Radiobiology - mums.ac.ir · 2017-10-04 · Radiobiology • is the interdisciplinary field of...

Radiobiology

By: Asadinezhad, MohsenPhD in Medical Physics

Ver:1-96

Reference

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Other References

انشگاه راديوبيولوژی و حفاظت، دکتر محمد باقر توکلی، د1.اصفھان

گ ، دکتر ھوشنپرتوھافيزيک و آثار زيست شناختی 2.، دانشگاه شيرازمھديزادهمحمدی، مھندس سيمين

ده ، فريدون ديکاسارتپ السنپرتوی، شناسیزيست 3.ور، محبوبه راعی، نشر دانشگاھی

ھرمان ،پرتوشناسیآشنايی با فيزيک بھداشت از ديدگاه 4.، سپھری، بينش، نشر دانشگاھیابوکاظمی، سمبر

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Other References

1. Radiation Biophysics, Edward L. Alpen, Prentice-Hall International Editions

، نشر دانشگاھیآلپنبيوفيزيک تابش، ادوارد 2.3. Radiologic Sciences for Technologists,

S.C.Bushong, The C.V.Mosby Company4. Primer of Medical Radiobiology, E.L.Travis, Year

Book Medical Pub.

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لجلد اوراديوبيولوژی برای راديولوژيست ھال. پروفسور اريک ج: نگارندهدکتر حسين مزدارانی: مترجم

عنوانفصلفيزيك و شيمي جذب تشعشع1و ناهنجاري هاي كروموزومي DNAپارگي هاي رشته 2منحني هاي بقاي سلول3حساسيت پرتوي و سن سلول در چرخة ميتوزي4ترميم آسيب تشعشعي و اثر آهنگ دز5اثر اكسيژن و اكسيژن دار شدن مجدد6انتقال خطي انرژي و اثر بيولوژيكي نسبي7آثار حاد تابش گيري كل بدن8محافظ هاي پرتوي9

سرطان زايي تشعشع10آثار وراثتي تشعشع11اثر تشعشع بر رويان و جنين12كاتاراكتزايي تشعشع13دزها و مخاطره ها در پرتونگاري تشخيصي، پرتونگاري مداخله اي، كارديولوژي و پزشكي هسته اي146حفاظت در برابر تشعشع15

Radiobiology

• is the interdisciplinary field of science that studies the biological effects of ionizing and non-ionizingradiation of the whole electromagnetic spectrum, including radioactivity (alpha, beta and gamma), x-rays, ultraviolet radiation, visible light, microwaves, radio wave, low-frequency radiation (such as used in alternate electric transmission, ultrasound, thermal radiation (heat) and related modalities.

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Contents

• A Brief History• Definitions and Units • Molecular Composition of Body• Cellular Biology• Is there RADIATION in this room?• Radiobiology• Biological effects at various levels• Law of Bergonie and Tribondeau

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Contents• Radio Sensitivity Factors• Radiation Dose-Response Relationships• Types of Radiation Effects• Target Theory• Factors Affecting on Cell Survival Curve • Early Responses to Radiation in Humans• Late Responses to Radiation in Humans• Risk Estimates• Principles of Radiation Protection

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A Brief History

Radiobiology

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Dr Rome Wagner and assistant

Advertising 1901

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ca. 1925“good for nervous disorders,insomnia, general debility,arthritis, and rheumatism”

“Empty contents in a quart ofhot water. After a few momentsadd to regular bath solution.Remain in bath 45 minuteswith cover over top of tub.Upon leaving bath relax in bedfor one hour”

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Shoe-Fitting Fluoroscope (ca. 1930-1940)

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Shoe-Fitting Fluoroscope (ca. 1930-1940)

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Generally 50 kV, 3-8 mA, 20 s

First Reports of InjuryLate 1896Elihu Thomson

burn from deliberate exposure of finger

Edison’s assistant, Clarence Dally, - hair fell out & scalp became inflamed & ulcerated

By 1904 Dally had developed severe ulcers on both hands and arms, which soon became cancerous and caused his early death17

Mihran Kassabian (1870-1910)

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Sister Blandina(1871 - 1916) 1898, started work as

radiographer in Cologne held nervous patients &

children withunprotected hands

controlled the degree ofhardness of the X-raytube by placing her handbehind of the screen.

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Sister Blandina After 6 months strong flushing & swellings of hands some fingers amputated then whole hand amputated whole arm amputated 1915 severed difficulties of breathing extensive shadow on the left side of her thorax large wound on her whole front- and back-side Died on 22nd October 1916.

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Memorial to Radiation Martyrs• At the Sankt Georg Hospital in Hamburg, Germany• The central stele, dedicated in 1936, contains the names

of 159 physicians, scientists, and others from 15 countries who died as a result of working with X-rays and radium.

• in 1959: 360 individuals•

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Early Protective Suit

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Definitions and Units

Definitions, Units

1. DefinitionsIonizing and Non-IonizingRadiation Types

ElectromagneticParticulate (Charged, Uncharged)

2. Units Activity, Exposure, Absorbed dose, Dose equivalent, Equivalent Dose, Effective DoseLET, RBE, WR, WT

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Ionizing Radiation• Type of radiation that produces the ejection of an orbital

electron from an atom or molecule and results in theformation of an ion pair. Ionization potential of mostbiological molecules is 10-15 eV.

Threshold in water ~ 13 ev

Non-Ionizing Radiation• Deposits insufficient energy to eject electron, but can

induce excitation or molecular vibration and heat.Examples include UV and microwaves.

