Fundamental of Radiobiology -SABBU.pptx

Presentation of Fundamentals of Radiobiology

1. Fundamentals of Radiobiology PRESENTED BY: Name:- Sabbu Khatoon B.Sc. MIT (1 st Year) Roll No:156 MMC, IOM

2. Presentation Layout Introduction to Radiobiology History of Radiobiology Introduction to Radiation, sources and its types Human biology Direct and Indirect effects of Radiation Radiosensitivity Radiobiology fundamentals - Law of Bergonie and Tribondeau - Physical and biological factors affecting radiosensitivity - Radiation dose- response relationships Human response to radiation

3. Introduction To Radiobiology Radiobiology is the qualitative and quantitative study of the effects of ionizing radiation on living matter. Radiation may induce cells to become malignant, alter their functionality, or directly induce cell death. It’s primary aim is to understand mechanism by which radiation interacts with biological tissue. Physical and biological factors affects the radio biologic response of tissue. It is important for determining the potential risks associated with low- dose radiation exposure and strategies to prevent them.

4. History of Radiation Biology 1895- WC Roentgen announces discovery of x-rays Late 1890s, the dean at Vanderbilt University sat for a skull radiograph, and his hair fell out three weeks post- exposure 1904- Death of Clarence dally, who was an assistant to Thomas Edison. Due to repeated x-ray exposures, Dally began to experience radiation burns, amputation of several fingers , eventually leading to his death due to Metastatic Carcinoma. Following this, Thomas Edison abandoned his research on x-rays. 1906- Pattern for differential radiosensitivity of tissue was discovered

5. Another of the early radiology pioneers, Mihran Kassabian (1870-1910), kept a detailed journal and photographs of his hands while suffering from necrosis and subsequent amputation. His intention was that the data he collected would be of importance after his death.

6. Introduction To Radiation Radiation refers to the emission or transmission of energy in the form of electromagnetic waves of particles. Naturally present in our environment and has been there since the birth of this planet. Comes from outer space (cosmic), the ground (terrestrial), and even from within our own bodies. All radiations are byproduct of the decay of the unstable atom; specially the nucleus of the atom.

7. Radiation sources Natural sources - Cosmic radiation - Terrestrial radiation - Internal radiation Man Made sources - Medicine (majority) - Nuclear reactors - Consumer products - Industrial and occupational

8. Man Made sources of Radiation In Medicine Conventional Diagnostic X-rays Nuclear medicine for therapy and diagnosis Fluoroscopic imaging Radiation therapy for cancer treatment

9. Fig:- Sources of Radiation

10. Radiation is broadly categorized into following: - Ionizing radiation - Non-ionizing radiation

11. Ionizing radiation Refers to radiation that possesses sufficient energy to remove tightly bound electrons from atoms or molecules. Characterized by it’s ability to penetrate matter and giving rise to ions and free radicals on ionizing. Higher energy electromagnetic waves. It has ability to damage cells and DNA, increasing the risks of cancer and genetic mutations. It includes particles such as alpha particles ( α ), beta particles ( β ) , high energy neutrons, gamma rays ( γ ), x-rays.

12. Non-ionizing radiation Refers to radiation that do not possess energy to remove tightly bound electrons from atoms or molecules. Are lower energy Electromagnetic waves. It causes electrons to move to higher energy levels( Excitation). Are less harmful to health compared to ionizing radiation. It includes micro waves, ultraviolet light, lasers, radio waves, infrared lights and radar.

13. Human Biology Basics At most basic level, the human body is composed of atoms. Structural and functional unit of human body is cell. Major components of the cell are nucleus and cytoplasm. The principal molecular component of the nucleus is DNA, the genetic material of the cell.

14. The human body is mainly composed of Six elements: Oxygen, hydrogen, nitrogen, carbon, calcium and phosphorus. Another trace elements that make up about 0.85% mass are potassium, sulphur,chlorine and magnesium The effects of x-rays in human body is result of interaction at atomic level. Atomic composition of the body

15. Water is the most abundant molecule in the human body. Macromolecules includes proteins, lipids, carbohydrates, nuclei acids. Radiation effects at molecular level leads to DNA damage. Molecular composition of the body

16. Tissue composition of the body  A group or layer of cells that work together to perform a specific function, is tissue. The cells of specific tissue are identified by their rate of proliferation and stage of development.

