Biological Effects of Ionising Radiation

1. From ionisation to the whole body

• Every exposure deposits energy by ionisation and excitation. Whether an effect follows, and how large, depends on dose, dose rate, radiation type and the tissue.
• Damage spreads upwards: atom → molecule → cell → tissue → organ → whole body.
• The events are fast at first (physical and chemical stages last fractions of a second) and slow later (repair within hours, cell death over days, cancer over years).

2. DNA damage and repair

• DNA is the critical target: two sugar–phosphate strands joined by paired bases (A–T, G–C).
• Base damage and single-strand breaks: common and usually repaired accurately, because the intact opposite strand acts as a template.
• Double-strand breaks (DSBs): the key lethal lesion. Repaired by non-homologous end joining (fast, error-prone) or homologous recombination (accurate, needs a sister chromatid, so only in S/G2).
• Breaks close together, or clustered with other damage, are the hardest to repair.

Chromosome and chromatid aberrations

• Irradiation before DNA synthesis (G1) gives chromosome aberrations, because the damage is copied into both chromatids.
• Irradiation after DNA synthesis (G2) gives chromatid aberrations, affecting one arm only.
• A single break usually rejoins (restitution). Mis-rejoining produces aberrations:

3. Direct and indirect action

• Direct action: the radiation (or its secondary electron) ionises DNA itself. Dominant for high-LET radiation such as α particles and neutrons.
• Indirect action: radiation ionises water; the resulting free radicals, chiefly the hydroxyl radical (OH•), then damage DNA.
• Because cells are mostly water, about two-thirds of the damage from X- and γ-rays is indirect.
• Oxygen reacts with the DNA radical and 'fixes' the damage in a non-repairable form, which is why oxygenated cells are more sensitive (section 6).

4. Which cells are most sensitive?

• Most sensitive: lymphocytes (the exception: mature but very sensitive, dying by apoptosis), bone marrow stem cells, gut crypt cells, spermatogonia, oocytes, lens epithelium, the embryo.
• Least sensitive: non-dividing, differentiated cells such as nerve and muscle.
• Cell cycle: most sensitive in M and G2; most resistant in late S phase, when homologous-recombination repair is available.
• Cells often die at their next mitosis or the one after (mitotic death), so tissues with fast turnover show damage first.

Blood counts after whole-body exposure

• Lymphocytes fall first, within the first 1–2 days; the rate of fall is used to estimate dose.
• Granulocytes and then platelets fall over the following days to weeks as marrow production stops.
• Red cells fall last and least, because of their long (~120-day) lifespan.

5. Cell survival curves

• Survival here means keeping the ability to divide (clonogenic survival). Curves plot dose on a linear axis against surviving fraction on a log axis.
• Low-LET (X, γ, β): a shoulder at low doses (repair of sublethal damage) followed by a steeper, straighter part.
• High-LET (α, low-energy neutrons): nearly straight from zero: little repairable damage.

Linear-quadratic (LQ) model

• S = e^(−αD − βD²)
• α (linear term): cell killing by a single track that causes a lethal, non-repairable lesion.
• β (quadratic term): killing by the interaction of two tracks whose separate sublethal lesions combine; this part can be repaired if the dose is spread out in time.
• α/β ratio: the dose at which both terms kill equally. About 10 Gy for tumours and early-reacting tissues, about 3 Gy for late-reacting tissues, which are therefore more spared by small fractions.

Multitarget model (older)

• D₀: the dose that reduces survival to 37% on the straight part of the curve; a larger D₀ means a more resistant cell.
• n (extrapolation number): where the straight part meets the y-axis; usually about 2–10 for mammalian cells.
• Dq (quasi-threshold dose): the width of the shoulder; Dq = D₀ · ln n.

6. Factors that modify the effect

Radiation type: LET, RBE and radiation weighting

• RBE: the dose of a reference radiation (classically 250 kVp X-rays) divided by the dose of the test radiation giving the same biological effect.
• Radiation weighting factor (wᵣ, ICRP 103): converts absorbed dose (Gy) to equivalent dose (Sv). Photons and electrons 1; protons 2; α particles and heavy ions 20; neutrons a continuous function of energy (about 2.5–20).

Dose rate and fractionation

• For low-LET radiation, the same dose given slowly kills fewer cells, because sublethal damage is repaired during exposure (the quadratic, β term shrinks).
• Radiotherapy uses this through fractionation. The four Rs: Repair (normal tissue repairs between fractions; at least ~6 h apart), Redistribution (cells move into sensitive phases), Repopulation (surviving cells divide) and Reoxygenation (hypoxic tumour cells become sensitive).

Oxygen

• Hypoxic cells are about 2.5–3 times more resistant to X- and γ-rays.
• OER = dose needed without oxygen ÷ dose needed with oxygen for the same effect: about 2.5–3 for low-LET radiation, about 1 for α particles.

Chemical modifiers

7. Deterministic and stochastic effects

Threshold doses to know (ICRP 118, acute exposure, ~1% incidence)

Table 1. Selected ICRP 118 threshold doses. Values are approximate and apply to single acute exposures.

8. Acute radiation syndrome (ARS)

• Follows high-dose, whole-body (or large-volume) exposure over a short time. It is a deterministic effect.
• Four phases: prodromal (nausea, vomiting) → latent (apparent well-being) → manifest illness → recovery or death. Higher doses shorten every phase.
• LD50/60 (ICRP 118): about 3.3–4.5 Gy without medical treatment and 6–7 Gy with supportive care (antibiotics, blood products, fluids).