• Excitation Threshold in water ~ 7.4 eV• Thermal Transfer (vibration, rotation, translation)

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Radiation Types

Electromagnetic (Photons)X RaysGamma Rays

Particulate (Charged, Uncharged)Electrons/PositronsProtonsAlpha ParticlesNeutrons

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Radiation units and dose quantities

Source strength:Activity (Ci, Bq)kVp, mAs…

Exposure (R, C/Kg)Exposure rate (R/h)

Absorbed dose (rad, Gy)

Equivalent Dose (rem, Sv)

Effective Dose

Radiation source Radiation beam Absorbing Medium

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New and Old Units of Radiation and Radioactivity

Quantity Definition Old Unit New Unit (SI) Equivalence

Activity

Exposure

Absorbed dose

Dose equivalent*

Equivalent Dose*

*measure of biological effects

A=dN/dt Ci (Curie) 3.7 x 1010 dps

Bq (Becquerel) 1 dps Bq1010x 3.7 Ci = 1

X=dQ/dm R (Roentgen)C/kg

(Coulomb/kg)1 R = 2.58 x 10-4 C/kg1 C kg-1 = 3876 R

D=dE/dm rad 100 erg/gr

Gy (Gray)J/kg

1 Gy = 100 rad1 rad = 0.01 Gy

…×fQ×DH= Rem Sv (Sievert) 1 Sv = 100 rem1 rem = 0.01 Sv

Rem Sv (Sievert) 1 Sv = 100 rem1 rem = 0.01 Sv

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Relation between absorbed dose and exposure

• It is possible to calculate the absorbed dose in a material if the exposure is known

• D [Gy] = f . X [R]– f = conversion coefficient depending on medium

• The absorbed energy in a quantity of air exposed to 1 [R] of X Rays is 0.869 [RAD]– f air = 0.00873 Gy/R = 0.873 RAD/R

– f med (Gy/R)= 0.00873 µen−medµen−air

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Example of conversion coefficient

f values (RAD / R)

Photon energy Water Bone Muscle

10 keV 0.91 3.5 0.93

100 keV 0.95 1.5 0.95

1 MeV 0.97 0.93 0.97

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Dose equivalent

• The dose equivalent, H, is the product of Qfand D at a point in tissue, where D is theabsorbed dose and Qf is the quality factor atthat point, thus:

H = D. Qf

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Quality Factor

• In the early 1960s, the radiation quality factor, Qf , was as a function of LET and denoted as L in the Q(L) function of Publication 26 (ICRP, 1977).

• Q(L) = 1 for L < 10 keV/µm= 0.32 L - 2.2 for 10 ≤ L ≤ 100 keV/µm= 300 / √L for L ≥ 100 keV/µm

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Linear Energy Transfer• LET is the energy transferred to the medium

per unit length of the ionization track. • LET is generally expressed in units of keV/μm

LET = dE / dlkeV/µm

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LET

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LET (keV/µm)Radiation< 3.5X-ray, Gamma< 3.5Electrons (Betas)approx 175Alpha

approx 5> 53> 175> 53approx 23

Neutrons- thermal- 0.01 MeV- 0.1 MeV- >0.1 - 2 MeV - > 2 MeV - 20 MeV

4000-9000Fission Fragments

Dose equivalent & Quality Factors

RADIATION TYPE QUALITY FACTORPhotons 1Electrons 1Neutrons

energy <10 keV 510 keV < energy < 100 keV 10100 keV < energy < 2 MeV 202 MeV < energy < 20 MeV 10energy > 20 MeV 5

Protons, energy > 2 MeV 5Alpha particles and other atomic nuclei 20

H = D. Qf

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Radiation Weighting Factors

In Publication 60 (ICRP, 1991b) the method ofradiation weighting was changed. TheCommission selected a general set of radiationweighting factors (wR) that were definedlargely on the basis of the relative biologicaleffectiveness (RBE) of the different radiations.

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Relative Biological Effectiveness

The ratio of the dose of standard radiationnecessary to produce a given effect to the doseof test radiation needed for the same effect.

RBE= Dose of 250 kVp X-rays for Observed Biological EffectDose of Test Radiation for the Same Biological Effect

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LET-RBE relationship

• Examples of 100 keV/μm radiation include 300 keV neutrons, low energy protons, and low energy alpha particles.

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Organ Equivalent Dose

• In 1991 the International Commission onRadiological Protection introduced a quantitycalled organ equivalent dose, based on theradiation weighting factor wR and DT,R themean absorbed dose in a tissue or organ.Accordingly, the organ equivalent dose HT,Rin a tissue or organ T by the radiation type Ris:

HT,R =WR .DT,R

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Organ Equivalent Dose

• In a mixed radiation field the following equationapplies for the overall organ equivalent dose HT in atissue or organ T:

RTR

RT DWH ,.

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Radiation Weighting Factors (ICRP report 60) 1991 RT

RRT DWH ,.

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Radiation Weighting Factors (ICRP report 103) 2007 RT

RRT DWH ,.

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WR for Neutrons (ICRP report 103)

2007

Calculate WR for 2 MeV neutrons. Answer: 17.34 43

Detriment

• Radiation exposure of the different organs andtissues in the body results in differentprobabilities of harm and different severity

• The combination of probability and severity ofharm is called “detriment”.

