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The biological effects of radiation

23. The biological effects of radiation

Author: Szabolcs Mózsa

Semmelweis University Department of Radiology and Oncotherapy, Budapest

This brief sketch delineates some important statements of radiobiology. In nowadays radiology can’t be done without radiobiology, and as well these are the principles of radiation protection. The importance of this subject is emphasized by: 1./ the increasing number of ionizing sources; 2./ the opportunity of environmental contamination; 3./ the human life span along with the time of exposure is extended. /Th.M.Fliedner, 1972./. We live in a radiation space. This space divided two parts: 1./ natural background radiation; 2./ artificial radiation. The world average in our days, after Chernobyl, is about 3.0 mSv/year.

Radiobiology examines the response of the ionizing radiation in living material. It is an interdisciplinary field of science, so the development depends on these interdisciplinary sciences’ advancing. The main directions of development are: general, experimental, clinical, military (cosmic) and environmental radiobiology.

The Grotthus /1815/- Draper /1895/’s law states that the primary effect of radiation is the absorption of energy. Biological effect redeemed by only absorbed radiation. The time elapsed between the absorption and the biological effect called primary radiation effect period. /Th.Herrmann, 1990./.
This effect can be divided three parts:
a./ physical
b./ physical-chemical
c./ chemical-biochemical
d./ biological part.
The length of these periods is growing the same sequence (nanosec, msec, minute, hour, day, month, year).

In medicine, it is appropriate to think that the effect of ionizing radiation is bionegative and cumulative. (But it’s true, that Lucky wrote down biopositive effect, the hormesis, but only in plant cell cultures. The plant cell contains less DNS than human cell. In other aspects there are many differences in radiobiological properties between plants and mammal cells. Because of this, an independent field of science is plant radiobiology.)

Regularly direct and indirect radiation distinguished. At the direct effect, the physical and the biological process occurs in the same medium, and at the indirect effect, the energy transferred by water. At the indirect effect the formation and the influence of free radicals are very important. These radicals are short-lived due their reactivity. Recent theories states the radical formation exists not only in water, but also in dry systems. In nowadays, direct and indirect radiation effects can’t be differenced.

The discovery of direct and indirect radiation led to the development of the target theory. This theory assumes that: 1./ the absorption of the energy occurs in sensitive volume, 2./ the energy releases in this volume. This release called hit. The graphic representations of the direct biological radiation effect are the dose-response curves, which have two types: 1./ exponential or single-hit curves, when only one hit required to the inactivation, 2./ non-exponential curves. The non-exponential curves divided to two groups: 1./ multi target curves, 2./ multi hit curves. /Sommermeyer, 1938., Lea, 1949., Donhoffer, 1962., Köteles, 2002., Herrmann, 2011./.

Another important classification is the deterministic /non-stochastic/ and the stochastic radiation. The deterministic effect has a limit-dose and the severity depends of dose. The stochastic effect has no limit-dose, and only the probability of the effect increases with dose. The acute radiation poisoning is a deterministic, the cancer with radiation origin is a stochastic process. The modern radiation protection is aiming to decrease the stochastic effects to tolerable range of the community. /Sztanyik, 1983./.

Somatic and genetic radiation effect also can be distinguished. /V.P.Bond, Th.M.Fliedner és J.O.Archambeau, 1965., Köteles, 2002./. The first effect important to the person, the second is to the descendants. Since the discovery of the X-ray mutagenity /H.G.Mueller, 1923./, research of the genetic radiation effects became the most developing field of radiobiology /N.Y.Timoféeff-Ressovszky, 1931./. Meantime it found that the genetic radiation effect has no limit-dose, and the gametes are very sensitive to radiation.

The biological radiosensitivity is relative. The susceptibility orders of tissues are described by H.Holthusen /1921/. From the most sensitive to the most resistant: the bone marrow, the mucosa of bowels, the lymphatic tissue, the testicle, stratum germinativum in the skin, the ovary, the lungs, the kidneys, the muscles, bones and connective tissues, the cartilage, the nerves, and the cells containing melanin. In practice, this order accepted till nowadays.
The species-dependent radiosensitivity in acute radiation were shown by Jacobson, Marks and Lorentz /1949/. They found the whole animal radiation sensitivity in growing order: rabbit, rat, mouse, chicken, human, goat, guinea pig, dog /whole animal radiation sensitivity/.

The specific tissue tumors’ radiation sensitivity follows the normal specific tissues sensitivity. /Borak, 1938/.

Bacteria and viruses are very resistant compared to other biological objects. The doses used to sterilization are adjusted this.

The LET (Linear Energy Transfer, keV/m) is very important physical factor in biological radiation effect. It describes the density of the ionization caused. This density can be high (alpha decay, n, p) or low (X-ray, gamma-ray, beta-decay or electron beam). Another factor, the relative biological effectiveness is also used to qualify the biological effect /RBE and RBW values: X-, gamma ray, beta decay: 1, neutron emission: 5-10, alpha decay: 20/.
Oxygen improves the biological effect (oxygen enhancement ratio, OER). In case of gamma ray, OER is between 2 - 3. In hypoxia, low LET, the radiation resistance increases.