Table 2. The acute radiation syndromes (dose ranges from ICRP 118). The ranges overlap, and survival depends heavily on medical care.

9. Late effects in the exposed person

Cancer

• Radiation acts mainly as an initiator (DNA damage); promotion and progression follow over years.
• Leukaemia appears first (minimum latency ~2 years, peak within about 5–10 years); solid cancers after 10 years or more.
• Risk is higher in children and younger adults.
• BEIR VII (LNT model): about 1 in 100 people would develop cancer from 0.1 Sv (100 mSv), against about 42 in 100 who develop cancer from other causes. A lifetime of natural background radiation (excluding radon) carries a similar ~1 in 100 risk.
• Below about 100 mSv the epidemiology cannot confirm or exclude a risk; LNT is used for protection because it is prudent, not because it is proven.

Other late effects

• Cataract: posterior subcapsular. ICRP 118 lowered the threshold to 0.5 Gy, and the occupational lens limit to 20 mSv per year (averaged over 5 years). Latency is years and shortens with higher dose.
• Skin: erythema, dry then moist desquamation, hair loss; later atrophy, telangiectasia and fibrosis (thresholds in Table 1).
• Gonads: spermatogonia and oocytes are highly sensitive; temporary male sterility from ~0.1 Gy; permanent sterility ~6 Gy (testes) and ~3 Gy (ovaries), lower in older women.
• Life-shortening and hormesis: non-specific life-shortening was seen in animals at high doses. Hormesis (benefit from low doses) is unproven and is not used in radiation protection.

10. Heritable effects

• Radiation can cause mutations in germ cells that could pass to children.
• No heritable effect has been demonstrated in humans, including the children of atomic-bomb survivors; the risk is inferred from animal studies.
• Radiation does not create new kinds of disease; it can only increase the frequency of mutations that occur spontaneously.
• Doubling dose: the dose that doubles the spontaneous mutation rate in a generation; about 1 Gy for humans (from mouse data).
• Genetically significant dose (GSD): the gonadal dose averaged over a population, weighted by each person's expected number of future children.

11. Embryo and fetus

• The embryo is highly sensitive because its cells divide rapidly and are undifferentiated. The effect depends on gestational stage and dose.
• Pre-implantation (0–2 weeks): all-or-none: the embryo is lost or develops normally.
• Organogenesis (2–8 weeks): malformations, mainly CNS and skeleton, above about 100–200 mGy.
• 8–15 weeks: the most sensitive period for the brain: severe intellectual disability from about 300 mGy; IQ falls by about 25 points per Gy.
• Childhood cancer: a small, dose-related increase in risk after exposure at any stage.

12. What this means in nuclear medicine

• Diagnostic studies: effective doses are a few mSv (e.g. bone scan ~3–4 mSv, FDG PET/CT ~7–10 mSv). Organ doses are far below every deterministic threshold, so the only relevant risk is a small stochastic one.
• Therapy is planned in absorbed dose (Gy): the aim is deterministic cell killing in the target. Effective dose (Sv) is a radiation-protection quantity for stochastic risk and should not be used to prescribe therapy.
• β⁻ emitters (¹³¹I, ¹⁷⁷Lu, ⁹⁰Y): low LET, ranges of millimetres. The crossfire effect treats cells that do not take up the drug, and dose is delivered slowly over days, allowing repair.
• α emitters (²²³Ra, ²²⁵Ac): high LET, range of a few cell diameters (~50–100 µm). High RBE, little dependence on oxygen or dose rate, and effective against hypoxic or resistant cells.
• Low dose rate: radionuclide therapy is continuous, low-dose-rate irradiation. The LQ model is extended as the biologically effective dose (BED), which allows for repair during delivery when comparing it with external-beam treatment.
• Pregnancy and breastfeeding: check before every study; for therapy, exclude pregnancy and stop breastfeeding where required (see the Radiation protection page).

Summary

1. DNA double-strand breaks, mostly caused indirectly by free radicals, are the key lesion.
2. Dividing, undifferentiated cells are most sensitive; M and G2 phases most, late S least.
3. The LQ model describes survival; α/β separates early- from late-reacting tissues.
4. High-LET radiation has a high RBE, an OER near 1 and little dose-rate effect.
5. Tissue reactions have thresholds (cataract 0.5 Gy); cancer and heritable risk are treated as having none.
6. Fetal risk depends on gestational stage; below 100 mGy, termination is not justified on radiation grounds.

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References

1. ICRP. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP Publication 103. Ann ICRP. 2007;37(2-4).
2. Stewart FA, Akleyev AV, Hauer-Jensen M, et al. ICRP Publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs – threshold doses for tissue reactions in a radiation protection context. Ann ICRP. 2012;41(1-2):1-322.
3. ICRP. Pregnancy and medical radiation. ICRP Publication 84. Ann ICRP. 2000;30(1).
4. National Research Council. Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, DC: National Academies Press; 2006.
5. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 8th ed. Philadelphia: Wolters Kluwer; 2018.
6. Saha GB. Physics and Radiobiology of Nuclear Medicine. 4th ed. New York: Springer; 2013.