Radiobiology

4.1 Cellular Effects of Radiation (Direct/Indirect)

Radiation causes cellular damage by depositing energy in biological tissues. This damage occurs through two basic mechanisms: direct action and indirect action.

4.1.1 Direct Action

4.1.2 Indirect Action3 questions

Radiolysis of water:

H₂O → H₂O⁺ + e⁻ (ionisation)

H₂O⁺ + H₂O → H₃O⁺ + OH• (hydroxyl radical)

e⁻ + H₂O → H• + OH⁻

Free radicals formed:

Properties of free radicals:

Figure 4.1: Mechanisms of direct and indirect (water radiolysis and OH•-mediated) action of radiation (schematic).

4.1.3 Oxygen Fixation Hypothesis

4.1.4 Cellular Effects of Radiation – Timeline

Radiation damage develops in successive stages:

1. Physical stage (~10⁻¹⁸ – 10⁻¹² seconds): Ionisation and excitation events 2. Chemical stage (~10⁻¹² – 10⁻² seconds): Free radical formation and reactions

3. Biological stage (seconds – years):

Figure 4.2: Physical, chemical and biological stages of radiation damage and their time scales.

4.2 DNA Damage and Repair Mechanisms

4.2.1 Types of DNA Damage2 questions

Radiation produces various types of damage in DNA:

1. Base damage:

2. Single-strand break (SSB):

3. Double-strand break (DSB):

4. DNA-protein cross-links:

5. Clustered damage (Multiply Damaged Sites):

4.2.2 DNA Repair Mechanisms2 questions

1. Base Excision Repair (BER):

2. Nucleotide Excision Repair (NER):

3. Homologous Recombination (HR):

4. Non-Homologous End Joining (NHEJ):

5. Mismatch Repair (MMR):

4.2.3 Consequences of Repair Failure

If DNA damage is not repaired there are three possible outcomes:

1. Cell death: Apoptosis (programmed cell death) or mitotic death (mitotic catastrophe)

2. Mutation: Permanent genetic change from misrepair → risk of carcinogenesis 3. Genomic instability: Chromosomal aberrations → translocations, deletions, inversions

Figure 4.3: Types of radiation-induced DNA damage, repair pathways and consequences of repair failure (schematic).

4.2.4 Types of Cell Death

1. Mitotic death (Mitotic catastrophe):

2. Apoptosis (Programmed cell death):

3. Necrosis:

4. Senescence:

4.3 Cell Survival Curves (LQ Model)

4.3.1 Basics of the Cell Survival Curve

The cell survival curve is a graph showing the fraction of cells surviving against the radiation dose given:

4.3.2 Linear-Quadratic (LQ) Model6 questions

The most widely used cell survival model today:

Formula:

SF = e^{−(αD + βD²)}

High α/β ratio (~10 Gy):

Low α/β ratio (~2-3 Gy):

Figure 4.4: Survival curves of early- and late-responding tissues in the linear-quadratic model and the meaning of the α/β ratio (representative values).

Biologically Effective Dose (BED)

To compare different fractionation schedules or different dose rates, the biologically effective dose (BED) derived from the LQ model is used:

BED = n × d × [1 + d / (α/β)]

4.3.3 Survival Curve Parameters

D₀ (Mean Lethal Dose):

Dq (Quasi-threshold dose):

n (Extrapolation number):

4.3.4 Effect of LET on the Survival Curve

Figure 4.5: Cell survival curve parameters (D₀, Dq, n) and comparison of low- and high-LET curves (schematic).

4.3.5 Sublethal Damage Repair (SLDR)1 questions

4.3.6 Potentially Lethal Damage Repair (PLDR)

4.4 Dose-Response Relationships (Stochastic/Deterministic)

4.4.1 Deterministic Effects (Tissue Reactions)1 questions

Deterministic effects are effects that appear above a certain threshold dose and whose severity increases as the dose increases.

