Cơ chế sinh học Vòng đời của hạt bức xạ (Radiation biology)

Stewart, PhD, DABMP 2 Take-a-Ways: Five Things You should be able to Explain after the Radiation Biology Lecture ¬ Consequences of the interaction of radiation and tissues, beginning wi

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©UW and Brent K Stewart, PhD, DABMP 1

Radiation Biology – Chapter 25

Brent K Stewart, PhD, DABMP Professor, Radiology and Medical Education

Director, Diagnostic Physics

a copy of this lecture may be found at:

http://courses.washington.edu/radxphys/PhysicsCourse04-05.html

Take-a-Ways: Five Things You should be able

to Explain after the Radiation Biology Lecture

¬ Consequences of the interaction of radiation and tissues, beginning with the chemical basis on which radiation damage is initiated

¬ Effects of radiation on DNA

¬ Variations in cellular radiosensitivity and associated expression as depicted in cell survival curves

¬ Varied response of organ systems to radiation

¬ Various risks associated with radiation-induced carcinogenesis, genetic effects, and special concerns regarding radiation exposure in utero

Determinants of the Biologic Effects of Radiation

¬ Many factors determine the biologic response to radiation exposure

¬ Radiosensitivity and complexity of the biologic system determinethe

type of response from a given exposure

¬ Usually complex organisms exhibit more sophisticated repair

mechanisms

¬ Some responses appear instantaneously, others weeks to decades

c.f Bushberg, et al The Essential Physics of Medical Imaging, 2 nd ed., p 814.

Classification of Biologic Effects

¬ Biologic effects of radiation exposure can be classified

as either stochastic or deterministic (non-stochastic)

¬ Stochastic Effect

¬ The probability of the effect, rather than its severity, with dose

¬ Radiation-induced cancer and genetic effects

¬ Basic assumption: risk with dose and no threshold

¬ Injury to a few cells or even a single cell can theoretically result

in manifestation of disease

¬ The principal health risk from low-dose radiation

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Classification of Biologic Effects (2)

¬ Deterministic or Non-stochastic Effect

¬ Predominant biologic effect is cell killing resulting in

degenerative changes to the exposed tissue

¬ Severity of the effect, rather than its probability, with dose

¬ Require much higher dose to produce an effect

¬ Threshold dose below which the effect is not seen

¬ Cataracts, erythyma, fibrosis, and hematopoietic damage are

some deterministic effects

¬ Dx radiology: only observed in some lengthy, fluoroscopically

guided interventional procedures

Interaction of Radiation with Tissue

¬ Ionizing radiation energy deposited randomly and rapidly (< 10-10sec) via excitation, ionization & thermal heating

¬ Interactions producing biologic changes classified as either direct or indirect

¬ Direct

¬ Critical targets (e.g., DNA, RNA or protein) directly ionized or excited

¬ Indirect

¬ Radiation interacts within the medium (e.g., cytoplasm) creating reactive chemical species (free radicals) which in turn interact with the a critical target macromolecule

¬ Vast majority of interactions are indirect (body 70%

-85% water)

¬ Results in an unstable ion pair, H2O+, H2O

-¬ Dissociate into another ion and a free radical (lifetime is less

than 10-5)

¬H2O+→ H++ OH•

¬H2O- → H• + OH

-¬ Combine w/ other free radicals to form molecules such

as hydrogen peroxide (H2O2) highly toxic to cell

¬ Oxygen enhances free radical damage via production of

reactive oxygen species (e.g., H• + O2 HO2•)

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Linear Energy Transfer

¬ Biological effect dependent on the dose, dose rate,

environmental conditions, radiosensitivity and the spatial

distribution of energy deposition

¬ Linear Energy Transfer (LET)

¬ Amount of energy deposited per unit length (eV/cm)

¬ LET ∝q2/KE

¬ Describes the energy deposition density which largely

determines the biologic consequence of radiation exposure

¬ High LET radiation: 2+, p+, and other heavy ions

¬ Low LET radiation:

¬Electrons (e-, -and +)

¬EM radiation (x-rays or γ-rays)

¬ High LET >>damaging than low LET radiation

Relative Biological Effectiveness (RBE)

¬ Although all ionizing radiation capable of producing a specific biological effect, the magnitude/dose differs

¬ Compare dose required to produce the same specific biologic response as a reference radiation dose (typically

250 kVp x-rays): Relative Biological Effectiveness (RBE)

¬ Essential in establishing radiation weighting factors (wR)

¬ X-rays/gamma rays/electrons: LET rays/gamma rays/electrons: LET ≈ 2 keV/≈ 2 keV/µm; wR= 1

¬ Protons (< 2MeV): LET Protons (< 2MeV): LET ≈ 20 keV/≈ 20 keV/µm; wR= 5-10

¬ Neutrons (E dep.): LET Neutrons (E dep.): LET ≈ 4≈ 4-20 keV/µm; wR= 5-20

¬ Alpha Particle: LET Alpha Particle: LET ≈ 40 keV/≈ 40 keV/µm; wR= 20

¬ H (equivalent dose, Sv) = D (absorbed dose, Gy) · wR

©UW and Brent K Stewart, PhD, DABMP 11 c.f Bushberg, et al The Essential Physics of Medical Imaging, 2 nd ed., p 817.

