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Teratology and Radiation

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					              Human Reproductive Biology 316 Investigative Review:
                          Teratology and Radiation
                                   Zillan Neiron – 10311899



The word ‘teratogen refers to any agent that causes a structural abnormality following fetal
exposure during pregnancy’ (University of South Dakota). Teratogens can either discontinue
the pregnancy or produce a congenital malformation by disturbing the development of the
fetus or embryo (MedicineNet 2004). Radiation is a type of teratogen. We are subjected to
radiation exposure everywhere; though it may not be harmful to us in small doses there is
direct evidence to suggest that the developing embryo/fetus is radiosensitive and there is a
critical period that should be avoided. Therefore radiation exposure to a pregnant woman
should be avoided at all cost to decrease the effects of prenatal death, congenital
malformations, microcephaly and possibly cancer in later life of the embryo/fetus. The atomic
bombs dropped on Hiroshima and Nagasaki in Japan in 1945 demonstrates the harmful effects
of massive radiation exposure in utero. Chernobyl is another case where huge amounts of
radiation have come into contact with humans, which had deadly effects on thousands of
people in close by European countries. Today people have medical examinations using X-rays
and CT scans that utilize radiation; it is of concern especially to pregnant women how it will
affect them and their developing child. There is evidence to indicate that no harm will come to
the embryo/fetus from these examinations due to their low levels of radiation, however once
the dose increases, the risks increase.


Many teratogenic agents as well as different types exist such as infectious agents, physical
agents, maternal health factors, environmental compounds and drugs (University of South
Dakota). Infectious agents include viruses and bacteria such as rubella, cytomegalovirus,
varicella, herpes simplex, toxoplasma and syphilis (University of South Dakota). Physical
agents include ionizing agents and hyperthermia (University of South Dakota). Maternal
health factors include diabetes, maternal PKU environmental chemicals (organic mercury
compounds, polychlorinated biphenyl or PCB, herbicides and industrial solvents); and drugs
(prescription, over- the-counter, recreational) (University of South Dakota). The
advancements made in technology and the introduction, hence the use of new synthetic
chemical compounds have increased the amount of teratogens in the environment (University
of South Dakota). It is possible that the clinical recognition of subtle malformations as
teratogenic effects may have increased therefore we see more teratogens around us today
(University of South Dakota). Fetal alcohol syndrome, fetal hydantoin syndrome, fetal
trimethadione syndrome, fetal warfarin syndrome and smoking associated with low birth
weight infants are examples of the clinically recognized malformations that have appeared in
recent years (University of South Dakota).


Congenital Malformations:
Congenital malformations are anatomical defects or chromosomal abnormalities that are
present at birth (National Perinatal Statistics Unit 2004). Major congenital abnormalities are
lethal or significantly affect the individual’s function or appearance (National Perinatal
Statistics Unit 2004). Severe congenital malformations occur in 3% of births, which include
birth defects that cause death, hospitalization, mental retardation, and the requirement for
significant or repeated surgical procedures, are disfiguring or interfere with physical
performance (Brent 2004). In the US 120,000 newborns are born with a severe birth defect
annually (Brent 2004). The type or severity of an abnormality caused by a teratogenic agent is
dependent on the genotype of the pregnant woman and the genotype of the fetus to some
degree (University of South Dakota). The genetic susceptibility of the fetus to a particular
teratogen will have an effect on the final outcome (University of South Dakota). For example
chronic alcoholic mothers have a 45% chance of having an infant with fetal alcohol syndrome
and 90% of phocomelia patients have a history of thalidomide exposure in utero (University
of South Dakota); this demonstrates the effect the mother’s body and what she is exposed to
has on the developing embryo/fetus.