17. Cell Proliferation Cell proliferation is the act of a single cell or group of cells to reproduce and multiply in number. Higher cell proliferation means higher radiosensitivity. This increased radiosensitivity is due to:- - Active DNA replication - Increased Metabolic activity - Increased Mitotic activity

18. Levels of Radiation Effects Initial interaction between radiation and tissue occurs at the electron level but observable radiation injury results from change at the molecular level. Radiation effects is seen from: - Cellular Level - Molecular Level - Organ Level - Whole body

19. Cellular Effects At Molecular Level By the absorption of energy from ionizing radiation resulting in ionization or excitation produces damage to molecules by direct and indirect actions. Through dissociation of excited and ionised water molecules (radiolysis) very reactive chemical compounds (radicals) are produced. It is direct when radiation interacts with DNA. It is indirect when radiation interacts with a water molecule resulting ions and free radicals that eventually produce toxic substances which can create biological damage.

20. Direct effects Interaction of ionizing radiation directly with DNA is named as Direct Effects. Atoms in DNA may ionized or excited which leads to biological change. When DNA is directly affected by radiation, energy absorbed by DNA undergoes to Strand breaks. Direct Effect ∝ LET of Radiation Direct effects can include: - DNA damage( break, alterations of strands) - Protein damage( Denaturation, Modification) - Membrane damage( permeability changes)

21. Indirect Effects Interaction of ionizing radiation happens with other molecules or atoms rather than DNA is named as Indirect Effects. Most probable phenomena due to 80% of water composition of human body. Radiation interacts with water molecules results free radical generation.

22. Radiolysis of Water Radiation interaction with water molecules in the body. When water is irradiated, it is ionized and dissociates into two ions. Н 2 О  Н О H + + е - These ion pair may rejoin into a stable water molecule. (No damage occurs). But, if the ions don’t rejoin, it is possible for -ve ion (e - ) to attach to another water molecule to produce another ion. Н 2 О + е -  Н О H - The Н О H + and Н О H - ions are relatively unstable can dissociate further: Н О H +  H + + OH* Н О H -  OH - + H*

23. CONTD… Final resultant of this is the formation of an ion pair H + and OH - , and two free radicals H* and OH*. The ions can recombine to form water so no biological damage would occur. But, the free radical are highly reactive and unstable, so exist with a lifetime of less than 1ms . Free radicals are energetic molecules having excess energy which can be transferred to other molecules (such as DNA) to cause point lesion or bond breaks. Radiolysis of water ultimately affects the target molecule, DNA, that contains genetic information.

24. Radiosensitivity Some tissue are more sensitive than others to radiation exposure, called highly radio sensitive. It is not clear why lack of differentiation of the cell results in radiosensitivity. It has been shown that undifferentiated cells or cells in the process of differentiation are easily killed by radiation. The longer the cell remains in active proliferation, the greater is its sensitivity to radiation. In 1960, two French scientists, Bergonie and Tribondeau, theorized and observed that radiosensitivity was function of the metabolic state of tissue being irradiated.

25. Radiobiology Fundamentals Law of Bergonie and Tribondeau Physical factors that affect radiation exposure Biological factors that affects radiation exposure Radiation dose-response relationship

26. Law of Bergonie and Tribondeau According to these early radiobiologist (1906), the law states that the radiosensitivity of living tissue varies with maturation and metabolism. They observed the effects of radiation by exposing rodents testicles to X-rays. They contain both immature and mature cells. After irradiation of the testes, they found that immature cells were injured at lower doses than mature cells. Their law maintains that actively mitotic and undifferentiated cells are most susceptible to damage from ionizing radiation. In diagnostic imaging, the law serves to remind us that fetuses are considerably more sensitive to radiation exposure than a child or mature adult.

27. CONTD.. The law of Bergonie and Tribondeau states that:- Stem or immature cells are more radiosensitive than mature cells Younger tissues and organs are more radiosensitive than older tissues and organs The higher the metabolic cell activity, the more radiosensitive it is. The greater the proliferation and growth rate for tissues, the greater the radiosensitivity.

28. Radiosensitive Cell

29. Cell Cycle and Radiosensitivity Mitosis, M phase is most radiosensitive where cells are continuously dividing Cells in S phase( DNA synthesis) are relatively resistant to radiation.

