1/31/2014. Radiation Biology and Risk to the Public

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1 Radiation Biology and Risk to the Public Dr. David C. Medich University of Massachusetts Lowell Lowell MA Introduction Definition: Radiation Biology is the field of science that studies the biological effects of ionizing radiation. Cellular response from Radiation Exposure Nucleus: Contains DNA Mitochondrion Provides Energy Golgi complex: Carb. Synthesis Ribosomes: Protein Synthesis 1

2 Critical Targets Ionizing Radiation produces biological effects because it interacts with one (or more) critical targets in a cell. Numerous studies prove DNA as the critical target. Target theory Habrobracon egg cell studies Studies using micro-surgery Interaction of Radiation with DNA Direct Action DNA directly ionizes a DNA atom ultimately producing a biological effect. Indirect Action DNA ionizes non-critical target resulting in production of free radical which then interacts with DNA producing a biological effect Interaction of Radiation with DNA Because it s the most common molecule in a cell (and nucleus), water is the main cause of indirect DNA damage excitation * H O H O H + OH 2 2 ionization + - H 2O H 2O + e + + H 2 O H + OH H 2 O + + +H 2 O H 3O + OH - - e +H 2O H 2 O H + OH - e - + H + H 2

3 DNA Damage Single vs. Double strand breaks in DNA Double strand break results: Clonogenic death Chromosomal aberrations DNA repair and the role of checkpoint genes Checkpoint genes (e.g. p53, prb) Repair mechanisms: chemical reversal, excision repair. Cell Radiosensitivity External influences of cell radiosensitivity Stage of Mitosis S phase low radio-sensitivity M phase high radio-sensitivity Presence of Oxygen Oxygen enhancement effect (OER) Hypoxic cells up to 3x more radio-resistant Effect plateau at ~30 mm Hg pressure (~4% O ) OER one of biggest factors in how we treat cancer 2 Cell Radiosensitivity Influences, cont. Influence of repair Mechanisms Potentially lethal damage (environment) Sublethal damage (dose rate) LET / RBE of radiation Relationship between LET and RBE Optimal LET for clonogenic death 3

4 Cell Radiosensitivity Law of Bergonie and Tribondeau the radiosensitivity of a tissue is directly proportional to the reproductive activity and inversely proportional to the degree of differentiation of the tissue cells. Based on above statement, tissues tend to be more radiosensitive if they have: High rate of mitosis Have a long dividing future (young) Are of an unspecialized type (stem cells) Relative Tissue Sensitivity Dose Tissue Type (rad) Blood forming organs 50 Reproductive organs Digestive organs Vascular systems Skin Bone / Teeth 1500 Respiratory system Urinary system Muscle and Connective Tissue >2000 Nerve cells/tissue >3000 Most sensitive least sensitive Least resistant Most resistant Radio-sensitivity Radio-resistance Whole-body response from Radiation Exposure 4

5 Effects of radiation exposure Whole body irradiation effects include: Acute Radiation Sickness (non-stochastic) Hereditary effects Risk to embryo / fetus Radiation Carcinogenesis Acute Radiation Sickness ARS occurs when a person receives a (whole body) high Radiation Dose (>100 rad) in a Short Duration: LD50/30 = 450 rad. LD50/30: Lethal dose to 50% of population exposed in 30 days without medical attention. Acute Radiation Sickness Stages of A.R.S. Prodromal Stage: Lasts from a few minutes to days (higher the dose, shorter the stage) Characterized by nausea, vomiting, diarrhea, lethargy, etc Latent Stage: Individual appears healthy Duration varies with dose (weeks at doses below 500 rad to hours at doses >10,000) Manifest illness stage: Subject becomes obviously ill and suffers from radiation induced organ damage. 5

6 Acute Radiation Sickness Hematopoietic Syndrome appears at about 300 rad Characterized by depression or destruction of red, white, and platelet blood cell supply. (survival: months) Gastrointestinal Syndrome rad Characterized by the destruction of the intestinal epithelium and complete destruction of the bone marrow (survival: weeks) Cerebrovascular Syndrome 10,000 rad +. Damages the central nervous system as well as all other organs and systems (survival: hours to days) Other Non-stochastic effects Effect Acute Dose (rad) Observed chromosomal breaks (whole body) 10 Transient blood changes (whole body) 25 Decreased sperm count 25 Mild radiation sickness (whole body) 100 Epilation 400 Threshold Erythema 500 Cataract formation 900 Permanent sterility (male) 3000 Induced menopause (female) 3000 Hereditary Effects Hereditary effects may occur if an organism s sex cells are irradiated. The cannot, by definition, occur if somatic cells are irradiated. Radiation does not create new genetic mutations, only increases the likelihood of a mutation occurring 6

7 Hereditary Effects Experimental evidence of hereditary effects Mullers Drosophila Experiments Provided experimental proof of potential hereditary effects from radiation exposure Fruit flies exposed to (high current) X-ray machine for 0, 24, and 48 minutes (equivalent to hundreds to thousand of rads of exposure). Observed statistically valid increase in specific sex-linked lethal defect (ClB mutation). Defects in drosophila were observed to be recessive Observed linear response with respect to level of radiation exposure Did not observe a dose-rate effect Hereditary Effects Mega-mouse Experiment In mid 60s, roughly 7 million mice were irradiated and 7 specific locus mutations were analyzed. Varied dose and dose rate Found significant variations in expression of different mutations. Observed substantial dose rate effect (contradicting Muller) Discovered that the consequences of a given dose are greatly reduced if time interval exists between irradiation and conception Estimated the Doubling Dose to be between rads in humans. Hereditary Effects Atomic Bomb Survivor data Cohort of ~31,000 children born from significantly irradiated parents (w/i 2km of hypocenter) compared against ~41,000 non-irradiated children. To date: no statistical differences observed to exist between groups. (~3 generations) Doubling dose estimated to be ~ 200 rads (no upper limit) with lower limit of 100 rads. 7