LET vs RBE

Cellular Targets

¬ Radiation-sensitive targets are located in the nucleus and not the cytoplasm of the cell

¬ Cell death may occur if key macromolecules (e.g., DNA) which have no replacement are damaged or destroyed

¬ Considerable evidence that damage to DNA is the primary cause of radiation-induced cell death

¬ Concept of key or critical targets has led to a model of radiation-induced cellular damage termed target theory

in which critical targets may be inactivated by one or more ionization events (hits)

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Radiation Effects on DNA

Cellular Radiosensitivity

¬ Studied through radiation-induced cell death (loss of reproductive integrity)

¬ Useful in assessing the relative biologic impact of various types of radiation and exposure conditions

¬ Cellular inability to form colonies as a function of radiation exposure cell survival curves

¬ Three parameters defining response to radiation: n, Dq and D0

c.f Bushberg, et al The Essential Physics of Medical

Imaging, 2 nd ed., p 822.

Cell Survival Curves: n

¬ n: Extrapolation number

-found by extrapolating the

linear portion of the curve back

through the y-axis

¬ Represents either the number

of targets in a cell that must be

“hit” once by a radiation event

to inactivate the cell or the

number of “hits” required on a

single critical target to

inactivate the cell

¬ For mammalian cells: [2,10]

Cell Survival Curves: D0

¬ D0: Mean lethal dose

¬ Radiosensitivity of the cell population under study

¬ Dose producing a 63%(1-e-1) reduction in viable cell number:

slope = y/ x = 63/D0 (e ≈2.72; e-1= 0.37)

¬ ∝reciprocal linear region slope

¬ Radioresistant cell D0>

radiosensitive cell D0

¬ D0 lesser survival/dose

¬ Mammalian cells: [1Gy,2Gy]

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Cell Survival Curves: Dq

¬ Dq: Quasithreshold dose

(Dq= D0·logen)

¬ Width of the shoulder region

and a measure of sublethal

damage

¬ Irradiated cells remain viable

until enough hits received to

inactivate the critical target or

targets

¬ Clear evidence that for

low-LET radiation, damage

produced by a single radiation

interaction with cellular critical

target(s) is insufficient to

produce reproductive death

Factors Affecting Cellular Radiosensitivity

¬ Conditional factors - physical or chemicals factors that exist previous to and/or at irradiation

¬ Dose rate

¬ LET

¬ Fractionation

¬ Presence of oxygen

¬ Inherent factors - biologic factors characteristic of the cell

¬ Mitotic rate

¬ Degree of differentiation

¬ Cell cycle phase

Conditional Factors – Dose Rate

Which has highest D0?

Which has highest n?

Which has highest D q ?

Conditional Factors - LET

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Conditional Factors - Fractionation

Conditional Factors – Presence of Oxygen

¬ Increases cell damage by inhibiting

¬ Free radical recombination to form harmless chemical species

¬ Repair of damage caused by free radicals

¬ Oxygen enhancement ratio (OER): ratio of dose producing a given biologic response in the absence of oxygen to that in the presence of oxygen

¬ Mammalian cells

¬ Low-LET: [2,3]

¬ High-LET: [1,2]

Conditional Factors - Oxygen

Inherent Factors - Law of Bergonié & Tribondeau

¬ Radiosensitivity greatest for cells with

¬ High mitotic rate

¬ Long mitotic future

¬ Undifferentiated

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Inherent Factors – Cell Cycle Phase

¬ Cells are most sensitive to

radiation during mitosis (M

phase) and RNA synthesis

(G2 phase)

¬ Less sensitive during the

preparatory period for DNA

synthesis (G1 phase)

¬ Least sensitive during DNA

synthesis (S phase)

¬ During mitosis (M), the

metaphase is the most

sensitive

Davis Notes – Radiation Biology

¬ 4 The quasi-threshold dose (Dq) for cell line C is:

¬ C 1,000

¬ D 1,500

¬ E impossible to determine from this data

Huda 2ndEdition – Chapter 10 – Radiation Biology

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(RBE)

radiation with tissues?

damage

radiosensitive?

