Detriment from irradiation of the gonads during radiological … · 2020. 4. 14. · Risk: failure...

© SCK•CEN Academy

Head Radiobiology Unit, Belgian Nuclear Research CentreGuest-professor, Faculty of Biosciences Engineering, Universiteit Gent

Invited professor, Faculty of Sciences, KULeuven

Sarah [email protected]

Detriment from irradiation of the gonads during radiological

examinationsPENTALFA conference, 12/12/2019, Leuven

mailto:[email protected]


Management of pregnant patient

One of the most commonly asked questions in relationship to the use of ionising radiation in medicine: management of the pregnant patient or female radiation worker.

Thousands of pregnant patients and radiation workers exposed to ionizing radiation each year.

Lack of knowledge responsible for great anxiety (and probably unnecessary termination of pregnancies).

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Prenatal effects of ionising radiation:Diagnostic versus therapy

Potential risk to embryo/foetus can vary widely depending of whether diagnosis or treatment is contemplated.

Prenatal doses from most properly done diagnostic procedures present no measurable increased risk of prenatal death, malformation, or impairment of mental development over the background incidence.

However, higher doses, such as those involved in therapeuticprocedures, can result in significant foetal harm.

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Effects of in utero irradiation: general background

ICRP, 2000. Pregnancy and Medical Radiation. ICRP Publication 84. Ann. ICRP 30.

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Effects of in utero irradiation: Deterministic (tissue reaction) & stochastic effects

Clinical radiation effects are due either to:

Cell killing (lethality, CNS anomalies, cataract, growth retardation, malformations, behavioural disorders): practical threshold the higher the dose above the threshold, the more

severe the effect→ “deterministic or tissue reaction effects”

Unrepaired/misrepaired DNA damage (cancer and potential hereditary effects): probability of such effects increases with the dose,

with no “safe” threshold dose below which the probability is known to be zero

→ “stochastic effects”

Protracted exposures are expected to have less overall effects than acute exposure

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Radiation sensitivity and age

Higher sensitivity of (young) children, due to smaller organs under development!

Less LeastMost

risk


Risk of stochastic effects in relation to age

Age (years)

Multiplicationfactor for risk

< 10 3.0

10 – 20 2.0

20 – 30 1.5

30 1.0

30 – 50 0.5

50 – 80 0.3

> 80 Negligible risk

relative attributable lifetime risk, according to ICRP 1990

Radiation sensitivity & age


Some diseases may have a developmental &/or environmental origin

What happens here can influence health here

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Evaluation of the potential risks of ionising radiation

on human health

To provide the scientific background for

occupational, accidental, medical or cosmic radiation exposure allowing a more accurate risk assessment

Neurobiology Cardiovascular risks Space research

Radiopharmaceuticals

Proton therapy

Objective radiobiology research @SCK•CEN

Immunology

Immunology


How are radiation dose and risks related?

1010

Linear, no-threshold

Linear, threshold

Hyper-sensitivityHormetic


Embryonic risks depend on the developmental stage at the time of irradiation

3 main periods of embryonic development:

Pre-implantation period: 1st week

general growth and functional maturation of newly formed organs includes the important period of central nervous system development

from the 8th to 25th week

from conception to implantation into the uterus mitotic divisions of undifferentiated cells (1-cell, 2-cell, 4-cell,….

blastocyst)

differentiation organs formed according to a well defined sequence for each species

Foetal period: 8th week until birth

Organogenesis period: 2nd to 8th week

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Development of mouse embryos & fetusStudies from SCK-CEN

Day 4 Day 7 Day 12

Day 16 Day 1812


Sensitivity to radiation induction of congenitalabnormalities: the organogenesis period

Month 1 Month 213


Radiation sensitivity of the embryo/fetusduring pregnancy : results of animal studies

AB

C

II III

REL

ATIV

E R

ISK

A) Prenatal deathB) Anomalies/MalformationsC) Neonatal death

I Pre-implantation periodII Organogenesis (2nd of 8th week)III Histogenesis (Foetal period)

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Sensitivity of the embryo to radiation-induction of developmental effects: the pre-implantation period


I Pre-implantation periodII Organogenesis (2nd to 8th week)III Histogenesis (Foetal period)

AB

C

II III

REL

ATIV

E R

ISK

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Fertilization (picture by T. Yamada) 1-cell embryos at the early pronuclear stage

The pre-implantation period

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2-cell stage 6-8-cell & morula stages

Blastocysts ready to implantMorulas17



Pre-implantation development after X-irradiation (1Gy) at the 1-cell stage: dead embryos (white circles)

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Sensitivity to radiation inductionof mortality: the pre-implantation period

Sensitivity highest at the very beginning of development (unicellular stage or “1-cell stage”): LD50 : 400 mGy 4-6 h post fertilization (early

pronuclear stage)….but LD50 : 4 Gy 12 h post fertilization → sensitivity related to the cell cycle phase

Risk: failure to implant or undetectable death of the conceptus (the “all-or-none” rule).

