Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course TakeTake-a-Ways: Five Things You should be able to Explain after the Radiation Biology Lecture ¬ Radiation Biology – Chapter 25 ¬ ¬ Brent K Stewart, PhD, DABMP Professor, Radiology and Medical Education Director, Diagnostic Physics ¬ ¬ a copy of this lecture may be found at: http://courses.washington.edu/radxphys/PhysicsCourse04http://courses.washington.edu/radxphys/PhysicsCourse04-05.html © UW and Brent K Stewart, PhD, DABMP Consequences of the interaction of radiation and tissues, beginning with the chemical basis on which radiation damage is initiated Effects of radiation on DNA Variations in cellular radiosensitivity and associated expression as depicted in cell survival curves Varied response of organ systems to radiation Various risks associated with radiationradiation-induced carcinogenesis, genetic effects, and special concerns regarding radiation exposure in utero © UW and Brent K Stewart, PhD, DABMP Determinants of the Biologic Effects of Radiation ¬ ¬ ¬ ¬ Classification of Biologic Effects Many factors determine the biologic response to radiation exposure exposure Radiosensitivity and complexity of the biologic system determine the type of response from a given exposure Usually complex organisms exhibit more sophisticated repair mechanisms Some responses appear instantaneously, others weeks to decades ¬ ¬ Biologic effects of radiation exposure can be classified as either stochastic or deterministic (non(non-stochastic) Stochastic Effect ¬ ¬ ¬ ¬ ¬ The probability of the effect, rather than its severity, with dose RadiationRadiation-induced cancer and genetic effects Basic assumption: risk with dose and no threshold Injury to a few cells or even a single cell can theoretically result result in manifestation of disease The principal health risk from lowlow-dose radiation c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 814 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 © UW and Brent K Stewart, PhD, DABMP Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Classification of Biologic Effects (2) ¬ Interaction of Radiation with Tissue Deterministic or NonNon-stochastic Effect ¬ ¬ ¬ ¬ ¬ ¬ ¬ Predominant biologic effect is cell killing resulting in degenerative changes to the exposed tissue Severity of the effect, rather than its probability, with dose Require much higher dose to produce an effect Threshold dose below which the effect is not seen Cataracts, erythyma, fibrosis, and hematopoietic damage are some deterministic effects Dx radiology: only observed in some lengthy, fluoroscopically guided interventional procedures © UW and Brent K Stewart, PhD, DABMP ¬ ¬ ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP Interaction of Radiation with Tissue Results in an unstable ion pair, H2O+, H2ODissociate into another ion and a free radical (lifetime is less than 10-5) ¬ ¬ ¬ Radiation interacts within the medium (e.g., cytoplasm) creating reactive chemical species (free radicals) which in turn interact with the a critical target macromolecule Vast majority of interactions are indirect (body 70% 85% water) ¬ ¬ Critical targets (e.g., DNA, RNA or protein) directly ionized or excited Indirect ¬ Interaction of Radiation with Tissue ¬ Ionizing radiation energy deposited randomly and rapidly (< 10-10 sec) via excitation, ionization & thermal heating Interactions producing biologic changes classified as either direct or indirect Direct H2O+ → H+ + OH• H2O- → H• + OH- Combine w/ other free radicals to form molecules such highly toxic to cell as hydrogen peroxide (H2O2) Oxygen enhances free radical damage via production of reactive oxygen species (e.g., H• + O2 HO2•) c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 816 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 © UW and Brent K Stewart, PhD, DABMP Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Linear Energy Transfer ¬ ¬ Relative Biological Effectiveness (RBE) Biological effect dependent on the dose, dose rate, environmental conditions, radiosensitivity and the spatial distribution of energy deposition Linear Energy Transfer (LET) ¬ ¬ ¬ ¬ ¬ Amount of energy deposited per unit length (eV/cm) LET ∝ q2/KE Describes the energy deposition density which largely determines the