Biological Effect of Ionizing Radiation The development of tissue injury from radiation exposure is a complex series of physical, chemical and biological events. Table 6.1: shows the different stages involved in the development of radiation damage.

Table 6.2: lists the biologically important ionizing radiations.

Stage 1: The nature and absorption of ionizing radiation Time involved: 10-16-10-12 seconds. Steps of the development of the radiation injury: Absorption of radiation energy by tissues (10-16 seconds ) leading to Ionization or Excitation (10-12 seconds). • Ionization > removal of binding orbital electron > dissociation of atoms within the molecule > chemical changes in the molecule. • Excitation > electrons are raised to higher energy level > excited atom or molecule > dissipation of energy causing reorganization of bonding electrons > bonds rupture > release of stable and unstable molecular fragments. The ultimate effect of ionization and excitation is the disruption of stable molecules with release of chemically reactive species.

Stage 2: Initial chemical changes Time involved: up to milliseconds. The ions and excited atoms produced by the absorption of radiation initiate chemical changes within the cell. Chemical changes occur either by direct action or indirect action of radiation. direct action: when the molecule that is being changed absorbs the energy directly from radiation. 2. indirect action: when the energy is absorbed by intermediate molecule in the cell , which is usually water, which transfers the energy to the molecule being changed. Products of water radiolysis like H2O2 are toxic and they can be powerful oxidizing agents that can interact with biologically important molecules like RNA, DNA, and enzymes. Figure: water radiolysis

Stage 3: Alteration of biologically important molecules Time involved: seconds to hours. Radiation is randomly absorbed by any type of molecules within the cell. Consequence damage to the cell is determined by the abundance of the damaged molecule in the cell. Alteration of small percentage of the abundant water by radiation will not affect the cell, while the damage of rare essential cell molecules like membrane phospholipids, enzymes and nucleic acids might affect normal cell function or cause cell death. Table 6-3: the radiation effect on some key cellular molecules.

Stage 4: Biologic Events Time involved: hours to years Stage 4: Biologic Events Time involved: hours to years. The key effects of radiation at the cell, tissue and whole body levels will be discussed. Table 6-4: Biological effect of radiation.

Radiation Effect on the Cell Radiation effect on the cell range from changes resulting in no permanent impairment of function to cell death. Among the important changes: • Chromosomal breakage (aberration) which might be induced by radiation dose of 10 rads or lower. Extensive chromosomal changes might result either in cell death or it might change the inheritable characteristics of the cell (mutation). • Effects at cell division: Mitosis may be delayed or completely inhibited by doses as low as 50 rads. Cell specific response is determined by cell type, its miotic rate, and irradiation factor.

Cells can also be killed by radiation. What does cell death means?? • Differentiated cell like nerve and muscle cells are considered killed if they lose their function. • Dividing cells like hemopoietic stem cells and crypt cells in the small intestine will show reproductive death if they lost their proliferative capacity. Figure 6-1: A typical survival curve for mammalian cells exposed to radiation (X-or gamma radiation) the fraction of colony formation (reproductive capacity) is plotted on a logarithmic scale against doe on a linear scale.

In the figure, the shoulder implies that damage must be accumulated before the lethal damage is evident. Low doses of radiation inactivate some but not all of the target sites. When more target sites inactivated, exponential killing is observed with dose increments. The slope in the above relation reflects the sensitivity of the cells. The slope is expressed in terms of D0 or D37 which is the dose require to reduce the number of the surviving cells by a factor of 0.37. For most mammalian cells D0 lies between 100 and 200 rads, indicating little difference in radiosensitivity.

Mammalian cells differ in their response to radiation. • Cells that divide regularly ( hemopoietic stem cells) are sensitive to radiation damage. • Differentiated cells (muscle, nerve cells) do not divide are radiation resistant. Accordingly, a law was formulated as: “radiosensitivity varies directly with the mitotic activity and with number of future divisions the cell will still undergo and inversely with the degree of morphologicand functional differentiation”. Among the exceptions of the above “law” the small lymphocyte that is very radiosensitive and yet does not divide. Table6-5: Relative radiosensitivity of mammalian cells.

Radiation Effect in Tissues Various tissues of the body differ in their responses to radiation, this variation in tissue sensitivity may be attributed to: a. Variation in the sensitivity of cells composing the tissue. Hemopiotic tissues are extremely sensitive showing effect like lymphopenia after whole body doses as low as 25 rad while muscles and nerves can withstand massive doses as high as 1000 rad without apparent injury. b. Interaction of various cell types in the tissue. c. Capacity of the tissue to repopulate. Table 6-6: Relative tissue radiosensitivity.

