Radiobiology.pdf

Chapter 14

BASIC RADIOBIOLOGY

N. SUNTHARALINGAM

Department of Radiation Oncology,

Thomas Jefferson University Hospital,

Philadelphia, Pennsylvania,

United States of America

E.B. PODGORSAK

Department of Medical Physics,

McGill University Health Centre,

Montreal, Quebec, Canada

J.H. HENDRY

Division of Human Health,

International Atomic Energy Agency,

Vienna

14.1. INTRODUCTION

Radiobiology, a branch of science concerned with the action of ionizing

radiation on biological tissues and living organisms, is a combination of two

disciplines: radiation physics and biology. All living things are made up of

protoplasm, which consists of inorganic and organic compounds dissolved or

suspended in water. The smallest unit of protoplasm capable of independent

existence is the cell.

Cells contain inorganic compounds (water and minerals) as well as

organic compounds (proteins, carbohydrates, nucleic acids and lipids). The two

main constituents of a cell are the cytoplasm, which supports all metabolic

functions within the cell, and the nucleus, which contains the genetic

information (DNA).

Human cells are either somatic cells or germ cells.

Cells propagate through division: division of somatic cells is called

mitosis, while division of germ cells is called meiosis. When a somatic cell

divides, two cells are produced, each carrying a chromosome complement

identical to that of the original cell. The new cells themselves may undergo

further division, and the process continues.

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Somatic cells are classified as:

●

Stem cells, which exist to self-perpetuate and produce cells for a differen-

tiated cell population (e.g. stem cells of the haematopoietic system,

epidermis and mucosal lining of the intestine);

●

Transit cells, which are cells in movement to another population (e.g. a

reticulocyte that is differentiating to become an erythrocyte);

●

Mature cells, which are fully differentiated and do not exhibit mitotic

activity (e.g. muscle cells and nervous tissue).

A group of cells that together perform one or more functions is referred

to as tissue. A group of tissues that together perform one or more functions is

called an organ. A group of organs that perform one or more functions is a

system of organs or an organism.

14.2. CLASSIFICATION OF RADIATIONS IN RADIOBIOLOGY

For use in radiobiology and radiation protection the physical quantity

that is useful for defining the quality of an ionizing radiation beam is the linear

energy transfer (LET). In contrast to the stopping power, which focuses

attention on the energy loss by an energetic charged particle moving through a

medium, the LET focuses attention on the linear rate of energy absorption by

the absorbing medium as the charged particle traverses the medium.

The ICRU defines the LET as follows:

“ LET of charged particles in a medium is the quotient dE/dl, where dE is

the average energy locally imparted to the medium by a charged particle of

specified energy in traversing a distance of dl. ”

In contrast to the stopping power, which has a typical unit of MeV/cm, the

unit usually used for the LET is keV/ µ m. The energy average is obtained by

dividing the particle track into equal energy increments and averaging the

length of track over which these energy increments are deposited.

Typical LET values for commonly used radiations are:

●

250 kVp X rays: 2 keV/ µ m.

Cobalt-60 g rays: 0.3 keV/ µ m.

● 3 MeV X rays: 0.3 keV/ µ m.

●

1 MeV electrons: 0.25 keV/ µ m.

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BASIC RADIOBIOLOGY

LET values for other, less commonly used radiations are:

— 14 MeV neutrons: 12 keV/ µ m.

— Heavy charged particles: 100–200 keV/ µ m.

— 1 keV electrons: 12.3 keV/ µ m.

— 10 keV electrons: 2.3 keV/ µ m.

X rays and g rays are considered low LET (sparsely ionizing) radiations,

while energetic neutrons, protons and heavy charged particles are high LET

(densely ionizing) radiations. The demarcation value between low and high

LET is at about 10 keV/ µ m.

14.3.

CELL CYCLE AND CELL DEATH

The cell proliferation cycle is defined by two well defined time periods:

●

Mitosis (M), where division takes place;

●

The period of DNA synthesis (S).

The S and M portions of the cell cycle are separated by two periods (gaps)

G 1 and G 2 when, respectively, DNA has not yet been synthesized or has been

synthesized but other metabolic processes are taking place.

