There are three types of electronic or Coulomb interactions, which can occur with or without energy loss from the incident particle. Elastic scattering of the particle in the atomic shell occurs with only neglectable energy transfer, as only the energy which needs to be transferred is that which is necessary to fulfill energy and momentum conservation. In this case, the incident particle is scattered and changes its direction. The two inelastic electronic processes are shown in Fig. 2.5 (left). The particle described through its atomic number z, its mass m, and its energy E is interacting with an atom of the matter characterized by the atomic number Z, the mass number A, and the density of the matter ρ. In the inelastic collision, the particle transfers energy to the hit electron. If sufficient energy is transferred, the electron will leave the atom, thus ionizing it. When the transferred energy is higher, the electron gets additional kinetic energy and can then itself act as particle radiation. If the energy is lower and fits the energy difference between two electron shells (the defined energies at which electrons “orbit”), the electron is excited, which means lifted to the higher shell. After a certain time, the electron falls back while emitting a photon with the energy corresponding to the energy difference between the shells.

An illustration of atoms depicts that the bombardment of a particle with electrons causes excitation and ionization, and with nuclei causes scattering. The orbital configurations for the particle during excitation, ionization, and ionization are also provided.

Fig. 2.5
Visualization of the electronic interactions (left) and the nuclear interaction (right) of a particle with atomic number z, mass m, and energy E with matter with atomic number Z, mass number A, and density ρ (Created with BioRender)


An illustration of atoms depicts that the bombardment of a particle with electrons causes excitation and ionization, and with nuclei causes scattering. The orbital configurations for the particle during excitation, ionization, and ionization are also provided.


In nuclear interactions, again three types can be defined. Firstly, elastic nuclear scattering, also called nuclear coulomb scattering, describes the elastic collision of a particle with the atomic nucleus. Here, the particle does not lose energy and only a deflection occurs (Fig. 2.5). In inelastic nuclear scattering, the particle is deflected and emits light, the so-called bremsstrahlung. Lastly, an interaction with the target nuclei itself is possible inducing nuclear reactions.


Charged particle radiation describes high-energy massive particles such as electrons, protons , and other ions. These particles interact with matter through the described electronic or nuclear interactions. In each interaction, only a small amount of the total energy is transferred, and although the whole process of interaction is statistical in its nature, one can say that the particles stop more or less uniformly at a certain distance called the range. Furthermore, in each interaction, a certain angular deflection happens, which causes the particle to travel in a crooked path, and which effectively causes the incident particle beam to widen, while traversing a medium. The types of interactions can be described through the occurring energy loss and deflection of particle radiation in matter.


Ionizations and excitations, which occur in the electronic interactions, can be differentiated into soft and hard collisions. Interactions of the charged particle with the electrons in the outer atomic shell are called soft collisions, as the energy transfer is low (a few eV). The electrons, which are ionized, have a low energy and therefore emit all the energy in close proximity to the point of interaction. These soft collisions are responsible for approximately 50% of the total energy transfer of a particle. As the energy transfer of a single collision is very low, the particle velocity decrease is also low. But as a lot of these interactions occur, the slowing is, although of statistical nature, on average happening continuously. For particles which have a very high energy and thus velocity, the Cherenkov effect can occur. This effect describes the emittance of light, when a particle flies through matter with a velocity larger than the speed of light in this corresponding matter. This light is called Cherenkov radiation and can be seen as blue in the cooling water of nuclear reactors. The Cherenkov effect does not play a role in the effects of particle radiation on biological matter.


Coulomb interactions with the electrons of the inner shells are called hard collisions. Here, the electrons produced in ionizations have a higher energy and larger deflection angles compared to the ones from soft collisions. These electrons are called δ-rays, and they transfer their energy via soft collisions to the matter, thus spreading the energy distribution of an incident particle up to several μm distance to the incident particle track. This effect plays a major role in the microdosimetry.


Electronic interactions are the main contributors to the energy loss for high ion energies (see Fig. 2.6) but have a negligible deflection per collision.

4 graphs. a and b of energy loss versus E over A and path length. a. 2 have an increasing trend, and 4 decline. b. 2 lines have a spike pattern. c of stopping power versus energy. 2 follow a declining trend, and 1 follows an increasing trend. d of dose deposition versus depth. 2 right-skewed curves.

Fig. 2.6
(a) Energy loss for protons (purple) and carbon (blue) ions depends on ion type and ion energy. For lower energies, the nuclear energy loss (dotted lines) starts to get an influence. At energies above ~0.0005 MeV/u for protons and ~0.005 MeV/u for carbon ions, the electronic energy loss is dominant (dashed lines) and the nuclear energy loss can be even neglected for higher energies. E/A is the energy divided by mass number. (b) Energy loss for a proton with initial energy of Ein = 200 MeV with a range in water of 256 mm on the left and for a carbon ion with initial energy of Ein = 375 MeV/u with a range in water of 251 mm on the right: at the end of range at a path length, the energy loss is increasing and rapidly goes to zero when the ion stops. The curve shape for the carbon ion is the same as for the proton but with a higher energy loss at all times. Energy losses are calculated via SRIM (SRIM—The Stopping and Range of Ions in Matter, J. Ziegler, http://www.srim.org/). (c) Stopping power of electrons depending on electron energy simulated using estar (https://physics.nist.gov/PhysRefData/Star/Text/ESTAR.html). (d) Energy loss of electrons in adipose tissue with penetration depth (inspired by Hazra et al. 2019) (licensed under CC-BY-4.0) [26]


4 graphs. a and b of energy loss versus E over A and path length. a. 2 have an increasing trend, and 4 decline. b. 2 lines have a spike pattern. c of stopping power versus energy. 2 follow a declining trend, and 1 follows an increasing trend. d of dose deposition versus depth. 2 right-skewed curves.


Energy loss through elastic nuclear scattering as described above is only an important contribution to the total energy loss for ion energies below approximately 0.01 MeV/u. Here, the ions are already close to stopping and have a remaining range in the order of nanometers. For high ion energies (E > several 100 MeV/u), elastic and inelastic nuclear scattering are again mainly responsible for deflection but also for energy loss through emission of bremsstrahlung. There are also other mechanisms possible, happening quite rarely at the energies used in society, but which should be mentioned here [21, 22]. These are direct interactions with the nuclei, namely transfer reactions like stripping or pickup, where nucleons are transferred from or to the incident particle. Also charge exchange can happen, which is a combination of stripping and pickup, where a neutron of the particle is exchanged with a proton of the atom or vice versa. Also, fragmentation can occur, where the incident particle and/or the atomic nucleus break up into (more than two) fragments. And finally, fusion reactions can occur, where the incident particle is fused into the atomic nucleus and both together form a new nucleus.


The exact energy loss during an interaction is described through the so-called stopping power S and is made up of the collision Scol and the radiation Srad stopping power [23]:

 (2.3)


The collision stopping power is the energy loss through collisions along the track in matter. For high energies of the impacting particles, the collisional stopping power can be described by the known Bethe–Bloch formula, which is based on perturbation theory and can also incorporate relativistic corrections.


For electrons or positrons, this is

 (2.5)


This formula includes the properties of the particle energy, charge number, and velocity characterized by moc2, z2, and β2 and the properties of the matter density ρ, charge number Z, and mass number A. re is the classical electron radius and u the atomic mass unit. The terms Rcol(β) and

 are called rest function for heavier particles or electrons and positrons, respectively. These are dimensionless quantities, which contain the complex energy and matter-dependent cross sections for collision stopping.


In practical use, especially in radiobiology, it is just important to know some proportionalities:

 (2.6)


The radiation stopping power does not play a role for protons and heavier particles, due to their heavy masses, but for electrons, which are more than three orders of magnitudes lighter.


The radiation stopping power for electrons is

 (2.7)


With Etot the total energy of the electron and α the fine-structure constant. Again, dimensionless rest functions occur describing the cross sections for interactions with nuclei Rrad, n and electrons in the atomic shell Rrad, e.


For quantification in radiobiology, the detailed description of the stopping power is not used, as it would be too complicated, and the perturbation parts only contain a small correction. Conventionally, the linear energy transfer

 is used instead. The LET only takes electronic interactions into account. The difference between LET and electronic stopping lies in their origin. The electronic stopping is focused on the energy loss of the impacting particle, and it has a negative sign as it acts as a friction force. The LET has a positive sign, and it is the energy that the target sees deposited in itself; this “positive amount of energy” creates the nonequilibrium dynamics, which are the first radiation-induced effects. The LET and the electronic stopping are equal for big samples, which is the case in radiobiology. Therefore, the LET is the same as the electronic stopping, which can be looked up in programs such as pstar, astar, or SRIM [24, 25].


For protons and heavier ions at energies larger than ~0.01 MeV/u, the electronic energy loss is the dominant process, as can be seen in Fig. 2.6, whereas for low ion energies, the nuclear energy loss becomes dominant, validating the use of LET as the most appropriate measurement quantity for radiobiologically relevant energies of >1 MeV. The energy loss has a peak at


For a single collision, considering a maximum energy ΔEmax which can be transferred through electronic interactions is


With me being the electron mass, m the ion mass, and E the ion energy. For protons, this maximum energy transfer per collision is ΔEmax, p ≈ 0.2 % Ep. For carbon ions, it is even lower at ΔEmax, C ≈ 0.02 % EC. Therefore, thousands of collisions are necessary before an ion stops, and the more energy it has lost, the slower it gets and therefore the interactions get closer together.


If one looks at the energy loss of an ion depending on the path length traveled in a target medium, a unique distribution is visible (Fig. 2.6b). The energy loss at the entrance is low and only slightly increasing with depth. Just in the last millimeters or even below, the energy loss sharply increases. After the peak, an even sharper decrease is visible until the ion stops only shortly after reaching the peak energy loss. This distribution is called the Bragg curve. Due to this distribution, a range of the particle can be defined, which is the average distance the ion travels before it stops. Due to the statistical nature of the interactions, the range can only be given as an average quantity. The ion range can be calculated as [23]:

 (2.10)


For example, for protons with therapy-relevant energies between approx. 10 MeV and 200 MeV, the range can be approximated to

 (2.11)


The unique energy loss distribution, with a peak energy loss just at the end of range, gives particles a great advantage in tumor therapy compared to photons, as the tissue behind the tumor will not get irradiated at all, as explained in Chap. 6.


For low-energy electrons, the collision stopping power is the dominant process, whereas for higher energies, the radiation stopping power gets dominant (Fig. 2.6c). The energy loss distribution with penetration depth is due to the contribution of the radiation stopping power different to protons and heavier ions (Fig. 2.6d). There is no clear range visible, but after a small buildup, the maximum is reached, followed by a decrease, and with higher depth the energy loss will be zero; this is when the electron has stopped. The possible penetration depth and especially the maximum of energy loss are dependent on energy. This is relevant for therapy, where low-energy electrons are used to irradiate skin tumors, whereas for deeper lying tumors, higher energies are necessary (Box 2.5).