30. Factors affecting radiosensitivity Physical factors Linear energy transfer (LET) Relative biologic effectiveness (RBE) Protraction and fractionation Biological factors Oxygen effects Age Recovery Chemical agents

31. Physical factors Linear energy transfer (LET) It is a measure of the rate at which energy is transferred from ionizing radiation to soft tissue. “As LET increases, biological response increases.” It is another method of expressing radiation quality. It also determines the Radiation weighting factor  (W R ). LET is expressed in units of kiloelectron volt (KeV) of energy transferred per micrometer of track length in soft tissue ( k eV/µm). The LET of diagnostic x-rays is approximately 3keV/µm.

32. CONTD.. The ability of ionizing radiation to produce a biological response increases as the LET of radiation increases. High LET radiation: This type of ionizing radiation deposits a large amount of energy in a small distance. Eg:- Neutrons, α - particles Low LET radiation:- This type of ionizing radiation deposits less amount of energy along the track or have widely spaced ionizing events. Eg:- X-rays, Gamma rays.

33. Fig:- Chart showing types of radiation with their corresponding LET values

34. Relative biologic effectiveness (RBE) It is a measure used in radiobiology to compare the biological effectiveness of different types of ionizing radiation. As the LET of radiation increases, the ability to produce biological damage also increases. ( ↑LET= ↑RBE) This relative effect is quantitatively described by the RBE. The RBE of diagnostic radiation is 1.( Maximum RBE is 3)

35. Physical Factors ( LET & RBE) As Linear energy transfer (LET) increases, Relative biologic effectiveness (RBE) also increases, but a maximum value is reached followed by a lower RBE because of overkill effect. Overkill (or wasted dose) refers to the deposition of radiation energy in excess of that necessary to produce the maximum biologic effect

36. Protraction and Fractionation If the time of irradiation is lengthened, a higher dose is required to produce the same effect , then such lengthening of time can be done in two ways i.e. protraction or fractionation. If the dose is delivered continuously but at a lower dose rate, the action is known as protraction. If the dose is fractioned and given in the certain interval of time, such action is known as fractionation. Such lengthening of time causes less effects because time is allowed for intracellular repair and tissue recovery.

37. Protraction and Fractionation Example Example:- Mouse Irradiation 600 rad given in 3min (200rad/min) -> LETHAL 600 rad given @ 200rad/min in 12 fractions of 50 rad each separated by 24 hours -> NON-LETHAL (Fractionation) 600 rad given @ 1 rad/min continuously -> NON-LETHAL (Protraction)

38. Biological Factors Oxygen effect Tissue is more sensitive to radiation in oxygenated state than anoxic or hypoxic conditions. This characteristics is called the oxygen effect and is described numerically by the oxygen enhancement ratio (OER). OER is the ratio of doses administered under hypoxic to aerated condition needed to achieve same biological effects.

39. Biological Factors

40. Age The age of a biologic structure affects its radiosensitivity. Humans are most sensitive before birth. In UTERO= higher cell proliferation However, humans are more radiosensitive again in old age. Old age= increase of oxidative stress, telomere attrition, a decline in DNA damage response

41. Recovery In-vitro experiments show that human cells can recover from radiation damage. If the radiation dose is not sufficient to kill the cell before its next division (interphase death), then in given sufficient time , the cell will recover from the sub lethal radiation damage it has sustained. If a tissue or organ receives a sufficient radiation dose, it responds by shrinking. This is called atrophy . If a sufficient number of cells sustain only sub-lethal damage and survive, they may proliferate and repopulate the irradiated tissue or organ. Combined process of intracellular repair and repopulation contribute to recovery from radiation damage. Recovery= Intracellular Repair+ Repopulation

42. Chemical agents Some chemical present at the time of irradiation can modify the radiation response of cells, tissues and organs. Radiosensitizers Are agents that enhance the effect of radiation. E.g. halogenated pyrimidines, actinomycin D, hydroxyurea, and vitamin K etc. Radioprotectors Radioprotective agents have not found human application because, to be effective, they must be administered at toxic levels. So it can be worse than the radiation. E.g. the molecules containing sulfhydryl group (cysteine and cysteamine).

43. TYPES OF BIOLOGICAL EFFECTS Deterministic effects If radiation response increases in severity with increasing radiation dose, it’s called Deterministic effects ( Non- Stochastic Effect) Occurs within few days after radiation exposure. Has threshold dose.(Minimum dose needed to produce a response) Has non-linear dose-response relationship. Due to cell killing that results in degenerative changes in the exposed tissue by high dose radiation. Erythema, fibrosis and hematopoietic damage are deterministic effects.

