dosimetry : absorbed dose equivalent and effective dose the w r and w t coefficients dna structure...
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Dosimetry : Absorbed dose Equivalent and effective doseThe WR and WT coefficients
DNA structure and functionMolecular organization of lifeDNA structure and functionDiversity and function of biological macromolecules
Radioprotection : Contamination and exposure to radiationsPassive and active protectionPhysiological effects of high and low dosesCancers : mutagenesis and radiotherapy
Biological effects of ionizing radiations
The effects of radioactivity on the living matter : Interaction between ionizing radiations and waterDNA damages and repairProtective mechanisms against genome mutations
Biological macromolecules
Molecular assemblies
Small molecules
Cells
Organisms
Population
Macromolecules
Energy flowGenome
Intracellular compartments
nm
m
mm
Plasma membrane
Organization levels in biology
proteins
small molecules
DNA (desoxyribonucleic acid)
mRNA (ribonucleic acid)
plasma membrane
promoter
transcription factors
receptors
enzymes
Information flow in living cells
3,4 Å
20 Å
34 Å
DNA structure
Direct strand
base 1
base 2
base 3 base 1
base 2
base 3
Complementary strand
5 ’
3 ’
5 ’
3 ’
sequence
Adenine thymine pair
Guanine-cytosine pair
Complementary strands are opposed
Interaction between DNA strands
procaryotes : a single circular chromosome typically 5.106 base pairs
eucaryotes : several linear chromosomestypically 3.109 base pairs
22 autosomal chromosome
pairs
2 sexual chromosomes
Example : human genome
+ about hundred circular
mitochondrial DNA molecules
telomer
centromer
DNA is organized in chromosomes
DNA-dependant RNA polymerasenucleotides
Transfert RNA (tRNA)aminoacyl tRNA transferase
ribosomes
NH3+-
-COO-
NH 3+ -
-COO-
TRANSCRIPTION
TRANSLATION
DNA, RNA and proteins
U/TCAG
U/TCAG
U/TCAG
U/TCAG
U/T C A G
U/T
C
A
G
Three consecutive nucleotides form a codon
that encodes an amino acid
START
Genetic engineering : production of new proteins,
using modified DNA
The genetic code
The various sets of biological molecules
genome
transcriptome
proteome
metabolome
protein synthesis
protein activity
Protein post-translational modifications
Protein degradation
proteins
small molecules
DNA
(m)RNA
mRNA editing and degradation
noncoding RNA and mRNA synthesis
DNA replication and repair
Homo sapiensEscherichia coli
Genome size
Number of genes
Number of proteins
Number of cell types
Number of cells
5.106 3.109
4639 ≈ 25000
4289 ≈106
2 ≈ 250
10141-109
Cell size 1-2 m 10-50 m
Molecular diversity in different model organisms
Saccharomyces cerevisiae
12
6607
6300
2
1-108
5 m
ENCODE project (summer 2012) : a function can be attributed to 75% of the human genome
Dosimetry : Absorbed dose Equivalent and effective doseThe WR and WT coefficients
DNA structure and functionMolecular organization of lifeDNA structure and functionDiversity and function of biological macromolecules
Radioprotection : Contamination and exposure to radiationsPassive and active protectionPhysiological effects of high and low dosesCancers : mutagenesis and radiotherapy
Biological effects of ionizing radiations
The effects of radioactivity on the living matter : Interaction between ionizing radiations and waterDNA damages and repairProtective mechanisms against genome mutations
From the absorbed radiation dose to the equivalent and the effective doses
absorbed radiation
dose
equivalent dose
cell deathcancer risk
ionizingradiation exposure
absorbance + diffusion
C/kg J/kg = gray sievert sievert(röngten) (rad) (rem) (rem)
effective dose
biological effectsphysico-chemical effects
ionization
Real-time measurements possible Delayed and multiple effects
http://www.euronuclear.org/info/
Unit : C/kg1 C/kg is the amount of radiation required to create 1 C of positive and negative electrostatic charges in 1 kg of matter. This corresponds to the generation of 6.1018 ion pairs.