Charged particles transfer their energy mainly through coulomb interactions with electrons and nuclei of the atoms of the matter.

The energy loss of the particle can be described by the Bethe–Bloch formula of the stopping power.

For ions, only collision stopping power plays a role, and for electrons also radiation stopping power.

Ions have a defined range, where energy loss follows the Bragg curve.


Charged particles transfer their energy mainly through coulomb interactions with electrons and nuclei of the atoms of the matter.


The energy loss of the particle can be described by the Bethe–Bloch formula of the stopping power.


For ions, only collision stopping power plays a role, and for electrons also radiation stopping power.


Ions have a defined range, where energy loss follows the Bragg curve.


The interaction of particles with matter is not only responsible for energy loss but also for a deflection of the incident particle. For the coulomb interactions with electrons, only negligible deflection occurs. The nuclear Coulomb interactions also give small deflections per collision. Furthermore, Rutherford scattering with the atomic nucleus can occur. Taking all the interactions into account, significant deflection of particles is common. This process is called multiple small-angle scattering. Additionally, the Rutherford scattering can lead to single large-angle scattering events, but this effect is very rare. The scattering of single ions leads to widening of the incident beam of particles with penetration depth. Due to the dominance of the multiple small-angle scattering, the lateral profile of the beam can be approximated by a Gaussian distribution. It is important to know that for larger lateral distances, the Gaussian distribution no longer holds, as the large-angle scattered ions are deflected in this region. But as already mentioned, this is a rare process and does not have an influence on the beam size. The lateral spread defined as the σ of the Gaussian distribution is

, with Ekin the kinetic energy of the particle, z the charge, and x the distance traveled (Box 2.6).


Coulomb interactions are responsible for scattering of the particle.

Multiple coulomb scattering leads to a deflection of the particle.

Single Rutherford scattering with the atomic nuclei leads to large deflections, but these are very rare.

An incident particle beam will have a Gaussian energy distribution profile in the lateral direction due to the statistical nature of scattering.


Single Rutherford scattering with the atomic nuclei leads to large deflections, but these are very rare.


An incident particle beam will have a Gaussian energy distribution profile in the lateral direction due to the statistical nature of scattering.


The existence of the neutron as a component of the atom was first proposed by Rutherford in 1911, though it was Chadwick who in 1932 detected the particle as a result of experiments involving gamma irradiation of paraffin [27]. Advances in particle physics have led to our current understanding of hadronic matter which includes neutrons, such that the quark model of the neutron envisages the particle as consisting of two down quarks and an up quark (udd), as shown in Fig. 2.7.

2 models for the proton and neutron depict triangular structures of u u d and u d d, respectively, connected by coiled gluons. U is an up quark, and D is a down quark.

Fig. 2.7
Quark structure of proton and neutron, with binding gluons shown (Created with BioRender)


2 models for the proton and neutron depict triangular structures of u u d and u d d, respectively, connected by coiled gluons. U is an up quark, and D is a down quark.


The neutron differs from the proton (uud) by a single quark such that it has almost identical mass (mn = 939.6 MeV/c2, mp = 938 MeV/c2) though the neutron has zero charge. It also differs further in that, while the proton is thought to be stable (current T1/2 of ~1038 years), the free neutron is unstable with a mean lifetime of approximately 879.6 s. While electrically neutral, the neutron does have a magnetic moment of approximately −1.93 ⌠N, where that for the proton is approximately 2.79 ⌠N (and where ⌠N is the nuclear magneton). As the neutron is a fermion, it has a spin of ½ [28].


Early experiments with neutrons relied upon their production in prototype nuclear reactors. Here, neutrons were classified according to their energies as thermal (E ~ 0.038 eV, on average associated with a Maxwell–Boltzmann distribution of particles at room temperature), slow (E < 0.1 MeV), fast (E > 10 MeV), or relativistic (with energies producing velocities of 0.1 c or above) [29].


Exploration of neutron interactions with matter has revealed that they have very complex energy cross sections, which vary substantially with the target material. However, the interactions may be broadly classified as elastic or inelastic interactions, with elastic collisions having a greater cross section at high neutron energies [29].


In elastic interactions, the neutron collides, typically, with a target nucleus, transferring some of its kinetic energy to the nucleus, which then recoils. It may be demonstrated that the maximum energy Q that a neutron of energy En and mass M may transfer to a recoil nucleus of mass m is given by [29].


In general, one may observe a cosine-squared spatial distribution of recoil energies for nuclei, Q, from which the original energy of the neutron beam may be estimated [29]:


In inelastic scattering events, either the neutron can promote the nucleus of element X to an excited state, from which the nucleus itself decays by re-emitting the neutron with different energy and momentum [(n,n′) reactions], or, for neutrons with energy below 0.5 MeV, the nucleus absorbs (“captures”) the incident neutron, causing it to transmute to a new elementary state, Y, generally with the emission of some product projectile, b, such as a proton, alpha particle, or gamma ray. The latter nuclear reactions are written as


The development of sources of neutrons for industrial purposes has been a highly complex undertaking. Spallation sources of neutrons, where a material is bombarded with a projectile particle and then emits a beam of neutrons, have existed for some time. However, these systems require acceleration of a projectile beam, which renders them costly from an energy-input perspective, though they produce highly intense beams which are useful in the imaging of materials, as well as for both breeding and burning of nuclear fuel. Most neutron beams are produced via collimation and focusing of neutron beams from nuclear reactors, for similar applications to those already highlighted, and importantly for therapeutic applications in medicine. The development of Wolter mirrors and lenses has provided the means to direct and focus beams of neutrons in a highly precise manner allowing for controlled therapeutic applications.


Humans are continuously exposed to low levels of ionizing radiation from the surroundings as they carry out their normal daily activities; this is known as background radiation, which is present on Earth at all times [30]. In addition, we are exposed to ionizing radiation from artificial sources during medical examinations and treatments, during processing and using radioactive materials, and during operation of nuclear power plants or accelerators (Figs. 2.8 and 2.9). Below we provide a summary of the possible scenarios of exposure to natural and artificial radiation.

A schematic representation exhibits the pathway of the inhalation or ingestion of cosmic, external, indoor, and terrestrial radiations that form the corresponding radionuclides, which are further inhaled or ingested by plants and animals.

Fig. 2.8
Natural sources of ionizing radiation and their pathways (Figure from European Commission, Joint Research Centre—Cinelli, G., De Cort, M. & Tollefsen, T., European Atlas of Natural Radiation, Publication Office of the European Union [41]) (licensed under CC-BY-4.0)

A pie chart provides the proportion of 80% natural and 20% artificial sources. The given data for the natural source are as follows. Radon inhalation, 42%. External terrestrial radiation, 16%. Cosmic radiation, 13%. Ingestion, 10%. The artificial data includes medical diagnosis, 20% and other, 0.4%.

Fig. 2.9
Worldwide average annual human exposure to ionizing radiation (from UNSCEAR (2008) Sources and effects of ionizing radiation) (Created with BioRender)


A schematic representation exhibits the pathway of the inhalation or ingestion of cosmic, external, indoor, and terrestrial radiations that form the corresponding radionuclides, which are further inhaled or ingested by plants and animals.


A pie chart provides the proportion of 80% natural and 20% artificial sources. The given data for the natural source are as follows. Radon inhalation, 42%. External terrestrial radiation, 16%. Cosmic radiation, 13%. Ingestion, 10%. The artificial data includes medical diagnosis, 20% and other, 0.4%.


Natural radiation is all around us, and we receive it from the atmosphere, rocks, water, plants, as well as the food we eat (Fig. 2.8). Naturally occurring radioactive materials are present in the Earth’s crust; the floors and walls of our homes, schools, or offices; and food. Radioactive gasses are also present in the air we breathe. Our muscles, bones, and other tissues contain naturally occurring radionuclides [31]. Hence, our lives have evolved, and our bodies have adapted to the world containing considerable amounts of ionizing radiation. As per the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), terrestrial radiation, inhalation, ingestion, and cosmic radiation are the four foremost sources of public exposure to natural radiation.1.
Terrestrial Radiation: One of the major sources of natural radiation is the Earth’s crust, where the key contributors are the innate deposits of thorium, uranium, and potassium. These minerals are called primordial radionuclides and are the source of terrestrial radiation. These deposits discharge small quantities of ionizing radiation during the process of natural decay, and these minerals are found in building materials. Therefore, humans can get exposed to natural radiation both outdoors and indoors. These radiation levels can fluctuate substantially depending on the location. Traces of radioactive materials can be found in the body where nonradioactive and radioactive forms of potassium and other elements are metabolized in the same way [32].
 2.
Inhalation: Humans are exposed to inhalation of radioactive gasses that are formed by radioactive minerals found in soil and bedrock. For example, uranium-238, during its decay, produces radon (222Rn) which is an inert gas and thorium produces thoron (220Rn). These gasses get diluted to harmless levels when they traverse the Earth’s atmosphere. However, at times, these gasses escape through cracks in the building foundations, are trapped, and accumulate inside buildings where they are inhaled by the occupants (indoor living) [30].
 3.
Ingestion: Vegetables and fruits are grown in the soil and groundwater, which usually contain radioactive minerals. We ingest these minerals and subsequently are exposed to internal natural radiation. Carbon-14 and potassium-40 are naturally occurring radioactive isotopes which possess similar biological characteristics as their nonradioactive isotopes. These radioactive and nonradioactive elements are used not only in building our bodies but also in maintaining them. Therefore, such natural radioisotopes recurrently expose us to radiation [30].
 4.
Cosmic Radiation: Space is permeated by radiation, not only of electromagnetic type but also constituted by ionizing particles with mass. The electromagnetic radiation in space spans all wavelengths, from infrared to visible, from X-ray to gamma rays. In general, however, “space radiation” mostly refers to corpuscular radiation, which has three main sources:(a)
Galactic Cosmic Rays (GCRs): The GCRs constitute the slowly varying, low-intensity, and highly energetic radiation flux background in the universe, mostly associated with explosions of distant supernovae. The GCR spectrum consists of approximately 87% hydrogen ions (protons) and 12% helium ions (α-particles), with the remaining 1–2% of particles being HZE (high charge Z and energy) nuclei. The energies are between several tenths and 10 × 10 GeV/nucleon and more. GCRs directly hit the top of the Earth’s atmosphere, generating secondary particle showers. However, some direct GCRs and generated secondary particles infiltrate the Earth’s atmosphere reaching the ground. Such radiation gets absorbed by humans, and it thus constitutes a source of natural radiation exposure. Since at higher altitude the amount of atmosphere shielding us from incoming radiation is less, the higher we go in altitude, the higher dose we receive. For example, those living in Denver, Colorado (altitude of 5280 ft = about 1610 m), receive a higher annual radiation dose from cosmic radiation than someone living at sea level (altitude of 0 ft) [32]. GCR ions are a major health threat to astronauts for missions beyond the near-Earth environment and for interplanetary travel [33]. For Mars, the thin atmosphere combined with the absence of a planetary magnetic field essentially offers very little shielding from the incoming GCRs [34, 35]. Also, GCRs directly reach the surface of airless bodies such as the Moon [36].
 (b)
Radiation from the Sun: This consists of both low-energy particles flowing constantly from the Sun (the solar wind) and of solar energetic particles (SEPs), originating from transient intense eruptions on the Sun [37]. The solar wind is stopped by the higher layers of the atmosphere of our planet (and other celestial bodies with an atmosphere). SEPs come as huge injections and are composed predominantly of protons and electrons. Typical proton energies range from 10 to 100 of MeV. They are generally quite efficiently stopped in the Earth’s atmosphere, but some direct SEPs and their high flux of secondaries could eventually be dangerous for high-altitude/latitude flights and their crew [38] and for astronauts of the International Space Station (ISS) in extravehicular activities. Finally, SEPs can be a strong concern also for astronauts during interplanetary travel, such as a trip to Mars, even inside the spacecraft [39], or for humans on the surface of the Moon.
 (c)
Trapped Radiation: This consists of GCRs and SEPs and their secondaries trapped by the Earth’s magnetic field into the Van Allen radiation belts. Such belts comprise a stable inner belt of trapped protons and electrons (energies are between keV and 100 MeV) and a less stable outer electron belt. The inner Van Allen belt comes closest to the Earth’s surface, down to an altitude of 200 km, in a region just above Brazil. This area is named the South Atlantic Anomaly [40]. An increased flux of energetic particles exists in this region and exposes orbiting human missions to higher-than-usual levels of radiation (Box 2.7).


