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CHAPTER 1

INTRODUCTION
THE TRACER CONCEPT and helium ions and free electrons. With time
A brief historical view the temperature decreased and after 700 million
years the electrons were able to attach to the
Big Bang ions forming neutral atoms and the plasma was
transformed to a large cloud of hydrogen and
helium gas. In the neutral gas gravity was able
to locally condense the gas, a process that again
increased the temperature, and the first stars, the
red giants were born. The temperature and the
density in the stars increased the probability of
other nuclear reactions like the formation of
beryllium-8 by two helium nuclides. This
nucleus could then pick up another helium ion
(or α-particle) to form carbon-12. In steps of
four mass units (2 protons and 2 neutrons) light
elements were formed, oxygen-16, neon-20,
manganese-24, sulphur-32 etc in a process
called fusion. Other reactions such as neutron
capture, splitting of the target nucleus in nuclear
reactions and radioactive decay contributed to
create other combinations of proton and
neutrons.
All matter in the universe has its origin in an
event called the “Big Bang”, a cosmic explosion The fusion process worked for elements up to
releasing an enormous amount of energy about iron but for more heavy elements other
14 billion years ago. Particles like protons and mechanisms took over. The iron nucleus picked
neutrons, the building stones of the nucleus, up neutrons creating instable proton and neutron
were condensed as free particles during the first combinations that decayed emitting a negative
seconds. However, it took several minutes until -
the decreasing temperature of the expanding charge in the form of a beta particle (β ). A new
universe reached a level that allowed the element (cobalt) with an extra proton in the
formation of particle combinations like nucleus was then created. The cobalt nucleus
deuterium (heavy hydrogen) as well as helium captured new neutrons and formed nickel nuclei
(see figure below). via radioactive decay. In such a way, step by
32
step, all the heavy elements we know were
16 S
15 Heavy ion fusion in red super giants
31
P created.
28 29 30
14 Si Si Si
12C-fusion 27
13 Al
When the red giants grow old they exploded.
n
O-fusio

24 25 26
12 n Mg Mg Mg
Number of protons

11
23
Na All their content of heavy material was spread
10 α 20Ne 21 Ne 22Ne around in universe. By gravity other stars
16

19
9 F
8 He-fusion in
16
O O O n
17 18 picked it up and formed planets. Actually, all
7 red giants
14 15
N N matter around us, including our-selves, was
α C C
12 13 n
6
10 11
once created in one of these red stars.
5 B B
4 α 8 Be 9 Be
3
4
6 7
Li Li Billion years have passed since our planet
2 He
Tellus was formed. Most of the unstable proton-
n p+n d (deuterium), d+d He
1 p d
0 n
H-fusion in gas clouds and stars neutron combinations once created has
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 undergone transformations (radioactive decay)
Number of neutrons into stable combinations. However, some with
very long half-lives remain: potassium-40, lead-
For several 100 million years the universe was a 204, thorium-232 and the natural occurring
large plasma composed by hydrogen, deuterium isotopes of uranium.

1
The pioneers
Almost at the same time (1913), George de
These “glowing” pieces after the cosmic Hevesy demonstrated the practical implication
cookery event were discovered by Henri of the isotopic theory. He and his colleagues
Becquerel 1896 and were further investigated used a radioactive isotope of lead, 210Pb, as a
by Marie Curie and her husband Pierre Curie. It tracer (or indicator) when they studied the
was the scientific sensation of that time, which solubility of sparingly soluble lead salts. Hevesy
still has great implications in our lives. was also the first to apply the radioactive tracer
technique in biology when he investigated lead
Suddenly several new elements were discovered uptake in plants (1923) using 212Pb. Only one
that emitted radiation of several types. First was year later, Blumengarten and Weiss carried out
polonium named after Poland, Marie Curie’s the first clinical study. They injected 212Bi into
country of birth. The second was radium, which one arm of a patient and measured the arrival
was soon found to have properties useful in time in the other arm. From this study, they
medicine (cancer treatment). However, some concluded that the arrival time was prolonged in
elements were chemically identical with already patients with heart disease.
known elements, such as lead, but emitted this
strange new radiation. This was puzzling for the Induced radioactivity
scientists at that time. They had only vague
knowledge about the structure of the atom, and So far, nature was the supplier of the radioactive
the neutron was still to be discovered. Soddy, in nuclides that were used. Isotopes of uranium
1913, introduced the concept of isotopes and thorium generated a variety of radioactive
(Greek: iso= same, tope= place). Isotopes heavy elements such as lead, but radioactive
occupied the same place in the periodical isotopes of light elements were not known.
system, were chemically identical, but differed Marie Curie’s daughter Irène, together with her
from each other in atomic weight and emission husband Frédéric Joliot took the next step.
of radioactivity. When Chadwick in 1932 Alpha-emitting sources had for long been used
discovered the neutron this concept was given a to bombard different elements. Rutherford
rational explanation. studied e.g. the deflection of alpha particles in
gold foils and discovered the small, charged
nucleus of the atom. But Joliot-Curie also
showed that the alpha particles induced
radioactivity in the bombarded foil (in their case
aluminum foil). The induced radioactivity had a
half-life of about 3 minutes.

Antoine Henri Becquerel Marie Curie

Frédéric Joliot Irène Joliot-Curie

Correctly, they identified the radiation to be


emitted from 30P created in the nuclear reaction.
27
Frederick Soddy George de Hevesy Al (α, n) 30P

2
the following weeks, they bombarded some 60
They also concluded that “These elements and
elements and found induced radioactivity in 40
similar ones may possibly be formed in
of them. They also observed that the lighter
different nuclear reactions with other
elements were usually transmuted into
bombarding particles: protons, deuterons and
radionuclides of a different chemical element,
neutrons. For example, 13N could perhaps be
whereas heavier elements appeared to yield
formed by capture of a deuteron in 12C,
radioisotopes of the same element as the target.
followed by the emission of a neutron.”
These new discoveries excited the scientific
community. From having been a rather limited
technique, the radioactivity tracer principle
could suddenly be applied in a variety of fields
and especially in life sciences. De Hevesy
immediately started to study the uptake and
elimination of 32P-phosphate in various tissues
of rats and demonstrated, for the first time, the
kinetics of vital elements in living creatures. 128I
was applied in the diagnosis of thyroid disease.
This was the start of the radiotracer technology
Ernest Orlando Lawrence Enrico Fermi in biology and medicine, as we know it today.

The same year this was proved to be true by One early cyclotron-produced nuclide was 11C.
Ernest Lawrence in Berkeley, California and It is of special importance since carbon is
Enrico Fermi, Rome. Lawrence had built a fundamental in life science. 11C has a half-life
cyclotron capable of accelerating deuterons up of only 20 minutes but by setting up a chemical
to about 3 MeV and it was by pure chance that laboratory close to the cyclotron, organic
this group had not yet discovered induced compound labeled with 11C can be obtained in
radioactivity. He soon reported the production large amounts. Photosynthesis was studied
of 13N with a half-life of 10 minutes. After this using 11CO2 and the fixation of carbon
the cyclotron was used to produce several other monoxide in humans by the use of inhalation of
11
biologically important radionuclides such as CO. However, 20 minutes was short and the
11
C, 32P and 22Na. use of 11C was limited to the most rapid
biochemical reactions. One must remember that
Fermi realized that the neutron was the radio-detectors used at that time were
advantageous for radionuclide production. Since primitive and that the chemical synthetic and
it has no charge, it could easily enter into the analytic tools were not adapted to such short
nucleus and induce a nuclear reaction. He times. A search to find a more long-lived
immediately made a strong neutron source by isotope of carbon resulted 1939 in the discovery
sealing up 232Ra-gas with beryllium powder in a of 14C produced in the nuclear reaction
glass vial. The alpha particle emitted from 232Ra 13
C (d, p) 14C
caused a nuclear reaction in beryllium and a
neutron was emitted. However, 14C produced this way was of limited
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use since the radionuclide could not be
Be (α, n) 12C separated from the target.
Fermi started a systematical search by
irradiating all available elements in the periodic During the bombardments, a bottle of
system with fast and slow neutrons to study the ammonium nitrate solution had been standing
creation of induced radioactivity. From close to the target. By pure chance, it was
hydrogen to oxygen, no radioactivity was discovered that this bottle also contained 14C,
observed in their targets, but in the ninth which had been produced in the reaction
element, fluorine, their hopes were fulfilled. In 14
N (n, p) 14C

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may say that reactor-produced radionuclides are
The deuterons used in the bombardment consist
most suitable for laboratory work, whereas
of one proton and one neutron with a binding
accelerator-produced radionuclides are more
energy of about 2 MeV. When high-energy
clinically useful. Some of the most used
deuterons hit a target, it is likely that the
radionuclides in nuclear medicine, such as 111In
binding between the particles breaks and that a
and 201Tl, are accelerator produced. When using
free neutron is created in what is called a
very short-lived radionuclides (11C, 13N, 15O and
“stripping reaction”. The bottle with ammonium 18
F) for positron emission tomography (PET)
nitrate had thus unintentionally been neutron
the need for an in-house accelerator is obvious.
irradiated. Since no carbon was present in the
bottle (except small amounts from solved air-
Radioactive nuclides with short half-life may
borne carbon dioxide) the 14C produced this
play an important role in the future laboratory
way was of high specific radioactivity. It was
use of the tracer technique. We know that
also very easy to separate from the target. In the
biological systems, such as pheromones, may
nuclear reaction, a “hot” carbon atom was
work at extremely low concentrations. The
created, which formed 14CO2 in the solution. By
radiotracer technique, as we know it today, is
simply bubbling air through the bottle, the 14C
often not useful to study such systems since it is
was released from the target.
not sensitive enough. The drawback with 14C is
its very long half-life of 5370 years. If we have
The same year, and in the same place, tritium
one million 14C-labeled molecules, in the mean
was discovered by deuteron irradiation of water.
only one will decay in an experiment lasting a
One of the pioneers Martin Kamen stated:
few days. Usually, the practical detection limits
“Within a few months, after the scientific world
are in the pico-mole area. When using the more
had somewhat ruefully concluded that
short-lived 11C, almost all labeled molecules
development of tracer techniques would be
contribute to the signal during an experiment
seriously handicapped because useful
lasting one hour. The sensitivity increases
radioactive tracers for carbon, hydrogen, oxygen
considerably to the femto-mole or even atto-
and nitrogen did not exist, 14C and 3H were
mole level.
discovered, and the situation greatly improved”.
This is indeed true. The role of 3H- and 14C-
DEFINITION OF IONIZING RADIATION
labeled tracers in biochemical research is a story
in itself.
Ionizing radiation is high-energy particles or
photons that can cause ionization, in other
Before the Second World War, the cyclotron
words, cause the emission of electrons from
was the main producer of radionuclides since
atoms or molecules. Subatomic particles with a
the neutron sources at that time were very weak.
mass (such as electrons, protons and neutrons)
But with the development of the nuclear reactor,
transfer their kinetic energy, in different
the situation changed. Suddenly, a tremendously
processes, to the orbit electrons of the atom.
strong neutron source was available, which
Photons (electromagnetic radiation) with
easily could produce almost unlimited amounts
wavelength of atomic dimensions or less behave
of radioactive nuclides including such
as discrete ”packets” of energy (quanta). These
biological important elements as 3H, 14C, 32P,
35 quanta, in different processes, also transfer their
S and clinically interesting radionuclides as
60 energy to matter creating ionization.
Co (for external radiotherapy) and 131I for
nuclear medicine. After the war, a new industry
In 1895, Wilhelm Conrad Roentgen discovered
was born which could deliver a variety of
X-rays, the first man made ionization radiation.
radiolabeled compounds at a reasonable price.
When fast electrons are slowed down in dense
material, they create radiation of electro-
However, accelerator-produced nuclides have a
magnetic nature similar to that of ordinary
special character, which makes them differ from
visible light. However, these quanta, roentgen
reactor-produced nuclides. Today, their
or X-rays, have considerably higher energy than
popularity is increasing again. Generally, one

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light. This type of continuous radiation is also Subsequent development was rapid. The
called bremsstrahlung. technology to accelerate charged particles to
high energy was developed. In the 1930’s, a
new ionizing particle, the neutron, was
The direction of the discovered. Like roentgen and gamma radiation,
field is perpendicular it had no charge. It was soon demonstrated that
to the plane of the the neutron caused nuclear reactions including
page. The heavy, nuclear fission in heavy elements.
positive α −particle is
deflected slightly to During the1940’s, physicists learnt to control
the left whereas the the fission process, which in nuclear weapons
light negative β- can liberate instantaneously enormous amounts
particle is deflected of energy in the form of ionizing radiation. In
markedly to the right. nuclear reactors, nuclear fission can be
Figure 1 A collimated The uncharged γ - controlled and used to produce energy and large
photons being amounts of radioactive material. The explosion
radium source in a of nuclear weapons, especially in the biosphere,
magnetic field. insensitive to the
magnetic field carry disperses enormous amounts of radioactive
straight on. material, which resulted in many people being
exposed to radiation. Nuclear power plants also
In 1896, Henri Becquerel demonstrated that contributed to an increase in radioactive
uranium mineral emits penetrating radiation nuclides in the environment even if during
with properties similar to X-rays. The couple, normal operation the increase is small.
Marie and Pierre Curie, showed in 1898 that
certain uranium minerals contained a previously HISTORICAL SUMMARY
unknown element, radium, which emits intense
ionizing radiation of different types. A magnetic 1895 Discovery of X-rays
field can separate the radium radiation into three 1896 Discovery of natural radioactivity
components (Figure 1). 1900 - Period of serious personal injuries
1920 amongst radiologists due to lack of
On closer analysis, it became apparent that knowledge.
α−radiation was identical with helium nuclei, 1920 National and international radiation
β-radiation consisted of electrons, and protection standards begin to be
instituted.
γ-radiation was of electromagnetic nature.
1930 The neutron and induced radioactivity
discovered. Construction of particle
Shortly afterwards, ionizing radiation was used accelerators begins.
in medicine for diagnostic radiology and the 1939 Nuclear fission discovered
irradiation of tumors. However, at that time 1945 Nuclear bombs used (Hiroshima and
there were little knowledge about the effects of Nagasaki).
radiation on matter, how radiation transferred 1950- Development of nuclear reactors
energy to the region irradiated and how to 1960- Use of reactors for production of
quantify radiation. Ionizing radiation is of energy, development of trace element
course invisible and humans have no sensory techniques, increased use of radiation in
organ that can detect it. Consequently, a series medicine, research and industry
of tragic events occurred in the early decades of
the use of ionization radiation. The need for
measuring techniques (dosimetry) and
protective procedures for those working with
ionizing radiation was soon perceived.

5
Energy of ionizing radiation
To cause ionization or excitation, it is essential
When ionizing radiation (in the form of high- that the incoming radiation has certain energy.
energy photons, neutrons or charged particles) This is expressed as electron volt eV. One eV is
collides with matter, the full energy or part of it the kinetic energy an electron or a proton
can be transferred to the matter in various types receives after acceleration in a potential drop of
of interaction. It is by such energy transfer that 1 volt (Figure 3).
radiation exerts its damaging effect on living
creatures. Part of the transmitted energy causes Generally, charged and non-charged particles
ionization or excitation in the material (Figure can be allotted a certain kinetic energy
2). Ionization means that electrons in the matter expressed in eV or
receive so much additional energy that they are keV (kiloelectron volt = 103 eV),
liberated completely from the atom or molecule MeV (megaelectron volt = 106 eV) and
to which they are bound. By excitation, the GeV (gigaelectron volt = 109 eV).
additional energy is insufficient for the electrons
to be liberated from the molecule. X-ray and gamma radiation does not have mass
or kinetic energy in the real sense. However,
Figure 2 Ionizing when their wavelength diminishes and begins to
radiation transfer approximate the dimensions of the atom and the
energy to the atom's nucleus, the electromagnetic radiation can be
orbital electrons. They regarded as particles (photons or radiation
can either be displaced quanta). Each photon has certain energy (E)
to a distal orbit E=hν
(excitation) or they can where ν is the frequency of the electromagnetic
be free electrons oscillations of the radiation, h is "Planck's
(ionization). constant", and E is energy in eV.
The electron is displaced only to an orbit with a On average, about 30 eV are needed to cause
lower binding energy. The atom or molecule one ionization in most materials. We define
does not change its charge number but the ionizing radiation to have energy higher than
process may change its chemical properties. 100 eV. Radiation with lower energy is called
non-ionizing radiation.
+1 volt
e-, electron PRODUCTION OF IONIZING
Ee= 1 eV
RADIATION
ve= 600 km/s

In electromagnetic fields, charged particles can


e+, proton
be accelerated to such energies that they can
Ep=1 eV
vp=14 km/s
penetrate matter. Important types of accelerators
are:
0
a for acceleration of electrons
Figure 3 An electron is accelerated from the
negative towards the positive electrode. At 1 X-ray tubes (0 - 300 keV)
arrival, the electron has acquired a kinetic 2 Linear accelerators (2 - 100 MeV)
3 Betatrons (15 - 100 MeV)
energy of 1 eV. A particle with positive charge,
e.g. a proton, undergoes a similar event from 4 Microtrons (5 - 50 MeV)
the positive to the negative electrode. However,
since the proton mass is about 2000 times the b for acceleration of heavy, charged
mass of the electron, the proton velocity is particles (protons, heavier ions)
considerably lower. 1 Van de Graaff accelerator (1-25 MeV)

6
2 Linear accelerator (1 - 800 MeV) and beam current (number of particles per unit
3 Cyclotron (1 - 1,000 MeV) of time or in microamperes). From the radiation
4 Synchrotron (1 - 300 GeV) protection point of view, an essential feature of
accelerators is that radiation production can be
Secondary ionizing radiation arises when the turned off easily. The only risk involved is the
accelerated particles meet a radiation target. possible occurrence of induced radioactivity.
Radioactive sources, which are the commonest
a X-ray photons, when for example source of radiation in the laboratory, do not
electrons are decelerated in an X-ray tube. have this convenient attribute.
Radiation protection when working with X-
ray equipment is dealt with in Chapter 5. Other examples are neutron and gamma
radiation, which arise as a result of nuclear
b Protons, neutrons, photons or other fission processes in a fission reactor.
radiation particles when protons, heavier
particles or photons cause nuclear reactions.

Figure 4 Cyclotron that accelerates protons to


17 MeV. Generally used for radionuclide
production.

Figure 5 Modern diagnostic X-ray laboratory


for tomographic information.

Important parameters specifying an accelerator's


performance are the type of accelerated particles
(electrons, protons etc.), maximum particle
energy (most often given in keV, MeV or GeV)

7
CHAPTER 2
NUCLEAR STABILITY AND INSTABILITY
Of these expressions only the isotope concept is
ORGANIZATION OF MATTER generally used. It is important to understand that
whenever we use the expression isotope, we
Chemists learnt during the late 19th century to must always relate it to a specific element or a
organize chemical knowledge into the periodic group of elements, e.g. isotopes of carbon (e.g.
11
system. Radioactivity, when it was discovered, C, 12C, 13C and 14C) or isotopes of the
conflicted with that system. Suddenly various halogens.
samples, apparently with the same chemical
NUCLIDE CHART
behavior, were found to have different physical
qualities such as half-life, emitted type of protons = neutrons
100 On this side
radiation and energy. The concept of isotopes or
neutron deficient

Number of protons
elements occupying the same place in the 80 nuclides which
periodic system (from the Greek: iso- = same
decay by β+
and topos = place) was introduced by Soddy 60 and EC
1913, but a complete explanation had to wait
for the discovery of the neutron (Chadwick 40 On this side
1932). neutron excess
20 nuclides which
The periodic system was organized according to decay by β-
the number of protons in the nucleus. This 0
related to the number of surrounding electrons 0 50 100 150
that determined the chemistry of the element. Number of neutrons
Since the number of neutrons in the nucleus is
of importance as well, the physicist’s way to Figure 1 Chart of nuclides. The black dots
organize matter, the nuclide chart, is somewhat represent 279 naturally existing combinations
different. Each proton-neutron combination is of protons and neutrons (stable or almost stable
identified in this chart. nuclides). Around this stable line are about
2300 proton/neutron-combinations that are
A proton-neutron combination is identified by radioactive.
A
ZX 9
17
F
18
F
19
F
20
F
21
F
22
F
23
F
24
F
25
F
13 14 15 16 17 18 19 20 21 22 23 24
8 O O O O O O O O O O O O
Number of protons

X = element name (e. g. C for carbon) 7


12
N 13
N 14
N 15
N 16
N 17
N 18
N 19
N 20
N 21
N 22
N 23
N
9 10 11 12 13 14 15 16 17 18 19 20
Z = number of protons in the nucleus 6
8
C C
10
C
11
C
12
C
13
C
14
C
15
C C
17
C C C
5 B B B B B B B B
N = number of neutrons in the nucleus 4
7 8
Be Be Be
9 10 11
Be Be Be
12 14
Be
A = mass number (A=Z+N) 3
6 7
Li Li Li Li
8 9 11
Li
3 4 6 8
2 He He He He
1 2 3
1 H H H
The expression above is over-determined. If the 0 n
element name X is known, so is the number of 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
protons in the nucleus, Z. Usually, the following Number of neutrons
simplified expression is used.
A
X Figure 2 A part of the nuclide chart where the
lightest elements are shown. The dark squares
Some relations of the numbers of protons and
represent stable nuclides that are important for
neutrons have special names such as
our existence. Nuclides to the left of the stable
Isotopes = number of proton is constant
ones are radionuclides deficient in neutrons and
(Z = constant)
those to the right, rich in neutrons.
Isotones = number of neutrons is constant
(N = constant)
The force that keeps the nucleons (protons and
Isobars = mass number is constant
neutrons) together in the nucleus is called the
(A = constant)
“strong force” or the “nuclear force”. Other

8
forces, e.g. the Coulomb force, tend to separate
the charged particles in the nucleus. In the
proton neutron
stable and in the radioactive nucleus, there is a Figure 4 Binding and
balance between binding and separating forces. separating forces in
The interplay between the forces is illustrated in the nucleus. A proton
Figure 4. A proton and a neutron are held and a neutron can
together by the strong force and create a stable proton proton form a stable nucleus
isotope of hydrogen, deuterium. Two protons do whereas two protons
not create a stable system since the Coulomb can not.
force exceeds the nuclear force.

Liquid drop model

It is far beyond the ambition of this book to give


electron a comprehensive understanding of these
proton
neutron processes. However, some penetration of the
topic is necessary to get a general feeling of the
Figure 3 Here, three isotopes of the element fundamental aspects of stability and nuclear
hydrogen are illustrated using a simple atomic decay. We use a model describing the exchange
model. 1H has only one proton, deuterium 2H of nuclear forces that is referred to as the “liquid
has a proton and a neutron in its nucleus, and drop model”. This model gives an empirical
tritium 3H has a proton and two neutrons. formula of the binding energy B of the nucleus.
Isotopes behave in the same way chemically
since it is the electron shell that determines
what happens in chemical reactions. Physically Figure 5 The range of
they are completely different. the nuclear force is
short. Only neighbors
Between two neutrons, no Coulomb force is are interacting.
present and one should expect this system to be
stable. However, this is not the case since
besides the strong force and the Coulomb force
a symmetry rule exist saying that a higher
nuclear stability is achieved when there are We explain the model step by step.
about the same number of protons and neutrons
in the nucleus. This symmetry rule prevents two B ≈ a1*A
neutrons from sticking together, but allows two
neutrons and a proton to form a radioactive The binding energy is in the first approximation
nucleus, 3H. proportional to the number of nucleons in the
nucleus. This is because the nuclear force has a
A useful measure is the binding energy that very short range. Only neighbors are affected
keeps the nucleons together. If the energy of 2.2 and can bind to each other. The nucleons in the
MeV is added to a deuterium nucleus, the two central part of the nucleus all have the same
nucleons are parted as a free proton and a free number of neighbors. In a large nucleus the total
neutron. Another way to express this is to binding energy, B, is then approximately equal
measure the differences in weight. The to a constant*A where A is the number of
deuterium nucleus is somewhat lighter than the nucleons. The same is true between molecules
sum weight of the free neutron and proton. This in a liquid, thus the model’s name.
mass difference can be converted into energy
using the Einstein formula E = mc2 and is found B ≈ a1*A - a2*A2/3
to be 2.2 MeV.

9
Nucleons at the surface have fewer neighbors well. A nucleus with an odd number of protons
and binding sites and are more loosely bound. or neutrons is less stable than a nucleus with an
The total binding energy is decreased by a factor even number of both protons and neutrons. The
that is proportional to the surface of the nucleus. most unstable nuclei have an odd number of
The number of nucleons, A, is proportional to both protons and neutrons, e.g. 14N (Z=7, N=7).
the volume of the nucleus. Thus, the nucleus In fact, only seven odd-odd stable nuclides
radius is proportional to A1/3 and the surface to exist, all of them among the light elements. This
A2/3. last factor a5 takes care of this effect in the
following way
B ≈ a1*A - a2*A2/3 - a3*Z2/A1/3
apair A-3/4 for even-even nuclei
When the numbers of protons start to increase, a5 = 0 for even-odd nuclei
the Coulomb repulsing force starts to become -apair A-3/4 for odd-odd nuclei
more important. The Coulomb force is the sum
When this model is fitted to experimental data
of all proton combinations, F =Σ(Zi*Zj)/(rij) 2. If
the following parameters are obtained
we integrate this function as a function of
distance, we obtain a measure of the energy a1=15.76 MeV
related to the force. It can then be shown that a2=17.81 MeV
the negative contribution to the binding energy a3 =0.7105 MeV
is proportional to Z2/A1/3 a4 =94.81 MeV
apair = 34 MeV
B ≈ a1*A - a2*A2/3 - a3*Z2/A1/3 - a4*(A/2-Z)2/A
An interesting parameter is the mean binding
Nature seems to prefer to have about the same
per nucleon, B/A.
number of protons and neutrons in the nucleus.
This is seen in Figure 1 where for light nuclides
the nuclide chart is very close to a straight line
(equal number of protons and neutrons). For
heavier elements there seems to be a tendency
towards an excess of neutrons. This is
understandable if one considers the Coulomb
force contribution. Adding neutrons will
increase the distances between the protons,
which will lower the Coulomb force and total
binding energy in the nucleus increases. The
expression a4*(A/2-Z)2/A is only empirically
found but gives the wanted relations. If Z=A/2
i.e. the number of protons and neutrons is equal
the binding energy is at a maximum. The
contribution of this term is also less important
for heavier nuclides, which agrees with
experimental findings.

B ≈ a1*A - a2*A2/3- a3*Z2/A1/3- a4*(A/2-


Z)2/A+a5
Figure 6 Mean binding energy per nucleon as a
Paired electrons in the outer electron shell give function of mass number A. The liquid drop
chemically stable compounds, whereas unpaired model is fitted to measured data. The area from
electrons give radicals. The most chemically 0<A<50 is enlarged in the lower part of the
inert atoms are the noble gases (He, Ne, Ar, Kr, figure. As seen, the crude empirical model fits
Xe, Ra), which have closed electron shells. The the data well except for the light elements.
same phenomenon is found in the nucleus as

10
This value, which gives the mean energy needed The carbon isotope 12C is stable. The element
to separate one nucleon from the nucleus, varies carbon has six protons (Z = 6) and the same
from a few MeV to about 9 MeV as illustrated number of neutrons (N = Z = 6). If one neutron
in Figure 6. The mean binding energy per is removed, the carbon isotope 11C (Z=6, N= 5)
nucleon is a smoothly varying curve that has a is obtained. This nuclide is not stable and will
maximum around the iron part (A ≈ 60). If two sooner or later undergo restructuring. If a
light elements are fused together they gain neutron is added, 13C (Z=6, N = 7) is obtained,
energy. This effect is used in the fusion which is stable. However, its natural abundance
principle to obtain nuclear power. If one heavy (1.1 %) is low compared with 12C.
element is split in two, the total binding energy
increases as well. The excess in energy is then Further addition of one neutron gives 14C(Z=6,
released and used in the fission principle to N=8), which also is radioactive. It is a general
obtain nuclear power. rule (with a lot of exceptions) that the further
you move from the stable combination of
As seen in Figure 6, the liquid drop model fits neutrons and protons, the more unstable the
experimental data quite well. However, at a nucleus becomes, which means that
closer look, especially for the light elements restructuring to a stable condition occurs more
there are some disagreements. This is because quickly (shorter half-life).
the nucleus can have closed proton and neutron
shells that are especially stable structures. Radioactivity and decay time
Critical numbers are 2, 8, 20, 28, 50, 82 and
126. This should be interpreted as if the nucleus The radioactive process, i. e. the decay of a
has eight protons (oxygen) there is a closed nucleus, is a statistical process. This means that
proton shell and 20 neutrons will give a closed the decay time of an individual radioactive
neutron shell, etc. Of special interest are nuclei nucleus can vary. But, for a large number of
with both a closed proton shell and a closed radioactive atoms (N) the same fraction (dN)
neutron shell e.g. 16O (Z=8, N=8) or 40Ca always decays during the same time (dt). We
(Z=20, N=20). It has long been known that can write this mathematically as
some nuclides (so called magic nuclides) were
especially stable, but not the reason why. In the dN = -λ N dt
close-up of Figure 6, these nuclides seem to where λ is called the decay constant and is the
have extra high binding energy in comparison probability for a nucleus to decay per time unit.
with the surrounding nuclides. We can integrate this equation to obtain
RADIATION FROM RADIOACTIVE N = No e- λ t
NUCLIDES
where No is the number of radioactive atoms at
Since radioactive material is the source of t=0.
radiation commonly encountered in a laboratory
(labeled compounds, calibration preparations), The number of decay per time unit (A = - dN/dt)
radioactive decay is reviewed fairly thoroughly is called radioactivity. The relation between the
in this section. radioactivity and the number of radioactive
atoms is then A = λ N. Replacing this in the
The concepts of nuclide and isotope are not formula above gives
related with whether the nucleus is stable or
unstable. There are stable (non-radioactive) A = Ao e- λ t
nuclides and isotopes, just as there are unstable where Ao is the radioactivity at t=0. Ao is also
(radioactive) nuclides and isotopes.
equal to λNo.
The number of neutrons and protons in the
Every radioactive decay is associated with a
stable nucleus obeys certain laws of symmetry. characteristic decay time. A common way to

11
express this is to use the half-life (T½) i.e. the The conversion factor from the old unit to the
time it takes to half the number of radioactive new unit is
atoms. If we insert this time in the decay
formula, we get the following relation between 1 Ci = 3.7 * 1010 Bq = 37 GBq (G = giga)
the half-life and the decay constant
Table 3 Conversion from Curie (Ci) to
Ao/2 = Ao e- λ T½ or Becquerel (Bq) and the prefixes in the SI-system

T½ = ln(2)/ λ Prefix Ci Bq Prefix


6 16 37 PBq P=peta
M=mega MCi 10 3.7*10
We can also write the decay formula as k = kilo kCi 103 3.7*1013 37 TBq T=tera

A = Ao 2-t/T½
Ci 1 3.7*1010 37 GBq G=giga
m = milli mCi 10-3 3.7*107 37 MBq M=mega
After one half-life the radioactivity is reduced to µ=micro µCi 10-6 3.7*104 37 kBq k = kilo
a half, after two half-lives to a quarter, after n = nano nCi 10-9 3.7*101 37 Bq
three half-lives to an eight, and after four half- p = pico pCi 10-12 3.7*10-2 37 mBq m = milli
lives to a sixteenth. Since 37 µBq µ=micro
f = femto fCi 10-15 3.7*10-5
( 1/2 )10 = 1/1024 ~ 10-3
a = atto aCi 10-18 3.7*10-8 37 nBq n = nano

one may use as a rule of thumb that ten half- Surface radioactivity is given in Bq /m2,
lives reduces the radioactivity by a factor radioactivity concentration in Bq /m3 and
thousand and 20 half-lives by a factor million of specific radioactivity in Bq /kg.
its initial value.
Radioactive decay
The half-life varies considerably for the various
radioactive nuclides. It can be fractions of Unstable nuclides have a surplus of energy
seconds, to hundreds of years or more. We compared with the surrounding nuclides. By
usually express the half-life in seconds (s), making a transformation within the nucleus, this
minutes (m), hours (h), days (d) and years (a). surplus energy decreases and the remaining
Note that a is the SI-unit for the mean year = nucleus will be more stable (the binding energy
365.24220 days. increases). There are many ways to rearrange
the nucleus to obtain a more stable nucleus. As
The unit of radioactivity in the SI-system is the an example, if we remove one neutron from e.g.
14
Becquerel, after the French physicist who in C we obtain the stable 13C. However, this is
1896 discovered natural radioactivity. The unit usually not a spontaneous process. As seen in
is abbreviated to Bq. Figure 6, one needs 5-8 MeV to remove one
nucleon. Even if the nucleus gains energy in the
1 Bq = 1 decay / s end it does not have access to the primary
energy needed to run this process. For very
Decay per second is also written as dps, after heavy nuclides the binding energy of the
the initial letters of the English words. An neutrons decreases and here we can find
alternative way to express radioactivity is dpm, spontaneous neutron emission. However, in
decays per minute. general this process is rare.

Curie (Ci) is an old unit for radioactivity that is


still used. From the beginning it was defined as
the radioactivity of 1 g radium, but was later
standardized to 3.7 * 1010 decays per second.

12
where ν is the neutrino. The bar above the
The β - decay ν indicates that the neutrino is an antiparticle
(antineutrino).
A process that can occur spontaneously is the
beta-decay. The number of nucleons is kept Symmetry is an important feature of nature. For
constant in the decay but a neutron is changed most particles, there is an associated antiparticle
into a proton, or vice versa. A particle of which has the same mass. Other properties like
positive (positron or β+ ) or negative charge charge will be the opposite. Charged particle-
(negatron or β− ) is removed from the nucleus antiparticle pairs can annihilate, i.e. the masses
along with energy (the β particle's rest mass + will disappear and the released energy will be
kinetic energy). converted to photons.
Formula 1b also fulfils another rule in particle
The β particle has the same weight and the physics that you can not create particles out of
same particle properties as an electron. In fact, it nothing. The number of heavy particles (the
can not, when it has lost its kinetic energy, be nucleons) is the same on both sides. The same is
distinguished from an electron. Still, we name it true for light particles like the electron and the
a beta particle to mark that it was created in a neutrino. Since particles and antiparticle cancel
nuclear process in the nucleus. We will below out the number of light particle is then also the
see that also electrons can be emitted in same on both sides (zero).
radioactive decays but they all will come from
the electron shells around the nucleus.
The decay of 14C is an example of beta minus
decay.
In a radioactive nucleus rich in neutrons, the
decay occurs as if a neutron (n) were converted 14
C(Z=6, N=8) -->14N(Z=7, N=7)+β−+ ν +energy (2}
to a proton (p):

n --> p + β− + energy (1a)

This reaction formula fulfils some criteria. On


both sides
1. the mass is about equal since the neutron
weight is the sum of the proton and the
electron weight
2. the charge is the same
3. the numbers of nucleons are the same

However, although the energy released per


decay is a constant it was found that the kinetic
energy of the beta particles varied between zero Figure 7 Decay scheme for 14C. The x-axis
and the decay energy. To explain the missing gives the number of protons in the nucleus and
energy the physicist Wolfgang Pauli 1930 the y-axis its energy content. By converting a
suggested an additional particle now known as neutron to a proton, the number of protons in
the neutrino. This uncharged particle with little the nucleus increases and at the same time it
or no mass was also emitted in the decay and becomes more stable. In the process, a
shared the decay energy with the beta particle. negatively charged beta particle is emitted.
25 years later the neutrino was experimentally
verified. The complete reaction formula for the The β+ decay can be regarded as a proton that is
beta decay can then be written as converted to a neutron.
n --> p + β− + ν + energy (1b) p --> n + β+ + ν + energy (3)

13
The β+ is now the antiparticle and cancel out the at the mass balance in equations (1b) and (3).
“real” neutrino to sum up light particles on the The mass of the neutrino can be neglected.
right side to be zero.
The mass of a neutron (Mn) is approximately
An example of the positron decay is: equal to the mass of a proton (Mp) and a beta
particle (Mβ). Equation (1b) is then in a mass
11
C(Z=6, N=5) -->11B(Z=5, N=6) +β+ +ν +energy (4} balance

Mn ≅ Mp + Mβ
11C
In equation (3) we have the mass of a proton on
Binding energy

Z=6, N=5
the left side and the mass of a neutron and a
beta particle on the right side. The only way to
∆E=2 MeV get the equation in balance is to add two beta
11B masses on the left side.
Z=5, N=6

5 6 2* Mβ + Mp = Mn + Mβ
Number of protons in the nucleus
According to the Einstein formula E = Mc2. The
mass of two beta particles corresponds to 1,022
Figure 8 Decay scheme for 11C. The x-axis MeV. In the 11C decay, a total energy release of
gives the number of protons in the nucleus and 2 MeV is available. Of this energy about 1 MeV
the y-axis its energy content. By converting a is taken to account for the extra mass created in
proton to a neutron, the number of protons in the decay, leaving 1 MeV to be shared by the
the nucleus decreases and at the same time it positron and the neutrino. In the decay scheme
becomes more stable. In the process, a in Figure 8, this is indicated by the broken
positively charged beta particle is emitted. arrow from 11C to 11B. The first vertical part
indicates the energy needed within the 11C
The radioactive nuclides used in laboratory nucleus to create the two electron masses. The
work usually have an excess of neutrons and diagonal part of arrow indicates the part of the
consequently emit their energy in the form a β- decay energy that is converted into kinetic
particle, which is ejected from the nucleus with energy of emitted particles.
a specific kinetic energy and decelerates in the
surrounding material. The decay energy

The kinetic energy of the emitted particles is The decay of 14C always releases 156 keV.
determined by the energy released in Other beta decays, i.e. 3H and 32P (see Table 1),
transformation of the nucleus. This may be are also associated with a unique energy release.
illustrated in an energy diagram or a decay
scheme. Figure 7 shows such a diagram for 14C Table 1 Decay parameters of some common
and Figure 8 for 11C. radionuclides.