Old unit : röentgen1 R is the amount of radiation required to create 1 C of positive and negative electrostatic charges in 1 cm3 of dry air at 20°C and 1 atm. 1 R = = 2.58×10−4 C/kg
Measurement : Geiger and scintillation counters
Measuring the exposure to ionizing radiations
Unit : Gray (J/kg)The amount of radiation energy adsorbed per mass unit
1 Gy = 1J/kg = 1 N.m/(N/(m.s-2)) = 1 m2.s-2
Old unit : rad = roentgen absorbed dose 1 rd = 10-2 Gy ( = 100 erg/g)
Measurement : passive and active dosimeters
Note : doses can also be calculated from the geometry of the beams, the radioactive decay rate (radionucleid activity) and the composition and shape of the irradiated material
Measuring the absorbed radiation dose
Passive dosimeter (dose integrated over time)
film dosimeters
thermoluminescent dosimeter
Differential sensitivity to radiations :open window : particlesplastic : particlescopper filter : photonsaluminium (cadmium) filter : photons > 150 keV, particles > 2 MeV
electronic dosimeters
Active dosimeter (dose rate)
PrincipleScintillation crystals and solid state detector
SpecificationsSensitive to X and μ radiation, ß particles Neutron response <2%Dose display and storage 0 μSv to >16 SvDose rate display 0 μSv/h to >4 Sv/h
Calculating the equivalent and the effective radiation doses
Equivalent radiation dose = absorbed radiation dose x radiation weighting factor(Sv) wR (quality factor, no unit)
Effective radiation dose = equivalent radiation dose x biological weighting factor(Sv) wT (weighting factor, no unit)
For several radiation types and for several cell types, contributions are linearly summed up :
The biological effect of radiations depends on :
The type of the radiation. It is greater for radiations that have a high ionization density along the track of particles (linear energy transfert LET).
The cell type. It is greater for cells that divide rapidly, cells that undergo DNA recombination and stem cells.
R
RRDwH T
TTHwE R T
TRTR DwwE ,
particles/radiations energy wR
photons all 1 particles all 20 particles all 1protons < 10 keV 5
10 -100 keV 10 > 20 MeV 5
neutrons 100 keV - 2 MeV 20 2 - 20 MeV 10> 20 MeV 5
wR factors
Photons, and particles : ICRP 60 (1990) Protons and neutrons : ICRP 92 (2003) ICRP : international commission on radiological protectionCIPR : commission internationale de protection radiologique
These values are based on cell death measurements
Cell type wT(1) wT
(2)
gonads (gamet organs) 0.20 0.08bone marrow 0.12 0.12colon 0.12 0.12lung 0.12 0.12stomach 0.12 0.12bladder 0.05 0.04breast 0.05 0.12liver 0.05 0.04 thyroid gland 0.05 0.04skin 0.01 0.01bone surface 0.01 0.01brain 0.01
(1) ICRP 60 (1990) (2) ICRP 92 (2003) ICRP : international commission on radiological protectionCIPR : commission internationale de protection radiologiqueThese values are based on fatal cancer occurrence
wT factors
Robert N. Cherry ENCYCLOPÉDIE DE SÉCURITÉ ET DE SANTÉ AU TRAVAIL, les rayonnements ionisants
wT = 1body
Dosimetry : Absorbed dose Equivalent and effective doseThe WR and WT coefficients
DNA structure and functionMolecular organization of lifeDNA structure and functionDiversity and function of biological macromolecules
Radioprotection : Contamination and exposure to radiationsPassive and active protectionPhysiological effects of high and low dosesCancers : mutagenesis and radiotherapy
Biological effects of ionizing radiations
The effects of radioactivity on the living matter : Interaction between ionizing radiations and waterDNA damages and repairProtective mechanisms against genome mutations
Explaining WR, the dependence of the biological effects on the radiation type
Most damages are due to water radiolysis, that generates reactive oxygen species The reactive oxygen species diffuse about 5 µm away from the ionizing particle/radiationThe linear energy transfer strongly depends on radiation type
Macromolecule damages induced by ionizing radiations
H2O
lipids
proteins
DNA
mRNA
cell lysis
reactive ion production
inactivation or spontaneous activationof metabolic or signaling pathways
70%
1%
5%
20%
<1%
adducts, breaks → mutagenesis
moleculecell fraction
(w/w)damage induced by radiation
Most DNA damages are indirect
Water radiolysis : end products
H2O
H2O2 hydrogen peroxide
O2- superoxide ion
e-aq + H2O+
OH- hydroxide ion
detoxification enzymes
superoxide dismutase
(SOD)
peroxidase
Reactive Oxygen Species (ROS)
Dissolved oxygen promotes the formation of reactive oxygen species
H2O*
Water radiolysis : detailed mechanisms
Sophie Le Caër (2011) Water Radiolysis: Influence of Oxide Surfaces on H2 Production under Ionizing Radiation. Water 3, 235-253
Diffusiontypically 5 µm
strong reducing agents
strong oxidizing agents
strong oxidizing agents
Water radiolysis products
A radical is a chemical (atom, ion, molecule) with unpaired electrons on the highest energy orbital. Radicals are often very reactive.