In the 1960s pregnant women in Europe and Canada used the drug Thalidomide to treat
morning sickness (CERHR 2002). Women who took the drug early during pregnancy gave
birth to children with severe birth defects such as missing or shortened limbs (CERHR 2002).
After the births were observed and it was recognized that Thalidomide was causing the
defects the drug was banned (CERHR 2002). More than 10,000 children were born with
major defects as a result of their mothers taking Thalidomide, the defects included missing
arms and legs if the mothers had taken the drug early on in pregnancy (CERHR 2002).
However mothers who had taken the drug later on in pregnancy when the arms and legs had
already started to form, gave birth to children with their limbs present but with some
deformities (CERHR 2002). One of the most common patterns of limb deformities as a result
of Thalidomide is a condition called phocomelia, where the arms are not present, and the
hands extend from the shoulders (CERHR 2002). Other malformations resulted apart from the
limbs due to the drug, such as malformations of the eyes and ears, heart, genitals, kidneys,
digestive tract (including the lips and mouth), and nervous system (CERHR 2002). Just a
single dose of thalidomide during early pregnancy had the ability to cause major birth defects
(CERHR 2002).


X-irradiation and Prenatal Radiation Exposure:
Radiation is energy that travels in waves and is present in two forms, non-ionzing radiation
and ionizing radiation. Ionizing radiation is the type that is given off by the nucleus of an
unstable atom in the process of decaying and reaching a stable state (EWG Action Fund
Report II Nuclear Relicensing 2005). Ionizing radiation is the type that can be released in an
accident involving high-level nuclear waste and can break molecular bonds, causing
unpredictable chemical reactions, including genetic mutations (EWG Action Fund Report II
Nuclear Relicensing 2005).


Wilhelm Conrad Röntgen discovered X-irradiation in 1895 and within a year of its discovery
X-rays was put to medical use (Kalter 2003). After World War I the availability of the X-
irradiation for therapeutics gained popularity, and the procedure was administered to many
women, pregnant and non-pregnant (Kalter 2003). The treatment was used for different types
of gynaecological disorders including cervical carcinoma (Kalter 2003). At the beginning of
the 1920s and throughout the decade many irradiated women had reported abnormalities in
their children, especially small head circumference, or microcephaly (Kalter 2003). Research
conducted learned of 625 women who had been exposed to therapeutic pelvic radium therapy
and found that irradiation after conception had possible serious outcomes such as stillbirth,
infant death and congenital abnormality (Kalter 2003). It was therefore shown that prenatal
maternal irradiation had caused a gross anomaly (Kalter 2003). Reviewing the data it had
been discovered that about 70% of the microcephalic children were exposed before the fifth
month of pregnancy (Kalter 2003). The microcephaly was present at birth in one third of the
affected children and became apparent in the other children over a period of 3 months to 12
years of age (Kalter 2003).


Prenatal radiation exposure can occur when the mother’s abdomen is exposed to radiation
from outside her body (Centers for Disease Control and Prevention 2005). Pregnant women
may accidentally swallow or breathe in radioactive materials that have the ability to absorb
into her bloodstream and the potential to cause prenatal radiation exposure (Centers for
Disease Control and Prevention 2005). This occurs as the radioactive materials are able to
cross the maternal blood and enter the fetal blood, or may pass through the umbilical cord
exposing the fetus to radiation (Centers for Disease Control and Prevention 2005). The
possibility of severe health effects depends on the gestational age of the neonate at the time of
exposure as well as the amount of radiation it is exposed to (Centers for Disease Control and
Prevention 2005). The most sensitive stage of pregnancy to radiation is during their early
development between weeks 2-15 of gestation (the first trimester) (Centers for Disease
Control and Prevention 2005). Health consequences that may develop, even at radiation doses
too low to make the mother ill include stunted growth, deformities, abnormal brain function
or cancer that may develop later on in the child’s life (Centers for Disease Control and
Prevention 2005). Due to the fact that the fetus is protected by the mother’s womb the fetus
receives a lower dose of the radiation than the dose the mother receives (Centers for Disease
Control and Prevention 2005).