The 14C-decay releases energy of 156 keV and Nuclide Half -life Residual Decay energy, Eo
the beta particle has a maximum kinetic energy T½ KeV
of 156 keV. The 11C decay releases 2 MeV but 3
H 12.26 a 3
He 18
the maximum energy of the β+ is only about 1 14
C 5 760 a 14
N 156
32 32
MeV. This is because two new electron masses P 14.3 days S 1710
are created in the β+ decay, which corresponds
to 1 MeV. We can understand this by looking The β-particles share this energy with the
neutrino randomly. The sum of the β−particle

14
and the neutrino kinetic energies are then equal Q-value
to the decay energy, Eo:
Each nuclear transition is characterized by a
Eβ + Eν = Eo fixed energy release or a Q-value. If the Q-value
is positive, surplus energy is emitted in the
In most beta decay the relative energy transformation. If the Q-value is negative,
distribution of the β-particles has the same additional energy is needed to enable the
shape (Figure 9). transformation. A spontaneous radioactive
decay has always a positive Q-value, whereas a
Relative number nuclear reaction in e.g. a nuclear reactor often is
of β -particles associated with a negative Q-value. The energy
released in a nuclear decay can be used to create
new mass or to give emitted particles kinetic
energy.

Pure beta decays go from the ground level of the


radioactive nucleus to the ground level in the
daughter nuclide. Three bodies share the decay
energy, the beta particle, the neutrino and the
recoiling rest nucleus. However, since the mass
of the recoiling nucleus is much larger than for
Figure 9 Energy spectrum of β −particles at the other particles, the energy of the recoil
radioactive β-decay. The energy is given on the nucleus is virtually zero. The total reaction
x-axis and the number of particles per energy energy is then statistically distributed between
bin on the y-axis. the beta and the neutrino, and the Q-value is
numerically close to (Eβ)max .
The distribution of energy to the particles is
determined statistics. The neutrino is an More generally, the decay may produce excited
uncharged particle of unknown, but very small, states in the daughter nuclide. The nucleons, i.e.
mass. It seldom interacts with matter and its the protons and the neutrons, create quantified
energy can in practice be ignored. Only the states of the nucleus. In the ground state,
β−energy, Eβ, can be transferred to the movements and energy contents are at a
surrounding material. The maximal beta energy minimum. In an excited or deformed state, the
and the mean beta energy can be written as: energy content is higher. The nucleus can
suddenly change its state, from a more excited
(Eβ)max = Eo E β ≈ Eo/3 state to a less excited or deformed state. In this
process electromagnetic photons, i.e. gamma
When calculating the maximum range of the rays, are emitted. The gamma rays carry away
β −particles, (Εβ)max is used. parts of the total decay energy. For each photon
(gamma quantum) emitted, the excitation
energy of the nucleus diminishes until it finally
Table 2 Maximum range of β -particles in air reaches the ground energy state.
and water.
Nuclide (Eβ)max Range (mm) An example is the decay of 60Co what can be
illustrated in the decay scheme below (Figure
(keV) Air Water
10). It is a beta minus decay emitting a beta
3H 18 6.5 0.007 particle with a maximal energy of 2.824 –
14C 159 300 0.3 2.506=0.318 MeV. The decay created an
excited daughter nucleus 60Ni. This excited
32P 1710 7700 7.9 levels emits a gamma of 2.506-1.332=1.173
MeV. A new excited level is created which also

15
emits a gamma of 1,332 Mev. If we ad up the common way to emit the energy in the excited
total energy emitted 0.318+1.173+1.332 we end state is by emitting a gamma ray. This is also
up with the Q-value of the decay (2.824 MeV). done in the 125I decay, but only in 7 % per
decay. The excited state, 35.5 keV, is very close
E n e rg y to the binding energy of the K-shell electrons
(M e V )
(33 keV). There is a probability that a K-shell
2 .8 2 4 electron is inside the nucleus due to the
2 .5 0 6
quantum mechanical nature of the electron.
1 .1 7 3 M e V There is also a probability that the excited state
gam m a
e m itte d
interacts with and transfers its energy to the K-
1 .3 3 2 shell electron. The transferred energy is higher
1 .3 3 2 M e V than the binding energy, and we obtain a
gam m a
e m itte d
monoenergetic electron, a conversion electron,
0 in 93 % of all decays.

Figure 10 A simplified decay scheme for 60Co. The excited state does not only interact with the
Only dominant radiation is included. K-shell but also with the L-shells and the M-
shells although the probability is less (the
Electron capture electrons are further away from the nucleus and
thus the probability of being inside the nucleus
The total energy release (the Q-value) in a is smaller). The energy of the conversion
positron decay has to be more than 1 MeV to electrons varies according with the formula
compensate for the increase in mass (see below
above). An alternative route of decay that does
not need this extra energy is electron capture. E = 35.5 keV - Eshell
Instead of converting a proton to a neutron and
a positron, the nucleus can attract an electron where Eshell is the binding energy of the shell
from the surrounding electron shells and join it from which the electron is emitted.
with a proton to create a neutron.
-
In the 60Co decay a small amount of conversion
e + p --> n + ν electrons is found as well. In fact, an excited
The effect is the same as in the positron decay; a state in a nucleus always has two ways to de-
proton is converted to a neutron. However, excite, either by emitting a gamma or by
since no beta particle is emitted the full excess converting the excited energy to a shell electron.
energy in the decay of the nucleus has to be The heavier the nuclide is, the higher the
given to the neutrino. Accordingly, in this type percentage of conversion electrons. A heavy
of decay monoenergetic neutrino particles are nucleus has many protons in the nucleus and a
emitted. The decay of 125I is a typical example strong attractive force on the shell electrons that
of this process (Figure 11 and 12). are close to the nucleus. Thus, the probability
that the excited state will interact with the
Although no beta particle is emitted the electron electrons increases.
capture is a variant of the beta decay since the
same physics is involved. There is then three Another important factor that affects the
branches of the beta decay, the beta minus, the probability of emitting conversion electrons is
beta plus and the electron capture. the energy of the excited level. Energies close to
the binding energy of the shell electrons give
Conversion electrons the highest probabilities.

The decay of 125I gives a new example of a The electron capture and the conversion
decay process ending in an excited state of the electrons both create holes in the electron shell.
daughter nuclide (Figure 11). As said above, the The process to fill these holes created a cascade

16
of events and the emission of electrons called energy is transmitted as X-rays or free electrons
Auger electrons and characteristic X-rays. that are dislodged from the atom (Auger
These processes are exemplified and explained electrons). This process is seen in more detail in
in more details in the decay of 125I. Figure 12.

Decay of 125I
125
I is a neutron deficient nucleus (the stable Electron
Decay of excited
125Te to ground
isotope of iodine is 127I). It decays to 100% by capture, EC
state by internal
electron capture since its Q-value of 186 keV is conversion
far to low for positron decay. The decay scheme Step 1 Step 4
is seen in figure 11 and shows that the decay in
100% yields an excited level in the daughter
Cascade of
nuclide Tellurium-125. This excited level of characteristic Conversion
35.5 keV is just above the binding energy of the X-rays electron
k-shell electrons (33 keV). This excited level is and Auger
de-excited by gamma emission but only in 7% Step 2 Step 5
per decay. More likely (93% per decay) is that a
conversion electron (energy 35.5-33=2.5 keV)
125Te
is emitted. 125Te in an in
excited state ground state

125I (Z = 53, N = 72)


Step 3 Step 6

Figure 12 Details of the 125I-decay


149 keV
Hence, the main radiation from 125I are K shell
EC (Electron capture)
X-rays of 27 keV and Auger electrons of low
125Te in an excited stage energy. The range of the electrons is
comparable to that of β − particles from 3H.
emitted gamma (7 %) or
35.5 keV Generally, the photon radiation is brought to a
conversion electron (93 %)
125Te (Z = 52, N = 73)
standstill practically by two millimeters of
brass, whereas several decimeters of water are
Figure 11 Decay scheme of 125I. The number of required.
protons in the nucleus is on the x-axis and the
energy content of the nucleus on the y-axis. By
capturing an orbital electron, a proton is Alpha decay
converted to a neutron and at the same time, the
nucleus becomes more stable. In the process, a Alpha emitting radionuclides are not commonly
neutrino is emitted and carries away the energy used in the laboratory and will only briefly be
which is formed. The new nucleus is formed in a treated here. The physics involved is different
excited state, but after a time it is de-excited to from the beta decay and can actually be
a more stable state. In this process, either a described as a tunneling effect through the
gamma ray or a conversion electron is emitted. potential barrier around the nucleus. The
following description is just to get an idea of
Both at the electron capture, when an electron is what this potential barrier is and the main
drawn into the nucleus, and at the forming of features of the decay.
conversion electrons, holes appear in the
electron shell around the nucleus. These holes Consider a free He++ ion outside a heavy
become filled by electrons from the outer shell. nucleus (see Figure 13). If you try to move the
In this process, the disparity in the binding He++ ion closer, an increasing Coulomb force

17
in-between occurs. This force tries to repel the Figure 13 Schematic view of the alpha decay
He++ ion until it is so close to the nucleus that The probability of decay is highly determined
the strong force starts to act. The He++ ion is by the thickness of the barrier, and the half-life
then trapped inside the so-called nuclear of useful radioactive sources varies from hours
potential, which is created in a balance between to many thousands of years. Alpha particles
the nuclear force and the Coulomb force. The appear in one or more energy groups that are,
barrier the He++ ion has to climb before it for all practical purposes, monoenergetic. For
reaches the attracting nuclear force is called the each distinct transition between initial and final
coulomb barrier. Its height depends on the nucleus, a fixed energy difference or Q-value
number of protons in the nucleus, but is in the characterizes the decay. This energy is shared
order of 5-7 MeV for heavy nuclei. between the alpha particle and the recoil
nucleus.
When particles are trapped in the nucleus they
loose their identity. However, the He++ ions The alpha particle energy correlates strongly
consist of two protons and two neutrons. Both with the half-life of the parent nuclide; the
the proton shell and the neutron shell are closed highest energies have the shortest half-lives.
and the He++ ion is a very stable combination of Above 7 MeV, the half-life can be expected to
nucleons. One might consider that this stable be less a few hours and. On the other hand, if
combination can exist in the nuclear “soup” in the energy drops below 4 MeV, the barrier
the form of a virtual α-particle. Also, these penetration probability becomes very small and
virtual α particles may populate different energy the half-life of the isotope will be very large.
levels in the nucleus. In the nucleus, the energy Probably the most commonly used source for
content is quantified and different quantified alpha particles is 241Am (T½=433 a) with an α-
energy levels exist. energy of 5.5 MeV.

In Figure 13, two such levels are indicated. In Because alpha particles lose energy rapidly in
the bound level 1, the virtual α particle cannot materials, alpha particle sources must be
escape the nucleus since it is bouncing against prepared in very thin layers. To contain the
an infinitely thick potential wall. In the bound radioactive material, typical sources are covered
level 2, however, a potential wall exists that with a metallic foil or other material that must
keeps the virtual α particle trapped but it is not also be kept very thin if the original energy and
infinitely thick. The α-particle may penetrate monoenergetic nature of the alpha emission is to
the wall by, what is known in quantum be preserved.
mechanics as, tunneling. Suddenly, the α-
particle appears in a materialized form outside Almost all naturally occurring alpha emitters are
the Coulomb barrier with energy corresponding heavy elements with Z >83. The principle
to the excited level. features of alpha decay can be learned from the
example of 226Ra:

He++ repulsive 226 Ra 222 4


+ coulomb bound level 2  Rn + He
+ force 88 86 2
The energy released (Q-value = 4.88 MeV) in
bound level 1 the decay arises from a net loss in the masses
MRa, MRn and MHe of the radium, radon, and
helium nuclei:
Q = MRa - MRn- MHe
Nucleus Z>80
heavy positivly
charged The general equation for the energy release in
the alpha decay is then

18
Qα=Mparent-Mdaughter-MHe Few lighter elements have naturally occurring
Spontaneous fission radioisotopes with that long half-live. The most
important from the standpoint of human
The fission process splits the nucleus into two exposure is 40K, which is about 0.01% abundant
parts of almost equal size. In the process free and has a half-life of 1.26 x 109 years (Figure
neutrons are also emitted. Fission fragments are 14). The nuclide can decay by β- emission
used to calibrate and test detectors intended for (89%), EC (11%), or β+ emission (0.001%).
general application in heavy ion measurements. The maximum β- energy is 1.314 MeV. This
isotope is an important source of human internal
The most widely used example is 252Cf, which radiation exposure, because potassium is a
undergoes spontaneous fission (3% per decay) natural constituent of plants and animals.
and alpha decay (97% per decay) with a half-life
of 2.65. Another important, naturally occurring
radioisotope is 14C, used in carbon dating. It is
Each fission gives rise to two fission fragments, produced by the bombardment of nitrogen in the
which, by the conservation of momentum, are atmosphere by cosmic rays, causing the reaction
emitted in opposite directions. Because the 14
N(n, p)14C. Its half-life is 5730 yr. The
normal physical form for a spontaneous fission radioisotope, existing as CO2 in the atmosphere,
source is a thin deposit on a flat backing, only is used by e.g. trees and becomes fixed in their
one fragment per fission can escape from the structure through photosynthesis. When an tree
surface, whereas the other is lost by absorption dies the incorporation of new 14C atoms stop
within the backing. The spontaneous fission of and the number will start to decrease due to the
252
Cf also liberates a number of fast neutrons. radioactive decay. By, in a sample, comparing
the number of 14C with the number of stable 12C
Natural radioactivity one can then calculate the time that has passed
since the tree was cut and used for e.g. building
Some heavy elements (232Th, 235U and 238U) has a house. Thus, the age of such objects can be
such long half-lives (109-1010 a) that they have determined. The atmospheric testing of nuclear
survived the time since the where created in the weapons has significantly added to the world's
Big Bang and are still to be found in appreciable inventory of 14C.
amounts. In there decays they produce a series
of more short-lived radioactive daughters. Some DATA ON RADIOACTIVE NUCLIDES
of these daughters we are very much aware of
e.g. the alpha emitter Radon-222, which is a
There are several books available, with all
noble gas and that can penetrate into our
relevant information on decay-time, type and
house
number of particles emitted per decay, energy
per particle, etc. However, the fastest and
40K
1461 keV
EC (11 %) cheapest way to obtain information today is by
(T½=1.28 109 a)
the Internet. One good site is
β- (89 %)
1312 keV http://www.nndc.bnl.gov/nudat2/indx_dec.jsp

β+ (0.001 %) 40Ca
Below there is an example of the 125I decay and
482 keV with some explanations.

40Ar

Figure 14 Decay scheme for 40K

19
20
CHAPTER 3
INTERACTION WITH MATTER
energy exceeds the binding energy and we
Matter is composed by a number of different obtain a free electron, ionization. The same
atoms in chemical combinations. A piece of thing is true for an electron or a beta particle
iron is in a macroscopic sense solid and difficult that will experience a force of the same strength
to penetrate. However, at the dimensions of but repulsive.
ionization radiation, matter is rather empty and
without any major mechanical obstructions to
prevent radiation to pass.

Consider a neutron entering a piece of iron. The


iron atom has a dimension of 10-10 meters but
the iron nucleus is only 10-15 meters, and the
neutron itself is even smaller. The electrons
have no known extension and since the neutron
has no charge it will not feel any electric forces.
The neutron will probably pass through a thin
iron foil without noticing the material.
However, if the foil grows thicker it will
increase the likelihood that the neutron will hit
one of the atom nuclei, cause a nuclear reaction
and transfer its energy to the matter.

If we exchange the neutron for a proton, a


dramatic change occurs. The proton will
experience that matter is full of charge. Each Figure 2 An α-particle transfers so much
orbit electron in the vicinity of the proton will energy that an ionization occurs. Since the α-
feel a force of attraction, the Coulomb force particle and the orbital electron have opposite
(Figure 1). polarity, there is an attractive in-between.

electron
mass m
charge -q

distance r
closest
distance d
F = q*q/r 2

proton
mass M
velocity v
charge +q

Figure 1 A proton that enters into matter


experiences an attractive force from all the Figure 3 The electrical field of a beta particle
orbit electrons in the vicinity. collides with that of an outer orbit electron. So
much energy is transferred that the orbital
We can say that we have a collision between electron is dislodged (ionization). Since the
two electrical fields and in which energy is incoming electron and the orbital electron have
transferred to the orbit electron. Sometimes the same polarity, a repulsive force is created.

21
However, the electron and the proton differ straightforward to the end of their range,
considerably; they have different masses and deviating only slightly from a straight line.
different speeds. An electron with the energy of Thus, heavy, charged particles have a well-
1 MeV has a speed close to the speed of light defined range and monoenergetic particles
(3*108 m/s). The time it will spend in the travel about the same distance in a given
vicinity of an atom and an orbit electron will be material.
10-18 - 10-19 seconds. The force will act during a
very short time and the impulse ∫F*dt When heavy, charged particles are obstructed
transferred from the incoming electron to the their speed diminishes. Consequently, they
orbit electron will be small. A proton of the spend a longer time close to the next orbital
same energy (1 MeV) will have a speed 20 electron and transfer more energy to it. Then,
times lower than the electron. The time spent in the number of ion pairs formed per unit of
the vicinity of the orbit electrons will be length increases (see Figure 5).
correspondingly longer and the transferred
impulse larger. From this simple consideration
we can draw two important conclusions that are
true for charged particles:

1. The heavier the particle is, the more energy


is transferred per collision.
2. The lower the kinetic energy of the particle
is, the more energy is transferred.

The expression "ionizing radiation" includes


many types of "radiation". The most important
kinds of radiation are classified according to
how they transfer energy to matter in the
diagram below (Figure 4). Figure 5 Deceleration of an α −particle in air.
The α -particle at high energy has high speed.
IONIZING RADIATION The time it spends near each orbit electron is
short; hence, the transferred energy is small
and the probability for ionization is relatively
small. When the energy diminishes so does the
Electro-magnetic Particles
radiation, photons (protons, electrons, velocity. The probability of ionization increases
(X-rays and gamma) alpha and neutrons) and a typical ionization peak at the end of the
particle track (the Bragg peak) occurs.

Uncharged particles Charged particles If the incoming charged particle is an electron,


(neutrons) (protons, electrones the rest mass of this particle is the same as for
and alpha)
the orbital electron. When two particles with the
same mass collide, a great deal of energy
(almost all) can be transferred in a direct impact
Light, charged Heavy, charged and the incoming particle will come to a
particles particles
(electrones) (protons and alpha) complete stop. For two electrons we have a
problem; they are identical. We cannot with any
Figure 4 Schematic subdivision of the different means know which one is the incoming particle
types of ionizing radiation. and which one is the orbital electron. For
practical reasons, therefore, we define the
The direction of heavy, charged particles is electron with the highest energy after the
scarcely affected by collisions with orbital collision to be the incoming particle.
electrons. They continue to travel mainly

22
At each collision, light charged particles can Bremsstrahlung
change direction very markedly and by repeated
large directional changes can even be scattered When electrical charges are accelerated or
backwards to the direction of their origin decelerated, they can emit electromagnetic
(Figure 6). Hence, the range of electrons differs radiation. We call this roentgen, continuous X-
considerably. However, a maximum range can rays or bremsstrahlung. Synchrotron light is of
be given (Figure 7). the same nature.

At these collisions, the energy that is transferred


is frequently sufficient to ionize an orbital
electron. The energy might even be so high that
the free electron, in turn, can cause new
ionization. Hence, part of the energy of the
primary charged particles is deposited at some
distance from the original track of the particle.
Secondarily formed electrons, δ−particles, can
give rise to further ionization tracks.

Back-scattered Figure 8a An incoming electron feels the


electron
Coulomb force from the nucleus and is
deflected. The electron speed and kinetic energy
Bremsstrahlung
2 0 4 0 6 0 8 0 1 0 0
S e r i e s 1
decreases in the process - the electron
decelerates. The difference in kinetic energy
between in-going and out-going electron is
emitted as an X-ray photon.

10
Coulomb collision
Energy loss (MeV/g*cm2)

Figure 6 Electrons, which penetrate material,


collide with orbit electrons of the same mass as
the incoming particles. They can effect marked 1.0
directional changes including scattering in the
Water
direction opposite to the original course. Lead

0.1

Bremsstrahlung
0.01
0.1 1.0 10 100
Electron energy (MeV)
Figure 8b Loss of energy by electrons per track
length (expressed in mass per unit area) as a
function of electron energy. A heavy and a light
material show how the atomic number of the
material influences the two ways by which
Figure 7 A schematic figure illustrating the electrons transfer energy to material.
range of monoenergetic electrons. Most of the
electrons are absorbed within a distance
Heavy particles lose only little energy per
shorter than the maximal range.
collision and are only decelerated in small steps.

23
Thus, for heavy particles the loss by and tabulated. Stopping power data for electrons
bremsstrahlung is of little importance. in lead and water are given in Figure 8.
Electrons, on the other hand, often lose a great Stopping power for water is given for electrons,
deal of their energy by deceleration in the strong protons and α- particles in Figure 9.
fields of heavy atoms; hence, the loss by
bremsstrahlung is of more importance. The Linear energy transfer, LET
result of continuous radiation increases with the
electron energy and atomic number of the The energy that charged particles lose by
absorber. For high electron energies and heavy deceleration is transferred to the irradiated
elements (e.g. lead), the highest X-rays yield is material in different ways. The energy can be
obtained (Figure 8b). deposited more or less concentrated around the
primary particles' track. Direct ionization results
Stopping power in energy deposition in the vicinity of the
particles' track. However, secondary particles,
Charged particles gradually lose their energy such as bremsstrahlung and neutrons (in nuclear
(they are decelerated) by many close reactions) with no charge, may deposit their
"collisions" with orbital electrons in the energy far away from the particle track. To
irradiated material. The ability of different understand the effect of radiation on living
materials to decelerate charged particles varies material, it is also important to have a measure
considerably depending on the charge and of how densely the radiation's energy is
energy of the charged particles, and the density deposited around the particles' track. Hence, the
and atomic number of the irradiated material. concept Linear Energy Transfer (LET) was
The deceleration capacity attributed to a given introduced. It denotes the amount of energy the
material is denoted by how much energy (∆Ε) is specified particle emits per unit track length and
expended in a given length (∆l) of the charged that is distributed near it.
particle’s track.
DNA double helix
Stopping power = (∆Ε) / (∆l)
cylinder diameter 2r
STOPPING POWER AS A FUNCTION OF
PARTICLE ENERGY
5.3 MeV α - track
10000
Stopping power (MeV/cm)

Figure 10 Illustration of the ionization pattern


1000
around an α-particle track. Each black spot
electron represent one ionization. Around the track, the
100 proton
alfa
ionization density is highest. The limited
stopping power or the linear energy transfer,
10
LETr, is given as the energy per track length
deposited inside a cylinder with the radius r.
1 The radius r can vary, which gives different
0.01 0.1 1 10
Particle energy (MeV) LET-values. Often, the radius r is set to be the
diameter of the DNA double helix. Instead of
Figure 9 Stopping power in water for electrons,
giving the radius length in nanometers, it is
protons and alpha particles as a function of
given as the energy of an electron with the
energy.
range r.
Stopping power is a parameter that describes the
When living tissue is irradiated, LET usually
material’s ability to stop charged radiation. For
denotes the energy absorbed per unit length
different combinations of particles and material,
around the particles' track within a cylinder. The
the ability to stop the radiation can be calculated
diameter of this cylinder is chosen to be in the

24
same order as a biological critical structure, e.g. Photon interactions
the cell nucleus or the DNA-molecule.
Non-charged particles such as photons and
High LET and low LET neutrons do not feel the Coulomb force and
cannot transfer their energy to matter this way.
It is of interest to understand how many However, in occasional interactions they may
ionization are created in the DNA molecule of transfer all or much of their energy to charged
different types of radiation. A rough estimate is particles in the irradiated material. Thus, these
made in the following. secondary charged particles (photons give rise
to secondary electrons and neutrons chiefly to
The stopping power for electrons, protons and secondary protons) can continue to ionize
alphas (see Figure 9) is recalculated and through the charge interaction. Since the
expressed in number of ionization/nm (Figure ionization of the primary interactions is small
11). It is seen that for electrons of all energies compared with the ionization of the secondary
the number is below 0.1 ionization per nm. The radiation, we sometimes refer to photons and
more correct use of LET, not stopping power, neutrons as indirect ionization radiation. Only
gives an even lower number. Since the DNA the interaction of photons is described here.
molecule has a diameter of 2 nm, this indicates
that it is very unlikely that electrons of any Regarding the interaction of photons with
energy will cause two ionizations so close that a matter, three processes can be distinguished.
double strand break occurs. The photoelectric effect implies that a bound
electron, mainly a K-shell electron, absorbs the
High energy protons (E > 10 MeV) have the photon in one of the innermost atom shells. This
same pattern but low energy protons with electron, the photoelectron, obtains a kinetic
energies <1 MeV yield more than 1 energy that corresponds to the photon energy
ionization/nm. Alpha particles over a wide minus the electron's binding energy in the shell.
range of energies also yield more than 1 An electron from one of the outer shells then
ionization/nm. If the probability of causing a fills the “hole” in the electron shell, and
double strand break is low, we have low LET characteristic X-rays (or Auger electrons) are
radiation whereas if the probability is high, high emitted. The energy balance in the transfer is
LET.

IONIZATION DENSITY Auger electron


Characteristic
10 X-ray

Incoming photon
1 Energy h* ν
0.01 0.1 1 10 Photo electron
Ions/nm

electron
0.1 proton
Figure 12 The photoelectric effect. A photon
alfa interacts with a K-shell electron. All the
photon's energy is used to displace the electron
0.01 and give it kinetic energy. When the "hole" of
the electron is filled with an electron from an
0.001
outer shell, energy is liberated as a photon
0.01 0.1 1
Particle energy MeV
10 (characteristic X-radiation) or is transferred to
another orbit electron (Auger electron) that
leaves the atom.
Figure 11 Stopping power in water given as
number of ionizations per nanometer for hν = Εel + Βe
electrons, protons and alpha particles and as a
function of particle energy.

25
where hν is the photon energy, Eel is the energy, which is transmitted to the Compton
electron's kinetic energy and Be is the binding electrons, is absorbed within a tiny volume
energy. around the region where the process occurs.
The amount of energy transmitted to the
The photoelectric effect is not significant in air scattered photons, however, is usually not
and soft tissue (which includes material of low absorbed in the immediate vicinity. The photon
atomic number) for photon energies over 200 can cover a considerable distance before being
keV. absorbed.

In the Compton effect, the electron binding The pair production effect (Figure 14) signifies
energy is always insignificant in relation to the that the photon interacts with the electrical field
photon energy (Figure 13). The Compton effect in the neighborhood of an atom's nucleus. The
can be interpreted as an impact process in which photon disappears and its energy is converted to
the photons collide with a free electron. an electron and a positron (see Figure 15). The
electron mass is equivalent to 0.511 MeV. Since
two electron masses are created the incoming
photon must have energy of at least 1.02 MeV.
Surplus energy is given as kinetic energy to the
electrons.

Incoming photon e-
Energy h*ν
Recoil
Figure 13 Compton effect. A photon interacts e+
with an electron in an outer orbit. Only part of
the photon's energy is used to dislodge the
electron and deliver kinetic energy. The Figure 14 Pair production. The incoming
remaining energy is transmitted to a new photon energy is so great that it can create two
photon that has a different direction and less new particles, an electron and a proton. The
energy than the incoming photon. entire energy of the incoming photon is
required to create the mass of these particles
Hence, in this process the main electrons (2*511 keV) and give these particles their
involved are the outer, loosely bound electrons. kinetic energy.
The physical laws of impact apply, since the
system's total energy and momentum are the A positron can be said to be a positive electron.
same before as after impact. This results in a It has the same mass as an electron but a
photon with lower energy and indeed greater positive, not a negative unit charge. On
wavelength. The energy and the angle between decelerating in matter, the positron behaves in
the scattered photons and electrons can be the same way as the electron except that the
calculated by using the laws on conservation of positron at the end of the track attracts an
energy and impulse. electron and is "annihilated" by it. This means
that the energy that is equivalent to two electron
The probability of “Compton scattering" per rest masses (2*511 keV) is converted to two
electron of per unit mass is about the same for 511 keV photons which are emitted in two
all material, but it decreases somewhat with directly opposite directions. This radiation is
increasing photon energy. The Compton effect called annihilation radiation.
is significant for photon energies between 100
keV and 10 MeV. Part of the incoming photon

26
Pair production and annihilation are thus two energies of the inner shell electron. Just below,
diametrically opposite processes. In pair the photon energy is too low to interact and the
production, a photon is lost and two light electrons in this shell do not contribute at all to
particles are formed, a negatron (ordinary the attenuation processes. Just above, the
electron) and a positron. Both of these particles probability of photon absorption is very high.
are decelerated whereupon the positron is
annihilated by an orbital electron during the 105
emission of two 511 keV photons.

Probability of the
photo effect (m-1)
100 104
Photoelectric Pair
80 effect production
Atomic number

103
60

40
Compton 102
0 100 200 300 400
20 effect Photon energy (keV)

0
0.01 0.1 1 10 100 Figure 16 The probability for the photo effect in
Photon energy (MeV) lead as a function of photon energy. Some
discreet jumps in the curve are seen at energies
Figure 15 Dependent on the energy of the corresponding to binding energies of the orbit
photons and the atomic number, the probability electrons.
of different photon interactions varies. In the
figure is shown a special case when the Heavy elements, where the binding energy of
probability for the Compton effect is equal to the K-shell electrons is high, are therefore likely
the probability of the photo-effect (the curve to to interact with high-energy photons. For
the left) and when the probability for the example: In lead (atomic number = 82) the
Compton effect is equal to the probability of photoelectric effect dominates for photons with
pair production (curve to the right). energies of < 0.5 MeV, the Compton effect at
photon energies > 0.5 MeV and < 5 MeV, and
The relative significance of the different pair conversion for photons with energies >
processes can be denoted as functions of photon 5MeV.
energy and absorbing material. The
combinations of energy and atomic number by Attenuation of photons
which the probability of obtaining the
photoelectric or the Compton effect are equally For photons, as for neutrons, matter looks
large (Figure 15). empty. Photons can pass a long way through a
piece of material before they interact. They may
For water and soft tissue with "effective atomic even penetrate a piece of matter without any
numbers" lower than 10, the photo-electric interaction. However, when the photons interact
effect dominates for photon energies < 100 they lose all or most of their energy, which is
keV, the Compton effect for > 100 keV and transferred to charged particles.
< 10 MeV, and pair production for photon
energies > 10 MeV. The formula for the attenuation (damping) of
photon radiation in material is:
For low photon energies and for high Z material N = No e -µ x
where the photoelectric effect dominates,
absorption discontinuities occur (Figure 16) at where
photon energies equivalent to the binding

27
N is the number of non-scattered photons that exponential attenuation and there is always a
leave the absorber certain finite probability that some photons will
No the number of photons incident on the penetrate even thick material. What we can
absorber and calculate is the fraction of photons that will
µ is the linear attenuating coefficient (m-1), interact in a certain thickness of irradiated
which is a measure of probability per unit material.
length for a photon to interact
x is the thickness of the absorber. The linear attenuation coefficient (µ) is the sum
of the photoelectric effect (τ), the Compton
effect (σ) and pair conversion effect (κ). The
photoelectric effect dominates at low photon
energies, the Compton effect for moderate
energies and the pair conversion effect for high
photon energies. The contributions of different
attenuating coefficients in aluminum are shown
in Figure 18.

The thickness of the absorber that decreases the


Figure 17 A narrow beam of photons, No, hit a number of incoming photons by a factor of two
piece of material with thickness x. Some is of special interest and has a special name, the
photons are absorbed or attenuated out of the half layer value (HLV). It is defined as
beam. The number of photons hitting the
detector is then N. 1/2 No = No e −µ HLV

104
It is related to the attenuation coefficient in the
following way
Probability for different photon

103
interaction effects (m-1)

HLV = ln 2/µ = 0.693/µ


102 µ=σ+τ+κ

So far, only the linear attenuating coefficient


10
has been mentioned. It is often more convenient
to deal with attenuation coefficient per unit
σ τ κ
1
σ
mass, which is given by µ divided by ρ, the
density of the material. This gives the mass
0.1 attenuation coefficient, which is also denoted by
0.1 1 10 100 1000
Photon energy (MeV) µ/ρ.

Figure 18 The probability in aluminum for the When using the mass attenuation coefficient per
three main ways in which photons interact as a unit mass, it is necessary to multiply by both the
function of photon energy. The different effects thickness of the material and its density to
are denoted. obtain a non-dimensional exponent in the
τ = photo effect expression.
σ = the Compton effect
N = No e - µ/ρ ∗ ρ · x
κ = the pair production effect
µ = the sum of the three separate effects gives
where
the total attenuation coefficient.
µ has the dimension m-1, ρ kg/m3. (µ/ρ) has the
Unlike charged particles, photon radiation has
dimension m2/kg and x m, hence it follows that
no fixed range or maximum range. The
the exponent has no dimension. Variations of
interaction of photon radiation leads to an

28
the mass attenuation coefficient for lead,
copper, water and air are illustrated in Figure
19.

lead
Mass attenuation coefficient (m2/kg)

10-1

copper

water
10-2 air

10-3
0.01 0.1 1 10
Photon energy (MeV)

Figure 19 Mass attenuation coefficients for


different materials.

There are other types of attenuation coefficients


besides the mass and linear coefficients. An
example is the mass energy absorption
coefficient, µen/ρ. Scattered photons (X-ray,
Compton and annihilation photons) can travel
some distance from their production site before
donating their energy in the form of secondary
electrons. They may even escape the absorbing
material completely. Secondary electrons
(photo-, Auger-, Compton-, and pair-electrons),
however, expend their energy in the immediate
vicinity of the primary interaction and
contribute to the dose absorbed in this region
(absorbed dose is defined in the next section).
To calculate the dose absorbed by these charged
particles, the mass energy absorption
coefficient, µen/ρ can be used. It is the product
of the mass attenuation coefficient µ/ρ and the
fraction of the photons' energy f, which is
converted to secondary electrons that lose their
energy locally.

µen /ρ = (µ/ρ) f

It is evident by definition that µen/ρ is less than


µ/ρ (µen /ρ < µ/ρ).

29
CHAPTER 4
Dosimetry
The absorbed dose D has the unit gray (Gy)
Absorbed dose equal to 1 J per kg. An old unit is

Ionization radiation carries energy. In different 1 rad = 0.01 Gy


processes this energy is transferred to matter.
Some of this energy is deposited locally; some One may reflect on the size of the unit Gy. A
travels away and might even escape the whole body absorbed dose of 4 Gy to man is a
irradiated mass volume. Since some ionizing lethal dose, but raises the body temperature by
radiation can participate in nuclear reactions, only 0.001 oC. Obviously, 1 Gy is a rather large
energy may also be created (or lost) inside the unit. Local absorbed doses of several Gy are
irradiated volume. given in radiation therapy whereas in laboratory
work and in radiation protection, mGy and µGy
are more commonly used.
Ein ∆m Eout Relative Biological Effect, RBE

The absorbed dose defined in equation 3 is a


macroscopic unit representing the mean energy
to a rather large mass volume. It does not
Figure 1 Absorbed energy ∆E in a mass consider the stochastic ionization pattern of the
element ∆m energy delivery. However, low LET and high
LET ionizing radiation can for the same
Generally we may write absorbed dose cause quite different biological
effects due to their different ability to cause
∆Ei = Ei,in -Ei,out +Qi (1) single and double strand breaks. Another
concept, Relative Biological Effectiveness
where (RBE) is introduced to describe this situation.