OH- : hydroxyl ion
OH : hydroxyl radical
O2- : superoxide ion
HO2- : hydroperoxyl radical
02 : dioxygen (a stable radical)
O O
O H
O O
H
O H
O O
Linear Energy Transfert (LET)
L (J.m-1): linear energy transfertEnergy decrease per unit length
Linear Energy Transfert (LET) and WR coefficients
Unlimited linear energy transfer L in water (keV.µm-1) Q(L)
< 10 110 – 100 0.32 L – 2.2> 100 300.(L)-0.5
http://www.euronuclear.org/info/encyclopedia/q/quality-factor.htm
L = 5300 keV/37 µm = 143 WR = 25
The Bragg peak
For fast moving particles and ions, most of the dose is deposited at the end of the particle track
photons all organs particles internal exposure, skinProtons, neutrons, carbon ions variable deepness (Bragg peak)
Application to radiotherapy
Explaining WT, the dependence of the biological effect on the type of tissue/organ
There are three levels of cell protection against DNA damages1. Scavenging DNA damaging molecules, especially reactive oxygen species2. DNA repair mechanisms3. Cell cycle checkpoints and apoptosis. Too many DNA damage leads to
programmed cell death4. Cell death induced by Natural Killer Cells and cytotoxic T cells from the
immune system (detect changes in protein expression)
1. Superoxide dismutase and hydrogen peroxidase
2 O2− + 2 H2O O2 + H2O2 + 2 OH−
Human mitochondrial SODMn cofactorPDB 1VAR
HOOH + electron donor (2 e-) + 2H+ 2H2O
Bovine gluthatione peroxidasePDB 1GP1
1 nm
3 genes in humans coding for extracellular, cytoplasmic, and mitochondrial isoforms
8 genes in humans expressed in different tissues+ 6 peroxiredoxins + catalase
2. Sources of DNA damage
Replication errors: DNA polymerase frequency 1/107
Molecular damages to DNA:
Origin DNA damage number/cell.day Possiblerepair
Exogenous sun (1h/day) T-T dimers 6-8.104 Ychemical adducts 102-105 N
(base modification)radioactivity single strand breaks 2-4.104 Y(natural double strand breaks ? ±background)
Endogenous temperature single strand breaks 2-4.104 Yfree radicals adducts/breaks 104 Ymetabolites adducts 102 Yviruses genome integration ? Ntransposons ? ?
DNA repair mechanisms
Damage type Repair
T-T dimers
Adducts
Single strand breaks
Double strand breaks
Restriction
Excision
Synthesis
Ligation
Excision
Recombination
Ligation
or direct ligation
Recognition
The COMET assay to measure DNA damages
also called single cell gel electrophoresis (SCGE)
Exemple of repair : thymine dimers
Tymine dimer repair enzyme : specific DNA endonuclease
(induced by UV light)
benzo[a]pyrene (BP)
Metabolism et carcinogenicity of Benzo[a]Pyrene
benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide
CYP1A1, CYP1A2epoxide hydrolase
the diol epoxide covalently binds to DNA (adduct)
Increased DNA
mutations & cancer
Benzo[a]pyrene is a product of incomplete combustion at temperatures between 300 and 600 °C. aromatic
molecule (L)
Aryl hydrocarbon
ReceptorAhR
AhR-L
induction of specific mRNA (AhRE)
AhR-L
GrowthDifferentiationMetabolism
(toxicity)
P450 cytochromes (phase I) : CYP1A1, CYP1A2, CYP1B1, CYP2S1
Phase II enzymes : GST, UGT(detoxification mechanism)
translocation to the nucleus
AhRE AhRE
Shimizu et al. (2000) PNAS 97 : 779-782Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor
Dossier INSERMDioxines dans l’environnement. Quels risques pour la santé ? http://ist.inserm.fr/basisrapports/rapport.html
Individual susceptibility to xenobiotics. Exemple of CYP genes
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
Indirect carcenogenicity of dioxin
Dioxins occur as by-products in the manufacture of organochlorides, in the incineration of chlorine-containing substances such as PVC, in the bleaching of paper, and from natural sources such as volcanoes and forest fires.