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Tissue weighting factor

• To reflect the combined detriment fromstochastic effects due to the equivalent dosesin all the organs and tissues of the body, theequivalent dose in each organ and tissue ismultiplied by a tissue weighting factor, WT,and the results are summed over the wholebody to give the effective dose E

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Effective dose, E• Effective Dose is used to compare radiation doses

on different body parts on an equivalent basisbecause radiation does not affect different parts inthe same way. The effective dose (E) to anindividual is found by calculating a weightedaverage of the equivalent dose (H) to different bodytissues, with the weighting factors (W) designed toreflect the different radiosensitivities of the tissues:

• The unit for effective dose is the sievert (Sv).46

Tissue weighting factors, WT (ICRP 60) 1991

Organ/Tissue WT Organ/Tissue WT

Gonads 0.20 Breast 0.05

Bone marrow 0.12 Bladder 0.05

Stomach 0.12 Thyroid 0.05

Colon 0.12 Bone surface 0.01

Lung 0.12 Skin 0.01

Oesophagus 0.05 Remainder 0.05

Liver 0.05 Total 1.00

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Tissue weighting factors, WT (ICRP 103) 2007

Organ/Tissue WT Organ/Tissue WT

Gonads 0.08 Breast 0.12

Bone marrow 0.12 Bladder 0.04

Stomach 0.12 Thyroid 0.04

Colon 0.12 Bone surface 0.01

Lung 0.12 Skin 0.01

Oesophagus 0.04 Remainder 0.12

Liver 0.04 Salivary Glands 0.01

Brain 0.01 Total 1.0048

Remainder tissues

• Adrenals, Extrathoracic (ET) region, Gallbladder, Heart, Kidneys, Lymphatic nodes,Muscle, Oral mucosa, Pancreas, Prostate (♂),Small intestine, Spleen, Thymus, Uterus/cervix(♀)

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Effective Dose (ICRP 103) 2007

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From Gy to Sv: Quantities and Units for Radiation

Exposure

Absorbed Dose

Equivalent Dose

Effective Dose51

Development of Radiation Injury

• Initial Physical Interaction Excitation, Ionization

• Physiochemical Free Radical Formation

• Chemical Damage Radical Attack

• Biomolecular Damage DNA, Proteins, etc.

• Early Biological Effects Toxicity, Mutation

• Late Biological Effects Cancer, Genetic Effects

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Development of Radiation Injury

• Initial Physical Interaction 10-24 - 10-14 s

• Physiochemical 10-12 - 10-8 s

• Chemical Damage 10-7s - hours

• Biomolecular Damage ms - hours

• Early Biological Effects hours - weeks

• Late Biological Effects years - centuries

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Molecular Composition of Body

Molecular Composition• There are five principle types of molecules

in the body:– Four are macromolecules , sometimes

consisting of hundreds of thousands of atoms.• Proteins• Lipids (fats)• Carbohydrates (sugars and starches)• Nucleic Acids (DNA)

– DNA is the most critical & radiosensitive molecule.

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Molecular Composition

• 80% Water• 15% Protein• 2% Lipids• 1% Carbohydrates• 1% Nucleic Acid (DNA)• 1% Other

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Cellular Biology

Human Cell Composition

• Two major structure ofthe cell are:

• Nucleus containing theDNA

• Cytoplasm makes upthe bulk of the cell andcontains all of the othercell structures.

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Nuclear Components

• Nuclear envelope• Chromosomes• Nucleolus• Nuclear sap – the liquid portion of a cell nucleus

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Nuclear Envelope

• Membrane– Separates the nucleus from the cytoplasm– A double-walled structure with a space within the walls– The only known materials that can pass through this

membrane are RNA’s and some proteins that are incorporated into the nuclear structure

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Chromosomes• Linear threads in the nucleus • Composed of protein and DNA

– DNA encodes the information that controls that cell’s metabolism and reproduction

– DNA is considered the genetic material• It serves as a template to produce an exact copy of itself used in cell

division

• Humans contain 46 (23 pairs) of chromosomes.

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DNA Structure

• Consists of deoxyribose– Sugar in the backbone

• Phosphoric acid– A phosphate in the backbone

• Four nitrogenous bases– Adenine, guanine, thymine, cytosine

• The actual genetic code

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DNA Structure

• DNA looks like a twisted ladder• The bases are the rungs• The backbones are the sides

– The backbones are made up of sugar, deoxyribose, and phosphoric acid

– The backbones are twisted around each other, forming a double helix

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Genes

• The basic unit of heredity• Made up of long sequences of DNA on a

chromosome• Genes are found in pairs• Some govern the number of organs and limbs• Others determine height, skin and eye color,

and gender

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Nucleolus

• A single spherical structure usually found in the nucleus

• Composed of RNA (ribonucleic acid)• Controls protein synthesis• Similar to DNA in structure

– Its sugar is ribose as opposed to deoxyribose– The base uracil replaces thymine– It is a single helix

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The Forms Of RNA• Messenger RNA

– Carries the code for specific amino acid sequences from DNA to cytoplasm for protein synthesis

• Transfer RNA– Transfer amino acid groups to ribosome for protein synthesis

• Ribosomal RNA– Exists in the ribosomes – Thought to assist in protein synthesis

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Cytoplasm

• All metabolic functions occur here– The duplication of DNA, production of hormones, and

converting of sugars to starches• Anabolism

– The breaking of the carbon-hydrogen bond to release the energy of glucose

• Catabolism

• These functions are used in energy conversion– This serves to store or release energy

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Cell Membrane

• A selectively permeable structure• Analogous to the skin of an organism – a limiting

mechanism• Composed of lipids and membranes• Transport proteins assist in the passage of

substances through the membrane and throughout the cell

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Cell Proliferation

• Cell proliferation is the act of a single cell orgroup of cells reproducing and multiplying innumber.

• It takes many thousands of rads to disruptmacromolecules, single ionizing events tosensitive cell sites can disrupt proliferation.

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Types of Cell Proliferation

• Genetic cells (oogonium of the female and spermatogonium of the male) undergo meiosis.

• Somatic cells undergo mitosis.

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Cell DivisionSomatic Cells

• Mitosis• Each daughter cell contains the same number

of chromosomes as the parent cell• This cycle has 5 phases

– Four are cell-reproduction phases• Interphase• Prophase• Metaphase• Anaphase• Telophase

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Cell Cycle

Meiosis

• Genetic cell division is called meiosis.• Genetic cells begin with 46 chromosomes like

somatic cells.• During the first division, the daughter,

replicated the DNA with 46 chromosomes.

