Ionizing radiation is a powerful source of energy that can liberate atoms' tightly bound electrons, creating ions. Ionizing radiation has two roles in modern science and medicine: it is a known carcinogen and is vital for cancer detection and management [1]. The primary source of its biological effects is its interaction with cellular structures, especially DNA, which can lead to chromosomal defects, mutations, and finally diseases like cancer [2]. The various types of ionizing radiation, their anthropogenic and natural distribution, their mutagenic mechanisms, resulting cellular and systemic effects, as well as how radiation is paradoxically used to treat cancer by means of radiotherapy are all described in this article. References to recent scientific literature and accepted radiobiological principles support the discussion.

Types of Ionizing Radiation Based on the type of particle or electromagnetic waves released, ionizing radiation can be classified in general as follows: 1. Radiation Alpha (α): A pair of protons and a pair of neutrons (a helium nucleus) form an alpha particle. Alpha particles can be stopped by an element of paper or the outer layer of human skin given their high mass and charge. However, exposure to or inhalation of alpha-emitting isotopes, such as radon-222, may end up in major localized tissue damage and increase the risk of cancer [3]. 2. Beta Radiation (β): High-energy, quick electrons (β⁻) or positive ions (β⁺) produced by radioactive decay are recognized as beta particles. They can still be stopped by a few millimeters of glass or plastic, but they can penetrate deeper than alpha particles. Tritium and carbon-14 are typical beta emitters that may be absorbed into biomolecules and damage those within themselves [4]. 3. Gamma Radiation (γ): Often accompanying alpha or beta decay, gamma rays are high-frequency electromagnetic waves generated from the atomic nucleus. Gamma rays are highly penetrating and must to be covered by dense materials like concrete or lead since they contain not much mass nor charge. They are capable of to circulate all over the human body and cause molecular damage to tissues [4]. 4. X-rays: Used widely in cancer treatment and medical imaging, X-rays are similar to gamma rays but come from electron shells rather than the nucleus. Excessive or repeated exposure is linked to an increased risk of cancer, despite their diagnostic value [4]. 5.Neutron Radiation: Having a high penetration and biological effect, neutron radiation emerges during nuclear reactions and from particular radioisotopes like californium-252. In opposition to charged particles, neutrons indirectly cause damage tissues by hitting with and retreating atomic nuclei [5]. Distribution of Ionizing Radiation Both natural and man-made producers of ionizing radiation are available. Natural Resources: Cosmic radiation occurs when high-energy space particles interact with Earth's atmosphere, resulting in secondary radiation like muons and neutrons. Exposure is higher in polar areas and at higher levels. - Terrestrial Radiation: Radioactive isotopes like uranium, thorium, and potassium-40 are found in soil and rocks. - Radon Gas: A decay product of uranium, radon is a leading cause of lung cancer in non-smokers, especially in poorly ventilated indoor environments[5]. - Internal Radiation: Naturally occurring isotopes like potassium-40 and carbon-14 are present in the human body and contribute to internal radiation doses[6]. Man-made Sources: Medical imaging: Nuclear medicine, CT scans, and X-rays are the primary forms of radiation exposure induced by humans [4]. Radiation therapy is the controlled use of radiation to treat cancer. Power plants, weapons testing, and incidents like Chernobyl and Fukushima are all involved in the nuclear industry [9]. Occupational Exposure: Chronic low-dose exposure is an option for workers in the nuclear, medical, and aviation sectors. Mechanisms of Radiation-Induced Mutation DNA damage is the main way that irradiated radiation (IR) causes mutations. When cells are exposed to infrared radiation, energy is deposited in biological tissues, leading molecules, especially water, which makes up around 70 percent of cells, to be charged and stimulated. Two major pathways of DNA damage are initiated by this process:

