European Nuclear Medicine Guide
When ionizing radiation crosses living matter, it deposits energy along its path. If the energy deposition is higher than the binding energy of an orbital electron, the latter leaves the atom which leads to the formation of ion pairs. This process is called ionization. At lower energies, the orbital electrons can gain enough energy to elevate them to higher energy shells, and the atom in the cell is raised from the ground state to a higher energy level. This process is called excitation. Both processes may convert atom and molecules into free radicals with very reactive unpaired electrons. Radicals can also react with neighbouring molecules after which chain reactions may occur. It is widely accepted that DNA within the cell is the critical target for radiation damage that can occur after direct or indirect action. In direct action, the atoms of the DNA itself may be ionized or excited leading to a chain of physical and chemical events which may eventually produce biological damage. Alternatively, the energy can also be deposited in cellular water after which a complex series of chemical changes occurs. This process is called radiolysis and must be seen as the indirect action of ionizing radiation in living cells. During radiolysis, free hydroxyl and other highly reactive radicals are produced. Despite their short existence (10-11-10-13 s), they are capable of diffusing a few micrometres to reach and damage cellular DNA. Moreover, oxygen can modify the reaction by enabling creation of other free radical species with greater stability and longer lifetimes.
Radiation exposure may lead to a wide range of lesions in DNA and proteins. These lesions comprise single strand breaks (SSBs), double strand breaks (DSBs), base damage, protein–protein cross-links, and protein–DNA cross-links. Per absorbed dose of 1 Gy, the number of lesions in the DNA are approximately 1000 base damages, 1000 SSBs and 40 DSBs. Nevertheless, DSBs must be seen as the most extensive expressions of radiation damage, since it was shown that both at high and low doses, unrepaired and misrepaired DSBs correlate with radiosensitivity and survival. There is also experimental evidence for a causal link between the generation of DSBs and the induction of chromosomal translocations with carcinogenic potential.
The repair of DNA lesions is essentially carried out by enzymatic reactions. There exist a variety of DNA repair mechanisms, but most of them depend on the presence of two copies of the genetic information, one on each strand of the double helix. If the damage is limited to base damage and SSBs, those mechanisms include base excision repair, nucleotide excision repair, and mismatch repair. The repair of DSBs is more complex and involves non-homologous end joining (NHEJ) and homologous recombination. If DNA repair fails, cellular injury may manifest as mutation, chromosome aberrations, transformation of cell morphology, reproductive failure, or cell dead. It is observed that radiosensitivity is a function of the metabolic state of the tissue being irradiated (law of Bergonié and Tribondeau). HighLow degree of differentiation, high proliferation rate for cells and high growth rate for tissues result in increased radiosensitivity. This is why a foetus is considered to be more sensitive to radiation exposure than a child or a mature adult.
When a tissue is irradiated, the response is determined principally by the amount of energy deposited per unit of mass: the absorbed radiation dose D (Gy). But, even under controlled conditions, the response to the radiation exposure may vary. ICRP defines the absorbed dose as the mean energy absorbed per unit of mass of tissue or organ. However, the density at which energy is deposited as a charged particle travels through matter by a particular type of radiation is an important element in the biological outcome. This density is denoted as the Linear Energy Transfer (LET) (keV/µm) and must be seen as the derivative dE/dx, where dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance of dx. X-, γ- and β-rays (electrons) have LET values between 0.2 and 10 keV/µm and are considered as low-LET radiation. Protons, neutrons, α-particles and Auger electrons have higher LET-values between 10 and 100 keV/µm and are therefore considered as high-LET radiation. The direct action of ionizing radiation is predominantly for high-LET radiation, whereas indirect action is the predominant reaction after exposure of cells with low-LET radiation.
In radiobiology the LET is limited in its use, because the value changes as the particle loses energy in its passage through tissue. For this reason, the term Relative Biological Effectiveness (RBE) is used as an indicator of the differing biological efficacies of various radiation types. The RBE is defined as the ratio of an absorbed dose of a reference low-LET radiation to an absorbed dose of the test radiation that gives an identical biological endpoint. Furthermore, the RBE of a specific radiation type is influenced by the studied biological endpoint, the biological system, and the dose fractionation. Low LET radiation will have an RBE of less than 1; high-LET radiations will have an RBE greater than 1. A LET of about 100 keV/μm is optimal in terms of producing a biologic effect, because at this density of ionization, the mean separation in ionizing events is equal to the diameter of the DNA double helix which results in the highest probability of causing DSBs (cfr targeted α-therapy, Auger therapy). Higher LET values will deposit more energy than is necessary to cause damage. This phenomenon is called ‘overkill effect’. Because the RBE is too specific to be used in radiation protection, the ICRP has selected radiation weighting factors WR for different radiation types to be used in the framework of stochastic effects at low doses.