Terrestrial Radiation: One of the major sources of natural radiation is the Earth’s crust, where the key contributors are the innate deposits of thorium, uranium, and potassium. These minerals are called primordial radionuclides and are the source of terrestrial radiation. These deposits discharge small quantities of ionizing radiation during the process of natural decay, and these minerals are found in building materials. Therefore, humans can get exposed to natural radiation both outdoors and indoors. These radiation levels can fluctuate substantially depending on the location. Traces of radioactive materials can be found in the body where nonradioactive and radioactive forms of potassium and other elements are metabolized in the same way [32].


Inhalation: Humans are exposed to inhalation of radioactive gasses that are formed by radioactive minerals found in soil and bedrock. For example, uranium-238, during its decay, produces radon (222Rn) which is an inert gas and thorium produces thoron (220Rn). These gasses get diluted to harmless levels when they traverse the Earth’s atmosphere. However, at times, these gasses escape through cracks in the building foundations, are trapped, and accumulate inside buildings where they are inhaled by the occupants (indoor living) [30].


Ingestion: Vegetables and fruits are grown in the soil and groundwater, which usually contain radioactive minerals. We ingest these minerals and subsequently are exposed to internal natural radiation. Carbon-14 and potassium-40 are naturally occurring radioactive isotopes which possess similar biological characteristics as their nonradioactive isotopes. These radioactive and nonradioactive elements are used not only in building our bodies but also in maintaining them. Therefore, such natural radioisotopes recurrently expose us to radiation [30].


Cosmic Radiation: Space is permeated by radiation, not only of electromagnetic type but also constituted by ionizing particles with mass. The electromagnetic radiation in space spans all wavelengths, from infrared to visible, from X-ray to gamma rays. In general, however, “space radiation” mostly refers to corpuscular radiation, which has three main sources:(a)
Galactic Cosmic Rays (GCRs): The GCRs constitute the slowly varying, low-intensity, and highly energetic radiation flux background in the universe, mostly associated with explosions of distant supernovae. The GCR spectrum consists of approximately 87% hydrogen ions (protons) and 12% helium ions (α-particles), with the remaining 1–2% of particles being HZE (high charge Z and energy) nuclei. The energies are between several tenths and 10 × 10 GeV/nucleon and more. GCRs directly hit the top of the Earth’s atmosphere, generating secondary particle showers. However, some direct GCRs and generated secondary particles infiltrate the Earth’s atmosphere reaching the ground. Such radiation gets absorbed by humans, and it thus constitutes a source of natural radiation exposure. Since at higher altitude the amount of atmosphere shielding us from incoming radiation is less, the higher we go in altitude, the higher dose we receive. For example, those living in Denver, Colorado (altitude of 5280 ft = about 1610 m), receive a higher annual radiation dose from cosmic radiation than someone living at sea level (altitude of 0 ft) [32]. GCR ions are a major health threat to astronauts for missions beyond the near-Earth environment and for interplanetary travel [33]. For Mars, the thin atmosphere combined with the absence of a planetary magnetic field essentially offers very little shielding from the incoming GCRs [34, 35]. Also, GCRs directly reach the surface of airless bodies such as the Moon [36].
 (b)
Radiation from the Sun: This consists of both low-energy particles flowing constantly from the Sun (the solar wind) and of solar energetic particles (SEPs), originating from transient intense eruptions on the Sun [37]. The solar wind is stopped by the higher layers of the atmosphere of our planet (and other celestial bodies with an atmosphere). SEPs come as huge injections and are composed predominantly of protons and electrons. Typical proton energies range from 10 to 100 of MeV. They are generally quite efficiently stopped in the Earth’s atmosphere, but some direct SEPs and their high flux of secondaries could eventually be dangerous for high-altitude/latitude flights and their crew [38] and for astronauts of the International Space Station (ISS) in extravehicular activities. Finally, SEPs can be a strong concern also for astronauts during interplanetary travel, such as a trip to Mars, even inside the spacecraft [39], or for humans on the surface of the Moon.
 (c)
Trapped Radiation: This consists of GCRs and SEPs and their secondaries trapped by the Earth’s magnetic field into the Van Allen radiation belts. Such belts comprise a stable inner belt of trapped protons and electrons (energies are between keV and 100 MeV) and a less stable outer electron belt. The inner Van Allen belt comes closest to the Earth’s surface, down to an altitude of 200 km, in a region just above Brazil. This area is named the South Atlantic Anomaly [40]. An increased flux of energetic particles exists in this region and exposes orbiting human missions to higher-than-usual levels of radiation (Box 2.7).


Galactic Cosmic Rays (GCRs): The GCRs constitute the slowly varying, low-intensity, and highly energetic radiation flux background in the universe, mostly associated with explosions of distant supernovae. The GCR spectrum consists of approximately 87% hydrogen ions (protons) and 12% helium ions (α-particles), with the remaining 1–2% of particles being HZE (high charge Z and energy) nuclei. The energies are between several tenths and 10 × 10 GeV/nucleon and more. GCRs directly hit the top of the Earth’s atmosphere, generating secondary particle showers. However, some direct GCRs and generated secondary particles infiltrate the Earth’s atmosphere reaching the ground. Such radiation gets absorbed by humans, and it thus constitutes a source of natural radiation exposure. Since at higher altitude the amount of atmosphere shielding us from incoming radiation is less, the higher we go in altitude, the higher dose we receive. For example, those living in Denver, Colorado (altitude of 5280 ft = about 1610 m), receive a higher annual radiation dose from cosmic radiation than someone living at sea level (altitude of 0 ft) [32]. GCR ions are a major health threat to astronauts for missions beyond the near-Earth environment and for interplanetary travel [33]. For Mars, the thin atmosphere combined with the absence of a planetary magnetic field essentially offers very little shielding from the incoming GCRs [34, 35]. Also, GCRs directly reach the surface of airless bodies such as the Moon [36].


Radiation from the Sun: This consists of both low-energy particles flowing constantly from the Sun (the solar wind) and of solar energetic particles (SEPs), originating from transient intense eruptions on the Sun [37]. The solar wind is stopped by the higher layers of the atmosphere of our planet (and other celestial bodies with an atmosphere). SEPs come as huge injections and are composed predominantly of protons and electrons. Typical proton energies range from 10 to 100 of MeV. They are generally quite efficiently stopped in the Earth’s atmosphere, but some direct SEPs and their high flux of secondaries could eventually be dangerous for high-altitude/latitude flights and their crew [38] and for astronauts of the International Space Station (ISS) in extravehicular activities. Finally, SEPs can be a strong concern also for astronauts during interplanetary travel, such as a trip to Mars, even inside the spacecraft [39], or for humans on the surface of the Moon.


Trapped Radiation: This consists of GCRs and SEPs and their secondaries trapped by the Earth’s magnetic field into the Van Allen radiation belts. Such belts comprise a stable inner belt of trapped protons and electrons (energies are between keV and 100 MeV) and a less stable outer electron belt. The inner Van Allen belt comes closest to the Earth’s surface, down to an altitude of 200 km, in a region just above Brazil. This area is named the South Atlantic Anomaly [40]. An increased flux of energetic particles exists in this region and exposes orbiting human missions to higher-than-usual levels of radiation (Box 2.7).


The natural radiation to which we are continually exposed has its sources in:
Cosmic radiation (the portion of it reaching the ground)

Radiation from radioactive elements in rocks

Radioactive gasses, generally at harmless concentration in the air but that can potentially also get trapped in building walls

Food, grown in soil and groundwater, which can contain radioactive minerals


Radioactive gasses, generally at harmless concentration in the air but that can potentially also get trapped in building walls


Food, grown in soil and groundwater, which can contain radioactive minerals


Nuclear power stations/plants use uranium to drive a fission reaction that heats water to produce steam. The latter drives turbines to produce electricity. During their normal activities, nuclear power plants release small amounts of radioactive elements, which can expose people to low doses of radiation. The water that passes through a reactor is processed and filtered to remove these radioactive impurities before being returned to the environment. Nonetheless, minute quantities of radioactive gasses and liquids are ultimately released to the environment. Such releases must be continuously monitored and are under the legislative framework of international organizations dealing with nuclear energy, such as the European Atomic Energy Community (EURATOM), established by one of the Treaties of Rome in 1958. Similarly, uranium mines and fuel fabrication plants release some radioactivity that contributes to the dose of the public [42]. The eventual release of radioactive materials should also be monitored and kept under established levels during the decommissioning of a nuclear power plant, from the shutdown of the reactor to the operation of radioactive waste facilities, and also including the short- and intermediate-term storage of spent nuclear waste to the transport to and storage in long-term geological disposal areas.


