Biological effects of radiation

Levels of radiation damage

• Every exposure to ionising radiation, natural or man-made, small or large, produces some biological effect. The only question is how significant that effect is.
• Radiation deposits energy by ionising atoms. The damage then passes up through the levels of organisation: atoms → molecules → cells → tissues → organs → whole body.
• Damage at a lower level is only expressed at a higher level if enough of it escapes repair.

DNA damage

• The nucleus is the most radiosensitive part of the cell, and the critical target in it is the DNA molecule.
• DNA is a double helix of two strands. Each strand is a chain of sugar units joined by phosphate bonds, the sugar–phosphate backbone.
• The two strands are held together by base pairs: adenine (A) with thymine (T) and guanine (G) with cytosine (C). Each base is bonded to a sugar on its own strand and to its partner base by hydrogen bonds.
• Radiation produces lesions of increasing seriousness (Figure 1):
• Hydrogen bond broken, base retained (B).
• Hydrogen bond broken, base lost (C).
• Single-strand break: one backbone is cut (D). It is repaired easily, because the intact strand serves as the template.
• Double-strand breaks far apart on the two strands (E): the molecule holds together and repair is still possible.
• Double-strand breaks close together, within a few base pairs (F): the molecule separates into fragments and repair is unreliable. This lesion is the main cause of cell death, mutation and chromosome aberrations.

Chromosome aberrations

• Chromosomes are damaged in two ways: through mutations in their DNA, and by direct cleavage of an arm, producing single or double breaks.
• These structural changes are called aberrations (also anomalies or lesions).
• Chromatid aberration: irradiation after DNA synthesis, so only one of the two chromatids is affected.
• Chromosome aberration: irradiation before DNA synthesis, so the damaged chromatid is duplicated and both daughter cells carry damaged chromosomes (Figure 2).
• One break in one arm (Figure 3, row 1): the two ends usually rejoin, a process called restitution. If the chromosome replicates before the ends rejoin, the broken fragments recombine at random, giving a dicentric chromosome (two centromeres) and an acentric fragment (no centromere).
• One break in each of two chromosomes (row 2): the four broken ends can rejoin in four ways. When a fragment carrying a centromere from one chromosome joins an acentric fragment from the other, a new chromosome is formed: a translocation.
• Two breaks in one arm (row 3): three fragments result. If the two outer fragments join and the middle piece is lost, it is a deletion. If all three rejoin with the middle piece reversed, it is an inversion.
• Dicentrics and acentric fragments are lost at mitosis, so these cells usually die. Balanced translocations and inversions can survive and be passed on, which links them to late effects.

Direct and indirect action

• Radiation damages DNA by two routes (Figure 4).
• Direct action: the ionising particle hits the DNA molecule itself and disrupts its structure. This route predominates with high-LET radiation such as α particles and neutrons, and at high doses.
• Indirect action: the particle ionises water, the main constituent of the cell, and the free radicals formed (mainly the hydroxyl radical, OH•) diffuse to DNA and damage it.
• The number of free radicals formed depends on the total dose, not on the dose rate.
• Water makes up about 70 % of the cell, so most radiation damage, about two thirds with x- and γ-rays, is by indirect action.

Radiosensitivity of cells

• Law of Bergonié and Tribondeau: cells that are undifferentiated and actively dividing are the most radiosensitive; fully differentiated, non-dividing cells are the least.
• Lymphocytes are an exception: although mature, they are highly radiosensitive, attributed to their large nucleus.
• Nerve and muscle cells are fully differentiated and highly radioresistant.
• After whole-body irradiation the blood counts fall in order of cell lifespan: lymphocytes the same day, granulocytes by about 3 days, platelets by about 6 days, red cells by about 10 days.

Cell cycle

• Radiosensitivity varies through the cell cycle (Figure 5).
• Most sensitive: mitosis (M) and the G2/M boundary. The DNA is condensed and not being repaired, so damage is fixed.
• Least sensitive: the late S phase of DNA synthesis, when active repair mechanisms are at work.
• Mitotic death: an irradiated cell may still divide once or twice before it dies, so cell death is often delayed by one or two cycles.

Cell survival curves

• Radiation damage to a cell population depends on the total dose, the dose rate, the LET of the radiation, the phase of the cell cycle and the type of cell.
• The response is shown as a cell survival curve: dose on a linear x-axis, surviving fraction on a logarithmic y-axis (Figure 6).
• A surviving cell keeps its reproductive and functional capacity. Cell death means loss of function in differentiated cells and loss of reproductive ability in dividing cells.