The conventional paradigm states that radiation effects occur only in cells in which energy was deposited. There is now more and more experimental evidence that in some conditions biological response is seen in cells that have not received a direct energy deposition from radiation. This is called the bystander effect.
Biological effects of ionizing radiation can be classified into deterministic effects (tissue reactions) and stochastic effects.
Deterministic effects (tissue reactions)
Deterministic effects are effects for which both the incidence and the severity increase above a threshold dose with increasing dose. The time at which tissue reactions can be detected after the radiation exposure varies. Early (days-weeks) tissue reactions may be of the inflammatory type resulting from the release of cellular factors, or they may be reactions resulting from cell loss. Late (month-years) tissue reactions can be of the generic type, if they arise as a direct result of damage to that tissue, or they can arise as a result of early cellular damage. Both early and late deterministic effects can appear after whole body exposure (acute radiation syndrome) and/or partial body (skin erythema, epilation, cataract…) exposure above a specific threshold dose. ICRP published thresholds doses (corresponding to doses that result in about 1% incidence) for various organs and tissues and judged that for doses <100 mGy (both for low and high LET radiation) no tissues express clinically relevant functional impairment.
Cell killing is crucial to the development of deterministic effects. Cell survival curves are commonly used to study the survival of tissue target cells. The cell survival fraction ‘S’ as a function of the radiation dose ‘D’ is predominantly described using the linear-quadratic model.
S=exp{-(αD+βD2)}
In this model αD describes the linear component as a single-track non-repairable event that is proportional to dose on a semi-log plot of survival (log) versus dose (linear). βD2 describes the increasing sensitivity of cells at higher radiation doses. The ratio α/β is the dose at which the linear and quadratic components of cell killing are equal and this ratio has been useful to compare the early and late responses of tissues. Early or acute tissues reactions have α/β ratios ~10 whereas for late effects values between 2 and 5 are found. LET, Dose rate, dose fractionation and the presence of oxygen can affect the survival curve, elements which are important in radionuclide therapy. Moreover because of the combination of radionuclide decay and biological clearance of the radiopharmaceutical the dose rate fluctuates in time. For this the reason the ‘biological effective dose’ (BED) was introduced to compare different treatment types.
Stochastic effects
Stochastic effects are effects for which the probability of occurrence increases with the dose. The two major stochastic effects are cancer and genetic effects.
It is generally assumed that DNA damage response processes in single cells are of critical importance to the development of cancer after radiation exposure. Cancer risks are estimated on the basis of probability and are derived mainly from epidemiological data from the Life Span Study of the atomic bomb survivors of Hiroshima and Nagasaki. Although there is no epidemiological evidence of stochastic effects at effective doses <100 mSv, the linear no-threshold (LNT) hypothesis was introduced by ICRP as the best practical approach to manage cancer risk from radiation exposures to low dose/low dose rates. According to ICRP Publication 103, the detriment-adjusted nominal risk coefficient for cancer for the whole population after exposure to radiation at low dose rate is 5.5% per Sv Effective dose. This figure must be seen as a mean value for the entire population, because there is strong evidence that cancer risk also depends on the age at exposure and the gender. Exposure at an early age results in higher nominal risk factors, whereas females are slightly more susceptible than males.
To date there have been no documented cases of radiation-induced genetic effects in humans. Nevertheless, the ICRP set the nominal risk coefficient for genetic effects for the whole population at 0.2% per Sv effective dose because of compelling evidence that radiation causes heritable effects in experimental animals.
Risk to embryo and foetus
The biological effects after radiation in utero can be both deterministic and stochastic.
The deterministic effects of radiation on the foetus depend on two factors: dose and stage of development at the time of exposure. The principal effects are neonatal death, malformations, growth retardation, IQ reduction, and congenital defects. The risk is most significant during organogenesis and in the early foetal period, less in the second trimester, and least in the third trimester. It is however assumed that these effects have a dose-threshold of 100 mGy.
For stochastic effects the life-time cancer risk after in utero exposure is considered to be similar to that following irradiation in early.