rayonnements ionisants ’une irradiation accidentelle · 3 • radiobiology for the radiologist,...
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1. Grandeurs et Unités - Mécanismes biologiques de l’action des rayonnements ionisants
2. Effets aigus d ’une irradiation accidentelle3. Cancers radio-induits4. Effets héréditaires radio-induits5. Effets de l ’irradiation in utero6. Législation: les normes de bases; principes de radioprotection
opérationnelle7. Travaux pratiques: emploi de détecteurs en situation de routine;
dosimétrie des travailleurs; visites des installations du contrôle physique
Prof. V. GrégoireDr. P. SmeestersMr M. Despiegeleer
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• Radiobiology for the Radiologist, Eric J. Hall. J.B. Lippincott Company, Philadelphia, 1994.
• 1990 recommendations of the International Commission on Radiological Protection, Annals of the ICRP, publication 60, 1991.
• Exposure to ionizing radiations: radiobiological effects and pathogenesis, A. Wambersie et al., Revue Médicale de Bruxelles, 17: 27-38 et 75-84, 1996 ou Louvain Med., 114: S97-S132, 1995.
• http://www.md.ucl.ac.be/IMRE/RPR2001.htm
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• Electromagnetic radiation (low LET): photons, γ-rays, X-rays
• Particulate Radiation(high LET)
- charged particles: electrons, protons, α particles- neutrons- heavy charged ions: carbon, neons, argon, …
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E = hν
ν = c/λ
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• Indirectly ionizing radiation: X-rays, γ-rays, neutrons- photoelectric process: ≈ Z3
- Compton process: higher photon energy- pair production
• Directly ionizing radiation: charged particles
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Low LET High LET
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Electrons Photons
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• X- and γ-rays are indirectly ionizing; the first step in their absorption is the production of fast recoil electrons.
• Neutrons are also indirectly ionizing; the first step in their absorption is the production of fast recoil protons, α-particles, and heavier nuclear fragments.
• Electrons and other charged particles are directly ionizing; they lost their energy by progressive collision.
• The shape of the depth-dose curves (and thus the absorption) depends on the type of ionizing radiation and their energy.
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• Biological effects of X-rays may be due to the direct or indirect action
• About two thirds of the biological damage by X-rays is due to indirect action
• High-LET radiations produce most biological damage by the direct action, which cannot be modified by chemical sensitizers and protectors
• The physics of the absorption process is over 10-15 second; the chemistry takes longer; the biology takes days to months for cell killings, years for carcinogenesis, and generations for heritable damage
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Absorbed dose: 1 Gray (Gy) = 1 joule/kg= increase of 0.0001 °C per gr water
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Equivalent dose = absorbed dose * radiation weighting factor (WR)
in Sievert (Sv)
Type and energy range WR
Photons, all energies 1Electrons, all energies 1Neutrons, < 10 keV 5
> 10 keV < 100 keV 10> 100 keV < 2 MeV 20> 2 MeV < 20 MeV 10> 20 MeV 5
Protons, > 2 MeV 5α-particles, fission fragments, heavy nuclei 20
From ICRP 60
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Effective dose = Σ absorbed dose * WR * tissue weighting factor (WT) in Sievert (Sv)
Tissue or organ WTGonads 0.20Bone Marrow 0.12Colon 0.12Lung 0.12Stomach 0.12Bladder 0.05Breast 0.05Liver 0.05Esophagus 0.05Thyroid 0.05Skin 0.01Bone surface 0.01Remainder 0.05
From ICRP 60
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Committed equivalent dose = equivalent dose over 50 years (70 years for children)
Committed effective dose = effective dose over 50 years (70 years for children)
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Collective equivalent dose = equivalent dose * number of persons exposed (in person-Sievert)
Collective effective dose = effective dose * number of persons exposed (in person-Sievert)
Collective effective dose commitment = committed effective dose * number of persons exposed (in person-Sievert)
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• For individuals- absorbed dose- equivalent dose- effective dose- committed equivalent dose- committed effective dose
• For populations- collective equivalent dose- collective effective dose- collective effective dose commitment
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Cellular processes involved in #cell death after ionizing radiations.
Free-radical production Direct effect
Initial genomic damage(DNA / chromosome)
Residual genomic damage(DNA / chromosome)
Clonogenic cell death
Ionizations / Excitations
Programmed cell death
Tumor shrinkage Loss of normal tissue functionalIntegrity including carcinogenesis
Repair processes Division delay
Cell surfacereceptor
Signal transductionpathways
Ionizing radiations
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Clonogenic cell survival.
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Time-lapse microcinematography
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Clonogenic cell survival.
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Clonogenic cell survival.
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Clonogenic cell survival.
From Schwartz et al.
