Radiobiology and the Biological Effects of Ionizing Radiation

Fundamental Principles of Radiobiology and Biological Effects

  • Radiobiology is defined as the scientific field concerned with the effects of ionizing radiation on living organisms.
  • The discipline is categorized into three primary branches:
    • Experimental Radiobiology: Focused on research, serving as the foundational source of knowledge.
    • Clinical Radiobiology: Focused on the practical application of radiobiological principles in medical practice.
    • Crisis (Urgent) Radiobiology: Dedicated to immediate response in the event of radiation accidents or emergencies.
  • The biological effects of ionizing radiation are analyzed across several hierarchical levels:
    • Molecular level
    • Cellular level: Focusing on the cell as the basic structural unit of living tissues, organs, and organisms.
    • Organ and tissue level
    • The Human Organism as a whole
    • Population level

The Cell Cycle and Radiosensitivity

  • The cell life cycle encompasses the period starting from the end of one cell division to the completion of the subsequent division.
  • INTERPHASE consists of several distinct stages:
    • G0G_0: The resting phase where the cell enters if it is not intended to divide further; during this phase, only basal life functions are maintained.
    • G1G_1: A growth period and preparatory phase for subsequent division, characterized by the creation of organelles and nucleotides necessary for DNA doubling.
    • SS (Synthetic Phase): The period of DNA replication, resulting in the doubling of chromosomes (4n4n).
    • G2G_2: The phase involving the creation of additional structures required for division, including the synthesis and activation of proteins for the formation of the mitotic apparatus and the destruction of the nuclear envelope.
  • MITOTIC PHASE (MM): The phase of nuclear division (mitosis).
    • This involves the distribution of genetic information between two daughter cells.
    • It is typically coupled with cytokinesis (the division of the cell body).
    • It consists of Karyokinesis (subdivided into prophase, metafase, anafase, and telofase) and Cytokinesis.
  • Regulatory Mechanisms (Checkpoints):
    • The main regulatory checkpoint is located at the end of the G1G_1 phase.
  • Relative Radiosensitivity:
    • Cells exhibit the highest degree of sensitivity to radiation during the division phase (MM phase).

Detailed Phases of Mitosis

  • Prophase: Includes the dissolution of the nuclear membrane and nucleoli; two centrioles emerge, leading to the formation of the mitotic spindle. Chromatin and nucleoli transform into ribbon-like doubled chromosomes joined at the centromere.
  • Metaphase: The chromosomes align in the equatorial (rovníková) plane via the action of the mitotic spindle.
  • Anaphase: The chromosomes are torn apart at the centromeres as the microtubules of the spindle shorten, causing the chromatids to move toward opposite poles of the cell.
  • Telophase: The mitotic spindle disappears, and daughter nuclear membranes and nucleoli form; this marks the beginning of cytokinesis.

Physical Principles: Linear Energy Transfer (LET)

  • The basic dosimetric quantity is the absorbed dose, but it does not account for the immediate local distribution of energy transferred to matter, which significantly influences physical, chemical, and biological effects.
  • Linear Energy Transfer (LET) is introduced to describe the energy that a particle or photon delivers to the surroundings (cells) relative to the distance (the path of the particle).
  • The formula for LET is given by:   L=DEDxL = \frac{DE}{Dx}
  • LET is determined by the energy of the radiation and its capacity for interaction with the environment.
  • Classifications of LET:
    • High LET: Associated with heavy particles that transfer their energy quickly/early in their path.
    • Low LET: Associated with lighter particles (such as X-rays) that transfer their energy later in their path.

Cellular Responses to Ionizing Radiation

  • Prokaryotic cells (e.g., bacteria) generally exhibit higher resistance to radiation than eukaryotic cells (e.g., plants, fungi, and animals).
  • The cellular reaction to exposure proceeds as follows:
    • Ionization and excitation of atoms in the electron shell occur upon interaction with radiation.
    • These lead to physical and chemical reactions, which in living tissue progress to biochemical changes.
    • These secondary effects result in changes, damage, or cell death.