Ei,in = energy of an incoming ionizing particle


(excluding rest mass) α
Number of chromosome abberations

8
Ei,out = sum of energies of all ionizing particles, γ
created by incoming particle, leaving the place 6
of interaction (excluding rest mass)
4
Qi = accounts for changes in the rest mass
energy of the nucleus and of all elementary
2
particles involved in the interaction.
Dα Dγ
The energy, ∆E imparted to a volume of matter 0
1 2 3 4
with weight ∆m (this volume is regarded as the Absorbed dose (Gy)
place of interaction) is then Figure 2 A comparison of two different
radiation qualities, α and γ. Photon radiation is
E = Σ Ei (2) always used as the reference since all the
produced electrons are low LET-radiation.
and the specific energy imparted, which is also
called absorbed dose, is A chosen biological system is irradiated and a
biological effect is measured (in Figure 2 this is
D = E/m (3) the number of chromosomal aberrations). Two
qualities of radiation are used to irradiate the
system (in Figure 2, α and γ) so that the same

30
biological effect is obtained. The relative values (WR) that can be used for radiation
Biological Effectiveness (RBE) is then defined protection purpose is shown in Figure 3.
as a ratio between the absorbed doses delivered
If we multiply the absorbed dose, D, with WR
RBE = Dγ/Dα (4) we obtain a new dose variable, the dose
equivalent, which includes both the energy
Photon irradiation (X-rays > 2-3 MeV or 60Co- concentration of the radiation and also its
gamma rays) is usually used as a reference. This capability to cause late biological effects.
is because photons produce a wide range of
electrons in a reproducible way. Electrons of all H = WR * D (5)
energies can be considered as low-LET
radiation. Hence, one should expect RBE-values The unit for the dose equivalent is Sievert (Sv)
close to one for all photon irradiation. This is if absorbed dose is expressed in Gy.
also found to be true, maybe except for very low
X-ray irradiation since low energy electrons (< Effective dose
100 keV) have a somewhat higher stopping
power than higher electron energies (> 100 The radiation sensitivity of different organs in
keV). the body varies. Tissues containing proliferating
cells, such as the bone marrow and the intestine,
Dose equivalent are generally more radiation-sensitive than e.g.
the liver. If the radiation dose is unevenly
The RBE-values vary with radiation quality and distributed in the body, we need to consider this
chosen biological system. In radiation therapy, when risks of biological damage are estimated.
where acute radiation effects are expected, the For radiation protection purposes, relative
RBE value has to be carefully measured for values for different organs are given below
each situation. The biological effects of (Table 1). These weight factors mainly relate to
neutrons, protons and heavy ions have to be the ability of ionizing radiation to create late
compared with established photon and electron effects such as radiation-induced cancer.
therapy not just in one biological system, but in
many. In radiation protection where radiation Table 1 Weighting factors recommended by
doses are lower and mainly late effects (such as ICRP 30 for calculation of effective dose.
the risk for induced cancer) are expected, we
may generalize somewhat more. Organ Weighting
Factor, WT
20 Gonads 0.25
Quality factor, WR

Breast 0.15
15 Red marrow 0.12
Lung 0.12
10 Thyroid 0.03
Bone surface 0.03
5
Remaining 0.30
01 10 100 1000 We can then define the effective dose as
Stopping power in water (keV/µm)
He = Σ WT * WR * Dorg (5)
Figure 3 The quality factor WR as a function of
stopping power in water where we sum over the different organs. The
unit for the effective dose is also Sievert (Sv) if
The measured RBE-values vary from 1 to 20 as the absorbed dose, D, is expressed as Gy. The
a function of the stopping power of the calculation of the effective dose is illustrated in
radiation. A weighted curve of measured RBE the following example.

31
Example 1. We want to compare the risk of late Dint (Gy) = 1.6*10-13 *n E β /m (7)
effects of two persons exposed to radiation of
different quality and distributions. One is
exposed to 1 Gy of gamma rays, whole body where E β is the mean energy in MeV of the
and the other to 1 Gy of alpha particles by beta energy emitted per decay, and n is the total
inhaling radon gas. number of decays in the mass m.

Type of γ α Comments For radioactive sources, the absorbed dose rate,


irradiation not the absorbed dose is of interest. Eq 7 can
Absorbed easily be rearranged to
dose (Gy) 1 1
WR 1 20 WR for α is 20 dH/dt = 1.6*10-13 * WR * n/h * E β /m (8)
WT 1 0.12 Ra-gas gives a local
irradiation of lung where

Effective 1 2.4 The Ra-exposed person dH/dt is the dose equivalent rate in Sv/h
dose (Sv) has a 2.4 higher WR is the weight factor for radiation quality
probability to express n/h is the number of absorbed particles per hour
late radiation effect E β is the mean energy in MeV per particle and
m is the mass unit in kg.
The effective dose is a theoretical concept used
to calculate risks of various types of irradiation The weight factor WR is 1 for radioactive
situations. In practical radiation protection work decays emitting only beta, electrons and
one need to define other measurable variables. photons.
Radiation protection instruments are calibrated
in a sphere (tissue equivalent material) of A more general treatment of the radioactive
diameter 30 cm. They are placed 10 cm or 0.07 decay is given in the following.
cm from the surface to give
Consider a radioactivity concentration A in an
Hp (10) = individual deep dose equivalent organ. The radioactive decay emits particles of
Hs (0.07) = individual surface dose equivalent different types i = 1, 2, 3 … The mean energy of
particle type i emitted per decay is then
Relation between dose and radioactivity
∆i= k ni Ei
The energy emitted in radioactive decay can, of
course, be expressed in units of Gy and Sv. where
However, since the radioactivity is usually
known in Bq and the energy of emitted particles k is a unit dependent constant
in MeV, we need to relate the absorbed dose ni is the mean number of particle i per decay
from radionuclides in these units. Ei is the mean energy of particle i per decay

The relation between the two energy units Joule ∆i has the dimension energy and can by the
and eV are proper choice of k be expressed in joules (J).
However, usually the dimension is given as
1 eV = 1.6 * 10-19 J (6)
(kg * Gy)/(Bq * h) or (g * rad) / (µCi * h)
From this relation, we can derive a simple
formula for particle irradiation, such as pure The time-integral of the radioactivity
beta-emitting radionuclides concentration in the organ, ∫A(t)dt has the

32
dimension Bq/kg * h. If we multiply the time detailed calculation of integrated radioactivity
integral with ∆i we get the absorbed dose of that concentrations in different organs.
organ if the absorption of the emitted particle is Mathematical standard phantoms have been
100 % localized in the organ. derived which allow the use of Monte Carlo
calculation techniques.
Sources

Figure 4 Distributed radioactivity in the body Figure 5 A MIRD phantom with standardized
gives a rather complicated irradiation pattern. organ sizes and positions. Each organ is given
a mathematical definition that makes it easy to
The radioactivity gives radiation that is locally represent it in a computer. The ∆i-values can be
absorbed (low energy beta, electrons and X- calculated for each radionuclide using nuclear
rays) and radiation that is partly locally spectroscopic data. The fraction of absorbed
absorbed (gamma, high-energy beta and energy per organ and the fraction of energy
electrons). This radiation may irradiate other absorbed in other organs can be calculated as a
organs (Figure 4) or may completely escape the function of particle type and energy using
body. A complete absorbed dose calculation Monte Carlo techniques. From physiological
after the administration of radioactivity in vivo models, the time integral radioactivity curves
also has to consider the kinetics of the labeled can be calculated for each organ. The dose
compound and its metabolism and excretion. equivalent can be calculated for each organ
and the effective dose by summing over all
If the emitted particle is not locally absorbed we organs.
can give a factor fi (the fraction locally
absorbed) by which we multiply the ∆i -value. Using such techniques, one can rather precisely
In the body, the situation becomes rather estimate the effective dose corresponding to a
complicated. given radioactivity of a certain radionuclide.
However, one has to remember that the MIRD
To facilitate dosimetry calculations in nuclear concept still uses a number of approximations,
medicine and in radiation protection, a such as standardized organ geometry and a
dosimetry concept (MIRD) has been developed. homogeneous distribution of the radioactivity in
MIRD stands for Medical Internal Radiation each organ.
Dose. An expert committee has agreed on
certain standard ways to express and calculate
data. Measured physiological and kinetic data
from human studies are used as input into
theoretical kinetic models, which allows a

33
approximate answers to radiation protection
Table 2 ALI values (Bq) for some common problems and to plan experiments. A number of
radionuclides. The ALI-values correspond to an simple relations have been derived from
effective dose of 50 mSv. equation 8 for different, typical irradiation
situations.
Nuclid ALI Nuclid ALI Nuclide ALI
3
H 3*109 65
Zn 1*107 129
I 2*105 Dose rate on the surface of a beta source
14
C 9*107 69m
Zn 2*108 130
I 1*107
18
F 2*109 67
Ga 3*108 131
I 1*106 The irradiation situation is defined in Figure 6.
22
Na 2*107 68
Ga 6*108 132
I 1*108
24
Na 1*108 73
As 6*107 129
Cs 9*106
32
P 1*107 74
As 3*107 130
Cs 2*109
33
P 1*108 75
Se 2*107 131
Cs 8*108
35
S 8*107 76
Br 1*108 134
Cs 3*106
36
Cl 9*106 77
Br 6*108 134m
Cs 4*109 C Bq/g Dose rate, Hβ/h
38
Cl 6*108 82
Br 1*108 137
Cs 4*106 on the surface
42
K 2*108 81m
Rb 9*109 131
Ba 1*108
43
K 2*108 81
Rb 1*109 133m
Ba 9*107
45
Ca 3*107 86
Rb 2*107 135m
Ba 1*108 Figure 6 A thin-walled tube contains a
47
Ca 3*107 88
Rb 7*108 140
La 2*107 radioactivity concentration of C Bq/kg. What is
51
Cr 7*108 89
Rb 1*109 169
Yb 3*107 the surface dose rate Hβ/h?
52
Mn 3*107 85m
Sr 8*109 192
Ir 8*106
52m
M 1*109 85
Sr 6*107 198
Au 4*107 We use equation 8
54
n Mn 3*107 87m
Sr 1*109 197
Hg 2*108
56
Mn 2*108 89
Sr 5*106 203
Hg 2*107 dH/dt = 1.6*10-13 * WR * n/h * E β /m
52
Fe 3*107 90
Sr 1*105 201
Tl 6*108
55
Fe 7*107 90
Y 2*107 204
Tl 6*107 WR is equal one for beta particles, E β is
59
Fe 1*107 99
Mo 4*107 210
Pb 9*103
56
Co 7*106 99m
Tc 3*109 212
Pb 1*106 about Emax/3 and n/h = C*m*fi.*3600. We then
57
Co 2*107 109
Cd 1*106 210
Po 2*104 obtain
58
Co 3*107 115
Cd 3*107 226
Ra 2*104
60
Co 1*106 111
In 2*108 232
Th 4*101 dH/dt = 1.92*10-10 * C * fi * Emax (9)
63
Ni 6*107 113m
In 2*109 238
U 2*103
64 This is the dose rate if all the particles emitted
Cu 4*108 124
Sb 9*106 241
Am 2*102
67 are absorbed. However, on the surface of the
Cu 2*108 123
I 1*108 244
Cm 4*102
62 source about half of the particles are emitted
Zn 5*107 125
I 1*106 252
Cf 1*103
inwards and do not contribute to the dose
equivalent. Therefore, we obtain
The effective dose has been calculated for many
radionuclides using the MIRD concept. The dH/dt = 10-10 * C * fi * Emax (10)
International Committee on Radiation
Protection (ICRP) has introduced a radiation where
protection variable, ALI (Annual Limit of
Intake) which has the unit of Bq. One ALI is the dH/dt is the dose equivalent in Sv/h
amount of radioactivity that corresponds to an C is the radioactivity concentration in Bq/kg
effective dose of 50 mSv. Emax is the maximum beta energy in MeV
fi is the number of emitted beta per decay that
Approximate dose calculations have the maximum energy of Emax
In the practical laboratory work, simpler
calculation methods are needed to obtain

34
Point source A beta point source

A common situation is that you work with a ∆E/∆d is the stopping power of the electrons.
concentrated radioactive source that can be As seen from Figure 8, the stopping power for
regarded as a point source. At some distance, high-energy electrons is about constant, about 2
this source gives a dose rate that is related to the MeV/cm (200 MeV/m). Only for low energies
radioactivity amount, and the type and energy of (< 300 keV) does the stopping power increase.
the emitted particles. However, these energies are not interesting
from the external radiation point of view since
their depth penetration is low (< 0.6 mm). Only
the high-energy electrons can penetrate skin and
protection gloves and represent a biological
hazard.

d ∆d 100
300 keV

PP
MeV/cm
10

2 MeV/cm
1
0.01 0.1 1 10
MeV

Figure 8 Stopping power for electrons as a


function of particle energy. Electrons with
energy > 300 keV have about the same stopping
power, 2 MeV/cm.
Figure 7 A schematic figure of the radiation
geometry around a point source P, which could If we put the value 200 MeV/m of the electron
either be a beta source or a gamma source. stopping power into equation (11) we obtain the
The radioactivity is A Bq. The distance from the approximate relation
point source to the body is d meter. Particles
are not absorbed until they hit the body surface. dH/dt = 10-11* A*f*/d2 (12)
A sphere is drawn with the point source at the
center and with the radius d. The dose rate is given as Sv/h, A in Bq and d in
meters.
Generally, the emitted particles are distributed
on a sphere with the surface S=4πd2. They lose A gamma point source
some of their energy ∆E in a thin layer ∆d with
density ρ. This thin layer has the mass of If we in Figure 7 change the external irradiation
4π*d2*∆d*ρ. The number of particles emitted from beta to gamma, we then have to change the
during one hour is f*A*3600. WR =1 for beta stopping power for charged particle to
and gamma. The density of tissue is 1000 something relevant for photons. A radioactive
kg/m3. If we put these values in equation 8 we decay can also emit gamma rays with different
obtain energies (Ei) and number per decay (fi), which
changes equation (11) accordingly.
dH/dt=1.6*10-13 * f*A*3600*∆E/(4π*d2*∆d*ρ)
The gamma γi with the energy Ei will have
Rearranging this equation will give some probability to lose its energy when passing
through the thin layer ∆d. We denote the total
dH/dt=0.458*10-13 *(f*A / d2)*∆E/∆d (11) energy that is entering the surface S with Eini

35
and the energy coming out from the surface
with Eouti. We can then derive the following Table 3 Gamma constants for some important
relation radioactive nuclides, 10-12 Sv*h-1*Bq-1*m-2

Eouti = Eini e-µeni* ∆d (13) Nuclide Γ Nuclide Γ


22Na 0.32 99mTc 0.016
The energy absorption coefficient, µeni, used in
the equation is related to the transfer of energy
24Na 0.47 103Ru 0.090
from photons to charged particles that are 28Al 0.23 110mAg 0.38
locally absorbed. 38Cl 0.19 122Sb 0.064
42K 0.035 124Sb 0.026
Since µeni*∆d is a small value, we can 46Sc 0.29 125I 0.037
approximate equation 13 to
51Cr 0.0043 131I 0.056
Eouti = Eini – Eini*µeni*∆d (14) 54Mn 0.13 134Cs 0.23
56Mn 0.22 137Cs 0.086
59Fe 0.16 140Ba 0.33
The energy released in the tissue volume is then 58Co 0.14 140La 0.30
60Co 0.34 141Ce 0.013
∆Ei = Eini - Eouti = Eini*µeni*∆d (15)
65Ni 0.083 160Tb 0.14
and 64Cu 0.032 177Lu 0.0027
65Zn 0.073 182Ta 0.18
∆Ei/∆d = Eini*µeni (16) 69m-69Zn 0.064 187W 0.080
75Se 0.051 192Ir 0.12
From equation (11) we then obtain
76As 0.064 194Ir 0.040
∆Hi/dt =4.58 10-14 *A*fi*µeni *Ei/d2 82Br 0.039 198Au 0.062
(17) 86Rb 0.013 201Tl 0.012
95Zr 0.11 203Hg 0.035
We can gather the decay-dependent parameters
99Mo 0.038 226Ra 0.22
into a constant
Some considerations about the attenuation
Γ=ΣΓi = 4.58*10-14 * ΣEi * fi* µeni (18)
coefficient
where
The energy absorption coefficient used in the
calculation of the Γ-constant gives the transfer
Ei is the energy of gamma i in MeV
fi is the number of gamma i emitted per decay of energy from photons to charged particles that
are locally absorbed (Figure 9). The following
µeni is the energy absorption coefficient in m-1
example demonstrates how the Γ−constant is
and rewrite equation (17) as calculated.

dH/dt = Γ ∗ A / d2 (19) Example 2. Calculate the Γ−constant for 60Co,


which has two gamma rays, 1.173 and 1.332
MeV. Both gamma rays are close to 100 % per
where
decay. The mass energy absorption coefficient
in water obtained from Figure 9 is 0.03 cm2/g.
the equivalent dose rate dH/dt is in Sv/h,
The density in water is 1 g/cm3 which gives an
the radioactivity A is in Bq, and
energy absorption coefficient of 0.03 cm-1 or 3
the distance d is in meter.
m-1. We use formula (18) to obtain

36
10000
−12
Γ=4.58*10 -14
* 2.505* 3 = 0.34 ∗ 10 LEAD
1000

The Γ− constant can be calculated for a number

Mass attenuation (cm2/g)


100
of radionuclides as seen in Table 3.

The theoretical background for the attenuation 10

coefficient is given in Chapter 3. The diagram


in figure 9 and figure 10 gives a somewhat 1

simplified information with two curves, which


gives the sum of a number of involved 0,1
processes. Here we will give some examples
how these curves are used in practical 0,01
calculations. 0,001 0,01 0,1 1 10 100
Photon energy (MeV)
For each element, we need to have a special set
of information. Here we will only deal with two Figure 10 Mass attenuation coefficients for
elements, water and lead. photons in lead. Two different attenuation
coefficients are given. The upper curve is the
10000 total mass attenuation and the lower the mass
energy absorption coefficient
1000
WATER
In the calculation of the Γ-constant for 60Co we
Mass attenuation (cm2/g)

100 used the lower curve in figure 9. Water is


usually a good approximation for tissue. We
10
wanted to know the amount of locally deposit
energy and used in this case the mass energy
absorption coefficient.
1

0,1

0,01
0,001 0,01 0,1 1 10 100
Photon energy (MeV)

Figure 9 Mass attenuation coefficients for


photons in water. Two different attenuation
coefficients are given. The upper curve is the
total mass attenuation and the lower the mass
energy absorption coefficient

Figure 11 The degradation of photon energy in


a thick radiation shield.

37
If we would like to calculate the thickness of a 10000

lead container to decrease the radiation from a LEAD


strong 60Co-source 100 or 1000 times, then we 1000

Mass attenuation (cm2/g)


have another situation.
100
The thick shield can be divided into a number
of thin layers. In each layer we can apply the 10
mass energy absorption coefficient to calculate
how much photon energy is transferred to the 1 E=1,2 MeV
next layer. However, this energy now consists
of the original gamma energy and of lower 0,1
M=0,06 cm2/g
energy Compton photons. The Compton
photons will be, due to their lower energy, more 0,01
easily absorbed than the higher original energy 0,001 0,01 0,1 1 10 100
in the next layer. So coming out from the thick Photon energy (MeV)
shield will finally mainly be the original gamma
photons, which have undergone no interaction The two gamma photons from 60Co are rather
in the shield and some Compton photons mainly similar in energy so we use a value in-between,
produced in the last layers. 1.2 MeV. From the diagram we get (using the
total mass attenuation coefficient) the value
The energy coming through a thick shield is 0.06 cm2/g. We multiply with the lead of 11, 3
then the number of undisturbed high-energy g/cm3 to get the total linear attenuation
gamma (can be calculated using the total mass coefficient 0.68 1/cm.
attenuation coefficient) times the gamma-
energy. We can then use the exponential relation
between incoming and outgoing photons.
Example 3 A strong 60Co source (100 GBq)
needs to be protected in a lead shield. An N/No = 1/17000 = e-0.68*X
acceptable dose rate from the protected source
would be 2 µSv/h at 1 meter distance. How X is the wanted lead thickness.
thick should the lead wall be?
X = ln(17000)/0.68 = 14.3 cm
The dose rate (0.034 Sv/h) of an unprotected
source at 1 meter can be obtained using the Γ- We have made some approximations to obtain
constant found in table 3. This is this answer. One is the use of a single energy
34000/2=17000 times larger than the wanted instead of doing separate calculations for the
dose rate. We need then to reduce the number of two gamma photons. The other is the use of the
60
Co-gamma by this factor. total attenuation coefficient, which gives a
somewhat to small value. The answer could
then be around 15 cm.

38
CHAPTER 5
THE EFFECT OF RADIATION ON HUMANS
Control of the cell is managed by the nucleus of
the cell which contains deoxyribonucleic acid
(DNA), the hereditary material or "memory
store" of the cell. DNA functions as a template
for the formation of ribonucleic acid (RNA),
which in turn acts as the template for the
formation of various protein molecules which
LOSS OF HAIR
3 -4 Gy
are workers within the cell and perform specific
functions.
DEATH OF BONE
MARROW TISSUE Further, there is flow of information from DNA
Renewal of blood cells to RNA to protein. Both DNA and RNA are
stops carriers of information. DNA keeps information
3-4 Gy in the form of a special sequence of nucleotides
DEATH OF BOWEL
– the building blocks of DNA. There are four
TISSUE different types: adenine, thymine, guanine and
Renewal of bowel cells cytosine, designated A, T, G and C respectively.
stops In a human cell, the total number of nucleotides
10-15 Gy
in DNA is about five thousand million.
STERILITY
1-5 Gy

REEDENING OF SKIN
6 Gy
BLISTERS and
WOUNDS
10 Gy

Acute effects of irradiation in humans


Figure 1 Schematic drawing of a cell and its
Biological System most important organelles.

Higher organisms are composed of numerous In the double spiral of DNA, A is combined
cells, which co-operate and share the various with T, and G with C. Thus, the information is
functions that they must fulfil. A human being found in two arrays, one being complementary
is formed of some 1014 cells. Some of them, the to the other. This can be regarded as "back up"
nerve cells, are responsible for signal of the information – something which nature
communication within the organism, while practiced long before humankind began using it
blood cells and other cells of the circulatory in our computers. In RNA, nucleotides are
system transport oxygen and nutrients and some combined in a similar way but with the
cells such as kidney cells deal with excretion. difference that uracil (U) is used instead of T.
Cells are the smallest units concerned with this Three consecutive nucleotides in RNA
division of labor and for an organism to correspond to a specific amino acid for forming
function, it is essential for particular cells to be protein molecules.
correctly located and perform their function.
Some examples of different functions of the cell
are described below. Mitochondria are cell

39
organelles that specialize in converting energy. Energy transfer – primary damage
They break down energy-rich sugar molecules
and convert the energy into small packets of The effect of radiation on living cells is usually
adenosine triphosphate (ATP). The different caused by charged particles like electrons (beta,
functions of the body like muscle and cellular Compton or photoelectrons) or alpha particles.
processes are then using ATP for energy The transfer of energy occurs very quickly –
support. Protein synthesis in the cell occurs in within pico-seconds. Two types of primary
the ribosome with RNA as the template. Storage biological effects can be distinguished: direct
of proteins for export occurs in the Golgi and indirect. In the direct type, the radiation
complex. Detoxification of harmful chemicals interacts with biomolecules to cause an initial
takes place in the endoplasmic reticulum and modification of their DNA, RNA or proteins. In
various substances are broken down in the the indirect type, which is the more usual in
lysosomes. living cells, the primary changes are in water.

Transfer of energy to the cells' molecules occurs


almost randomly. Hence, it can be expected that
in 60-70 % of all primary events, water receive
the energy. The amount of energy transferred to
the water molecule is indeed small but
significant since it undergoes ionization and
loses an electron. By restructuring, the water
radicals ·OH and ·H, and hydrated electrons are
formed.
Direct action Indirect action
e- e-

Figure 2 The flow of information in a cell and


comparison with ionization density in sparsely
ionizing (e-) and densely ionizing (α) radiation.

Many other functions are fulfilled within this Changes in DNA


small unit with a diameter of 10 – 20 µm. Figure 3 Transfer of radiation energy to
Different environments in the organelles can be material in a cell
maintained by membrane separation. Hence,
appropriate conditions exist for simultaneous Radicals are very reactive and react with each
energy turnover in the mitochondria, duplication other or with biomolecules within a short time.
of DNA in the cell nucleus and break down of If they react with each other they form water,
proteins in the lysosomes. hydrogen peroxide or hydrogen gas. Water
radicals can react with all biomolecules and
Of the cell content are 60-70 % water and about
after irradiation, a spectrum of various changed
15 % protein. The RNA content is a few percent
biomolecules is obtained. The reactions with the
and less than 1 % is DNA. Large molecules –
water radicals occur in less than milliseconds.
macromolecules – which form structures in a
biological system, include DNA, RNA and
The energy deposited in a cell is not distributed
proteins. From the radiation point of view,
uniformly but often in "clusters" (in clumps) of
DNA is the most important biological molecule.
numerous ionization events and accompanied
Each cell contains some 5 · 10-12 grams or 1.5
by primary damage within a small volume.
meters of DNA whose diameter is only 2 nm.
When an electron passes a cell, the close dose is
about 3 mGy and the number of primary injuries

40
to biomolecules is about 100 in the cell nucleus High-LET ionizing radiation, such as alpha
(the critical organelle of the cell where DNA particles, creates several ionization events per
occurs). In Sweden, where the background nm and therefore very probably creates double
radiation is 1 mGy (1 mSv) per year, only every strand breaks. In practice, high-LET ionizing
third cell is hit yearly by an electron and the radiation increases the biological response and
other cells are unaffected. At very low doses, a creates more biological damage per physical
step-by-step increase of radiation dose occurs at dose unit. Permanent double strand breaks can
the cellular level, i.e., each cell is hit zero, one, occur in DNA (fragmentation) or the
two or three times etc. The radiation dose to a information on both strands can be changed in a
larger part of the body, such as an organ, is then small segment of DNA, a mutation.
the mean dose for all included cells.
-17
10 seconds Energy absorption with subsequent
ionization or excitations
-15 -14
10 – 10 Changes in biomolecules caused by direct
or indirect effects
-3
10 to Biological mechanisms of repair splicing
minutes affect the molecular damage
100 ionizations The time scale for following processes is
in the nucleus considerably longer

Information changes Submicroscopic


in the cell injuries
Figure 4 The distribution of energy transferred Hours Microscopically
(ionization events) along an electron track and Mutation visible injuries
when an electron passes through a cell.
Genetic Somatic
damage damage
Cell death
Days
Death of
organisms
Weeks

Years Leukaemia
Cancer

Generations Genetic
damage
to the
offspring

Figure 5 Repair of DNA in a cell and the ability


to repair after different types of irradiation. Figure 6 Time sequence of processes induced in
a cell by radiation.
As DNA is the critical molecule, the damaging
effect of different types of radiation varies A repair system exists, which functions more or
according to how the energy is distributed in the less effectively for most injuries to DNA, when
molecule. Low-LET radiation creates mainly the injury is confined to one strand. This strand
single strand damage, which most cells can is cut and a small portion broken down and is
repair effectively and accurately. At a low dose, then repaired using the other complementary
it is unlikely that such low-LET radiation strand as template whereupon the split in the
creates, simultaneously, two ionization events DNA is closed and the DNA repaired. Besides
within a few nanometers to create a double this simple repair system, several more or less
strand break. sophisticated systems for repairing damage to
the DNA exist. Since DNA is particularly
important for the cell, many endogenous

41
systems have been developed during evolution If a whole body radiation dose exceeds 1 Gy
to prevent changes or loss of information (see and is given during a relatively short time (less
also Chapter 6). than 1 hour) some people will feel sick and
dizzy and have bouts of vomiting. The duration
Relative Biological Effect RBE of these symptoms depends on the radiation
dose. Early symptoms may give some idea of its
The same dose, irrespective of the radiation magnitude.
type, produces different effects depending on
the density of ionization. The relative biological Acute radiation damage in multi-cellular
effectiveness (RBE), defined in Chapter 4 is a organisms is due to more or less widespread cell
way to express this. The RBE can be inactivation. Some cell types in the human body
determined in many ways and often gives are more prone to cell inactivation than others,
different values depending on which effect is which results in some organs being unable to
studied. function. The law of Bergonie and Tribondeau
often applies; "Cells undergoing division
Thus, the RBE for a given type of radiation is (proliferating cells) are more radiosensitive than
not constant and can, for alpha radiation, vary non-proliferating cells". The organs in which
from 2 up to 10 - 20. From the different RBE the formation of new cells is important include
values that are reported, the weighting factors the red bone marrow where blood cells are
for different types of radiation are derived. formed, the intestine – particularly the small
Often these are based on some of the highest bone, the spleen and lymph nodes, the skin and
RBE values that have been observed. This testicles. These organs are also the most
weighted RBE is called the quality factor and radiosensitive in our bodies. In the red bone
usually denoted as WR (Q in older literature). marrow, some 1011 cells are produced daily and
about the same number are produced in the
Acute effects on organisms intestine. After intense radiation with some Gy,
new formation of cells in the bone marrow will
Acute effects appear relatively soon after an be reduced drastically and furthermore many
irradiation. They can arise only after high doses bone marrow cells will die through apoptosis.
of radiation, and in the case of human beings The same is true for the small intestine,
generally, within two months. This occurred in although at higher doses.
the Chernobyl disaster in which 29 people died
because of acute radiation damage. In the 1940s The cause of death in people exposed to whole
and 1950s, some people died from radiation body irradiation for a short time with doses
after receiving relatively high radiation doses in between 3 and 10 Gy is found in the bone
connection with experiments with fissionable marrow. These doses inhibit the development of
material. A few have died because they were cells and cause marked reduction in the number
exposed to radiation from sealed radioactive of cells, which have a short life span.
sources that had gone astray. In Hiroshima and
Nagasaki, many died from irradiation although Thrombocytes
most died from burns or mechanical injury.
Because of the chaotic experiences and Granulocytes and lymphocytes
numerous events following the nuclear bomb Stem
explosions, people’s acute response to cells
irradiation could not be confirmed.
Red blood cells
People involved in radiological work and
obeying safety rules are exposed to doses well Figure 7 Blood cells develop in the red bone
below those giving any acute effects. Persons marrow. The number of granulocytes and
exposed to radiation doses below 0.5 Gy will thrombocytes in the blood are influenced
hardly notice it if they do not carry a dosimeter. markedly by high doses of radiation.

42
Figure 8 Reduction in the number of
The life span of red blood cells is about 120 granulocytes and the sequel in humans after
days, which means that their reduction in high doses of radiation.
number is small. White blood cells such as The small intestine is the critical organ at doses
granulocytes and lymphocytes have a much of 10-15 Gy or more. Cells covering the inner
shorter life span (some days). Hence, any arrest part of intestine continuously migrate upwards
of their formation very quickly results in on the intestinal villi. If the producing stem cells
marked reduction in their number in circulating in the crypts are irradiated the development of
blood. Lymphocytes are highly radiosensitive these cells protecting cells stops. The cells
and become markedly reduced after irradiation, already formed continue to migrate but are not
partly due to reduction of stem cells in the red replaced and increasing ulcers develop in the
bone marrow but also due to extensive small intestine. This leads to massive loss of
apoptosis. These cells are important for the water and salts, and to an invasion of the
immuno-defence of the body and irradiated intestine content.
individuals become therefore very infection
prone.

Thrombocytes are important for the coagulation


of blood. Small ulcers and considerable
hemorrhages arise in the mouth, intestine and
skin. The number of thrombocytes is also
markedly and quickly reduced after irradiation.

People exposed to whole body radiation doses


of 3 to 5 Gy may die within 3 - 4 weeks. About
50 % of those irradiated with 4 Gy survive. Figure 9 Transverse section of the small
Bone marrow transplantation may improve the intestine and details of the villi and crypts.
prognosis after exposure to doses of between 3 -
10 Gy and was carried out in a number of Other acute effects also are generally related to
people irradiated in the Chernobyl disaster, but the influence of proliferating cells, but there are
with limited success. Bone marrow some exceptions such as the reaction of
transplantation necessitates that an reddening and feeling of warmth of the skin,
immunologically compatible bone marrow which depends on increased blood flow.
donor is available. In some hospitals, bone
marrow transplants are used routinely after Effects on the fetus
radiation therapy for the treatment of certain
leukemia. Purified stem cells from the patient The dose of radiation required to cause acute
are then often used. effects in humans is apparently high. Since
proliferating cells are radiosensitive, the embryo
and fetus are particularly sensitive to radiation.
Fetal development is divided into three phases.

The pre-implantation phase extends over some


10 days after fertilization. The growing embryo
is particularly radiosensitive during the early
cell divisions where the ‘all or nothing’ law
applies. This means that if the embryo is
damaged by radiation in this phase, spontaneous
abortion occurs at an early stage but the risk of
malformations during is relatively small.

43
The organogenesis phase embraces the period individuals were referred to institutional care.
from 10 to 60 days of fetal development. During The risk of serious damage was found to be
this phase the foundation of all the organs greatest if the radiation occurred during weeks 8
occurs except certain parts of the central - 15 of fetal development.
nervous system. Ionizing radiation can cause
fetal injury mainly during a short period when The result does not exclude the absence of a
the organ begins to form and there is active cell threshold value; that is to say, there might be a
proliferation. The period of high radiosensitivity linear dose-effect relation. However, it is
for most organs is short. Skeletal malformations important to realize that in the group with low
are relatively common after radiation (compared radiation doses, the number of mentally retarded
with malformations in other organs). A slight was only three and the statistical errors are
increase in the frequency of defects in the large.
skeleton has been detected after very low doses
(in mice irradiated with 0.05 Gy at day 7). The risk of mental retardation, when the fetus
During the growth period, radiosensitivity is was irradiated in weeks 8-15 of the pregnancy
lower than in earlier stages with one important was calculated to be 0.04 per Gy. This shall be
exception that concerns the dangerous influence interpreted as follows: If 1000 fetuses at this
radiation has on the development of the central developmental stage are exposed to 1 Gy each,
nervous system. This occurs late in fetal life. then 40 of the children will be mentally
retarded. If irradiated after week 16, the risk is
Development of the cerebrum is a very four times less. With low doses of radiation, the
protracted and radiosensitive period compared effect on the central nervous system seems to be
with the development of other organs. Cerebral the greatest risk.
effect has been confirmed amongst children
born after the explosion of the atom bombs in
Hiroshima and Nagasaki. In an investigation of
1,599 children irradiated during fetal
development, excess in the frequency of mental
retardation was observed.

Figure 11 Frequency of mental retardation in


children irradiated during weeks 8 to 15 of fetal
development.

In Hiroshima and Nagasaki, a smaller head has


Figure 10 Frequency of microcephaly, reduced been observed to occur with the same increased
size of head, in children born after explosion of frequency as mental disorders. The critical
the atom bombs in Hiroshima and Nagasaki. induction period for the head size occurs earlier
Irradiation occurred during weeks 6 to 11 of in fetal development and there does not appear
fetal development. to be a clear association between these two
effects.
The individuals had difficulty in doing simple
calculations, making simple conversation or
taking care of themselves. Most of these

44
Early findings indicated a threshold under
which radiation was not harmful and would not
cause cancer. However, with time people
became more and more concerned about the
risks involved. The increasing use of ionizing
radiation in society (X-ray diagnostics and
therapy) also promoted the interest to quantify
these risks.