Technologically enhanced naturally occurring radioactive materials (TENORM): All minerals and raw materials contain radionuclides, commonly denoted as naturally occurring radioactive materials (NORM). When concentrations of radionuclides are increased by technological processes, the term technologically enhanced NORM (TENORM) is applicable. Coal-fired power stations, for example, emit an amount of radioactivity compared to or even higher (especially in the past) than nuclear power plants. Just for example, US coal-fired electricity generation in 2013 gave rise to 1100 tonnes of uranium and 2700 tonnes of thorium in coal ash. Other TENORM industries include oil and gas production, metallurgy, fertilizer (phosphate) manufacturing, building industry, and recycling [43].


Accelerators: The operation of accelerators, such as the Large Hadron Collider (LHC) at CERN for fundamental high-energy physics experiments, results in the production of radiation, in particular protons, because of the nuclear interactions between high-energy beams and accelerator components. Thus, the radiation levels around accelerators must be monitored continuously to ensure the protection and safety of the workers and of the public [44].


Radionuclide production facilities: Radionuclides are used worldwide in (a) medical imaging, fundamental to make correct diagnoses and provide treatments, in which radionuclides are injected into patients at low doses for functional imaging to detect diseases, and (b) therapy, in which radionuclides bound to other molecules or antibodies can be guided to a target tissue, for a local treatment of cancer. Facilities that produce radionuclides and facilities in which radionuclides are processed are reactors and particle accelerators. Radionuclides used in imaging and therapy are often beta or alpha emitters, or both. Thus, the facilities, reactors, and particle accelerators can present radiation hazards to workers and must be properly controlled and monitored, as is the case with the subsequent processing of radioactive material. Among the 238 research reactors in operation in 2017, approximately 83 were considered useful for regular radioisotope production [45]. Approximately 1200 cyclotrons worldwide were used to some extent for radioisotope production in 2015 [46]. The facilities must ensure the application of the requirements of the IAEA [47] (2014) intended to provide for the best possible protection and safety measures.


Hospitals: Daily, healthcare workers and patients are exposed to various diagnostic and therapeutic radiation sources [48, 49]. The radiation environment in different hospital departments (nuclear medicine, diagnostic radiology, radiotherapy, …) can be generated by different sources. Hospitals providing radionuclide-based treatments need to protect the staff involved and keep their dose within the acceptable levels. Similarly, the discharged patient must be monitored and measurements for protection purposes must be taken to keep dose to the public within acceptable levels. This may require hospitalization with isolation during the first hours or days of treatment [50, 51]. Waste should be minimized and segregated, and packages labeled and stored for decaying. Measures should also be in place for patients’ household waste related to, for example, urine. In a radiology department, the radiation emitted during fluoroscopic procedures is responsible for the greatest radiation dose to the medical staff. Radiation from diagnostic imaging modalities, such as mammography, computed tomography, and nuclear medical imaging, is a minor contributor to the cumulative dose incurred by healthcare personnel [52]. In radiotherapy departments, photons and electrons are mainly produced by linear accelerators. Rarely, cobalt sources are used to produce radiation. With the current safety regulations, radiotherapy staff will get almost no dose during normal operation. The same is true for modern brachytherapy machines, which are almost all after loading machines avoiding direct contact between the radioactive source and the operator.


Ion radiotherapy facilities: Most currently existing ion radiotherapy facilities use protons, with new facilities now being built for the acceleration of other ions, such as carbon. They are mostly cyclotrons or synchrotrons. For such facilities, the major issue is the massive production of neutrons. Ionizing radiation results from the passage of such neutrons through matter and from the radioactivity induced in exposed materials. In accelerator facilities, radioactivity is produced in the very material components, such as their beam delivery/shaping components, as well as in all the structural components and other materials in the facility. Induced radioactivity in treated patients could also reach considerable levels.


Nuclear bombs: Nuclear weapons have an explosive power deriving from the uncontrolled fission reaction of plutonium and uranium. This yields a large number of radioactive substances (isotopes) that are blown into the atmosphere. These radioactive isotopes gradually fall back to Earth. If a weapon is exploded near the Earth surface, radioactive fallout is formed in the vicinity of the burst point in a matter of tens of minutes to a couple of days (depending on the burst yield and the distance to the burst point); if a weapon is detonated aboveground (e.g., in Hiroshima and Nagasaki, the bombs exploded about 500 m above the ground level), local fallout is not formed but the radionuclides fall worldwide over a period of many years. Gamma-ray and neutron exposures leading to increased cancer incidence have been studied in the survivors of the atomic bombings in Japan since 1950 (the so-called Life Span Study, LSS, cohort), and currently all potentially suitable risk estimates are built on the excess risk from the LLS study [53]. Interestingly, the numerous tests of nuclear weapons performed by many countries since after World War II and the ensuing fallout have contributed minimally to the overall background radiation exposure (Box 2.8).


Artificial radiation sources are:
Medical and radionuclide production facilities, accelerators for ion beam cancer therapy

Technologically enhanced naturally occurring radioactive materials (TENORM)

Nuclear power plants

Accelerators for purely fundamental research in physics


Medical and radionuclide production facilities, accelerators for ion beam cancer therapy


The interaction of ionizing radiation (IR) with matter leads to biological damage that can impair cell viability. Biological damage induced by IR arises from either direct or indirect action of radiation. Direct effects occur when IR interacts with critical target molecules such as DNA, lipids, and proteins, leading to ionization or excitation, which causes a chain of events that ultimately leads to the alteration of biomolecules. Indirect effects occur when IR interacts with water molecules, the major constituent of the cell. This reaction, called water radiolysis, generates high-energy species known as reactive oxygen species (ROS) that are highly reactive toward critical targets (cell macromolecules) and, when associated with reactive nitrogen species (RNS), lead to damage to the cell structure. Mechanism and critical targets for ionizing radiation to produce biological damage through direct and indirect effects are shown in Fig. 2.10. Damages to cell macromolecules may be multiple and are detailed in Chap. 3.

A diagram depicts the direct and indirect effects of oxidative stress on the structure and function of D N A, proteins, and lipids. The altered biomolecules affect cell viability.

Fig. 2.10
Mechanism and critical targets for ionizing radiation to produce biological damage through direct and indirect effects (Created with BioRender)


A diagram depicts the direct and indirect effects of oxidative stress on the structure and function of D N A, proteins, and lipids. The altered biomolecules affect cell viability.


Direct effects occur when the ionization takes place within a critical target with relevance to cell functions, such as DNA, lipids, and proteins. These effects are produced by both high and low linear energy transfer (LET) radiation. However, it is the predominant mode of action of high LET radiation such as alpha particles and neutrons, comprising about two-thirds of the radiation effects.


When critical molecules in the cell are directly hit by radiation, their molecular structure may be altered resulting in their functional impairment. While molecules from all cell organelles (including mitochondria, endoplasmic reticulum, or Golgi apparatus) may be hit, the nuclear DNA molecule has always been seen as the most critical target (because, unlike proteins, lipids, and carbohydrates, only a single copy of DNA is present in a cell) and was, therefore, the most thoroughly studied. The DNA damage produced by radiation includes base alterations, DNA–DNA cross-links, single- or double-strand breaks (SSB or DSB), or complex damages (described in Chap. 3).


Indirect damages produced by IR in the cell macromolecules are mediated by ROS (resulting from water radiolysis) and by RNS (formed following the reaction of O2 with endogenous nitric oxide). The indirect effects contribute to about two-thirds of the damages induced by low LET radiation (X-rays, gamma-rays, beta particles), which is explained by the fact that they are more sparsely ionizing compared to high LET radiation.


When radiation deposits energy in a biological tissue, it takes time until perceiving that an effect has occurred. The succession of the generation of events determines the four sequential stages that translate into the biological effects. These stages, with very different duration, are physical, physicochemical, chemical, and biological [54–56].


The physical stage is very transient, lasting less than 10−16–10−15 s, during which energy (kinetic if particles, or electromagnetic if waves) is transferred to the electrons of atoms or molecules, determining the occurrence of ionization and/or excitation. It is at this stage that ions are formed, which will initiate a sequence of chemical reactions that end up in a biological effect. In the case of water radiolysis (decomposition of water molecules due to IR), the ions H2O+ and e− are formed, as well as the excited water molecule (H2O*) [54–56].


Very soon (10−12 s) after the formation of these ions, the physicochemical stage begins, with their diffusion in the medium and consequent intermediate formation of oxygen and nitrogen radical species, i.e., atoms, molecules, or ions that have at least one unrepaired valence electron and hence are very reactive chemically. Following the example of water radiolysis, it is at this stage that Ḥ + HO·, H2 + 2HO, HO· + H3O+, HO· + H2 + OH−, and e−aq are formed [55, 56], but also superoxide anion (O2·−) and hydrogen peroxide (H2O2). Peroxynitrite anion (ONOO−) is also formed following the reaction of O2·− with endogenous nitric oxide (NO). Together with peroxynitrous acid (ONOOH), nitrogen dioxide (NO2·), dinitrogen trioxide (N2O3), and others, they are referred to as RNS. The activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the mitochondrial electron transport chain (ETC), or the nitric oxide synthase by IR can also contribute to ROS/RNS generation.


In the next chemical stage, the formed radicals and ions recombine and interact with critical cellular organic molecules (DNA, lipids, proteins), inducing structural damages that will translate into disruption of the function of these molecules. Within the DNA molecule, possible chemical reactions with nitrogenous bases, deoxyribose, or phosphate group may result in breaks and recombinations with the consequent formation of abnormal molecules. Among ROS, OH, which has a strong oxidative potential, is a main contributor to cell damages. The chemical stage can last from 10−12 s to a few seconds [55, 56]. ROS and RNS have also been largely implicated in the so-called non-targeted effects of IR (further discussed in Sect. 2.8.2).


Finally, the biological phase occurs, as a consequence of the spreading of chemical reactions involving various biological processes. The existence of more or less effective cellular damage repair mechanisms is responsible for the more or less belated appearance of biological effects and explains the possible long duration of this stage: from a few minutes to decades, depending on the type of radiation, the dose and dose rate, and the radiosensitivity of the irradiated tissue.


Differences in tissue radiosensitivity can be partially explained by the cellular antioxidant capacity, which may vary between cell types. Indeed, to counteract oxidative insults, cells have evolved several defense mechanisms that consist of enzymatic and nonenzymatic systems. When the amount of ROS/RNS exceeds the antioxidant capacity of the cells, a state of oxidative stress arises, characterized by a decreased pool of antioxidants and modifications in nucleic acids, lipids, and proteins. Oxidative stress can persist for much longer and extend far beyond the primary targets as well as can be transmitted to progeny of the inflicted cells. Responsible for this seems to be the continuous production of ROS and RNS, which can last for months.


