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DOSE-EFFECT CURVES; DETERMINISTIC AND STOCHASTIC EFFECTS OF RADIATION Module IX Biological effects of radiation in time perspective Time scale Effects Fractions of seconds Energy absorption Seconds Changes in biomolecules (DNA, membranes) Biological repair Change of information in cell Minutes Hours Days Weeks Months Cell death Mutations in a Germ cell Somatic cell Organ death Clinical changes Leukaemia or Cancer Years Decades Module Medical IX. Generations Hereditary effects 2 Radiation effects Early (deterministic only) Local Radiation injury of individual organs: functional and/or morphological changes within hrs-days-weeks Module Medical IX. Common Acute radiation disease Acute radiation syndrome (LD50/60 ~ 3.5Sv LD ~ 5 Sv) Late Deterministic (Above DQ, cummul.) - Rad. Dermatitis - Rad. Cataracta - Teratogenic (DQ,F~0,1Sv) Stochastic (Probability increases with dose) - tumours, leukaemia - genetic effects 3 Deterministic (a) and stochastic (b) effects of radiation Det Module Medical IX. 4 Sources of data on human effects of radiation overexposure Number x103 1 110 2 Occupational exposure 1.1 Early radiologist and medical physicists 1.2 Ra-dial painters 1.3 U-miners, nuclear industry workers Medical overexposure 3 A-bomb victims 86.5 Overexposure due to nuclear weapons test 4.1. Inhabitants of Marshall Islands 4.2 Personnel of nuclear weapon tests (NWT) 4.3 Inhabitants living around NWT sites 5 Accidents – a) deterministic effects 5.1 Radiation accidents 5.2 Nuclear accidents (Chernobyl) -stochastic effects Registered thyroid cc. 6 Inhabitants of high natural background areas Total number of registered overexposures 10 4 96 95 4 0.25 ~ 100* ~ 500* 3 2.8 0.2 3 ~600* (~30M*) (~60M*) 300 Note: *Effects of radiation exposure are not proved in these population groups, but studied recently (M - million) Module Medical IX. 5 Typical dose-effect relationships for deterministic effects in population Module Medical IX. 6 Threshold doses for some deterministic effects in the most radiosensitive tissues Tissue and effects Total dose single brief exposure (Gy) Bone marrow Depression of haematopoesis Annual dose rate received in highly fractionated or protracted exposure for many years (Gy/y) 0.5 > 0.4 Temporary sterility 0.3 0.4 Permanent sterility 3.5-6.0 2.0 Testes Module Medical IX. 7 Threshold doses for some deterministic effects Tissue and effects Total dose received in single brief exposure (Gy) Annual dose rate received yearly in highly fractionated or protracted exposure for many years (Gy/y) Ovaries Sterility 2.5-6.0 > 0.2 Lens Detectable opacities 2.0 > 0.1 Visual impairment 5.0 > 0.4 (cataract) Module Medical IX. 8 Time of onset of clinical signs of skin injury depending on dose received Symptoms Dose range (Gy) Erythema Epilation Dry desquamation Moist desquamation Blister formation Ulceration Necrosis 3-10 >3 8-12 15-20 15-25 >20 >25 Time of onset (day) 14-21 14-18 25-30 20-28 15-25 14-21 >21 Ref.: IAEA-WHO: Diagnosis and Treatment of Radiation Injuries. IAEA Safety Reports Series, No. 2, Vienna, 1998 Module Medical IX. 9 Acute radiation syndrome (ARS) ARS is the most notable deterministic effect of ionizing radiation Signs and symptoms are not specific for radiation injury but collectively highly characteristic of ARS Combination of symptoms appears in phases during hours to weeks after exposure - prodromal phase - latent phase - manifest illness - recovery (or death) Extent and severity of symptoms determined by - total radiation dose received - how rapidly dose delivered (dose rate) - how dose distributed in body (whole vs partial body irradiation) Module Medical IX. 10 Principle syndromes contributing to death after acute whole body radiation exposure Whole body dose, Gy Syndrome Time of death after the exposure - days 3-10 bone marrow 30-60 10-30 gastrointestinal tract 10-20 >30 Module Medical IX. neurovascular system 1-5 11 Special deterministic effects Teratogenic effects of radiation Module Medical IX. 12 Frequency of severe mental retardation in prenatally exposed survivors of A-bombing in Hiroshima and Nagasaki % Sv Module Medical IX. 13 Microcephaly: Hiroshima data 45 40 35 % 30 25 20 15 10 5 0 0 10-90 100-190 200-290 300-490 500-1490 >1500 Foetal dose, mSv Module Medical IX. 14 Stochastic effects Cancer induction and genetic effects Module Medical IX. 15 Phases of cancer induction and manifestation Norma l Ce lls Initia tion Muta te d Ce lls Elimia tion Re pa ra tion Pre -c a nc e r Promotion Minima l Ca nc e r Clinic a l Ca nc e r Progre ssion Spre a ding Module Medical IX. 16 Stochastic Effects of Radiation Exposure Frequency proportional to dose No threshold dose No method for identification of appearance of effect of ionizing radiation in individuals Increase in occurrence of stochastic effects provable only by epidemiological method Module Medical IX. 17 Stochastic effects of radiation exposure (continued) Stochastic effects observed in animal experiments Dose-effect relationship for humans can be studied only