The time between successive divisions (mitoses) is called the cell cycle

time. For mammalian cells growing in culture the S phase is usually in the range

of 6–8 h, the M phase less than an hour, G 2 is in the range of 2–4 h and G 1 is 1–

8 h, making the total cell cycle of the order of 10–20 h. In contrast, the cell cycle

for stem cells in certain tissues is up to about 10 days.

In general, cells are most radiosensitive in the M and G 2 phases, and most

resistant in the late S phase.

The cell cycle time of malignant cells is shorter than that of some normal

tissue cells, but during regeneration after injury normal cells can proliferate

faster.

Cell death of non-proliferating (static) cells is defined as the loss of a

specific function, while for stem cells and other cells capable of many divisions

it is defined as the loss of reproductive integrity (reproductive death). A

surviving cell that maintains its reproductive integrity and proliferates almost

indefinitely is said to be clonogenic.

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14.4. IRRADIATION OF CELLS

When cells are exposed to ionizing radiation the standard physical effects

between radiation and the atoms or molecules of the cells occur first and the

possible biological damage to cell functions follows later. The biological effects

of radiation result mainly from damage to the DNA, which is the most critical

target within the cell; however, there are also other sites in the cell that, when

damaged, may lead to cell death. When directly ionizing radiation is absorbed

in biological material, the damage to the cell may occur in one of two ways:

direct or indirect.

14.4.1. Direct action in cell damage by radiation

In direct action the radiation interacts directly with the critical target in

the cell. The atoms of the target itself may be ionized or excited through

Coulomb interactions, leading to the chain of physical and chemical events that

eventually produce the biological damage. Direct action is the dominant

process in the interaction of high LET particles with biological material.

14.4.2. Indirect action in cell damage by radiation

In indirect action the radiation interacts with other molecules and atoms

(mainly water, since about 80% of a cell is composed of water) within the cell

to produce free radicals, which can, through diffusion in the cell, damage the

critical target within the cell. In interactions of radiation with water, short lived

yet extremely reactive free radicals such as H 2 O + (water ion) and OH

(hydroxyl radical) are produced. The free radicals in turn can cause damage to

the target within the cell.

The free radicals that break the chemical bonds and produce chemical

changes that lead to biological damage are highly reactive molecules because

they have an unpaired valence electron.

About two thirds of the biological damage by low LET radiations

(sparsely ionizing radiations) such as X rays or electrons is due to indirect

action.

Indirect action can be modified by chemical sensitizers or radiation

protectors.

The steps involved in producing biological damage by the indirect action

of X rays are as follows:

●

Step 1: Primary photon interaction (photoelectric effect, Compton effect

and pair production) produces a high energy electron.

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BASIC RADIOBIOLOGY

●

Step 2: The high energy electron in moving through tissue produces free

radicals in water.

●

Step 3: The free radicals may produce changes in DNA from breakage of

chemical bonds.

●

Step 4: The changes in chemical bonds result in biological effects.

Step (1) is in the realm of physics; step (2) is in chemistry; steps (3) and

(4) are in radiobiology.

14.4.3. Fate of irradiated cells

Irradiation of a cell will result in one of the following nine possible

outcomes:

●

No effect.

●

Division delay: The cell is delayed from going through division.

●

Apoptosis: The cell dies before it can divide or afterwards by fragmen-

tation into smaller bodies, which are taken up by neighbouring cells.

●

Reproductive failure: The cell dies when attempting the first or

subsequent mitosis.

●

Genomic instability: There is a delayed form of reproductive failure as a

result of induced genomic instability.

●

Mutation: The cell survives but contains a mutation.

●

Transformation: The cell survives but the mutation leads to a transformed

phenotype and possibly carcinogenesis.

●

Bystander effects: An irradiated cell can send signals to neighbouring

unirradiated cells and induce genetic damage in them.

●

Adaptive responses: The irradiated cell is stimulated to react and become

more resistant to subsequent irradiation.

14.5. TYPE OF RADIATION DAMAGE

14.5.1. Timescale

The timescale involved between the breakage of chemical bonds and the

biological effect may be hours to years, depending on the type of damage.

If cell kill is the result, it may happen in hours to days, when the damaged

cell attempts to divide (early effects of radiation). This can result in early tissue

reactions (deterministic effects) if many cells are killed.

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