Direct Action on DNA In direct ionization, radiation deposits energy directly onto DNA molecules, leading to cleavage of covalent bonds in the sugar-phosphate backbone or nitrogenous bases. This damage includes: • Single-Strand Breaks (SSBs) o Breakage in one strand of the DNA double helix. o Easily repairable via base excision repair (BER), unless clustered with other damage. • Double-Strand Breaks (DSBs) o Breakage of both DNA strands within close proximity. o Highly lethal and mutagenic; if misrepaired, can result in translocations or deletions. o Most critical lesion induced by ionizing radiation[11]. • Base Modifications o Alterations in purines or pyrimidines (e.g., 8-oxo-guanine formation). o Leads to base mispairing during replication. • DNA-Protein Crosslinks and Interstrand Crosslinks o Disrupt transcription and replication. o Often caused by high LET radiation or indirectly by ROS[12]. II. Indirect Action via Reactive Oxygen Species (ROS) Ionizing radiation interacts with water to produce free radicals, particularly: • Hydroxyl radical (•OH) • Hydrogen peroxide (H₂O₂) • Superoxide (O₂⁻)[6] These ROS are highly reactive and diffuse short distances, attacking nearby molecules like DNA, lipids, and proteins. ROS-mediated DNA damage includes: • Oxidative base damage (e.g., guanine → 8-oxoG → GC to TA transversions) • Sugar ring fragmentation, leading to strand breaks • Clustered lesions: multiple nearby SSBs and base lesions, often leading to DSBs if unrepaired[17] III. DNA Repair Pathways and Misrepair-Induced Mutations Cells have evolved complex repair systems to counteract DNA damage. The fidelity and pathway chosen influence whether mutations will occur. A. Non-Homologous End Joining (NHEJ) • Major pathway for DSB repair in mammalian cells. • Error-prone: can lead to insertions, deletions, or chromosomal translocations. • Active throughout the cell cycle, especially in G1 phase[14]. B. Homologous Recombination (HR) • High-fidelity repair using a sister chromatid as a template. • Active in S and G2 phases of the cell cycle. • Deficiency in HR (e.g., BRCA1/2 mutations) increases radiosensitivity and cancer risk[25]. C. Base Excision Repair (BER) • Repairs small base modifications (oxidation, deamination). • If overwhelmed by clustered damage, can become inefficient, leading to mutations. D. Mismatch Repair (MMR) • Corrects base-base mismatches and replication errors. • MMR-deficient cells (e.g., in Lynch syndrome) show increased radiosensitivity and mutation rates[21]. IV. Types of Mutations Induced Depending on the repair outcome, the following mutations can result: Mutation Type Description Consequence Point mutations Base substitutions (e.g., GC → AT) May activate oncogenes or inactivate tumor suppressors Insertions/Deletions Addition or loss of nucleotides Frameshifts, truncations Chromosomal aberrations Translocations, inversions, deletions Common in radiation-induced cancers Micronuclei formation Chromosome fragments form separate nuclear bodies Marker of genomic instability Gene amplification Duplication of DNA segments Can drive oncogene overexpression V. Factors Influencing Mutation Likelihood 1. Linear Energy Transfer (LET) • High LET (e.g., alpha particles, neutrons): Dense ionization along a short track → complex DNA damage, less repairable. • Low LET (e.g., X-rays, gamma rays): Sparse ionization → more likely to be repaired[15]. 2. Cell Cycle Phase • Cells are most radiosensitive during G2/M and least in S phase (when HR is most active). 3. Oxygen Effect • Oxygen enhances radiation damage ("oxygen fixation hypothesis") by stabilizing DNA radicals. • Hypoxic tumor cells are more resistant to radiation. 4. Dose Rate • High dose rates overwhelm repair mechanisms → more permanent damage. • Low dose rates may allow repair and adaptation (known as the "low-dose hypersensitivity" phenomenon). 