Basic features:

Examples:

4.4.2 Stochastic Effects7 questions

Stochastic effects are probabilistic effects; as the dose increases the probability of the effect increases but its severity does not change.

Basic features:

Examples:

Nominal risk coefficients (ICRP 103, low dose rate, detriment-adjusted):

Figure 4.6: Dose-response relationship in deterministic and stochastic effects (schematic).

4.4.4 Off-Target and Systemic Radiation Effects2 questions

According to the classical view (the Grotthus-Draper law), the effect of radiation appears only in the cells in which energy is absorbed. It is now known, however, that responses also arise in cells that received no energy and in distant tissues:

Adaptive response:

Bystander effect:

Abscopal effect:

4.4.3 Dose-Response Models2 questions

1. Linear No-Threshold Model (LNT):

2. Linear-Quadratic Model:

3. Threshold Model:

4. Hormesis Model:

Figure 4.7: Dose-response models for risk estimation in the low-dose region (schematic).

4.5 Radiosensitivity and Modifying Factors (OER, LET, RBE)

4.5.1 Determinants of Radiosensitivity2 questions

Factors determining the sensitivity of cells to radiation:

Law of Bergonié and Tribondeau (1906):

Radiosensitivity increases with:

Radiosensitivity ranking (most sensitive to most resistant):

1. Lymphocytes (most radiosensitive somatic cell) 2. Spermatogonia, erythroblasts 3. Myelocytes 4. Intestinal crypt cells 5. Basal epidermal cells 6. Endothelial cells 7. Hepatocytes, nephron epithelial cells 8. Osteocytes, chondrocytes 9. Muscle cells 10. Nerve cells (most radioresistant somatic cell)

4.5.2 Cell Cycle and Radiosensitivity1 questions

Radiosensitivity varies across the phases of the cell cycle:

Why is the S phase resistant?

Why is the M phase sensitive?

Figure 4.8: Radiosensitivity by phase of the cell cycle: G2/M most sensitive, late S most resistant (schematic).

4.5.3 Linear Energy Transfer (LET)2 questions

LET is the energy transferred to the medium by ionising radiation per unit path length (keV/µm).

LET classification:

As LET increases:

Optimal LET: ~100 keV/µm → maximum RBE. Above this value the "overkill" effect begins: more energy is deposited than is needed to kill the cell → wasted energy → RBE begins to fall.

Overkill effect:

LET in nuclear medicine therapies:

4.5.4 Relative Biological Effectiveness (RBE)1 questions

RBE is a ratio comparing the biological effectiveness of a test radiation with that of a reference radiation (250 kVp X-rays or Co-60 gamma).

Formula:

RBE = Dose of reference radiation / Dose of test radiation (for the same biological effect)

Important RBE values:

Factors affecting RBE:

1. LET: RBE increases as LET increases (up to 100 keV/µm), then decreases because of overkill 2. Dose: RBE is higher at low doses (shoulder effect with low-LET radiation)

3. Dose rate: RBE increases at low dose rate 4. Biological endpoint: RBE differs for different biological effects 5. Cell/tissue type: Different cells show different RBEs

4.5.5 Oxygen Enhancement Ratio (OER)5 questions

OER is the ratio of the dose needed for a given biological effect under hypoxic conditions to the dose needed for the same effect under oxygenated (aerobic) conditions.

Formula:

OER = Dose required under hypoxic conditions / Dose required under aerobic conditions

Important OER values:

Clinical importance of OER:

Relationship between OER and LET:

Hypoxic cell radiosensitisers:

Figure 4.9: Ionisation density at low and high LET and variation of RBE and OER with LET (schematic).