Multitarget model

• Low-LET radiation (x- and γ-rays) gives a curve with an initial shoulder followed by a straight line. High-LET radiation (α particles, low-energy neutrons) gives a straight line from the lowest doses.
• The model has three parameters: D₀, n and D_q.
• D₀ is the dose that reduces survival to 37 % on the straight part of the curve, that is, it kills 63 % of the cells. It is found from the slope. A large D₀ means a radioresistant cell type.
• n, the extrapolation number, is the intercept on the y-axis when the straight part is extrapolated back to zero dose. For mammalian cells it is between 1 and 10.
• D_q, the quasi-threshold dose, is the width of the shoulder. In this region almost all cells repair the small amount of damage, so there is little cell killing.

Linear-quadratic model

• The linear-quadratic model describes radiation cell killing more accurately.

• For low-LET radiation, βD² is negligible at low doses, so survival falls linearly with dose; at higher doses the quadratic term dominates and the curve bends downward.
• For high-LET radiation the curve is linear throughout.
• The dose at which the linear and quadratic contributions are equal is α/β. It is high (about 10 Gy) for early-responding tissues and tumours, and low (about 3 Gy) for late-responding tissues.

Factors that modify radiation damage

Dose rate

• Dose rate is the dose delivered per unit time.
• At low dose rates mainly single-strand breaks occur and are repaired between ionising events. At high dose rates double-strand breaks occur, and the cell has too little time to repair them.
• In radiotherapy, when the total dose is given in fractions, the interval between fractions should be short enough to limit repair of the abnormal cells.

Linear energy transfer (LET)

• LET is the average energy deposited by a charged particle per unit length of its track in tissue, in keV/μm. It describes the density of ionisation along the track.

• Factors that raise LET: a higher particle charge and a lower speed. So heavy charged particles (α, heavy ions) have high LET, and LET rises further towards the end of the track as the particle slows (the Bragg peak).
• Typical values (Figure 7): γ-rays and x-rays about 0.2 to 2 keV/μm; β particles about 0.3 keV/μm; protons 0.5 to 5; neutrons (through recoil protons) 10 to 20; α particles 100 to 200 keV/μm; heavy ions up to 1000 keV/μm. The table summarises the differences.

Relative biological effectiveness (RBE)

• RBE compares the biological effectiveness of a radiation with a reference radiation, usually 250 kVp x-rays.

• Example: if 2 Gy of neutrons kills the same fraction of cells as 6 Gy of x-rays, the RBE of the neutrons is 6/2 = 3.

• Factors affecting RBE:

• The radiation weighting factor (w_R) is the regulatory simplification of RBE used in radiation protection. It converts the absorbed dose (D, in gray) to the equivalent dose (H, in sievert), which allows doses from different radiations to be added and compared.

• Example: 1 mGy from α particles gives 20 mSv; 1 mGy from γ-rays gives 1 mSv.

Oxygen enhancement ratio (OER)

• Oxygen is the most important chemical modifier of radiation damage. The OER measures how much it sensitises cells.

• Example: if hypoxic cells need 9 Gy of x-rays to reach the same survival as oxygenated cells at 3 Gy, the OER is 9/3 = 3. An OER of 3 means hypoxic cells are three times more resistant.

• Mechanism: oxygen reacts irreversibly with the free radicals formed on DNA by water radiolysis, fixing the damage before it can be repaired chemically. Oxygen must be present during irradiation or within milliseconds of it.
• Factors affecting OER: LET (about 2.5 to 3 for x- and γ-rays, falling to about 1 above 100 keV/μm); oxygen tension (most of the sensitisation is reached at a partial pressure of about 3 mmHg, and full effect by about 30 mmHg); dose (a little lower, about 2, at doses below 2 Gy).
• Clinical link: hypoxic tumour cells are radioresistant, and high-LET radiation or oxygen-mimic sensitisers (next section) are ways to overcome this.

Radiosensitisers and radioprotectors

Radiosensitisers

• Radiosensitisers increase the response of cells to radiation.