It is still not strictly proved that the induction of


cancer is without a threshold value. However, it
must be stated that our knowledge of risks with
ionizing radiation is far more accurate than with
any other type of biological hazard. The risk
Figure 12 The development of cells in the estimates in radiation protection are
human cerebrum. conservative and assume that all doses can
cause biological damage but that the risk is
Effects on the development of the central proportional with the dose – if the dose is
nervous system after low radiation doses can be reduced ten times, the risk is also reduced ten
seen in low frequency in experimental animals. times.
The effects studied included the size of the
cerebrum, the incidence of cell death and The risk assessment is based on experience of
disorientation of nerve cells. Most people groups of people who have been irradiated.
working in this experimental field think that
there is a threshold value somewhere between 1. Survivors of the nuclear bomb explosions in
0.05 and 0.1 Gy. Hiroshima and Nagasaki in Japan. Knowing
where people were located at the time of the
Late effects on organisms explosion, the radiation dose has
subsequently been calculated for the
Fairly soon after the discovery of X-rays by individuals. Of course, individual dose
Roentgen in 1895 and natural radioactivity by estimations are associated with gross errors
Becquerel in 1896, it was established that but are still precise enough to permit risk
radiation had harmful effects. Pioneers in the assessment.
field of radiation worked without protection and
received very high doses, particularly to the 2. People who had radiation therapy for
hands and arms. After reddening of the skin and relatively benign conditions such as back
slow healing ulcers in the acute stages of the and joint complaints. The doses were
injury, forms of cancer appeared sufficiently correctly determined and entered in their
often for the risk to be noticed. clinical records along with the region of the
body, which was irradiated (the radiation
Genetic effects became evident somewhat later. field).
In 1927 Muller demonstrated that X-rays could
produce mutations in the banana fly. Other late 3. Miners who were exposed to radon-222 and
effects include opacity of the optic lens and its radioactive daughter products. The lungs
fibrosis, e.g. collections of fibrous tissue. are the critical organs in these cases.

4. Children who during fetal development


Induction of cancer were exposed to X-rays in connection with
diagnostic X-ray examination of the
Quite soon it became apparent that ionizing maternal pelvic region.
radiation could both cause and cure cancer.

45
of dying of radiation-induced cancer. For adults
the risk is 4 % per Sv.

During the fetal development the risk appears to


be still somewhat higher. This assessment is
based on examination of children who during
fetal life were exposed to radiation during X-ray
investigation of the maternal pelvic region.

Figure 13 Excess frequency of cancer in


Hiroshima and Nagasaki after the nuclear
bomb explosions.

In addition, several epidemiological


investigations in this field exist. Some of these
comprise a great number of people and
therefore provide important information. Figure 14 Relation between radiation dose and
Without doubt, the most important group are the excess frequency of leukemia.
survivors of the Hiroshima and Nagasaki
nuclear bomb explosions. In investigations of Genetic effects
small groups, results are often obtained that
sometimes suggest increased risk and Changes in the genetic information (mutations)
sometimes lesser risk from low doses depending are first apparent in the future generations. The
on the random frequency of cancer cases. It is in cause is a change in the information material
such instances important not to draw prejudiced (DNA) in the sex cells (spermatozoa and egg
conclusions from isolated investigations. cells). If the change is small, it is called point
Instead evaluations must be made from all the mutation and if large, it is usually called
epidemiological investigations taken together. chromosome change.

In Hiroshima and Nagasaki, at the end of the Quantification of genetic risks is more difficult
40s and beginning of the 50s, an increasing than for cancer. For example, an increase in
frequency of leukemia was confirmed. hereditary damage has not been discerned in the
Later, a number of other types of cancer showed offspring of irradiated people in Hiroshima and
increased frequency. The total number of cancer Nagasaki. This does not mean that the
cases related to irradiation was ”only” about irradiation did not induce any genetic changes
500. amongst these people but that no statistical
increase was demonstrated. It is thought that the
A problem, which is discussed in many risk of genetic injury is less than the risk of
contexts, is the shape of the dose-effect curve at cancer.
low radiation doses. Different interpretations
are given but the truth is that it cannot be shown Internal irradiation
how the curve looks at low doses. ICPR
(International Commission on Radiological The risk of external radiation is low when
Protection) states in its risk assessment (low working with low energy beta-emitting
radiation doses and dose rates) a 5 % risk per Sv radionuclides like 3H, 14C and 35S. In fact, these
of getting radiation related cancer if a beta particles can not even penetrate the skin.
population of normal age distribution is However, there is always a risk of internal
irradiated. This implies that if an individual is contamination by inhaling, through the mouth
exposed to 1 mSv, there is a risk of 1 in 20,000

46
or by absorption of lipophilic labeled happens if inactive thymidine is given together
compounds. with 3H-thymidine. But this way to protect
against internal contamination is usually not
Generally, it is difficult to make assessments of very effective and not very practical.
the risks because possible uptake and effects
depend on which compound is labeled. The Comparison: Radiation – Chemicals
biological half-life of e.g. 3H depends not only
on its decay but also on the metabolism and In certain situations, it is desirable to be able to
biological half-life of the labeled compound. compare the risk assessments of radiation and
Thymidine, labeled either with 3H or 14C, is chemicals that affect us. With the establishment
incorporated in the DNA of proliferating cells. of limited concentrations of chemicals in our
Naturally, if 3H is a part of DNA, the critical environment, it is taken for granted that there is
biomolecule, the dose effect should be greater a threshold value. No one can affirm with
than if it is incorporated into e.g. a protein. Beta certainty whether this threshold value really
particles from 3H decay have a maximum range exists or whether in most cases, it is tenable. In
of 7 µm, which is about the diameter of the general, there is an attempt to stop the use of
nuclei in our cells. One might guess that in this carcinogenic substances.
situation the biological half-life should be long
and thus the radiation risk large. However, Regarding radiation, since a limiting value is
thymidine is rapidly metabolized in the body established it is equivalent to accepting the risk
and only a few labeled thymidine molecules are of cancer but at a very low level. Note that the
actually incorporated into DNA. Rapidly natural background radiation gives the same
proliferating cells incorporating thymidine also risk as a similar amount of added radiation
renew and replace their DNA fast. Cells in the dose. Knowledge of the effects of radiation is as
small intestine, for example, are renewed within a rule more widespread than that of chemicals
a few days. The time the 3H will stay in the even if it is usually easier to understand the
DNA is therefore short. effects of chemicals. Radiation hits very non-
specifically, whereas a chemical substance often
The risks are greater if the radionuclides are has a specific effect. Radiation, however, has
incorporated into structures that are stable. This from the beginning been considered dangerous
can apply to the incorporation of 3H-thymidine in that some of the early pioneers developed
in the cells of growing individuals in whom the cancer and this risk has been documented
biological half-life can be very long. The same further after the Hiroshima and Nagasaki
is true for radionuclides such as the isotopes of nuclear bomb explosions. Besides, there are
Ca, Sr, Ba and Ra that are incorporated into only a few types of radiation to consider, which
bone tissue. Often, these elements are reused makes epidemiological research easier.
and are not metabolized in the same way as
organic compounds. Iodine isotopes are mainly On the question of chemicals, people as a rule
taken up by the thyroid gland and are have had a basically different approach – it is
incorporated into the thyroid hormone, which is only in the last 10 years that a greater awareness
stored in the gland for a long period and can of their dangers has been revealed. In addition,
give high doses locally. there are numerous chemicals and it is
impossible for anyone to have a detailed
As a rule only marginal measures can be taken knowledge of the dangers of all of them. This is
to reduce the effect of radionuclide intake. The valid especially when a long-term view is taken.
uptake of radioactive iodine in the thyroid gland
can be reduced by the intake of non-radioactive In most cases, from a risk point of view, direct
iodine but this should, preferably, occur before comparisons of radiation and chemicals are very
that of radioactive iodine. Similarly, the uptake difficult to make. Naturally, there are gaps in
of Sr-isotopes is reduced if stable Ca is our knowledge of radiation but the gaps are
supplied. In principle, the same thing also even greater for chemicals. If a comparison is

47
made it must proceed from a number of instructions on how people in Sweden should
premises that furnish the final comparison with work with wood ashes and sludge, which in
large errors. certain regions was contaminated by high
concentrations of radiocesium.
Radionuclides in nature
During the spring and summer of 1986,
The cosmic radiation from outer space consists comprehensive restrictions and measures were
of particularly high-energy particles, especially adopted concerning the agricultural production
protons. When cosmic radiation hits the earth's of food. The reason for introducing restrictions
atmosphere, large numbers of secondary was that radiocesium was deposited directly on
particles are formed. This radiation can also grasslands. From 1987 onwards, the uptake of
create radionuclides such as 14C in the cesium by their roots caused the contamination
atmosphere. of the crops, which normally resulted in low
cesium concentrations in agricultural products.
A number of radionuclides have such long half-
lives that they have survived since the ”creation In the future, the problem will instead be with
of elements”. Some of these decay to other foodstuffs produced in the natural ecosystem.
radioactive elements. In certain cases, long The radiocesium content in these products now
chains of decays occur by which a radioactive is much greater than in products of the
substance - by successive radioactive decays - is agricultural system and besides, diminution of
converted into one daughter nuclide after the content occurs slowly or not at all. The latter
another, until a stable (non-radioactive) end applies particularly to the radiocesium content
product is formed. Most radioactive material in elk and roe deer, which was the same in 1993
occurring in nature is included is one of four as in 1986. Fish in the forest lakes have shown a
such chains, all of whose links have atomic slow reduction but in reindeer, the reduction has
numbers over 81. occurred more quickly.

In Sweden, the largest contribution to natural The recommendation that is usually given, is
background radiation comes from radon-222 that the radiation dose arising from the intake of
and its decay products ("radon-daughters"). radiocesium from Chernobyl should fall below
They form part of a chain of decay, which 1 mSv per year, which corresponds to the intake
begins with uranium-238 and ends in lead-206, of 80,000 Bq of 137Cs. The fallout from
which is stable. Chernobyl also contained 134Cs and the intake
of 60,000 Bq of this cesium isotope corresponds
Besides these chains, some other radionuclides to 1 mSv. 134Cs can be disregarded since it
occur in nature. One example is potassium-40 "only" has a half-life of 2 years compared with
which forms 0.01 % of all natural potassium. 30 years for 137Cs. As mentioned earlier, the
Another is carbon-14, known for its use in risk of 1 mSv is equivalent to 1 in 20,000 dying
determining the age of organic archaeological sometime in the future from radiation-related
findings. cancer. This is considered to be an acceptable
risk. Note that of these 20,000 persons, more
The Chernobyl accident than 6000 will obtain cancer due to other
reasons.
The Chernobyl disaster in 1986 resulted in the
deposition of radiocesium, mainly 137Cs, in the
ground, vegetation and in the lakes in large
areas of Europe. In the worst affected regions
problems arose concerning the production of
food of acceptable quality. Apart from this, the
fall out caused only minor disturbances. SSI
(Swedish Radiation Protection Institute) issued

48
Dose limits for radiological workers

In different countries legal rules for radiological


workers may vary somewhat. In Sweden, the
authority is SSI (Swedish Radiation Protection
Institute), has given the following limits.

Period of time
Quantity
Limits
(mSv)/year
Workers in Annual
General Effective dose 50
Dose equivalent to 150
the lens of the eye
Dose equivalent to 500
the skin
Dose equivalent to 500
hands, forearms feet
and ankles
In addition, for 5 100
consecutive years.
Effective dose

Students and Effective dose 6


Trainees aged Dose equivalent to 50
16 - 18 years the lens of the eye
Dose equivalent to 150
the skin
Dose equivalent to 150
hands, forearms
Feet and ankles

Table 1 Dose limits for people working with


ionizing radiation from external sources

49
CHAPTER 6
Radionuclide targeting
where Emean is the mean energy (MeV) of the
INTRODUCTION beta particle (Emean= Emax/3), m is the mass
of the tumor (kg) and N is the number of
Tumor cell-specific targeting for delivery of radioactive decays given by the relation
toxic agents is an attractive approach for the
killing of spread cells whose positions cannot N=A x T½eff / ln(2)
be determined through available diagnostic
methods. The targeting process might not in where
itself give a satisfactory treatment of large A is the radioactive uptake (Bq) and
tumors because the radiation dose may not be (T½eff)-1 = (T½phys)-1 + (T½biol)-1 in seconds.
sufficiently high or the targeting substance may
not penetrate well. However, large tumors with
The formula predicts, for example, that if a total
rather well defined margins can often be treated
of 10 MBq of the radionuclide 90Y is taken up
by surgery, or radiotherapy with external or
in a tumor with the mass 20 g (20 cm3) then the
internal radiation sources. In the latter case,
tumor dose will be about 10 Gy.
encapsulated radiation sources are positioned in
the tissue interstitium or in body cavities.
The formula has to be corrected if a certain
Therapies based on targeting such as radio-
fraction of the electrons escape from the tumor
immunotherapy and boron neutron capture
mass. The same formula applies for alpha
therapy can be complementary with the major
particles if Emax is used instead of Emean and can,
aim to kill spread cells.
in principle, be used also to calculate the dose to
different organs due to background irradiation
The radiation biology considered in connection
by photons. Calculations of photon-mediated
with the use of targeted radionuclides is mainly
doses require that a reasonable assumption can
concerned with the effects of the radiation from
be made about the radioactivity uptake in a
the radionuclides on the targeted cells or their
defined mass of tissue and the average
close neighbors. This means that the targeting
absorption of the photons. It is actually possible
process is mainly based on the desire to
from modern scintigraphy to make reasonable
optimize the biological action of electrons from
assumptions about the relative photon release
beta decays (beta minus and beta plus) and on
from different parts of the body and by knowing
alpha particles from the decay of heavy nuclei.
the total amount of injected radioactivity, it
Photons (gamma- and X-rays), which are used
might be possible to make good approximations
in medical diagnosis and which most often also
of the number of Bq in different body regions.
accompany alpha and beta decays of
radionuclides used for therapy, are not of direct
PRIMARY INTERACTIONS
interest. Photons do not deliver their energy in
the local environment around the targeted cells.
Most of the radiation damage is mediated via
Instead, they deliver their energy to large
ionization of cellular water, which gives free
volumes of the body and give an increased
radicals with the capacity to damage critical
background dose, which is undesirable.
biomolecules. Only a small part of the
radiation-induced damage is obtained through
ABOSRBED DOSE direct ionization of the biomolecules (Fig. 1).
Mainly high-energy beta (e.g. from 131I or 90Y)
DNA is the most important biomolecule when
and alpha particles (e.g. from 211At) are
the action of radiation is considered. The
considered to contribute to the local dose in
formation of radicals is increased in the
targeted radiotherapy. The tumor dose for beta
presence of oxygen, and oxygen can also react
particles can be calculated approximately by
with primary lesions in DNA causing fixation of
damage. Oxygen is in fact a powerful radiation
Dose (Gy) =1.610-13 N Emean / m
sensitizer. Low molecular weight thiols (e.g. SH
containing amines or amino acids) are

50
protecting substances because of their normally Since parts of DNA are lost, this repair type
high proton-donating capacity. The main is most likely when introns are damaged. In
intracellular protector of this type is the tri- a slower type of repair, a near homologous
peptide glutathione DNA sequence is “lined up”. Strand
exchanges convert the double strand break
into two single strand breaks (one on each
strand) that are repaired by excision repair.
Gene rearrangements or translocations can
occur if the damage DNA sequence
exchanges genetic material in the lining up
process. This process is probably necessary
when exons are damaged.
d. Cross-links. The two DNA strands are
covalently linked. This is a serious damage
since it prevents strand separation at
transcription and DNA synthesis. This
repair mechanism is not well understood,
but probably involves mechanisms similar
Figure 1 Schematic drawing of the primary to those described for double strand breaks.
interactions taking place after irradiation. The
sensitizer O2 and the protectors of SH-type act DNA DAMAGE AND REPAIR
both at the primary radical formation level and
at the fixation of DNA damage level. DNA is the critical target for radiation damage
as has been shown in numerous experiments.
. One Gy of low-LET radiation gives about 1000
a b single strand breaks, 1000 base damages, 30-50
double strand breaks and a few cross-links in
DNA. The single strand breaks and the base
damage can effectively be repaired by the
c d excision repair system as indicated in Fig 2.
Double strand breaks can also be repaired
although the mechanism is not clear and the
(fidelity correctness?) of the repair is not
Figure 2 Schematic descriptions of proposed necessarily high. Errors in the repair of double
DNA repair mechanisms. strand breaks in DNA might give rise to
rearrangements (translocations) of genes. It is
a. Single strand breaks. Taken care of by assumed that, several hours after the irradiation
excision repair. Exo- and endonucleases with a dose of 1 Gy, there are on average one or
remove sugar-phosphate and bases from the two unrepaired or seriously miss-repaired
damage. Polymerases synthesize a new double strand breaks or cross-links in DNA.
strand using the intact stand as a template. This remaining damage probably gives rise to
Finally, ligase closes the opened ends. inactivation of cell proliferation. If such damage
b. Base damage. Glycosylases remove the is randomly distributed among cells and all of
damaged bases, which introduces a single them, with a high probability, inactivate cell
strand break. This is repaired by the proliferation then the shape of the cell survival
mechanism described above (see a). curves in Figures 4-8 can be qualitatively
c. Double strand breaks. In one proposed fast understood. The only assumption that has to be
mechanism, enzymes trim the two near ends made is that the lethal damage is Poisson
so that they fit together. Thereafter, the ends distributed among the cells. This gives a certain
are brought together, similarly to how it is probability of survival for each cell independent
made in a plasmid using DNA technology. of how high the dose is.

51
it is assumed that transcript factors are mutated
INTRINSIC RADIOSENSITIVITY or defective, which prevents the slowing down
of the cell cycle. The cells do therefore not have
Knowledge of the factors that determine enough time to repair DNA damage before they
intrinsic radiosensitivity is limited. However, it are forced into mitosis. In Blooms syndrome
is known that cells react strongly after radiation there is a defect in the ligase activity, and in
damage. More than 40 genes have been reported Fanconi´s anemia it seems to be difficult to
to be activated by ionizing radiation. The repair certain DNA cross-links.
molecular genetic knowledge about the
regulation and trigging of DNA repair is not The most dramatic increased radiosensitivity is
known in detail although some insight has been seen in Ataxia telangiectasia. This indicates that
gained the last years. Figure 3 is highly cell cycle block and cell cycle check points are
speculative but includes some of the most critical, not only for genetic stability as
recent theories of the relations between the previously has been proposed, but also for the
genes involved. The DNA is checked regarding determination of radiosensitivity. However,
structural damages by unknown mechanisms more basic research is needed to obtain better
(DCM). When severe such damage is found, knowledge about the factors that determine
certain genes code for transcript factors. These intrinsic radiosensitivity.
activate genes that code for inhibitors to cyclins
and the corresponding cyclin-kinases. This SURVIVAL CURVES
gives a block in the cell cycle and the cell will
then have a reasonable time for enzymatic The initial events at the radiochemical level
repair of critical DNA damages before it is give rise to different types of biological effects
forced into mitosis. The DNA-histone complex that can be measured at the cellular level. The
is, if necessary, opened in preparation for the most important effect, from the therapeutic
repair enzymes to reach the damaged sites. point of view, is of course the inactivation of
tumor cell proliferation and this will mainly be
Radiation discussed below. The arrest of cell proliferation
Cell division is mediated through severe damage in DNA.

DNA check The shape of cell survival curves is well known


mechanism from experiments with external radiation. Cell
No! DNA repair survival is defined as the relative number of
DNA damage ? cells that, after irradiation, has the capacity to
DNA-histone form colonies containing at least 50 cells. This
Yes!
opening is analyzed through the sparse seeding of the
Gene activation mechanisms analyzed cells as monolayers or as suspension
cultures in agarose gel. One or two weeks after
Transcript factors Growth delay irradiation, the exact time being dependent on
the growth rate of the cells, the number of
colonies containing at least 50 cells is scored.
Gene activation Cell cycle inhibitors Cell survival is "fractional" in that a certain
fraction of cells always seem to have survived
as shown in Fig. 4. This is due to heterogeneity
Figure 3 A schematic overview of assumed in local energy deposition and heterogeneity in
mechanisms involved in cellular and molecular structural DNA damage and repair. Thus, with
reaction on radiation induced DNA damage. an increasing dose the probability of lethal hits
increases for each cell, giving rise to the type of
Some diseases are known to be due to defects in "fractional" curves seen in Fig. 4.
the DNA repair system or closely related
systems. Ataxia telangectasia is a disease where

52
Figure 5 Schematic drawings of cell survival
curves with the functional parameters Do, n,
α, β and S2Gy indicated in the curves.

Table 1. The table shows crude estimates of the


Figure 4 Typical clonogenic cell survival functional parameters Do, n, α, β and S2Gy.
curves after irradiation with low- or high-LET Typically, glioma, melanoma and osteosarcoma
radiation. cells are radioresistant (Low), adenocarcinoma
cells are intermediate sensitive (Medium)
MODELS whereas lymphoma, myeloma, leukemia and
Cell survival can be mathematically modelled. small-cell lung cancer cells can be regarded as
Commonly used models are the single-hit, radiosensitive cells (High).
multi-target and linear-quadratic models. The Degree of radiosensitivity
former is described by
Low Medium High
Do (Gy) 1.0 - 3.0 1.0 – 2.0 0.5 – 1.2
S = 1-(1-exp{-D/Do})n
n 2 – 10 2-3 <2
where D is dose (Gy) and Do is a constant (Gy) α (1/Gy) 0.01-0.5 0.03-1.0 0.05-2.0
giving the slope of the curve in the high dose β (1/Gy2) 0.001-0.05 0.001-0.1 0.005-0.2
region. The extrapolation number n gives the
radiosensitivity in the low dose "shoulder" S2Gy > 0.5 0.3 – 0.5 < 0.3
region (Fig. 5a). The linear-quadratic model is
described by the simple relation DOSE RATE

S = exp{-(αD + βD2)} One main difference between external


irradiation and irradiation by targeted
radionuclides is that the latter most often gives a
where α is the slope of the curve near the dose
much lower dose rate. A low dose rate means
zero and β is the constant describing the shape
that critical radiation damage in DNA can be
of the curve at high doses (Fig. 5b). Both
repaired during the irradiation, which gives a
formulas are used to give a simple two-
less efficient inactivation of cell proliferation as
parameter description of the radiosensitivity of
shown in Fig. 6. The shifts in Figure 6
normal and tumor cells.
illustrates the changes in survival seen when the
dose rate is shifted from about 1 Gy/min to
It has been claimed that the survival of cultured
about 1 Gy/hour and further to 1 Gy/day. One
tumor cells at 2 Gy correlates, to some degree,
Gy/hour allows DNA repair to take place during
with the clinically observed radiosensitivity of
the irradiation, which means that more dose is
the corresponding types of tumors. Typical
needed to inactivate the cells.
values of Do, n, α and β are given in Table 1
along with typical survival levels at 2 Gy, S2Gy.

53
Figure 6
Examples of
cell survival
curves
when the
dose rate is
changed

ion

electron
One Gy/day allows both DNA repair and cell
proliferation to take place during the irradiation
and the latter means that the number of cells
increases during the irradiation, making it
necessary to kill more cells. It is likely that the
dose rate in targeted radiotherapy is so low that
DNA repair, and sometimes cell re-population, Figure 7 A crude comparison between the
during irradiation have to be taken into account. ionization densities and the size of DNA when
low- and high-LET radiation types are applied.
The low dose rate makes targeted radiotherapy
inefficient when cell inactivation per dose unit Considering that the diameter of the double
is considered. However, this does not at all stranded DNA molecule is 2 nm and that high-
disqualify targeting of radionuclides for therapy. LET delivers in the range 200-400 eV over that
The tumor cell specificity is the main critical distance, it is easy to realize that densely
aspect and if the tumor cells obtain a low dose ionizing radiation can give severe and clustered
rate, in spite of a good tumor specificity of the damage, which is difficult to repair. High-LET
targeting agent, then the normal tissues must radiation can be considered to give few particle
have an even lower dose rate. Thus, normal tracks, but everything that is traversed is
tissues will in such cases always have better destroyed. Low-LET radiation gives more
possibilities to repair unwanted damage. It is the randomly scattered ionization separated by
differential uptake between normal and tumor rather large distances along the DNA molecule
tissue that is important. If the tumor specificity (Fig. 7) and the cell has a good chance to repair
is too low then it will be difficult to obtain high such damage.
tumor doses without also giving too high doses
to normal tissues, independent of the dose rate. There are nearly no dose rate effects when high-
LET radiation (e.g. alpha particles) is applied in
HIGH-LET targeted radiotherapy. It does not matter if two
severe damages on DNA are made within a few
Conventional radiation with low ionization hours or within only a few minutes. The damage
density, low-LET (LET = Linear Energy can probably not be effectively repaired and
Transfer), delivers an ionization density in the each damage might be severe enough to inhibit
range of 1 eV per nm, which seldom gives further cell divisions. Thus, provided the uptake
dense clusters of ionization. The corresponding of the radionuclides is tumor specific, it might
values for high-LET radiation (e.g. alpha be an advantage to use high-LET radiation
particles) are 100-200 eV per nm. A delivered because the probably low dose rate is not an
energy of about 30 eV is needed for each obvious disadvantage. It might in fact be
ionization, since about 10-15 eV is needed for enough to administer the radionuclides over a
the release of a bound electron and the rest of very long time.
the energy is converted to thermal energy.

54
that the cells really are radioprotected. The
OXYGEN partial oxygen tension has to be much below 10
mm Hg for the cells to be fully radioprotected.
Acute hypoxia or anoxia in a tumor gives Another unsolved question is whether severely
radioresistance due to the decreased number of hypoxic cells still have the capacity to
formed free radicals and the lack of oxygen- proliferate. Furthermore, some scientists have
mediated fixation of damage. When oxygen is claimed that even if there are hypoxic areas with
depleted there are better chances for proton clonogenic cells in certain regions of a tumor,
donation from glutathione, which also means these cells might not exert a problem because of
increased protection. The quantitative reoxygenation during the course of fractionated
determination of the oxygen effect is given as a radiotherapy. It can be concluded that in spite of
dose-quotient as shown in Fig. 8. Chronic several years of research there are still
hypoxia can under certain conditions also give uncertainties regarding the importance of
radioresistance. hypoxia for the curability of tumors and the
uncertainties regarding this problem are not
The problems with hypoxia and anoxia are the smaller when targeted radiotherapy is
same when targeting of radionuclides and considered.
external radiation are applied. However, one
specific problem relating to targeting is that CYCLING CELLS
hypoxia and anoxia is an indication of bad
vascularization, which might in itself prevent .
the targeting agent from reaching all tumor
cells. Thus, it is possible that hypoxia and bad
uptake of radionuclides might correlate. This
has to be analyzed further. Something that is
well known is that high-LET radiation is
equally effective on hypoxic cells and normoxic
cells, which means that it could, in some cases,
be an advantage to use such radiation.

Figure 9 Examples of reported variations in the


radiosensitivity for resting cells and cells in the
cycle when exposed to low- and high-LET
radiation.

Cells in the cycle are, on average, more


sensitive to low-LET radiation than cells in
resting phase and this applies equally to both
normal and tumor cells. Furthermore, the
radiosensitivity has been reported to vary over
Figure 8 The influence of hypoxia on cell the cell cycle as shown in Fig. 9 when
survival. The method to calculate the oxygen conventional low-LET radiation is applied and
enhancement ratio, OER, is indicated. there is no difference whether the radiation
comes from an external or an internal radiation
However, it is far from clear to what extent source.
human tumors suffer from such severe hypoxia

55
High-LET radiation prevents the cells in the late
S and early G1 phases from being protected. In Table 2. Examples of radionuclides of
fact, it is assumed that cells out of the cycle are therapeutical interest. The last column indicates
as sensitive as cells in the cycle when high-LET the labeling mode. Ch stands for chelator
is applied, and it might therefore be an mediated whereas H stands for halogen
advantage to use high-LET radiation in those labeling.
cases when the targeted cancer cells not are in
the cycle.
Characteristics of emitted
RADIONUCLIDES radiation
Energy Ranges
Different radionuclides are of interest and some Max Mean
considered for therapy are listed in Table 2. The Type of
interesting radionuclides can be divided in at MeV (mm) (mm)
least two groups: those that give long range decay
effects so that neighbors to the targeted cells can 90
also be damaged, and those that give short range Y β 2.3 12 4
effects so that mainly the targeted cells suffer. Ch
131
Among the long-range agents are high-energy I β 0.6 2.4 0.8 H
beta emitters such as 90-Y (max. range 12 mm) 211
At α 5.9 0.05 0.05 H
and 131-I (max. range 2.4 mm), suitable when 125
I Auger <0.03 <0.005 <0.001 H
the uptake is high but heterogeneous. Another
interesting nuclide is 32-P (max. range 8
mm).however, so far, it is mainly available in
the form of phosphate and therefore has been
considered too dangerous to use since
dephosphorylation and phosphorylation
processes might give unwanted incorporation of
the radioactivity in normal tissue such as bone.
The other extreme are the Auger electron
emitters, such as 125I, which have to be inside
the cell nucleus to give a significant radiation
dose to DNA. The range of most auger electrons
is only about 1-2 µm. Radioactive alpha
emitters, such as 211At, give alpha particles with
a range of about 50-70 µm and therefore belong
to an intermediate group.

The therapeutical efficiency of high-energy


beta-emitting radionuclides varies with the
tumor size and is highest at diameters Figure 10 Tumor recurrence probabilities versus tumor
comparable to the range of the beta particles. cell number when 131I (left) and 90Y (right) radionuclide
therapy is applied. The influences of type 1 heterogeneity
This has clearly been shown for 131I and 90Y by are indicated with dashed lines.
Wheldon. It was shown that these nuclides are
not efficient for small cell clusters or single For single cells or small cell clusters, it is better
isolated cells because the emitted electrons have to target the tumor cells with short-range
such high energy and range that they deliver radiation such as alpha emitters or agents other
large fractions of their energy outside the small than radioactive nuclides, such as toxins or
cell clusters or single targeted cells. This is stable nuclides for neutron capture therapy. In
shown in the recurrence probability curves the latter case, 10-B can be applied because the
shown in Figure 10. induced high-LET fission fragments have a

56
range of 6-9 µm, which is ideal to kill a single monoclonal antibodies can be heterogeneous,
targeted cell. The auger electron emitters can which might also apply to other targets and
only be used when there are reasons to believe targeting substances. The heterogeneity
that the radionuclides are taken up in the cell develops as a result of the karyotypic and
nucleus. phenotypic instability which characterizes most
malignant tumors and which is most
TARGETING PRINCIPLES accentuated in large tumors.

Several targeting principles for tumor selective Type 2 If there is homogeneous uptake of the
delivery of radionuclides to tumor cells have targeting substance, there is heterogeneity in the
been described in the literature. The most specific energy deposition. This applies both to
popular so far is to tag the nuclides to radionuclide therapy and external radiotherapy
monoclonal antibodies either with more or less and is most pronounced for high-LET
specific methods or by attaching the treatments where the dose is delivered through
radioactivity to certain parts of the antibodies few particle tracks.
such as the carbohydrate moiety. Antigenic
structures have been identified as potential Type 3 If a sub-population of cells is selected on
targets such as the membrane-associated form the basis of similar specific energy deposition,
of the carcinoembryonic glycoprotein antigen, then there is heterogeneity because not all
CEA, in colon carcinomas. particle tracks give similar damage. Some tracks
might give no, or only a few, breaks in DNA
A new group of interesting targets are the whereas other tracks might pass longitudinally
sometimes overexpressed growth factor through a DNA molecule causing several breaks
receptors, such as the EGF-receptor which is and severe fragmentation. Thus, all cells with a
overexpressed in several malignant gliomas, certain energy deposition do not suffer from
adenocarcinomas and various squamous identical damage.
carcinomas, and the PDGF-alpha receptor
which is overexpressed in certain gliomas. In Type 4 If we select a subgroup of cells that all
these cases, monoclonal antibodies with have about the same specific energy deposition
specificity for the receptors and the and similar types of DNA-damage, then there
corresponding ligands loaded with radioactivity might be differences in the effects on cell
could be applied. The latter is presently being proliferation due to differences in repair. Some
tried with EGF-dextran conjugates loaded with cells might be near mitosis and there will be
radioactivity. Overexpressed signal pathways only a few hours before the chromatin is
and other related uptake mechanisms, such as condensed and chromosome or chromatide
the mIBG (catecholamine precursor analogue) damage is expressed whereas other cells might
uptake mechanism, can be used in certain cases, be in an early cell cycle phase or in a quiescent
e.g., for neuroblastomas. state and therefore have long time available for
repair.
HETEROGENEITY
All four types of heterogeneity must be
The therapeutical response of any type of considered in targeted therapy whereas types 2-
radiotherapy is more or less heterogeneous and 4 only apply in external radiotherapy. Types 2-4
the targeting processes give extra heterogeneity. also account for the "fractional survival" always
The heterogeneity problems in targeted seen in radiation cell survival curves in vitro.
radiotherapy are of at least four different types:
RECURRENCE
Type 1 There might, in targeted therapy, be
heterogeneity in the expression of targets, or in Considering typical cell survival values for
the uptake of the targeting substances, or both. radiotherapy recurrence, probability curves can
Antigenic expression and the uptake of be constructed for radionuclide therapy as

57
described by Wheldon. Such curves are shown therapy, somewhat higher values (about 1.5
above in Fig. 10. These curves show that the higher) can be applied.
recurrence probability is low at certain tumor
sizes and increases for both smaller and larger
tumors. Heterogeneity does not appreciably
change the optimal tumor size for treatment, but
decreases the total dose and thereby increases
the risk of recurrence and the curves are then
shifted upwards along the y-axis in Fig. 10.

WHOLE BODY IRRADIATION

Photons, which most often accompany alpha


and beta decays, are not of immediate interest
for targeting but they give an undesired
background dose to large areas of the body. The
most critical tissue is the bone marrow, which,
if the whole marrow is irradiated, sets the LD50
dose for humans to about 4 Gy. The bone
marrow syndrome is, after doses higher than 4
Gy, fully expressed after one month in humans,
which corresponds to the time it takes for most
blood cells and lymphocytes to die. The persons
then die because new blood cells and
lymphocytes have, due to the irradiation, not
been formed from the stem cells in the bone
marrow. A life can only be saved if bone
marrow transplantation can successfully be
carried out.

When whole body doses above 10 Gy are


applied, the gastrointestinal system shortens the
lifetime to about one week corresponding to the
time it takes for the gastrointestinal epithelium
to be degraded. The probability of saving a
human life after a total body dose higher than
10 Gy is zero.

