Unit 1. Biological Effects of Ionizing Radiations

1. Unit 1. Biological Effects of Ionizing Radiations

2. Dominion Dental Journal, 1897 Excerpts: “Danger in X-rays” “So as to better diagnose the dental troubles of which Miss Josie McDonald of New York complained, Drs. Nelson T. Shields and George F. Jernignan a month ago decided to have an X-ray photograph taken of the young woman’s face. The picture was taken by Mr. J. O’Connor, and as a result of the exposure to the strong mysterious light, Ms. McDonald is now suffering from burns.

3. A few days after being photographed. The skin on the young woman’s face, neck, shoulder, left arm and breast became blistered and finally peeled off. One ear swelled to three times its natural size and it is said there has been no hearing in it since.

4. The first picture taken of the young woman, O’Connor admits, was unsatisfactory, and a second and successful attempt was made. The first exposure lasted eight minutes and the last one thirteen minutes. Besides the burns, large patches of Miss McDonald’s hair have fallen out”

5. Biological Effects • First case of radiation-induced human injury was reported in the literature in 1896. • Who discovered X rays and when? • First case of X-ray induced cancer was reported in 1902

6. Biological Effects • X-radiation energy is transferred to the irradiated tissues primarily by Photoelectric and Compton’s processes which produce ionizations and excitations of essential cell molecules such as DNA, enzymes, ATP, coenzymes, etc. • The functions of these molecules are altered. • The cells with damaged molecules can not function normally.

7. Biological Effects • The severity of biological effect is related to the type of molecule absorbing radiation. • Effect on DNA molecule is more harmful than on cytoplasmic organelles

8. Mechanism of Action • Two mechanisms of radiation damage, mostly on DNA: • Direct action: Damage or mutation occurs at the site where the radiation energy is deposited. • Indirect action: The radiation initially acts on water molecules to cause ionization. The water is abundantly present in the body (approx. 70 % by weight) • Indirect effect accounts for 2/3rd of the damage, direct effect is responsible for the remainder.

9. Indirect Action • The ions, H2O+ and H2O-, are very unstable and break up into free radicals.

10. Indirect Action • Free radicals: • highly reactive atoms and molecules • react with and alter essential molecules that come in contact with them. • These altered molecules have different chemical and biologic properties from the original molecules. This translates to biologic damage.

11. Indirect Action • Free radicals may also combine with each other to produce hydrogen peroxide OH• + OH•-------> H2O2 • Hydrogen peroxide is a cell poison which may contribute to biological damage

12. Radiation Effects at Cellular Level • Point mutations: Effect of radiation on individual genes is referred to as point mutation. • The effect can be loss or mutation in a gene or a set of genes. • The implication of such a change is that the cell may now exhibit an abnormal pattern of behavior.

13. Radiation Effects at Cellular Level • Chromosome alterations: Several kinds of alterations in the chromosomes have been described. Most of these are clearly visible under the microscope. • The effect upon chromosomes can result in the breaking of one or more chromosomes. The broken ends of the chromosome seem to possess the ability to join together again after separation.

14. Chromosome Breaks

15. Chromosome Breaks • Such damage may be repaired rapidly in an error-free fashion by cellular repair processes (restitution) using the intact second strand as a template. • However, if the separation between broken fragments is great, the chromosome may lose part of its structure (deletion).

16. Chromosome Breaks • If more than one break, the broken fragments may join in different combinations. • inversion of the middle segment followed by recombination

17. Chromosome Breaks • Double-strand breakage: when both strands of a DNA molecule are damaged. Sections of one broken chromosome may join sections of another, broken chromosome.

18. Chromosome Breaks • A large proportion of damage will result in misrepair which can result in the formation of gene and chromosomal mutations that may cause malignant development.

19. Arrested Mitosis • Ionizing radiations also affect cell division, resulting in arrested mitosis and, consequently, in retardation of growth. This phenomenon is the basis of radiotherapy of neoplasms. • The extent of arrested mitosis varies with the phase of the mitotic cycle that a cell is in at the time of irradiation. Cells are most sensitive to radiation during the last part of resting phase and the early part of prophase.

20. Cytoplasmic Changes • Cytoplasmic changes probably play a minor role in arrested mitosis and cell death. • Swelling of mitochondria and changes in cell wall permeability have been observed.

21. Radiation Effects at Tissue Level • Two types of biological effects may appear in tissues after exposure to ionizing radiation. • Somatic effects • Genetic effects

22. Radiation Effects at Tissue Level • Somatic effects include responses of all irradiated body cells except the germ cells of the reproductive system. • Somatic effects are deleterious to the person irradiated. • Somatic effects may be stochastic or deterministic.

23. Radiation Effects at Tissue Level • Genetic effects. Include responses of irradiated reproductive cells. • Genetic effects become primarily important when they are passed on to future generations. • Genetic effects are of no consequence in persons who do not procreate or who are in the post-reproductive period of life.

24. Somatic Effects • Somatic tissues do not always react to doses of ionizing radiation so as to give immediate clinically observable effects. There may be a time-lapse before any effects are seen. • Basically, somatic effects are classified in two categories: • Acute or immediate effects • Delayed or chronic (latent) effects

25. Acute Somatic Effects • Appear rather soon after exposure to a single massive dose of radiation or after several smaller doses of radiation delivered within a relatively short period of time. • In general, effects which appear within 60 days of exposure to radiation are classified as acute effects.

