☢️Radiobiology Unit 10 – Radiation Effects on Tissues and Organs

Basic Radiation Concepts

• Radiation is the emission or transmission of energy in the form of waves or particles through space or a medium
• Ionizing radiation has sufficient energy to remove electrons from atoms or molecules, creating ions (includes X-rays, gamma rays, and high-energy particles)
• Non-ionizing radiation does not have enough energy to ionize atoms or molecules (includes radio waves, microwaves, and visible light)
• Radiation exposure can occur from natural sources (cosmic rays, radon) or artificial sources (medical X-rays, nuclear power plants)
• Radiation dose is measured in units of gray (Gy) or sievert (Sv), which take into account the biological effects of different types of radiation
  • 1 Gy = 1 joule of energy absorbed per kilogram of matter
  • 1 Sv = 1 Gy × radiation weighting factor (depends on the type of radiation)
• Linear energy transfer (LET) describes the amount of energy deposited per unit length along the path of the radiation
  • High LET radiation (alpha particles, neutrons) causes more dense ionization and greater biological damage
  • Low LET radiation (X-rays, gamma rays) causes more sparse ionization and less biological damage per unit dose
• Inverse square law states that radiation intensity decreases with the square of the distance from the source

Cellular Radiation Response

• Radiation can cause direct damage to cellular components (DNA, proteins, membranes) or indirect damage through the production of reactive oxygen species (ROS)
• Radiolysis of water produces free radicals (hydroxyl radical, hydrogen atom) and other reactive species (hydrogen peroxide, superoxide) that can damage cellular components
• DNA is the critical target for radiation-induced cell death and mutations
  • Double-strand breaks (DSBs) are the most lethal type of DNA damage
  • Single-strand breaks (SSBs) and base damage are more easily repaired
• Cells have evolved various mechanisms to detect and repair DNA damage (base excision repair, nucleotide excision repair, homologous recombination, non-homologous end joining)
• Radiation can induce cell cycle arrest, allowing time for DNA repair before replication or mitosis
  • G1 arrest prevents cells with damaged DNA from entering S phase
  • G2 arrest prevents cells with damaged DNA from entering mitosis
• Apoptosis (programmed cell death) can be triggered by irreparable DNA damage to eliminate potentially harmful cells
• Senescence (permanent cell cycle arrest) can occur in response to chronic low-dose radiation exposure

DNA Damage and Repair Mechanisms

• Radiation induces various types of DNA damage, including base modifications, single-strand breaks (SSBs), and double-strand breaks (DSBs)
  • Base modifications involve chemical changes to DNA bases (oxidation, alkylation, deamination) that can lead to mutations if unrepaired
  • SSBs are breaks in one strand of the DNA double helix, often caused by reactive oxygen species (ROS) generated during radiolysis of water
  • DSBs are simultaneous breaks in both strands of the DNA double helix, considered the most lethal type of DNA damage
• Cells have evolved several DNA repair pathways to maintain genomic integrity
  • Base excision repair (BER) corrects small base modifications and SSBs by removing the damaged base and replacing it with the correct nucleotide
  • Nucleotide excision repair (NER) removes bulky DNA lesions (pyrimidine dimers, cisplatin adducts) by excising a segment of the damaged strand and filling in the gap
  • Homologous recombination (HR) repairs DSBs using the sister chromatid as a template, ensuring accurate repair but limited to S and G2 phases
  • Non-homologous end joining (NHEJ) repairs DSBs by directly ligating the broken ends, which is error-prone but can occur throughout the cell cycle
• DNA damage response (DDR) pathways detect DNA lesions and coordinate repair, cell cycle arrest, and apoptosis
  • Sensor proteins (ATM, ATR) recognize DNA damage and activate transducer proteins (Chk1, Chk2) to relay the signal
  • Effector proteins (p53, BRCA1, BRCA2) carry out the appropriate cellular response based on the type and extent of DNA damage
• Defects in DNA repair genes (BRCA1, BRCA2, ATM) can lead to increased radiosensitivity and cancer predisposition (hereditary breast and ovarian cancer syndrome, ataxia-telangiectasia)