In targeted radiotherapy, it is important to keep


the whole body dose, and especially the bone
marrow dose, well below 2-3 Gy. If it is not
possible to avoid this, preparations must be
made for bone marrow transplantation. In the
latter case, it might be possible to increase the
whole body dose up to about 7-8 Gy.
The dose values given in this section apply to
high dose rate situations (about 1 Gy/min),
commonly used in external radiation therapy. At
low dose rate (< 1 Gy/hour), which is the
common situation for systemic radionuclide

58
CHAPTER 7
DETECTORS
instrument, the type of radiation it can indicate,
Our five senses are limited and to understand how it is calibrated and - not least - how to
what really occurs around us we must handle the instrument.
sometimes use devices -- detectors. Our
unassisted senses have limited means of Common types of laboratory and radiation
detecting ionizing radiation. Heavy ions protection instruments and detectors will be
passing through the vitreous body of the eye described in this chapter as well as their
may produce light, which is perceived and ions characteristics and a range of applications.
in the air present blurred perceptions of
"something". Roentgen discovered that his rays Detection Principles
gave rise to “phosphorescent" light when they
met certain material. Becquerel discovered Most detectors for ionizing radiation use its
natural radioactivity by demonstrating that ability to cause ionization and excitation (see
mineral photographic plates become blackened. Chapter 1). This chapter will just deal with
The Curie couple learned to make use of the instruments based on this principle. Other
electroscope to measure charges that radium detectors may be based on the ability of certain
produced in air. So we have gradually learnt to types of radiation to cause nuclear reactions
construct and use instruments that augment our (e.g. in the detection of neutrons).
senses.
"Counts" of electrons
Using heat as a detector
When matter is ionized a large number of
Ionizing radiation transmits energy to the electrons are set free. Binding energies of outer
irradiated material. Like all other energy shell electrons are in the order of 3-6 eV, but
deposition, it gives rise to an increase in since the energy transfer is a statistical process
temperature that can be used to monitor the an excess of energy is needed. On average, in
irradiation. The absorbed dose of 1 Gy (1 J/kg) most materials about 30 eV are required to
will increase the temperature by about 2.5 •10-4 create one ionization. Energy not used for
oC in water, which is a fairly good equivalent to ionization causes excitations, vibrations and
tissue. Thus, irradiation with 4 Gy, which is a other atomic processes. A 1-MeV particle,
fatal whole body dose, should then increase the which deposits all its energy in a detector,
creates 30,000 primary, free, electrons. If all
body temperature by only 0.001 oC. In radiation
electrons are collected and counted in a proper
protection, where the doses are in the range µGy
way, we should be able to register not just that
– mGy, the warming effect is accordingly quite
the detector was hit by the particle but also the
negligible.
energy, position and direction of the particle.
How much information we can get depends not
Hence, measuring instruments in the laboratory
only on the detector principle but also on the
must be founded on other principles. They must
sophistication level of the detector system.
be sufficiently sensitive to give warning at dose
rates > 10 µGy/h. But they must also be able to Materials that are insulators, such as gases and
measure low radioactivity concentrations in certain solid materials, allow a direct count of
laboratory work or to measure radioactivity the ionized electrons. If a high tension is applied
distributions in Nuclear Medicine. no current will flow in an isolator. If the
material is irradiated, free electrons are
Varying measurement problems make different produced that can move affected by the electric
demands on the instruments' performance. A field (Figure 1a) and a measurable electric
single instrument is seldom idealistic from all current is produced (Figure 2).
viewpoints. Therefore, many different types of
instruments and equipment are developed. To If many particles hit the detector they may
be able to interpret the measurements correctly, contribute to a constant current at the level of a
we need to know the principles of the

59
few pA, which can be measured by an electrical will fill this hole and release energy that can be
instrument. This current is just related to the emitted as a light photon (Figure 1b). Such
total energy deposited in the detector. No photons can be "counted" by light-sensitive
information of the number or type of particles is detectors (photo-multipliers or photo-diods).
obtained. The number of photons is proportional to the
number of ionizations and excitations in the
If we instead measure the current from each material. This is also related to the total energy
individual particle as a short current pulse more released in the detector by the ionization
information is obtained. We can count the radiation. Materials of this type are called
number of particles per second hitting the scintillators and may be gases, fluids or solids.
detector, and we can integrate the pulsed current
and obtain information about how much energy "Counts" of changed chemical states
each particle deposits in the detector etc.
However, to measure current pulses, consisting Change in the chemical state occurs when an
of a few thousands of electrons only, is atom or molecule undergoes ionization and
technically more difficult and puts other excitation (Figure 1 c). For example, if the
demands on the detector material. irradiated substance initially contains divalent
ions (e.g. Fe+ +) and an electron is knocked out,
trivalent ions are formed (Fe+++). These ions
a b c can be distinguished chemically and the number
of trivalent ions formed can be determined. The
number of ions formed gives a measure of the
Excited or
ionized atom
energy that the radiation has deposited. Liquid
and solid material can be used in these types of
detectors.

At deexcitation particle
a light photon
Free electron
is emitted path
with kinetic
energy
A changed
chemical state -
-
-
+
Figure 1 Different effects of ionizing radiation.
a. Free electrons are produced by ionization. In
an electric field, an electric current or pulse is
produced which can be measured. Figure 2 Principles of a gas detector. An
b. On ionization or excitation, a hole appears in ionizing particle creates a number of ion pairs
one of the electron shells. An electron from an in a gas between two electrodes. The electrons
outer orbit fills this hole. A photon is emitted move towards the positive electrode and the
with energy equal to the difference in binding positive ions towards the negative electrode. A
energies. For certain material, these photons current flows through the detector and can be
are emitted as detectable light photons. measured either as pulses or in a dc-mode.
c. The ionization changes the chemical state of
the material permanently. The number of such Most radiation protection instruments are
changes can chemically be measured. constructed on the basis of these three
principles: counting the number of electrons,
"Counts” of light photons photons or changed chemical states. The
construction and use of the most common types
On ionization and excitation, a hole appears in will be described.
one of the electron shells around the atom.
Sooner or later, an electron from an outer level

60
becomes less than the number of primarily
Gas detectors formed ion pairs.
c. If the voltage is increased a little, the
The principles of a gas detector are illustrated in primarily formed ion pairs move towards their
Figure 2. The factors that determine the detector respective electrodes. The current measured is
function are: equal to the number of primarily formed ion
pairs.
1. The voltage between the electrodes. d. If the voltage is further increased the
2. The design of the electrodes. electrons formed acquire such a high energy
3. The composition and pressure of the gas. that secondary ions are produced. The current
4. The wall construction of the detector. through the detector becomes greater than the
primarily formed ion pairs.
Influence of high tension e. It the voltage is the same as in d, but the
primary events occur nearer the positive
If no voltage is applied, the ion pairs, which electrode, fewer secondarily formed ion pairs
have formed, recombine (Figure 3a). This are created. The measurability of the process
means that the positive ions and the electrons depends on the geometry of the detector.
attract one another to reform neutral molecules
or atoms. No current is measured and hence, no If the voltage is increased further (Figure 3 d
ionizing radiation is detected. and e) the electrons will, between collisions,
gain that much energy that they, in turn, can
If a small voltage is applied produced ion pairs give rise to secondary ionization. This will
can either recombine or are separated by the create ion pairs that were not produced directly
electric field. The number of separated ion pairs by the ionizing radiation. Figures 3 d and e also
increases with increasing voltage, but is still show how the collected charge varies depending
less than the number produced by the ionizing on where the primary ionization took place. By
radiation (Figure 3b). designing the electrodes suitably, detectors can
be constructed so that the collective charge is
Increasing the voltage further a stage is reached practically independent of where the primary
where all the produced ion pairs are separated ionization occurred.
and picked up by the electrodes (Figure 3 c).
The electrons and the positive ions are
accelerated in the electric field but collide I II III IV V
1012
occasionally with neutral gas particles and lose
Recombination area

their kinetic energy.


Ion chamber area

1010
Number of collected ion pairs

Proportion counter area Geiger-Muller Spark area


a b c d e area
108
0 - - - -

106

104 N2 Number of ion pair


from a α - particle

102
0 + + + + N1 Number of ion pair
from a β - particle
100
0 300 600 900
Figure 3 The influence of the voltage between High voltage (V)
the electrodes of a gas detector.
a. If the voltage is zero, the ion pairs formed Figure 4 The number of collected ion pairs in a
recombine. No current flows through the gas detector as a function of the electrode
detector. voltage. A detailed explanation of the diagram
b. If the voltage is small, the ion pairs formed is given in the text.
can recombine or travel to their respective
electrodes. The current through the detector

61
The influence of the voltage is summarized in
Figure 4 that gives the number of collected ion
pairs as a function of the increased voltage. The
diagram shows, as a comparison, the number of
primary produced ion pairs from a beta particle
(N1) and an alpha particle (N2) and how they
relate to the number of collected electrons.

l Recombination region
The number of collected ion pairs is smaller
than N1 and N2.

ll Ion chamber region


The number of collected ion pairs is equal to the
number of primary ion pairs N1 and N2.
Figure 5 A portable ionization chamber for
lll Proportional region radiation protection use. The current measured
The number of collected ion pairs is equals the primary formed ion pairs.
proportional to the number of primary ion pairs
formed. The proportional factor, also called the An ionization chamber with a capacity of 1 liter
gas multiplication factor, can be as large as exposed to an irradiation of 1 µGy/h produces
100,000. an ion flux of about 10-14 A. In a portable
instrument, it is difficult to amplify and measure
lV Geiger-Müller region smaller currents. Hence, 1 µGy/h is usually the
The number of collected ion pairs does not lower measurement limit of such instruments.
depend on the number of primary ion pairs By refining the electronics or increasing the
formed. Even if the deposited energy varies, the ionization volume, instruments with higher
detector gives the same pulse height. sensitivity can be made but they become bulky
and cumbersome.
V Discharge region
A spark occurs between the electrodes for each Proportional Counters
ionizing particle, which gives rise to ion pairs in
the detector. By increasing the voltage, primary produced
electrons can be accelerated to such a high
Ionization chamber velocity that in turn they can cause further
ionizations.
A detector that works within the saturation particle
region in which all the formed ion pairs are path
assembled is called an ionization chamber
(Figure 2) and is generally a portable
- -
instrument. The ion flux produced in the -
+
instrument can be measured directly.

Figure 6 A proportional counter. The


measured current is proportional to the number
of ion pairs formed. The ratio between
measured and primary formed ion pairs is
called the gas multiplication constant.

62
As is illustrated in Figure 3 d and e, the number Geiger-Müller counter (GM-tube)
of assembled electrons depends on where the
primary ion pairs are formed. By shaping the If the high tension is increased above the
positive electrode suitably, this dependency on proportional region, the proportionality between
position can be eliminated. If a thin straight pulse size and primary ionization is lost. In
filament or loop is used as the positive region IV of Figure 4, the so-called Geiger-
electrode, the field intensity close to it is so Müller tube's plateau, the detector pulses
great that it causes secondary ionization (Figure become equally large for α- and β-particles. The
6). gas amplification can amount to 108 but the
pulse size does not vary very much. If the
In the large volume of the detector, the primary voltage is increased still further, there is an
formed electrons migrate towards the positive electrical breakthrough creating a spark.. We
electrode without causing secondary ionization. then enter into the spark chamber area where
Only the electrons within the nearest light or sounds from the sparks are counted.
millimeters of the thin filament are exposed to
such high field intensity that they can cause In the GM-tube, the electron avalanche close to
secondary ionization. Within this region, each the filament advances along the whole filament
primary formed electron causes repeated (Figure 7) with a speed, usually 10 cm/µs. In the
ionization, which results in intensification of the gas cylinder around the filament, all electrons
primary current pulse. This ionization avalanche are picked up by the electrode creating
can intensify the primary yield by a factor of positively charged plasma. This decreases the
100 to 100,000. The phenomenon is called gas electrical field gradient in the immediate
multiplication. It is mainly the composition and environment of the filament that is essential for
the pressure of the gas that determine the the genesis of an electron avalanche. When the
sensitivity and the working voltage of the positive ions have diffused towards the casing
proportional counter. of the tube, the high electrical field intensity
around the filament is restored and the tube is
The size of the current pulse obtained from the again ready to trigger a new event.
counting tube is proportional to the number of
primary ionization created by the penetrating particle
particle. This can be used in a mixed radiation
path
field to separate between particles, such as
alpha and beta particles, giving away different - -
specific ionizations. Such pulse screening -
demands precisely stabilized high tension and +
pulse height discriminators. The area around
the central
electrode will be
By working the proportional counter at competely ionized
atmospheric pressure, the chamber can be
designed so that a weak radioactive sample can
be introduced into it. Thus a favorable Figure 7 Geiger-Müller detector. The discharge
measuring geometry is achieved and at the same around the filament produces so much positive
time the method makes it possible to measure charge that the region of high electrical field
particles whose energy is so low that they strength disappears. When the positive ions
cannot penetrate the chamber walls. This type of have diffused towards the surface, the high field
detector is called a "flow counter". After strength returns and the detector is again
entering the sample, a suitable gas composition sensitive.
in the detector is established by a slow flow of
counter gas (Figure 9 c). When the positive ions reach the wall of the
tube, they can knock out electrons from it and
thereby create new pulses unintentionally. This
can be prevented either by electronic

63
"quenching-circuits" that reduce the tube
voltage briefly (between 10-3 and 10-4 seconds) Figure 9 Different constructions of gas
or by making a gas mixture so that the tube detectors
becomes "self-extinguishing".
However, low-energy photons and electrons can
As a rule, the gas mixture consists of an inert not readily penetrate thick detector walls. For
gas such as argon at a pressure of 10 cm these types of radiation, detectors with thin
mercury and a quenching gas, commonly walls must be chosen so that the radiation can
ethanol (10 %) or halogen (0.1%). Tubes enter the detector gases. For low energy
containing an alcohol admixture have a limited electrons (e.g. beta particles from 14C)
lifetime (1010 pulses) since the alcohol extremely thin windows (1-10 µm) are essential.
molecules are consumed, whereas halogen tubes Often a combination is used in that a thick-
have the practical advantage of unlimited walled detector is provided with a thin foil at
lifetime. one side. Such a construction is usually called
an end-window counter (Figure 9 b).

To detect 3H-beta (energy < 18 keV) a


windowless detector (gas flow counter, Figure 9
c) has to be used. To achieve stable conditions,
the detector gas is allowed to flow at uniform
speed through the detector out by an opening
where the investigated object is introduced.
Radiation protection instruments that work
according to this principle have been
constructed to detect 3H but are generally
expensive and difficult to use.
Figure 8 This instrument contains a small GM-
tube. A larger GM-tube can be connected if a The ionization chamber is principally the best
more sensitive measurement is required. This instrument (Figure 5) to measure the radiation
tube may be of the end-window type, equipped energy deposited or the dose equivalent. The
flow of ions through the chamber is directly
with a very thin foil that allows low energy β-
proportional to the absorbed energy.
particles to penetrate.
Disadvantages are that the instrument is
relatively insensitive and can be heavy and
Gas detectors can be made in many different
awkward to use.
ways for different uses. An instrument for
photon radiation with energy higher than 50
The proportional counter gives a pulse that is
keV requires a thick wall around the gas (Figure
proportional to the energy, but it is not
9a). Photons with high energy have very little
especially suitable for measuring the absorbed
likelihood to interact with the gas itself. The
dose. When the proportional counter is used as
thick wall increases the probability for
a radiation protection instrument, it is usually to
interactions where high-energy photo- or
differentiate sparse and massive ionizing
Compton electrons are formed. These can then
enter and ionize the detector gas. radiation (e.g. α and β).
Sample
The Geiger-Müller counter gives no energy
information. However, by a suitable assembly
of the detector walls, the instrument can be
Gas calibrated to show the dose rate equivalent
inlet (µSv/h) for photons within a wide energy range
(50 keV - 3 MeV). It must be stressed that this
Stright, cylindrical tube End window tube Gas flow tube is only an approximate calibration and valid

64
only for photon irradiation within this energy
range. The great advantages of GM-detectors Ionizing
are that they can be of robust make, easy to radiation
handle, relatively sensitive, and cheap. Deposition of energy as
ionizations and excitations.
Material: Crystals, organic
Scintillation Detectors liquids and gases.

A part of the energy is


Many solid and fluid materials can convert the transformed into light
energy of absorbed radiation into light. This emitted in flashes or
phenomenon, luminescence, has for a long time scintillations.
been used in nuclear physics to demonstrate The scintillations are registered
Photomulti- by a light sensitive detector
particles and to make direct observations on plier tub which transforms the light into
fluorescent screens, e.g., patients undergoing electric signals.
radioscopy. As early as 1910, Rutherford used a
scintillation detector (zinc-sulfide) when he The electric pulses are analyzed
and recorded by a special type
made scattering experiment with α-particles. He Electronics
of electronics, pulse electronics.
then observed the light flashes from the screen,
the scintillations, with his naked eye.
Figure 10 Principles of a scintillation detector.
Today, sensitive light detectors (photo-
multiplier tubes and photo-diodes) can convert Both organic and inorganic material can work
transmitted light to an electric signal, which is as scintillators. Organic scintillators can be
then recorded. The principles of a scintillation regarded as organic scintillating molecules in
detector are given in Figure 10. Requirements solution, either in a liquid form or in a solid
for scintillating material to be used for detector phase. They usually have a density and an
purposes can be summarized as follows: elementary composition corresponding to the
body tissue. They are also characterized by great
1. High efficiency in converting energy in the speed, that is to say the light flashes are of short
form of ionization and excitation to light. If a β- duration. An advantage is that they can be made
particle deposits 100 keV in a scintillator with a in large volumes where several photo-
10 % conversion factor, only 10 keV is emitted multipliers collect the light.
as light energy (photon of blue light ~ 3 eV).
Accordingly, at each scintillation about Inorganic crystals have greater density (2,000 -
10,000/3 ~ 3,000 light photons are obtained. 8,000 kg/m3 ) and often have greater light yield
with longer after-glow time than organic
2. A scintillator must be transparent for the scintillators. The most common crystal in the
light it produces. inorganic group, sodium iodine activated by
thallium, NaI(Tl) is available commercially in
3. The light photons must be emitted during a sizes up to several dm3 and in thin slices with
short period (< 10 -5 s). diameters of 1 m or more. Due to favorable
characteristics, absorption, light emission, speed
4. The frequency of the emitted light must be in and costs, NaI(Tl)-detectors have a great
accordance with the light detector's response significance in γ−radiation detection. These
function. A photo-multiplier tube usually has a crystals are very sensitive to humidity and are
sensitivity of about 20 % to detect a blue therefore encased in an internally white,
photon. For the example above, this means that reflecting wrapper with a window that permits
if 3000 blue photons hit the PM-tube only light to reach the photo-multiplier tube.
3000*0.2 = 600 photons are detected.

65
NaI(Tl) - detectors
Scintillation Radiation
The principle of a scintillation detector is shown
in Figure 11. For gamma detection it is an Scintillator
advantage if the scintillator contain high atomic
number materials, such as iodine, since it has a Photocathod
high probability to interact with gamma. A high
probability to absorb the total gamma energy is
also of advantage since it determines the
incoming gamma energy.

The produced light photons in the detector hit etc


the photoelectric cathode of the photo-
Dynods
multiplier tube. Generally, this consists of a
bivalent alkaline compound, e.g. SbKCs, which
has many loosely bound orbital electrons. Light
photons can expel these electrons in a photo
absorption process. The freed electrons are
accelerated in vacuum by an electric field Anode
towards an electrode. The kinetic energy
transferred creates more electrons, which in turn
are accelerated towards a new electrode and so R C
on. The electrodes are called dynodes and give -V+
rise to secondary electrons (compare gas
multiplication).

Typically, each dynode hit gives rise to 2 - 5 Figure 11 The principle of a NaI(Tl) detector.
electrons. Generally a photo-multiplier tube has A crystal of sodium iodide, usually in the form
6-10 dynodes and may yield an electron of a cylinder, is attached to a photo-multiplier
amplification of about 106 times. Consequently, tube with good optical contact. Other surfaces
for each light photon that produces a are coated with reflecting material to force light
photoelectron, 106 electrons are obtained from photons to hit the photo-multiplier tube no
the photo-multiplier tube. A 100 keV deposition matter where they are formed in the crystal.
in the crystal may produce about 3,000 light X-ray from Photo peak
photons. Typically will this produce 600 photo- the K-shell
electrons (20 % conversion efficiency) and in
the end a current pulse containing 600 · 106
Back scatter Compton
electrons will emerge from the photo-multiplier
Number of pulses/keV

1000
peak edge
tube.

The entire detector must be encased in a light-


and airtight covering to protect the photo-
multiplier from outside light and the crystal 100

from humidity.

10
0 200 400 600 800
Pulse height, γ-energy (keV)

Figure 12 Gamma energy spectrum of 137Cs

66
Generally, the sodium iodide crystal is "doped" Plastic Crystal Detector
with a small amount of thallium (0.2 %) to
increase the light yield. Because of its high If the sodium iodide crystal is exchanged for a
density and the high atomic number of iodine, plastic crystal, a detector is obtained that can be
the sodium iodide (thallium) detector is best suitable for both beta- and alpha- detection. The
suited for the detection of gamma- and X- light proof wall of the crystal can be made
radiation. When the pulse coming from the extremely thin to let low-energy particles
detector is proportional to the deposited energy, penetrate.
and the radiation frequently deposits its entire
energy in the crystal, the detector can be used This type of detector is also sensitive to photon
for energy analysis. A typical gamma energy radiation but, due to its low density, not to such
spectrum is shown in Figure 12. a high degree as the sodium iodide detector. The
plastic crystal detector is not suitable for energy
analysis of photon radiation. The low atomic
number of plastic material makes the photons,
especially incoming photons, deposit only part
of their energy in the detector (Compton
interaction). The probability of photo absorption
is of course low.

Liquid Scintillation Detectors

A scintillator in the form of a liquid makes it


possible to mix the sample to be measured with
the actual detector material (Figure 14).

Solved
radioactive Liquid
sample scintillator

Figure 13 Scintillator detector for radiation


protection purposes. There is either a thin
Photomultiplicator
NaI(Tl)-crystal adapted for photon energies
tube “viewing” the
from disintegration of 125I or a thick NaI(Tl)-
scintillations
crystal designed for detection of higher gamma
energies.
Sample and Electronics counting
Thin crystals make suitable detectors for scintillator pulses and analysing
photons of low energy. The total crystal volume are mixed pule height
is small and hence the efficiency for other
radiation, e.g. cosmic radiation, is small. Hand Figure 14 Principles for Liquid Scintillation
instruments intended for the detection of 125I are Counting. The advantage of this method is the
available and can be made sufficiently sensitive intimate contact obtained between sample and
to detect small amounts in the thyroid gland (a detector. No walls prevent a direct transfer of
few hundred Bq). At high photon energies, one β-energy to the scintillator.
needs to increase the crystal volume to increase
the efficiency. Thereby the background This technique maximizes the energy transfer
contribution from cosmic radiation increases from sample to detector and hence is well suited
and these detectors become less suitable for for measuring low-energy radiation from, for
detecting radiation of low energy.

67
example 3H, for which suitable radiation Photographic Emulsions
protection instruments are lacking.
Ionizing radiation such as visible light can
affect the silver halide granules of photographic
emulsions so that in the development process
they can be reduced to silver. Thus, blackening
of photographic films may occur as for X-ray
photographic examinations. Photographic films
can also be used for dosimetry.

Figure 15 Liquid Scintillation Detector. The


instrument is very useful for radiation
protection work e.g. in contamination tests.
Figure 16 Two types of personal dosimeters. A
One common way to use the liquid scintillation track film type is on the left. In films e.g. nitrate
detector for radiation protection is to make a cellulose films, high ionizing particles cause
sweep test. A bench surface or part of the body tracks, which can be developed and counted. To
suspected of being contaminated is washed with the right is seen a dosimeter based on
absorbent material moistened in a suitable photographic film. When the film is irradiated it
solvent. The absorbed material is then put in a gets blackened. The density can be measured to
scintillation flask (Figure 15), then put in the give an idea of the dose of ionizing radiation
scintillator and the sample is measured in the received.
detector. By analyzing the pulse heights,
information can be obtained as to whether the Electrons or γ-radiation causes a general
material emits radiation energy. blackening of film emulsions whereas heavy,
charged particles, which have proportionately
Semiconductor Detectors short range, give rise to trajectory tracks that
can be studied under the microscope. Such track
Solid material may be used as an alternative to detectors may also be used for non-charged
letting the radiation interact with a gas and radiation, e.g. neutrons. In the plastic film
collecting the ions formed in it. Suitable backing, the fast neutrons are scattered against
semiconductor materials are silicon and the protons. In this process, low-energy protons
germanium. Sometimes such detectors must be with high LET produce tracks that can be
cooled to a low temperature. measured and used to quantify the neutron dose.

Semiconductor detectors that often have very In radiation protection work, film dosimetry is
good energy resolution have frequently been of great importance for routine individual dose
used for α- and β- spectrometry. measurements. Two emulsions of different
sensitivities are often used to ensure detection
in a wide dose range.

The density of the blackness is obtained by


using densitometers, instruments that record the

68
amount of light that passes through the film Free electrons
emulsion. The densitometer scale is graded to
give a direct reading of the density and dose. Ionizing radiation hit the
thermolumiscent material.
Bound electrons are lifted up
By protecting different parts of the film with in the conducting band.
different types of filters, one may separate Bound
electrons
between charged particles and photons. Low-
and high-energy gamma radiation can also to a
certain degree be separated. This is sometimes A certain proportion of the Free electrons
essential for estimating the risks associated with free elctrons are immediately Electron trap Light emitted
irradiation. falling back to the bound state
while emitting the excess energy Forbidden in an allowed
as a light photon. Other are transition transition
Thermoluminescence Dosimeters trapped in intermediate levels
with long life-time. Bound
electrons
In certain materials such as LiF, CaSO4, CaF2,
and BeO, the ionizing radiation can cause
excited conditions that can persist for a long The trapped electrons Free electrons
time. By heating the material, de-excitation can are lifted up to the conducting Electron trap Light emitted
band by heating the material.
be achieved whereby light photons are emitted They may then fall back to the Forbidden in an allowed
and can be recorded. The amount of light bound state emitting a light transition transition
emitted is proportional to the amount of photon which is detected.
Bound
radiation to which the dosimeter is exposed. electrons

The radiation transfer energy to the bound Figure 17 Principle of operation of the
electrons in the material. Some are energetically thermoluminescence dosimeter.
raised up into the conducting band (Figure 17a).
When these electrons fall back towards their
bound electron state, they may be trapped in an
excited level between bound and conducting
energy levels (Figure 17 b). These traps are
caused by impurities in the material. The
electrons cannot energetically fall down into the
bound energy levels since such changes are
"prohibited". Depending on the material, the
electrons can remain for months in these
"traps". The energy added in the heating process
during read-out lift up the trapped electrons into
the conducting level (Figure 17) from which
they can fall directly to the ground levels,
emitting light photons that are recorded.

The thermoluminescent dosimeter can to a


certain extent replace film as a personal
dosimeter and is also suitable for special
appliances such as finger dose measurements. It
is light, available in different forms, and easy to
tape securely to the fingers.

69
CHAPTER 8
Scintillators in the laboratory
rather thick samples emit measurable amounts
SUMMARY of radiation. However, the detector material has
to be heavy and dense to detect high-energy
The following table lists different detector photons with some efficiency. The detector
principles for ionization radiation should also surround the sample to increase the
detection efficiency.
Type of Type of instrument Detector From such considerations two main detection
signals material techniques have developed to measure
Electrical Ionization chamber Gas radioactive biochemical or biological samples
pulses Proportional counter Gas • the liquid scintillation counter and
Geiger-Müller tube Gas • the gamma well counter based on NaI(Tl)
Semi-conductor Solid state Since such instruments are commonly used we
Chemical Film Photographic will here consider the technique in some detail.
Changes emulsions The measuring results depend on different
Chemical dosimeters Solids/fluids experimental conditions such as the type of
radionuclide used, the volume and the chemical
Prompt Scintillation counter Crystals or conditions of the samples, etc. Although
photons liquids modern instruments tend to automatically
Čerenkov counter Crystals or correct for a number of variables, untrained and
liquids non-experienced personnel may introduce
Delayed Thermo- Crystals severe measurement errors.
photons Luminescence
LIQUID SCINTILLATION COUNTING
Phosphorous Crystals
Imaging The main idea in this technique is that both the
Raising Calorimeter Solid or fluid sample and the detector are liquids, which are
mixed to have a close contact. The detector
of temp.
material converts the beta energy into light
photons.
DEFINITION OF THE PROBLEM
Sample Liquid scintillator
Most radionuclides of biological importance,
such as 3H and 14C, are pure, low energy beta
emitters. The maximum beta energy of 3H (18 Low energy beta will not penetrate
keV) has a penetration of about 10 µm in water. detector walls.
Solve the sample!
The mean energy of 6 keV yields about 200
Add liquid scintillator!
ionization events in total (30 eV per ionization). Shake!
Measure!
If we want to measure 3H with some efficiency
we can then conclude that Figure 1 The radioactive sample is mixed with
• the sample has to have negligibly mass or the liquid scintillator detector in a plastic or
thickness to avoid self-absorption glass vial (usually 2-20 ml in volume).
• the detector should not have an absorbing
window The vial with the sample and the scintillator is
placed inside a measuring chamber (Figure 2)
If a gamma- or X-ray-emitting nuclide, such as where all the emitted light is reflected into 2 or
125
I, is used the self-absorption in the sample is 3 photo-multiplier tubes.
of minor concern. The HVL of 125I-photons in
water is about 2 cm, which means that even

70
The detector Radioactive
decay
The energy transfer process from the radioactive Energy transfer
decay to the emission of light is described
Excited solvent
below. Chemicals that convert absorbed energy
molecule
to light are called “fluors”. Usually 5-10 gram Energy transfer
fluor is solved in one liter of aromatic solvent. N
The aromatic structure of the solvent is essential Excited fluor
O molecule
since it provides a first excited electron level
about 3-4 eV above the ground state. The
number of excited states is proportional to the Emission of
energy delivered by the beta particle. This light
excited level in the solvent has a rather long
lifetime but is sooner or later transferred to the Figure 3 A schematic figure of the energy
first excited level in the fluor (of somewhat transfer from the beta energy to the emission of
lower energy). This excited level in the fluor blue light photons.
has a short half-life (in the order of some
nanoseconds). In the decay a blue light photon Typically, about one blue photon is emitted per
is emitted. 200 eV deposited by the beta particle. The
detection efficiency for the PM-tube is about 20
MEASURING CHAMBER %. On average, it takes about one keV to create
one photoelectron as seen in Table 1. Thus, a
Reflectors Liquid scintillation vial
beta particle of 1 keV or less will probably not
give rise to a signal at all.
Photomultiplier Photomultiplier
tube 1 tube 2 Table 1 The table shows typical radionuclide
photon and photo electron yields for a single
decay event

Scintillation pulse Radio- Max Mean Typical Photo


nuclide Decay decay photon electrons
Background pulses Energy energy yield in the
(keV) (keV) PM tubes
Coincidence circuit. Accept simultaneous 3
H 18 5.6 30 6
pulses only. The summed output pulse is 14
proportional to the total energy delivered C 159 50 250 50
32
in the vial by the beta particle. P 1700 650 3300 660
Summed pulse
There is also a background to overcome. Now
and then, a spontaneous emission of an electron
Figure 2 A liquid scintillation sample is placed
from the cathode surface occurs (called the dark
inside the measuring chamber. The light
currant of the PM-tube). To distinguish the true
photons from the scintillation are forced to hit
signal from the background modern instrument
one of two photo-multiplier tubes. A coincident
use two or three PM-tubes coupled in
circuit sorts out background pulses coming
coincidence (see Figure 2).
stochastically from each PM-tube from true
events, which create simultaneous pulses in the
The solvent
two PM-tubes.
Pure benzene is a highly flammable liquid with
a high vapor pressure, which should be avoided
due to environmental reasons. Therefore, early

71
scintillators were usually based on toluene or The scintillator
xylene. Modern scintillators are., from this The solvents themselves are rather poor
aspect, based on even better solvents (Table 2). scintillators since the decay time of the excited
states is rather long and the PM-tubes are not
Table 2 Some data of commonly used solvents sensitive to the wavelength emitted. A more
in liquid scintillation detection. efficient scintillator, a fluor, with short half-life
and with a suitable frequency of emitted light is
Solvent Flash Equilibrium vapor therefore added. The most widely used primary
point concentration, 25 oC scintillator is 2,5-Diphenyloxazole, better
(oC) (parts per million) known as PPO (see Figure 4). It emits light with
fluorescence maximum at 365 nm.
Toluene 4 36 000
Xylene 9 11 000 N
Phenyl-ortho-
149 1 400 O
xylyl ethane, PPO, 2,5-Diphenyloxazole
PXE
Di-isopropyl- CH3 CH3
naphthalene, 148 1 600
DIN Scint CH=CH CH=CH

´HiSafe´
Bis-MSB, 1,4-Di-(2-methylstyryl)-Benzene

The high flash point solvents have several


advantages. They may be stored during normal Figure 4 Commonly used primary scintillator,
room conditions. The low vapor pressure lowers PPO and secondary scintillator, Bis-MSB.
the ventilation demands. These solvents have a
much lower penetration through the standard A problem may arise if the sample absorbs light
polyethylene vials, which enables long term in the frequency region of PPO emission. This
counting. The health hazard is considered to be may be solved if a wavelength shifter
lower than for toluene but contamination by the (secondary scintillator) is introduced, which
skin should be avoided. A slight disadvantage is converts the 365 nm to a somewhat longer
that the counting efficiency is somewhat lower wavelength. A common secondary scintillator is
than that for a toluene-based scintillator. 1,4-Di-(2-methylstyryl)-Benzene (Bis-MSB).

Water-based samples cannot directly be mixed Detection efficiency


with organic solvents. Usually, a detergent such
as Triton X100 is introduced into the scintillator As seen in Table 1 the number of photo-
liquid to cope with this problem. Small amounts electrons, i.e. the number of electrons emitted
of water (up to 1.5 ml sample per 10 ml from the cathode surface of the PM-tube, is few.
scintillator) can then be solved in the The coincidence condition requires that at least
scintillator. If more water is added (5-10 ml one photoelectron is created in each PM-tube,
per10 ml scintillator) a stable gel is formed that which corresponds to a deposited energy of
also can be used for counting. The intermediate about 2 keV. In a continuous beta spectrum,
volume area, (1.5 -5 ml sample per 10 ml there will always be beta particles present with
scintillator) creates an unstable two-phase such low energy that they do not trigger the
system, which is not suitable for counting. The coincidence circuit. The counting efficiency is
borders between the different phases vary with thus always below 100 %. It is easy to realize
temperature, and chemical composition of the that this creates most problems in low-energy
sample, and details have to be taken from each beta spectra, such as 3H where the relative
individual producer of the scintillation cocktail. amount of such particles is high. Typical
detection efficiencies for 3H are about 65 %, for
14
C 95 % and for 32P better than 99 %.

72
CPM per energy 3H losses in the energy transfer process (Figure 3).
There are three main types of quenching
14C processes that occur in the system:
32P

• Physical quenching
• Chemical quenching
• Color quenching

18 159 1700 Physical quenching


Energy (keV)
In gel counting, the scintillation system forms
Figure 5 Energy spectrum of three typical beta- small micro-droplets. The hydrophilic part of
emitting nuclides. The energy scale is the detergent is directed against the water
logarithmic to enable a simultaneously display droplets whereas the lipophilic part is in contact
of the varying beta energy distributions. with the organic solvent. The diameter of the
droplets varies with the system parameters and
The number of counts is often referred to as the amount of water in the scintillator, but is in
counts per minutes (CPM) and is related to the the range of 20-200 nm. If the radioactivity is in
number of disintegration per minute (DPM) by the aqueous phase, the beta particles have to
the detection efficiency ε as penetrate a layer of water before they can start
CPM = ε * DPM
to interact with the detector part. During this
water passage energy is lost that is not available
Another important parameter is the pulse height for light production.
since it is related to the total deposited energy.
14
C counting gives, in the mean, 8 times higher Another example of physical quenching is
pulses than 3H counting. This makes it possible counting radioactivity absorbed in a solid phase,
to separate between these two radionuclides in e.g., a filter disc.
dual labeling experiments. The common way to
display this is in an energy spectrum as seen in Chemical quenching
Figure 5. Since there is a large difference in the
beta energies between different nuclides (a Any compound in the system that does not have
factor of 100 between 3H and 32P) the energy an aromatic structure similar to the solvent
scale is usually logarithmic. The area of the interacts with the excited states. Such molecules
spectrum gives the total numbers of counts. may steal the excited state and de-excite it in
small steps without creating a light photon. The
A common way to handle this is to amplify the most severe quenching agents are halogenated
summed pulse (see Figure 2) with a logarithmic compounds (CCl4 > CHCl3 > CH2Cl2), ketones
amplifier. This pulse is analyzed by an analogue and aldehydes. Less severe are salt solutions,
to digital converter (ADC) and is presented by a bases, acids, alcohol and water.
multi-channel analyzer (usually 1024 channels
or more). It is then easy to sum different parts of Color quenching
the spectrum.
Color quenching occurs after the fluorescence
Quenching stage, when light-absorbing compounds
interpose. The number of photons that leave the
In an ideal world the energy transfer in the scintillation vial and hit the PM-tubes
scintillation system would be both perfectly decreases. The fluorescence emission takes
efficient and undisturbed by environmental place in the blue region of the spectrum. A
factors. In the real word, however, energy losses sample collared in yellow preferably absorbs in
are substantial and depend on several factors. blue and therefore the order of severity of color
Quenching is a term used to describe energy quenching is:

73
Sample Channels Ratio
Red > orange > yellow > green > blue
To calculate the DPM of an unknown sample,
In all types of quenching, energy is lost. The the counting efficiency of the sample must be
pulse out is lower and the energy spectra in known. Spectral shifts are directly related to
Figure 5 are moved to the left. This means that energy losses and thus to counting efficiency. A
differently quenched samples are measured with correction method, which uses the radioactivity
different counting efficiency. However, if the in the sample itself can be designed as follows:
quenching in an experiment can be proved to be
constant, then the CPM value may be used as a  A number of calibration samples with
substitute for DPM values. known amount of radioactivity are quenched
differently. The samples are measured
Quench Correction (CPM) and the counting efficiency (ε =
CPM/DPM) of each sample is determined.
A methodology is therefore required to evaluate
the level of quench, determine the detection  The spectral shift due to the quenching is
efficiency, and correct the CPM result to give also quantified. The classical method is to
DPM. split the spectrum into two parts or two
''counting windows''. A ratio is formed
Quench correction adding an internal
standard Count window 1
Sample Channel Ratio ( SCR ) =
Count window 2
One method available is to add a known amount
of a radioactive isotope to the scintillator
sample mixture. This is called ''spiking''. Ideally  SCR is measured in all the calibration
the isotope added should be in the same phase samples and will vary with the degree of
as the sample. Using the following equation, the quenching. We can now make a plot with
efficiency of the energy transfer process can be the efficiency (ε) on the y-axis and the
determined. quench-measure (SCR) on the x-axis.