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Meiosis

• During the second meiosis, there is no S phase so the DNA does not replicate. Granddaughter cells have 23 chromosomes.

• There is some exchange of chromosomal or crossover resulting in the genetic constitution and changes in inheritable traits.

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Cell development

• Underdiffentriated cell, precursor cells or stem cells are immature cells. They are more sensitive cells to radiation than mature cells.

• The sensitivity of cells to radiation is determined to some degree by its state of maturity and its functional role.

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Cell development

• The tissues and organs of the body contain both stem and mature cells.

• There are several types of tissue classified by their structural or functional appearance. These features influence the degree of radiosensitivity of the tissue.

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Some Terms

• Mutagen• Clastogen• Carcinogen• Teratogen

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Mutagen• A physical or chemical agent that changes the

genetic material, usually DNA, of an organism and thus increases the frequency of mutations.

• As many mutations cause cancer, mutagens are therefore also likely to be carcinogens.

• Mutagen causes changes to the DNA that can affect the transcription and replication of the DNA such as translocation, deletion, and inversion

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Translocation

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• rearrangement of parts between nonhomologouschromosomes

Deletion

• A part of a chromosome or a sequence of DNA is missing

• Type:– Terminal Deletion– Interstitial Deletion– microdeletion

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Mutagen• Types of mutagens:

– Physical: Ionizing radiations & UV– Chemical: Benzene– Metals: arsenic, cadmium, chromium, nickel– Biological: Rous sarcoma Virus, Helicobacter pylori

bacteria• Mutagen Sensitivity:

– DNA > mRNA > tRNA > rRNA > amino acid > Protein

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Clastogen

• A material (Mutagen) that can cause breaks in chromosomes, leading to sections of the chromosome being deleted, added, or rearranged.

• Known clastogens include benzene, ethylene oxide, arsenic, Ionizing Radiation, ….

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Carcinogen• An agent directly involved in causing cancer.• This may be due to the ability to damage the

genome or to the disruption of cellular metabolic processes.

• Common examples are Ionizing radiation, inhaled asbestos and tobacco smoke.

• Protection against carcinogens– Antioxidants are important groups of

anticarcinogenic compounds. Example of antioxidants are vitamin A, vitamin C, vitamin E.

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Teratogen

• An agent, such as a virus, a drug, or radiation capable of interfering with the development of an embryo fetus that may lead to birth defects or developmental malformations.

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Do not adjust your set87

Is there RADIATION in this room?

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Radiation - We live withNatural Radiation: Cosmic rays, radiation within our

body, in food we eat, water we drink, house we live in, building material etc.

Human Body: K-40, Ra-226, Ra-228e.g. a man with 70 kg wt. 140 gm of K

140 x 0.012%=0.0168 gm of K-400.1 Ci of K-40

28,000 photons emitted/min(T1/2 of K-40 = 1.3 billion yrs)

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Radiation - We live withFood Radioactive levels (Bq/kg)

Daily intake (g/d)

Ra-226 Th-228 Pb-210 K-40

Rice 150 0.126 0.267 0.133 62.4Wheat 270 0.296 0.270 0.133 142.2Pulses 60 0.233 0.093 0.115 397.0Other Vegetables 70 0.126 0.167 -- 135.2Leafy Vegetables 15 0.267 0.326 -- 89.1Milk 90 -- -- -- 38.1

Composite Diet 1370 0.067 0.089 0.063 65.0

Dose equivalent = 0.315 mSv/yrTotal dose from Natural sources = 1.0 to 3.0 mSv/yr

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Radiation from Natural Sources

• Normally 1-3 mSv/year• In areas of high background, 3-13 mSv/year

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Radiobiology

• Radiobiology is the study of the effects ofionizing radiation on biologic tissues.

• The ultimate goal of research is to developdose-response relationships so the effects ofplanned doses can be predicted and theresponse to accidental exposure bettermanaged.

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Radiobiology

• The effect of x-ray radiation on humans is the result of interactions at the atomic level.

• The forms of interaction:– Ionization of the tissue– Excitation of orbital electrons

• Results is the disposition of energy in the tissues.

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Effects of Irradiation in Humans

• Most of the observed effects have beenobserved after rather large doses.

• As operators of x-ray machines, we mustassume that even small doses can be harmful.

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Human Populations in Which Radiation Effects Have Been Observed

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EffectPopulationLeukemia, reduced life spanAmerican radiologistsMalignant diseaseAtomic bomb survivorsAcute lethalityRadiation accident victimsThyroid cancerMarshall IslandersLung cancerUranium minersBone cancerRadium watch dial paintersThyroid cancerPatients treated with 131IThyroid cancerChildren treated for enlarged thymusChildhood malignancyIrradiation in uteroFertility impairmentVolunteer convicts

Radiation Interaction at the Atomic Level

• At the most basic level, the human body ismade up of atoms.

• Radiation interacts at this level.• The atomic composition of the body

determines the character and degree of theradiation interaction.

• The molecular and tissue composition definesthe nature of the radiation response.

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Radiation Interaction at the Atomic Level

• Over 85% of the body is composed ofhydrogen and oxygen.

• Radiation interaction at the atomic level resultsin molecular change, and this in turn canproduce a cell deficient in normal growth andmetabolism.

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Summary of Biological EffectsSummary of Biological Effects

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Effects of Ionizing Radiation Exposure

• When the atom is ionized, its chemicalbonding properties change.

• If the atom is part of a large molecule, it mayresult in breakage of the the molecule orrelocation of the atom within the molecule.

• The abnormal molecule may functionimproperly or die.

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Effects of Ionizing Radiation Exposure

• This may result in serious impairment of thecell function or cell death.

• This process can be reversible if the atomattracts a free electron.