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Raphex 2003 General Question

include all of the following except:

Organ Systems Response: Regeneration & Repair

Organ

Systems

Response:

Skin

c.f Bushberg, et al The

Essential Physics of Medical

Organ Systems Response: Reproductive Organs

¬ Gonads are very radiosensitive

¬ Females

¬ Temporary sterility: 1.5 Gy (150 rad) acute dose

¬ Permanent sterility: 6.0 Gy (600 rad) acute dose*

¬*reported for doses as low as 3.2 Gy

¬ Males

¬ Temporary sterility: 2.5 Gy (250 rad) acute dose*

¬*reported for doses as low as 1.5 Gy

¬ Permanent sterility: 5.0 Gy (500 rad) acute dose

¬ Reduced fertility 20-50 mGy/wk (2-5 rad/wk) when total dose >

2.5 Gy

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Organ Systems Response: Ocular Effects

¬ Eye lens contains a population of radiosensitive cells

¬ Cataract magnitude and probability of occurrence ∝to the dose

¬ Acute doses

¬ = 2 Gy (200 rad) cataracts in a small percentage of people exposed

¬ > 7 Gy (700 rad = 700 cGy) always produce cataracts

¬ Protracted exposure

¬ 2 months: 4 Gy threshold

¬ 4 months: 5.5 Gy threshold

¬ Unlike senile cataracts that typically develop in the anterior pole of

the lens radiation-induced cataracts begin with a small opacity in the

posterior pole and migrate anteriorly

Acute Radiation Syndrome (ARS)

¬ Characteristic clinical response when whole body (or large part thereof) is subjected to a large acute external radiation exposure

¬ Organism response quite distinct from isolated local radiation injuries such as epilation or skin ulcerations

¬ Combination of subsyndromes occurring in stages over hours to weeks as the injury to various tissues and organs is expressed

¬ In order of their occurrence with increasing radiation dose:

¬ Hematopoietic syndrome

¬ Gastrointestinal syndrome

¬ Neurovascular syndrome

ARS Sequence of Events

¬ Prodromalsymptoms typically

begin within 6 hours of exposure

¬ No symptoms during the latent

period, which may last up to 6

weeks for dose < 1 Gy

¬ Manifest illnessstage: onset of

organ system damage clinical

expression which can last 2-3 wks

¬ Most difficult to manage from a

therapeutic standpoint

¬ Treatment during the first 6-8 wks

essential to optimize recovery

¬ Higher risk of cancer and genetic

abnormalities in future progeny if

patient survives

Acute Radiation Syndrome Interrelationships

c.f Bushberg, et al

The Essential Physics of Medical Imaging, 2 nd ed., p

836.

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Epidemiologic Investigations of

Radiation-Induced Cancer

¬ Dose-response relationships for cancer induction at high

dose and dose rate have been well established

¬ Not so for low dose exposures like those resulting from

diagnostic and occupational exposures

¬ Very difficult to detect a small increase in the cancer rate

due to radiation

¬ Natural incidence of many forms of cancer is high

¬ Latent period for most cancers is long

¬ To rule out simple statistical fluctuations, a very large

irradiated population is required

Difficulties in Quantifying Low Dose Risk

¬ If excess risk proportional to dose, then large studies are required for low absorbed dose to maintain statistical precision and power; the necessary sample power increases approximately as the inverse square of dose

¬ This relationship reflects a decline

in the signal (radiation risk) to noise (natural background risk) ratio as dose decreases

¬ 500 persons needed to quantify the effect of a 1,000 mSv dose

¬ 50,000 for a 100 mSv dose

¬ 5 million for a 10 mSv dose (a single body CT = 7.5 mSv)

National Research Council (1995) Radiation Dose Reconstruction for Epidemiologic Uses Natl Acad Press

SS = c/D2

What is the Evidence?

¬ Major epidemiological investigations that form the basis

of current cancer dose-response estimates in human

populations:

¬ Atomic-bomb survivors (Japan) life span study (LSS)

¬ Anklyosing spondylitis (UK)

¬ Postpartum mastitis study (New York)

¬ Radium dial painters (Tritium)

¬ Thorotrast (radioactive Thorium x-ray contrast agent)

¬ Massachusetts tuberculosis patients (multiple chest fluoroscopy)

¬ Stanford University Hodgkin’s disease patients (x-ray therapy)

Risk Estimation Models Dose-Response Curves

¬ Dose-response models predict cancer risk from exposure to low levels of ionizing radiation dose-response curves

¬ Linear, non-threshold (LNT)

¬ Effect = ·Dose

¬ Linear-quadratic, non-threshold

¬ Effect = ·Dose + ·Dose2

¬ / : [1Gy-10Gy]

¬ appears linear for low dose

¬ appears quadratic (non-linear) for higher dose

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