Efficiency = CPM increase/DPM added  For an unknown sample we can determine


SCR. From the plot we can then determine
The advantages of this method are that only the measurement efficiency of the unknown
simple arithmetic is required to obtain a DPM sample.
result. However, the disadvantages are many
and the method is only used in special Multi-channel analyzer (MCA) technology
situations. The disadvantages are: where one can use thousand windows instead of
two to quantifying the spectrum shift of the
• Costly in terms of the amount of radioactive sample has improved this technique somewhat.
isotope needed However, the main drawback is that one need to
have fairly high levels of radioactivity in the
• Costly in extra handling time.
samples to obtain good statistics in the quench
• Costly in extra counting time (it is necessary parameter.
to count the sample before and after
spiking). External Standard Channels Ratio
• Additional potential health hazard in extra
sample handling. Samples with low radioactivity content are thus
• Physical quenching can lead to errors in the still a problem. The common way to overcome
efficiency calculation. this is to irradiate the samples for a short
• Increased errors due to multiple pipetting. moment with a strong, gamma-emitting source.
This irradiation produces Compton electrons in
the sample that will interact with the

74
scintillation solution as the beta particles do. However, the most commonly used gamma
We can then measure a Compton electron detector in a biological laboratory is by all
spectrum, which is shifted in a quenched sample means a well counter based on NaI(Tl) (see also
like a beta spectrum. Chapter 7). We will below discuss different
aspects of NaI-systems in some detail.
We can then create a quench measure, External
Standard Channels Ratio (ESCR), which can be Sodium iodide spectroscopy
used to monitor sample efficiency in the same
way as above. It is independent of the sample Because NaI(Tl) detectors have energy
radioactivity and high statistical confidence is resolution, they can discriminate between
achieved rapidly. gamma rays of different energies and hence can
map the energy spectra of radionuclides. Before
Modern equipment, which analyses the data going into a detailed discussion of the features
with MCA, can create special Quench of NaI(Tl) spectroscopy, it is useful to briefly
Parameters based on the external standard and review the physics of gamma ray interactions
can from these measurements automatically (see also Chapter 3). Over the range of energies
correct for various types of quenching. typically encountered in nuclear medicine and
biology procedures (30 keV to 1 MeV) there are
CRYSTAL SCINTILLATION COUNTING two gamma-ray interaction modalities:
photoelectric absorption and Compton
In liquid scintillation we measure the energy scattering.
deposition of charge particles. Due to the low Z-
number, gamma is detected with low efficiency. In photoelectric absorption, the gamma ray’s
However, all gamma-emitting nuclides also energy is completely absorbed by an inner-shell
emit charged particles such as beta particles, atomic electron, The electron is ejected from the
conversion electrons, Auger electrons etc. and atom with an energy equal to the gamma-ray
can thus be effectively detected in a scintillation energy minus its atomic binding energy. The
detector. empty vacancy left by this event is quickly filled
by outer-shell electrons with the emission of
So why use a gamma detector if you already characteristic X-rays and Auger electrons. The
have a liquid? The answer is that gamma cross-section (that is the probability that an
counting is more simple and reliable. The interaction occurs) for photoelectric absorption
gamma rays penetrate even large samples so depends on the cube of the atomic number (Z3)
there is no need to solve the sample. The sample of the absorbing materials. Because of the high
composition does not influence the effective Z of NaI(Tl), photoelectric absorption
measurements and no quenching corrections are is an important interaction up to 1 MeV and is
needed. However, there is still a need to the dominant interaction up to about 300 keV.
understand the system in order to avoid pitfalls. In low-Z materials such as soft tissue,
photoelectric absorption accounts for a small
A gamma detector needs to be of high density fraction of photon interactions.
and to have a high Z-number to be efficient.
There are a number of crystal materials that In Compton scattering, the incoming gamma ray
fulfill the following criteria: dissipates only a portion of its energy as it
scatters off a loosely bound electron. The energy
1. High atomic number and density lost by the gamma ray is imparted to the
2. High light output electron. The energy transferred to the scattered
3. High transparency electron depends on the scattering angle and is
4. Fast decay time at a maximum when the gamma ray is scattered
5. Stable in time back in the direction it originally came from
6. Inexpensive (back-scatter). The cross section for Compton
scattering is only slowly varying with Z and

75
energy. As a result, Compton scattering is the fraction and depends on the detector thickness
dominant interaction for low-Z materials (such and the gamma-ray energy.
as soft tissue) and becomes increasingly
important in all materials as energy increases. Compton features

When the gamma ray energy exceeds 1.02 MeV It is possible for a gamma ray to be Compton
another interaction known as pair production scattered in the detector and for the scattered
becomes possible. The gamma ray disappears photon to escape without further interaction.
and is replaced by an electron and a positron. The energy deposited in the detector varies with
The electron dissipates its energy and remains the scattering angle. This results in the so-called
stable. The positron dissipates its energy and Compton plateau, which represents the range of
then captures an electron, resulting in mutual possible energy deposition from Compton
annihilation and the emission of two 51l keV scattering events (Figure 7). On the high-energy
photons (annihilation radiation). The cross- side, there is a sharp drop off. This is the
section for pair production depends on the Compton edge, and it corresponds to a gamma
square of the atomic number (Z2) of the ray that is scattered at 180 degrees in the
absorbing material and increases as the gamma detector. The energy of the Compton edge is
ray energy increases above the 1.02 MeV calculated from Eγ -Eγ /(1 + Eγ/255) where Eγ
threshold. is the energy of the gamma ray (in keV).

Photopeak Only a part of The gamma is


the energy stay scattered backward
The most evident feature of the gamma-ray
spectrum is the photopeak, which results from NaI-detector NaI-detector
gamma rays whose energy is totally absorbed in
the crystal (Figure 6).
Counts per channel

Total absorption
Compton
NaI-detector edge
Counts per channel

Distribution of
Compton electrons
Photopeak or
Full value peak

Photon energy

Figure 7 Gamma spectrum of a NaI(Tl)-


detector. The shaded part shows the Compton
Photon energy scattered energy deposit in the detector.
Figure 6 Gamma spectrum of a NaI(Tl)-
detector. The shaded part corresponds to the Escape peaks
photopeak or full energy peak.
When a gamma ray interacts with the sodium
Because this is generally the result of a iodine crystal, it is possible that only a portion
photoelectric absorption, it is referred to as the of the energy is absorbed. This is how the
photopeak but any combination of interactions Compton edge and plateau are formed (as just
that result in the complete absorption of the described). Energy from interactions can escape
gamma ray contributes to the peak. The fraction the crystal in other ways that yield discrete
of counts in the energy spectrum that fall within peaks in the spectrum, so called escape peaks.
the photopeak is referred to as the photo-

76
Lead X-rays
Iodine x-ray leaves crystal
Lead x-ray is detected
NaI-detector
Counts per channel

Lead shield

NaI-detector

Counts per channel


Iodine Escape Peak Lead shield
Energy = Eγγ - 27 keV
Lead x-ray
Energy = 80 keV

Photon energy

Figure 8 Gamma spectrum of a NaI(Tl)- Photon energy


detector. The shaded part corresponds to a loss
of energy from the full energy peak due to an X- Figure 9 Gamma spectrum of a NaI(Tl)-
ray escape. detector. The shaded part corresponds to an
For example, when photoelectric absorption incoming lead X-ray, which is created by
occurs, the characteristic X-rays from iodine are Compton scatter in the detector shield.
emitted isotropically. Normally, these X-rays
are absorbed and contribute to the total energy Because most detectors are shielded with lead,
peak. However, if the interaction takes place it is common to see a peak corresponding to the
near the edge of the detector, the X-rays may lead X-ray energy (approximately 80 keV). This
leave the crystal. This creates an additional peak is emitted when the gamma ray undergoes a
called the iodine escape peak with a pulse photoelectric absorption in the lead shielding
height 27 keV less than the total gamma-ray and the lead characteristic X-ray is absorbed by
energy (Figure 8). Iodine escape peaks are the detector (Figure 9).
usually only evident for low-energy photons (<
100 keV), in which a substantial fraction of the Coincidence sum peaks
gamma rays are absorbed near the crystal
surface. Two gamma in the
same decay are
detected simultaneously NaI-detector
Another type of escape peak may be observed
when high-energy gamma rays are counted and
Counts per channel

pair production is possible. If the annihilation


takes place in the crystal, one of the 511 keV
annihilation photons, or both, may escape the
crystal. Thus two additional peaks can be seen, Coincident
Sum Peak
one at 511 keV below the true photopeak and E=Eγγ1+Eγγ2
the other at 1.02 MeV below. It should be noted
that if pair production occurs in the vicinity of Eγγ1 Eγγ2
the detector (for example, in the lead shield), a
peak at 511 keV also shows up in the spectrum.
Photon energy
Figure 10 Gamma spectrum of a NaI(Tl)-
detector. The shaded part corresponds to the
summation of two simultaneous gamma-ray
energies.

77
If two gamma rays or X-rays are absorbed in the Backscatter peak
crystal within a short time, the magnitude of the
scintillation corresponds to the sum of the When a radioactive source is located some
photon energies. This produces a peak on the distance from a detector and has material behind
spectrum whose apparent energy is equal to the it, a distinct peak is evident on the spectrum that
sum of the two absorbed photons and is referred is due to gamma rays that have been Compton
to as the sum peak (Figure 10). scattered at 180 degrees and then totally
absorbed in the detector. These gamma rays
Coincidence sum peaks can occur from a initially are directed away from the source but
variety of situations: multiple gamma-ray are, after being backscattered, detected (Figure
emission in a cascade (111In), emission of a 12).
gamma and characteristic X-ray in electron
capture (125I) or counting a high-activity source. The reason for a distinct peak is that gamma
Coincidence sum peaks are much more likely in rays scattered at other angles cannot reach the
well-counter geometry where the gamma rays detector. Backscatter peaks are most intense
and X-rays have a much higher probability of when the material behind the source is dense
being simultaneously detected. and has a high Compton cross-section. The
energy for backscatter peak is Eγ /(1 + Eγ /255),
Characteristic X-rays where Eγ is the energy of the gamma ray (in
keV).
Radionuclides that decay by electron capture
necessarily emit characteristic X-rays and Auger Media scatter
electrons because of the inner-shell vacancy that
results from the capture. As a result, there is a If the gamma rays travel through any material
peak on the spectrum corresponding to the on their way to the detector, Compton scattering
absorption of these X-rays (Figure 11). This may occur and the scattered gamma rays may be
peak is often very prominent especially when detected (Figure 12). These scattered gamma
the rate of gamma emission is low. An example rays span the range from the backscatter peak to
of this is 201Tl, in which the 68- to 80-keV X- primary gamma-ray energy for single
ray peak is the most obvious feature in the interactions. If the medium is thick enough,
spectrum. multiple interactions are likely to occur, and the
scattered photons will cover an even wider
Gamma and characteristic x-rays range. Compton photons produced outside the
are emitted in the decay detector and in the detector are not possible to
separate. As a result, when it is important to
NaI-detector discriminate scatter radiation, only photopeak
Counts per channel

events are considered.

Characteristisc
x-ray Peak

Photon energy

Figure 11 Gamma spectrum of a NaI(Tl)-


detector. The shaded part corresponds to the
absorption of a characteristic X-ray emitted in
the decay.

78
energy peaks are broadened as shown in Figure
13.
NaI-detector
OBJECT Peak maximum counts
or NaI-detector
SHIELD

Counts per channel


Counts per channel

Forward
Backward Half maximum counts
spread Compton γ
Compton γ

∆E
E
Compton electrons
from the detector Photon energy
Photon energy
Figure 13 Gamma spectrum of a NaI(Tl)-
Figure 12 Gamma spectrum of a NaI(Tl)- detector. The figure illustrates the way to
detector. Scatter from the detector shield or quantify the energy resolution of a detector.
from an object is scattered into the detector.
Most scatter have energies from zero to the Energy resolution is quantified by determining
energy of the gamma. However, backscatter the amount of spread with respect to the
(photons scattered backwards)l have a more gamma-ray energy. The spread of the peak is
defined energy which appears as an extra peak measured in kiloelectron volts at the half-
in the spectrum. maximum level (full-width-at-half-maximum,
FWHM). Thus, energy resolution is defined as
GENERAL PROPERTIES OF NaI(Tl) Energy resolution = 100% x ∆E/E =
SYSTEMS
=100% *FWHM (keV)/Eγ(keV)
Although NaI(Tl) counters can be configured
Energy resolution improves (gets smaller) as the
and used for a number of different purposes,
photon energy increases. The 662-keV gamma
they have some common characteristics
ray from 137Cs is often used to measure the
including energy resolution energy calibration
energy resolution of NaI(Tl) detectors, and 7%
energy linearity, detection efficiency and count
is a typical result.
rate performance. These will be detailed in the
following sections.
Calibrating a spectrometer
Energy resolution
Because of the proportionality that exists
between the pulse height of the detected signal
Gamma rays are monoenergetic. A detector with
and the energy absorbed from the gamma-ray
perfect energy resolution would generate pulses
interaction, it is possible to calibrate the
with the same pulse height for each gamma ray
equipment in terms of energy. Typically, the
that was totally absorbed and the energy
pulse height analyzer (PHA) has a multi-turn
spectrum for these pulses would be a single line.
dial for adjusting the baseline (lower level) and
Sodium iodide detectors do not have perfect
another dial for adjusting the energy window. In
energy resolution because of statistical
many cases, it is useful to calibrate the PHA
fluctuations in the number of electrons liberated
(MCA) to a true gain of; that is, where 1 unit on
at the photocathode of the PMT. As a result, the

79
the baseline dial corresponds to exactly 1 keV gamma rays (such as the 662-keV gamma rays
of energy. This can be done as follows: from l37Cs) will fall exactly at their expected
settings. Although this is not a problem when
1. Take two radionuclides with different setting up the spectrometer for gamma rays, that
energy gamma rays such as 131I and 99mTc. are relatively close in energy, it must be
The gamma-ray energies should be neither considered when using radionuclides whose
too close in magnitude nor too far away. emissions fall at the extremes of the energy
2. Adjust the baseline and window settings for range.
a 10% energy window centered on the
higher energy gamma ray assuming a true Detector efficiency
gain of 1. For the 364-keV peak of 131I, this
would correspond to a window setting of 36 Not all gamma rays emitted from a source are
and a baseline setting of 346. detected. Some of the gamma rays never reach
3. Put the high-energy source in front of the the detector and of those that do, not all interact.
detector. Adjust the gain of the amplifier or The detector efficiency quantifies the fraction of
the high voltage to maximize the detector gamma rays that are detected. This can be
count rate. considered from two points of view: the fraction
4. Readjust the PHA (MCA) for a 10% of photons hitting the detector or the fraction of
window on the lower energy gamma-ray photons emitted from the source. The first
energy, again assuming a true gain of 1. For depends on the intrinsic efficiency of the
the l40-keV peak of 99mTc this would detector whereas the latter depends on both the
correspond to a window setting of 14 and a intrinsic efficiency and the source detector
baseline setting of 133. geometry.
5. Put the low-energy source in front of the
detector and verify that the count rate is Geometric efficiency
maximized. If it is not the amplifier gain
and the high voltage must be readjusted. The intensity of gamma rays emitted from a
Steps 3, 4 and 5 should be repeated until point source obeys the inverse square law:
maximum count rates are achieved for both
radionuclides at their respective settings. I(r) = I(0)/r2
With the detector set at a true gain of 1, the
appropriate settings can easily be calculated The inverse square-law is a natural consequence
if it is necessary to change the coarse gain of the fact that gamma rays travel in straight
on the amplifier. For example, if there is a lines. Imagine that there is a point radioactive
true gain of l and the coarse gain is source at the center of a sphere. The density
increased by a factor of 2, the baseline (gamma rays per square centimeter) at the
settings are all multiplied by 2. In this surface of the sphere is I(0)/4πr2 where I(0) is
instance, a 20% window centered on 99mTc intensity of the gamma rays emitted from the
has a window width of 56 and a baseline of source and 4πr2 is the surface area of the sphere.
252. Suppose we have a detector located on the
surface of the sphere at a distance, r, from the
Energy linearity source. The fraction of gamma rays that hit the
detector is directly proportional to the area that
The pulse height of the scintillation signal is the detector covers on the surface of the sphere.
proportional to the energy deposited in the The geometric efficiency is defined as
gamma-ray interaction. This statement is not
true over a wide range of energies because of gp = (Area of detector) x cos(φ) / 4πr2 Eq(1)
non-linearity in the spectrometer. For example,
if the spectrometer is set to a true gain of 1, it is where gp is the geometric efficiency for a point
unlikely that both the low-energy photons (such source and φ is the angle between the surface
as the 27-keV X-rays from 125I) and high-energy and the detector. If the detector is pointed

80
directly at the source φ = 0 and cos(φ) = 1. The Because the attenuation coefficient for NaI(Tl)
geometric efficiency can be improved by either decreases rapidly with gamma-ray energy, the
increasing the area of the detector or decreasing thickness of the detector must increase to
the distance between the source and the maintain intrinsic efficiency. In Table 3, the
detector. For scintillation detectors, geometric thickness of NaI(Tl) required for an intrinsic
efficiency is maximized with a well design, in efficiency of 0.9 is calculated at selected
which a channel is bored into the surface of the energies. The table also includes the thickness
NaI(Tl) crystal. The source is placed inside the required for a photo-peak efficiency of 0.9.
well and is surrounded in nearly all directions
by the detector. It should be noted that Eq(1) is
not appropriate for very small source-to- WELL COUNTER
detector distances. When the diameter of the
detector is large compared with the source-to- A well counter is a NaI(Tl) detector that has
detector distance, then the appropriate equation been specially designed to maximize efficiency.
is gp = ½(1 - cos(φ)) where φ is the angle As shown in Figure 14, the channel (or well) is
between the source and the edge of the detector. made in the center of the crystal. With this
For example, if the source is sitting right on the design, the source can be placed inside the well
detector, then φ = 90 degrees and gp = 0.5. If the to obtain a high measuring efficiency. The
source is positioned in a well chamber in which intrinsic efficiency can be high since large
φ = 160 degrees, then crystals (5 x 5 or 7.5 x 7.5, diameter x height in
cm) can be used.
gp = ½(l - (-0.94)) = 0.97

Intrinsic efficiency

The intrinsic efficiency (ε) is the fraction of


photons that hit a detector and are detected. It is
determined by the thickness (t) and the linear
attenuation coefficient (µ) of the detector
material, ε = 1 - exp(- µt). The intrinsic
efficiency is high (that is, close to 1) when the
product µt is large, thus we want either µ, or t,
or both to be large.

Table 3 Sodium iodine intrinsic efficiency of


some selected gamma energies. A gives the
thickness needed to have 90% intrinsic
efficiency of any energy deposition in the
crystal. B gives the thickness needed to have
90% intrinsic efficiency of total gamma ray
energy absorption in the crystal.

Gamma Thickness of Thickness of


energy (keV) NaI(Tl) (mm)A NaI(Tl) (mm)B Figure 14 A schematic view of a well counter
30 0.5 0.5 for gamma counting. The well, i.e. the hole in
140 5.5 9 the crystal, may be different in commercial
172 8 14 instruments due to how the samples are
247 20 40 changed automatically. It is easier to arrange
364 31 50 this technology in a through-hole detector but
511 52 69 the counting efficiency is somewhat lower due
662 52 84 to the larger hole.

81
approximately 10% losses when the total count
Well counters that are used routinely to assay rate is 20,000 cps. If a high-energy sample is
large number of samples are usually automated. being counted (for example 18F) the photopeak
In these devices, the samples to be assayed are count rate at which these losses appear may be
loaded into counting tubes that sit in special below 10,000 cps.
racks. A transport mechanism allows each
sample to be counted sequentially for a pre- Sample volume
selected time interval, and the results are stored
as a computer file. It is possible to accurately The volume and geometry of the samples being
assay the absolute activity of samples in a well assayed should be kept constant for two reasons.
counter. This, of course, requires a calibration
source to relate the detected counts to
radioactivity units. It also requires knowledge of
the problems presented by count rate losses,
background correction, and the sample
geometry. These problems are briefly discussed
in the following sections.

Figure 15 A commercial gamma counter

Dead time losses

The finite temporal resolution of the NaI(Tl)


detector results in count losses. These become
increasingly important as the total count rate
seen by the detector rises. Count rate losses are
a particular concern when assaying samples that
span a wide range of activities. For
radionuclides with short half-lives, the best
alternative is to wait until the samples decay Figure 16 Illustration of sample volume and
down to the point when the losses can be detector geometry for optimal and reproducible
ignored. It should be noted that in many well counting.
counters, the count rate at which dead time
losses are manifested could be relatively low, First, the detection efficiency depends on the
especially for high-energy radionuclides that source distribution in the well.
have a small photo fraction. For example, if the
pulse width at the amplifier is 5 µsec, there are

82
Second, the amount of self-absorption within
the sample also depends on the source
distribution.

It should also be noted that absorption of low- 0.4


energy gamma rays is highly dependent on the 0.3
N = 20
p = 0.05 p = 0.15 p = 0.5
material and wall thickness of the source
0.2
containers. Therefore, if assays from a large
number of samples are made, care should be 0.1
taken to ensure the uniformity of the source 0
containers as well as the source volumes 0 5 10 15 200 5 10 15 200 5 10 15 20
r, the number of outcomes in N tries
Background
Figure 17 The binominal distribution
Background refers to detected counts that do not illustrated for some values of the number of
originate from the desired sample. Because of tries and probability for one of the outcomes.
the high sensitivity of NaI(Tl) detectors for
gamma rays, they must be heavily shielded to The distribution P(r) is illustrated in Figure 17
reduce the counts from sources outside the well. for some values of N and p. In a statistical
Usually, several centimeters of lead surround distribution the sum over the number of
the detector. If many samples are to be counted outcomes should be one.
over a long interval, several background checks
should be made just in case there is a time-
dependent factor associated with the
background.

Dynamic range Important parameters in a statistical distribution


are the mean and the variance and they can for
The magnitude of activities that can be this distribution be expressed as
accurately measured with a well-counter range
from approximately 20 Bq to 20 MBq. On the
lower end, the limitation is the uncertainty in
the background count rate, and the upper end is
limited by dead time losses.

COUNTING STATISTICS If we consider the radioactive decay the


probability for decay, p, is small. During one
The radioactivity decay can from a statistical second, a nucleus changes its conditions 1010
point of view be regarded as tossing a coin. times or more, but may still not be able to
There are two outcomes since during a time decay. However, the number of tries, i.e. the
interval, either the nucleus decay or it does not. number of nuclides, is also large, 1010 or more.
Events of this type have statistically a binominal We know that each nuclide has a specific decay
distribution. The probability to decay can be set constant, which somehow is a measure of this
to p, and the probability not to is then 1-p. nuclide’s probability to decay. If we in the
binominal distribution let N --> ∞ and p --> 0
In N tries, e.g. N radioactive atom are while we are keeping N*p= constant = µ we
investigated during the time interval, r atoms obtain the following relations
may decay. The relation between the number of
tries and the probability gives a distribution of
the number of outcomes, which can be
described by the relation below

83
This relation is called the Poisson distribution
and is said to be the statistical distribution for Table 4. Counting statistics
rare events, such as the radioactivity decay. The
distribution has the mean µ and the variance of Number of One standard Relative error
the distribution is also equal µ. In fact, the only Counts, N deviation, N N /N as %
variable in the distribution is the mean value µ. 100 10 10
If we vary this value, the distribution varies as 1000 32 3.2
shown in Figure 18. 10000 100 1
0.4 100000 320 0.32
λ=1
0.3 t=1 t=3 t=10
Since we are working with a Gaussian
0.2
distribution we can apply all knowledge about
0.1 error propagation in this type of distributions.
0 The only thing to remember is that the variance
0 5 10 15 200 5 10 15 200 5 10 15 20 is equal to the mean, which simplifies the
r, the number of outcomes calculations.

Figure 18 The Poisson distribution shown for If we have two measurements, N1 and N2,
some values of the distribution parameter µ. obtained during the same time, we obtain the
following relations for the error propagation in
For low values of µ, the distribution is rather addition and subtraction
skew but with increasing value of µ it becomes
more symmetric. In fact, it is possible to show N1 + N2 ± N1 + N 2
that for large values of µ the distribution
converts into a Gaussian distribution.
N1 - N2 ± N1 + N 2
However, this Gaussian distribution is special
since the variance is equal to the mean of the The relative errors are 1/ N1 and 1/ N 2 . If
distribution. This can be used in nuclear we divide or multiply the data, we use the
counting to estimate the counting statistics from relative error the following way
one single measurement.
Consider the following example. We measure M = N1 x N2 or M = N1/N2
one sample with a nuclear detector and obtain
the number of counts N. The sample or detector ∆M/M = 1 / N1 + 1 / N 2
is of little interest and so is the measuring time.
Only the number of obtained counts is
A common situation is that we would like to
important. We know that the measurement is
subtract the background from the sample and to
restrained by the Poisson statistics. The Poisson
calculate the error. If the count rate is 300 CPM
distribution can be approximated with a
for the background and 600 CPM for the sample
Gaussian distribution (if N > 25) and with the
and we measure the two values for one minute,
mean = variance. Large values of N twill give a
we obtain Ns = 600 and Nb = 300. We then
rather narrow distribution ´, which means that N
obtain
is a good approximate value of the mean and the
variance i.e. µ≈N and σ2≈N. The error in the
M = Ns - Nb = 300 ± 600 + 300 = 300 ± 30
measurement can then be written as N ± N.
If we increase the time we measure the
One must remember that it is an approximation. background to 100 minutes, we obtain
However, it enables us to estimate the error of
Nb=30000 ± 173 and
the measurement from one single value.

84
M = Ns - Nb/100 = 300 ± 600 + 1.73 * 1.73
or M = 300 ± 24.6

Another example illustrates the error


propagation if a variable does not follow
Poisson statistics but normal Gaussian statistics.
We measure a sample and get N = 6000 CPM.
We would like to know the absolute value of
the radioactivity and the uncertainty in the
determination. For the detector we need two
values, the efficiency which is 50% and the
relative error (standard deviation) of this
determination, which is 5%. We then obtain

A = N / 0.5 = 6000/60/0.5 = 200 Bq and

∆A/A = 1 / 6000 + 0.05 * 0.05 = 0.052

A = 200 ± 10.3 Bq

85
CHAPTER 9
NUCLEAR BIOLOGY AND MEDICINE: NUCLIDE PRODUCTION
enzymatic function may be slowed down
GENERAL ASPECTS considerably.

Nuclides are divided into two groups: stable and The use of stable nuclides has advantages
unstable, i.e. radioactive. The number of known especially in vivo, since no radioactivity and
nuclides is more than 2000, of which 280 are associated biological hazards are involved.
stable and the remainder radioactive. Half-lives However, sensitivity is limited due to a natural
vary from a millionth of a second to millions of background. The detection of natural isotopes is
years. Most radionuclides are very short-lived. also somewhat more technically complicated
Radionuclides undergo transformations or and expensive, whereas radioactive nuclides can
decay, emitting α, β−, β+, γ, X-rays, neutrinos, be detected more easily and at lower
conversion electrons, Auger electrons, protons, concentrations. Examples are auto-radiographic
neutrons and heavy ions. techniques that have provided regional
information down to the sub-cellular level and
The use of nuclides, both stable and radioactive, at concentrations of pM.
has steadily grown in importance in science,
technology and medicine during the last 70 Non isotopic labeling
years. If we restrict ourselves to the area of
biology and medicine, the dominant use is the However, in Nuclear Medical diagnostic
tracer technology, i.e., to label bio-molecules to procedures there wass a problem. Very few
follow their chemistry, kinetics, metabolism and radionuclides of biogenic elements emit suitable
catabolism in vitro and in vivo. The application γ rays that could easily be detected outside the
areas are in fundamental science such as body. Instead one had to rely on radioisotopes
investigating new biochemical pathways as well of non-biogenic elements, such as 67Ga, 99mTc,
111
as diagnostics and therapy. Other areas of In and 131I. They had the right physical
application are external and intra-cavity therapy. properties, were easily available and could
easily be labeled to biomolecules.
Isotopic labeling
However, small molecules, such as amino acids,
2
Stable nuclides of biogenic elements such as H, were found to lose their specific biological
13
C and 15N and even more radioactive nuclides activity when labeled with such nuclides. 125I-
such as 3H, 14C, 32P, and 35S have played an thyrosine could be transported across the cell
important role in biology. The reason for this is membrane but could not be incorporated into
simple. Important biomolecules can be labeled the proteins, i.e. the membrane transport system
by exchanging an adherent common, stable was fooled but not the more specific tRNA-
nuclide, i.e. 12C, to a stable non-common system. Other molecules, such as 125I-IUdR,
isotope, such as 13C or a radioactive isotope of could mimic the biogenic molecule thymidine
the same element, i.e. 11C or 14C. This is and were incorporated into the DNA-molecule
referred to as isotopic labeling. The small but at a lower rate. In this case the iodine
change in weight of the two isotopes is usually replaces a methyl-group, a quite dramatic
negligible and from a chemical and biomedical change. However, the iodine atom has about the
point of view, they are identical. The labeled same van der Waal radius as the methyl-group,
molecule can be administered as a tracer in which is enough to trick the biology.
amounts and in such a way that it does not
disturb the normal metabolic pathways. Labeling with analogs

However, some care must be taken. If one Elements of the same group in the periodic
replaces H with 2H or 3H, the change in weight system may to some extent replace each other in
is dramatic. Usually, this does not matter but if the biological system. Strontium can exchange
the labeling position is critical e.g. close to a calcium in the bone metabolism and rubidium
chemical bond cleaved by an enzyme, the can replace potassium. Even more heavy

86
elements were found to work, such as 201Tl+, which use higher photon energies (511 keV) but
which also replaces potassium and is a in coincidence (Positron emission tomography,
commonly used radionuclide in heart studies. PET). The labeling of the biomolecule should
Thallium is a well-known poison but small keep the biological activity and the kinetics of
amounts, well below toxic levels, are given in the labeled molecule intact. The label should be
the clinical investigations. In fact, the amounts stable in vivo for the time of the investigation,
given are even below the levels contained in and the radiation dose to the patient should be
foodstuffs in the market. small. In therapy, about the same conditions
should be fulfilled but the radiation dose should
The approach to use analogs to label be high in the tumor but small in normal tissues.
biomolecules was tried. One found, for
example, that selenium could replace sulfur in The different aspects of radioactive labeled
biomolecules e.g. 75Se-methionine had about compounds are illustrated in Figure 1. Different
the same metabolism as biogenic methionine. nuclides have to be produced both in an
optimal, efficient and economical way.
Radionuclide therapy Different production routes give a product that
might be useful in some circumstances, but not
Isotopes of iodine, 125I and 131I, were suitable all. In order to understand these problems, it is
for non-isotopic labeling of a variety of necessary to have an understanding of all the
biomolecules. However, iodine is also a underlying techniques, their advantages and
biogenic element but only in a very special shortcomings.
organ, the thyroid. The natural high uptake of
iodine in thyroid (30-50 % of administered Physical aspects
iodine) was early used, not only for diagnostic Radionuclide Biochemical aspects
• type of decay
purpose but also for therapy in malignant • half-life Antigen
TUMOR
thyroid tissues as well as in metastasis. A • production • tumor specificity
• distribution after • tumor density
suitable amount of 131I (about 1 GBq) gave a MAb catabolism • binding availability
sufficiently high radiation dose to kill the Imaging device Antibody
• radionuclide
tissues taking up iodine but with minor effects • resolution
• specificity
• affinity
to other tissues. One may consider this as the • sensitivity • size
• availability • pharmacokinetics
first use of “targeting” therapy. The same • catabolism
situation was found in bone metastasis, where Clinical aspects Radiolabeling method
the calcium analog 89Sr could be used for Diagnostic value
• efficiency
• effect on antibody
• tumor to tissue contrast
therapeutic treatment of severely spread • cost/benefit
• in vivo stability
malignant bone diseases. Side effects ANTIBODY
• dosimetry
• HAMA
When the first tumor selective molecules were
developed during the 70s (Mabs) one had a
great hope to use the specific uptake in the Figure 1 Different important aspects when
tumors for tumor treatment with radionuclides. choosing the optimal condition for a nuclear
The technique has found some applications but medical application.
is still under development. Smaller molecules
such as tumor receptor specific peptides and RADIONUCLIDE PRODUCTION
hormones are today used for the same goal.
There are two major ways to produce radio-
Different applications set different demands on nuclides: using reactors or particle accelerators.
the radionuclide used. A radionuclide used for We can say that we irradiate either with
diagnosis should emit photons in the range 100 neutrons (thermal, slow or fast) or with charge
-200 keV in order to be optimal with today’s particles such as protons, deuterons, alpha or
common detector, the Anger gamma camera. heavy ions. Since the target is a stable nuclide,
Other detection modalities have been developed we generally obtain either a neutron-rich

87
radionuclide (reactor produced) or a neutron-
deficient radionuclide (accelerator produced).

Figure 2 The radioisotopes of iodine to the


right of the stable 127I are said to be neutron
rich and are mainly produced by reactor
irradiation. The isotopes to the left are said to
be neutron deficient and are mainly produced
by accelerators. However, there are many
exceptions. An accelerator may produce 131I
and 125I is in fact routinely produced by Figure 3 A top view of a nuclear reactor core
reactors. used for radionuclide production (TRIGA II).
Some of the tubes seen are part of a pneumatic
Reactors for radionuclide production rabbit system for placing samples in different
positions of the core for irradiation. The targets
A nuclear reactor is a facility in which fuel such are encapsulated into closed tubes adopted for
as natural uranium or uranium enriched in 235U, the transport system.
233
U, or 239Pu undergoes fission. In the process,
neutrons are produced from about 10 MeV and Nuclear reactors especially designed for
downwards. The neutrons are moderated and in radionuclide production and for neutron
different parts of the reactor one may find activation are available. Some may even be
different qualities of neutrons. The neutron has found in research hospitals for the clinical use
no charge and does not feel the Coulomb of short-lived radionuclides. Reactors used for
barrier. Even neutrons with very low energy radionuclide production usually have a rabbit
(thermal neutrons = 0.025 eV) can enter the system (mechanically or pneumatic) to enter
target nucleus and cause a nuclear reaction. On target into irradiation position and to take the
the other hand, reactors do not produce very fast target out. In Table 1, possible nuclear reactions
neutrons (En < 12 MeV). Neutrons are not able for radionuclide production with a reactor are
to knock out many nucleons from the nucleus reviewed.
since the mean binding energy of nucleons is in
the range 8 MeV (see Chapter 2). The most typical neutron reaction is the
gamma capture i.e. a thermal neutron is
A reactor produces a neutron cloud in which we captured by the target nucleus and since there is
place our target. Usually, we irradiate the target no momentum in the reaction the decay energy
isotropically. One has to consider that heat is is emitted as a prompt gamma ray. The reaction
evolved in the reactor core and the temperature in Table 1
at irradiation positions may easily reach 200 oC.
The reactor is characterized by the energy 59
Co (nth, γ) 60Co
spectrum, the flux (neutrons/cm2/s), and the
temperature at the irradiation position. is an important application when producing
strong γ-emitting sources for external therapy,
but is more or less of no value when labeling
biomolecules. Since the produced radionuclide
is of the same element as the target the specific

88
radioactivity, i.e. the radioactivity per mass of the production yield, one needs to work with
sample, is very low in this type of nuclear expensive enriched targets which, however, can
reaction. The ideal production route is when the be reused several times.
produced radionuclide is of a different element
than the target. This gives what is called a non- A general feature with reactor-produced
carrier added production route. radionuclides is that most emit high-energy β-
particles that give relatively high absorbed
Table 1 Typical nuclear reactions in a reactor doses to patients. However, there is a possibility
used for radionuclide production to produce neutron-rich radionuclides that do
not emit beta particles. An example is given
Type of Reaction T½ σ (mb) below
Neutrons
59
98
Mo(n, γ)99Mo (T½=66 h)  99mTc (T½= 6 h)
Thermal Co(nth, 5.3 a 2000
γ)60Co

14
N(nth, p)14C 5730 a 1.75
33
S(nth, p)33P 25 d 0.015
35
Cl(nth, p)35S 87 d 0.19

35
Cl(nth, α)32P 14 d 0.05

fission  131I 8d

24
Fast Mg(n, p)24Na 15 h 1.2

35
Cl(n, α)32P 14 d 6.1 Figure 4 A cross-section of a 99Mo/99mTc -
generator (Courtesy of Mallinckrodt Medical
The reaction 6Li(n, α)3H has a large cross- Inc.)
section for the production of 3H+-ions of some
energy. These ions can be used for the The 99Mo can also be produced by fission. The
production of e.g. 16O(3H, n)18F. The target used system 99Mo/99mTc forms a generator system.
may be 6LiOH. In such a way, a reactor may The mother nuclide 99Mo has a reasonably long
produce some typically neutron-deficient half-life for centralized production and
radionuclides. A drawback with such a distribution to hospitals.
production is that the crude reaction solution is
heavily contaminated with 3H-water that might The generator system consists of a column on
be difficult to remove. which 99Mo is attached. By eluting the column
with saline the daughter nuclide 99mTc is
Another reactor-produced neutron-deficient removed with negligible losses of 99Mo. The
radionuclide can be exemplified by the generator system can work for one week before
production of 125I it has to be renewed. By “milking” the generator
once a day, the hospital obtains supply of a
124
Xe(nth, γ)125Xe (T½=17 h)  125I (T½= 60 short-lived radionuclide which has ideal γ-
d) energy (140 keV) for the detectors, gives low
radiation dose to the patient (the decay of a
A drawback with this production is that 124Xe meta-stable nucleus gives mainly γ rays and few
has a natural abundance of 0.1 %. To increase conversion electrons).