Tissue Radiosensitivity

• Radiosensitivity varies among different tissues and cell types, depending on factors such as proliferation rate, differentiation status, and DNA repair capacity
• Highly radiosensitive tissues have a high proportion of rapidly dividing cells and include bone marrow, thymus, spleen, intestinal epithelium, and reproductive organs
  • Bone marrow suppression is a common acute side effect of radiation therapy, leading to anemia, leukopenia, and thrombocytopenia
  • Intestinal epithelial damage can cause acute radiation enteritis, characterized by diarrhea, abdominal pain, and electrolyte imbalances
• Moderately radiosensitive tissues have a lower proportion of dividing cells and include skin, lungs, and kidneys
  • Radiation dermatitis is a common skin reaction to radiation therapy, ranging from mild erythema to moist desquamation
  • Radiation pneumonitis is an inflammatory reaction in the lungs that can occur 1-6 months after thoracic radiation therapy
• Radioresistant tissues have a low proportion of dividing cells and include brain, spinal cord, muscle, and bone
  • Central nervous system (CNS) tissues are relatively radioresistant due to the low proliferation rate of neurons, but high doses can still cause cognitive deficits and necrosis
  • Muscle and bone are less sensitive to radiation due to their low turnover rate, but high doses can lead to fibrosis and osteoradionecrosis
• Stem cells in various tissues (hematopoietic, intestinal, skin) are critical targets for radiation damage and can lead to long-term effects on tissue function and regeneration

Acute Radiation Syndrome

• Acute radiation syndrome (ARS) is a constellation of symptoms that occur within days to weeks after whole-body exposure to high doses of radiation (>1 Gy)
• ARS is divided into three main subtypes based on the primary organ system affected: hematopoietic, gastrointestinal, and neurovascular
  • Hematopoietic ARS (2-6 Gy) is characterized by bone marrow suppression, leading to pancytopenia and increased risk of infections and bleeding
  • Gastrointestinal ARS (6-10 Gy) involves damage to the intestinal epithelium, causing severe diarrhea, electrolyte imbalances, and sepsis
  • Neurovascular ARS (>10 Gy) affects the central nervous system and cardiovascular system, leading to cerebral edema, cardiovascular collapse, and rapid death
• The clinical course of ARS follows a characteristic pattern: prodromal phase, latent phase, manifest illness phase, and recovery or death
  • Prodromal phase (hours to days) includes non-specific symptoms such as nausea, vomiting, fatigue, and fever
  • Latent phase (days to weeks) is a period of apparent clinical improvement, but ongoing cellular damage and depletion continue
  • Manifest illness phase (weeks to months) is characterized by the specific symptoms and complications of each ARS subtype
• Treatment of ARS is primarily supportive care, including fluid and electrolyte management, antibiotics for infections, and blood product transfusions
• Hematopoietic growth factors (G-CSF, GM-CSF) can be used to stimulate bone marrow recovery in hematopoietic ARS
• Stem cell transplantation may be necessary for severe cases of hematopoietic ARS with prolonged marrow aplasia

Late Effects of Radiation Exposure

• Late effects of radiation exposure are health problems that occur months to years after the initial exposure and can be progressive and irreversible
• Carcinogenesis is a major concern for long-term survivors of radiation exposure, with an increased risk of solid tumors and hematologic malignancies
  • Radiation-induced cancers typically have a long latency period (>10 years) and can occur in various organs (thyroid, breast, lung, bone, skin)
  • The risk of developing a radiation-induced cancer depends on factors such as age at exposure, total dose, and fractionation schedule
• Cardiovascular disease is another potential late effect of radiation exposure, particularly in patients who receive thoracic or neck irradiation
  • Radiation can cause endothelial cell damage, leading to accelerated atherosclerosis and increased risk of coronary artery disease, valvular heart disease, and pericardial disease
  • The risk of cardiovascular disease is related to the total dose, volume of heart irradiated, and presence of other risk factors (smoking, hypertension, diabetes)
• Pulmonary fibrosis is a progressive scarring of the lungs that can occur after thoracic radiation therapy, leading to dyspnea, cough, and hypoxemia
  • The risk and severity of pulmonary fibrosis depend on the total dose, volume of lung irradiated, and concurrent chemotherapy
  • Pulmonary function tests and imaging (chest X-ray, CT) are used to monitor for the development of fibrosis
• Cognitive impairment and neurological deficits can occur after cranial radiation therapy, particularly in children
  • Radiation can cause white matter damage, vascular injury, and neuronal loss, leading to deficits in memory, attention, processing speed, and executive function
  • The severity of cognitive impairment is related to the total dose, volume of brain irradiated, and age at exposure
• Endocrine disorders can result from radiation exposure to the hypothalamic-pituitary axis, thyroid gland, or gonads
  • Hypothalamic-pituitary dysfunction can lead to growth hormone deficiency, central hypothyroidism, and hypogonadism
  • Thyroid disorders include hypothyroidism, hyperthyroidism, and thyroid nodules or cancer
  • Gonadal dysfunction can cause infertility, premature ovarian failure, and testosterone deficiency

