Radiation Biology RADL 70 Kyle Thornton

Definition of Radiation Biology Joins two branches of science to study the effects of radiation upon living matter Radiation physics The spread of energy through space Biology The study of living organisms Most effects begin at the cellular level All radiation injuries to tissue, organs, fetus, and entire body began from an injury to a cell

How Does Ionizing Radiation Do Harm? It damages by removing electrons the atoms that compose the molecular structures of living systems X and gamma rays can transfer energy to orbital electrons in their path Alpha particles strongly attract negative electrons as they pass by This alters the chemical bonds of the atom, changing its composition or structure Different types of atoms unite through chemical bonds to form molecules Molecules have specific functions Altering the structure of the atom alters the moleculecular structure and its function

Linear Energy Transfer The average amount of energy deposited per unit length of travel Measured in units of keV per micron The amount of ionization produced is affected by the amount of energy absorbed Chemical and biological effects are determined by the degree of ionization that takes place within the tissue

Linear Energy Transfer Low LET radiations From x or gamma rays Short wavelength, high energy waves Sparsely ionizing Randomly interact They do not give up their energy quickly Damage is usually caused indirectly Free radicals are formed Occasionally may cause single-strand breaks in one side of the DNA ladder Damage is usually sublethal Repair enzymes reverse the damage

Linear Energy Transfer High LET radiation From particles that do possess mass and charge Alpha particles, particles released from interactions between neutrons and atoms Lose energy more rapidly than x or gamma rays Produce more ionization per unit length of travel Their energy is exhausted sooner than that of an x or gamma ray

Linear Energy Transfer Radiation of a high LET is far more likely to do damage than that of a low LET Damage potential is greatest when a radionuclide has been ingested, planted, inhaled, or injected into the body The damage done by high LET is usually irreparable High LET radiation is far more likely to interact with DNA than low LET radiation

Electron/Alpha Particle Damage Comparison

Relative Biological Effectiveness Biologic damage increases as LET increases RBE is the ability of radiation with different LET to produce a biologic reaction

Oxygen Enhancement Ratio The ratio of radiation damage done when oxygen is present compared to the amount when it is not Cells that are normally hypoxic are less responsive to cells are that are highly oxygenated This is only important when high doses outside the realm of diagnostic are used This impact is very important in radiation therapy procedures

Direct Action Biologic damage occurs from interaction between radiation and a master molecule DNA, RNA, enzymes, and proteins Occurs from photoelectric and Compton interaction This results in breakage of the macromolecule’s chemical bonds This will result in a malfunction of that particular molecule This sets off a biologic domino effect

Indirect Action The byproduct of radiation interacted with the macromolecule, not the radiation itself Radiolysis of water is one of the main precursors of indirect action

Indirect Action

Indirect Action: Radiolysis of Water X-ray photons are highly likely to interact with water molecules in the body This interaction creates an ion pair A water molecule with a positive charge HOH+ An electron - e- One of several reactions might occur

Reaction I The positively charged water molecule recombines with an electron A stable water molecule is reformed No damage is done

Reaction II The electron joins with a water molecule A negative water ion is formed The positive and negative water molecules are unstable These can break apart into smaller molecules Free radicals can be formed by this breakup These are atoms that have no net electrical charge These objects are highly reactive and can do cellular damage

Reaction III Two of these free radicals can recombine to form hydrogen peroxide This is highly toxic to a cell About two-thirds of all biologic damage is caused by the two latter reactions

Another way to look at it…

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Effects on DNA Macromolecules Point mutation Ionizing radiation that ruptures the chemical bond of a macromolecule severing one of the sugar-phosphate chain siderails of the DNA ladder (Single-strand break) Gene mutations may result These can occur with low-LET radiation Repair enzymes can reverse this damage

Double Strand Breaks One or more breaks in each of the two sugar-phosphate chains Not repaired as easily as single strand breaks More common with high LET radiation

Cleaved Chromosomes Two interactions hit on each side of the sugar phosphate chain The macromolecule is broken in two Each new portion contains an unequal amount of genetic material This chromosome can then divide into defective daughter cells This loss or change is known as a mutation

Let’s play mutation identification!