89
choose a nuclear reaction that is also practical
Inlet needle and economical.
for eluant
Elutions
Aluminium
crimp cap 1.0
99 Mo
Rubber stopper
0.5
Glass casing

Glass wool
0.2 99m Tc

99Mo
0.1
absorbed
onto aluminia
0.05
Glass filter

Rubber stopper 0.02


Aluminium
0.01
crimp cap Figure 7 A cyclotron that can accelerate
0 12 24 36 48
Outlet needle
hours
protons up to 17 MeV; generally used for
for 99mTcO4-
radionuclide production.

Figure 5 A cross- Figure 6 Elution profile Another advantage with accelerator production
section through the of a 99Mo/99mTc- is that, since we irradiate with protons or heavy
generator column generator ions, we produce a compound nucleus that is of
a different element than the target. It is often
Accelerators for radionuclide production much easier to produce non-carrier added
products in an accelerator than in a reactor.
An accelerator can be huge as in CERN (with a
diameter of more than 1 km) and used for A technical difference between reactor and
particle physics. However, when using accelerator irradiation is that in the reactor the
accelerators for medically useful radionuclides, particles come from all directions but in the
much lower energy is needed. One can do very accelerator there is a direction of the particles.
well with a proton accelerator of < 80 MeV or The number of charge particles is often smaller
even less (< 40 MeV protons) if one also has the and is usually measured as an electric current in
possibility to accelerate deuteron- and alpha- µA (6*1012 particles/s for protons but 3*1012 for
particles. During the last decade, small alpha-particles which have 2 charges per
accelerator yielding 16 MeV protons and 8 particle).
MeV deuterons have become fairly common at
larger hospitals for positron emission A drawback in accelerator production is that the
tomography (PET) applications. charged particles are stopped much more
efficiently than neutrons. Protons of 16 MeV are
Although such accelerators are much compact stopped in 0.6 mm Cu. If we have a typical
than a reactor, the particle energy they can production beam current of 100 µA and a beam
provide is 2-8 times higher than for the reactor area of 2 cm2 we stop 1.6 kW in a volume of 0.1
neutrons. That energy transferred to the nucleus cm3 which will evaporate all types of material if
is much higher and more particles can be kicked not efficiently cooled. The acceleration of the
out of the nucleus. We may produce nuclides beam is done in vacuum but the target
farther from the stable nuclide line and we have irradiation is made outside in atmospheric
better opportunities to choose a suitable pressure or in gas targets at 10-20 times over
radionuclide for our specific application. Since pressure.
we have more bombarding particles to choose
between, we also have a better opportunity to

90
He-gas Table 3 Cyclotron produced non- positron
emitting radionuclides. Examples from current
25 µm folie Solid target research program in Uppsala.
Particles from Water cooling
accelerator in of target
vacuum PET- T½ Decay Application
Nuclide Area
114
Cd(p, n)114mIn 50 d EC Therapy
197
He-gas Au(p,2p5n)191Pt 2.8 d EC Therapy
25 µm folie Gas target under pressure
α α-source
209
Bi(p,2n)208Po 2.9 a
Particles from
accelerator in 209
Bi(α,2n)211At 7.2 h α, EC Therapy
vacuum
Water cooling of
the target walls The accelerator production offers great
flexibility in producing one radionuclide in
Figure 8 Schematic targets for radionuclide different ways as seen in the example below,
production. The upper part of the figure which gives some of the available ways to
illustrates the use of solid target while the lower produce 123I (T½ = 13 h).
figure the use of a gas target. 127
I (p, 5n) 123Xe  123I
124
Table 2 Cyclotron produced positron-emitting Xe (p, np) 123Xe  123I
123
radionuclides. Examples from current research Te (p, n) 123I
122
program in Uppsala. Te (d, n) 123I
124
Te (p, 2n) 123I
121
Sb (αα, 2n) 123I
PET- T½ β+ Application 121
Sb (3He, n) 123I
nuclide (h) (%) area 123
Sb (3He, 3n) 123I
14
N(p,α)11C 0.34 100 Org. synthesis
18
O(p,n)18F 1.16 97 Halogenation
Factors to consider are economy, radionuclide
45
yields, amounts of radionuclide impurities,
Sc(p,n)45Ti 3.9 85 Chelators separation, and radiochemical aspects.
52 52
Cr(p,n) Mn 134 29 Mn kinetics
58
Ni(p,3p4n)52Fe 8.3 56 Fe kinetics Nuclear physical considerations
58
Ni(p,α)55Co 17.5 76 Chelators
If we want to observe an object, we usually
60 61
Ni(d,n) Cu 3.4 61 Cu kinetics illuminate it with light. The way the light is
76
Se(p,n)76Br 16.2 54 Halogenation reflected, diffracted and absorbed informs us
85
Rb(p,3n) Sr 83
32.4 24 Sr kinetics about the object and its properties. We may
88 86
learn whether it is transparent or opaque. If it is
Sr(p,3n) Y 14.7 33 Chelators transparent we can measure the refraction index,
110 110
Cd(p,n) In 1.15 62 Chelators and if it is opaque we can find its absorption
124 124
Te(p,n) I 100 23 Halogenation capacity. If monochromatic light is used, we
may find how these properties vary with
wavelength. The object may emit radiation of a
Usually, one uses thin foils (about 25 µm thick)
different kind (e.g. photo effect emitting
to separate vacuum and the target. Two such
electrons). If the light beam is shut down, the
foils are used with a stream of He-gas in-
object may continue to reemit light
between to cool the foils. He-gas is preferable
(phosphorescence).
since it has excellent cooling capacity and little
radioactivity is produced in the gas.

91
If we want to “see” an object as small as the We may write a nuclear reaction in the
atomic nucleus, we need to use “light” of a following way
much higher frequency, which also means much
higher energy. However, the same type of a+Ab+B+Q
experimental approach can be used although we
need to design special particle detectors to where a is the incoming particle and A is the
replace the eye. It is not by chance that one of target nucleus in their ground states (the
the most powerful nuclear models is called “the entrance channel). Depending on the energy and
optical model”. We can regard particle beams of the particle involved we may open different
electrons, protons, neutrons and mesons as outgoing channels, where b is the outgoing
“matter beams” that have wavelengths suitable particle and B is the rest nucleus in excited
to “see” the atomic nucleus. These beams may states. Q is the reaction energy and can be both
be reflected, refracted and absorbed too. negative and positive. If the incoming particle is
absorbed we have a capture process type (n,γ)
dΩ and in a reaction of type (p,n) we obtain charge

IoN dΩ exchange. If many particles are expelled we can
dΩ
refer to the reaction according to the process
N
Φ such as (p,3n). Each such reaction further
distinguished by their excitation state is called a
Incident beam Io reaction channel.
Target Scattered
particles
Different reaction mechanisms can use the same
reaction channel. Here we differentiate between
Figure 9 A principle experimental setup. A two ways
nuclear physicist is usually interested in the
particles coming out, their energy and angle • The formation of a compound nucleus
distribution, but the radiochemist is mainly • Direct reactions
interested in the transformed nuclides in the
target. The compound nucleus has a large probability
to be formed in a central hit of the nucleus. The
A large difference between neutrons and charge incoming particle is absorbed and an energy-
particles is their possibility to penetrate the rich compound nucleus is formed. It has usually
nucleus (Figure 10). a lifetime of about 10-14 seconds. This time is
long enough for the nucleus to forget the
NEUTRON direction of the incoming particle. However, the
nucleus needs to get rid of its energy excesses,
CROSS-SECTION

and sooner or later one or several particles


“evaporate” from the nucleus. The rest nucleus
formed is usually left in an excited state and
PROTON
cools off further by emitting gamma-radiation.

ENERGY
The out-coming particles are emitted
isotropically since the compound nucleus has
forgotten about the direction of the incoming
Figure 10 General cross-section behavior for
particle. The energy of the emitted particles has
nuclear reactions as a function of the particle
a typical distribution (evaporation spectrum).
energy. Since the proton has to overcome the
Most emitted particles have a low energy but
coulomb barrier there is a threshold that is not
some can have up to 5-6 MeV.
present for the neutron. Even very low-energy
neutrons can penetrate into the nucleus to cause
a nuclear reaction.

92
Elastic reaction is high when the particle energy is just above
(p, p)
(see Figure 13).
Threshold
Incident Compound 56Fe

Cross section (barn)


nucleus
(n, n´)
proton
Direc

(p, p´) inelastic


Total
t re a c

(p, d) picup
Compound
tions

(p, n) charge exchange


etc
Inelastic reactions
Direct reactions
Figure 11 A schematic figure showing some
0 1 2 3 4 5 6 7 8
reaction channels at proton irradiation. MeV
Figure 13 A schematic view of particle energy
The direct reactions preferably occur at the edge
variations of cross-section for direct nuclear
of the nucleus (see Figure 12). The incoming
reactions and for forming of a compound
energy is directly transferred to a nucleon
nucleus.
(knock-on reaction) giving two out-coming
particles or you may have a stripping reaction of
When producing radionuclides, a detailed
type (d,n). The outgoing particles usually have
knowledge of different reaction probabilities is
high energy and are emitted in about the same
a necessity. The reaction probability is
direction as the incoming particle.
expressed as a cross-section or a surface. The
unit is barn (b), which is an area of 10-28 m2.
a + A C B This is a rather large unit, so mb is a more
Compound commonly used unit. The cross-section unit is
Before Delay After nucleus related but not identical to the nucleus projected
formation area. The probability of a hit is a combination of
b the area of both the nucleus and the incoming
particle. Particles of low energy can act like a
a + A B + b mass wave of low wavelength and cover a large
area in space. One may then obtain cross-
Before After Direct section values of magnitudes higher than the
stripping area of the nucleus.

After hitting the nucleus, one has also to


consider the physical and statistical laws of
Before After Direct distributing the energy so that a specific
knock-out reaction channel is opened. Some cross-sections
may therefore be very small. Figure 14
Figure 12 An illustration of the difference illustrates a well-known thumb rule in
between direct nuclear reactions (lower part of radionuclide production. The maximum cross-
the figure) and the formation of a compound sections found at about 10, 30 and 40 MeV for
nucleus (upper part of the figure). the (p,n)-, (p,3n)- and (p,4n)-reactions,
respectively. Thus, it takes about 10 MeV to
Most reactions are probably a mixture of these kick out a nucleon, i.e. a proton of 50 MeV can
two types of reactions. The probability of these cover radionuclide productions that involve the
two events varies with energy in a different emission of about 5 nucleons. Figure 14 also
way. The direct reactions are heavily associated shows an example of using the cross-section
with the geometrical size of the nucleus. The information for an optimal production of 73Se
compound nucleus, however, is formed just with protons. At low energy there is a disturbing
across the reaction threshold and the probability production of 75Se and if one uses excessively

93
high proton energy one obtains another This then gives a radioactivity yield of the
unwanted radionuclide impurity, 72Se. The last desired radionuclide at end of bombardment
impurity can be avoided completely by (EOB) mainly dependent on the beam current
restricting the proton energy to an energy lower and the irradiation time. The yield is usually
than the threshold for the (p, 4n)-reaction. The expressed in GBq/µAh, i.e. the produced
impurity from the (p, n)-reaction is not possible radioactivity per time integrated beam current.
to avoid but can be minimized by using a target If possible, one tries to keep the radioactivity of
thickness that avoids the lower proton energies the contaminants small (< 1 %). However, after
(having the highest (p, n)-cross-sections). EOB, the long-lived radio-contaminants start to
increase with the decay of the product.
75As(p,n)75Se
103
75As(p,3n)73Se
Specific radioactivity
102
In a target irradiation, we produce a number or a
mass of radioactive atoms. The most common
101
way to express this number is to give a measure
75As(p,4n)72Se
of the radioactivity in Bq. However, this is an
100 indirect way since it only tells us how many
nuclei decay per second. To tell how many
0 10 20 30 40 50 radioactive nuclei we had from the start, we
Proton energy, Ep (MeV) need to add up all decays from the start to
Figure 14 Excitation functions of infinity.
75
As(p,xn)72,73,75Se reactions. The optimal
energy range for the production of 73Se is Ep = Radioactive decay is a statistical process. If we
40  30 MeV. have a number of radioactive nuclei N they all
have the same probability of decaying. This
As seen in Figure 14, the chosen production probability does not change in time, nor is it
parameters are a compromise. A proton range affected by chemistry, environment etc. During
from 40  30 MeV uses the (p,3n) cross- a small time, dt, the number of decayed atoms is
section well. Some 72Se-contamination is dN. The radioactivity of the sample is expressed
acceptable in order to increase the yield of 73Se. as A = dN/dt. The relative number decayed,
An important factor is the half-life, 75Se λ∗dt = dN/N is always the same and is constant.
(T½=120 d), 73Se (T½= 7.1 h) and 72Se (T½= λ is called the decay constant and has the unit
8.5d). Sometimes it is possible to wait for the seconds-1. We can write this as a differential
decay of the radioactive contaminants. This is equation (the minus sign is due to the decrease
not the case here, instead the longer half-lives of of N in the decay process).
the radioactive contaminants help to keep the
radioactivity of these low. The cross-sections dN/dt = - λ * N
give a number of the produced atom nuclei of
each isotope. If the half-life is long, then the This equation has the unique solution
decay is spread out over a longer time, hence
the radioactivity is lower than for a short-lived
radionuclide. The relation between the number N = No * e-λ*t
of nucleus produced and radioactivity is set by
the specific radioactivity. where No is the initial number of radioactive
nucleus.
The practical setup when doing a radionuclide
production looks like this. A suitable As-target Since the radioactivity A = dN/dt we get a
is made and irradiated with 40 MeV protons. relation between radioactivity and the number
The thickness of the target is such that it of radioactive nucleus, A = λ * N. This means
decreases the proton energy down to 30 MeV.

94
that the radioactivity also will decrease in the the labeling chemistry does not differ between
same way as the number of radioactive atoms e.g. the radioactive 131I and the stable 127I, we
have to include the number of stable iodine
A = Ao * e-λ*t atoms that might have been in the target or
added during the separation process.
where Ao is the initial radioactivity at time 0.
Spec. Radioact. = Ao/(No + Nstable)
In the decay process, the half-life (T½) of the
radionuclide, is an important parameter. Its is Since in many cases the stable atoms are more
defined as numerous than the radioactive, the mass does
not change with time but the radioactivity does.
A = Ao 2-t/T½ The specific radioactivity decreases with time.

The relation between λ and T½ is given by In radionuclide production and radiochemical


separations the following expressions are used:
λ = ln(2)/T½ Carrier free: Only the radioactive atoms are
present in the preparation, i.e. no stable isotopes
By integrating the radioactivity decay curve of the same element are present.
(Figure 15, left) from t= 0  ∞, we add
together all the decayed nuclei, No = ∫A dt No carrier added: In the separation process, no
(Figure 15, right). stable isotope of the same element has
deliberately been added. However, one cannot
EXPONENTIAL DECAY DECAY INTEGRAL
exclude that some stable istope may have been
RADIOACTIVITY FRACTION

1 1
DECAYED ATOM FRACTION

0,8 0,8
added through uncontrolled processes, such as
stable carbon being added from glass wear etc.
0,6 0,6

0,4 0,4
Carrier added: In the separation process one
0,2 0,2 deliberately adds some amounts of the same
0 0
element to facilitate or stabilize the separation
0 1 2 3 4 5
0 1 2 3
TIME IN T½
4 5
TIME IN T½ process. This will decrease the specific
radioactivity of the product..
Figure 15 By integration of the exponential
decay curve (left figure) one obtains a number For radioactive labeled compounds one usually
of totally decayed atoms (right figure). calculates specific radioactivity as radioactivity
per number of labeled and unlabeled molecules.
The relation between radioactivity and the This means that we might here obtain values
number of atoms that are producing this higher than the theoretical values for radioactive
radioactivity is called specific radioactivity atoms since we may have more than one
radioactive label per molecule (i.e. from 14C-
Ao ln(2) labeled benzene where all six atoms are 14C-
Spec. ac t. = =
No T ½ atoms).
The number of radioactive atoms can be To illustrate how the theoretical specific
expressed in mass units such as gram or moles, radioactivity is calculated, the following
and specific radioactivity can then be expressed example is given.
in units such as MBq/g or GBq/µmole.

If we only consider the radioactive atoms, we


can always give a unique value of the specific
radioactivity. If we include the stable isotopes
we have to modify the concept somewhat. Since

95
radionuclides of other elements from our
Example. How to calculate the maximal specific preparation.
radioactivity of 125I.
Figure 16 A hot-lab
The physical half-life of 125I is T½=59.41 days. equipped with a hot-
The number of radioactive atoms is then cell for high
59.4*24*3600/ln(2)= 7.41*106atoms/Bq. radioactivity work.
We consider the radioactivity 1 GBq = 109 Behind 5-10 cm
disintegration/s. This correspond to 7 .41*1015 lead one can work
atoms. By using the Avogadro´s number we get with a radioactivity
that 1 µmol of 125I-atoms corresponds to of 100 GBq.
6.023*1017 atoms. We can then calculate the Automated systems
specific radioactivity (SA) of 125I or manipulators are
used to protect
6.023 * 1017 personnel.
SA(125I)= = 81 GBq/µmol
7 .41 * 1015
Time is essential. If we work with a short-lived
In literature, specific radioactivity is often given radionuclide such as 110In (T½ = 69 minutes)
in the old unit for radioactivity, Curie (1 Ci=3.7 and the separation procedure takes 4-5 hours,
1010 Bq). the radionuclide is of no practical interest. The
separation procedure should take at most about
1 Ci = 3.7 1010* 59.4 * 24 * 3600 / ln(2) = 1 half-life.
2.74*1017 atoms
C15O2 C15O
17
6.023 * 10 Deutron-irradiation
SA(125I)= = 2.2 Ci/µmol
2.74 * 1017 TARGET Fast on-line
d+14N-->15O+n chemistry
Radiochemistry
15O
2 H215O
During target bombardment, a heavy shielding N2+1% O2
is necessary around the reactor/accelerator to
protect from prompt radiation. But even after Figure 17 Target system for production of 15O
shut down, radiation shielding is advisable. (T½= 2 minutes) and on-line production of a
Besides the wanted radioactivity, the target may number of labeled ligands.
contain several other reactions, either of the
same element (radio-contaminants) or other Gaseous or liquid targets are disadvantageous in
elements. Some radionuclides may be short- the irradiation but advantageous in the
lived and before processing it may be of separation since the separation system may
advantage to let them decay. In the subsequent easily be automated.
processing, the target is usually transported in a
lead shield to a hot-laboratory and placed in a
1 2
lead shielded hot-box.
4 5
In the radiochemical process we want to remove 3
the small amount of desired radioactivity (≈ 1100ºC 200ºC
nanomole) from the bulk of target (0.1-1 g). We 6
want the separation efficiency to be as high as Argon
possible and the separation time as short as
possible. We also want to separate all Figure 18 A schematic description of the 76Br
separation equipment. (1) Furnace, (2)

96
Auxiliary furnace, (3) Irradiated target, (4)
Deposition area of selenium, (5) Deposition Table 4 Specific radioactivity of some
area of 76Br, (6) Gas trap. commonly used radionuclides in biology and
nuclear medicine
Solid targets usually have to be dissolved
(usually in boiling acids) before wet chemical Radio- T½ Specific radioactivity
separation methods are applied. In general, two Nuclide Common values
principles are used: liquid extraction and ion Max for compounds
exchange. Occasionally, thermal separation GBq/µmole GBq/µmol
techniques may be applied, which have the 3
H 12 a 1.08 0.01-5
advantage that they do not destroy the target 14
(important when expensive enriched targets are C 5730 a 0.0023 0.0001-0.01
35
used) and that they lend themselves to S 87 d 55.5 0.0001-0.01
automation. 32
P 14 d 340 0.001-10
33
P 25 d 197 0.001-1
As an example of such dry methods the thermal 131
separation of 76Br (T½ = 16 h) is described. The I 8d 599 0.01-1
target is Cu276Se, a selenium compound that can 125
I 60 d 81 0.01-1
withstand some heat. The nuclear reaction used 57
Co 270 d 18 0.1-10
is 76Se(p,n)76Br. 58
Co 71 d 68 0.1-10
75
1. The target is placed in a tube and heated, Se 120 d 40 0.001-0.1
under a stream of argon gas, to evaporate 197
Hg 64 h 1776 0.01-1
the 76Br activity by dry distillation (Figure 203
Hg 47 d 104 0.001-1
18). 11
C 20 min 3.55 *105 1-100
18
2. A temperature gradient is applied to F 2h 6.59 *104 1-100
separate the deposition areas of 76Br and
traces of co-evaporated selenide in the tube
by thermal chromatography.

3. The 76Br activity deposited on the tube wall


is dissolved in small amounts of buffer or
water.

Separation yields of 60-70% are achieved and


the separation time is about one hour. Since dry
distillation permits the extraction of
radiobromine without destroying the target, the
Cu2Se targets are reusable. Considering the
rather expensive 76Se-enriched target material,
this is practically a prerequisite for this type of
production. The chemical form of the 76Br
activity after separation, analyzed by ion-
exchange high-performance liquid
chromatography (HPLC) and thin-layer
chromatography (TLC), was almost exclusively
found to be bromide.

97
CHAPTER 10
NUCLEAR BIOLOGY AND MEDICINE: IMAGING
Several factors, such as the thickness of sample
Imaging techniques have always been important and detector as well as the energy and
in the application of radionuclides and tracer penetration ability of emitted radiation,
techniques. Henri Becquerel did not only determine the information one can obtain from
discover the natural radioactivity but he also, by such a system (Figure 1). Other important
chance, invented the autoradiographic technique factors are how firm the radioactivity is bound
when he discovered the impact of the uranium to the sample. For example, a labeled ligand
salts on a photographic film. This technology that diffuses in the sample during preparation
has developed considerably and can today give gives a low-resolution image.
quantitative information of tracer distributions
from the organ level to the cell nucleus Several sample preparation techniques for
structures. External detection of gamma- different applications are possible to use, such
emitting nuclides has developed from scanning as
with a collimated gamma sensitive probe to to-
day’s sophisticated systems for Single Photon • Macro-autoradiography (Whole Body). The
Emission Computed Tomography (SPECT) and animal is frozen in a liquid that prevents
Positron Emission Tomography (PET). freeze artifacts. A frozen block is cut by a
saw or placed in a whole body tomograph.
Autoradiography Sections with a thickness of 20 µm or more
are mounted directly on a plastic tape.
Autoradiography in biomedical applications is a
technique for the visualization of radioactive • Embedded sample, tomographic section.
materials in cells, cell cultures, tissues and Normal histological embedding and
organs. A thin sample (cell culture) or a thin mounting techniques on glass are used.
section obtained by tomographic techniques is Tomographic sectioning gives samples with
placed in close contact with a detector that can a thickness of 3 µm or less.
register the position of the decays.
• Frozen sample, tomographic section, freeze-
dried mounting on glass backing. This
Sample thick
thin technique can be used when the labeled
Detector thin ligands are expected to diffuse. Samples can
thick be obtained with a thickness of about 3-5
µm.
Eββ high Eββ high Eββ low
Sample thick Sample thin Resolution good • Ultra-tomographic techniques used in
Resolution bad Resolution good independent of electron microscopy. Sample thickness of
independent if if film is thin sample and film
film thick or thin thickness
about 100 nm.

Figure 1 General principles of autoradio- The thinner the sample, the smaller the
graphy. The sample and the detector in close radioactivity contents in the sample. One has to
contact give the best resolution and sensitivity. adopt the radioactivity concentration in the
If spatial resolution is desired in the same sample to the desired resolution. When using
range as e.g. the beta particle range, then the ultra-thin sections, one also has to consider the
thickness of sample and detector is of less specific radioactivity of the ligand and whether
importance. If the desired resolution is better it is theoretically possible to obtain detectable
than the range of emitted particles, then the radioactivity amounts in the sample.
thickness of sample and detector are the
dominating factors. An important factor is of Generally any radionuclide can be used for
course the intrinsic resolution of the detector. autoradiography. However, if high resolution is
important, then one prefers to use radionuclides
that emit radiation with low penetrating ability

98
such as 3H and 125I. These radionuclides can be (about 100 nm). Ideally a monolayer of silver
used to label a variety of biomolecules at high bromide crystals is used and exposed. After the
specific radioactivity. development procedure the silver grains are
hardly visible even in light microscopy with the
Photographic film best resolution. However, in electron
microscopy the high atom number of silver
Photographic emulsion is still the dominant gives a good contrast and images of a high
detector. It is also the only choice when spatial resolution may be obtained.
resolution of a few µm or less is desired. There
is a large choice of different types from standard
X-ray films to liquid film emulsions for high
resolution. Measuring the film density can be
used to quantify the autoradiography, e.g. by a
computerized image analyzer system. A
calibration curve of (radioactivity
concentration)*(exposure time) to density can
then be used. It is important to obtain a correct
exposure of the film due to the limited linear
range of the system.

B Figure 2 Whole-body
autoradiography
showing the distribution
T of 14C-methionine.
L u Some structures are
L i marked, such as brain
(B), lungs (Lu), liver
(Li), intestine (I) and Figure 3 Electron microscope autoradiogram
tumor (T). showing labeled acetylcholine on receptors in a
The density can be neuromuscular junction. More information at
T measured and related to www.nbb.cornell.edu/neurobio/salpeter/salpeter.html
I radioactivity
concentration by
comparing with a Phosphorous imaging techniques
calibration scale.
The photographic film has some disadvantages
such as

• Low sensitivity, which means long exposure


If closer contact is needed the film emulsion
without backing can be applied directly onto the times.
sample. The two techniques used here are the • Low linearity. The exposure has to be right.
strip film technique and the dipping technique. If the film is over- or underexposed, one
needs to redo the process. Sometimes it is
Another way to quantify is to measure the difficult to cover the dynamics in the sample
number of silver grains in the film emulsion. It by one single exposure.
is often necessary to do manually using a • Time consuming handling. The samples
microscope and it is a tedious work. An have to be dry before applying the film
alternative is to use an electron microscope. A emulsion. The developing process takes
diluted fine-grain film emulsion is used. Using time. Digitalization or grain counting is
the surface tension in a loop, a thin film is necessary in order to quantify.
produced that is applied onto a thin sample

99
Lately, new types of detectors have been
developed to overcome such drawbacks. They
are based on different physical principles such
as multi-wire chamber (gas detector), multi-
channel detectors (scintillator detector), and
phosphorus imager (trapped excited electrons
similar to thermo-luminescence detectors), strip
detectors and pixel detectors (solid state
detectors). Their resolutions are limited to about
25 µm and upwards. Here, we will just describe
one type of these detectors, the phosphorous
detector, in some detail. Figure 5 The read-out as a function of number
of disintegration for a phosphorous system and
An image plate of this type contains photographic film.
BaFBr:Eu+2 crystals. When a radioactive sample
is placed on the plate the emitted ionizing
radiation excites electrons in the crystal. In the
de-excitation process, a small fraction of
electrons are trapped in an excited stage and a
latent image of the radionuclide distribution is
formed.

Scanning
Laser (red)
Unstable state

Trap
Figure 6 The read-out system of one of the
PM-tube commercial systems for phosphorous imaging.
A red laser spot is scanned over an exposed
image plate by an optical system.
Ground state
Figure 4 Principle of the phosphorus imaging
technique. The technique is more sensitive than the film
since a denser material is used as detector. It is
A scanning red laser beam is used to “develop” also more useful for high-energy particle for the
the imaging plate. The size of the laser beam same reason. Besides, it is linear over a larger
spot determines the resolution (25-200 µm). range of exposures than the film.
The energy in the red light photons is enough to
lift up the trapped electrons to the unstable Gamma camera
state. It has then a high probability to fall down
to the ground state emitting a blue light photon The Anger gamma camera is used to detect
that is counted by a photo-multiplier tube (PM- single photons. A main component is the lead
tube). The number of blue photons registered in collimator (Figure 7) which selects the photons
each position is proportional to the radioactivity that are emitted perpendicular to a large
concentration of the sample. Exposing the NaI(Tl)-crystal.
image plate to an intensive white light will
anneals remaining trapped electrons and the
image plate can be used again.

100
its sensitivity would be unacceptably low.
Typical values are in the order of 15 mm at a
distance of 10 cm from the collimator. The
resolution varies with the depth.

Salivary glands

Liver

Bladder

Figure 7 A schematic view of the gamma Front Back


camera.

Photons of another direction are ideally Figure 8 Diagnosis of Disseminated Malignant


absorbed by the lead in the collimator. A photon Pheochromocytoma using 123I-Meta-
hitting the crystal may give rise to scintillation Iodobenzyl-Guanidine (MIBG).
(a number of light photons). This light spark is
viewed by a number of PM-tubes. Depending The collimator also sets restrictions to the
on their position they “see” varying numbers of gamma energy, which one may use. High-
light photons. Knowing the position of the PM- energy photons may penetrate the thin lead
tubes we can calculate the x, y-coordinates of walls between the holes (the septa) of a high-
the scintillation and the energy deposited in the resolution collimator. For high gamma energies,
crystal. the septa have to be bigger and the resolution of
the collimator decreases. High-energy photons
Each photon detected by the crystal can then be may also penetrate the crystal without giving a
registered, and an image of the radionuclide scintillation, which decreases the sensitivity.
distribution can be constructed from a number
of such events. The technique lends itself to Optimal gamma-ray energies to be used in
dynamic investigations. typical gamma camera systems are in-between
80-200 keV. One of the most used radionuclides
The weak point in the gamma camera is its is 99mTc (140 keV).
collimator. It is made up of a slice of lead (3-10
cm thick dependent on the desired performance) The gamma camera image is a depth integrated
with thousands of narrow holes. From an radionuclide distribution. Gamma rays from
isotropic source the collimator picks out a very different depth are detected with different
small fraction of photons (the exact number sensitivity and resolution. Gamma rays from
depending on the thickness and the hole different depth are also absorbed and scattered
dimensions). This means that the counting in different ways. Hence, the gamma camera
efficiency for the system is low. gives information that is difficult to quantify in
absolute terms.
The intrinsic resolution of the gamma camera,
e.g. how well the system can decide the position
of the scintillation, is about 4 mm. However, if
one made a collimator with the same resolution,

101
SPECT

Each gamma camera exposure gives a depth-


integrated measurement of the radionuclide
distribution. In Figure 8, the patient is viewed
from two sides: the frontal projection and the
back projection.

Figure 10 Perfusion measured in a normal


female volunteer using SPECT and 99mTc-
HMPAO. Data are presented in 20 tomographic
slices through the brain.

Figure 9 The gamma camera is stepwise


rotated around the patient (typically 3.6 o per
step). For each step a projection is obtained,
i.e. a measurement of the integrated Figure 11 A dedicated SPECT system. Three
radionuclide distribution from that angle. gamma camera detectors rotate together in to
speed up the data collection.
If we have a time stable radionuclide
distribution, i.e., we have reach an equilibrium, A typical time to make a SPECT investigation
the two measurements should give about the is about one hour. The time per projection is
same radioactivity distribution, however about one minute, and 50 projections or more
mirrored (Figure 9). The difference is due to are needed. The long exposure time also
somewhat different attenuation of photons. requires that the radionuclide distribution is
“frozen”, i.e. does not change substantially
By a proper mathematical treatment of all these during the investigation time. To speed it up
measurements (about 50 projections) it is two or more gamma camera heads can be placed
possible to describe the radionuclide together as in Figure 11.
distribution in 3D. We obtain what is called
tomographic information since we slice the PET
patient, not by knife but with the help of the
computer. For each slice we can present the In positron emission tomography (PET)
radionuclide distribution as an image. The most positron-emitting nuclides, such as 11C are used.
common reconstruction method is called The positron travels 2-3 mm in tissue before it
filtered back-projection. is stopped. When stopped it attracts an electron

102
and forms a strange atom, a positronium, which In PET, data is collected in all directions
exists for a short while before annihilation of randomly. There is no need to move the detector
the electron masses. The energy is emitted as but all projections are collected simultaneously.
two anti-parallel 511 keV photons as indicated Each event is sorted into a set of parallel
in Figure 12. coincidence channels defining one projection.
This means that a full set of data for
Positron Decay tomographic information may be collected
Coincidence Detection during 2-10 seconds only. There is no need for a
15N
radionuclide distribution in steady state but very
15O tube fast kinetic investigations can be performed.
r|PM
ν V Ph
oton detecto
5 11 ke
positron β+
TRANSMISSION
hoton
or 11 keV P
e |detect 5 Rotating
P M tu
b
e - electron source
Coincidence Detection
Time Window: 10 ns (BGO-detectors)

Figure 12 The emission of two annihilation


photons in the positron decay.

detector rings

Bed

Detectors

annihilation photons Figure 14 A transmission scan. A line source of


68
Ge/68Ga is circulated around the patient. The
density of a patient slice is seen viewing lungs,
Figure 13 A schematic view of a positron heart, spine and muscle. The bed upon which
camera system. the patient lies is of a light material with low
density and is hardly seen.
The photon energy of 511 keV is high. It comes
out of the patient efficiently but it penetrates At present, the most common detector material
lead and detector materials almost equally well is bismuth germinate (BGO), a scintillating
too. It is difficult to collimate these photons as it crystal with a high Z-number (Z=83) and a
is done in the gamma camera, and NaI(Tl) is not density close to 8 g/cm3. These properties make
efficient enough. In PET, one or several rings of a detector with a fairly high efficiency to 511
small detectors are placed around the patient keV photons. A crystal with the length of 25-30
(Figure 13). Each one of these detectors is mm has a detection efficiency of about 70 %,
coupled in coincidence with all opposite which in the coincidence channel corresponds
detectors. If two such detectors are hit to 50 % efficiency of detecting coincidences.
simultaneously (within 10 ns) the PET camera There is no need for a lead collimator. Instead,
assumes that it has been hit by two photons we can say that we use an “electronic
originating from the same decay. A straight line collimator” by measuring the two opposite
is defined by the known positions of the two directed photons by coincidence. This makes
detectors and the PET camera assumes that the the system rather sensitive
decay has occurred somewhere close to that Commercial systems with a spatial resolution of
straight line. about 4 mm in all directions are available today.
The resolution is mainly set by the crystal

103
dimensions but there are factors, such as the attenuation in the body and can then obtain a
range of the positrons that set the theoretical correct quantification within a few per cent.
limit of resolution to 2-3 mm.

An advantage of PET is that the radionuclide


distribution can be quantified in absolute values
(Bq/cm3). In an investigation, two
measurements are made: transmission and
emission. The transmission is performed as
described in Figure 14.

EMISSION

Figure 15 An emission scan of a human heart.


A ligand (acetate) labeled with a positron
emitting nuclide (11C) is given.

A line source containing a long-lived positron


emitter is rotated around the patient. We still
use the coincidence technique. One of the
photons hits a detector directly whereas the
other has to pass through the patient before it
hits an opposite detector. We call this a
transmission scan since we have an external
source and one of the photons is transmitted
through the patient. Since we view the patient
from all angles we have the same situation as in
an X-ray investigation using computerized
tomography (CT). We measure the density of
the patient but with the same photon energy as
we do later on in the emission scan.