10 -3
10 -2
10 -1
10 0
0 2 4 6 8 10 12 14
SCC 61 SCC 12 B2
Absorbed dose (Gy)
Surv
ivin
g fra
ctio
n
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The key function of DNA
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Structure of DNA
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Structure of DNA
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DNA damages
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DNA damages
Type of lesion Number per GrayDouble strand breaks (dsb) 40Single strand breaks (ssb) 500-1000Base damage 1000-2000Sugar damage 800-1600DNA-DNA crosslinks 30DNA-protein crosslinks (dpc) 150Alkali-labile sites 200-300
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Quantification of DNA damages
0
0.1
0.2
0.3
0.4
0.5
0 10 20 30 40
Frac
tion
of a
ctiv
ity re
leas
ed
Absorbed dose (Gy)
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DNA Repair
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DNA Repair
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Non-homologous end-joining
Re-ligation Fill-in or deletion, ligation
Homologous recombination
3’
3’
Joint molecule formation
Repair DNA synthesis
Resolution of intermediates, ligation
HR and NHEJ
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HR versus NHEJ
• NHEJ– Repairs most DSB - 80%– Important for
radiosensitivity– Error prone– All parts of the cell cycle– ½ time ~2-4 hours– Defects rare in cancer– Non-proliferating tissues
• HR– Repairs fewer DSB – 20%– Important for radiosensitivity– Error free– S and G2 phase– responsible for change in
sensitivity in the cell cycle– ½ time long – 24hours?– Varies more between cell lines
(high in stem cells)– Defects common in cancer– Proliferating tissues
Early versus late responding tissue
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Quantification of DNA Repair
Repair time (min.)0 60 120 180 240 300 360
100
10
HF19
180BRPe
rcen
t of i
nitia
l dam
age
From Badie et al.
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Structure of chromosome
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Chromosome and chromatid aberrations
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Chromosome aberrations
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Quantification of chromosome breaks
From Hittelman et al.
0
10
20
30
40
50
60
0 1 2 3 4 5 6
SCC 61
SCC12 B2
Absorbed dose (Gy)
Chro
mos
ome
brea
ks p
er c
ell
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Quantification of chromosome dicentrics and rings
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HR and Human Disease• Many diseases associated with the sensors and
transducers– Ataxia Telangiectasia – mutations in ATM
• Patients are radiosensitive• Elevated risk of cancer• Have several developmental and neural abnormalities
– AT like disorder – mutations in MRE11– Nijmegen breakage syndrome – mutations in NBS– Familial (inherited) breast cancer - BRCA1, BRCA2
• Inherited breast and ovarian cancer
– Fanconi’s Anemia – FANCA,B,C,D1,D2,E• FANCB,D1=BRCA2• Sensitive to crosslinking agents• Increased risk of cancer 46
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Overview of the cell cycle
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Cell cycle control: G1-S transition
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Tumor suppressor gene: the retinoblastoma example
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Programmed cell death - apoptosis >< necrosis
phagocytose
APOPTOSE
NECROSE
inflammation
gonflement cellulaire, lésion des organites, altération de la chromatine.
lyse cellulaire, destruction des organites, destruction de la chromatine.
condensation de la chromatine, diminution du volume cellulaire, changements membranaires.
chromatine fragmentée, organites intacts.
formation des corps apoptotiques
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Programmed cell death - apoptosis
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Programmed cell death - apoptosis: an active process
FasL, TNFα
privation en facteurs de croissance perforine
granzyme B autres
1° signal
3° exécution
Bcl-2, Bcl-xL mitochondrie mitochondrie
caspases
CrmA p35
ZVAD YVAD DEVD
ψm, cytochrome c AIF, radicaux libres
Apoptose
boucle d ’auto- amplification
2° contrôle
point de non retour
stress oxidatif radiations ionisantes lésions à l’ADN (p53)
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Programmed cell death - apoptosis: DNA fragmentation
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The p53-dependant signaling pathways
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The p53-dependant signaling pathways
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Hypersensitivity syndromes
Deschavanne & Malaise, 1986
Mean inactivating dose (Gy)
AT+ +
AT+ - FA
Nl.99
.9
.7
.5
.2
.1
.010 0.5 1 1.5 2 2 .5 3
Cum
ulat
ive
frequ
ency
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Relative Biological Effectiveness (RBE)
High LET
Low LET
Surv
ivin
g fra
ctio
n
Dose (Gy)
RBE = Dlow LET / Dhigh LET
Dhigh LET Dlow LET
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RBE and LET
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• Many single-strand damages are produced in DNA by radiation but are readily and faithfully repaired using the opposite DNA strand as a template.
• Damages in both strands that are opposite, separated by only a few base pairs, or locally multiple may lead to a double-strand break (dsb).
• In mammalian cells, double-strand breaks are mainly repaired by non-homologous end joining (NHEJ).
• Damages that are not repaired or that are mis-repaired in pre-replication phase (G0-G1 cells) may lead to chromosome aberrations.
• Damages that are not repaired or that are mis-repaired in post-replication phase (late-S or G2 cells) may lead to chromatid aberrations.
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• #Asymetrical exchange aberrations (dicentrics and rings) are mainly lethal.
• Symetrical exchange aberrations (translocations and deletions) resulting from mis-repaired DNA damages may lead to carcinogenesis.
• Techniques available to study DNA dsbs are not sensitive enough to be used as biological dosimetry in case of accidental irradiation.
• Scoring aberrations in lymphocytes from peripheral blood may be used to estimate total-body doses in humans with a sensitivity of ≈ 0,25 Gy.
• Ionizing radiation induce a cell cycle arrest at the G1-S border to prevent damaged DNA to be replicated in S-phase.
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• #After exposure to ionizing radiation, cells mainly die from necrosis (clonogenic cell death).
• Apoptosis is an “active” form of cell death which is involved in tissue homeostasis after ionizing radiation (e.g. preventing carcinogenesis).
• Genetic predisposition (e.g. mutations in p53, Rb, or AT gene) may render cells more sensitive to ionizing radiations.
• Hight LET radiations (e.g. neutrons, α-particles) are much more effective than X-rays or γ-rays (RBE > 1).