• Molecules can be mended by repair enzymes.• Cells and tissue can regenerate.

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Biological effects at various levels

Biological effects of radiation• Biological effects at various levels

– Molecular (DNA)– Sub-cellular– Cell– Organ– Organism

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Biological effects of radiationMolecular level

• DNA is the principal target for the biological effects of radiation– Cell killing – Mutation– Carcinogenesis

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Doubling Dose

• The dose of radiation, if given uniformally to an entire population, needed to double the spontaneous mutation rate for that population.

• For humans, this is currently estimated to be 1 to 2 Sv

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DNA Radiation Injuries

Base Pair Deletion• Pyrimidines (T, C) more

sensitive than purines (G, A).

Cross Linking InjuriesSingle Strand Break (SSB) Double Strand Break (DSB)

• Involves breakage of both strands at points less than 3 nucleotides apart

Multiple (Complex) Lesions106

LET RBE relationship• DSB of DNA is maximal at a LET of 100 keV/μm.• Examples of 100 keV/μm radiation include 300 keV

neutrons, low energy protons, and low energy alpha particles.

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• For this average LET, spacing of ionizing events equals the diameter of a DNA double helix. Greater LET energies may have closer spacing of ionizations, but such additional path ionizations do not yield additional double strand breaks.


• Macromolecules in vitro1. Main Chain Scission2. Cross-linking3. Molecular or Point lesion

108

Biological effects of radiationMolecular levelRadiolysis of Water

H2O + Radiation HOH+ + e-

H2O + e- HOH-

HOH+ H+ + OH*HOH- OH- + H*OH* + OH* H2O2

H* + O2 HO2*HO2* + HO2* H2O2 + O2

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• Radiolysis of Water

110

Biological effects of radiationSub-cellular level

Effects at sub-cellular level– DNA damage can result in chromosome aberrations– Various types of aberrations are shown schematically and

in practice:

• Chromosome Aberrationsresult if cell is irradiated early in interphase (G1), before

chromosome material has been duplicatedBreak Dicentric Ring

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DICENTRIC CHROMOSOME

112

DICENTRIC CHROMOSOME

113

CENTRIC RING

CENTRIC RING

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Biological effects of radiationSub-cellular level

• Chromatid Aberrations

• result if cell is irradiated later in interphase after DNA has doubled (G2) and chromosome consist of 2 strands of chromatinGapDeletionExchange

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Anaphase BridgeResults from breaks that occur late in cell cycle (G2), after chromosome has replicatedBreaks may occur in both chromatids of the same chromosome, sticky ends may rejoin incorrectly to form a sister unionAt anaphase, when the 2 sets of chromosomes move to opposite poles, the section of chromatin between the centromeres is stretched across between the poles, hindering separation into new daughter cellsDifficult to see in human cell cultures since bridge is only evident at anaphase

117

ANAPHASE BRIDGE

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Cellular Irradiation

• When the critical macromolecular cellularcomponents are irradiated, a dose of about 1MRad or 10 kGy is required to produce ameasurable change in the physicalcharacteristics of the cell.

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• When such a molecule is incorporated into theapparatus of a living cell, only a few rad arenecessary to produce a measurable response.

• Some single cell organisms require massiveexposure to produce a lethal dose.

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• Human cells can be killed with a dose lessthan 100 rad (1Gy).

• The nucleus is much more sensitive than thecytoplasm to radiation exposure.

• Interference with any phase of proteinsynthesis could result in cell damageparticularly DNA.

123

Biological effects of radiationCellular level

• Effects at cellular level– Irradiated cells can loose their

capacity for proliferation

Cell most sensitive to radiation

124

1

2

5

4

3

Radiation-induced Bystander effect• The phenomenon which non-irradiated cells exhibit effects

along with their different levels as a result of signals received from nearby irradiated cells.

125

Radiation-induced Bystander effect• Responses of non-irradiated cells may include:

– changes in process of translation– gene expression– cell proliferation– Apoptosis– Cells death.

• Most well-known important factors affecting radiation-induced bystander effect include:– free radicals– immune system factors– expression changes of some genes involved in

inflammation pathway– epigenetic factors. 126

Law of Bergonie & Tribondeau (1906)

“The radiosensitivity of a tissue is directly proportional to its reproductive capacity and inversely proportional to its degree of differentiation”

127

Law of Bergonie & Tribondeau

The radiosensitivity of living tissue increases as follows:

1. Undifferentiated cells Stem cells are radiosensitive.2. The younger tissues and organs3. High level of metabolic activity4. As the proliferation rate for cells and the growth rate for

tissues increases

128

Radio Sensitivity

MuscleBonesNervous system

SkinMesoderm organs (liver, heart, lungs…)

Bone MarrowSpleenThymusLymphatic nodesGonadsEye lensLymphocytes (exception to the RS laws)

Low RSMedium RSHigh RS

129

130

Woman of Reproductive Age: 10 days rule

Radio Sensitivity Factors

Radio Sensitivity Factors1. Physical factors:Dose Radiation type (QF)Dose rate (Protraction)Fractionation (acute & chronic)Whole body or partial body2. Biological factors:AgeSexOxygenRecovery Dose modifiers132

Oxygen

• The Oxygen Enhancement Ratio (OER) reflects the increased number of reactive free radicals (leading to increased indirect damage) generated in the presence of oxygen in irradiated tissues.

133

OER= Dose in Hypoxic Condition to produce a given effect Dose in Aerated Condition to produce same effect

Oxygen• This phenomenon is valid only for low LET

radiation (i.e. cannot be demonstrated for particles with LET >150 keV/μm).

134

Oxygen

• The OER for most mammalian cells is 2.3-3.0

135

30 mm Hg

PO2 in arterial blood 80-100 mm Hg

Air(21% O2)

160 mm Hg

Recovery

• Repopulation• Repair

136

Repair• Cellular mechanisms are in place which can

repair most if not all types of radiation injury to the DNA.

