Lima J.J.Pedroso, de (ed.). Nuclear Medicine Physics

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478 Nuclear Medicine Physics

0.9

Diarrhea

(0.55)

Lung fibrosis

(2.7)

Skin burns

(8.6)

Ovulation

(0.85)

Hypothyroidism

(2.3)

0.8

0.7

0.6

0.5

Ris

0.4

0.3

0.2

0.1

Dose (G

)

0123456789101112131415161718192021222324252627282930

(Threshold in parenthesis, Gy)

Morbidity

(

Lower acute exposures and/or irradiations

extending over several years)

Sperm count

(0.46)

Cataracts

(1.3)

Vomiting

(0.49)

FIGURE 8.24

Biological effect of radiation (morbidity). In parenthesis: dose threshold.

It can be seen, for example, that vomiting and diarrhea are the ﬁrst symp-

toms with dose thresholds of 490 and 550 mGy, respectively (Figure 8.24).

However, we must also consider the mortality due to radiation exposure,

where the dose thresholds have higher values (Figure 8.25).

Knowing typical values for some of the serious effects of the radiations, it

is interesting to compare these values with the dose limits. This comparison

is made in the following ﬁgures:

In the graph of Figure 8.26, a vertical line is included, which corresponds to

theall-body annual doselimit forradiation workers, 20mSv,which means that

for photons we have 20 mGy, or 0.02 Gy. As can be seen, the scale was reduced

to a maximum of 1 Gy, instead of the 30 Gy of Figure 8.24. In Figure 8.27, the

scale is reduced still further to a maximum of 0.55 Gy = 550 mGy. As can be

seen, the dose threshold for the decrease in the sperm count has a value 23

timeshigher than the currentdose limit for workers; whereasfor vomiting, the

dose threshold is 24.5 times higher than the dose limit; and diarrhea appears

with a threshold 27.5 times higher than the dose limit. This difference of values

still increases more when these threshold values are compared with the dose

limits for the members of the public, which is 1 mSv, equal to 1 mGy for

photons, signiﬁcantly smaller than the thresholds of 460, 490, and 550 mGy

for sperm count, vomiting, and diarrhea, respectively.

With data of this type, it is possible to trace scenarios of the consequences

of a radiological accident, in particular when there is release of radioactivity

Dosimetry and Biological Effects of Radiation 479

Bone marrow

syndrome

without

medical

care

(1.5)

Bone marrow

syndrome

with medical care

(2.2)

Mortality

(Threshold in parenthesis, Gy)

Gastrointestinal

syndrome external

(9.8)

Pneumonitis

(5.5)

Gastrointestinal syndrome

internal

(23)

0.9

0.8

0.7

0.6

0.5

Risk

0.4

0.3

0.2

0.1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Dose (Gy)

16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

FIGURE 8.25

Biological effects of radiation (mortality).

Risk

0.9

All body annual limit

Sperm count

(0.46)

(reshold in parenthesis, Gy)

Vomiting

(0.49)

Diarrhea

(0.55)

Morbidity

(Lower acute exposures and/or irradiations

extending over serveral years)

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5

Dose (Gy)

0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 10.55

FIGURE 8.26

Comparison of some radiation effects with the dose limits for stochastic effects.

480 Nuclear Medicine Physics

0.009

0.01

0.008

0.007

0.006

0.005

Risk

0.004

0.003

0.002

0.001

Dose (Gy)

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35

Sperm count

(0.46)

Diarrhea

(0.55)

Vomiting

(0.49)

(Threshold in parenthesis, Gy)

All body annual limit

Morbidity

(Lower acute exposures and/or irradiations

extending over several years)

0.4 0.45 0.5 0.55

FIGURE 8.27

Comparison of deterministic effects with the dose limit for stochastic effects.

in the environment or when an incident results in high exposures of a group

of individuals.

As can be seen in the ﬁguresjust cited, a fundamental element in the forecast

of the consequences from the irradiation of a population is the determination

of the absorbed dose, which allows us to determine the associated risks.

As can be appreciated, these graphs have a multidisciplinary characteris-

tic; in the abscissa axis, we found a physical quantity, and the ordinate axis

represents the biological effect. Therefore, this type of graph has biophysical

characteristics.

One important component of radiation protection is the determination of

the risks related to radiation exposure. This subject is polemic due to the

deﬁnition of risk with supporters and detractors. The defence of this type of

analysis is found in Pochin [33].

This presents, for example, the importance that these studies have had at

the level of radiological surveys on populations, allowing the conclusion,

for example, that the risk is larger than the beneﬁt for ages less than 30

years in stomach cancer surveys. In another example, Pochin [33] pointed

out that the production of hydroelectric energy has a death risk almost 2.5

times higher than the nuclear production for a GW per year of produced

electricity.