8 Teratogenic Effects The embryo and fetal stage in mammals are highly radio-sensitive stages of development Have a high mitotic index Are stem cells (undifferentiated) Are young In addition, loss of a few cells in an embryo has a higher biological impact that loss of a few cells in an adult Embryonic cells are precursors to a large number of adult cells Loss of a few hundred cells in an embryo could lead to lack of tissue differentiation in an organ Teratogenic Effects For purposes of Radiation Exposure, gestation divided into 3 development periods Pre-implantation (0-9 days): period prior to fertilized egg attaching to uterus Most radiosensitive stage of mammal development everything or nothing stage : if embryo survives, it is unlikely to develop future abnormalities 200 rad of exposure found to kill up to 80% mouse embryos If 10 rads are delivered to fertilized cell on 1 st day of gestation, chances of re-absorption increase from 4.7% to 11.9% Teratogenic Effects Organogenesis (10-50 days): characterized by major organ development High radiation exposures therefore could lead to congenital malformations ( rads effects are likely temporary) including: Microcephaly Microophthalmia Cerebral hypoplasia Testicular atrophy Skeletal malformations Dental malformations If death occurs as result of exposure, it will (most likely) be neonatal death. 8

9 Teratogenic Effects Fetal development Stage (51 days to term): all major organs developed, body shape essentially complete Death unlikely outcome of irradiation Irradiation may result in morphologically smaller organs, smaller birth size and/or weight ~100 rads may result in permanent growth retardation Temp. depression in birth weight proportional to exposure Mental retardation observed at high doses since CNS is a late developing tissue Fetal mice: 40 rad produced observable nerve cell necrosis Adult mice need ~1500 rads to get same effect Carcinogenesis CANCER is the risk of highest concern when discussing risks from radiation exposure. Most human data from Atomic Bomb survivors ~120,000 survivors studied By 1990, there were ~6,000 cancer deaths 400 of which were attributed to radiation exposure. Additional data from animal studies Uncertainty in human radiation exposures Better experimental controls Carcinogenesis Development of cancer Latent period observed between exposure and appearance of malignancy leukemia has latent period ~7-12 years solid tumors have latent periods of ~10 50 years. Studies suggest latency period dependent on age of person at time of irradiation Current risk models assume a relative risk dependence: Risk = r 0 * (1+a*Dose) 9

10 Estimates for Total Risk Carcinogenesis as the controlling factor when discussing radiation exposure risk: Other factors contribute <10% towards total risk Even with the large number of atomic bomb survivors studies, difficult to adequately estimate risk Therefore, to assist in making regulatory decisions, agencies developed conservative models to estimate risk. Present model called the Linear-no-threshold model. Competing models exist, LNT most conservative for low dose exposures (<10 rad) (Linear-quadratic, linear with threshold, etc ) Linear-no-threshold Model absolute risk model of radiation exposure Also assumes risk is linearly related to dose at all exposure levels Data based on observe risks from high (<50 rad) dose and extrapolated to low doses Highly conservative model used to estimate personal risk and assign regulatory protection levels 1. LNT 2. Linear Quadratic 3. Threshold Linear-no-threshold Model ICRP recommended risk estimates (assumes LNT) High Dose High Dose Rate Low Dose Low Dose Rate Working Population 8 x 10-4 per rem 4 x 10-4 per rem Whole Population 10 x 10-4 per rem 5 x 10-4 per rem Note: REM should not be used to estimate risk above 50 rads exposure. 10

11 Linear-no-threshold Model In context of LNT, ICRP numbers represent total risk of mortality from radiation exposure This risk is assumed to be above that expected for average person Cancer lifetime fatality risk for average person estimated to be * To statistically observe radiation risk of 4E-4 above a baseline risk of 0.20, would need ~11,000,000 test subjects and similar number of controls * Study results from SEER (1999) and NCHS (2000) respectively Conclusion: Radiation Regulations and Protection Factors Regulatory Limits - Exposure Radiation Exposure Limits: Organ Limit (rem/year) Rad Worker (whole body) 5 Member of public (w/b) 0.1 Lens of the Eye 15 Extremities (skin) 50 Organ 50 NOTE: Limit of 5 rem/year or originally based on equivalence to mortality risk working at an average blue collar job. Limits also must include radiation exposure from internally deposited radionuclides. 10CFR20 gives tables correlating limits on intake (ALI) where 1 ALI = limiting case of either 5 rem whole body or 50 rem to an organ 11

12 Regulatory Limits - Contamination Radioactive Contamination The federal government does not regulate contamination control only exposure (both external and internal) - but guidelines do exist Contamination is not an external hazard. Action levels developed to limit internal exposures Common action level for radiation contamination 500 DPM per 100 square cm (0.2nCi/100sq.cm) for beta/gamma radiation Look at following assumptions: continual exposure of 2000 hrs per year Most limiting internal radionuclide allowable intake (e.g. I-125 (ALI(I- 125) = 40uCi)) 100% intake each hour of contamination contained in 100 sq. cm area.; equivalent to intake of 0.4 uci in one year. Equals ~500 mr/yr (thyroid) (0.2 mr/yr if C-14 (ALI(C-14) = 2000 uci)). NOTE: Average banana has ~475 mg Potassium. Of this, % (56 ug) exists as radioactive K ug of K-40 has activity of ~900 DPM Questions? 12