26. Delayed Somatic Effects • Delayed effects may occur anywhere from two months to as late as 20 years or more after exposure to radiation. The time lapse between the exposure to radiation and the appearance of effects is referred to as the "latent period." • In radiobiology, the term “latent period” is usually used only in relation to stochastic effects (malignancy)

27. Variables in Somatic Effects • The magnitude of somatic effects depend on the following variables: • Individual • Species • Cellular and tissue • Extent of exposure (full or partial body) • Total dose • Dose rate

28. Variables in Somatic Effects • Individual Variability. Certain individuals are more sensitive or resistant than others in their response to radiation. • The expression, “LD50 (30 days)”, is frequently used in radiobiology which means that a certain dose kills 50% of the exposed animals within 30 days. • The 50% who survive are due to the individual variability.

29. Variables in Somatic Effects • Species variability. The phenomenon of species variability is well known. The reason is not well-understood.

30. Variables in Somatic Effects • Cellular and tissue variability. In 1907 Bergonie and Tribondeu advanced the first generalization in radiobiology by stating that "cells are sensitive to radiation in proportion to their proliferative activity and in inverse proportion to their degree of differentiation.“ • Simply stated, it means that the rapidly dividing cells are more sensitive to radiation than more differentiated, slowly dividing cells.

31. Bergonie and Tribondeu’s Axiom • One of the most notable exceptions to this generalization is the lymphocyte, not capable of proliferative activity, is a differentiated cell, and is one of the most radiosensitive cells in the body.

32. Variables in Somatic Effects • Total-body vs localized-area exposure. A single radiation dose of 4.5-5.0 Gy may produce only erythema of the skin if given to a localized part of the body. • However, if the same dose is given to the entire body, it will cause the death of 50 percent of the people exposed. • This quantity of radiation is identified as LD50, the lethal dose for 50 percent of the people thus exposed

33. Variables in Somatic Effects • Specific area protection

34. Variables in Somatic Effects • Total dose: The higher the dose of radiation, the greater is the probability and severity of occurrence of biological effects.

35. Variables in Somatic Effects • Dose rate dependence: radiation dose that would be lethal if given in a short time, such as a few hours, may result in no detectable effects if given in small increments during a period of several years. • This is due to the ability of somatic cells to repair damage caused by exposure to radiation. However, tissues do not return to their original state following radiation damage, as there are some irreparable alterations produced.

36. Variables-Dose Rate • In general, it may be stated that four-fifths of somatic damage is repaired. But the irreparable damage is cumulative. When this cumulative damage reaches a high level, clinical manifestations may appear.

37. Variables-Dose Rate • Local somatic effect (Alexander, p.149 Revised Edition)

38. Dose-effect Relationships • Threshold response: An increase in radiation dose may not produce an observable effect until the tissue has received a minimal level of exposure called the threshold dose. • Once the threshold dose has been exceeded, increasing dose will demonstrate exceeding observable tissue damage. • Cataract and erythema of skin are well-known threshold responses

39. Dose-effect Relationships • Linear response: A linear dose-response suggests that all exposure carries a certain probability of harm and that the effects of multiple small doses are additive. • The dose response curve for most radiation-induced tumors is linear which implies that there is no "safe" dose, i.e., no dose below which there is absolutely zero risk. • Every exposure carries some risk.

40. Dose-effect Relationships • Linear-quadratic response (curve) A linear-quadratic response implies lesser risk at lower dose rate than linear response or when the exposure is fractionated. However, there is no safe dose.

42. Variables in Somatic Effects • Age. "The radiosensitivity is very high in new-born mammals; it decreases until full adulthood is reached and then remains constant; old mice (about 600 days) are again more radiosensitive." (Bacq and Alexander, P.299) "The embryo is . . . most sensitive during the period of most active organ development, which lasts from the second to the sixth week after conception." (Alexander, p. 156 Revised Edition)

43. Variables in Somatic Effects • Sex The female is more radioresistant in some species possibly due to high levels of estrogens, some of which have radioprotective properties. (Arena, p. 463)

44. Variables in Somatic Effects • Metabolism. The lower the metabolic rate and the lower the state of nutrition, the higher the resistance of the organism to the effects of radiation. Higher metabolic rate seems to magnify the radiation effect.

45. Variables in Somatic Effects • Linear Energy Transfer (LET) The dose required to produce a certain biological effect is reduced as the LET of the radiation increases. Thus alpha particles are more efficient in causing biological damage than low LET radiations.

46. Variables in Somatic Effects • Oxygen effect The radioresistance of many biological tissues increases 2 to 3 times when irradiation is conducted with reduced oxygen (hypoxia).

47. Types of Biological Responses • Chronic deterministic effects: • These effects are observed after large absorbed doses of radiation. Doses required to produce deterministic effects are, in most cases, in excess of 1-2 Gy. • There is usually a threshold dose below which the effects are not manifested. • With increasing dose the severity of the effect increases.

48. Deterministic Effects • Skin. Excessive exposure of the skin to ionizing radiation may result in erythema or reddening of the skin, which is produced by dilatation of small blood vessels beneath the skin. • The dose of radiation required to produce erythema of the skin is between 1.65-3.5 Gy. • Higher doses are associated with dermatitis.

49. Deterministic Effects • Hair. Epilation, or loss of hair, results from exposure of the skin to 2.0-6.0 Gy. A latent period of about 3 weeks ensues before the hair is lost. • The hair usually grows back in a few weeks. • For permanent epilation, considerably higher doses are required.

50. Deterministic Effects • Sterility. • Sterility results from destruction by X-radiation of gonadal tissues which produce mature sperm or ova. • A single dose of 4.0 Gy to the male gonads is necessary to produce permanent sterility. • The dose required to produce permanent sterility in the female may be 6.25 Gy or more.