biologic consequence of radiation exposure High LET radiation: 2+, p+, and other heavy ions Low LET radiation: ¬ ¬ ¬ - ¬ ¬ ¬ ¬ ¬ ¬ ¬ + Electrons (e-, and ) EM radiation (x(x-rays or γ-rays) ¬ High LET >> damaging than low LET radiation © UW and Brent K Stewart, PhD, DABMP Although all ionizing radiation capable of producing a specific biological effect, the magnitude/dose differs Compare dose required to produce the same specific biologic response as a reference radiation dose (typically 250 kVp xx-rays): Relative Biological Effectiveness (RBE) Essential in establishing radiation weighting factors (wR) X-rays/gamma rays/electrons: LET ≈ keV/µ keV/µm; wR = Protons (< 2MeV): LET ≈ 20 keV/µ keV/µm; wR = 55-10 Neutrons (E dep.): LET ≈ 420 keV/µ µ m; w = 54 keV/ 5-20 R Alpha Particle: LET ≈ 40 keV/µ µ m; w = 20 keV/ R H (equivalent dose, Sv) = D (absorbed dose, Gy) · wR © UW and Brent K Stewart, PhD, DABMP LET vs RBE 10 Cellular Targets ¬ ¬ ¬ ¬ RadiationRadiation-sensitive targets are located in the nucleus and not the cytoplasm of the cell Cell death may occur if key macromolecules (e.g., DNA) which have no replacement are damaged or destroyed Considerable evidence that damage to DNA is the primary cause of radiationradiation-induced cell death Concept of key or critical targets has led to a model of radiationradiation-induced cellular damage termed target theory in which critical targets may be inactivated by one or more ionization events (hits) c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 817 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 11 © UW and Brent K Stewart, PhD, DABMP 12 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Radiation Effects on DNA Cellular Radiosensitivity ¬ ¬ ¬ ¬ Studied through radiationradiationinduced cell death (loss of reproductive integrity) Useful in assessing the relative biologic impact of various types of radiation and exposure conditions Cellular inability to form colonies as a function of radiation exposure cell survival curves Three parameters defining response to radiation: n, Dq and D0 c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 822 c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 819 © UW and Brent K Stewart, PhD, DABMP 13 © UW and Brent K Stewart, PhD, DABMP Cell Survival Curves: n ¬ ¬ ¬ Cell Survival Curves: D0 n: Extrapolation number found by extrapolating the linear portion of the curve back through the yy-axis Represents either the number of targets in a cell that must be “hit” once by a radiation event to inactivate the cell or the number of “hits” required on a single critical target to inactivate the cell For mammalian cells: [2,10] ¬ ¬ ¬ ¬ ¬ ¬ ¬ c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 822 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 14 15 D0: Mean lethal dose Radiosensitivity of the cell population under study Dose producing a 63% (1(1-e-1) reduction in viable cell number: slope = y/ x = 63/D0 (e ≈ 2.72; e-1 = 0.37) ∝ reciprocal linear region slope Radioresistant cell D0 > radiosensitive cell D0 D0 lesser survival/dose Mammalian cells: [1Gy,2Gy] c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 822 © UW and Brent K Stewart, PhD, DABMP 16 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Cell Survival Curves: Dq ¬ ¬ ¬ ¬ Factors Affecting Cellular Radiosensitivity Dq: Quasithreshold dose (Dq = D0 · logen) Width of the shoulder region and a measure of sublethal damage Irradiated cells remain viable until enough hits received to inactivate the critical target or targets Clear evidence that for lowlowLET radiation, damage produced by a single radiation interaction with cellular critical target(s) is insufficient to produce reproductive death ¬ Conditional factors - physical or chemicals factors that exist previous to and/or at irradiation ¬ ¬ ¬ ¬ ¬ Dose rate LET Fractionation Presence of oxygen Inherent factors - biologic factors characteristic of the cell ¬ ¬ ¬ Mitotic rate Degree of differentiation Cell cycle phase c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 822 17 © UW and Brent K Stewart, PhD, DABMP Conditional Factors – Dose Rate © UW and Brent K Stewart, PhD, DABMP 18 Conditional Factors - LET Which has highest D0? Which has highest n? Which has highest Dq? c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 