• Repair is a time sensitive process.• Repair is a cell cycle dependent process.

– From most to least repair capability: S, G1/G0, G2, M• Repair is a dose rate dependent process.• Repair is dose dependent.• Repair is radiation type dependent.

137

Radiation Damage Type• LD (Lethal Damage)

– Fatal to cell– Irreversible– Irrepairable

• SLD (Sub Lethal Damage)– Repairable injury to the DNA– Two SLD may result LD

• PLD (Potentially Lethal Damage)– Damage which is lethal unless modified by post

irradiation events138

Sub Lethal Damage Repair• 3 R

– Repair– Reassortment– Repopulation

• Additional R– Re-Oxygenation

139

Reoxygenation & Fractionation

140

Dose Modifiers

• Radiation Sensitizers• Radiation Protectors

141

Radio Sensitizers• Oxygen mimics • Metronidazole, Misonidazole, Adriamycin,

Bleomycin, Actinomycin-D, Methotrexate • Dose Enhancement Factor (DEF)

142

DEF= Dose with Radiation AloneDose with Radiation + Drug for the same biological effect

Hyperthermia

• Tumor cells in general are more sensitive to thermal damage than normal cells.

• Cells subjected to thermal stress (43 C for 30-60 minutes) are more sensitive to radiation injury than non-heated cells.

• Dose-modifying factors of 2-10 have been reported.

143

Radio Protectors• Agents that, when given before or during radiation,

reduce the likelihood of early and/or late effects of radiation by Scavenging of Free Radicals.

• Most radio protectors are Sulfhydryl compounds (contain -SH groups).

• Examples: cysteine, cysteamine, cystamine

144

Radio Protectors

• Dose Reduction factor (DRF) of 1.2-2.7• Unfortunately, most of them produce toxicity at

radioprotective doses.

145

DRF= Dose of radiation in the presence of the drug Dose of radiation in the absence of the drug

To produce a given level of lethality

Radio Protectors

• Amifostine (WR-2721), a non-sulfhydryl molecule has been used more effectively for radioprotection in humans.

• Suitable for low LET radiations

146

Radiation Dose-Response Relationships


Response

Radiation Dose

148

Response

Radiation Dose

Linear Nonlinear


Response

Radiation Dose

149

Response

Radiation Dose

Threshold Nonthreshold


Response

Radiation Dose

150

Ambient or Natural Response Level


Radiation Dose

151

Response

Inflection Point

Sygmoid Type or S-Type Relationship

Target Theory

Target Theory

• Target Molecule• Target• Hit• Cell Survival Kinetics

153

Target Theory

• Plating Efficiency (P.E)

• Cell Survival Fraction (S.F)

• Single Target, Single Hit Model

• Multi Target, Single Hit Model

154SF=تعداد کلونی ھای شمارش شده

تعداد سلول ھای کشت شده× %PE

PE= تعداد کلونی ھای شمارش شدهتعداد سلول ھای کشت شده

Single Target, Single Hit Model

155

تعداد مربعهاي خشك

تعداد قطرات باران

37100142005300

Single Target, Single Hit Model

156

10

درصد سلولهاي زنده مانده

1

100

)راد(دز

37

37D

در صد دزبقا

3737D142 ×37D53 ×37D

37

0

. DD

eNNFS

مدل مورد استفاده هدف هاي بيولوژيك مثل آنزيم ها، ويروس ها و سلول هاي ساده مثل باكتري ها

Multi Target, Single Hit Model

157

Multi Target, Single Hit Model

158

0D 0

0

n

)1(1. 0

DD

Ln

eNNFS

Q

nDD

0/1

اكسر بق

0/01

1

)راد(دز 0/001

0/037

QD

n

D10

• D10= 2.3 D0

159

rad)(0Drad)(QDنوع سلول9162اووسيت موش135350پوست موش

137100مغز استخوان انسان150160فيبذوبالست انسان400100لنفوسيت انسان

The linear-quadratic model

• The effects of low doses of low LET radiation

• S.F = e –αD-βD2

• If αD = βD 2 or D=α/β

160

The linear-quadratic model

• At dose D Linear contribution to cell killing = Quadratic contribution to cell killing

• Continuous bending of cell-survival curve

• No final straight portion

161

Factors Affecting on Cell Survival Curve


• Dose rate• LET• Fractionation• Oxygenation

163

0/1

اكسر بق

0/01

1

)راد(دز 0/001

Low Dose Rate

High Dose Rate



164

Low LET

High LET



165



166

0/1

اكسر بق

0/01

1

)راد(دز 0/001

Low LETHigh LET

HypoxicWell Oxygenated

Types of Radiation effects


• Somatic & Genetic

• Somatic Effects appear in the exposed person.• Result of radiation damage to the somatic cells.

168


• Somatic & Genetic

• Genetic, or heritable effects appear in the future generations of the exposed person as a result of radiation damage to the reproductive cells.

• They have been extensively studied in plants and animals, but risks for genetic effects in humans are seen to be considerably smaller than the risks for somatic effects.

169


• Early & Late

• If the response to radiation happens in minutes or days it is referred to as Early (or Prompt) effects.

• typically 10 rad or greater to the whole body in a short period of time

• e.g: the temporary hair loss: occurs about three weeks after a dose of 400 rad to the scalp

170


• Early & Late

• If the responds is not observed for six months or more, it is termed to be Late (or Delayed) effects.

• e.g: an increased potential for the development of cancer and cataracts.