Radiation Protection Principles

• Radiation protection aims to minimize the harmful effects of ionizing radiation on individuals and populations while allowing the beneficial uses of radiation in medicine, industry, and research
• The three fundamental principles of radiation protection are justification, optimization, and dose limitation
  • Justification requires that any exposure to radiation should produce a net benefit to society, considering both the benefits and the risks
  • Optimization, also known as the "as low as reasonably achievable" (ALARA) principle, states that radiation doses should be kept as low as possible, taking into account economic and societal factors
  • Dose limitation sets maximum permissible doses for occupational and public exposures to ensure that no individual faces an unacceptable risk from radiation
• Occupational dose limits are set by regulatory agencies (ICRP, NCRP) to protect workers who are exposed to radiation as part of their job
  • The current occupational dose limit is 20 mSv per year, averaged over a 5-year period, with a maximum of 50 mSv in any single year
  • Additional dose limits apply to specific organs (lens of the eye, skin, hands and feet) and pregnant workers
• Public dose limits are set to protect members of the general public from exposure to radiation sources
  • The current public dose limit is 1 mSv per year, with higher limits for medical exposures and natural background radiation
  • Dose constraints are used to ensure that public exposures from a single source or practice do not exceed a fraction of the overall dose limit
• Radiation shielding is the use of materials (lead, concrete, water) to reduce the intensity of radiation and protect individuals from exposure
  • The effectiveness of shielding depends on the type and energy of the radiation, as well as the thickness and density of the shielding material
  • Shielding is used in various settings, including medical X-ray rooms, nuclear power plants, and radioactive waste storage facilities
• Personal protective equipment (PPE) is used to minimize external exposure to radiation and prevent contamination of the body or clothing
  • Examples of PPE include lead aprons, thyroid shields, gloves, and respirators
  • The type and level of PPE required depend on the specific radiation hazard and the potential for exposure
• Radiation monitoring is the measurement of radiation levels and doses to ensure compliance with safety standards and detect any abnormal exposures
  • Personal dosimeters (film badges, thermoluminescent dosimeters, optically stimulated luminescence dosimeters) are worn by individuals to measure their cumulative radiation dose
  • Area monitors (Geiger counters, ionization chambers) are used to measure radiation levels in specific locations and identify any contamination or leaks

Clinical Applications and Case Studies

• Radiation therapy is a common treatment modality for various types of cancer, using ionizing radiation to kill tumor cells and shrink the tumor mass
  • External beam radiation therapy (EBRT) delivers high-energy X-rays or gamma rays from a linear accelerator to the tumor site
  • Brachytherapy involves the placement of radioactive sources directly into or near the tumor, allowing for high doses to the tumor while sparing surrounding normal tissues
  • Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) use precise targeting and high doses per fraction to treat small tumors in the brain or body
• Radiation accidents and incidents can occur in various settings, including nuclear power plants, industrial facilities, and medical institutions
  • The Chernobyl nuclear power plant accident (1986) resulted in widespread contamination and exposure of workers and the general public to high levels of radiation
  • The Goiânia accident (1987) involved the theft and dismantling of a radiotherapy source, leading to contamination and exposure of several individuals
  • The Therac-25 accidents (1985-1987) were caused by software errors in a radiation therapy machine, resulting in massive radiation overdoses to patients
• Radiation emergency preparedness and response are critical for minimizing the impact of radiation incidents on public health and safety
  • Emergency plans should include provisions for sheltering, evacuation, decontamination, and medical management of exposed individuals
  • Radiation triage involves the rapid assessment and categorization of individuals based on their exposure level and symptoms, allowing for appropriate medical care and follow-up
  • Biodosimetry techniques (cytogenetic assays, gene expression profiles) can be used to estimate an individual's radiation dose and guide medical management
• Radiation protection in medical imaging is important for minimizing the risks associated with diagnostic and interventional procedures
  • Justification of each imaging study based on clinical indications and patient factors is essential to avoid unnecessary radiation exposure
  • Optimization techniques, such as adjusting exposure parameters, using protective shielding, and selecting appropriate imaging modalities, can reduce patient doses while maintaining image quality
  • Dose tracking and reporting systems can help monitor cumulative patient doses and identify opportunities for dose reduction
• Radiation-induced long-term effects in cancer survivors require ongoing surveillance and management by healthcare providers
  • Regular follow-up with a multidisciplinary team (oncologists, endocrinologists, cardiologists) is necessary to monitor for and treat potential late effects
  • Screening for second malignancies should be based on the patient's age, radiation exposure, and other risk factors
  • Counseling on healthy lifestyle behaviors (smoking cessation, physical activity, diet) can help reduce the risk of cardiovascular disease and other chronic conditions
  • Psychosocial support and educational resources can help survivors cope with the long-term impact of cancer treatment on their quality of life