The first trimester of pregnancy is a particularly critical period, except for the first ten days
after the onset of the menstrual period when there is no risk to the conceptus (Jumah 1992).
During the first two weeks of pregnancy the radiation health effect of greatest concern is the
death of the embryo (Centers for Disease Control and Prevention 2005). During this period
the embryo is only made of a few cells, hence damage to one cell can cause death of the
embryo. Conversely most embryos that survive exposure will not have any birth defects
regardless of the dose of radiation they are exposed to (Centers for Disease Control and
Prevention 2005). For the duration of the more sensitive stages of development, between
weeks 2-15, large radiation doses can cause birth defects especially to the brain (Centers for
Disease Control and Prevention 2005). During this period the cells are quickly dividing and
developing into different types of tissues and organs. Between birth and the 16th week of
gestation, radiation induced health effects are unlikely unless the fetus receives extremely
large doses of radiation (Centers for Disease Control and Prevention 2005). At such high
doses it is possible for the mother to show signs of acute radiation syndrome, also referred as
radiation sickness (Centers for Disease Control and Prevention 2005). After the 26th week of
pregnancy, the fetus is completely developed however not completely grown and therefore
birth defects are unlikely to occur, only a slight increase risk of developing cancer later on in
life is expected (Centers for Disease Control and Prevention 2005).


At week six the developing fetus has a primitive beating heart, and its head, mouth, liver and
intestines begin to take shape (WPRC org.). By week 10 the fetus is about an inch in length.
Its facial features have started to form in addition to its limbs, its hands, feet, fingers and toes
become apparent. At this stage the nervous system is responsive and many of the internal
organs begin to function (WPRC org.). The first trimester is when the fetus is the most
vulnerable, by the second trimester all of its major organs have already developed, therefore
there is less of a risk for developing deformities in the second and third trimester of
pregnancy. Due to a lack of knowledge about radiation, congenital malformation and fetal
death pregnant women opt for an abortion as they panic about the idea of having a malformed
child. Research has found that prenatal dose from properly performed diagnostic procedures
does not increase the risk of prenatal death, malformation or impairment of mental
development (Unlubay & Bilaloglu 2003). Fetal doses below 50 milligray (mGy) should not
be considered a reason for aborting pregnancy, therefore it is important to understand that for
example a low dose procedure such as a chest X-ray does not cause harm to the fetus
(Unlubay & Bilaloglu 2003). However according to Kusama and Ota (2002), fetal doses
below 100mGy are not considered a reason to terminate. The threshold doses for fetal death,
malformations and mental retardation are reported to be 100-200 mGy or higher (Kusama &
Ota 2002). During the period from 8-25 weeks after conception, the central nervous system is
particularly sensitive to radiation and hence fetal doses above 100mGy can result in a
decrease in IQ (Kal & Struikmans 2002). Between 8-15 weeks after conception, a fetal dose
of 1000mGy reduces IQ by about 30 points, however this reduction is less during the 16-25
week period (Kal & Struikmans 2002). At this high dose during the period from 8-15 weeks
after conception the risk of severe mental retardation is around 40% (Kal & Struikmans
2002). Risk estimates for fatal cancer risk for ages 0-15 years after in utero irradiation are
about 6% per Gy (0.06% per 10mGy) (Kal & Struikmans 2002). It is of concern that
preconception irradiation of either parents’ gonads will have an effect on future
embryos/fetuses, as it is believed that the radiation can alter germ cells. Though gonadal
radiation has not been proven to result in an increase in cancer or malformations in children
(Kal & Struikmans 2002).


Recently other sources of radiation have been suspected of being teratogenic. These include
electromagnetic fields for example heated waterbeds, electric blankets and appliances, ceiling
heating coils, video display terminal and medical diagnostic procedures (Kalter 2003). Other
suspected teratogenic radiation sources are fetal ultrasound, microwave ovens, irradiated food,
high-voltage power lines, atomic power plants accidents (for example the Chernobyl nuclear
reactor accident), nuclear weapons tests (Kalter 2003). However none of them have been
proven to be a human teratogen (Kalter 2003).