44. Fig:- Deterministic Dose- Response relationship

45. TYPES OF BIOLOGICAL EFFECTS Stochastic effects If the incidence of radiation response increases with increasing radiation dose, it’s called Stochastic effects. It is not observed for months or years. Has no threshold dose. (Assumes no dose is safe) Has linear dose-response relationship. Due to damage in a single or a small number of cells. Radiation-induced cancer and genetic effects are stochastic in nature.

46. Radiation Dose-Response Relationships It is a mathematical relationship between various radiation dose levels and magnitude of the observed response. It has two important applications:- - to design therapeutic treatment routines for patients with cancer - to yield information on the effects of low-dose radiation Every dose-response relationships has two characteristics. Either linear or nonlinear, and is either threshold or non-threshold.

47. Linear Dose- Response Relationships A,B: Linear, non threshold type = any dose regardless of its size, is expected to produce a response. RN, natural response level. C,D: Linear, threshold type = At radiation dose below DT, no response is observed.

48. Nonlinear Dose Response Relationship A,B: Nonlinear, nonthreshold type Curve A shows that a large response results from very small radiation dose Curve B, Incremental doses in the low dose range produce very little response C: nonlinear, threshold (sigmoid type) , At doses below DT , no response is measured.

49. LD 50/60 LD 50/60 : the dose which will kill 50% of the exposed population within 60 days ( If no treatment is given). If death is to occur, it usually happens within 60 days of exposure. Acute radiation lethality is measured quantitatively by the LD 50/60 which is approximately 3.5 Gyt (350 rad) for humans. People have survived up to 850 rad if treatment is given.

50. Human response to radiation It refers to the physiological and biological reactions that occur when the body is exposed to ionizing radiation It is categorized under two types:- - Early effects of radiation - Late effects of radiation

51. Human response to Radiation Early effects of radiation Acute radiation syndrome Hematological syndrome Gastrointestinal syndrome Central nervous system syndrome Local tissue damage Skin Gonads Eye Hair loss

52. Human response to Radiation Late effects of radiation Somatic effects Genetic effects In- Utero

53. Acute radiation syndrome Prodromal period Classic symptoms include nausea, vomiting, possibly diarrhoea occurring within minutes - days following exposure. Symptoms last from minutes - several days. Latent period Where patient looks and feels healthy for few hours - weeks. Manifest Illness Depends on the specific radiation syndrome (BMS, GIS, CNSS). Illness last between hours – months. Recovery or Death Stage Patient either recovers or dies. In case of CNSS there is no recovery and death within days of exposure. Recovery may occur for BMS although the LD 50/60 is about 2.5 - 5 Gy.

54. Four stages in ARS

55. Hematological syndrome Also known as bone marrow syndrome(BMS) Occurs betn. (200-1000 rad or 2-10 Gray) Caused by damages to the blood system and stem cell. Prodromal stage :- mild symptoms appear within a few hours and lasts for several days Latent period :- may last up to 4 weeks Manifest illness :- vomiting, fatigue, fever and diarrhea- Decline in blood cells Recovery in 2-4 weeks, may last up to 6mon. Possible death due to infection, dehydration or hemorrhage.

56. Gastrointestinal Syndrome (GIS) Occurs betn. (1000-5000 rad or 10-50 Gray) Prodromal stage :- Vomiting and diarrhea occur within hours and lasts up to 1 day Latent period :- lasts 3-5 days Manifest illness :- Nausea, vomiting and diarrhea- Worsens to bloody stools Death:- within 4-10 days due to intestinal cell damage, damage to blood forming tissue, hence leading in hemorrhaging and dehydration.

57. Central Nervous System Syndrome (CNSS) Occurs after the dose of (5000 rad or 50 Gray). Prodromal stage :- Severe nausea and vomiting within a few minutes- Nervousness, confusion , burning skin, vision loss Latent period:- May last up to 12 hours, or not at all Manifest illness :- Disorientation, loss of muscle control, breathing problems, seizures, coma Death:- Always within few days of exposure- due to increased fluid in brain- Death occurs before hematologic and gastrointestinal symptoms appear.