Sensitivity decreases during following stages, since cellular death can be compensated by other (undifferentiated) cells

LD 5

0 (c

Gy)

Time after fertilization (hrs)

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X-irradiation

1hr after fertilisation

mating


Chromosome aberrations (fragments) in an irradiated mouse 1-cell embryo

These fragmentswill lead to early embryonic mortality

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Sensitivity of the embryo to radiation-induction of developmental effects: the organogenesis period

AB

C

II III

REL

ATIV

E R

ISK


I Pre-implantation periodII Organogenesis (2nd to 8th week)III Histogenesis (Foetal period)

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Sensitivity to radiation induction ofdevelopmental defects: the organogenesis period

Congenital abnormalities: main effect of radiation in small rodents, when irradiation during organogenesis

“congenital anomaly”: gross or microscopic structural defect present at birth, whether detected at that time or not

Other potential effect : growth retardation (dwarf), results from cell depletion Dwarf: Recovery quite possible, smaller newborn animals may achieve normal

weight as adults Threshold : 100-200 mGy Dwarf mouse foetus

with exencephaly

and gastroschisis

Normal mouse foetus

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Congenital anomalies

For each species, well determined period of sensitivity to induction of each malformation.

Specific time when a malformation is produced coincides with main stage of differentiation and organization of the considered structure.

Increasing the dose results in an extension of the period of sensitivity and an increase of the incidence of malformations.

Dose-effect relationship generally sigmoid, the frequency of malformations per unit of dose increasing with the dose.

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Examples of malformations

Curly tail

Polydactyly

Hypodactyly

Gastroschisis

ExencephalyViable Non-viable

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Postaxial (forelimb) Postaxial (forelimb)

Postaxial (forelimb) Preaxial (hindlimb)

tab

Examples of limb malformations

forelimb hindlimb

postaxial (little finger)preaxial (thumb)

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Month 1 Month 2

(Rugh)26



Month 1 Month 227


Sensitivity of the embryo to radiation-induction of developmental effects: the foetal period

A) Prenatal deathB) AnomaliesC) Neonatal death

I Pre-implantation periodII OrganogenesisIII Histogenesis (foetal period)

AB

C

II III

REL

ATIV

E R

ISK

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Sensitivity of the embryo to radiation-induction of developmental effects: the foetal period

Exposure of rodent embryos during the foetal period: less spectacular effects anomalies in development of tissues but no big malformations generalized or localized growth retardation

Growth retardation frequently persists during all extra-uterine life (>< irradiation during organogenesis)

Late foetal period very sensitive to the carcinogenic effect of radiation (>< pre-implantation and organogenesis periods) solid tumours in adults, but not leukaemia in either juvenile or adult mice tendency for higher susceptibility of females (ovary, uterus and breast!)

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In rodents


Embryonic radiation sensitivity duringpregnancy in humans

Growth retardation and malformations

1920’s and early 1930’s: ionising radiation widely used to treat diverse diseases

Growth retardation when irradiation during foetal period

Radiation-induced malformations: exceptional in humans unless heavy irradiation

Doses ≥ 2.5 Gy of X-rays during organogenesis consistently caused fetal damage

Microcephaly, mental retardation, microphtalmy, cataracts, retinal lesions, genital and skeletal malformations …

The child on the right was exposed to

radiation during the second trimester

resulting in growthretardation

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Embryonic radiation sensitivity during pregnancy in humans

Hiroshima and Nagasaki In utero exposure during weeks 8-15 of

pregnancy or, at a lesser extent, during weeks 15-25, can lead to a mental retardation associated or not to microcephaly

Weeks 8-15: great mitotic activity and proliferation of immature neurons, and their migration from the ventricular and sub-ventricular proliferative zones to the cerebral cortex

Weeks 16-25: neuronal differentiation and synaptogenesis

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Embryonic radiation sensitivity duringpregnancy in humans

Severe mental retardation

At a foetal dose of 1 Gy during weeks 8-15: probability of severe mental retardation (SMR) ~ 40 %

SMR: “affected individuals were unable to perform simple calculations, to make simple conversation, to care for themselves, or they were completely unmanageable or had been institutionalised”

Threshold doses? Last estimates by Otake and Schull(1996): 0.55 Gy (CI: 0.31-0.61Gy)

Intelligence quotient Foetal irradiation may also result in a decrease of the IQ:

