Dosimetry : Absorbed dose Equivalent and effective dose The W R and W T coefficients DNA structure and function Molecular organization of life DNA structure

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






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






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



Radioprotection : Contamination and exposure to radiationsPassive and active protectionPhysiological effects of high and low dosesCancers : mutagenesis and radiotherapyTeratogenic effects



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

Documents

Dosimetry : Absorbed dose Equivalent and effective dose The W R and W T coefficients DNA structure and function Molecular organization of life DNA structure