Dioxins build up primarily in fatty tissues over time. The major source of dioxins is food, especially from animals. TCDD has a half-life of approximately 8 years in humans.
TCDD activates the AhR and thus induces CYP expression. This either increases or reduces carcinogenicity of other aromatic molecules such as Benzo[a]Pyrene and 7,12-dimethylbenz[a]anthracene, respectively.
Travailleurs exposés aux phénoxy-herbicides et aux chlorophénols. Exposition : 3 à 389 pg/g de matières grasses Teneur du lait maternel en France : 16,5 ± 5 pg/g de matières grasses Dossier INSERM Dioxines dans l’environnement.
The rad genes in yeast
A systematic study was conducted in yeast to identify genes responsible for the cell sensitivity to radiation 55 “rad” genes were found. Most of these genes have counterparts in the human genome. From current estimates, 240 genes are involved in DNA repair in humans
P Perego (2000) Yeast Mutants As a Model System for Identification of Determinants of Chemosensitivity. Pharmacol Rev 52: 477–491
3. The cell cycle
Gap 1
DNA Synthesis
Mitosis
Gap 2
In the resting state (G0), cells don’t divide
G0
In tissues, most cells are in the resting state. Division occurs to self repair the tissue
See ‘wound repair’ and ‘breast cancer cells’ movies
Cell cycle checkpoints
APOPTOSIS
p53
APOPTOSIS
Retinoblastoma protein (Rb)
APOPTOSIS
Anaphase Promoting Complex (APC)
Apoptosis is an organized (programmed) cell death mechanism
Apoptosis
Apoptosis is one form of programmed cell death, often observed in higher eukaryotes during development, selection of immune system cells, and cancer prevention by NKC
Apoptosis can be triggered by intracellular processes, such as DNA damages, or by extracellular molecules, for instance activation of the Fas receptor by the Fas ligand, or the secretion of permeabilizing molecules by NKC.
Apoptosis involves mitochondrial inactivation and the release of cytochrome c in the cytosol.
The lack of ATP induces phosphatidyl serine exposure to the plasma membrane (the “eat-me” signal) and cell blebbing.
Cell fragments are internalized by macrophages and digested. No inflammation (activation of the innate immune system) occurs .
See movie 18.1 apoptosis
The p53 protein holds the cell cycle at the G1/S checkpoint in the presence of DNA damage
p53 is a tetrameric 393 aa protein
p53 consists of 3 domains :
1 100 200 300 393
transcription activation domain
DNA binding domain
regulatory domain
NLSphosphorylations
The transcription activation domain interacts with the Mdm2 protein that triggers p53 degradation.
The DNA binding domain interacts with a specific DNA sequence that controls p21CIP expression
The conformation and the localization of p53 is controlled by phosphorylation and acetylation
acetylations
p53 DNA binding domains in complex with DNA
TRANSCRIPTION of p21 inhibitor
Pcdk2
cyclineEp21
p53synthesis degradation
p53-PDNA polymerase
ADN intact damagedChk inactive activep53 absent bound to DNA
(mdm2) (phosphorylated)p21 repressed expressedCDK active inactiveCycle G1S G1 stop
p53-UbMdm2
+
Double strand break
Single strand break (30 to 40 bases lacking)
Base mispairing
Chk1/2 +
Mdm2 = murine double minute oncogeneChk = checkpoint kinasep21= CIP (cdk2 inhibiting protein) = WAF1 (Wild Type p53-activated fragment)
p53 mutations are found in 50% of human cancers
Arg248
Arg175, 249, 273, 282, Gly245
Mutation frequency
Séquence primaire de p53
These mutations decrease p53 interaction with DNA, which eliminates the G1/S restriction point controlled by the Cdk2-cyclinE complex
4. Natural Killer Cells and cancer prevention
Natural Killer Cells (NKC) are components of the (innate) immune systems. They are cytotoxic against tumor cells and cells infected by viruses. They also play an important role in graft rejection.