171

Types of Radiation effects• Stochastic & Deterministic

• Stochastic effect:– An all-or none phenomenon– The probability of occurrence increases with

increasing absorbed dose– The severity of the effect dose not depend on the

magnitude of the absorbed dose– No dose threshold

• Two major examples of stochastic effects: – Hereditary/Genetic Effects – Carcinogenesis 172


• Stochastic & Deterministic• Deterministic or nonstochastic effect:

– A somatic effect that increases in severity with increasing absorbed dose

– dose threshold– e.g: cataract, blood changes, erythema

173

Types of effects

• Stochastic & Deterministic

Severity

Radiation Dose

Threshold

Radiation Dose

Risk

Deterministic effectsErythema, Cataracts

Stochastic effectsCANCER and Hereditary defects

174

Biological effects of radiationOrgan level

• Effects at organ levelDeterministic and Stochastic effects1. Deterministic effects: skin (Erythma, Epilation,…),

Lens (Cataract), Gonads (Fertility), …2. The most important stochastic effects: – carcinogenesis (Leukaemia, Cancers of Thyroid, Bone,

Skin, Breast, Lung, Liver, …)– genetic effects

175

Biological effects of radiationOrganism level

• Effects on organisms– Cellular changes such as cell death and changes in the cell

population can lead to diseases and death.– All somatic effects are based on cell death or tumour induction.– It is important to know whether the irradiation concerns the

whole body or part of it. – In the case of partial body irradiation, repair can occur through

migration of cells from unirradiated to irradiated areas, e.g. haematopoietic tissue

– In the case of whole body irradiation, the radiation syndromes can occur.

176

Early Responses to Radiation in Humans


• Local tissue damage– Skin– Gonads– Hematologic effects

• Acute Radiation Syndrome

178


Local tissue damageSkin :– Erythma: peaking in 1-2 weeks post-exposure of 2 to 6

Gy– SED50=600Rad– Epilation: Temporary epilation occurs at doses from 3 to

7 Gy. Above 7 Gy, hair loss is permanent. – Ulceration

179

Early Responses to Radiation in HumansLocal tissue damage

Gonads: Testis'sSpermatogonia Spermatocyte Spermatid Sperm0.1 Gy decreased in number of sperm cells2 Gy Temporal Sterility 2-12 months5 Gy Permanent Sterilitypatients whose radiologic exam will contain the gonads or

when gonads will likely receive significant exposure from scatter allow at least 2 cell renewal times (approximately 130 days) before attempting to start a family.180


Local tissue damageGonads: OvariesOogonia Oocyte Ovum0.1 Gy Delayed fluor2 Gy Temporal Sterility5 Gy Permanent Sterilitypatients whose radiologic exam will contain the gonads or

when gonads will likely receive significant exposure from scatter allow at least 3 ovulatory cycles before electing to become pregnant.

181

Radiation risks to the fetus

• Fetal demise • Congenital malformation • CNS/cognitive effects • Carcinogenesis • Intrauterine growth retardation

182

Effects of Irradiation on the Human Embryo

EffectsPeriod ofDevelopment

Days afterFertilization

Most probable effects: death with little chanceof malformation

pre-implantation1 to 9(1-21)

Reduced lethal effects; malformation unlikely;intra-uterine growth retardation predominantEffect

implantation10 to 12

Production of congenital malformation; retardedGrowth

organo-genesis13 to 50(22-64)

Effects of CNS; growth retardation at highDoses

fetal51 to 280(65-280)

Increased incidence of cancer and leukaemia(4th week -)

fetal/neonateAll

183

Effects of Irradiation on the Human Embryo

184


Local tissue damageHematologic Effects:– Lymphocytes lymphopenia– Granulocytes Granulocytosis Granulocytopenia– Platelets Thrombocytopenia– Erythrocytes

185

Acute Radiation Syndrome (ARS)

• An acute illness caused by a dose greater than 50 rads of penetrating radiation to most or all of the body in a short time, usually a matter of minutes.

• Examples of persons who suffered from ARS are the survivors of the Hiroshima and Nagasaki atomic bombs and the firefighters that first responded after the Chernobyl Nuclear Power Plant event in 1986.

187

Acute Radiation Syndrome

1. The Prodromal Stage2. The Latent Stage3. The Overt or Manifest Illness Stage4. Recovery or Death

188


The Prodromal Stage• classic symptoms are nausea, vomiting, and

possibly diarrhea (depending on dose) that occur from minutes to days following exposure.

• Recovery after 2-3 days (may be shorter for very mild cases)

• More common in women than men. Age <10 years or >60 years at higher risk.

189


The Latent Stage

• the patient looks and feels generally healthy for a few hours or even up to a few weeks

190


The Overt or Manifest Illness Stage

• symptoms depend on the specific ARS syndrome and last from hours up to several months

191


Recovery or Death

• Most patients who do not recover die within several months of exposure.

• For those who recover, the process lasts from several weeks up to two years.

192

StageMin. Dose (Gy)

Mean Survival

Time (Days)

LatentPeriode Signs

Primary cause of

death

Prodromal Syndrome 1 -- -- nausea, vomiting, and possibly

diarrhea

Bone marrow or Hematologic

syndrome3 10-60 2-4

weeks

Prodromal + anemia, leucopenia, internal bleeding,

fatigue, bacterial infections, and fever.

infection and hemorrhage

Gasterointestinal(GI) syndrome 7 4-14 3-5

days

Hematologic + dehydration, electrolytic imbalance, loss of

digestion ability, bleeding ulcers

infection, dehydration

and electrolyte imbalance

Cardiovascular (CV) or Central Nervous System (CNS) syndrome

> 50 0-3 minutes to hours

Gasterointestinal + loss of coordination, loss of vision,

burning sensations of the skin, confusion, ataxia, edema,

vasculit, meningitis, coma, convulsions, shock

internal bleeding, and

fluid and pressure

build-up on the brain 193

Mean Survival Time

194

LD 50/30

LD 50/30 (Rad)Species250Pig275Dog300Human425Guinea Pig475Monkey620Mouse700Gold Fish700Hamster710Rat725Rabbit1500Turtle2000Armadillo3000Newt195

Late Responses to Radiation in Humans

Late Responses to Radiation in Humans

• Local tissue damage– Skin (Malignant changes)– Lens (Cataract: age-dependent, threshold: 0.5-2 Gy for

acute exposures & 5-6 Gy for prolonged exposures, non-linear)

– A single dose of direct irradiation of 2 to 6 Gy or Fractionated doses of 6 Gy are also likely to result in cataract.