The line source is removed and the ligand


labeled with a positron emitter is injected. Both
photons have to pass through parts of the
patients and we call this an emission scan. By
combining the transmission scan and the
emission scan we are able to correct for

104
CHAPTER 11
Labeling methods
radioactive isotopes of bromine through the use
A correct labeling of biomolecule is important of bromoperoxidase. The reaction is initiated by
for the outcome of all experimental applications the addition of H2O2. After a suitable reaction
of nuclide technique. The measuring technique time, the reaction is ended by addition of
is just giving information about the radioactivity sodium metabisulphite. A drawback is that it is
but the labeling technique couples this often difficult to purify large protein product
information to the information we want – the from the enzyme. This is usually easy in the
fate of the biomolecule. tyrosine labeling method described in Figure 2
since only low-molecular-weight reagents are
Important general aspects of labeling have already used.
been mentioned in Chapter 9. Here we will go into
particulars about labeling of biomolecules.

Protein labeling through tyrosine Figure 2 Labeling of tyrosine with iodine by the
Chloramine-T method.
The most common labeling method is to label a) The structure formula for Chloramine-T.
tyrosine with halogen isotopes. The tyrosine can
either be labeled as a part of a protein (direct a) CH3 SO2 N Cl Na+
labeling) or as a part of a precursor, which is then
attached to the protein in a suitable reaction
(indirect labeling). Halogens such as iodine and
bromine are introduced into the ring structure of
tyrosine by oxidative processes. Iodine might also O H Cloramine-T O H
be attached to tryptophan or sulphydryl groups. At and 125I-iodide 125I
b)
a high pH (>8) histidine might also be labeled.
Oxidation of
the iodide
The most commonly used agents for the oxidation gives H2O125I+
is Chloramine-T either in solution or immobilized CH2 CH2
on polystyrene beads (Iodogen). This method is R1 -NH - CH - C - R2 R1 -NH - CH - C - R2
O O
used for labeling with radioactive isotopes of
iodine such as 125I for basic biology and 131I for b) A schematic view of the labeling procedure.
medical applications such as imaging and nuclide The oxidative reaction is, after a suitable
therapy. The last years, 123I for planar gamma time stopped by adding sodium bisulfide.
camera/SPECT as well as 124I for PET, have also
been applied using the tyrosine labeling strategy. Indirect protein labeling

Chloramine-T is the sodium salt of N-monochloro- Amino group labeling


p-toluene-sulfonamide (see Figure 2). It is a mild
oxidizing agent. In an aqueous solution it releases The so-called Bolton-Hunter reagent provides a
hypochlorous acid, which oxidizes iodine probably general method to label amino group. This
to an active iodonium ion [H2OI+]. This ion is reagent labels proteins at the epsilon amino
incorporated into the tyrosine residue of the groups (i.e. lysine) and can, but more slowly,
proteins. The exact mechanism for this reaction also react with the alpha amino group at the
with carrier-free radioactive iodine isotopes is not amino terminus of a protein or polypeptide. The
known in detail. Bolton-Hunter reagent, already labeled, is
commercially available. The reagent contains a
Enzymatic labeling tyrosine ring that carries the iodine and a
succinimidyl group that can react with amino
Enzymes such as lacto-, chloro- or bromo- groups (Figure 3).
peroxidase can be used to label protein. One
example is the labeling of antibodies with

105
Thiol labeling

If the succinimidyl group in the above-


mentioned reagents is exchanged for a
maleimide, the reagents can be used for reaction
with thiol groups. In principle, this means that
reactions can be made with free SH groups in
the protein (i.e. cystein). Such reagents can
contain for example 3H or 14C and are
commercially available.

Conjugations

Figure 3 The Bolton-Hunter reagent is seen in the There are numerous biochemical conjugation
upper part to the right. It is pre-labeled in the ring methods described in the literature.
with radioactive iodine. The succinimidyl group Conjugation, in this context, generally means to
reacts with the amino group on the lysine and bring molecular components together. Thus, any
thereby an indirect labeling is achieved. method by which two components (e.g.
carbohydrate to protein, protein to protein,
Several Bolton-Hunter "like" reagents have been protein to nucleic acid etc) are coupled together
described. All contain the succinimidyl group can be used as a labeling method if one of the
while the tyrosine ring is modified to allow for components is pre-labeled. One example of
different properties. Thereby one can counteract, at conjugation mediated labeling is that
least partly, degradation or dehalogenation in vivo. radiolabeled carbohydrates are connected to
amino groups of proteins via activation of the
carbohydrate (using e.g. activation agents such
as periodate or CDAP). Several methods to use
COOH and NH2 groups in conjugation
chemistry have been described and all such
methods are of potential interest for
radiolabeling.

Chelators

The coupling of chelators to antibodies or other


proteins and the subsequent addition of
radioactive metals that are trapped by the
Figure 4 The reagent is pre-labeled with 3H chelator is one possibility for protein labeling.
through a carbon chain. The succinimidyl group The requirement is that suitable radioactive
reacts with the amino group on lysine. The protein metals are available.
is "tritiated".
Many types of chelators are described in the
It is also possible to modify the ring so that not literature and the most often used is DTPA
only iodine but also the halogens bromine and (diethylene triamine penta-acetic acid) which
astatine can be coupled. Furthermore, there are
binds metals such as indium (110In for PET,
similar reagents where the ring is exchanged for
111In for SPECT) and yttrium (89Y or 90Y,
other groups and which allow for 35S or 3H
both for nuclide therapy). DTPA is also, for
labeling. It is still a succinimidyl group that
some applications, coupled to ligands such as
accounts for the binding to the amino group of
the eight-amino acid somatostatin analogue,
the protein (Figure 4).
octreotide, giving the commercially available

106
product OctreoScan suitable for characterization harvested, homogenized and the protein purified
of tumors with somatostatin receptors. from the homogenate. The advantage of
biosynthetic labeling is that no extra chemistry
Chelator has to be applied and the product protein does
DTPA not suffer from conjugation or other labeling-
induced modifications. The disadvantage is that
Protein
it is often difficult to obtain a high specific
Conjugation radioactivity. Radioactive amino acids can be
chemistry purchased commercially containing, for
example, radioactive carbon (14C) or hydrogen
(3H).

Protein Add radioactive


111In Protein aminoacid
Chelation

Figure 5 Labeling of a protein with 111In by


the use of the chelator DTPA.
Synthesis
There are many different types of chelators
(DTPA "like" and others) with different
substituted side groups to allow for coupling via
different biochemical methods. The advantage
of using chelators is that all chemistry involved
can be made a long time in advance whereas the
addition of the radioactive metal can be made
directly before the use of the whole complex Harvest
(Figure 5). A simple "desalting" is then enough radioactive protein
to get rid of the excess radioactive nuclides.

Biosynthetic protein labeling


Figure 1 Biosynthetic labeling. Radioactive
amino acids are added (top), the protein
Most labeling methods modify the molecule to
synthesis produce labeled proteins (middle) and
some extent, which may change the molecules
the product are harvested for purification
behavior regarding e.g. distribution and binding
(bottom).
properties. A way to evade this and to label
exact copies of biomolecules (e.g. amino acids,
Labeling of nucleic acids
anti-bodies, structural proteins, and enzymes)
with radioactive nuclides is to feed a cell culture
Nucleic acids can be labeled with several
with amino acids containing radioactive
different methods. The rapid development in the
nuclides. The requirement is of course that the
area of DNA techniques have speeded up the
cultured cells synthesize the proteins of interest.
development of both "radioactivity" and
The radioactive precursors are given to the cell
"fluorescence" based methods for labeling and,
culture medium with the cells. If the cells
in some cases, interesting combinations of these
excrete the protein, the culture medium can be
approaches. The main radiolabeling methods
harvested (Figure 1) and the product purified.
used are nick translation labeling, 5´ end
The cell culture can be used repeatedly. If the
labeling, 3´ end labeling, hybridization labeling
protein is not excreted, the cells have to be
and biosynthetic labeling. Furthermore, special

107
methods to label small primers or probably disturbs the function if the DNA is
oligonucleotides (e.g. random primer labeling) used for further tests. Thus, this type of labeling
exist. The field is still developing and new is convenient for analytical purposes if certain
methods might be expected in the near future. base sequences are to be found, but it might not
be a good labeling method if the nucleic acid
Nick-labeling must be functional afterwards.

Nick labeling means that intact DNA, in a cell- Biosynthetic labeling


free system, is exposed to enzymes, which
opens up the double stranded DNA. Short A direct way to label nucleic acids, DNA or
segments of single stranded DNA (only 5-8 RNA, is to feed a cell culture with radioactive
bases) are formed. These single strand DNA thymidine or uridine, respectively. The
segments are restored to double strand DNA by radioactive precursors are given to the cell
enzymatic "repair synthesis" using e.g. culture medium and the cells are allowed to
radiolabeled thymidine in this process. Thus, the grow in physiological conditions. After a
DNA is labeled with radioactivity but is not suitable time (often 1-24 hours) the cells are
chemically modified since only enzymes from harvested, homogenized and the nucleic acids
the normal repair processes are used. purified from the homogenate. The advantage of
such labeling is that no extra chemistry has to be
5´ end-labeling applied and the product does not suffer from any
chemical modifications. The disadvantage is
5´ end labeling means cell-free labeling of the 5´ that it is difficult to obtain high specific
end of DNA or an oligonucleotide often using radioactivity. The radioactive precursor is
polynucleotide kinase to add phosphate at the usually 14C- or 3H-labeled.
end. The radioactive nuclides in the added
phosphate can be 32P or 33P (high- and low- The nucleic acids can also be labeled with 32P-
energy beta emitters, respectively). phosphate, using a biosynthetic route but in this
case many other cellular components are also
3´ end labeling labeled by general phosphorylation processes.

3´ end labeling is a method that uses e.g. Special labeling methods


deoxynucelotidyl transferase to add radioactive
dATP to the end of DNA or an oligonucleotide. Labeling of arginine
dATP is, in these applications, labeled with 32P.
There are also special reagents (e.g. ddATP) that Arginine residues in proteins have a general role
ensure that only one labeled nucleotide is added in positively charged recognition sites for
to the end, and there are special types of dAPT anionic ligands. This is especially the case when
that are labeled with 35S instead of 32P. the ligands contain important carboxyl- or
phosphate groups. Arginine also occurs in the
Hybridization based labeling active site of many enzymes, especially those
enzymes that catalyze phosphorylation. Arginine
As described above, oligonucleotides can be can be labeled with radioactive phenylglyoxal,
labeled with nick translation or end labeling. If which reacts with the guadino group of arginine.
such oligonucleotides are made single stranded It is claimed that proteins after such treatment
they can then be used for hybridization to RNA are more resistant to trypsine-mediated
or to partially or totally denatured DNA if there cleavage.
are homologous sequences. This is a powerful
technique to find and label certain genes (base Carbohydrate labeling (OH)
sequences). However, the procedure leaves the
hybridized nucleic acid blocked in certain Carbohydrates with free OH groups can be
sequences by the oligonucleotide probe and this labeled via enzymatic or oxidizing

108
transformation of the OH groups to aldehyde Labeling of dextran
groups, which then can react with radiolabeled
sodium-, potassium- or cyano-borohydride. Dextran and other polysaccharides can be
Another alternative is to allow the aldehyde labeled via activation with periodate or CDAP
groups to react with radiolabeled aniline (to activate the OH groups) so that any amine-
forming a Schiffs base, which is then stabilized containing radiolabeled substance attaches. This
with unlabelled borohydride. Radioactive has, for example, been applied in the attachment
reagents for such reactions are commercially of radiolabeled glycine or tyrosine to dextran.
available. Another labeling method is based on the fact
that dextran in nature is synthesized by the
Fast labeling with 11C, 15O and 18F for PET enzymatic addition of glucose from the
applications disaccharide sucrose. The sucrose is cleaved by
the enzyme sucrase, which then adds the glucose
Very fast methods have been developed for part on to the 6´ end (the growing end) of
labeling of low-molecular-weight sub-stances dextran. The fructose part of sucrose is left in
the monomer form. Thereby dextran slowly
with 11C (T1/2=20 min) (e.g. methionine), 15O
grows to form large chains. By introducing
(T1/2=2 min) (e.g. O2) and 18F (T1/2=110 min) radiolabeled sucrose, which must be labeled on
(e.g. fluorodeoxy-glucose). The short physical the glucose part, radioactive glucose attaches to
half-lives of these nuclides make it necessary to the dextran. This gives a "normal" not
apply fast organic chemistry processes, and chemically modified dextran that is
several such methods have been developed by radiolabeled. These methods are of interest since
organic chemists working with PET dextran in some cases will probably be used as a
applications. The nuclides mentioned here are part of conjugates in tumor therapy for targeted
mainly used for diagnostic purposes in PET treatments and thereby will serve as a carrier for
based applications. drugs and nuclides (Figure 6).

Labeling with "long lived" positron emitters.


EGF-receptors

There are several so-called "long lived" positron 10B dextran


emitters, such as 55Co (T1/2=18 hours), 76Br
(T1/2=16 hours) and 124I (T1/2=4 days). They 131
I 111
In
are suitable for labeling of macromolecules with 76
Br
long biological turnover rate like antibodies. 211
At
Using such positron emitting labels and PET EGF-dextran can
will give a detailed pharmaco-kinetic be labeled with
EGF Tumour cell
information of such molecules, which is of various nuclides
importance in diagnostics, therapy and in the
development of new drugs. The physical half- Figure 6 Schematic picture of radiolabeled
lives of these nuclides are sufficiently long that EGF-dextran binding to the EGF-receptor
standard protein labeling methods can be (EGF=epidermal growth factor).
applied. Such methods are chelator-based
labeling for the metal ion 55Co and for the Purification
halogens, 76Br and 124I, direct or indirect or
enzymatic protein labeling can be applied. The After radiolabeling, the product must be
use of such nuclides has so far been limited but purified. Usually this is a simple step but
with improved possibilities for macromolecular- sometime it might be necessary to consider
based gene-, immuno- and nuclide-therapy, the various sophisticated purification methods.
requirements to follow macromolecular
distributions with PET cameras are being met.

109
The purification is in most cases only a question way is to store the compound in a refrigerator
of removing excess radionuclides and the or, if it can stand it, frozen. Some
reagents applied. In many cases the product is a macromolecules are in fact very sensitive to
macromolecule whereas the nuclides and freezing and a large fraction might be
reagents are of low molecular weight. In that biologically inactivated. Long-term storage can
case, it is often enough to use a small, simple also be made in the frozen state using
"desalting" column to purify the product and at cryoprotective agents (DMSO, sucrose, and
the same time, if necessary, change the buffer glucose), which minimize the risk of ice crystal
system. In other cases it might be more formation. However, the general rule is to use
complicated, such as after enzymatic labeling or fresh preparations and to avoid long-term
when the product is of low molecular weight. It storage.
might also be complicated to purify if the
labeling technique induces heterogeneity; e.g. Stability during incubations
some product proteins are labeled whereas
others are not or when other forms of the Another problem to consider is that radioactive
product are produced due to the labeling substances might be modified during biological
chemistry. experiments. The substance might, in the
When a simple desalting technique is not experimental situation, be exposed to reduction,
adequate, one has to find more sophisticated oxidation or enzymatic degradation. Such
methods. A number of preparative processes might be of interest to study in the
chromatographical methods are available such experiment. However, such processes might
as large-sized exclusion columns with good also be undesired, and destroy or make the
molecular weight separation properties, ion planned study difficult to interpret. The stability
exchanger columns, affinity or hydrophobic of radioactive substances can, in principle, be
interaction columns or other methods such as controlled through the extraction of biological
preparative electrophoresis or precipitation material during the experiment. The samples are
techniques. then analyzed for the chemical form of the
radioactivity to allow for analysis of degradation
Quality control products.

After purification or storage of a radiolabeled Labeling services


product, it is often necessary to perform quality
control to ensure that the product has the same If possible one should buy your radiolabelled
properties as a standard. All available analytical chemicals commercially instead of doing the
methods in chemistry and biochemistry can then labeling yourself. There are several commercial
be considered as well as functional biological companies that offer a large collection of
test. especially low molecular molecules like amino
acids and nucleotides. When working with
Storage conditions macromolecules it may be more cost effective to
buy kits for labeling and then do the labeling in
Radiolabeled products might be destroyed due your own laboratory. In house labeling is also
to oxidation or radiolysis. Oxidation damage is necessary e.g., when the applied nuclides have a
most common for sulfur-containing substances very short physical half-life (as in many PET
such as methionine and cystein. Storing the applications). Another case is when a new
compound in nitrogen atmosphere (e.g. in liquid substance are discovered and synthesized in
nitrogen) can minimize oxidation. Radiolysis your laboratory. The pioneering laboratory must
means that the substance irradiates itself and then analyze and characterize the labeled
thereby causes its own decomposition. molecule e.g. to investigate how the labeling
procedure affects the biological function and
There are several ways to reduce radiolysis. The behavior. This is a research topic in itself.
compound may be stored diluted. A common

110
CHAPTER 12
Applications
factors and oncogenes etc.). Thymidine is
Accuracy and sensitivity available as a commercial product labeled with
3H or 14C and those products are among the
Radioactive nuclides give the possibility to most sold radiochemicals.
study biological and medical processes with
high accuracy and sensitivity. The accuracy can Genes
be very high since the measurements are, in
most cases, not only quantitative but also The presence of certain gene sequences in DNA
possible to calibrate in detail against standard can be accurately analyzed by hybridization
preparations, and this can be made for very low experiments in which radiolabeled
concentrations of substances. The sensitivity is oligonucleotides, containing the gene sequence
very high since single decays can be detected. to be analyzed, are allowed to hybridize with
This allows the presence of only a few labeled denaturated DNA. The presence of the
molecules (and even single molecules) to be interesting gene can then be analyzed
detected. The applications given below are quantitatively by measurement of the
divided in two groups: biological applications radioactivity. Such analysis is called "southern
(basic biology and preclinical investigations blot" when the reaction is made on a blotting
using to a large extent pure beta emitters) and paper to which the DNA has been transferred.
diagnostic nuclear medicine (applying gamma The analysis is called in situ hybridization when
and positron emitters). the DNA is still in the cell (or at least in a
chromosomal conformation).
BIOLOGICAL APPLICATIONS
Oligonucleotides for such analysis are most
DNA synthesis often synthesized in a non-radioactive form in a
"DNA synthesizer" and are then labeled with
DNA synthesis in cells or tissues can be radioactive nucleosides by a process called nick-
quantitatively studied through the use of or end labeling. In cell analysis, it is necessary
radiolabeled thymidine (Figure 1). to first degrade RNA with RNAse to eliminate
the otherwise dominating binding to mRNA.
O
X RNA synthesis
N X CH3 (3H) RNA synthesis can be studied by applying
CH3 (14C) radioactive uridine, which is specifically used
O by cells for the synthesis of all forms of RNA.
N 125I, 76Br,
Uridine easily passes the cellular membrane and
dR and other the incorporation process is, principally, parallel
(deoxyribose) halogens to the use of thymidine for studies of DNA
synthesis. Radioactive forms of uridine are
Figure 1 Radiolabeled thymidine and iodinated available commercially. Studies using uridine
and brominated analogs give an overall measure of the total RNA
synthesis in the cell. For gene-specific analysis
Thymidine easily passes the cell membrane. It of mRNA synthesis, see below.
is, in the cell, only used for the synthesis of
DNA and for no other macromolecular Gene activity and transcription
structure. Thus, it provides a very specific way
to detect which cells or cell populations have an The activity of a gene in terms of "transcription
ongoing DNA synthesis. Scientific history is full activity" (synthesis of mRNA) can be measured
of exciting discoveries obtained with the help of quantitatively through hybridization between a
radioactive thymidine (characterization of the radiolabeled oligonucleotide, containing the
cell cycle, analysis of the action of growth gene sequence of interest, and the formed

111
mRNA with that gene sequence. Such analysis different amino acids are sometimes used for the
is called "northern blot" when the reaction is measurement of total protein synthesis. If the
made on a blotting paper to which the mRNA synthesis of only specified types of proteins is
has been transferred and in situ hybridization studied, then the use of radioactive amino acids
when the mRNA is still in the cell. Undesired must be combined with other methods, such as
binding to DNA is normally not a problem as gel electrophoresis or immunoreactions.
long as the DNA is in double stranded form. If
necessary, DNA can be degraded with DNAse. Phosphorylation and basic metabolism
Oligonucleotides for such analysis are made the
same way as described above for gene analysis. The regulation of energy flow in biological
systems involves phosphorylation and de-
Specific proteins phosphorylation (AMP ADP ATP). The energy
flow is to a large extent related to energy
The presence of specific proteins or other forms generation in the glucolysis and the citrate cycle,
of biological material in cells can be analyzed and the energy consumption to the synthesis of
using radiolabeled antibodies with specificity different molecules and the active transport of
for the protein to be analyzed (see also below molecules. In all cases, it is possible to study the
regarding sandwich techniques with labeled metabolic steps by using 32P or 33P labeled
secondary antibodies). The biological sample is phosphate, PO4. The radioactive phosphate is
exposed to the radioactive antibody and when given to cells and tissues. After different
the protein is present the quantity can be incubation times the compounds of interested
determined through analysis of the radioactivity. are isolated with biochemical methods (column
Such analysis is called "western blot" when the chromatography, thin layer chromatography,
reaction is made on a blotting paper to which electrophoresis, etc) and their content of
the biological sample has been transferred. It is radioactivity is measured. . The appearance and
called radioimmuno detection when the analysis disappearance of radioactivity reflects
is made directly on a more or less intact phosphorylation and dephosphorylation,
biological sample. Many forms of radioimmuno respectively. The analysis is easily quantified so
detection are described in the chapter on that the number of molecules involved in the
antibodies. Protein specific antibodies can often processes can be estimated. Radioactive
be purchased from companies specialized on phosphate is commercially available at
immunology products. In most cases, it is reasonably low prices and is one of the most
necessary to do the radioactive labeling at one’s used radioactive chemicals.
own laboratory using methods as described in
Chapter 9. In a few cases, it is possible to buy Phosphorylation and signaling
already labeled antibodies.
One of the most interesting processes studied in
Protein synthesis recent years is phosphorylation related to
intracellular signaling. Many intracellular signal
The overall protein synthesis in cells or tissues systems seem to be mediated via
can be studied accurately through the use of phosphorylation and dephosphorylations. One
radioactive amino acids. The amino acids are example is receptor-ligand interactions (e.g.
incorporated in the proteins and thereby give an growth factor-receptor), which initiate primary
intracellular accumulation of radioactivity. All phosphorylation of the receptor itself and related
most common types of amino acids are proteins leading to cascades of phosphorylation
commercially available in radioactive forms. to exert signal transduction, often all the way
into the cell nucleus. In the last steps, the
It should be noted that different amino acids are phosphorylation initiates DNA mRNA
taken up with different efficiency over cell transcription (activation of genes). Such
membranes but this is normally not a big phosphorylation can easily be analyzed by using
problem in basic biology studies. Cocktails of 32P labeled phosphate. The radioactive

112
phosphate is given to cells that exert the studied molecule can be isolated through available
reaction. Thereafter, the studied molecules are purification methods.
isolated (most often using electrophoresis) and
the amounts of 32P associated to the molecules Other metabolic processes
are a measure of the phosphorylation. By
incubating the cells for longer times with Carbohydrate and lipid synthesis can be studied
radiolabeled phosphate, dephosphorylation by using more or less specific radioactive
processes can also be studied. precursors. Methylation processes can be
studied by applying relevant radiolabeled
Phosphorylation in cell free systems precursors and melanin synthesis can be studied
through the use of radiolabeled thioureas. Pre-
Radioactive phosphate can be used for end- or formed melanin can be analyzed with several
nick-labeling of nucleic acids in cell-free substances since melanin is used by the body as
systems. This allows detection of the DNA a scavenger for toxic agents. Radiolabeled
when processed with different biochemical analogues of such agents might then be used for
methods for purification, size determination and the analysis. The list of possibilities for
sequencing. Radioactive phosphate is, as metabolic studies using radioactive substances
mentioned above, commercially available and at can be made very long and it seems that most
reasonably low prices so there are no severe metabolic processes can be studied if action is
economic limitations for the use of the taken to radiolabel relevant precursors. In
described methods. principle, at least one precursor must be known
and radiolabeled and this precursor then serves
Glucolysis and energy metabolism as a starting point for the studies under
consideration. The limitations thereafter are the
The amount of glucolysis can be measured limitations of the biochemical methods to
through the use of radioactive glucose. analyze metabolites of the radioactive test
However, "natural" glucose is quickly substances. An economic limitation might be
metabolized and does not give an accumulation the high costs to develop a radiolabeling
in cells and tissues with high glucolysis. Instead, technique for a new substance.
the synthetic analog deoxyglucose is used since
it is to a large extent phosphorylated in cells and Uptake and processing of new compounds
might bind irreversibly to key enzymes in the
glycolytic pathway and thereby accumulate and In compound development (e.g. development of
allow accurate detection. Radioactive new chemotherapy agents, metabolic inhibitors
deoxyglucose without phosphorylation easily or targeting agents for radionuclide therapy) it is
passes cell membranes and is commercially necessary to characterize the biological
available. This is the most often used precursor properties of the compounds in some detail.
when energy metabolism is analyzed. The steps This means analysis of the cellular binding,
in the "citrate cycle" (or Krebs cycle) can be internalization, retention and degradation as
analyzed through the use of other radioactive well as the in vivo properties such as half-life in
tracers. the systemic circulation, uptake and metabolism
in the liver, uptake and release from the kidneys,
Glycosylation and uptake in many other organs. By labeling
the compound with radioactive nuclides, it is
The glycosylation of any macromolecule in a possible to follow such processes. If the
biological system can be analyzed by adding compound is of low molecular weight, the most
radioactive carbohydrates of the suitable type attractive approach is to exchange stable
and then analyzing how much radioactivity is nuclides, most often carbon or hydrogen, for the
associated with the studied macromolecule. One same type of nuclides in the radioactive form, in
limitation is the accuracy by which the studied this case e.g. 14C or 3H. With this procedure
the chemical and biological properties of the

113
compounds are not disturbed. If the compound binding should under such conditions be
is macro-molecular (protein, glycoprotein, displaced more or less completely. As for
carbohydrate etc.) it is often possible to label ligand-receptor interactions one can also in this
with, for example, radioactive iodine without case analyze binding versus concentration, at
disturbing the biological properties of the 4oC, and gradually displace the radioactive
molecule too much. The availability of antibody by increasing amounts of non-
radiochemical reagents for the radiolabeling radioactive antibody to obtain input data for
varies from case to case. "Scatchard analysis". An application is, also in
this case, the development of targeting agents
Receptor-ligand interactions for imaging and/or therapy of spread tumor cells
and metastatic growth.
If the binding of a ligand (e.g. a growth factor)
to a receptor is characterized in some detail it is DIAGNOSTIC IN NUCLEAR MEDICINE
convenient to use a radioactive ligand. The
binding of the radioactive ligand can be Development
quantified in detail and related to the number of
cells or the mass of the biological sample under From the historical point of view, the initial and
physiological conditions. The specificity of the most common strategy for the diagnostic use of
radiolabeled ligand can first be analyzed using
radionuclides has been to give e.g. 99mTc (pure
native non-radioactive ligand in excess (at least
gamma emitter) in salt form (or associated to
tenfold excess) during the time of analysis. If
some biomolecule) and then to study the uptake
the radiolabeled ligand binds specifically, the
pattern in normal healthy persons. The spatial
binding should under such conditions be
distribution of the radioactivity was studied in
displaced more or less completely. If there are
pictures obtained using different types of
unspecific inter-actions between the radioactive
gamma cameras. Different diseases could then
ligand and the biological test material, the signal
be studied by analyzing aberrations in relation to
of the radioactivity cannot be efficiently
the so-called "normal" pictures. One striking
displaced. In cases when the radioactive ligand
example is the studies of the breakdown of the
binds specifically, one can, at 4oC, analyze blood brain barrier. It was found that this barrier
binding versus concentration of the added ligand was locally disrupted in patients with malignant
(to obtain saturation) and also gradually displace gliomas, and analysis of this is today an
the radioactive ligand by increasing amounts of established type of investigation.
non-radioactive ligand. Such analysis gives
input data for a so-called "Scatchard analysis" in Today, the use of radioactive nuclides for
which the affinity and the number of binding diagnosis of different diseases is very advanced.
sites can be quantitatively determined for the Radioactive precursors can be synthesized for
ligand-receptor interaction. Such applications specific studies (as described above in the
are of importance in the development of section on biological applications) and the
targeting agents for imaging and/or therapy of spread of these precursors can be followed more
spread tumor cells and metastatic growth. or less quantitatively over the body by using
advanced scintigraphy (e.g. SPECT and PET).
Antibody-antigen interactions The spatial resolution is so good (in the order of
1 cm) that one can fairly well calculate the
If the antibody binding to an antigen is uptake of radioactivity in different tissues and
characterized in some detail it is, in the same organs. The metabolic processing of the
way as described above for ligand-receptor precursors can sometimes be followed by
interactions, convenient to use a radioactive chromatographic analysis of blood and urine,
antibody. The specificity of the radiolabeled and counting of the amount of radioactivity in
antibody can be analyzed using native non- the different molecular preparations.
radioactive antibody in excess. If the
radiolabeled antibody binds specifically, the

114
Basic biology versus clinical tests short half-life of 11C). The technique is fairly
new, and tests are in progress to analyze DNA
In principle, the same radioactive precursors as synthesis in growing tumors. Brominated
described above for basic biology studies can thymidine (Figure 1) has to be synthesized at
also be applied in clinical patient studies to try special laboratories designed for fast synthesis
to analyze aberrant processing in the studied of radioactive nuclides.
metabolic steps. The main difference is due to
the fact that in the clinical work, gamma Genes and transcription
radiation has to be used to allow for external
detection with high efficiency and precision. The presence of certain gene sequences in DNA
Thus, the pure beta emitters (3H, 14C, 32P and and the corresponding DNA-mRNA
35S) often used in basic biology are of no or transcription activity may, in the future, be
limited interest since it is in most cases not analyzed in the intact body via hybridization
possible to obtain tissue samples for analysis. techniques. Oligonucleotides containing the
Instead, high-energy gamma or positron (giving gene sequence to be analyzed should then be
rise to gamma radiation after annihilation) labeled with radioactivity and injected into the
emitters have to be applied. Examples of such patient. The analysis at the clinic should in most
cases be non-invasive and made by external
nuclides are 11C, 15O, 18F, 76Br, 99mTc,
monitoring of the localization of the applied
110In, 111In, 123I, 124I and 131I. The fact that
radiolabeled oligonucleotides. Of course, there
some of these nuclides have a very short are still many unsolved problems relating to this
physical half-life puts special requirements on problem like: How can the oligonucleotides find
the radiolabeling and the handling of the their way to the target organs? How can they
nuclides. It also gives certain advantages since find their way over the cell membranes to finally
few radioactive molecules need to be attached to reach the nucleic acid of the targeted cell? How
the test compound to have a certain number of to prevent degradation of the oligonucleotides
radioactive decays during the time of analysis. before they reach the target? The expected
developments in gene therapy will hopefully
The discussion on clinical applications below help to obtain suitable transport means for such
follows, due to pedagogical reasons, the same oligonucleotides. Thus, the technique is not
order as for the biological applications. This is a available today but will hopefully be available
somewhat unusual order in comparison to what in the future. The only realistic possibility
is used in clinical textbooks on nuclear medicine available today is the analysis of operation
where simpler methods such as the use of free material and biopsies with the same techniques
iodine for studies of uptake in the thyroid are as applied in basic biology (in vitro diagnosis).
mentioned first and more complicated
investigations employing macromolecules are
mentioned later. However, to start with RNA synthesis
discussions on genes and DNA-mRNA
transcription (as in most biological textbooks) it RNA synthesis can in principle be studied using
is clearly seen how much more biologically radioactive uridine in parallel to the use of
advanced all laboratory techniques are in radioactive thymidine for studies of DNA
relation to the available clinical methods. This is synthesis. However, the use of gamma emitters
hoped to serve, for the reader, as an inspiration for studies of uridine is not so developed, and
for further efforts to develop the clinical we therefore have to wait for further progress
methods. from the involved research laboratories.

DNA synthesis can probably be fairly well Specific proteins


studied in different tissues in patients through
Radiolabeled antibodies with specificity for the
the use of 76Br labeled thymidine (11C labeled
protein to be analyzed can in some cases be used
thymidine is probably less suited because of the
to externally visualize the presence of the

115
protein in different parts of the body. Whether
the analysis can be made in a quantitative Glycosylation and other metabolic processes
manner depends on the availability of the
protein in the tissue, the antibody penetration The glycosylation of any macromolecule can, in
properties and on the scintigraphy technique principle, be analyzed by adding relevant
applied. This technique, often called radioactive carbohydrate and then analyzing
immunoscintigraphy, radioimmunolocalization how much radioactivity is associated with the
(RIL) or radioimmunodiagnosis (RID), is studied macromolecule. The limitation is, if
presently under intense development and we blood or urine samples are not enough for the
foresee interesting applications in the near analysis, that tissue samples have to be taken
future. from the patient and the studied molecule
isolated through available purification methods
Protein synthesis (chromatography, gel electrophoresis).

The overall protein synthesis in tissues and Carbohydrate, lipid and melanin synthesis and
organs can, at the clinic, be studied rather methylation processes can be studied by using
accurately through the use of radioactive amino more or less specific radioactive precursors and
acids. One amino acid used for PET-based following similar strategies as indicated for the
analysis is 11C labeled methionine which has, studies of glycolysation. Some progress has
for example, been used to monitor the increased been made along these lines but there is a lot of
amino acid uptake (and possibly also increased developmental work before even a minor part of
protein synthesis) in different types of tumors. all potential possibilities can be exploited.
In principle, all types of amino acids can be
labeled with gamma or positron emitters and Therapeutical compounds
applied in such studies. An interesting aspect is In the development of new chemotherapy
to try to distinguish between amino acid agents, metabolic inhibitors and targeting agents
accumulation due to changed transport in certain for radionuclide therapy, it is necessary to
diseases and the changed protein synthesis. The characterize the biological properties of the
parallel use of amino acid analogs, one that can compounds. This is partly made in the
only be taken up intracellularly and one that can laboratory but it is also important to study
also be incorporated in proteins, might give parameters like uptake in different tissues to
future possibilities to study this. allow for estimation of the half-life in the
systemic circulation, uptake and metabolism in
Phosphorylation the liver, uptake and release from the kidneys,
and uptake in many other organs. By labeling of
Phosphorylation processes in patients will the compound with gamma- or positron-
hopefully be studied in the future applying emitting nuclides it is, in principle, possible to
phosphate analogs. This is at present the subject follow such processes in the patient or in
for research and development. volunteers. The investigations should be
complemented by chromatographic analysis of
Glucolysis and energy metabolism blood and urine to give knowledge about the
presence of degradation products.
The amount of glucolysis in different tissues can
be measured quite accurately applying 18F- Molecular interactions
labeled deoxyglucose, often called FDG. The
If the binding of a ligand or an antibody to a
uptake in different tissues is assumed to reflect
receptor or antigen is to be characterized
the amount of glucolysis, and it has in many
directly in a patient, the difficulties are much
cases been found that tumors have an increased
larger than when analyzing such phenomena in
uptake. Suitable precursors for studies of the
the laboratory. The difficulties partly relate to
citrate cycle will hopefully be developed in the
the large volume of the patient requiring
future.

116
enormous amounts of compounds for studies of
saturation and displacement. It is also very
difficult to assure that the transport systems in
the body allow for interactions to take place in a
representative and reproducible way.
Furthermore, there are difficulties due to
metabolism of the labeled ligands and
antibodies (a correct "Scatchard analysis"
normally requires inhibition of degradation at
4oC). It is of course not possible to distinguish
degradation products from the original
substance through the necessarily non-invasive
analysis systems (gamma cameras). In spite of
these difficulties, scientists are seriously
attempting to develop models through which
scintigraphic dynamic data can be treated in
terms of molecular flow and interactions.

Analysis of operation material and biopsies

If, at the clinic, there are possibilities to obtain


fresh living tissue samples that either can be
cultured or prepared otherwise as any biological
sample in experimental biology, then all the
possibilities for analysis listed above (see
biological applications) are available. This is
often called in vitro diagnostics and is a growing
research area. However, we foresee an
interesting development regarding in vitro
diagnostics in the future.

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