NKC are sensitive to the molecules present at the surface of the cells. All cells in the body express MHC-I complexes that present fragments of endogenous proteins synthesized in the cell. Any change in the nature of MHC-I or in the surface concentration of MHC-I leads to NKC activation
Upon activation, NKC bind to the target cell and locally release perforin and granzyme molecules at the plasma membrane of the target cell, which triggers apoptosis.
In addition, NKC are able to recognize and kill cells with antibodies bound at their surface (adaptative immune system). Antibodies directed against surface antigens are indeed often present in cancers.
Defects in NKC production severely increases the risk of cancer
Tumor cells develop inhibitors that prevent NKC activation
See movie 24.4 killer T cells
proteins
DNA (desoxyribonucleic acid)
mRNA (ribonucleic acid)
Transcription factors
DNA state sensors
Repairenzymes
Replication factors
Apoptosis factors (mitochondrial inactivation, caspases)
p53
CELL DIVISION
CELL APOPTOSIS = CELL DEATH
UNCONTROLLED CELL DIVISION = CANCER
DNA repair mechanisms and cell fate
Radiations DNA damage apoptosisRapidly dividing cells are more sensitive to radiations
Molecular origins of cancer and possible molecular therapies
xenobiotics radiationsoxidative stress viruses & transposons
DNA damage monitoring(p53, Mdm2)
Response to growth factors(RTK, Ras, CTK, etc…)
Cell cycle checkpoints(Retinoblastoma)
permanent mutations
DNA damage
DNA repair(Xp)
cell apoptosis cell killing (NK cells, cytotoxic T cells)
permanent insertions
detoxification(AhR, CYP)
immune systemtanning
DNA integration
metastasis & angiogenesisescaping the
immune system
accelerated mutagenesis and clonal selection
proliferation
radiotherapy
apoptosis
cell division inhibitors
(taxol)
immunotherapyangiogenesis inhibitors
(angiostatin)
growth inhibition
(tamoxifen)
tumor dormancy cell killing
Angiogenesis
Decreased adhesion, Rupture of basement membraneEpithelio-Mesenchymatose Transition
Protection mechanisms
Cell cycle regulationApoptosis Immune system (Natural killer cells)Cell cycle checkpoints
Precancerous cells
Tumor (1 mm)
Vascularized tumor
MigrationImplantation
Metastasis formation
Initial mutations
Increasing variability
Clonal selection
Cancer progression
Cell evolution Genome alteration
Treatments to stop cancer progression- Anti-angiogenesis ( VEGF)- Anti-metastasis ( VEGF + cell growth)
See movies 20.2 contact inhibition20.1 breast cancer cells
Cell cycle (G1/S)
phosphatase
DNA monitoring
Cell cycle (G1/S)
DNA repair
One functional copy of retinoblastoma or p53 or APC (anaphase promoting complex cyclin degradation)
DNA repair
DNA repair & cell cycle
DNA repair
DNA repair & cell cycle
Dosimetry : Absorbed dose Equivalent and effective doseThe WR and WT coefficients
DNA structure and functionMolecular organization of lifeDNA structure and functionDiversity and function of biological macromolecules
Radioprotection : Contamination and exposure to radiationsPassive and active protectionPhysiological effects of high and low dosesCancers : mutagenesis and radiotherapyTeratogenic effects
Biological effects of ionizing radiations
The effects of radioactivity on the living matter : Interaction between ionizing radiations and waterDNA damages and repairProtective mechanisms against genome mutations
High and low doses
Average annual radiation dose : 4 mSv (large variability, from 2 to 20 mSv)2.7 mSv : natural radiation exposure1.3 mSv : artificial radiation exposure, mainly for medical imaging
Low dose : < 100 mSv
It should be remembered that individuals exhibit variable radiosensitivity, because of genetic variability in DNA repair mechanisms. About 1/1000 are more radiosensitive than the average population.