The effect of ionizing radiation can increased by: 1./ radiosensitizers (e.g. Misonidazole), 2./ membrane specific pharmacons (e.g. I-acetamide), 3./ DNA precursor analogues, 4./ cytotoxic substances (e.g. Cu 2++) 5./ reparation inhibitors (Actinomycin-D) 6./ thiols, 7./ scavengers. The effect can decreased by: 1./ amino acids with sulfur compound (e.g. cysteine, glutathione, cysteamine) 2./ some enzymes (catalase, superoxide dismutase, glutathione peroxidase), 3./ hypoxia.
The primary target of ionizing radiation is the DNA, and the G2 phase in the interphase (W.K.Sinclair, 1968.). The major damage types are: single or double-strand breaks, damage of the bases or the sugar component, DNA-protein cross-link, bulky lesion. The damage of the linear macromolecules in mammal cells and its results can be understood with this sketch:

DNA \rightarrow m-DNA \rightarrow polypeptides\rightarrow structure \rightarrow function
genotype phenotype

The quantum chemistry enables the modern interpretation of the radiation damage in DNA. The delocalized electron system and the structure make the DNA to an inhomogeneous electric semiconductor. The conductive electrons came from the intramolecular impurities (e.g. iron strain).
The electron drift in the axis of the helix enabled by the base pair’s \pi-electron overlaps and the exciton interaction. After radiation the intramolecular electron system changes: excitation and \pi-electron emission (positive hole formation) occurs. These lead to the tautomeric rearrangement of the base pairs, and the formation of abnormal pairs. These abnormal pairs can’t fulfil the Chagaff-Watson-Crick’s rules about the base correlation, and they don’t fit in the DNA-helix’s spatial structure, so the hydrogen bonds break. It has a chance that abnormal m-RNS, polypeptide chain, structure or function formed. In radio- and chemotherapy, this malformation provoked exactly. It’s expected to became an universal tumor treatment theory by the results of quantum chemistry /A. és B. Pullman, 1959., P.-O.Löwdin, 1961., Ladik J., 1967./.

The radiation effect will be specific to a biological system itself, because radiation specific biological answer doesn’t known. The programmed cell death (apoptosis) researches became a new direction of radiobiology.
The discovery of stem cells and cell reproduction systems (differon-correlaton models) made a brand new approach. In radiobiology stem cells and the tissue-systems based on differon function (bone marrow, the mucosa of bowels, skin, testicles, etc.) are very important. The outcome of an effect depends on how the radiosensitive stem cells can restore the oscillating peripheral cellular equilibrium (e.g. the nuber of red blood cells in veins) through the differon function. The differons loaded by four fields: 1./ physical, 2./ chemical, 3./ gas, and 4./ microbiological field. If the load goes higher than the limit of physiological adaptation, the pathophysiological base of radiation poisoning evolves. The modern clinical radiobiology and radiation protection is the question of the physiology and pathophysiology of stem cells and differons.

Maybe the most important principle of radiobiology is the Bergonié- Tribondeau’s law /1903/: The more a cell or tissue dedifferentiated and immature, closer to embryonic stage, and faster it’s division, the more it’s sensitive to radiation, and vice versa. The radiobiology and radiation protection are mainly based on this law.

The symptoms of acute radiation syndrome (early deterministic injuries) are very divesre (erythema, ulcer, pigmentation or depigmentation, epilation, fibrosis, cytopenia, infections, diarrhea, infections caused by cytopenia, bleeding caused by thrombocytopenia). Nowadays the opinion is 6-8 Sv full body exposure causes death in 100% in humans. The classification of radiation sickness based on:
1./ latency,
2./ leading symptoms, and
3./ the organ system leads to death.
According this, we can talk about 1./ hematologic, 2./ gastrointestinal, 3./ skin and 4./ neurologic radiation syndrome.
All of this cases four prognostic category exist: 1./ the recovery is certain, 2./ likely, 3./ probable 4./ improbable (Th.M.Fliedner, 1965.).
The prolonged injuries are: decrease of life expectation, cataract, leucosis, degenerative diseases, tumors, malformations. The prolonged injuries can be deterministic or stochastic.

Very early shown, the ionizing radiation not only mutagenic but also teratogenic /Th.Herrmann, 1990., Farkas, 1995., Köteles, 2002./.