4.5.6 Dose-Rate Effect

The same total dose given at different dose rates produces different biological effects:

Low dose rate:

High dose rate:

Inverse dose-rate effect:

Clinical application:

4.5.7 Biological Basis of Fractionation – the 4 Rs (or 5 Rs)2 questions

The biological basis of radiotherapy fractionation is explained by the "4 Rs" (or "5 Rs"):

1. Repair:

2. Reassortment / Redistribution:

3. Repopulation:

4. Reoxygenation:

5. Radiosensitivity – the 5th R:

4.5.8 Radioprotectors and Radiosensitisers2 questions

Radioprotectors:

Radiosensitisers:

4.6 Acute and Chronic Radiation Syndromes

4.6.1 Acute Radiation Syndrome (ARS) – General Information

ARS is the clinical picture that appears after high-dose (>1 Gy) whole-body irradiation over a short period (minutes-hours).

Conditions for the development of ARS:

The four clinical phases of ARS:

1. Prodromal phase (nausea-vomiting phase):

2. Latent phase (apparent well-being):

3. Manifest illness phase:

4. Recovery or death phase:

4.6.2 Haematopoietic Syndrome (Bone Marrow Syndrome)5 questions

Clinical findings:

Order in which blood cells fall after irradiation:

1. Lymphocytes (hours-days) → fall fastest 2. Neutrophils (2-3 weeks) 3. Platelets (3-4 weeks) 4. Erythrocytes (last) → fall most slowly

Treatment: Supportive care, antibiotics, blood products, cytokines (G-CSF, GM-CSF), bone marrow transplantation LD₅₀/₆₀: ~3.5-4.5 Gy (untreated), ~6-7 Gy (with supportive treatment)

Figure 4.10: Order and timing of the fall in blood cells in acute radiation syndrome (schematic).

4.6.3 Gastrointestinal (GI) Syndrome1 questions

Clinical findings:

Cause of death: Sepsis, dehydration, electrolyte imbalance

Time of death: ~10-14 days Treatment: Supportive (fluids, electrolytes, antibiotics), usually lethal

4.6.4 Neurovascular (Cerebrovascular) Syndrome2 questions

Clinical findings:

Cause of death: Cerebral oedema, vascular collapse Time of death: 24-72 hours Treatment: No effective treatment, always lethal

Figure 4.11: Dose ranges, latent periods and clinical course of the acute radiation syndromes.

4.6.5 Cutaneous Radiation Syndrome

Develops when the skin is exposed to high-dose local radiation:

4.6.6 Chronic (Late) Radiation Effects1 questions

Effects appearing after prolonged exposure at low dose rate or months-years after acute exposure:

Late somatic effects:

Genetic (hereditary) effects:

4.7 Radiation Effects in Pregnancy

4.7.1 Radiation Effects by Gestational Period4 questions

The effect of radiation on the fetus depends on the gestational timing and dose of exposure:

1. Preimplantation period (0-9 days / conception – implantation):

2. Organogenesis period (2-8 weeks / 10-56 days):

3. Fetal period – early (8-15 weeks):

4. Fetal period – late (16-25 weeks):

5. Late fetal period (>25 weeks):

Figure 4.12: Fetal radiation effects by gestational period and approximate threshold doses.

4.7.2 Radiation Dose Thresholds in Pregnancy

Fetal dose in nuclear medicine procedures:

4.7.3 Childhood Cancer Risk1 questions

4.7.4 Nuclear Medicine Procedures in Pregnancy – Practical Rules

4.8 Basic Cell and Tumour Biology for Nuclear Medicine

Most of the processes that nuclear medicine images and targets in therapy, such as metabolism, proliferation, hypoxia, receptors and immune checkpoints, arise from basic cell and tumour biology.

4.8.1 Regulation of the Cell Cycle

4.8.2 Apoptosis Pathways1 questions

Extrinsic pathway (death receptor pathway):

Intrinsic pathway (mitochondrial pathway):

Figure 4.13: Extrinsic and intrinsic apoptosis pathways (schematic).

4.8.3 Angiogenesis, Hypoxia and Tumour Metabolism1 questions

4.8.4 Cell Surface Receptors and Immune Checkpoints1 questions

The three main classes of cell surface receptors:

Metastasis and migration:

Immune checkpoints:

Key Points for the Board