DNA Damage and Repair Mechanisms

  • DNA (deoxyribonucleic acid), located in the cell nucleus, is the primary target of radiation-induced cell damage.
  • There is a direct correlation between the energy of the radiation and the extent of cellular damage.
  • The most severe form of damage is a DNA strand break.
  • Recognition and Signaling:
    • The cell recognizes damaged sites using specific proteins (such as the MRN complex).
    • The protein ATMATM/ATRATR is activated, sending signals that trigger a complex of repair activities or, in cases of extreme damage, cell death.
  • Outcomes of DNA Damage:
    • Apoptosis: A process of programmed cell death (self-destruction) aimed at eliminating damaged cells.
    • Repair: The cell halts growth to fix damaged structures.
  • Types of DNA Repair:
    • Homologous Repair: A perfect, highly complex, and precise process where the broken DNA finds a corresponding segment in another part of the DNA to fill in what is missing.
    • Non-homologous Repair (End-joining): An imperfect and simpler process that involves joining the ends of double-strand breaks. This carries a high risk of error and changes to genetic information, leading to damage in the DNA sequence and resulting in mutations.

Cellular Effects and Mutations

  • Cell outcomes after radiation can be summarized as:
    • Successful Repair: Managed through the cell's internal self-repair mechanisms.
    • Mutation: A change in the genetic information due to chemical changes in the DNA.
    • Gametic mutations occur in germ cells and are passed to future generations.
    • Somatic mutations occur in other tissues/organs and can lead to conditions such as cancer in the affected individual.
    • Cell Death:
    • High Doses (>100 Gy>100\,Gy): Cause cell necrosis, resulting in the immediate killing of the cell.
    • Low Doses: The cell loses the ability to divide (dying during the division phase), known as mitotic death. This is particularly significant in tissues with high radiosensitivity.

Factors Influencing Radiation Damage in the Human Organism

  • The degree of radiation damage depends on several factors:
    • Properties of the irradiated tissue or organ (Cell type: H-type vs. F-type).
    • Type and energy of the radiation.
    • Method of irradiation (Single vs. fractionated dose).
    • Dose and dose rate (expressed in Gy/sGy/s or μGy/h\mu Gy/h).
    • Type of radiation damage (High vs. Low LET).
  • Comparison of Healthy Tissue Types:
    • Hierarchical Type (H-type):
    • High proliferation capacity of stem cells leading to rapid renewal.
    • High radiosensitivity.
    • Distinct sensitivity to the number of radiation fractions.
    • Responsible for early post-radiation reactions.
    • Examples: Hematopoietic tissue, epidermis, mucous membranes.
    • Flexible Type (F-type):
    • Low proliferation capacity of stem cells leading to slow renewal.
    • Low radiosensitivity.
    • Damage depends more on the size of the individual dose than the number of exposures (lower doses cause minimal damage).
    • Responsible for late post-radiation reactions.
    • Examples: Nerve tissue, kidneys, blood vessels, connective tissue.

Law of Bergonié and Tribondeau (1906)

  • This radiobiological law characterizes the sensitivity of cells to ionizing radiation.
  • The influence of radiation is more pronounced in cells with a higher capacity for reproduction and a lower degree of differentiation.
  • Radiosensitive tissues: Contain a large number of rapidly dividing, poorly differentiated cells.
  • Radioresistant tissues: Contain few or no dividing cells and are highly differentiated.
  • Developmental factor:
    • Children's tissue is more sensitive to radiation effects due to lower tissue maturity, higher water content, and a larger extent of hematopoietic tissue.