< 100 mSv : no symptoms, but increased risk of cancer0.1 Sv-2 Sv : immunodepression, reversible male sterility> 2 Sv : acute radiation syndrome : immunodepression, male sterility, gastrointestinal epithelium destruction, bleeding, neuronal effects > 10 Sv : 100% mortality
Effective dose = Absorbed dose.wR.wT
Worker reglementary limit : 20 mSv per year
Cosmic rays
Water and food
Others (nuclear tests, nuclear accidents, industrial activity)
Telluric radiations
Radon gasMedical exposure to radiations
Number of individuals whose annual dose exceeded 20 mSv in the six last years
Exposure to radiations
Medical workers
Nuclear industry
Non-nuclear industry
Dentists
Rayonnements ionisants et santé 2004
Source : rayonnements ionisants et santé IRSN 2004
DE: entry doseMedical exposure to radiations
1 year of natural exposure
pulmonary radiography
tumor scintigraphy
Medical exposure to radiations : X-rays
Average effective
dose
Natural radiation
dose equivalent
Computed tomodensitometry
Contrast agents (heavy atoms)
Medical exposure to radiations : scintigraphy
Average effective
dose
Natural radiation
dose equivalent
It is necessary to properly calibrate the medical imaging apparatus or techniques using ionizing radiations (X-rays, CT-scan, PET-scan, SPEC, PET/CT…)
CT : computed tomographyPET : positron emission tomographySPEC : single photon emission computed tomography
Medical use of radiations : radiotherapy
http://www.cancer.gov/cancertopics/factsheet/Therapy/radiation#q11
absorbed radiation dose
Curative lymphomas 20-40 Gysolid tumors 60-80 Gy
Preventive (to prevent metastasis or relapse)45-60 Gy in 1.5-2 Gy fractions
The dose depends on- Cancer type : some cancer cells are more radioresistant- Oxygenation level : hypoxic cells are more radioresistant- The tumor size : large tumors are more radioresistant- The use of radiosensitizers : cisplatin
Cancers induced by the radiotherapy may occur about 20 years after the treatment
The main concern is the proper localization of the tumor image assisted radiotherapy
About 50 years exposure Local exposure equivalent to 1000 years !
High dose exposure
Radiations DNA damage cell death by apoptosis, thanks to the cell cycle checkpoints, if they are effectiveCell survival curves to estimate cell sensitivity to radiations Cytogenetic dosimetry to estimate whole body radiation exposureThe Acute Radiation Syndrome
As a consequence to DNA damage, radiations inhibit mitosis and induce apoptosis.
Dividing cells are more sensitive to radiation : embryonic cells, immune system, intestinal epithelial cells
2 Gy induce about 100 double strand DNA breaks per cell and kill a dividing cell
Physiological high dose effects (immediate cell death)
Because of DNA repair mechanisms, cell death probability depends on dose fractionation
1 hit model → linear survival curve
Several hit model or repair mechanisms → curved survival curve
The survival fraction SF dependence on the dose D is often described by a “linear-quadratic model” :
SF = exp[-(αD+βD2)]The ratio (in Gy) is indicative of the cell radiosensitivity
Survival curves
dose
Sur
viva
l fra
ctio
n
Radiation induced DNA damages : cytogenetic dosimetry
Radiations damage DNA. The relative biological efficiency (RBE) depends on the radiation LET.
The frequency of chromosomal modifications in blood lymphocytes allows measuring the effective dose
Physiological sensitivity to radiations : cell death and the acute radiation syndrome
Dividing cells are more sensitive to radiation :
Cell type E50%
Embryonic cellsSpermatogonies
oligozoospermy 0.15 Svmale sterility 2-4 Sv
Cristalline epithelial cells 1 SvLymphocytes 2-3 SvIntestinal epithelial cells 10 SvSkin basal cells 6-10 SvLung epithelial cells 6-10 SvSpermatozoids 100 Sv
Robert N. Cherry, Jr. LES RAYONNEMENTSIONISANTS. ENCYCLOPÉDIE DE SÉCURITÉ ET DE SANTÉ AU TRAVAIL 48.1
Internal and external exposure to radiations and particles
External exposure : radiations and particles. The effective dose depends on protective materials.