Radiation Effect on Parental Genes and Germ Cells:
Inherited genes from both parents can spontaneous mutate in the fetus as a result of radiation
exposure (Hanford Health Information Network 1994). Two types of radiation induced
mutations may occur, germline and somatic (Hanford Health Information Network 1994). A
germline mutation, or inheritable genetic effect arises when the DNA of a gamete is damaged
(Hanford Health Information Network 1994). Damage of the gametes in this fashion may
cause health problems including miscarriages, stillbirths, congenital defects, premature death,
chromosomal abnormalities and cancer in later life. A somatic mutation is not inheritable but
rather a mutation that occurs when the DNA of a non-reproductive cell is damaged (Hanford
Health Information Network 1994). Radiation induced somatic mutations also may cause
health problems but only affect the exposed individual (Hanford Health Information Network
1994). A birth defect can arise from either mother or father’s exposure before conception, for
example if a male with a defected sex cell fertilizes a female’s ovum it may result in an
acquired birth defect in the child (Hanford Health Information Network 1994). Birth defects
may also arise if the child was exposed to radiation in utero (Hanford Health Information
Network 1994). Male and female germ cells differ in their sensitivity to the mutagenic effects
of radiotherapy (a technique used to treat cancer patients), depending on their stage of
maturation as well as the agent used (Arnon et al. 2001). Though sperm DNA damage may
occur after treatment, no increase in genetic defects or congenital malformations was detected
among children conceived to parents who have undergone previous radiotherapy (Arnon et al.
2001). When radiation affects germ cells, mutations can occur at the gene level or the
chromosome level, however mutations at the gene level may not appear for several
generations (EWG Action Fund Report II Nuclear Relicensing 2005). Chromosomal
mutations can result in more profound and immediate changes (EWG Action Fund Report II
Nuclear Relicensing 2005). On the other hand Jacquet (2004) only found that ionizing
radiation could induce DNA damage in the germ cells of laboratory animals leading to
deleterious effects in their progeny, however there was no clear evidence to suggest that the
effects of exposure has been found in people exposed to radiation. The risks of hereditary
effects of any kind resulting from parental exposure to low doses of radiation remain low
(Jacquet 2004).


Diagnostic Radiation and CT scans:
Ionizing radiation is a potential hazard to the developing fetus; hence avoiding unnecessary
radiation exposure to pregnant women is of standard medical procedure ((Miller & Phil 2004)
and Phil 2004). Ultrasound examinations are preferred for establishing fetal maturation,
placental localization and fetal viability, which is safer as this procedure does not utilize
ionizing radiation (Jumah 1992). There are about 65 million Computer Tomography (CT)
examinations, which uses special X-ray equipment to obtain image data from different angles
of the body, performed in the US every year ((Miller & Phil 2004) and Phil 2004). The CT
examinations contributes to more than two thirds of the total medically related radiation
exposure to patients and results in a higher dose than many of the other nuclear imaging
procedures ((Miller & Phil 2004) and Phil 2004). The question is whether the radiation
exposure due to the CT scan is of concern or not to the developing fetus. For a pelvis CT scan
where the uterus is in the direct pathway of the X-ray beam, the absorbed doses to the embryo
is about 20-80 mGy and to the fetus around 10-20mGy (Kusama & Ota 2002).


The absorbed dose of an X-ray beam during an X-ray examination that does not penetrate the
embryo/fetus directly such as maternal skull and chest X-ray is less than 0.01 mGy, extremely
low and hence of no problem (Kusama & Ota 2002). The adult exposure from the CT scan of
the abdomen and pelvis is 200-250 times greater than from a chest X-ray, and will expose the
fetus to 10mGy and 20mGy still less than the threshold fetal dose of 100mGy ((Miller & Phil
2004) and Phil 2004). However the health effect of this type of exposure on a fetus is an
increase risk of leukemia by a factor of 1.5-2, which means 1 in 2,800, though low caution
should still be applied ((Miller & Phil 2004) and Phil 2004). The accepted cumulative dose of
ionizing radiation during pregnancy is 50mGy and no single diagnostic examination exceeds
this maximum (Toppenberg, Hill & Miller 1999), therefore if it is essential to have an X-ray
scan it is possible to do so without harming the embryo/fetus. Accidental exposure can expose
the fetus to 50-250 mGy, which is the minimum dose for causing a congenital malformation
((Miller & Phil 2004) and Phil 2004), so great care by medical technicians must be carried
out. A study performed on rats indicated that prenatal X-irradiation can decrease the number
of neurons, however the neurons that survive the radiation can proliferate and produce
connections normally (Miki et al. 1995). After the first ten days of ones menstrual cycle the
abdominal area, lumbar spine, pelvis, coccyx and hips, should not be irradiated to prevent any
harm (Jumah 1992).


