et al., 1991), France (Hill and Laplanche, 1990), Germany
(Michaelis et al., 1992), and Canada (McLaughlin et al., 19931. Moreover, the
findings among children at Sellafield were significantly at variance with those
among the children of the atomic bomb survivors (Little, 1990, 1991, 19921. A
further complication in the acceptance of the findings and hypothesis of Gardner
and colleagues has been the finding of similarly raised levels of leukemia around
potential nuclear facilities in Britain (Cook-Mozaffari et al., 1989) and Germany
OCR for page 60
60
ADVERSE REPRODUCTIVE OUTCOMES
(Michaelis et al., 19921. This illustrates anew the difficulties inherent in attempt-
ing to interpret any cluster of cases. Nonetheless, the issue remains contentious,
and at least one other multi-institutional case-control study has reported findings
that suggest an increased risk of infant leukemia among the children of fathers
exposed to diagnostic X rays prior to the conception of the child (Shu et al.,
1994~. That study, however, could not confirm the effect of maternal exposure
prior to conception that had been reported by Bithell and Stewart (1975), nor did
its design permit the assessment of the dose-response relationship for exposed
fathers.
IMMUNE DEFICIENCY
Various genetic abnormalities cause severe immunologic deficiencies in the
offspring, and these deficiencies predispose them to infection and non-Hodgkin's
lymphoma. Among these diseases are congenital agarnmaglobulinemia, ataxia-
telangiectasia, Wiskott-Aldrich syndrome, Bloom syndrome, and Chediak-
Higashi syndrome (Seibel et al., 19931. An excess of such syndromes, infections,
or lymphomas has not been observed as causes of mortality in the F. generation
among survivors of the · atomic bomb blasts in Hiroshima and Nagasaki
(Yoshimoto et al., 19911.
NEUROLOGIC DEFICIT, INCLUDING
MENTAL RETARDATION
Definitions of the terms "necrologic deficit" and "mental retardation" vary
widely. This is perhaps inevitable when there is a continuum of intellectual or
necrologic potentials. Still, it complicates the comparison and integration of the
findings from different studies when the definition has not been the same among
studies. For example, among the survivors exposed in utero to the atomic
bombing of Hiroshima and Nagasaki, an individual was considered to be se-
verely mentally retarded if he or she was unable to form coherent sentences, to
perform simple arithmetic tasks, or to manage his or her own affairs or was insti-
tutionalized. The World Health Organization restricts the term "severe mental
retardation" to those individuals with an IQ of less than 50; individuals with IQs
in the range of 50 to 70 are described as mildly retarded.
Diagnosis of mental subnormality may rest on the clinical experience of the
examining physician, on structured tests of mental performance, or commonly,
on both. The frequency of the diagnosis depends on the severity of the handicap
and the age, at least through the school years, at which the individual is exam-
ined (Gesell and Amatruda, 19751. Subtle limitations of mental performance
that are readily recognizable in the pubertal child may be very difficult to diag-
nose in a newborn. This difference is well illustrated by the findings of the Col-
laborative Perinatal Project conducted by the National Institute of Neurological
OCR for page 61
AD VERSE REPRODUCTI VE OUTCOMES
61
Diseases and Stroke. That study, which began on January 1, 1959, and ceased
registration in December 1965, involved 15 university-affiliated medical centers
and led to the study of 55,908 pregnancies (DHEW, 1973~. Although the study
had a number of objectives, one of the major aims, as initially stated, was to
"determine the relationship between factors in the perinatal environment and the
continuum of human reproductive failure, with particular reference to the central
nervous system for: (a) early manifestation of deficits (infancy and early child-
hood), and (b) later manifestations of deficits (5 to 15 years)."
Although this study remains one of the better sources of information on the
frequency of congenital malformations, including necrologic deficits, available
for the population of the United States, it also illustrates that, since a necrologic
handicap is not a single disease entity and the potential causes of a deficit are
many, it can be extremely difficult to recognize the cause in a specific instance
It is known that inherited gene and chromosomal defects, as in Down syndrome
or the fragile X syndrome, can lead to the occurrence of mental retardation, but
attempts to estimate the contribution that genetic factors make to the overall fre-
quency of mental retardation have generally been unsatisfactory. Most instances
of mental retardation are idiopathic; that is, they have no clear identifiable cause.
The situation is different, however, with respect to the exposure of a preg-
nant woman to noxious agents, particularly early in her pregnancy, when unto-
ward effects on the mental development of the child have been demonstrated
Among those agents for which the evidence is most persuasive are ionizing ra-
diation, methyl-mercury, lead, and alcohol. The effects of exposure in these
instances can manifest themselves in a variety of ways: a possible increase in the
frequency of overt mental retardation, a loss in performance on standard intelli-
gence tests, and poorer performance in school. The findings, particularly with
respect to ionizing radiation, have been reviewed in some detail in the 1993 re-
port of the United Nations' Scientific Committee on the Effects of Atomic Ra-
diation (UNSCEAR, 19931. These effects are not genetic in origin, although the
possibility that individuals may differ in their sensitivities to noxious agents for
genetic reasons cannot be rejected. The effects stem from the exposure of the
developing embryo or fetus itself to the noxious agent at vulnerable stages in its
development.
Unfortunately, little evidence dealing with the risk of mental retardation
among infants conceived following parental exposure to ionizing radiation is
available. Clinical studies of the children of the atomic bomb survivors con-
ceived after the exposure did not extend beyond the 10th month following birth
and thus provide limited information. The data that are available from the study
of atomic bomb survivors fail to demonstrate an increased risk of any form of
mental retardation, including an increased risk of Down syndrome.
Representative terms from entire chapter:
adverse reproductive