Virtually all cell molecules and organelles may be damaged by IR, with consequences for the cell function depending on the impact of the damage inflicted.


According to the radiobiology paradigm, a nucleus is regarded as the main target of IR due to the genetic information contained in the DNA. Therefore, damages to this molecule are considered the most critical ones for cell survival. While efficient repair mechanisms exist to preserve the genome integrity, IR may break bonds in purine and pyrimidine nitrogenous bases in the DNA (which may lead to mutations), SSBs or DSBs, cross-linking, and complex damages. Among these lesions, DSBs and complex damages are the most serious due to the difficulty of their repair. A thorough description of DNA lesions is provided in Chap. 3.


Mitochondria can also be subject to radiation damage, both directly and indirectly. These organelles may represent more than 30% of the total cell volume, and the mitochondrial circular DNA can suffer strand breaks, base mismatches, or even deletions of variable length. In this context, mitochondria constitute a major target of IR [57]. Besides the DNA, changes in mitochondrial morphology have also been observed [58]. Absorption of IR may lead to the enlargement of mitochondria and the increase in length and number of branches of the cristae [58, 59], rupture of the outer and inner membranes, as well as vacuolization and loss of the matrix. These alterations are accompanied by the decreased activity of the respiratory chain, with special emphasis on complexes I, II, and III, which are systematically referred to as especially sensitive to the direct effects of IR. Additionally, there is a decrease in the respiratory capacity driven by succinate and the ATP synthase, with a consequent impact on oxidative phosphorylation. The radiation-induced decrease in the rate of oxidative phosphorylation can recover over time, depending on the cell type [60, 61]. The electrons in the respiratory chain can leak during their transport and reduce oxygen molecules leading to the formation of superoxide anions, which are precursors of most ROS. Upon irradiation, the level of ROS produced in the mitochondria greatly increases, although under physiological conditions, it is already high.


Irradiation may also cause morpho-functional changes in the endoplasmic reticulum (ER). After exposure to IR, ER dilates, vesicles appear, and its cisternae break into fragments. In the case of rough endoplasmic reticulum, irradiation induces degranulation accompanied by transformation of the membrane-bound ribosomes into free organelles [59, 62].


Likewise, irradiation may also disorganize the structure of the Golgi apparatus due to the induced fragmentation and rearrangement of its cisterns. In view of the effects of IR on the endoplasmic reticulum-Golgi apparatus complex, the ensuing alterations in the synthesis and maturation of proteins in the irradiated cells come as no surprise. Lysosomes may also increase in number and volume in the irradiated cells, which is accompanied by upregulation of the enzymatic activity in these organelles [58, 59] (Box 2.9).


Direct effects predominate after exposure to high LET radiation (e.g., alpha particles, neutrons).

Exposure to low LET radiation (e.g., X-rays, gamma rays, beta particles) induces mostly indirect effects.

Indirect effects are mediated by ROS/RNS produced during and after the radiolysis of water.

Apart from nuclear DNA, other cellular molecules and organelles may be altered by IR, including mitochondrial DNA, plasma membrane lipids, endoplasmic reticulum, Golgi apparatus, and lysosomes.


Direct effects predominate after exposure to high LET radiation (e.g., alpha particles, neutrons).


Exposure to low LET radiation (e.g., X-rays, gamma rays, beta particles) induces mostly indirect effects.


Indirect effects are mediated by ROS/RNS produced during and after the radiolysis of water.


Apart from nuclear DNA, other cellular molecules and organelles may be altered by IR, including mitochondrial DNA, plasma membrane lipids, endoplasmic reticulum, Golgi apparatus, and lysosomes.


Radiation and radioactivity have been existing ever since the Earth was formed and long before life started to evolve. All living organisms on Earth are continuously exposed to both natural and artificial radioactivity, and without it, life in the present form would have not evolved. Since the first experiments with radioactivity, our understanding of this phenomenon has increased, and consequently, today radioactivity has numerous applications important to human life and health.


The rate of decay of a radioactive source is proportional to the amount of the substance that is present at any given instant. Therefore, if the number of radioactive nuclei in a sample is N, then we may say the following:

 (2.15)


where λ is the decay constant, which describes the rate of decay for a particular radioactive isotope.


If we integrate both sides of Eq. (2.15), we get the following more familiar equation:

 (2.16)


If we let the variable T1/2 be the “half-life of the substance,” i.e., the time taken for the activity of the substance to reduce from its initial value to half of its initial value, then we may modify Eq. (2.16) as

 (2.17)


The activity, A, of a given sample of a radioactive substance, i.e., the number of decays per second (in Bq), is given by the following equation:


where calculations based on activities may be performed using Eqs. (2.2) and (2.3) above with the values of A inserted instead of N. The radioactivity of a sample is quoted in terms of the units of Curies, Ci (the radioactivity of a gram of 226Ra), where 1 Ci =3.7 × 1010 decays per second. This is more commonly quoted in terms of the S.I. unit the Becquerel, Bq, where 1 Bq = 1 decay per second. Therefore, 1 Ci = 3.7 × 1010 Bq (Box 2.10).


The activity (A) of a radioactive substance is given in becquerel (1 Bq is the number of decays per second).

The radioactivity of a sample can also be expressed in curies (Ci), where 1 Ci = 3.7 × 1010 Bq.


The activity (A) of a radioactive substance is given in becquerel (1 Bq is the number of decays per second).


The radioactivity of a sample can also be expressed in curies (Ci), where 1 Ci = 3.7 × 1010 Bq.


In nature, the abundance of the isotopes of certain radioactive nuclei depends on the abundance of their precursors, and the rate at which these precursors decay. Hence, the rate of production of each daughter nuclide of a certain radioactive isotope depends upon the rate at which its parent nuclide decays. All naturally occurring radioactive nuclides that are located below plutonium, 239Pu, in the periodic table are produced from the decay of just four parent (progenitor) isotopes: thorium (4n series), neptunium (4n + 1 series), uranium/radium (4n + 2), and actinium (4n + 3). Each of these nuclides then has a decay series or chain (see example in Fig. 2.11) with associated rates of decay at each step that determine the abundance of all other radionuclides in the universe.

A graph of the number of neutrons versus the atomic number. It depicts alpha decay or beta decay of U 238, T h 234, P a 234, U 234, T h 230, R a 226, R n 222, P o 218, P b 214, P o 214, P o 210, and P b 206.

Fig. 2.11
Uranium, 238U/radium, 226R (4n + 2) decay series. Radioactive decay series. (2020, September 8). [Retrieved August 16, 2021, from https://chem.libretexts.org/@go/page/86256 (open-source CC-BY textbook)]


A graph of the number of neutrons versus the atomic number. It depicts alpha decay or beta decay of U 238, T h 234, P a 234, U 234, T h 230, R a 226, R n 222, P o 218, P b 214, P o 214, P o 210, and P b 206.


The neptunium series is not observed in nature at the present time as 237Np, and all of its daughter nuclides have decayed since the birth of the universe, although the product of the series, bismuth 209Bi, is observed as a stable isotope in nature, pointing to the existence of the series at one time in the past. Each decay series begins with a radioactive isotope and ends with a stable daughter product. The parent isotopes of the isotopes at the beginning of the thorium, neptunium, and actinium series are produced as follows:


Th series: 252Cf → 248Cm → ® 244Pu → ® 240U → ® 240Np → ® 240Pu → ® 236U


Np series: 249Cf → ® 245Cm → ® 241Pu → ® 241Am → ® 237Np


If we consider a hypothetical decay series as in Fig. 2.12, the three daughter isotopes of isotope A (namely isotopes B, C, D) are produced at different rates, each dependent on the decay constants of the isotope that is their parent. Say only N0 atoms of A exist at time t = 0; then

 (2.19)

 (2.20)

 (2.21)


From Eqs. (2.19) and (2.20):


And multiplying across by

 gives

 (2.23)


If the parent is very much shorter lived than the daughter, i.e., if λA > λB, we then have radioactive equilibrium (Fig. 2.12a). If the parent is longer lived than the daughter, then λA < λB and a particular case called transient equilibrium arises (Fig. 2.12b). In Fig. 2.12b, the daughter product C is stable and so no further decrease in activity occurs. Finally, secular equilibrium occurs when the parent is much longer lived than its daughter λA <<λB. In this case, Eq. (2.23) reduces to the following (also see Box 2.11)

 (2.24)

 A flow diagram and 2 graphs. A diagram depicts the decay of A to B to C to D, with lambda A, lambda B, and lambda C as decay constants. a and b plot N versus t. a. 2 follow an increasing trend. b. Curve A slopes downward, curve B follows a right-skewed trend, and curve C follows an increasing trend.

Fig. 2.12
Hypothetical decay series involving four nuclides A, B, C, and D, with various different decay constants λA, λB, etc. (a) Radioactive equilibrium. (b) Transient equilibrium


A flow diagram and 2 graphs. A diagram depicts the decay of A to B to C to D, with lambda A, lambda B, and lambda C as decay constants. a and b plot N versus t. a. 2 follow an increasing trend. b. Curve A slopes downward, curve B follows a right-skewed trend, and curve C follows an increasing trend.


The natural abundance of radionuclides is largely determined by the nuclear decay series of four parent nuclides, thorium, neptunium, uranium/radium, and actinium.

Each decay series starts from an unstable radioactive parent isotope and ends with a stable daughter product.

Various states of equilibrium can be reached depending on the relationship between the lifetime of the parent and daughter isotopes.


The natural abundance of radionuclides is largely determined by the nuclear decay series of four parent nuclides, thorium, neptunium, uranium/radium, and actinium.


Each decay series starts from an unstable radioactive parent isotope and ends with a stable daughter product.


Various states of equilibrium can be reached depending on the relationship between the lifetime of the parent and daughter isotopes.


Experiments demonstrating the production of radioactive nuclei in the laboratory were performed by Irène and Frédéric Joliot-Curie in 1934 through the bombardment of aluminum and boron atoms with alpha particles. Those scientists observed that positrons were produced long after the bombardment and neutron production had ceased. They postulated that radioactive isotopes of phosphorus and nitrogen had been produced, which decayed to silicon and carbon in the following reactions:


Neither of the two radioactive isotopes of phosphorus and nitrogen produced in these reactions occurs in nature. The majority of the artificially produced isotopes are produced via the same bombardment as illustrated here, and most of them decay by the production of β+/βb−, the ratio of n/p in the nucleus determining which of the two reactions occurs.