823 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 824 19 © UW and Brent K Stewart, PhD, DABMP 20 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Conditional Factors - Fractionation Conditional Factors – Presence of Oxygen ¬ Increases cell damage by inhibiting ¬ ¬ ¬ ¬ Free radical recombination to form harmless chemical species Repair of damage caused by free radicals Oxygen enhancement ratio (OER): ratio of dose producing a given biologic response in the absence of oxygen to that in the presence of oxygen Mammalian cells ¬ ¬ LowLow-LET: [2,3] HighHigh-LET: [1,2] c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 825 © UW and Brent K Stewart, PhD, DABMP 21 © UW and Brent K Stewart, PhD, DABMP Conditional Factors - Oxygen Inherent Factors - Law of Bergonié & Tribondeau ¬ Radiosensitivity greatest for cells with ¬ ¬ ¬ c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 825 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 22 High mitotic rate Long mitotic future Undifferentiated c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 826 23 © UW and Brent K Stewart, PhD, DABMP 24 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Inherent Factors – Cell Cycle Phase ¬ ¬ ¬ ¬ Davis Notes – Radiation Biology Cells are most sensitive to radiation during mitosis (M phase) and RNA synthesis (G2 phase) Less sensitive during the preparatory period for DNA synthesis (G1 phase) Least sensitive during DNA synthesis (S phase) During mitosis (M), the metaphase is the most sensitive ¬ The quasi-threshold dose (Dq) for cell line C is: ¬ A 500 B 700 C 1,000 D 1,500 E impossible to determine from this data ¬ ¬ ¬ ¬ c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 827 © UW and Brent K Stewart, PhD, DABMP 25 Huda 2nd Edition – Chapter 10 – Radiation Biology © UW and Brent K Stewart, PhD, DABMP Huda 2nd Edition – Chapter 10 – Radiation Biology ¬ Radiological LD50 is the radiation dose that kills: ¬ 10 Stochastic effects of radiation ¬ (A) (B) (C) (D) (E) 50% of exposed cells 50 exposed cells All exposed cells within 50 days e-50 of exposed cells e/50 of exposed cells ¬ (A) Can be recognized as caused by radiation (B) Have a dose-dependent severity (C) Have a threshold of 50 mSv/year (D) Include carcinogenesis (E) Involve cell killing ¬ ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 ¬ ¬ ¬ ¬ 27 26 © UW and Brent K Stewart, PhD, DABMP 28 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Huda 2nd Edition – Chapter 10 – Radiation Biology ¬ ¬ (A) Between 0.3 and keV/ m (B) Cannot be defined for energies greater than MeV (C) Greater than the LET for alpha particles (D) Independent of relative biological effectiveness (RBE) (E) Low energy threshold ¬ ¬ ¬ ¬ The LET of x-rays is: Huda 2nd Edition – Chapter 10 – Radiation Biology ¬ Which is not true of the interaction of ionizing radiation with tissues? ¬ (A) Cellular DNA is a key target (B) Direct action is more frequent than indirect action (C) Indirect action causes most of the biological damage (D) Ions can dissociate into free radicals (E) It can produce chromosome aberrations ¬ ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 29 Huda 2nd Edition – Chapter 10 – Radiation Biology ¬ Which cells are considered to be the least radiosensitive? ¬ (A) (B) (C) (D) (E) ¬ ¬ ¬ ¬ Bone marrow cells Lymphoid tissues Neuronal cells Skin cells Spermatids © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 © UW and Brent K Stewart, PhD, DABMP Huda 2nd Edition – Chapter 10 – Radiation Biology ¬ The cell division stage most sensitive to radiation is: ¬ (A) (B) (C) (D) (E) Anaphase Interphase Metaphase Prophase Telophase ¬ ¬ ¬ ¬ 31 30 © UW and Brent K Stewart, PhD, DABMP 32 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Organ Systems Response: Regeneration & Repair Raphex 2003 General Question ¬ G87 Deterministic or non-stochastic effects of radiation include all of the following except: ¬ A Bone marrow damage B Skin damage C Cataract induction D Leukemia E Infertility due to gonadal irradiation ¬ ¬ ¬ ¬ c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 828 © UW and Brent K Stewart, PhD, DABMP 33 Organ Systems Response: Skin © UW and Brent K Stewart, PhD, DABMP Organ Systems Response: Reproductive Organs ¬ ¬ Gonads are very