• Life Span Shortening• Different kinds of Cancers197

Late Responses

to Radiation in Humans

Life Span Shortening

Bernard L. CohenUniversity of

Pittsburg

198

Life Span Shortening (Days)

Risk Factor

2800Being male rather than female2100Heart disease2000Being unmarried1600One pack of cigarettes a day1100Working as a coal miner980Cancer90013.6 kilograms overweight435All accidents200Motor vehicle accidents12Radiation worker1Airplane crashes

Cancers• Leukemia

– Survivors of bombing attacks at Hiroshima and Nagasaki– Radiation Therapy Patients for ankylosing spondylitis

• Thyroid Neoplasms (malignant or benign)– Survivors of bombing attacks at Hiroshima and Nagasaki – Children have greater sensitivity than adults – Chernobyl fallout (radioactive iodine) to downwind

children in Belarus – Children undergoing radiotherapy, such as for enlarged

thymus– Children undergoing radiation oncology for cancer 199

Cancers• Breast Cancer

– Female survivors of bombing attacks at Hiroshima and Nagasaki

– Female tuberculosis patients (in Nova Scotia) who received multiple fluoroscopic studies for to follow therapeutic penumothorax

– No radiogenic breast cancer risk in men has been observed in any study.

200

Cancers• Lung Cancer

– Survivors of bombing attacks at Hiroshima and Nagasaki – Patients who received radiation therapy for ankylosing

spondylitis – Underground Uranium miners (radon exposure)

• Bone Cancer – Patients who received radiation therapy for ankylosing

spondylitis – Luminous watch dial painters, who ingested radium from

their brush tips 201

Cancers• Skin Cancer

– Lack of radiation safety precautions among radiation workers of the early 20th century

• Liver Cancer– Thorotrast – a radiographic contrast agent used in the

1930s to 1950s – thorium decay released alpha particles leading to organ damage and neoplasms

202

No-Threshold Models of Risk

203

Alternative relationships for cancer risk vs. radiation dose as extrapolate to low-dose exposures: supra-linearity (A), linear (B), linear-quadratic (C) and hormesis, which implies a biologically beneficial effect at low dose (D).

Risk Estimates

Risk Estimates

Relative Risk• Estimate of late effects of radiation on a large

population without having any precise knowledge of the radiation dose to which they are exposed

205

Risk Estimates

Relative Risk• Relative Risk = Observed cases / Expected cases• Computed by comparing the number of persons in

the exposed population showing a given late effectwith the number who developed the same late effectin an unexposed population.

• RR for radiation induced late effects in human: 1-10

206

Risk Estimates

Absolute Risk• If some information is available regarding the

radiation dose and if at least two different doselevels are involved, then it may be possible todetermine an absolute risk factor.

• Number of cases/106 persons/Rad/year• Range from 1 to 10 cases/106 persons/Rad/year

207

Risk Estimates

Absolute Risk• Assume a linear dose-response relationship• If non-threshold relationship, only one dose level is

required

208

Risk Estimates

209

ifetime attributable cancer mortality risks per unit dose as a function of age at a single acute exposureestimated by National Academy of Sciences BEIR V (Biological Effects of Ionizing Radiations) committee (solid line) and in ICRP (International Commission on Radiological Protection) report 60 (dotted line).

Risk Estimates

Excess Risk• Often when an investigation of human radiation

response indicates the induction of some late effect,the magnitude of the effect will be expressed by theexcess case induced.

• Excess cases = Observed - Expected

210

Principles of Radiation Protection

Principles of Radiation Protection

1. The ICRP recommendations2. Basic principles

JustificationOptimizationDose limitation

3. Time, distance, shielding

212

• Justification of practices

• Optimization of protection

• Limitation of doses

Fundamental principles of radiation protection

213

Justification of a practice

• Justification means that anyexposure produces sufficientbenefit to offset the radiationharm that it might cause.

• Thus, if the exposure has notany benefit it is not justified.

214

Optimization of protection• When radiation is to be used

then the exposure should be optimized to minimize any possibility of detriment.

• Optimization includes the criterion: doses should be “As Low As Reasonably Achievable” ALARA

• Optimization means that minimum risk and maximum benefits should be achieved

215

As Low As Reasonably Achievable

• refers to the continual applicationof the optimization principle in theday-to-day practice.

216

Dose limitation

• No dose limitation for medical exposure of the patient - it is always assumed that the benefits for the patient outweigh the risks

• Limits need to be applied for public and occupational exposures.

217

218

Maximum Permissible Dose (MPD)

Radiation Workers(mSv)

General Public(mSv)

Date

500501931

300301936

150151948

5051958

2011990

Basic radiation protection strategies

• Radiation cannot be seen, heard or felt. Therefore it is essential to know about it.

• Can be accurately measured using appropriate instruments

• Need appropriately qualified expert

• Need signs and interlocks

Smart Ion from Mini-Instruments

219

Basic radiation protection strategies

• Hazard Reduction Methods:– Time– Distance– Shielding

220

TimeDose is proportional to

the time exposed

Dose = Dose-rate x Time

221

Distance

distance

dose

-rat

e

Dose-rate 1/(distance)2

Inverse square law

222

Shielding

incident

radiationtransmitted

radiation

223

Shielding

224

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