Consider a situation where a nuclear reaction occurs by bombardment of nucleus X with particle a, producing a nucleus Y and another projectile particle b:

 (2.25)


Assuming that the rate of production, R, of Y is constant and its decay is also constant, then the infinitesimal change, dN, in the numbers of product atoms of Y over infinitesimal time, dt, is

 (2.26)


where Rdt provides the number of nuclides of Y produced per unit time and λNdt the number decaying over this time period. We can then rearrange to obtain a differential equation for the system:


for which we can obtain a general solution for the number of nuclides of Y at any time t > 0:

 (2.28)


And since activity A = λN, we may obtain a relationship for the variation in activity with time as

 (2.29)


We may use a Taylor expansion in e-λt to then obtain

 (2.30)


which allows a solution to be obtained for the special case where t << T1/2 for the nuclide Y such that the following is true: (also see Box 2.12)

 (2.31)


In 1934, Irène and Frédéric Joliot-Curie demonstrated for the first time that artificial, i.e., not occurring in nature, radioactive nuclei can be produced.

Artificial nuclides are produced by bombarding a nucleus (X) with a particle (a) resulting in the production of a new nucleus (Y) and a projectile particle (b).


In 1934, Irène and Frédéric Joliot-Curie demonstrated for the first time that artificial, i.e., not occurring in nature, radioactive nuclei can be produced.


Artificial nuclides are produced by bombarding a nucleus (X) with a particle (a) resulting in the production of a new nucleus (Y) and a projectile particle (b).


Unstable nuclei will transform spontaneously or artificially into an energetically more stable configuration by the emission of certain particles or electromagnetic radiation. This process, termed nuclear decay, is characterized by a parent nuclide (P) transforming into a daughter nuclide (D), which differs from the former in atomic number (Z), neutron number (N), and/or atomic mass number (A) [63]. The different types of nuclear decay are summarized in Table 2.1 (Box 2.13).Table 2.1
Summary of the different types of nuclear decay

Mode of radioactive decay

Released particles

General reaction

Example

α-Decay

Helium nucleus

ZAP → Z − 2A − 4P + 24He

92238U → 90234Th + 24He

β-Decay
β–
β+

Electron
Positron

a
ZAP → Z − 1AD + e+ + νb

a
611C → 511B + e+ + νb

γ-Decay

γ-Emission

Gamma ray

ZAP → ZAD + 00γ

92238U → 24He + 90234Th + 200γ

Internal conversion

Internal conversion electron

ZAP → ZAD + IC e−

Electron capture (EC)

Atomic X-ray

ZAP + e− → Z − 1AD + νb

47Be + e− → 37Li + νb

Spontaneous fission (SF)

2 fragment nuclei

ZAP → Z1A1D1 + Z2A2D2

100256Fm → 54140Xe + 46112Pd

Proton emission (PE)

Proton

ZAP → Z − 1A − 1D + 11p

711N → 610C + 11p

Neutron emission (NE)

Neutron

ZAP → ZA − 1D + n0c

413Be → 412Be + n0c

a⊽ Antineutrino
bNeutrino
cn0 Neutron


During nuclear decay, unstable nuclei transform into an energetically more stable configuration by emission of certain particles or energy.

Different modes of nuclear decay exist, each with their own mode of reaching this energetically stable configuration (Table 2.1).


During nuclear decay, unstable nuclei transform into an energetically more stable configuration by emission of certain particles or energy.


Different modes of nuclear decay exist, each with their own mode of reaching this energetically stable configuration (Table 2.1).


The term nuclide refers to an atom characterized by the number of protons and neutrons present in the nucleus. Nuclides can be sorted according to their number of protons and neutrons in a chart of nuclides. In contrast to the well-known periodic table, a chart of nuclides organizes the currently known radionuclides according to the number of protons and neutrons in their nucleus. Furthermore, it summarizes basic properties of these nuclides, such as atomic weights, decay modes, half-lives, and energies of the emitted radiations [64, 65].


In 2018, the tenth version of the Karlsruhe chart of radionuclides was published, containing nuclear data on 4040 experimentally observed nuclide ground states and isomers [66]. As mentioned earlier, this chart organizes data of currently known radionuclides according to the number of protons and neutrons present in their nucleus (Fig. 2.13a). Stable nuclides are shown in black, while the colored boxes indicate the decay mode of each nuclide (Fig. 2.13c). Data on individual nuclides can be found in the individual nuclide boxes (Fig. 2.13b). When a single nuclide has different decay modes, it is represented by different sizes of triangles, representing the branching ratios for each decay mode (Fig. 2.13b, 226Ac). A nuclide box can also be subdivided into different sections with a vertical line (Fig. 2.13b, 135Cs). An undivided box refers to the ground state of a nuclide, while when subdivided, the right section corresponds to the ground state and the subsections on the left represent the nuclear isomers (nuclides with the same number of protons and neutrons in the nucleus, but a different energy). Nuclides with a black upper section in the nuclide box represent primordial nuclides, formed during the formation of terrestrial matter and still present on Earth due to their extremely long half-lives. For such nuclides, the upper section provides information on the isotopic abundance, while the lower section indicates decay modes and half-lives (Fig. 2.13b, 232Th) [66]. Radionuclide charts are available in printed or online versions.

A schematic diagram and 2 charts. a plots number of protons versus number of neutrons for nuclides. b. A close-up view depicts certain examples of the nuclide box structure. c. The modes of radioactive decay are color-coded, such as atom, alpha, beta, and neuron particles.

Fig. 2.13
(a) Schematic representation of the complete Karlsruhe radionuclide chart. (b) Detailed representation of different radionuclide boxes. (c) Different colors of boxes representing the different decay modes, from left to right: stable isotope, proton emission (p), alpha decay (α), electron capture or beta-plus decay (ε or β+), isomeric transition (IT), beta-minus decay (β−), spontaneous fission (SF), cluster decay (CE), and neutron decay (n). [(Figure adapted from Soti et al., 2019) (licensed under CC-BY-4.0)]


A schematic diagram and 2 charts. a plots number of protons versus number of neutrons for nuclides. b. A close-up view depicts certain examples of the nuclide box structure. c. The modes of radioactive decay are color-coded, such as atom, alpha, beta, and neuron particles.


A chart of nuclides can be used to investigate decay chains and nuclear reactions of different radionuclides. By following the specific decay rules of each type of nuclear decay, complete decay chains can be obtained manually. In a similar way, the chart can be used to obtain different activation and reaction products of nuclear reactions [66]. In this way, this chart can be of great assistance to obtain information on nuclear decay chains and isotope stability. It can help with both planning of experiments and interpretation of results [64, 65] (Box 2.14).


A “nuclide” refers to an atom with a certain number of protons and neutrons in the nucleus.

Nuclides can be sorted based on their characteristics in a nuclide chart.

A nuclide chart can be used to investigate nuclear decay chains of different radionuclides.


A “nuclide” refers to an atom with a certain number of protons and neutrons in the nucleus.


Nuclides can be sorted based on their characteristics in a nuclide chart.


A nuclide chart can be used to investigate nuclear decay chains of different radionuclides.


The pioneering experiments performed by Wilhelm Conrad Roentgen (1895), Henri Becquerel (1896), and Marie and Pierre Curie (1898 and 1911) showed the potential of different radioactive elements. Over the decades to follow, radioisotopes have been applied in various fields, including medicine and food industry. In this section, some of the most common applications of radioisotopes will be discussed.


Radiometric dating is a technique used to date materials such as rocks or fossils, in which trace radioactive impurities were selectively incorporated when these materials were formed. The method compares the abundance of a naturally occurring “parent” radioactive isotope within the material to the abundance of its decay products (“daughter isotopes”), arriving at a known constant rate of the decay process.


Today, there are more than 40 different radiometric dating techniques based on different parent-daughter isotope pairs (each with a different half-life) that are useful for dating various geological materials and samples of biological origins. The relative amounts of the parent and daughter isotopes can be measured by different chemical and mass spectrometric techniques. Table 2.2 lists some of the most commonly used isotope pairs in radiometric dating.Table 2.2
Naturally occurring radioactive isotopes commonly used in radiometric dating [67]

Radioactive isotope (parent)

Decay product (daughter)

Half-life (years)

Samarium-147

Neodymium-143

106 billion

Rubidium-87

Strontium-87

48.8 billion

Rhenium-187

Osmium-187

42 billion

Lutetium-176

Hafnium-176

38 billion

Thorium-232

Lead-208

14 billion

Uranium-238

Lead+-206

4.5 billion

Potassium-40

Argon-40

1.26 billion

Uranium-235

Lead-207

0.7 billion

Beryllium-10

Boron-10

1.52 million

Chlorine-36

Argon-36

300,000

Carbon-14

Nitrogen-14

5715

Uranium-234

Thorium-230

248,000

Thorium-230

Radium-226

75,400


One of the most well-known examples is the dating using radioactive 14C (half-life of 5730 years) formed by nuclear reactions in the atmosphere. The constantly produced 14C reacts with oxygen, leading to the formation of 14CO2. This radioactive form of carbon dioxide is absorbed by plants via photosynthesis and will eventually become incorporated into all living organisms through the food chain. Once an organism dies, its metabolism stops, halting the incorporation of 14C. Therefore, by knowing the characteristic half-life and the ratio of 14C to the total carbon content, the age of the sample can be determined. The same principle applies to dating with the potassium-argon pair, which is commonly used to estimate the age of rocks, volcanic layers around fossils, and artifacts [68].


Sterilization is the complete killing or removal of all living organisms from a particular location or material. Several methods can be used to achieve sterilization, each with their own benefits and limitations. Irradiation with gamma rays (from a cobalt-60 or cesium-137 source, with a dose of around 15–25 kGy) is often used for the sterilization of medical products and pharmaceuticals, including implants, artificial joints, blood bags, and ointments. Sterilization by radiation has several benefits, the most important of which is that it can be used on heat-sensitive items that cannot be sterilized by other common methods such as autoclaving. It is also safer and cheaper because it can be done after the item is packaged. The sterile shelf life of the item is then practically indefinite provided that the seal is not broken. Indeed, it is estimated that irradiation technologies are used to sterilize almost half of the global supply of single-use medical products.


The use of gamma rays is, however, not strictly limited to the medical world. By irradiating food, we can significantly reduce their microbial burden, depending on the dose delivered. This prolongs the shelf life of the food in cases where microbial spoilage is the limiting factor. Some foods, e.g., herbs and spices, are irradiated at sufficient doses (5 kGy) to reduce the microbial counts by several orders of magnitude; such ingredients do not carry over spoilage or pathogenic microorganisms into the final product. It has also been shown that irradiation can delay the ripening of fruits or the sprouting of vegetables. Insect pests can be sterilized (be made incapable of proliferation) using irradiation at relatively low doses. The use of low-level irradiation can also be used as an alternative treatment to pesticides for fruits and vegetables that are considered hosts to a number of insect pests, including fruit flies and seed weevils. Food irradiation is currently permitted by over 50 countries, and the volume of food treated is estimated to exceed 500,000 metric tons annually worldwide [69].