radiosensitive Females ¬ ¬ Temporary sterility: 1.5 Gy (150 rad) acute dose Permanent sterility: 6.0 Gy (600 rad) acute dose* ¬ ¬ ¬ Temporary sterility: 2.5 Gy (250 rad) acute dose* ¬ Permanent sterility: 5.0 Gy (500 rad) acute dose Reduced fertility 2020-50 mGy/wk (2(2-5 rad/wk) when total dose > 2.5 Gy ¬ © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 35 *reported for doses as low as 3.2 Gy Males ¬ c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 830 34 *reported for doses as low as 1.5 Gy © UW and Brent K Stewart, PhD, DABMP 36 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Organ Systems Response: Ocular Effects ¬ ¬ ¬ ¬ ¬ = Gy (200 rad) cataracts in a small percentage of people exposed exposed > Gy (700 rad = 700 cGy) always produce cataracts ¬ Protracted exposure ¬ ¬ ¬ ¬ Eye lens contains a population of radiosensitive cells Cataract magnitude and probability of occurrence ∝ to the dose Acute doses ¬ ¬ Acute Radiation Syndrome (ARS) months: Gy threshold months: 5.5 Gy threshold Unlike senile cataracts that typically develop in the anterior pole pole of the lens radiationradiation-induced cataracts begin with a small opacity in the posterior pole and migrate anteriorly ¬ Characteristic clinical response when whole body (or large part thereof) is subjected to a large acute external radiation exposure Organism response quite distinct from isolated local radiation injuries such as epilation or skin ulcerations Combination of subsyndromes occurring in stages over hours to weeks as the injury to various tissues and organs is expressed In order of their occurrence with increasing radiation dose: ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 37 ARS Sequence of Events ¬ ¬ ¬ ¬ 38 © UW and Brent K Stewart, PhD, DABMP Acute Radiation Syndrome Interrelationships Prodromal symptoms typically begin within hours of exposure No symptoms during the latent period, which may last up to weeks for dose < Gy Manifest illness stage: onset of organ system damage clinical expression which can last 22-3 wks ¬ ¬ Hematopoietic syndrome Gastrointestinal syndrome Neurovascular syndrome Most difficult to manage from a therapeutic standpoint Treatment during the first 66-8 wks essential to optimize recovery Higher risk of cancer and genetic abnormalities in future progeny if patient survives c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., pp 832832-3 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 39 © UW and Brent K Stewart, PhD, DABMP c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 836 40 10 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Epidemiologic Investigations of RadiationRadiation-Induced Cancer ¬ ¬ ¬ DoseDose-response relationships for cancer induction at high dose and dose rate have been well established Not so for low dose exposures like those resulting from diagnostic and occupational exposures Very difficult to detect a small increase in the cancer rate due to radiation ¬ ¬ ¬ Difficulties in Quantifying Low Dose Risk ¬ ¬ Natural incidence of many forms of cancer is high Latent period for most cancers is long If excess risk proportional to dose, then large studies are required for low absorbed dose to maintain statistical precision and power; the necessary sample power increases approximately as the inverse square of dose This relationship reflects a decline in the signal (radiation risk) to noise (natural background risk) ratio as dose decreases ¬ To rule out simple statistical fluctuations, a very large irradiated population is required ¬ ¬ SS = c/D2 500 persons needed to quantify the effect of a 1,000 mSv dose 50,000 for a 100 mSv dose million for a 10 mSv dose (a single body CT = 7.5 mSv) National Research Council (1995) Radiation Dose Reconstruction for Epidemiologic Uses Natl Acad Press © UW and Brent K Stewart, PhD, DABMP 41 © UW and Brent K Stewart, PhD, DABMP Risk Estimation Models DoseDose-Response Curves What is the Evidence? ¬ Major epidemiological investigations that form the basis of current cancer dosedose-response estimates in human populations: ¬ ¬ ¬ ¬ ¬ ¬ ¬ 42 ¬ AtomicAtomic-bomb survivors (Japan) life span study (LSS) Anklyosing spondylitis (UK) Postpartum mastitis study (New York) Radium dial painters (Tritium) Thorotrast (radioactive Thorium xx-ray contrast