Radioprotectors

• Radioprotectors reduce radiation damage. They must be present at the time of irradiation.
• The classical agents contain a sulfhydryl (–SH) group: cysteine and cysteamine. They scavenge free radicals before the radicals reach DNA, and donate hydrogen to repair radical damage on DNA. They are therefore most effective against low-LET radiation, where indirect action dominates, and give little protection against high-LET radiation.
• The early compounds caused nausea and vomiting at effective doses. Phosphorothioate prodrugs, WR-638 and WR-2721 (amifostine), are better tolerated. Amifostine is given shortly before irradiation to protect normal rapidly dividing tissues such as bone marrow and salivary glands.
• The dose reduction factor (DRF) is the dose needed with the protector divided by the dose needed without it, for the same effect. For amifostine it is about 2 to 2.7 for bone marrow.

Deterministic and stochastic effects

• Radiation effects on the body are classified by their dose–response relationship (Figure 8).

Deterministic effects (tissue reactions)

• Caused by the killing of a large number of cells, so that the tissue or organ can no longer function.
• There is a threshold dose, which differs between tissues. Below it no effect is seen.
• Above the threshold the severity increases with dose.
• Onset is usually hours to weeks after exposure.
• Examples: skin erythema and epilation, mucositis, cataract, sterility, the acute radiation syndromes, and bone marrow failure.

Stochastic effects

• Caused by damage to a single cell that escapes repair: a mutation that may lead to cancer in the exposed person or, in a germ cell, to a heritable effect in the offspring.
• The probability of the effect increases with dose, with no threshold: any dose, however small, carries some risk.
• The severity of the effect does not depend on the dose. A cancer induced by a small dose is no milder than one induced by a large dose.
• Onset is years to decades after exposure.
• Examples: leukaemia, thyroid, breast and other solid cancers; heritable disease.
• Radiation protection assumes a linear no-threshold (LNT) relationship for stochastic effects, so every dose is kept as low as reasonably achievable (ALARA).

Acute radiation syndromes

• Acute radiation sickness follows a large whole-body dose delivered over a short time. The syndromes are deterministic effects with threshold doses, and the organ affected depends on the dose (Figure 9).
• The lethal dose LD_50/60 is the dose that kills 50 % of those exposed within 60 days. For humans it is about 3.5 to 4.5 Gy without treatment, and about 6 to 7 Gy with intensive supportive care (antibiotics, transfusions, growth factors).
• Each syndrome passes through four stages: a prodromal stage (nausea, vomiting, fatigue), a latent stage of apparent well-being, the stage of manifest illness, and then recovery or death. The higher the dose, the earlier and shorter each stage.

• The lymphocyte count in the first 48 hours is the most useful early guide to the dose received: the faster and deeper the fall, the higher the dose.

Long-term effects

• Late effects appear months to years after exposure, either after recovery from acute radiation sickness or after repeated low-dose exposure.
• Somatic effects occur in the exposed person: carcinogenesis, cataract, skin damage, damage to the reproductive organs, and life-shortening.
• Genetic (heritable) effects occur in the offspring, through mutations in germ cells.

Carcinogenesis

• Radiation is a complete carcinogen: it can both initiate and promote cancer.
• Initiation: DNA damage producing a mutation. Agents include chemicals, ultraviolet light, viruses and ionising radiation.
• Promotion: promoters cannot start a cancer, but encourage the growth of cells that already carry a mutation. Examples are oestrogen, phorbol esters, a high-fat diet and radiation itself.
• Progression: the mutated cells become increasingly abnormal, invade and metastasise.

Dose–response and risk estimates

• Human data come mainly from the atomic-bomb survivors, radiotherapy patients, occupationally exposed groups and the Chernobyl population.
• Below about 100 mGy the data are inconclusive, because of small numbers, lack of controls and uncertain dosimetry.
• The linear no-threshold (LNT) model assumes that risk is proportional to dose down to zero, with no safe dose. The BEIR VII report (2006) supports LNT for solid cancers; for leukaemia the curve is linear-quadratic, rising more steeply at higher doses.

• Leukaemia: about 20 % of radiation-induced cancer deaths; risk higher at young ages; shortest latent period, average 5 to 10 years; about 1 to 2.6 excess cases per 10,000 person-years per Gy.
• Breast cancer: risk highest for exposure at young ages; BEIR V excess risk per 10,000 person-years per Gy about 5 at age 25, 4 at 35, 2 at 45; BEIR VII about 10 per 10,000 person-years per Gy for exposure at age 50. Modern mammography carries a very low risk.
• Thyroid cancer: about 4.4 excess cases per 10,000 person-years per Gy; the risk is greatest for exposure in childhood (Chernobyl).
• Lung, bone and skin cancers are induced less often.