Classification of Cell Sensitivity

  • Radiosensitive (Sensitive) Cells:
    • Lymphoid organs
    • Hematopoietic cells and bone marrow
    • Germ cells (Reproductive cells)
  • Radioresistant (Insensitive) Cells:
    • Muscle cells
    • Nerve cells
    • Stem cells

Timeline of Radiation Effects

  • The progression from exposure to biological outcome occurs in distinct stages:
    • Physical Stage (10−1510^{-15} to 10−12 s10^{-12}\,s): Absorption of energy, direct ionization of DNA, or ionization of water (H2O→H+,OH−H_2O \rightarrow H^+, OH^-).
    • Chemical Stage (10−910^{-9} to 10−3 s10^{-3}\,s): Formation and reaction of radicals (e.g., OH−OH^- radicals), oxidation of DNA, and chemical recombination of radicals.
    • Biological Stage (1 s1\,s to years/decades):
    • Breakdown into repair mechanisms vs. cell death or mutation.
    • Immune mechanisms of the organism come into play.
    • Leads to either no effect, deterministic effects (cell death leading to organ issues), or stochastic effects (mutations leading to cancer or genetic issues).

Temporal and Dose-Based Classification of Effects

  • Temporal Classification:
    • Early Organ Damage: Occurs immediately or within 1 year of exposure. Most common in hematopoietic cells, lymphatic organs, germ organs, and intestinal epithelium. Can result in temporary or permanent organ suppression or total functional loss (e.g., Radiation dermatitis).
    • Late Organ Damage: Manifests between 1 and 10 years post-irradiation. Characterized by repair processes like fibrosis and demyelination. Affects lungs, kidneys, gonads, sensory organs, and endocrine organs.
    • Decennial Organ Damage: Manifests 10 to 30 years post-irradiation, typically presenting as post-radiation neoplastic diseases (cancer).
  • Dose and Protection Classification:
    • Deterministic Effects: Non-stochastic, non-probabilistic, and threshold-based. The severity increases with the dose once the threshold is crossed (no effect below threshold).
    • Local dermatitis: Threshold at 3 Gy3\,Gy (erythema, depilation).
    • Lens opacification (Cataracts): Threshold around 1 Gy1\,Gy.
    • Fetal damage (1st trimester): Threshold from 0.05 Sv0.05\,Sv.
    • Fertility disorders:
      • Men: Temporary sterility at 0.25 Gy0.25\,Gy, permanent sterility from 33 to 8 Gy8\,Gy.
      • Women: Permanent sterility at 3 Gy3\,Gy.
    • Acute Radiation Sickness.
    • Stochastic Effects: Probabilistic effects caused by damage to a small number of cells. Can occur after a single small dose or repeated exposures. The probability of damage increases with dose, but severity does not. Usually late effects.
    • Examples: Malignant tumors, genetic changes.

Acute Radiation Sickness (ARS)

  • Also known as Acute Post-radiation Syndrome.
  • Occurs after total-body or large-volume exposure to doses ranging from units to tens of Gray (specifically doses greater than 0.7 Gy0.7\,Gy).
  • Three Forms based on dosage and target organ:
    • Hematopoietic (Blood/Marrow) Form: Occurs at units of GyGy; this is the only form with a chance of survival.
    • Gastrointestinal Form: Occurs at tens of GyGy.
    • Central Nervous System (Nerve) Form: Occurs at several tens of GyGy.
  • Phases of the Sickness:
    • Prodromal: Symptoms include nausea, vomiting, loss of appetite, headache, and diarrhea.
    • Latent: Partial or total disappearance of subjective complaints.
    • Manifest: Full development of the disease and complex damage to the organism.
    • Convalescence: Recovery phase.

Therapeutic Applications and Hormesis

  • Benign (Non-malignant) Conditions: Treatment for heel spurs (ostruha pat), tennis elbow, and epicondylitis using high-kilovoltage (therapeutic) X-ray machines.
  • Malignant Tumors: Cells with the most active metabolism are the most sensitive to radiation.
    • Teletherapy: The radiation source is located outside the body (e.g., Cobalt units).
    • Brachytherapy: The source is introduced into contact with the tumor through natural body cavities (e.g., uterine or bladder tumors).
    • Endotherapy: Used in nuclear medicine; a radionuclide source is introduced via metabolic processes (e.g., treating thyroid tumors).
  • Hormesis: The phenomenon where small doses of radiation have a stimulating effect; used in treating rheumatism, degenerative changes, and infectious diseases of the Central Nervous System.