Internal exposure : ingestion of radioactive atoms. The effective dose depends on the biological life time (clearance time) and the radioactive decay time.
Passive protection : gloves, shields, fallout shelters etc…
Active protection : potassium iodide (KI) protects the thyroid from ingested radioactive iodineNeumune (5-Androstenediol) reduces the consequences of acute radiation syndrom by stimulating immune cell proliferation. This product has been withdrawn, probably because of side effects (similar to androsterone)
Low dose exposure
Radiations DNA damage mutations cancers or teratogenicityThe effects of radiations on the embryonic development are well describedThe relationship between low doses and the apparition of cancers is not easy to study : linear – no threshold model cumulative effects are possibleThe possible “hormesis” effectThe future of research in the biological effects of ionizing radiation and in radioprotection
Physiological sensitivity to radiations : teratogenic and cancer risks
Embryos are very susceptible to radiations< 100 mGy : apparent threshold> 200 mGy : significant risk of malformation and spontaneous abortion
Radiation exposure increases cancer risk. (cancer is responsible for 30% of deaths)
The linear dose-effect relationship at low dose is a matter of debate
R0 : natural cancer probabilityf(D) : dose-effect relationship. f(D) is linear for most cancers, quadratic for leukemiag(b) : individual susceptibility
Protective effect of low doses : the hormesis* effectExperimental evidence in mice
Sykes et al. (2006) Dose-Response, 4(4):309–316, published by the International Hormesis Society
0.1 Gy
*Greek word meaning "rapid motion, eagerness"
At the cell level, a low level of radiation may induce DNA repair mechanisms and may protect from subsequent radiation exposure
At the level of the whole organism, the beneficial effects of low dose exposure is a matter of debate
As a consequence, low dose effects are described by a linear no threshold model (LNT model). Low dose radiation exposure could therefore be cumulative.
T. D. Luckey 1999 Radiation Hormesis Overview*RSO Magazine ▪ Volume 8, Number 4T. D. Luckey (2011) Biological Effects of Ionizing Radiation: a Perspective for Japan. Journal of American Physicians and Surgeons 16: 45-46
Robert N. Cherry, Jr. LES RAYONNEMENTSIONISANTS. ENCYCLOPÉDIE DE SÉCURITÉ ET DE SANTÉ AU TRAVAIL 48.1
?
ZEP : zero equivalence point
Perspectives in the study of the biological effects of ionizing radiations
Genome analysis of individuals and populations is becoming possible
The radiosensitivity of individual cells can be explained and numerically simulated at the molecular level
Drugs could be developed against the acute radiation syndrome or to improve DNA repair mechanisms
http://www.genome.gov/sequencingcosts/
Eschrich et al. 2009. Systems Biology Modeling of the Radiation Sensitivity Network: A Biomarker Discovery Platform. Int J Radiat Oncol Biol Phys. 75: 497–505.
Information accessible on internet :
http://www.cancer.gov/cancertopics/understandingcancer
http://www.photobiology.com/educational/len/
http://en.wikipedia.org/wiki/DNA_repair
http://fr.wikipedia.org/wiki/Dose_efficace
http://fr.wikipedia.org/wiki/Dose_Equivalente
http://www.radscihealth.org/rsh/Papers/FrenchAcadsFinal07_04_05.pdf
http://www.euronuclear.org/
http://www.cancer.gov/cancertopics/factsheet/Therapy/radiation
Apoptosis
Apoptosis is one form of programmed cell death, often observed in higher eukaryotes during development, selection of immune system cells, and cancer prevention by NKC
Apoptosis can be triggered by intracellular processes, such as DNA damages, or by extracellular molecules, for instance activation of the Fas receptor by the Fas ligand, or the secretion of permeabilizing molecules by NKC.
Apoptosis involves mitochondrial inactivation and the release of cytochrome c in the cytosol.
The lack of ATP induces phosphatidyl serine exposure to the plasma membrane (the “eat-me” signal) and cell blebbing.
Cell fragments are internalized by macrophages and digested. No inflammation (activation of the innate immune system) occurs .
See movie 18.1 apoptosis
Further readings :
http://www.who.int/mediacentre/factsheets/fs303/en/index.html