Hiroshima and Nagasaki Attacks:
Atomic bombs dropped on Hiroshima on August the 6 and Nagasaki on August 9 in 1945,
caused abnormalities in Japanese children who were in utero at the time of the attacks (Kalter
2003). Studies of the survivors have demonstrated significant increases in perinatal deaths and
cases of microcephaly and retardation in children exposed in utero to the bombs (Kappy
1984). Long-term studies of these exposed fetuses that survived after the attacks were
conducted and it was demonstrated that children exposed to the bombs during the 8-15 week
stage of pregnancy were found to have a high rate of brain damage that resulted in lower IQs
and even severe mental retardation (Centers for Disease Control and Prevention 2005). These
children also suffered stunted growth and an increased risk of other birth defects (Centers for
Disease Control and Prevention 2005). One of the earliest studies was conducted on the
children who were exposed while in the first trimester of pregnancy of women within the city
limits of Hiroshima at the time of the attack (Kalter 2003). 205 of these children had survived
to 4.5 years of age and only one type of malformation, microcephaly, had been significantly
increased in frequency (Kalter 2003). Microcephaly is a condition where the circumference of
the head is considerably reduced, defined as being greater than or equal to two standard
deviations below the mean for age and sex (Kalter 2003). Most of the microcephalic children
were mentally retarded (Kalter 2003). Yamazaki and Schull (1990) have identified weeks 8-
15 after fertilization corresponding to the critical time when neuronal production increases
and migration of immature neurons to their cortical sites of function occurs.
The dose of irradiation the mothers received is related to the frequency of the defect (Kalter
2003). Seven of eleven children of mothers who were within 1200 m of the point directly
beneath the bomb when it exploded (hypocenter) were affected (Kalter 2003). The seven
mothers were between 11-17 weeks of gestation at the time of the explosion, while the other
four mothers were at 6-16 weeks of gestation indicating that sensitivity occurs at different
times (Kalter 2003). One child presented a reduced head size however was mentally normal,
perhaps because she had been irradiated early at 7 weeks of gestation (Kalter 2003). The most
sensitive period for the central nervous system teratogenesis is between 10-17 weeks of
gestation (Toppenberg, Hill & Miller 1999). If this exceptional child was irradiated at 7 weeks
then it is possible that her brain function would have been unaffected.


A similar study conducted in Nagasaki found that mothers close to the hypocenter had
delivered children with significantly reduced head size (Kalter 2003). Microcephaly was
present in 33 of the 169 (20%) surviving children in Hiroshima, whose mothers were less than
1200-2200m from the hypocenter and about two thirds of them were at 7-25 weeks of
gestation (Kalter 2003). 54% of children whose mothers were within 1800m of the hypocenter
and at 7-15 weeks of gestation were mentally retarded (Kalter 2003). In conclusion of the
study the only teratogenic effect of fetal exposure was microcephaly, the predominant
sensitivity to which was during weeks 7-15 of gestation and whose frequency and severity
increased with dose (closeness to the explosion) (Kalter 2003). It was calculated that in
Hiroshima, the minimum dose producing an effect at less than 18 weeks of gestation was 100-
190 mGy, but in Nagasaki, there was strangely no consistent effect below 150 mGy, the
inconsistency perhaps due to the difference in radiation quality of the two bombs (Kalter
2003). Animal studies has shown that radiation destroys brain cells, which in early embryos
inhibits expansion of the skull and causes small head size, and with increasing cell death
mental retardation eventuates (Kalter 2003). However a closer analysis of the effects of
radiation noted that while microcephaly resulted from exposure at all stages up to 25 weeks of
pregnancy, especially 8-15 weeks, exposure before 8 weeks of gestation did not cause mental
retardation, the explanation being the difference in brain cell composition and possibly cell
behavior or replenishment at various times (Kalter 2003). The only proven congenital
abnormality produced by the atomic bombs was microcephaly, whose degree is proportional
to the dose received (Kalter 2003). No increase has been found of major congenital
malformations among later conceived children of atomic bomb survivors of Hiroshima and
Nagasaki, so no malformations occurred as a result of mutations induced in parental gonads
(Kalter 2003). Therefore the effects of the radiation from the bombs were not carried on to
further generations.