agent) Massachusetts tuberculosis patients (multiple chest fluoroscopy) Stanford University Hodgkin’s disease patients (x(x-ray therapy) ¬ DoseDose-response models predict cancer risk from exposure to low levels of ionizing radiation dosedose-response curves Linear, nonnon-threshold (LNT) ¬ ¬ Effect = ·Dose ·Dose LinearLinear-quadratic, nonnonthreshold ¬ ¬ ¬ ¬ Effect = ·Dose ·Dose + ·Dose ·Dose2 / : [1Gy[1Gy-10Gy] appears linear for low dose appears quadratic (non(non-linear) for higher dose c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 844 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 43 © UW and Brent K Stewart, PhD, DABMP 44 11 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Risk Estimation Models - Risk Models ¬ ¬ ¬ Risk Estimation Models - Risk Expression Multiplicative risk model: after a latent period, the excess risk is a multiple of the natural ageagespecific cancer risk for the population in question Additive risk model: fixed or constant increase in risk unrelated to the spontaneous ageage-specific cancer risk at the time of exposure Latency periods: ¬ ¬ ¬ Relative Risk ¬ ¬ ¬ ¬ Ratio of the cancer incidence in the exposed population to that in the general (unexposed) population RR of 1.2 would indicate 20% increase over the spontaneous rate Excess relative risk is simply RR - Absolute Risk ¬ ¬ Expressed as the number of excess radiationradiation-induced cancers per 104 people/Svpeople/Sv-yr For a cancer with a radiationradiation-induced risk of per 10,000 person/Svperson/Sv-yr and a latency period of 20 years, the risk of developing cancer from a dose of 0.1 Sv (~13x body CT dose) within the next 40 years would would be: ¬ ¬ Leukemia 10 yrs average Solid tumors 25 yrs average (40(40-20) or 20 years x 0.1 Sv x per 10,000 person/Svperson/Sv-yr = per 10,000 or 0.08% c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 845 © UW and Brent K Stewart, PhD, DABMP 45 © UW and Brent K Stewart, PhD, DABMP Radiation Standards Organizations ¬ ¬ ¬ ¬ ¬ BIER - National Academy of Sciences/National Research Council Committee on the Biological Effects of Ionizing Radiation UNSCEAR - United Nations Scientific Committee on the Effects of Radiation RERF - Radiation Effects Research Foundation ¬ ¬ Experts draw upon this collective knowledge to develop recommendations for systems of radiation protection ¬ ¬ ¬ BEIR V Risk Estimates Independent bodies of experts evaluate information on radiation health effects ¬ NCRP – National Council on Radiation Protection and Measurements ICRP – International Commission on Radiological Protection ¬ Radiation protection regulatory framework ¬ ¬ NRC – Nuclear Regulatory Commission EPA - Environmental Protection Agency © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 46 ¬ 47 BEIR published a report in 1990 entitled, “The Health Effects of Exposure to Low Levels of Ionizing Radiation” or the BEIR V report report Single best estimate of radiationradiation-induced mortality at low exposure levels is 4% per Sv (0.04% per rem) for a working population (ICRP (ICRP - 5% per Sv for the whole population - takes children into account) The single best estimate of radiationradiation-induced mortality at high doses applied at high dose rate is 8% per Sv (0.08% per rem) The BEIR V Committee believed that the LNT dosedose-response model was best for all cancers except leukemia and bone cancer; for those those malignancies, a linearlinear-quadratic model was recommended According to the LNT model, an exposure of 10,000 people to 10 mSv would result in approximately cancer deaths in addition to the 2,200 (22%) normally expected in the general population © UW and Brent K Stewart, PhD, DABMP 48 12 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course ICRP 60 Risk Estimates Specific Cancer Risk Estimates - Leukemia ¬ ¬ ¬ ¬ ¬ c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 849 c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 847 © UW and Brent K Stewart, PhD, DABMP 49 © UW and Brent K Stewart, PhD, DABMP Specific Cancer Risk Estimates – Thyroid Cancer ¬ ¬ ¬ 6-12% of total mortality from radiocarcinogenesis Females 33-5x greater risk than males Latency period ¬ ¬ ¬ ¬ ¬ ¬ ¬ ¬ Benign nodules: 55-35 yrs Thyroid malignancies: 1010-35 yrs ¬ ¬ ¬ Gy for external irradiation 