Radioimmunoassays were first developed in the 1960s by Solomon Berson and Rosalyn Sussman Yalow for which they received the Nobel Prize in 1977. It was the first technique being able to determine hormone levels in blood. This type of in vitro assay can be used to measure the concentration of any antigen with very high sensitivity. To date, radioimmunoassays are among the most sensitive and specific laboratory tests employed by immunologists and other specialists. The general principle of an immunoassay is competition for binding to an antibody (Fig. 2.14). More specifically, the unlabeled antigen (sample) is incubated together with a fixed amount of the radiolabeled antigen and the antibody, resulting in competition between the unlabeled and labeled antigens for binding to the antibody. With increasing amounts of an unknown sample (unlabeled antigen), decreasing amounts of labeled antigen (tracer) will bind to the antigen [70]. The antibody–antigen complexes are separated from the free antigen by precipitation using a secondary antibody or chemical solutions. The antibody–antigen complexes are then measured in a scintillation counter. By running a set of standards, a standard curve is generated from which the concentration of the unknown sample can be calculated. The most commonly used radioisotopes for radioimmunoassays are iodine-125, iodine-131, and tritium (3H) [71] (Box 2.15).

An illustration depicts the mixing and incubating processes of the antibodies, antigens, and radiolabeled antigens. The free fraction has only antigens. The bound fraction has antigen-antibody complexes used to measure radioactivity.

Fig. 2.14
General principle of the radioimmunoassay (Created with BioRender)


An illustration depicts the mixing and incubating processes of the antibodies, antigens, and radiolabeled antigens. The free fraction has only antigens. The bound fraction has antigen-antibody complexes used to measure radioactivity.


Radioactive decay can be used as a natural clock to determine the age of different materials.

The strong ionizing ability of gamma rays, along with their high penetration range, can be used for the killing or reduction of microorganisms in different items, ranging from medical to food products.

The use of radioisotopes in immunoassays provides a very high level of sensitivity allowing the measurement of antigens in pictogram quantities.


Radioactive decay can be used as a natural clock to determine the age of different materials.


The strong ionizing ability of gamma rays, along with their high penetration range, can be used for the killing or reduction of microorganisms in different items, ranging from medical to food products.


The use of radioisotopes in immunoassays provides a very high level of sensitivity allowing the measurement of antigens in pictogram quantities.


In radionuclide therapy (RNT), radioisotopes are administered to patients with cancer or other medical conditions. Particles emitted from the isotopes will deliver cytotoxic levels of radiation to target sites within the human body, resulting in destruction of the targeted tissue (Fig. 2.15).

A diagram depicts radiolabeled antigen as a key and cancer cells as lock. The radioactive substance enters the cell via a surface receptor and alters the nucleus and other cellular components.

Fig. 2.15
Schematic representation of the mechanism of action of radionuclide therapy. The blue line represents the path of ionizing radiation (Created with BioRender)


A diagram depicts radiolabeled antigen as a key and cancer cells as lock. The radioactive substance enters the cell via a surface receptor and alters the nucleus and other cellular components.


Three types of ionizing radiation can be used for radionuclide therapy (RTN), namely alpha and beta particles and Auger electrons (their most important characteristics are summarized in Fig. 2.16). The linear energy transfer (LET) and tissue particle range are the most important parameters to be considered for this type of therapy. Ideal therapeutic radionuclides have a short particle range so it only damages targeted tissue and a high LET so it deposits as much radiation as possible on its short path length. All of the above-listed particles fulfill these criteria to ensure lesion-specific damage.

A schematic diagram presents the range and linear energy transfer of beta-emitting radionuclides, alpha-emitting radionuclides, and Auger electron-emitting radionuclides.

Fig. 2.16
Schematic representation of the energy deposition of the ionizing radiation and tissue range of the different emission types used for targeted radionuclide therapy, being β−, α, and Auger electron emitters (Created with BioRender)


A schematic diagram presents the range and linear energy transfer of beta-emitting radionuclides, alpha-emitting radionuclides, and Auger electron-emitting radionuclides.


The major breakthrough for RNT was in 1946, when iodine-131 was first used for the treatment of thyroid cancer. In the following years, a large variety of other radionuclides were introduced for the treatment of different cancer types, palliation of bone pain due to metastases, and treatment of inflammatory processes such as rheumatoid arthritis [72]. This was followed by the development of the peptide receptor radionuclide therapy (PRRNT), utilizing low-molecular-weight radiolabeled peptides targeted at specific cell surface receptors which are very often upregulated on cancer cells. Lutathera® (177Lu-DOTA-TATE) was the first-in-class PRRNT drug to be formally approved (by the EMA in 2017 and the FDA in 2018) for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The initial success of Lutathera® led to the development of new radiopharmaceutical-based strategies for treating other cancer types. These include the PSMA-targeted radionuclide therapy for prostate cancer and radioimmunotherapy with nanobodies for glioblastoma (Table 2.3) (Box 2.16).Table 2.3
Examples of radionuclides used for therapy (World Nuclear Association)

Radioisotope

Half-life

Therapeutic applications

Actinium-225

10 days

Targeted alpha therapy (TAT)
Prostate cancer

Bismuth-213

46 min

TAT
Leukemia, cystic glioma, and melanoma

Erbium-169

9.4 days

Arthritis pain relief in synovial joints

Holmium-166

26 h

Diagnosis and treatment of liver tumors

Iodine-131

8 days

Thyroid cancer treatment
Nonmalignant thyroid disorders

Iridium-192

74 days

High-dose-rate brachytherapy
Prostate, head, and breast cancer

Lead-212

10.6 h

TAT, alpha radioimmunotherapy, or PRRT
Melanoma, breast, pancreatic, and ovarian cancer

Lutetium-177

6.7 days

Imaging and therapy of multiple tumor types (e.g., endocrine, prostate)

Phosphorus-32

14 days

Polycythemia vera treatment (excess red blood cells)

Radium-223

11.4 days

TAT brachytherapy in the bone

Samarium-153

47 h

Pain relief of bone metastases from, e.g., prostate and breast cancer


In radionuclide therapy (RNT), radioisotopes are used to treat cancer or other medical conditions by administration of radiation sources to patients.

Three types of radioisotopes can be used for RNT, namely alpha and beta particles and Auger electrons.

The most important applications to date of RNT are iodine-131 for thyroid cancer, Lutathera® for neuroendocrine tumors, and PSMA-targeted RNT for prostate cancer.


In radionuclide therapy (RNT), radioisotopes are used to treat cancer or other medical conditions by administration of radiation sources to patients.


Three types of radioisotopes can be used for RNT, namely alpha and beta particles and Auger electrons.


The most important applications to date of RNT are iodine-131 for thyroid cancer, Lutathera® for neuroendocrine tumors, and PSMA-targeted RNT for prostate cancer.


Nuclear imaging techniques such as positron-emission tomography (PET) and single photon emission tomography (SPECT) are noninvasive procedures, which make use of radiolabeled probes to examine biological processes on the cellular or molecular levels in vivo. These techniques enable 3D visualization, quantification, and characterization of the target (enzyme, receptor, transporter, protein aggregates, etc.) under investigation [73]. For these purposes, the compounds are labeled with a radioisotope, with a fairly short half-life (T1/2, min to days). Both PET and SPECT allow visualization and quantification of targets expressed in very low quantities (nano-to-femtomoles per milligram tissue) or detection of molecular aberrancies before phenotypical or morphological changes have occurred [74] (Fig. 2.17).

2 models explain the SPECT and PET concepts for diagnostic purposes. a. SPECT uses a detector and collimator made of photons and crystals. PET uses coincidence detectors based on the annihilation reaction of orbital electrons and positrons in the nucleus.

Fig. 2.17
Comparison of the SPECT (a) and PET (b) imaging techniques used for clinical diagnostic (adapted with permission of Hicks and Hofman, 2012) [75]


2 models explain the SPECT and PET concepts for diagnostic purposes. a. SPECT uses a detector and collimator made of photons and crystals. PET uses coincidence detectors based on the annihilation reaction of orbital electrons and positrons in the nucleus.


SPECT makes use of the inherent decay properties of specific radionuclides, which decay with the emission of a photon (X-ray) (Hutton 2014).


The nuclides of choice are those which emit electromagnetic rays in the energy range of 100–200 keV. This is determined based on the absorption of the electromagnetic rays by the subject and the designated detector and is a trade-off between sensitivity and resolution. Low-energy rays are more easily absorbed by surrounding tissue (tissue not under investigation), leading to higher patient doses and less efficient detection. However, higher energy levels are not optimally detected (stopped) by the scintillation NaI crystals. Additionally, the half-life (T1/2) of the radionuclide should be tailored to the conducted experiment.


A SPECT apparatus typically contains two cameras which rotate around the body of the patient and are focused on an area under investigation. The cameras contain a lead collimator to directionalize the incoming radiation. As such, only rays parallel to the holes of the collimator will reach the detector, and radiation coming from scatter or other tissues not under investigation will be absorbed less by the scintillation detector, leading to less interference in image reconstruction and in turn increase in the contrast and hence the resolution but decrease in the sensitivity significantly.


Compared to planar (2D) X-ray imaging, where the electromagnetic rays are projected on an imaging detector leading to reduced contrast of the tissue under investigation compared to the background, SPECT imaging provides a noninvasive 3D method to determine the accumulation of administered diagnostic radiopharmaceuticals [73]. The term tomography indicates the use of a combination of individual “slices” to generate a 3D image.


The most widely used SPECT radioisotope, 99mTc, is metastable and decays via isomeric transition with emission of γ-rays of approximately 140 keV with a T1/2 = 6 h. Further, 99mTc is a radiometal that can be complexed by various chelators and can be incorporated into different ligands used in different investigations of a plethora of diseases (bone, heart, cancer, brain, liver). Another benefit of 99mTc is the cost and the ease of acquirement via a 99Mo/99mTc generator.


