Effects on the Embryo/Fetus

Teratogenic

abnormalities induced by exposure in utero

A high dose of ionizing radiation during pregnancy is just one of the recognized agents that can produce

• mental retardation

• neurobehavior effects

• convulsive disorders

• congenital malformations

• fetal growth retardation

• embryonic death

• cancer (primarily leukemia)

Effects fall broadly into the following categories

• lethal effects

• malformations

• growth disturbances without malformations

• childhood cancer (high uncertainty)

Effects are determined by

• gestational stage

• dose

• dose rate

Is it easy to distinguish between the incidence of effects caused by a given contaminant exposure and the background incidence?

no

Is there a lot of data on human in-utero exposure?

no (atomic bomb survivors, pelvic x-rays, pelvic radium brachytherapy)

Pre-implantation

Day 0-9, time of fertilization to the time at which the embryo attaches to uterine wall

Organogenesis

Day 10-Week 6, period during which major organs are developed

Fetal period

Week 6-39, growth of structures already formed throughout birth

Who has a longer fetal period: humans or mice?

humans

Does irradiating the pregnant rat’s maternal organs before the fertilized embryo enters the uterus increase the risk for birth defects, pregnancy loss, or fetal growth retardation?

no

When doses were such that pregnant rat exhibit signs of radiation sickness, what occurred?

growth retardation and embryonic death

What is the threshold for congenital malformations and fetal growth retardation?

doses above 0.2 Gy

The pre-implantation stage is most sensitive to

lethal effects

In other animals, pre-implantation effects are expressed as

decreased litter size

Pre-implantation typically results in a

binary response (embryo dies or is unharmed)

Is irradiation at pre-implantation easy to detect?

no

Is growth retardation observed at pre-implantation?

no

For doses to the embryo less than 100 mGy, lethal effects in pre-implantation will be _____ for humans

very infrequent

For doses in the range of 150-200 mGy during the preimplantation, the risk of embryonic loss ______

may increase

Why can organogenesis see developmental abnormalities?

cells are still undergoing differentiation and are sensitive

What is the dose threshold for mice organogenesis effects?

100 mGy

What is the no-adverse-effect level (NOAEL) in humans for early organogenesis?

200 mGy

What causes growth retardation in animals?

~1 Gy x-rays, threshold of 250 mGy

The greatest growth retardation is seen in _____ organogenesis

early

Neonatal death peaks at around ___ of mice receiving 2 Gy on day 10 (which is about day 29 for humans)

70%

In the fetal period, what predominates?

cellular growth

Various systemic effects have been observed in the fetal period, such as

hematopoietic system, liver, kidney, relatively high radiation doses

Exposure in the fetal period can result in

stunted growth

Irradiation in early fetal stage exhibits a greater degree of

permanent growth retardation

Which type of embryo has a better ability to recuperate from growth retardation?

preimplanted and early organogenesis

For the fetal period, it takes a ____ to kill than earlier stages

higher

What are the most likely mechanisms?

1. Cell death or mitotic delay beyond the recuperative capacity of the embryo or fetus

2. Inhibition of cell migration, differentiation, and cell communication

3. Interference with histogenesis by processes such as depletion, necrosis, or scarring

Radiation induced cell death may be minimally important at one stage because

an embryo can replace the killed cells

Cell death may be a primary factor once an embryo has lost the ability to

replace damaged cells (the fetus may be permanently cell-depleted)

Biological plausibility is most likely due to

vascular disruption, amniotic band syndrome, or a placental embolus to the limb

A malfunction like biological plausibility has been mistakenly allged to have resulted from an

in-utero exposure despite there being no indication that radiation exposure had even occurred

A unilateral malformation in a child, who had a normal weight at birth, had normal intelligence, and a normal head circumference could not have resulted from

an exposure to ionizing radiation

What are the principle effects from the atomic bomb survivors?

microcephaly and mental retardation

Microcephaly

head size less than 2 standard deviations below the mean, frequency associated (but not always) with mental retardation, increased occurrence in 0-7th week post-conception irradiated group but none mentally retarded

Radiation-related small head size is related to a generalized

growth retardation (reduced weight and height)

Mental retardation

IQ < 70 and microcephaly

The most vulnerable period for the induction of mental retardation is considered to be from

8th-15th week post-conception

From the 15th-25th week, much higher doses were required to produce _____ and the incidence was lower

mental retardation

What is the threshold for mental retardation?

0.3 Gy

Effects for <2-3 weeks

few severe abnormalities, increased resorption/abortion

Effects for 4-11 weeks

abnormalities in many organs

Effects in 11-16 weeks

eye, skeletal, genital abnormalities; stunted growth, microcephaly, mental retardation

Effects for 16-20 weeks

microcephaly, mental retardation, stunted growth

Effects for >30 weeks

few detected abnormalities

Animal experiments show embryonic death during

pre-implantation

Animal experiments show gross congenital malformations during

organogenesis

Animal experiments show ______, which is temporary during organogenesis and permanent during the fetal period

growth retardation

Japanese A-bomb survivors show ______ from irradiation during much of gestation

microcephaly

Japanese A-bomb survivors show severe

mental retardation

There were reports of an increase in the frequency of medical terminations in Russia following

Chernobyl

Carcinogenic

induction and formation of cancer

Pelvic irradiation

images of maternal pelvis and fetal structures within pelvis to determine method of delivery with lowest risk

Doses to the maternal ovaries and fetus ranged over __ orders of magnitude from obstetrical abdominal x-ray procedures

two

Studies on exposure in utero to x-rays “show”

• increased risk of developing childhood cancers (primarily leukemia)

• risk greatest during first or third trimester

• ionizing radiation is causative

• no dose can be regarded as “completely” safe

Although the statistical association from case-control epidemiological studies is not generally debated, investigators have argued about

• causality

• if the association is causal, the likely magnitude of the leukemogenic risk

The risk of cancer per Gy from case-control and most of the cohort studies of cancer risk in offspring of mothers undergoing diagnostic radiologic procedures are not based on

actual dose reconstructions

Do dose limits apply for medical exposure?

no

Termination of pregnancy at fetal doses of less than 100 mGy is not

justified based on radiation risk

When is termination of a pregnancy justified based on radiation risk?

100-500 mGy