Notice that the problem of the risk associated with radiation exposures and

radiation dosimetry always appears to be connected, in a global perspective of

Dosimetry and Biological Effects of Radiation 481

radiological protection. For a consultation on the risk philosophy in radiation

protection, see Lindell [34].

8.10.1 The Cell as a Target of Ionizing Radiation

The cell is one of the important targets of ionizing radiation; its structure and

function have, naturally, inﬂuenced the evolution of radiation dosimetry. Due

tothis, several physical considerationswill be made, relatedwith this complex

target, which is the biological tissue. The cell is the fundamental unit of life.

It is the structural unit constituent of plants and animals and, therefore, is an

important target that cannot be neglected in the study of the mechanisms of

radiation effects and radiation protection. Due to the complexity of biological

matter, radiation dosimetry also tends to be complex, for example, through

microdosimetry. Consider the following question: Is the cell the fundamental

target in radiation dosimetry or should we consider only the cell nucleus,

or, on the other hand, is the DNA molecule the most important target? Will

other cell constituents also be important such as enzymes, ribosomes, cellular

membranes, centrosomes, etc.? Are these questions for radiobiology or are

they also for radiation dosimetry?

8.10.2 Composition, Shape, and Size

Although, often only implied, several approaches toward radiation protec-

tion are directly related with the hierarchy of life, which can be presented

in the following way: molecules, organelles, cells, tissues, organs, organisms,

populations, communities, ecosystems, and biosphere. Related to this hierar-

chy, we ﬁnd, for example, studies in environmental radioactivity whose main

focus are ecosystems, populations, and communities, where there are also

included epidemiological studies of the radiation effects or the determination

of the radioactivity in several types of soils or rivers and their transference to

living organisms, or the spread of radioactive clouds in atmosphere, etc. Stud-

ies of the absorbed dose in living matter, in particular in the human body, in

their organs, or tissues, are the goal, for example, of several surveys to deter-

mine the dose in medical practices, such as radioadiagnostics or the rigorous

determination of absorbed dose in radiotherapy. The radiobiological study

of the radiation effects in tissues, cells, and their constituents and molecular

biology is applicable, in studying the DNA molecule, an important target of

ionizing radiation. In this latter ﬁeld, studies have appeared of the biophysi-

cal mechanisms of the action of ionizing radiation, from which has emerged

the subdiscipline of radiation dosimetry, microdosimetry, which extends to

nanodosimetry.

As such, the fundamental unit of life, the cell, and its constituents cannot

be ignored in radiation protection.

Approximately 70–80% of the cell is water. For this reason, water is often

used as a human tissue equivalent. However, the diversity of structuresfound

482 Nuclear Medicine Physics

in cells and the metabolic capacities, growth, and reproduction are so complex

that the above-mentioned approximation can only be accepted as an interme-

diate step toward the full understanding of the biological effects of ionizing

radiation, which is a fundamental goal of radiation protection.

In radiation dosimetry, an immediate question emerges about the size of

cells. The diversity of cell sizes is rather large, such that ﬁnding typical sizes

is only a ﬁrst approximation.

Table 8.2 shows the dimensions of typical biological molecules and cells to

give an idea of the size scales involved.

Life at all levels can be seen as a process that organizes matter and energy

into ordered systems. It can be considered, at another level, as a process of

decreasing the entropy of the system. The interaction of radiation with matter

supplies energy through processes which increase the entropy of the biologi-

cal system, sometimes at levels that the organism cannot reorganize, leading

to lethal radiation effects. The concept of entropyallows new insights of radia-

tion physics, as have been shown above. It can eventually be a link connecting

physics and biology. Systems theory in the future will also play an important

role in radiation protection.

How far can we ignore the question of the spatial scale? How can we

not question the concept of uniform irradiation, in which we assume that

TABLE 8.2

Typical Sizes of Biological Molecules

and Cells

0.1 nm diameter of hydrogen atom

0.8 nm amino acid

2 nm diameter of DNA helix

10 nm thickness of cell membrane

11 nm ribosome

25 nm microtube

50 nm nuclear pore

100 nm virus

200 nm centriole

200 to 500 nm lysosome

1–10 nm generic size of prokaryotes

1 μm diameter of a human nerve cell

3 μm mitochondria

6 (3–10) μm cell nucleus

4 μm leukocyte (white blood cell)

9 μm erythrocyte (red blood cell)

10–30 μm generic size of eukaryotic animal cells

20 μm liver cell

90 μm amoeba

100 μm (0.1 mm) human ovum

Dosimetry and Biological Effects of Radiation 483

in a uniformly irradiated region the value of the absorbed dose is the same

everywhere within the region? It seems difﬁcult, following the above con-

siderations, to accept the concept of uniform irradiation, where the absorbed

dose value is the same for any point inside the volume exposed.