5. Genetic Background • Individuals with defects in DNA repair (e.g., ataxia telangiectasia, xeroderma pigmentosum) are hypersensitive to radiation and at higher cancer risk[17]. VI. Radiation-Induced Genomic Instability (RIGI) RIGI refers to the delayed appearance of genetic alterations in the progeny of irradiated cells. Mechanisms include: • Persistent oxidative stress • Dysfunctional DNA repair • Altered cell signaling (bystander effect) RIGI is believed to contribute to secondary malignancies, chronic inflammation, and transformation years after exposure. Summary Table: DNA Lesions and Outcomes Lesion Repair Pathway Mutation Risk Relevance Single-strand break (SSB) BER, ligase Low Common, low-risk Double-strand break (DSB) HR (accurate), NHEJ (error-prone) High Cancer-driving Base oxidation (8-oxoG) BER Moderate Point mutations Clustered damage NHEJ Very high High LET radiation Chromosomal break NHEJ, faulty HR Very high Translocations, cancer 1. Radiation-Induced Carcinogenesis Carcinogenesis caused by ionizing radiation is a multistep process involving: • Initiation: DNA damage (especially double-strand breaks) initiates mutations in critical genes like proto-oncogenes and tumor suppressor genes[8]. • Promotion: Damaged cells proliferate due to failure of cell cycle checkpoints and apoptosis, increasing the chance of clonal expansion of mutated cells[10]. • Progression: Accumulation of further mutations promotes transformation into malignant cells[11]. Key Molecular Targets • TP53: A tumor suppressor gene often mutated in radiation-induced cancers. Its protein product regulates cell cycle arrest and apoptosis. • RET/PTC rearrangements: Especially found in radiation-induced papillary thyroid carcinoma, common in children post-Chernobyl [15]. • Chromosomal aberrations: Translocations (e.g., t(9;22) in CML), deletions, and micronuclei are biomarkers of radiation exposure and carcinogenic transformation[16]. 2. Types of Cancers Caused by Radiation A. Hematologic Malignancies • Leukemias (especially acute myeloid leukemia and chronic myeloid leukemia) are among the most sensitive to radiation. • Latency is typically 5–7 years. • Notably increased in atomic bomb survivors and radiotherapy patients receiving total body irradiation [2]. B. Solid Tumors • Thyroid Cancer: Especially in children; papillary type most common after exposure to radioactive iodine. • Breast Cancer: Seen in young women who received chest irradiation (e.g., for Hodgkin lymphoma). • Lung Cancer: Particularly in uranium miners and radon-exposed populations. • Skin Cancer: Basal cell carcinoma and squamous cell carcinoma may arise in radiated areas. • Brain Tumors: Particularly meningiomas and gliomas in radiotherapy-treated patients. C. Second Primary Malignancies • Patients treated with radiotherapy for a primary cancer (e.g., Hodgkin lymphoma, breast cancer) are at increased risk for secondary malignancies due to scattered or off-target radiation exposure. • These include sarcomas, leukemias, and cancers of the lung, breast, colon, and esophagus Non-Cancerous Radiation-Induced Diseases A. Cataracts • Ionizing radiation damages lens epithelial cells, leading to posterior subcapsular cataracts. • Occupational hazard in radiology staff, astronauts, and radiologic interventionalists[3]. B. Cardiovascular Disease • Radiation-induced endothelial damage can initiate atherosclerosis. • Radiation to the chest (e.g., during breast or Hodgkin lymphoma therapy) increases the risk of coronary artery disease, pericarditis, and cardiomyopathy[16]. C. Pulmonary Fibrosis • Seen after chest irradiation; radiation causes inflammation, collagen deposition, and fibrotic remodeling[3]. D. Infertility and Endocrine Dysfunction • Gonadal exposure may lead to infertility, particularly in males. • Hypothyroidism and hypopituitarism can occur after cranial or neck irradiation. E. Growth and Developmental Defects • In utero exposure, particularly during organogenesis (8–15 weeks gestation), can cause microcephaly, intellectual disabilities, and growth retardation. Effects of Radiation on Cancer Cells Radiation therapy aims to exploit the differential sensitivity of cancer cells to ionizing radiation compared to normal tissue. The key mechanisms include: 1. DNA Damage and Cell Death Cancer cells are targeted by radiotherapy primarily through DNA double-strand breaks (DSBs), which they cannot repair efficiently due to defective checkpoints or repair pathways. Cancer cell death types include the following: • Mitotic catastrophe: usually seen in solid tumors, this occur when cells with damaged DNA enter mitosis [12]. • Apoptosis: Common in hematologic tumors such as leukemias and lymphomas [13]. • Senescence: While cancer cells can not be fixed, their growth is completely stopped. • Necrosis: Less prevalent, but it can occur in areas of growths that are both hypoxic and poorly vascularized [21]. 