Radiation effect differ according to the tissue type. • Irradiation of somatic tissues ► hypoplasia ► alteration of tissue function and transformation of cells ► cancer of the tissue. Depending on the tissue type and the dose , functional alteration can occur within hours or days of exposure. Carcinogenesis of the tissue usually takes many years to develop. • Irradiation of germinal tissues ► mutation induction (might occur at very low doses) ► mutations can have serious consequences to succeeding generations.

Whole Body Effects of Radiation Man response to ionizing radiation can be divided into two general classes: • Acute effect where radiation syndrome is evident within days of exposure, it may take up to two months to occur, • late effect which requires several months to years for full manifestation. Acute Effects Acute effect results from killing of cells in a critical populations (like bone marrow) and expressed soon after radiation exposure. Information regarding acute effects of radiation are obtained from animal studies, Nagasaki and Hiroshima 1945 atomic bomb radiation, radiation accidents and radiation therapy patients. Figure 6-2: the sigmoid dose-response curve describes the relation between radiation dose and percent lethality in the exposed population.

According to figure 6-2 Doses below 200 rads cause no lethality to any individual. Intermediate doses 200-600 rads are lethal to a fraction of the population and lethality is directly proportional to dose. High doses >600 rad are lethal in 100% of the population. The lack of a sharp transition from 0 to 100% lethality indicates that many factors, some known and others unknown, determine the response of the individual to a specific radiation dose. LD50: the radiation dose that kills 50% of the exposed individuals. LD50 for man is believed to be in the range of 250-450 rads (X-and gamma rays). Compared with other mammals, man is relatively sensitive. Table 2: LD50 of various species.

Subclinical Syndrome: at minimum exposure, the person After about two months of whole body exposure to radiation, different syndromes might develop. During this latency period radiation damage is being developed. Subclinical Syndrome: at minimum exposure, the person will show psychic anxiety, fast pulse and irregular blood pressure. Other syndromes are shown in table 6-7.

For Hemopoietic and Gastrointestinal Syndromes; irradiation will inhibit production of stem cells which give rise to the formed elements of the blood or to the cells lining the villi in the gastrointestinal mucosa, this will result in rapid deterioration of function in these systems. Death occurs because without replacement of functional elements, these became fewer and fewer until the functioning of the system is no longer compatible with life. As the central nervous system is a nonproliferating tissue, the syndrome might be related to vasculitis, encephalitis, meningitis and edema.

Late Effects Long term effects are thought to be due to irreparable damage of genetic material of cells that survived the radiation insult. Late effect occur many months or years after exposure, affected individuals are either survived acute effects or exposed to doses lower than those required to produce acute syndrome. Late effect occur either in somatic or germinal tissues. Somatic tissues Effect appears at the well-being of the individual exposed which is mainly induction of cancer (others involves cataracts and life-shortening). Figure 6-3: the three most probable shapes of dose-response curves that can be assumed for the late somatic effects of ionizing radiation.

Leukemia is the most frequent radiation induced cancer. Males were more susceptible than females according to Hiroshima and Nagasaki data. Thyroid cancer is the second most readily induced cancer according to data from the Japanese atomic bomb survivors, individuals receiving radiation therapy for head and neck lymphoid tissue hyperplasia, inhabitants of the Marshall Islands who were exposed to radiation fallout from nuclear tests in the Pacific in 1954. Thyroid cancer was more frequent in women than men. Radiation induced cancer has long latency period up to 30 years. Leukemia has shorter latent period of 5-20 year. Germinal Tissues It has significant consequences for the offspring of the exposed individual and can affect the individual by affecting his ability to reproduce normal offspring. Fertility and genetic effects due to mutations in hereditary materials are examples of late radiation effects in germinal tissues.

Factors Influencing Biological Effects • Radiation dose How to minimize the radiation dose ?? In nuclear medicine use: metastable radionuclide, radiopharmaceuticals with short T0.5,phys., and T0.5, biolog. • For a given radiation dose, higher dose rate produces greater biological effect, Single or acute exposure produces greater effect than exposure delivered in a fractionated pattern, • The greater the volume of tissue irradiated, the greater the biological effect, • The nature and quality of the radiation. High LET radiation is more damaging than radiation with low LET. Figure: Estimated days of life expectancy lost from various risk factors.