Clinical obsevations show the blastogenesis can damage on the 1-10th days in utero. Some sources assume that embryonic death can occur by 0.05 Sv of radiation. Else the pregnancy advances without any disorder. Beside the mutagenic and the teratogenic effects, the carcinogen effects also proved. Between the 10-60th days of pregnancy, we have to count on organ malformations, if the radiation dose higher than 0.05 Sv. It’s not expected at lesser doses. It’s observed that influence of 0.2 SV, the frequency of malformations double. In point of the fetus, the risk of radiation occurred after the 60th day in utero is slightly decreases (except the development of brain vesicles) (Th.Herrmann, 1990.).
The laboratory diagnostics of clinical radiation syndrome is a part of internal medicine. It’s complemented by modern methods of marker diagnostics (cytogenetics, micronucleus, comet assay, in situ hybridization, gel electrophoresis with denaturation, DNA sequence analysis, etc.). It’s necessary to take care of the collect, the store and the administration of biological materials (saliva, sweat, sputum, CSF, blood, urine, defecation, hair, vomit, etc.).
In the treatment of radiation sickness, the important principles are:
1./ strict indication
2./ individual therapeutic plans;
3./ the main task according to clear radiobiological bases to eliminate cytopenias (infection, bleed, critical period) and the reasons of sickness. The clinical classification and the treatment have not only to be based on the exact dose but also the leading symptoms (symptom groups) and the knowledge of their latency (Th.M.Fliedner, 1972., Th.Herrmann, 1990.).

Recommended reading

1./ D.F.Lea: Actions of Radiations on Living Cellas.
University Press, cambridge, 1946.
/2nd Ed.: 1955./.
2./ V.P.Bond, Th.M.fliedner and J.O.Archambeau:
Mammalian radiation Lethalithy. Academic
Press, New York and London, 1965.
3./ Sztanyik B.L.: A sugárbiológia negyedszázada.
Orvosi Hetilap, 124., 34., pp.2223-2232.,
4./ J.J.Conklin and R.I.Walker: Military Radiobiology.
Academic Press, Inc., New York and London,
5./ Th.Herrmann: Strahlenbiologie – kurz und bündig.
2.überarbeitete Auflage, VEB G.Fischer
Verlag,Jena /DDR/, 1990.
6./ Farkas Gy.: Sugárvédelmi és belsődozimetriai ismeretek.
ETI, Budapest, 1995.

7./ Dr.Mózsa Sz.: Az ionizáló sugárzások biológiai hatása.
Főiskolai jegyzet. PHARE HU 94.05 0201 L001-06.,
HIETE, Budapest, 1998

8./ W.Köhnlein und R.H.Nussbaum /Hrsg./: Die Wirkung niedriger
Strahlendosen im Kindes-und Jugendalter, in der
Medizin, Umwelt und Technik, am Arbeitsplatz.
Gesellschaft für Strahlenschutz e.V., Berlin und
Bremen, 2001.

9./ R.Graeub: Der Petkau-Effekt mit oxidativer Stress.
/In: W.Köhnlein und R.H.Nussbaum /Hrsg./: Die Wirkung niedrieger Strahlendosen…,
pp.312-320., Gesekschaft für Strahlen –
schutz e.V., Berlin und Bremen, 2001./.

10./ I.A.Gusev, A.K.Guskova and F.A.Mettler: Medical Management of
Radiation Accidents. 2nd Ed., CRC Press, Boca Raton –
- London – New York – Washingtob, D.C., 2001.

11./ Dr. Köteles Gy.: Sugáregészségtan. Medicina Könyvkiadó,
Budapest, 2002.

12./ Y.A.Jablokov, V.B.Nesterenko and A.V. Nesterenko:
Chernobyl: Consequences of the Catastrophe
for People and Nature. New York Academy
of Sciences, New York, N.Y., 2009.

13./ Janette D.Sherman, M.D.: Was kommt als nächstes bei
WHO und LAEA? – Tschernobyl, 25 Jahre da –
Nach. –Zeit-Fragen /Zürich/, 19., 26., p.6., 27
Júni 2011.
14./ Lamm Vanda: Huszonöt évvel Csernobil után –
A nukleáris károkért való nemzetközi felelősségi
Szabályozás fejlődése. Magyar Tudomány,
172., 6., pp.694-703., 2011.

1./ V.P. Bond, Th. M. Fliedner and J.O. Archambeau:
Mammalian radiation lethality. Acad.Press, New York, 1965.
2./ Sztanyik B.L.: A sugárbiológia negyedszázada.
Orvosi Hetilap, 124., 34., pp.2223-2232., 1983.
3./ Th.Herrmann: Strahlenbiologie – kurz und bündig.
2. überarbetitete Auflage, VEB G.Fischer Verlag, Jena /DDR/, 1990.
4./ Farkas Gy.: Sugárvédelmi és belsődozimetriai ismeretek. ETI, Budapest, 1995.
5./ Dr.Mózsa Sz.: Az ionizáló sugárzások biológiai hatása. Főiskolai jegyzet.
Phare HU 94.05 0201 L001-06., HIETE, Budapest, 1998.
6./ Dr.Köteles Gy.: Sugáregészségtan. Medicina Könyvkiadó, Budapest, 2002.

Translated by János Norbert Gyebnár

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