Effects of Ionizing Radiation Upon Chromosomes If chromosomes are broken, two or more fragments are produced Each fragment has a fractured extremity These can join to another fractured extremity These new formations are known as an aberration

Restitution – No Visible Damage

Deletion

Broken-end Rearrangement

Broken End Rearrangement

DNA Mutations

Target Theory Cell death will occur if the master molecule in that cell is inactivated by radiation exposure This theory is used to explain cell death and nonfatal cell abnormalities caused by radiation exposure

Target Theory

Characteristics of Radiation Mutation If the mutation is genetic, it may be expressed in future generations If it is somatic, it holds possible consequences for the individual only Radiation effects are non-specific There are no radiounique effects Most mutations are undesirable Mutagenic effects are probably cumulative A threshold exists

Cellular Effect of Irradiation Instant death Occurs when a volume is irradiated with 1000 Gray of x or gamma ray in a period of seconds or a few minutes Radiation doses this high do not occur in the diagnostic or therapeutic ranges

Cellular Effect of Irradiation Reproductive Death Occurs from a dose of 1 – 10 Gray The cell does not die, but becomes sterile The cell will continue to metabolize and synthesize nucleic acids and proteins Transmission of damage to future generations is prevented

Cellular Effect of Irradiation Interphase Death Depends upon the radiosensitivity of the cell This death interrupts a programmed occurrence in normal development

Cellular Effect of Irradiation Mitotic Death Occurs when the cell dies after one or more divisions Can occur from very small doses

Cellular Effect of Irradiation Mitotic Delay Can occur from a dose of as little as 1 rad The cell fails to divide on time Interference of function This can be temporary or permanent The cell can recover and continue to function if repair enzymes are able to fix the damage

Cell Radiosensitivity Cells vary in their degree of radiosensitivity Radiosensitive cells include basal cells of the skin, intestinal crypt cells, and reproductive cells Radioinsensitive cells include brain, muscle, and nerve cells Radiosensitivity varies from one tissue or organ to another

Cell Radiosensitivity Other factors LET Presence of oxygen Cancer cells are often hypoxic Patients often undergo hyperbaric oxygenation to oxygenate cancer cells This makes them more sensitive to radiation

Law of Bergonié and Tribondeau Experimented on rabbit testicles Their conclusion: These cells are most radiosensitive by virtue of these factors: Least maturity Least specialization or differentiation Greatest reproductive activity Longest mitotic phases True for all cells in the human body

Effects of Radiation on Various Cell Types Blood Cells Whole body dose of 25 rad (0.25 Gy) produces hematologic depression within a few days Most blood cells are manufactured in the bone marrow Radiation causes a decrease in the production of immature blood cells (stem, or precursor cells) This produces a decrease in the number of mature cells in the bloodstream The higher the dose, the greater the severity of cell depletion

Radiation and Blood Cells Lymphocytes White blood cells Live for about 24 hours 25 rads will depress the number of these cells in circulating blood These are the most sensitive cells in the human body

Epithelial Tissue Lines and covers body tissue These cells lie close together Contains no blood vessels Regenerates through mitosis Found in the lining of intestines, mucous lining of respiratory tract, pulmonary alveoli, and lining of blood and lymphatic vessels It is constantly regenerated by the body and is very radiosensitive

Muscle Tissue Contains fibers that affect organ, or body movement Highly specialized, non-dividing tissue Insensitive to radiation

Nervous Tissue Conductive tissue – found in the brain and spinal cord Nerve cells are highly specialized in the adult and do not divide A single exposure of 5000 rads may lead to death within hours or days Developing nerve cells are highly radiosensitive in the fetus Irradiation of the fetus can lead to congenital anomalies

Reproductive Cells These cells are relatively radiosensitive Radiosensitivity depends on cell maturity A radiation dose of 200 rad can cause temporary sterility for about a year in the male 500 – 600 rads can cause permanent sterility 10 rads can depress the sperm count

Reproductive Cells Few diagnostic therapy come close to delivering a dose of 10 rads In the female, ova do not divide constantly Temporary sterility occurs from a dose of 200 rads to the ovaries 500 rads can cause permanent sterility 10 rads may produce menstrual irregularities

Dose-response Relationship Curves Linear-nonthreshold curve estimates the risk of associated with low-level radiation Leukemia, breast cancer, and heritable damage are presumed to follow this curve Leukemia occurrences in Hiroshima and Nagasaki support the use of this curve This curve somewhat exaggerates the seriousness of effects at low-level radiation It accurately reflects the effects of high-LET radiation at higher doses

Dose-response Relationship Curves Linear-threshold curve Used for nonstochastic effects such as skin erythema and hematologic depression Non-linear-threshold curve Used to determine high dose response in radiation therapy Indicates the existence of a threshold

Threshold Curves

Threshold Curves

The Factors that Determine Somatic and Genetic Damage The quantity of ionizing radiation received The ability of the ionizing radiation to cause ionization of human tissue The amount of body area exposed The specific body parts exposed The greatest amount of biologic damage is produced by a large dose of high-LET delivered to a large or radiosensitivity area of the body