Frequently clinically used radionuclides are depicted in Table 2.4.Table 2.4
SPECT radionuclides [73, 76]

Radionuclide

T1/2

Nuclear reaction

Mode of decay

Energy (keV)

67Ga

3.26 days

67Zn(p,n)67Ga
68Zn(p, 2n)67Ga

EC (100%)

93

67Cu

3 days

68Zn(γ,p)67Cu

β− (100%)
γ (52%)

185

299mTc

6.06 h

99Mo/99mTc-generator

IT (89%)

140

111In

2.83 days

111Cd(p,n)111In
112Cd(p,2n)111In

EC (100%)

245

123I

13.2 h

123Xe/123I generator
124Xe(p,pn)123I

EC (100%)

159

201Ti

73 h

203Ti (p,3n) 201Ti

EC (100%)

69–80 (Hg X-rays)
135 (9%)
167 (27%)

EC electron capture, IT internal transition, thermal neutron bombardment


PET probes generally consist of a pharmaceutical vector molecule, which carries a coupled radionuclide to the target. Because of the radioactive decay, only a low mass amount of the tracer needs to be administered to the subject. As such, pharmaceutical or toxicological effects are avoided. The radioactive decay further enables highly sensitive detection of emitted γ-rays by a dedicated ring of detectors. PET allows to detect early molecular changes and follow-up of disease progression [74]. Typically, low atomic mass radioisotopes (C, N, O, F), with a rather short T1/2 of minutes to hours, are coupled to the pharmaceutical vector. Additionally, these radioisotopes are commonly found in different small molecules and biomolecules, so they can be incorporated without changing the chemical structure of the compounds. Advances in radiolabeling techniques are continuously increasing the radiochemical and -pharmaceutical space, which allows for a more robust and quicker radiolabeling [77]. PET is increasingly used in the drug development stream, as it enables examination of pharmacodynamics, drug-target interaction, and dose occupancy [78].


Radionuclides with an excess of protons in their core will decay by conversion of a proton to a neutron with emission of a positron (β+, a positively charged electron) and a neutrino (ν, a quasi-massless particle) over which the decay energy is distributed to fulfill the quantum mechanical rule of conservation of energy and angular momentum. Based on the kinetic energy obtained from the decay, the β+ particle will travel a short distance (positron range, up to 0.5 cm for 18F, 1–2 cm for 11C) and collides with an electron in the environment after which the masses of both are converted into energy in an annihilation event. Two γ-ray photons of 511 keV are emitted back-to-back over an angle of approximately 180°. These two γ-rays travel through the body and can be coincidentally detected by a ring of detectors (within a time interval of 10 ns), allowing to localize the imaginary “line of response” along which the annihilation event occurred. Many response lines can then be combined to determine the position of the PET radionuclide of which tissue concentrations can be derived. Compared to SPECT, thicker scintillation crystals are necessary to detect the higher γ-ray energy of 511 keV. These detectors typically consist of bismuth germanate (BGO) or lutetium oxyorthosilicate (LSO) and are more expensive compared to NaI crystals used in conventional SPECT and gamma counting. Hybrid imaging techniques such as PET/MRI and PET/CT allow a combination of morphological and functional imaging, where molecular and anatomical changes can be detected simultaneously with high accuracy. State-of-the-art PET technology research is investigating total-body PET with increased sensitivity (up to 40-fold) compared to normal PET scanners [79]. The worldwide workhorse of PET imaging is a radiolabeled glucose derivative, 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG), which visualizes the glucose metabolism and is hence taken up and trapped in organs with extensive glucose metabolism such as brain and heart and aberrant growth. Because of this, [18F]FDG can be applied in the diagnostic imaging of cancer, inflammation, cardiology, and neurology [80]. [18F]FDG differs from glucose by the replacement of the hydroxyl moiety by 18F at C-2. This has consequences for the metabolization process of [18F]FDG and is depicted in Fig. 2.18. Both glucose and [18F]FDG are taken up by glucose transporters (Glut) and processed by glycolysis. Hexokinase will phosphorylate the C-6 OH-moiety of both molecules. As this brings a negative charge to the molecules, they will remain trapped inside the cell. Glucose is then further processed to fructose-6-phosphate by glucose-6-phosphate isomerase on the C-2 OH-moiety, and further metabolization will yield pyruvate. As [18F]FDG lacks the C-2 OH-moiety, further metabolization will not take place and the molecule will remain trapped in the cell until decay (T1/2 = 109.7 min) of 18F to 18O, after which metabolization can resume.

A set of reactions in a cell depicts the conversion of glucose to pyruvate and also F D G to F D G 6 phosphate, which inhibits the synthesis of glucose-6-phosphate isomerase.

Fig. 2.18
Metabolization of glucose and its radioactive analogue [18F]FDG (Created with BioRender)


A set of reactions in a cell depicts the conversion of glucose to pyruvate and also F D G to F D G 6 phosphate, which inhibits the synthesis of glucose-6-phosphate isomerase.


PET radiopharmaceutical development has been favored over investigation into SPECT tracers over the last years. PET omits the use of mechanical collimation, replacing it with electronic collimation, increasing detector efficiency 100-fold compared to SPECT. The spatial resolution of PET is also higher with less influence of scattered photons. Attenuation correction is more efficient, and the imaging contrast is also better compared to SPECT [81]. A disadvantage of PET is the cost and the availability of PET radioisotopes, which need to be generated in a cyclotron (except for 68Ga, which is generator based). Furthermore, the short T1/2 of routinely used PET isotopes (carbon-11, fluorine-18, nitrogen-13, oxygen-15) requires production by an in-house cyclotron [82, 83].


Typical radionuclides, used for PET imaging, are listed in Table 2.5 (Box 2.17).Table 2.5
PET radionuclides (Vermeulen et al. 2019)

Radionuclide

T1/2

Nuclear reaction

Mode of decay

Energy (MeV)

11C

20.4 min

14N(p,α)11C

β+ (100%)

0.960 (β+ Emax)

13N

10.0 min

16O(p,α)13N

β+ (100%)

1.199 (β+ Emax)

15O

2.0 min

14N(d,n)15O

β+ (100%)

1.732 (β+ Emax)

18F

109.7 min

18O(p,n)18F
20Ne(d,α)18F

β+ (97%)
EC (3%)

0.634 (β+ Emax)

64Cu

12.7 h

64Ni(p,n)64Cu

β+ (18%)
EC (24%)
β− (37%)

0.653 (β+ Emax)
0.3293–1.675
0.5794

68Ga

67.6 min

68Ge/68Ga-generator

β+ (89%)
EC (11%)

1.899 (β+ Emax)
0.227–2.821

76Br

16.0 h

76Se(p,n)76Br

β+ (55%)
EC (45%)

3.382 (β+ Emax)
0.599

82Rb

1.3 min

82Sr/82Rb-generator

β+ (100%)

3.378 (β+ Emax)

86Y

14.7

86Sr(p,n)86Y

β+ (32%)
IT (68%)

1.221, 1.545, 1.988 (β+1,2,3 Emax)
0.433–1.920

89Zr

78.4 h

89Y(p,n)89Zr

β+ (23%)
EC (77%)

0.902 (β+ Emax)
0.909

124I

4.2 days

124Te(p,n)124I

β+ (26%)
EC (74%)

2.138, 1.535 (β+1,2 Emax)
602

EC electron capture, IT isomeric transition


SPECT and PET are noninvasive imaging techniques that allow to functionally diagnose different pathologies, including cancer, neurodegenerative diseases, and cardiovascular aberrations.

SPECT and PET make use of radiolabeled drugs to specifically target aberrantly expressed receptors, enzymes, etc.

SPECT makes use of the inherent γ- or X-ray decay of the used radioisotope, whereas the PET principle is based on the coincidental detection of the emission of 511 keV γ-rays, resulting from the annihilation of a β+ and an electron.

The most frequently used SPECT radioisotope is 99mTc, which can be incorporated in a plethora of vector molecules.

The most widely used PET radiotracer is [18F]FDG, a radioactive glucose analogue.


SPECT and PET are noninvasive imaging techniques that allow to functionally diagnose different pathologies, including cancer, neurodegenerative diseases, and cardiovascular aberrations.


SPECT and PET make use of radiolabeled drugs to specifically target aberrantly expressed receptors, enzymes, etc.


SPECT makes use of the inherent γ- or X-ray decay of the used radioisotope, whereas the PET principle is based on the coincidental detection of the emission of 511 keV γ-rays, resulting from the annihilation of a β+ and an electron.


The most frequently used SPECT radioisotope is 99mTc, which can be incorporated in a plethora of vector molecules.


The most widely used PET radiotracer is [18F]FDG, a radioactive glucose analogue.


Dose or absorbed dose is the mean energy imparted by ionizing radiation to a material.


where dE is the mean energy imparted by ionizing radiation and dm is the mass of the material.


The SI unit of dose is gray (Gy) and is defined as absorbed energy per unit of mass of tissue, given by one joule per kg. The old unit is rad, and the conversion is defined as 1 Gy = 100 rad [84].


Dose rate is defined as the dose of ionizing radiation absorbed or delivered per unit time. It is measured in gray per hour.


The biological effect of a certain dose is dependent on its dose rate, known as the dose rate effect. The biologic effect of a given dose is reduced if the exposure time is extended, and so if the dose rate is lowered. This is due to repair of sublethal damage that occurs during long radiation exposure. It is also due to redistribution of cells in cell cycle and cell proliferation (see Chap. 5 for details).


On the contrary, inverse dose rate effect is observed when increased biologic effects of a given dose at lowering the dose rate occur. This only happens at a limited range of dose rates. This is attributed to progression of cells through the cell cycle and accumulation in the G2 cell cycle phase, which is a radiosensitive phase. Further lowering of the dose rate below this critical level leads to lowering of biologic effects as cells cross the G2 block and divide, leading to cell proliferation.


Importantly, dose rate reduction has a differential effect between most tumors or early-responding normal tissues and late-responding normal tissues. Late-responding normal tissues are more sensitive to dose rate changes, like changes in fraction size in external beam radiotherapy [85].


The dose rate of environmental exposure is low (around 0.1 μGy/min). Clinically, the concept of dose rate is utilized in brachytherapy. Accordingly, there are different categories such as1.
Ultralow dose rate (ULDR)—less than 0.4 Gy/h
 2.
Low dose rate (LDR)—0.4–2Gy/h
 3.
Medium dose rate (MDR)—2–12 Gy/h
 4.
High dose rate (HDR)—more than 12 Gy/h


Ultralow dose rate (ULDR)—less than 0.4 Gy/h


Low dose rate (LDR)—0.4–2Gy/h


Low-dose-rate irradiation can be considered as an extreme form of fractionation.


There is another entity called pulsed dose rate (PDR), which is used in brachytherapy. Dose and treatment time are prescribed for LDR, but radiation is delivered in a pulsed manner every 1–4 h in many small fractions. Contrastingly, in FLASH radiotherapy, an ultrahigh dose rate of more than 1,44,000 Gy/h is administered [86].


The biological effect will be explained in Chaps. 5 and 6 (Box 2.18).