Research has found no difference between the rates of inherited birth defects in children
whose parents were exposed to radiation due to the atomic bomb explosions and in those
whose parents were not exposed (Hanford Health Information Network 1994). However these
researchers believed that genetic damage did occur as a result of radiation exposure (Hanford
Health Information Network 1994). Though they found no difference in exposed and non-
exposed, animal research has suggested that inherited genetic effects from radiation exposure
should occur in humans (Hanford Health Information Network 1994). Investigation indicates
that there is a relationship between X-ray exposure before birth and development of childhood
cancer. Research conducted by Stewart and MacMahon have found an association between
medical X-ray exposure before birth and childhood cancer (Hanford Health Information
Network 1994).     The findings indicated that the most sensitive period of exposure for
developing leukemia is about the seventh month of pregnancy, while for all other cancers it is
the sixth month (Hanford Health Information Network 1994). It is important to note that to
develop congenital malformations the most crucial time is during the first four months, while
to develop cancer is during the sixth and seventh month. Therefore there is no real ‘safe’ time
to be exposed to radiation while pregnant, as there are possible health problems associated
with the majority of the duration of pregnancy.


Chernobyl:
On April 25-26 in 1986, a chain reaction in reactor number 4 of the Chernobyl nuclear power
plant in Ukraine went out of control creating explosions and a fireball which blew off the
reactor’s heavy steel and concrete lid (BBC World Report). This explosion emitted tons of
radioactive material into the air, releasing 30-40 times as much radioactivity as the Hiroshima
and Nagasaki atomic bombs combined (BBC World Report). At least 5% of the radioactive
reactor core was released into the atmosphere (MedicineNet 2004). A study conducted on
minisatellite mutations in post-Chernobyl families in the Ukraine found a statistically
significant 1.6 fold increase in the mutation rate in the germline of exposed fathers, however
the maternal germline mutation rate had not increased (Dubrova et al. 2002). The data from
this study suggested that elevated minisatellite mutation rate could be credited to post-
Chernobyl radioactive exposure (Dubrova et al. 2002). A study performed on evaluating the
impact of Chernobyl suggested that it had no detectable impact on the prevalence of
congenital anomalies in Western Europe; therefore the widespread fear in the population
about the possible effects of exposure on the unborn fetus is not justified (Dolk & Nichols
2000). As this was an accident due to the disregard of safety during the reactions in the power
plant the Ukraine government did not extensively notify people of the radiation they were
being exposed to. Therefore it may be concluded that not a lot of research has been conducted
to suggest that the radiation caused congenital anomalies in Chernobyl and its surrounding
countries, however from the information being presented such high doses of radiation would
definitely have caused death and harm to developing embryos/fetuses.


Pregnancy is a very fragile and delicate time for the rapidly dividing zygote and growing
embryo/fetus and the interruption caused by teratogens in particular radiation may be
devastating. Time of exposure is an important concept, prenatal irradiation has only been
exceptionally associated with congenital abnormalities, however irradiation between weeks 8-
25 has shown to be able to induce severe mental retardation (Jacquet 2004). Though it has not
been proven the risk of developing a childhood cancer following prenatal irradiation may also
be a result (Jacquet 2004). Congenital malformations, prenatal and postnatal deaths not only
affect the child physically but also mentally and emotionally. Though it may not affect a large
amount of people compared to the world population of 6 billion, perhaps over time, defects
and chromosomal and gene mutations which have not been proven but are suggested possibly
could be passed on to future generations, more research still needs to be conducted. The
nature and sensitivity of induced biological effects depend upon the dose and developmental
stage at irradiation (Streffer et al. 2003). The greater the radiation fetal dose, the greater the
effect (University of South Dakota), but a dosage of less than 100mGy is not strong enough to
cause abnormalities and not of a large enough concern to terminate the pregnancy. All
medical examinations using technology that utilizes irradiation should not cause the mother to
stress, however caution in handling the technology is mandatory.




References:

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