50 Gy for internal radiation (radioactive materials like 131I) © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 ¬ 51 50 Specific Cancer Risk Estimates – Breast Cancer ¬ DoseDose-response curve: LNT Associated mortality rate: 5% However, other responses such as hypothyroidism and thyroiditis with thresholds: ¬ Natural incidence in US population: in 104 (0.01%) 17% of total mortality from radiocarcinogenesis The incidence of leukemia greatly influenced by age at the time of exposure BEIR V: nonlinear dosedoseresponse model predicting excess lifelife-time risk of 10 in 104 (0.1%) after exposure to 0.1 Gy (10 rad) Average latent period = 10 yrs One of US women at risk of developing breast cancer 180,000 new cases/yr in 30 women die of breast cancer Low LET radiation risk age dependent, ≈ 50 times greater for the 15 yo age group (≈ 0.3% per year) after exposure of 0.1 Gy than those those > 55 yo The risk estimates for women in the 25, 35 and 45 yo age groups are 0.05%, 0.04% to 0.02% respectively (BEIR V) DoseDose-response curve: LNT w/ dose of ≈ 0.8 Gy doubling the natural incidence Latent period [10yrs,40yrs]; longer latencies with younger women © UW and Brent K Stewart, PhD, DABMP 52 13 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Increased Risk of Induced Breast Cancer Before 65 Years of Age per 25 mSv Breast Organ Dose for Age at Exposure Comparison of the Risks of Some Medical Exams Increased Risk/25 mSv 0.160% Procedure Chest Radiograph Skull Exam Mammography Thoracic Spine Pelvis Abdomen CT Head Lumbar Spine Intravenous Urography CT Pelvis CT Abdomen CT Chest Barium Enema (with fluoro) 0.140% 0.120% 0.100% 0.080% 0.060% 0.040% 0.020% 0.000% 10 20 30 40 50 60 Years of Age at Exposure © UW and Brent K Stewart, PhD, DABMP 53 G89 The currently accepted model of radiation dose versus effect used by regulatory agencies to determine dose standards is ¬ A Cubic B Exponential C Linear no threshold D Linear quadratic E Linear threshold ¬ ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 Equivalent to Number of Cigarettes Smoked Equivalent to Number of Highway Miles Driven 0.04 0.1 0.1 1.0 1.1 1.2 1.8 2.1 1.6 4.0 4.0 40.0 44.0 48.0 72.0 84.0 12 29 29 292 321 350 526 613 29 71 71 714 786 857 1286 1500 4.2 7.1 7.6 7.8 168.0 284.0 304.0 312.0 1226 2073 2219 2277 3000 5071 5429 5571 8.7 348.0 2540 6214 © UW and Brent K Stewart, PhD, DABMP Raphex 2002 General Question ¬ Effective Dose (mSv) Risk of Fatal Cancer (per million) 54 Raphex 2001 General Question ¬ G78 The latent period for radiation-induced carcinogenesis (solid tumors) is about years ¬ A B C 10 D 20-30 E 40-50 ¬ ¬ ¬ ¬ 55 © UW and Brent K Stewart, PhD, DABMP 56 14 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Raphex 2000 General Question Davis Notes – Radiation Biology ¬ G88 For a total dose of 100 mrem received over the course of one year, the excess risk of cancer induction during the individual's lifetime is about cases/106 ¬ The overall fatal cancer risk per rad of whole body low LET radiation of a population selected at random would be on the order of: ¬ ¬ ¬ A 0.05 B 0.5 C D 50 E 500 ¬ A B C D E ¬ mSv · 0.04/Sv (BEIR V) · 106 = 40; 0.05/Sv (NCRP) ¬ Risk ¬ ¬ ¬ ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 57 ¬ ¬ ¬ ¬ 24 February and March 2005 58 Radiation Effects In Utero Genetic effects the result of radiation exposure to the gonads Epidemiological investigations have failed to demonstrate radiationradiation-induced genetic effects Current risk estimates are based on animal experiments For workers, the risk of severe hereditary effects is 0.8% per Sv of gonadal radiation according to the ICRP For a whole population, the risk of severe hereditary effects is 1.3% per Sv which is higher because of the inclusion of children © UW and Brent K Stewart, PhD, DABMP cSv (1 rad) · 0.04/Sv = 0.0004 = 4x10-4 © UW and Brent K Stewart, PhD, DABMP Genetic Effects in Humans ¬ 104 102 10-4 10-6 106 59 ¬ Gestational period divided into stages: ¬ ¬ ¬ ¬ ¬ Relatively short preimplantation stage (day 00-9) Extended period of major organogenesis (day 99-56) Fetal growth stage (day 45 to term) Preimplantation: conceptus extremely sensitive and radiation damage can result in prenatal death: “All“All-orornothing response” Animal experiments have