Chapter 7 Molecular & Cellular Radiation Biology What is Radiation Biology? A branch of biology concerned with how ionizing radiation effects living systems. Biological damage that occurs from different types of ionizing radiation Charge, mass, and energy vary among different types of ionizing radiation Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 1 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 2 Ionizing Radiation Removing electrons from an Atom. This ionized Atom will not bond properly in molecules. Energy Transfer Determinants LET Linear Energy Transfer RBE Relative Biological Effectiveness OER Oxygen Enhancement Ratio Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 3 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 4 1
Linear Energy Transfer (LET) Low-LET/High-LET A method of expressing radiation quality. kiloelectron volts (kev) per micron (1 micron [µm] =10-6 m) A measure of the rate at which radiation energy is transferred to soft tissue (track). An important factor in assessing tissue and organ damage from exposure to ionizing radiation. Low-LET: x-rays electron shells. Gamma rays - short-wavelength, high-energy waves emitted by the nuclei of radioactive substances High-LET: particles that possess substantial mass and charge (alpha particles, ions of heavy nuclei, low-energy neutrons, and charged particles released from interactions between neutrons and atoms). Dense ionization along the length of the track. Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 5 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 6 Low LET Low LET It does not relinquish all of its energy quickly. Indirect action from free radicals Less destructive to biological matter. Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 7 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 8 2
High LET High LET Particles with mass and charge Dense ionization along the track. More ionization per unit of distance traveled. Lose energy more rapidly More destructive to biological matter. Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 9 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 10 LET Low LET vs. High LET Low LET More penetration Less destruction to biological matter Gives up less energy (less interaction) Less ionizing Electromagnetic radiation Indirect action High LET Less Penetration More destruction to biological matter Gives up more energy (more interaction) More ionizing Particle radiation Direct action 11 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 12 3
Relative Biologic Effectiveness (RBE) As LET increases the ability to produce biological damage also increases. Radiations with different LETs will produce different biological effects. RBE is used for specific experiments with specific cells or animal tissues. It is not used for radiation protection doses in humans. Relative Biologic Effectiveness (RBE) The relative biological effectiveness for a given test radiation, is calculated as the dose of a reference radiation (usually x-rays) required to produce the same biological effect as was seen with a test dose, D T, of another radiation. Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 13 http://www.hps.org/publicinformation/ate/q647.html. 14 RBE - Example If it took 200 mgy of x rays but only 20mGy of neutrons to produce the same biological effect, the RBE would be 200/20 = 10 using x rays as the reference radiation. Which means: The 20 mgy of neutrons is 10 times as effective in producing the biological reaction as the 200 mgy of x-ray. RBE For radiation protection purposes, the International Commission on Radiological Protection, ICRP, has described the effectiveness of radiations of differing qualities by a series of Quality Factors (ICRP 1977) and more recently by a series of Radiation Weighting Factors (ICRP 1991). 15 http://www.hps.org/publicinformation/ate/q647.html. 16 4
Radiation Weighting Factors Oxygen Enhancement Ratio (OER) OER describes the sensitivity of oxygenated tissue mathematically by dividing the dose necessary under anoxic conditions to produce a given effect by the dose necessary under aerobic conditions to produce the same effect. http://www.hps.org/publicinformation/ate/q647.html. 17 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 18 OER OER High LET (direct action) presence or absence of oxygen is of no consequence Low LET (predominately indirect action) the presence of oxygen makes the damage caused by free radicals permanent (the oxygen fixation hypothesis) Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 19 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 20 5
Molecular Effects Direct Hit an x-ray photon hits a critical molecule and damages or kills it (DNA) Indirect Hit an x-ray photon hits a water molecule and produces a free radical that hits a critical molecule and damages or kills it (DNA) Direct/Indirect Action Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 21 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 22 INDIRECT HIT THEORY Radiolysis of H 2 O molecule Shared electron Water to Hydrogen peroxide (And kill indirectly) 95% of cellular damage Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 23 Shared electron H-O-H HOH + + e - (ionization) H-O-H - H 0 +OH - (free radicals) Module Medical VIII. - 24 6
Radiolysis of H 2 O molecule Free Radicals Shared electron Shared electron H-O-H HOH + + e - (ionization) H-O-H + H + +OH 0 (free radicals) Module Medical VIII. - 25 Configuration of one or more atoms that have an unpaired electron but no electrical charge. Free radicals are formed by the rupture of a bond in a stable molecule with the production of two fragments, each with an unpaired electron. The resulting free radicals may participate in further reactions or may combine to reform the original compound. Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 26 Reactions with free radicals Target Theory OH 0 + OH 0 H 2 O 2 (hydrogen peroxide) O 2 + H 0 HO 2 0 (hydroperoxl) Radical This free radical and hydrogen peroxide are among the primary substances that produce biological damage directly after interaction of water and radiation. - 27 Master molecule is responsible for the survival of the cell. DNA is the master molecule. Destruction of the master molecule results in cell death. Takes more than one hit. Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 28 7
Cellular Effects of Irradiation Radiosensitive Cells Instant death (1000 Gy) Reproductive death (1-10 Gy) Apoptosis, or programmed cell death (interphase death) Mitotic, or genetic, death Mitotic delay (0.01 Gy) Interference of function Chromosome breakage Lymphocytes Erythroblasts Cancer cells Spermatogonia Crypt cells of the small intestine Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 29 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 30 Radioinsensative Cells Cell Sensitivity Nerve Cells Muscle Cells 32 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 31 8
System sensitivity If a cell type in a system is sensitive, then Oxygen Enhancement Effects Oxygen increases radio sensitivity. Why would a patient undergoing radiation therapy treatments also have hyperbaric treatments? the entire system is sensitive Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 33 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 34 Law of Bergonie & Tribondeau RADIOSENSITIVITY is a function of: Metabolic state of the cell Differentiation: most mature or specialized. (inversely proportional) Reproductive rate (directly proportional) Radiosensitivity Least mature Least specialized Highly reproductive Longest mitotic phase What cells qualify? Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 35 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 36 9
Lympocytes Leukocytes refers to white blood cells. Lymphocytes refers to a subgroup. Provide protection from antigens. Lymphocytes produced in bone marrow are the most radiosenstive blood cell in the human body. Nerve Tissue In adults less radiosensitve than in the embryo-fetus stage. Adult single dose of 50Gy may lead to death within a few hours or days. Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 37 Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 38 Nerve Tissue Radiosensitve during the embryo-fetus stage of development Window of maximal sensitivity 8-15 weeks after gestation. Lower risk from this stage through 25 weeks. After 25 weeks risk not found to be significantly different from that of young adults. Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 39 Radiosensitive. Reproductive cells Irradiation can cause depression to sterility in men. Dose as low as 0.1Gy in a male could depress sperm count or cause genetic mutations in future generations. Dose of 5Gy in women can cause sterility in woman. Women 20-30 exhibit the lowest degree of sensitivity Elsevier items and derived items 2009 by Mosby, Inc., an affiliate of Elsevier Inc. 40 10
Questions? 41 11