2. Cell Cycle Sensitivity • Cancer cells are most sensitive to radiation in the G2/M phase. • Fractionated radiotherapy aims to capture cells in vulnerable phases over multiple sessions. 3. Oxidative Stress • Ionizing radiation induces ROS generation[6]. • Cancer cells often have higher baseline oxidative stress; additional ROS overwhelms their antioxidant defenses, tipping the balance toward cell death[22]. 4. Vascular Effects • Radiation damages tumor blood vessels, leading to: o Hypoxia (which can both hinder and help therapy)[16] o Impaired nutrient delivery o Vascular collapse in high-dose settings (e.g., SBRT)[18] 5. Immunogenic Cell Death By releasing damage-associated molecular patterns (DAMPs), radiation may make tumors more apparent to the immune system [18]. • Tumor cells carrying more MHC-I • Improving T-cell infiltration and dendritic cell activation A promising area of oncology research is the combined use of immunotherapy and radiation treatment, and this is based on this effect [24]. 6. Radiation-Induced Bystander Effect It's interesting to note which irradiated cancer cells can use cytokines, nitric oxide, or reactive oxygen species, also known as ROS, to induce apoptosis or senescence in nearby, non-irradiated cells. Beyond the targeted cells, it boosts the local anti-tumor effect. Radiotherapy: Harnessing Ionizing Radiation to Treat Cancer For the purpose of to eliminate cancer cells while maintaining normal tissues as much as possible, radiotherapy uses controlled doses of ionizing radiation. Radiation treatment is given to between 50 and 60 percent of cancer patients. Mechanism of Action: Radiation therapy leads to mitotic death in cancer cells by affecting their DNA. Cancer cells are more at risk than healthy cells given their rapid division and impaired DNA repair systems. Types of Radiotherapy: 1. External Beam Radiotherapy (EBRT): - Uses linear accelerators to direct X-rays, electrons, or protons at the tumor[19]. - Techniques: 3D Conformal Radiotherapy (3D-CRT), Intensity-Modulated Radiotherapy (IMRT), Image-Guided Radiotherapy (IGRT), Stereotactic Body Radiotherapy (SBRT)[20]. 2. Brachytherapy: - Radioactive sources are placed within or near the tumor (e.g., cervical or prostate cancer)[19]. 3. Systemic Radiotherapy: - Radioisotopes (e.g., I-131 for thyroid cancer) are administered orally or intravenously. - Targeted delivery via molecular markers (radioimmunotherapy)[19]. Radiobiological Principles in Cancer Treatment The Four R’s of Radiobiology: 1. Repair: In comparison to cancer cells, normal cells have better repair systems. 2. Reoxygenation: Reoxygenation improves efficacy whereas tumor hypoxia lowers radiation sensitivity. 3. Redistribution: During certain phases of the cell cycle, such as G2/M, cells are more sensitive to exposure to radiation. 4. Repopulation: Fractionation minimizes tumor growth while enabling normal tissue regeneration. Fractionation: restoring normal tissues and raising the therapeutic ratio becomes accessible by breaking the total radiation dose into numerous tiny doses, or fractions [16]. Challenges and Advances in Radiotherapy Resistance to Radiation: -Hypoxia in tumors -Enhanced DNA repair pathways; genetic mutations (such as p53 loss) [16]. Sensitizers and Radioprotectors: -Amifostine: maintains healthy tissues [24]. -Radiosensitizers which promote tumor death consist of cetuximab and cisplatin [23]. -Accurate Radiation Therapy: -Proton therapy deposits the most energy at the tumor with the smallest amount of exit dose by using the Bragg peak [19]. -The relative biological effectiveness (RBE) of carbon ions is high in heavy ion therapy. Adaptive radiotherapy uses imaging data to change therapies in real time [20].

Ionizing radiation is a powerful tool for both healing and destruction. Its role in the development of cancer is shown by its capacity to induce genetic mutations, particularly after ongoing or high-dose exposure. Still, the same feature is successfully used by radiotherapy to treat cancer by specifically targeting tissues that are cancerous. Advancement in imaging, planning, and radiation methods of delivery are greatly improving the therapeutic ratio of radiotherapy. To reduce adverse outcomes, prevent secondary cancer risks, or develop radioprotective actions, it is still important to fully understand the biological effects of radiation.

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