58. Mean survival time As the whole-body radiation dose increases, the average time between exposure and death decreases. This time is known as the mean survival time.

59. Local tissue damage Skin Damage to basal cells results in the earliest manifestation of radiation injury to the skin. Skin effects are more likely to occur with exposure to low energy gamma, X-ray, or beta radiation. Erythema perhaps is the first observed biologic response to radiation exposure. Erythema may occur after (3-10 Gray) exposure. Fig: Dose response effect- Erythema on skin

60. Gonads Produces germ cells that control fertility and heredity so critically important target organ. Minimum Response dose observed is 10 rad. The cells of testes and ovaries respond differently to radiation . During female germ cell development , most radiosensitive is the oocyte in the mature follicle. At fetal life and early childhood, ovaries are highly radiosensitive. Just 10 rad (100mGy) may delay or supress menstruation in mature female. 200 rad (2 Gy) – temporary infertility 500 rad (5 Gy) – permanent sterility.

61. Gonads In testes, spermatogonial stem cells are the most radiosensitive phase in spermatogenesis. Maturing cells, spermatocytes and spermatids are relatively radioresistant and continue to mature. So no significant reduction in spermatozoa occurs until several weeks after exposure. Just 10 rad (100mGy) can reduce the number of spermatozoa. 200 rad (2 Gy) – temporary infertility (approx. 2-12 months after exposure). 500 rad (5 Gy) – permanent sterility.

62. Epilation Commonly known as hair loss Similar to skin effects. can occur after acute doses of about 500 rad. Cataracts a clouding of the lens of the eye. appear to have a threshold of about 50-200 rad.

63. Late effects of radiation (Low dose radiation) Risk is directly proportional to dose, without any threshold so ALARA should be maintained. 3 general categories of effects resulting from exposure to low doses of radiation. Genetic suffered by the offspring of the individual exposed. Somatic primarily suffered by the individual exposed. In- Utero Some mistakenly consider this to be a genetic consequence of radiation exposure. Actually a special case of the somatic effect.

64. Genetic Effects It occurs in germ cells. It is suffered by offspring of the individual exposed. Mutations of the reproductive cells are passed to the offspring of the individual exposed. Radiation is an example of a physical mutagenic agent. Radiation increases the spontaneous mutation rate, but does not produce any new mutations.

65. Somatic Effects Somatic cells are those in human body other than reproductive cells. Depending on the type and severity of ionizing radiation, it can lead to long-term and short-term somatic effect. Since cancer is the primary result, it is sometimes called the Carcinogenic Effect. Cancer induction is the most significant risk from exposure to ionizing radiation at low doses All radiation-induced malignancies are stochastic i.e. has no threshold value. The specific types of cancers associated with radiation exposure include leukemia, multiple myeloma, breast cancer, lung cancer, and skin cancer thyroid cancer etc.

66. In- Utero Effects Involves the production of malformations in developing embryos. May be Intrauterine death, growth retardation, developmental abnormalities, childhood cancers. It’s not a genetic effect since it is the embryo that is exposed, not the reproductive cells of the parents. A higher incidence of mental retardation was found among children irradiated in- utero during the bombings of Hiroshima and Nagasaki.

67. In Utero Effects The actual effects of exposure in- utero that will be observed will depend upon the stage of fetal development at the time of the exposure. Radiation risks are more significant during organogenesis and in early fetal period, somewhat less in 2 nd trimester, and least in 3 rd trimester. ​​ The total occupational dose to the fetus of a declared pregnant worker must  not exceed 500 mrem (5 mSv)

68. SUMMARY The primary aim of radiobiology is to understand mechanism by which radiation interacts with biological tissue. Fetuses are considerably more sensitive to radiation exposure than a child or mature adult. ( By law of Bergonie and Tribondeau). Because ionizing radiation has biological effects, it is important to limit the amount of radiation (dose) received by a person. Lack of differentiation of the cell results in radiosensitivity. The ability of ionizing radiation to produce a biological response increases as the LET of radiation increases. All radiation-induced malignancies are stochastic i.e. has no threshold value. Diagnostic x-ray beams are neither intense enough nor large enough to cause human lethality but only for academic interest.

69. References Radiologic Science for Technologists -Stewart Carlyle Bushong ( 11 th Edition) The Essential Physics of Medical Imaging by Bushberg Various Websites

70. THANK YOU!!!