Weeks 8-15: decrease of the order of 20-30 points per Gy Weeks 16-25: decrease of the order of 10-20 points per Gy

Threshold dose ? If yes, it is probably at a dose of 100 mGy or less for the 8-15 group, but… All the clinical observations on significant IQ reduction and severe mental retardation (SMR) relate to

foetal doses of about 500 mGy and above and at high dose rates

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Heterotopic gray matter (arrows) near the ventricles in a mentally retarded individual occurring as a result of high dose in-utero

radiation exposure

ICRP INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION

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Cortical cells (grey matter) are present in inappropriate locations in the brain, due to interruption in their migration to their correct location in the cerebral cortex


Embryonic radiation sensitivity duringpregnancy: experience in humans

Leukaemia and childhood cancer: OSCC survey

Oxford Survey of Childhood Cancers (OSCC, Alice Stewart) : investigated the notable rise in childhood leukaemia mortality over several decades in Great Britain (1953-1981):

association between obstetric examinations (radiographic examination of the abdomen of the pregnant mother) of pregnant women and childhood (age 0-16) cancer or leukaemia

all types of childhood cancers increased approximately equally

Significant methodological weaknesses and uncertainties, but not so severe as to completely invalidate the study

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Leukaemia and childhood cancer: Hiroshima/Nagasaki and Chernobyl studies

Japanese atomic bomb in-utero survivors: no increase in childhood cancers or leukaemia (mean dose: 180 mGy)

Chernobyl fallout: study in Greece: increased risk for infant leukaemia

(i.e. before 1 year of age) not confirmed in a similar study in Germany (same fetal

doses as in Greece) nor in an analysis of childhoodleukaemia data from 35 countries or regions in Europe

studies in Belarus and Ukraine: no clear evidence forincreased risk of infant leukemia

low statistical power and exposure measures were crude→ association leukaemia/in utero exposure still unclear

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Adult leukaemia and cancer (Japanese atomic bomb study)

Atomic bomb survivors data: the magnitude of cancer risk in adulthoodfrom in utero exposure may be similar to that from radiation exposurein early childhood (age < 5 years)

In both groups, greater risk for females than for males

Excess cancers among females: principally female cancers (breast and ovary) and digestive cancers

Leukaemia: very few cases, no dose-response but interpretation verydifficult

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Normal diagnostic medical exposures (using X-rays or radionuclides) should never result in foetal doses in excess of 100 mGy (assumed threshold for deterministic effects)

Foetal doses following diagnostic medical procedures

DoseExamination Mean (mGy) Maximum (mGy)

Abdomen 1.4 4.2Chest <0.01 <0.01

Intravenous uro-gram; lumbar spine 1.7 10

Pelvis 1.1 4

Skull; thoracic spine <0.01 <0.01

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“At the doses used, no deterministic effects of practical significance should be expected to occur in humans” (ICRP, 2007)

Examinations lying in the highest foetal dose group (10-50 mGy) could result in an approximate doubling of the natural baseline risk of childhood cancer

In such case, delay examination until birth, unless health of the mother (and indirectly that of the unborn child) would be compromised

Foetal doses following diagnostic medical procedures

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Conclusions: summary of recent estimates

Pre-implantation period Malformations unlikely or very rare Main effect: failure to implant or undetectable death of the conceptus Spontaneous abortion : > 15%

Organogenesis period Malformations with a threshold of 100 mGy or higher “Spontaneous” major congenital malformations rate: 2-4 %

Foetal period SMR (severe mental retardation) possible if exposure during weeks 8-25, and

especially weeks 8-15 Decline in IQ during weeks 8-15: about 25 points/Gy, very small (and undetectable!)

at 100 mGy

Leukaemia and childhood cancers Results still controversial

EC directive (2000): Pregnant medical radiation workers may work in a radiation environment as long as there is reasonable assurance that the fœtal dose can be kept below 1 mGy

during the course of pregnancy39


Research needs

Better understanding of :

- Low dose effects- Genetic & epigenetic changes- Windows of sensitivity during plasticity periods?- Peri-conception period- Father and mother's exposure- Long-term effects on metabolic, cardiovascular, skeletal & other systems

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Lisa DaenenBrit ProesmansEllina MacaevaBjorn Baselet

Thank you for your attentionDr Paul JacquetDr Louis de Saint-GeorgesDr Hanane DerradjiDr Rafi BenotmaneDr Roel Quintens

Dr Mieke VerslegersJasmine BusetMieke NeefsLiselotte LeysenTine VerreetKai Craenen

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Detriment from irradiation of the gonads during radiological … · 2020. 4. 14. · Risk: failure...

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