For a man with average height and weight, there are about 10

cells. In

addition to their normal metabolism, cells undergo four more processes:

1. Merge

2. Differentiate

3. Die

4. Divide

The process of division produces new cells in number and for a period of

time, which is determined by the needs inherent to the organism and by the

internal and external environmental circumstances. In a mammal, there are

active centers for cellular division, for example, the skin, the regions of blood

formation in bones, or some intestinal cells. Radiosensitivity is associated

with the reproducibility of cells.

8.11 Action Modes. Target Theory Models: Survival Curves

The biological effects of radiation can be studied at different levels of bio-

logical organization, such as molecular, subcellular, cellular, organ or tissue,

whole body, and population. Examples of the effects of ionizing radiation at a

molecular level are damage to DNAor proteins; at a subcellular level, they are

injury on cell membranes or chromosomes; at a cellular level, they are inhi-

bition of cell division or loss of function; at a tissue or organ level, they are

lesions in GI or hematopoietic systems; at the whole body level, they include

cancer or death; and, ﬁnally, at the population level, they are the genetic or

chromosomal mutations.

The inactivation of individual biological structures by the action of ionizing

radiation, resulting from a discrete and localized transfer of energy, is one of

the postulates in model development for the study of the effects of radiation

on cells. In these models, two possibilities of interaction of ionizing radiation

with molecular structures relevant in cellular function must be considered

(Figure 8.28): direct action and indirect action, the latter resulting from the

participation of intermediary products.

Direct action concerns the effects that occur when radiation directly hits

molecules or microstructures of vital importance in the cells. It is normally

described on the bases of a so-called target theory.

Target theory is the mathematical development of direct action with exper-

imental grounds, but without taking into account the biological mechanisms

of cellular attack. Target theory sets on two postulates:

484 Nuclear Medicine Physics

Indirect action

Radiation

Radicals

active

molecules

Cellular death

genetic eﬀects

somatic eﬀects

teratogenic eﬀects

•

; OH

•

; HO

•

; H

; O

70%

Direct action

Radiation

Normal cells

Repair

Molecular damage

Biological eﬀect

DNA

FIGURE 8.28

The two possibilities of interaction of the ionizing radiation with molecular structures relevant in

cellularfunction: directaction andindirectaction,resultingfromtheparticipation ofintermediary

products (radicals and chemically active molecules).

•

The statistical nature of energy deposition; and

• The existence of a direct relationship between the number of hits and

the ﬁnal biological effects.

A problem inherent to this method is the difﬁculty to relating biological

effects with speciﬁc physical or chemical causes [35].

According to target theory, the probability of a radiobiological event occur-

ring depends on the probability that the primary physical action has taken

place in speciﬁc zones of the cell. This is the concept of sensitive zones of the

cell that correspond to the vital structures already mentioned.

The number of target molecules is generally small when compared with the

total number of molecules in the cell; but the effects can be important if the

molecules involved are enzymes or molecules from genes or chromosomes.

It is known, for example, that for some cellular enzymes, the number of

moleculesin acell is minimal, limited toa fewunits, buttheir actionis decisive.

Inactivation of molecules of such enzymes can irreparably compromise the

function in which they participate.

It was already known, using sampling and observation of cellular alter-

ations after irradiation, that for a particular preparation in constant condi-

tions, if the intensity of radiation is decreased but its quality is maintained,

the lesions observed were no less severe but they occurred in a smaller

number.

Dosimetry and Biological Effects of Radiation 485

Target theory of cellular death was proposed by Lea in 1946 and experimen-

tally developed using data from inactivation of microorganisms and active

biomolecules [36].

In the implementation of the theory, a set of variables capable of alter-

ing the inactivation properties of radiation, such as temperature, type

of radiation, chemical composition of the medium, etc., were taken into

account.

The statistical treatment of experimental data and its systematic analysis

led to the knowledge of the minimal energy necessary to damage a particular

sensitive zone as well as its volume.

There are more complex situations than those resulting from a simple

impact. Other effects can occur if a second photon collides with the molecule

within a time of 10

−8

to 10

−4

s after the ﬁrst hit and before the molecule has

lost the excitation energy received.

Target theory has been shown to be applicable in a large number of clono-

genic

∗

survival situations in mammals, but its application as a general theory

has always had some opposition [37].