demonstrated an increase in the spontaneous abortion rate after doses as low as 50 to 100 mGy (5 to 10 rad) © UW and Brent K Stewart, PhD, DABMP 60 15 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Relative Incidence of RadiationRadiation-Induced Health Effects at Various Stages in Fetal Development Critical Periods for RadiationRadiation-induced Birth Defects p r e i m p l a n t a t i o major n organogenesis fetal growth c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 860 c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 855 © UW and Brent K Stewart, PhD, DABMP 61 © UW and Brent K Stewart, PhD, DABMP Radiation Effects In Utero (2) ¬ ¬ ¬ ¬ 62 Radiation Effects In Utero (3) Exposures > Gy associated with a high incidence of CNS abnormalities Growth retardation after in utero exposure ≥ 100 mGy demonstrated Fetal doses generally are much less than 100 mGy in most diagnostic and nuclear medicine procedures and thought to carry negligible risk compared with the spontaneous incidence of congenital abnormalities (4%(4%6%) A conservative estimate of the excess risk of childhood cancer from in utero irradiation is ≈ 6% per Gy (0.06% per rad) ¬ ¬ Recommendations from Wagner* are: If radiation dose received during or prior to the first two weeks post conception (< 14 days) ¬ ¬ Exposure to diagnostic radiation is not an indication for therapeutic abortion For patients exposed to radiation between the 2nd and 8th weeks postpost-conception (days 1414-56): ¬ ¬ Therapeutic abortion based solely on radiation exposure is not advised for dose less than 150 mGy (15 rad) Dose exceeding 150 mGy (15 rad) may be an indication for therapeutic abortion in the presence of less severely compromising factors However, diagnostic studies rarely result in such dose levels * Wagner, et al Exposure of the Pregnant Patient to Diagnostic Radiation, pp 166166-7 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 63 © UW and Brent K Stewart, PhD, DABMP 64 16 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Radiation Effects In Utero (4) ¬ Radiation Effects In Utero (5) For a conceptus exposed between the 8th and 15th week postpost-conception (days 5656-105): ¬ ¬ Up to a 6% probability the child could be mentally retarded ¬ Probability the child will develop cancer < 3% ¬ Radiation not a sufficient risk to justify therapeutic abortion Fetal dose between 5050-150 mGy (5(5-15 rad) ¬ ¬ Fetal dose at 150 mGy: Fetal dose below 50 mGy (5 rad) ¬ ¬ ¬ ¬ therapeutic abortion is not advisable on the basis of the radiation radiation risk alone ¬ Fetal dose above 150 mGy (15 rad) ¬ * Wagner, et al Exposure of the Pregnant Patient to Diagnostic Radiation, pp 166166-7 © UW and Brent K Stewart, PhD, DABMP ¬ ¬ Natural incidence = 1.4% Probability of small head size ≈ 15% (but does not necessarily affect normal mental function) ¬ In this time interval there is scientific evidence that may support support a recommendation for therapeutic abortion based on the radiation exposure However, this does not mean an abortion is necessarily recommended Diagnostic studies rarely result in such dose levels levels Natural incidence = 0.4% Natural incidence = 4% IQ may fall a few points short of its full potential Except for possible effects to individual organs from radionuclide radionuclide studies, no other risks have been demonstrated However, always practice ALARA! * Wagner, et al Exposure of the Pregnant Patient to Diagnostic Radiation, pp 166166-7 65 Effect of In Utero Risk Factors on Outcome © UW and Brent K Stewart, PhD, DABMP 66 In Utero Irradiation Summary c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 860 c.f Bushberg, et al The Essential Physics of Medical Imaging, 2nd ed., p 858 © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 67 © UW and Brent K Stewart, PhD, DABMP 68 17 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Huda 2nd Edition – Chapter 10 – Radiation Biology ¬ 15 When is gross malformation most likely to occur? ¬ (A) (B) (C) (D) (E) ¬ ¬ ¬ ¬ Early fetal period Early organogenesis Late fetal period Late organogenesis Preimplantation Huda 2nd Edition – Chapter 10 – Radiation Biology ¬ 16 What “threshold” embryo/fetal dose corresponds to a radiation risk smaller than those normally encountered during pregnancy? ¬ (A) (B) (C) (D) (E) ¬ ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 69 © UW and Brent K Stewart, PhD, DABMP Davis Notes – Radiation Biology A barium enema was performed on a 25 year-old female who was determined to be three weeks pregnant at the time of examination As the consulting radiologist, you should: ¬ A Recommend a therapeutic abortion B Counsel the patient that the embryo is at a significantly high risk for gross malformations as a result of the radiation exposure; however, an abortion is not necessarily warranted C Discuss the implications of the radiation exposure with the hospital’s legal department D Do not discuss any potential effects of the radiation exposure on the embryo because very little is known about in utero radiation exposure and your comment would be totally speculative and unsubstantiated E Explain to the referring physician and patient that the radiation received by the embryo by this diagnostic procedure is relatively small and that the increase in risk is negligible compared to the spontaneous incidence of congenital abnormalities ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 70 Raphex 2001 General Question ¬ ¬ Less than 10 mGy (1 rad) 10 mGy (1 rad) 30 mGy (3 rad) 100 mGy (10 rad) More than 100 mGy (10 rad) 71 ¬ G80 In radiation protection the embryo/fetus is considered more vulnerable to radiation than an adult, for all of the following reasons except: ¬ A In a given volume, more embryonic cells are proliferating than adult cells B In a given volume, more embryonic cells are differentiating than adult cells C An embryo consists of fewer cells, making the loss of cells by radiation injury potentially more damaging D The higher oxygen tension of the embryo/fetus results in a higher oxygen enhancement ratio (OER) ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 72 18 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Raphex 2002 General Question ¬ G93 The estimated increased risk of birth defect in a fetus receiving rem (10 mSv) in the 12th week of gestation is about _ % ¬ ¬ A 0.01 B 0.1 C 1.0 D 10 ¬ Maximum incidence of 1% per rem for small head size ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 73 © UW and Brent K Stewart, PhD, DABMP Huda 2nd Edition – Chapter 10 – Radiation Biology ¬ 14 Which group of irradiated individuals has demonstrated genetic effects of radiation? ¬ (A) (B) (C) (D) (E) ¬ ¬ ¬ ¬ Atomic bomb survivors Cancer radiotherapy patients No human group Thyroid treatment (131I) patients Uranium miners Raphex 2000 General Question ¬ G89 Concerning the genetically significant dose (GSD), which of the following is true? ¬ A It depends on the number of radiographs the person has had during the year B It can be used to estimate an individual's risk from gonadal irradiation C It is an index of potential genetic damage done to the population from gonadal irradiation D It is estimated to exceed the gonadal dose from background irradiation by a factor of two E It has been shown to be increasing steeply each year ¬ ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 75 74 © UW and Brent K Stewart, PhD, DABMP 76 19 Radiation Biology – Bushberg Chapter 25 Diagnostic Radiology Imaging Physics Course Raphex 2003 General Question Raphex 2001 General Question ¬ G88 According to NCRP there is a negligible increase in the risk of adverse effects to the fetus, compared with other risks of pregnancy, up to a total dose of _ mGy ¬ A B 20 C 100 D 500 E 1000 ¬ ¬ ¬ ¬ ¬ G79 Perinatal death (at or around the time of birth) is most likely to occur as a result of irradiation in humans which occurs in the gestational period of: ¬ A Implantation of the embryo B Major organogenesis (21-40 days) C Second trimester D Just before birth (30-36 weeks) ¬ ¬ ¬ © UW and Brent K Stewart, PhD, DABMP 24 February and March 2005 77 © UW and Brent K Stewart, PhD, DABMP 78 20 [...]... required for low absorbed dose to maintain statistical precision and power; the necessary sample power increases approximately as the inverse square of dose This relationship reflects a decline in the signal (radiation risk) to noise (natural background risk) ratio as dose decreases ¬ To rule out simple statistical fluctuations, a very large irradiated population is required ¬ ¬ SS = c/D2 500 persons needed