Skin

• The skin is sensitive because of its rapidly dividing basal layer, hair follicles and sebaceous glands.
• Skin effects are deterministic. Transient erythema appears within hours above about 2 Gy; the main erythema at about 6 Gy appears in the third or fourth week, with warm, red, oedematous, tender skin.
• Temporary epilation occurs above about 3 Gy, permanent epilation above about 7 Gy.
• Dry desquamation follows about 14 Gy, moist desquamation about 18 Gy, and necrosis above about 24 Gy. Normal skin takes 2 to 3 months to regrow.
• The effects depend on the dose, dose rate, LET and area exposed. Skin cancer is a rare late result.

Reproductive organs

• The gonads are highly radiosensitive. In the testis the spermatogonia are the most sensitive cells; spermatids and spermatozoa are resistant. In the ovary the oocytes in developing follicles are the most sensitive.
• Males: temporary sterility from about 0.15 Gy (15 rad); permanent sterility from an acute dose of about 3.5 to 6 Gy.
• Females: permanent sterility from about 2.5 to 6 Gy depending on age, lower in older women who have fewer oocytes left.
• Lymphocyte and sperm counts are both used as biological dosimeters after accidental exposure.

Life-shortening and hormesis

• In animal studies, whole-body irradiation shortened the life span, mainly through cancer.
• The evidence is inconsistent at low doses, where some studies found a longer life span. This led to the idea of radiation hormesis, that low doses are beneficial, possibly through stimulation of the immune system and DNA repair. It is not accepted as a basis for radiation protection.

Cataract

• The lens of the eye is radiosensitive, and radiation produces posterior subcapsular cataract.
• Cataract is a deterministic effect. ICRP 118 (2012) lowered the threshold to about 0.5 Gy, whether given in one or several exposures, and reduced the occupational lens limit to 20 mSv per year. Older texts give 2 Gy for a single exposure.
• High-LET radiation is more effective; neutrons roughly double the incidence.
• The latent period is at least 1 year and is shorter with higher doses.

Genetic effects

• Radiation damage to the DNA of germ cells causes mutations that are passed to future generations.
• Genes mutate spontaneously even without radiation. Radiation and chemical mutagens raise the frequency of mutation, not the kind: radiation-induced mutations are the same as spontaneous ones, only more frequent.
• Inherited disorders that could in principle increase include Down syndrome, achondroplasia, retinoblastoma, cystic fibrosis, sickle-cell anaemia and Tay–Sachs disease.
• No heritable effect of radiation has yet been demonstrated in humans, including the children of atomic-bomb survivors. The estimates come from mouse data.
• Doubling dose: the dose that doubles the spontaneous mutation rate in one generation. For humans it is estimated at about 1 Gy.
• Genetically significant dose (GSD): the average dose to the gonads of a population, weighted by the number of people exposed and their expected number of future children. It is a measure of the genetic burden of a practice such as diagnostic radiology.

Embryo and foetus

• The embryo is extremely radiosensitive because its cells are dividing and differentiating rapidly. The effect depends on the stage of development, the dose and the dose rate.
• Preimplantation (0 to 2 weeks after conception): the all-or-none period. The main effect is death of the embryo, with a threshold of about 100 mGy; an embryo that survives develops normally.
• Organogenesis (2 to 8 weeks): malformations, mainly of the central nervous system and skeleton, and growth retardation; threshold about 100 to 200 mGy.
• Early foetal period (8 to 15 weeks): the most sensitive time for the developing brain. Severe mental retardation has a threshold of about 300 mGy, and IQ falls by about 25 to 30 points per Gy above it. Between 16 and 25 weeks the sensitivity is lower.
• Late foetal period: foetal cells are more radioresistant and much higher doses are needed to cause death.
• Childhood cancer: in-utero exposure of about 10 mGy raises the risk of childhood leukaemia and other cancers by about 40 % (relative risk about 1.4), from a baseline of about 1 in 500.
• ICRP 84: a foetal dose below 100 mGy is not a reason to terminate a pregnancy; nearly all diagnostic nuclear medicine and radiology procedures give far less than this.

Test yourself

Revise this chapter with the Biological effects deck in Flashcards.

10 quick questions. Pick an answer to see the explanation.

Spotted an error or something out of date? Report an error