Proliferation by cellular division is an essential property of cells in any

biological system. The alterations in this capacity after irradiation with ion-

izing radiation results from chemical alterations in the genome and is of

fundamental interest in radiotherapy and radioprotection.

In general terms, in the absence of radiation or any other external active

entity, thefactors that limitthe cellular divisioncapacity in healthycells arethe

shortage of nutrients, the increase in cellular concentration, and the presence

of regulatory systemic factors.

Apart from direct action, an indirect action that takes place between the

initial physical events and the biological phenomena, which is equally capable

of producing molecular alterations, also has to be taken into account.

In fact, radiation can act on the intracellular ﬂuids or the extracellular

environment, producing active radicals that, in turn, act upon the cells.

Water contributes to about 70% of total mass in living beings and reaches

more than 80% in embryonic and young tissues. It is the main intervenient in

indirect action.

Biological damage resulting from low LET radiation is mainly due to indi-

rect action. About two thirds of biological damage, produced by x-rays,

results from indirect action.

†

It is, therefore, of relevant interest to con-

sider the products that arise from the action of ionizing radiation on

water. The formation process of these intermediary structures is called water

radiolysis.

∗

Cells starting from a single cell are able to indeﬁnitely proliferate and form large colonies called

clonogenic. Tumor cells indeﬁnitely proliferate in cellular cultures.

†

Assuming low levels of chronic irradiation from external sources, strong probabilities exist of

repairing such biological damage without errors.

486 Nuclear Medicine Physics

8.11.1 Water Radiolysis

The reaction

O → H

−

(8.92)

represents the ionization of the water molecule; the recombination of the ions

produced is not probable.

These ions will lead to further reactions

→ H

+OH

•

(8.93)

whereas the free electron will combine with another water molecule.

−

O → H

−

→ H

•

+OH

−

(8.94)

•

and OH

•

radicals can diffuse and react with each other or initiate

oxidation-reduction reactions with other molecules of the medium.

∗

In the case where the radicals react with each other, the probable reactions

are

•

→ H

(8.95)

•

+OH

•

→ H

(8.96)

•

→ H

O (8.97)

with the two radicals in Equation 8.97 having chemical activity.

In summary, about 10

−7

s after the passage of an ionizing particle in

water and around its track, H

•

,OH

•

, and H

are found. The relative

proportionsofthese intermediaryreactionproductsdepend on radiation TLE.

What happens next (from 10

−7

to 10

−3

s) depends on a number of factors,

such as water purity.

Of special interest is the presence in water of dissolved oxygen. When this

is present, free electrons can react with the O

molecule

−

→ O

−

(8.98)

which reacts with a water molecule, leading to

−

; +H

O → OH

−

+HO

•

. (8.99)

A reaction between the radical H

•

and O

can also occur:

•

→ HO

•

(8.100)

∗

Free radicals are chemical species with a free valence and are very reactive. These radicals can

react with molecules such as DNA and lipid membranes.

Dosimetry and Biological Effects of Radiation 487

This radical can react with another HO

•

or with H

•

giving

•

+HO

•

→ H

(8.101)

•

→ H

(8.102)

The HO

•

radical is less reactive as an oxidant than OH

•

, but it can diffuse to

longer distances. The presenceof this radical and a higher H

concentration

are the main consequences of the presence of O

in the solution.

Other reactions are possible by combination of the radicals available when

oxygen is present.

The set of phenomena that make up the strengthening of radiation effects

resulting from O

presence is designated oxygen effect.

This effect can be quantiﬁed, for a given biological action, through the oxy-

gen enhancement ratio (OER), which is deﬁned as the ratio between absorbed

dose in anoxic conditions (D

) and dose in good oxygenation conditions (D

)

necessary to have the same biological effect in a given tissue, or

OER =

δ (8.103)

8.11.2 Effects in Aqueous Solutions

Let us consider an aqueous solution of RH molecules and that radicals such

as H

•

,OH

•−

, and HO

•

appear in solution by radiolysis.

The following reactions can occur:

RH +H

•

→ R

•

(8.104)

RH +OH

•

→ R

•

O (8.105)

RH +O

•

→ R

•

(8.106)

•

O (8.107)

If the O

concentration in the medium is high, a reaction with radical R

•

can occur, with peroxide radical as the product.

•

→ ROO

•

(8.108)

This can react with an RH molecule

ROO

•

+RH → ROOH +R

•

(8.109)

The radical R

•

can, in turn, react with O

to produce another peroxide

radical, in a process that repeats itself in a chain reaction.

Other reactions are possible, particularly in the presence of oxygen.