in human population groups Dose-effect relationship in low dose range (below 100 mSv) not yet verified Extrapolation down to zero excess dose accepted only for radiation protection and safety Module Medical IX. 18 Human data on radiation cancerogenesis Type or localization of cancer Population groups A-bomb survivors Leukemia Thyroid gland + + Lung Breast + + Exposed in a nuclear accident Module Medical IX. Skin + Ra-dial painters Early radiologists U-miners Bone + + + + 19 Latency periods for radiation-induced cancer Module Medical IX. 20 Risk of leukaemia depending on age at exposure to A-bomb Module Medical IX. 21 Age dependency of incidence of leukaemia in British population and radiotherapy patients Leukaemia per million/yr 10000 1000 100 10 1 10 20 30 40 50 60 70 AGE, years General Population Module Medical IX. Radiotherapy patients 22 Cancer deaths attributable to A-bomb In 86 572 survivors of Hiroshima and Nagasaki, 7827 persons died of cancer in 1950-90 Observed All tumours 7578 Leukaemia 249 All cancers 7827 Expected 7244 162 7406 Excess (%) 334 (4.4) 87 (35.0) 421 (5.4) Ref: Pierce et al, Rad.Res. 146: 1-27, 1996 Module Medical IX. 23 LEUKAEMIA CASES per 100,000 person per year DOSE DEPENDENCE OF LEUKAEMIA IN A-BOMB SURVIVORS 140 120 100 80 60 40 Hiroshima 20 0 Nagasaki 0 0.01-0.49 1.0-1.9 >4.0 ABSORBED DOSE, Gy Module Medical IX. 24 Cancer mortality of nuclear industry workers Observed/Expected deaths Dose ranges, mSv <10 10- 20- 50- 100- 200- 400- Total Trend number test of deaths (p-value) O/E number of deaths from cancers other than leukemia 2234/ 462/ 445/ 276/ 196/ 161/ 56/ 2228.3 465.4 479.6 254.3 190.5 147.6 67.3 3830 -0.28 (0.609) O/E number of deaths from leukemia other than CLL (chronic lymphocytic leukemia) 60/ 19/ 14/ 8/ 8/ 4/ 6/ 62.0 17.2 17.2 9.0 6.4 4.7 2.3 119 1.85 (0.046) The ERR (excess relative risk) per Sv among the 95,673 nuclear industry workers of Canada, UK and USA (having a mean cumulative dose of 36.6 mSv in the combined cohort for the total period of observation, ie. 34 yrs in the USA and UK, and 29 years in Canada ) is –0.07 for all cancers excluding leukemia, and 2.18 for leukemia excluding CLL. Ref.: Cardis, E. et al: Combined Analyses of Cancer Mortality Among Nuclear Industry Workers in Canada, the UK and the USA. IARC Technical Report No.25, Lyon, 1995 Module Medical IX. 25 Childhood leukaemia around UK nuclear facilities STUDY GROUP: 46 000 children (followed till the age of 25 yrs) born to parents working in nuclear industry FINDINGS: 111 cases of acute leukaemia observed, i.e. fewer than expected in a group of this size and age Study found 3 cases of leukaemia in children of male workers who had received a pre-conceptional exposure of 100 mSv or more Two of these three cases had already been identified in the 1990 Gardner report (proposed theory that paternal pre-conception radiation leads to increased risk of leukaemia in offspring) Conclusions No substantial evidence found to support Gardner’s theory Study did not confirm theory Ref. ICRF, LSHTM & LRF: Nuclear Industry Family Study (NIFS). BMJ, 28-05-1999 Module Medical IX. 26 Lifetime mortality in population of all ages from cancer after exposure to low doses Organ or tissue Bladder Bone Marrow Bone Surface Breast Colon Liver Oesophagus Ovary Skin Stomach Thyroid Remainder1 Total Module Medical IX. Fatal Cancer Probability Coefficient -4 -1 (10 Sv ) 30 50 5 20 85 15 30 10 2 110 8 50 500* * For general public (all age groups) only Summary factor of cancer risk for working population taken to be 400x10-4 Sv-1 Reference ICRP, Publ. 60, 1991 27 Nominal probability coefficients for stochastic radiation effects Detriment (10- 2 Sv-1) Exposed population Fatal cancer Non-fatal cancer Severe hereditary effects Total Adult workers only 4.0 0.8 0.8 5.6 Whole population (all age groups) 5.0 1.0 1.3 7.3 1 2 Rounded values For fatal cancer, detriment coefficient is equal to probability coefficient Ref. ICRP, Publ. 60, 1991 Module Medical IX. 28 Genetic radiation damage Increase of chromosome aberrations in human spermatogonia following radiation exposure of testes has been detected inheritance of radiation damage in human population (including A-bomb survivors) not yet detected Module Medical IX. 29 Review of topics discussed Biological effects of radiation in time perspective Main characteristics of deterministic and stochastic effects Sources of data on human effects of radiation overexposure Threshold doses of deterministic effects in the most radiosensitive tissues Teratogenic effects of radiation: severe mental retardation, microcephaly Phases of cancer induction Sources of human data on radiation cancerogenesis (3 groups) Latency periods of radiation induced cancers (lag 2 & 10 yrs) Risk of cancer depending on age at exposure (reverse dependence) Cancer deaths attributable to A-bombs – 5.4% in 40-yr follow up Cancer mortality studies of nuclear industry workers and offspring – leukaemia probable in workers Genetic effects of radiation – not proved in human population Module Medical IX. 30