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Modelling Exposure-Response Relationships for Ionizing and Non-Ionizing Radiation

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Modelling Exposure-Response Relationships for Ionizing and Non-Ionizing Radiation Modelling Exposure-response Relationships for Ionizing and Non-ionizing Radiation Daniel Krewski, PhD, MHA Professor and Director McLaughlin Centre for Population Heath Risk Assessment & Risk Sciences International American Association of Physicists in Medicine (AAPM) Denver, Colorado August 2, 2017 Outline • A New Framework for Risk Science • Key Characteristics of Human Carcinogens • Ionizing Radiation – Sources of exposure – Medical uses of radiation – Occupational and environmental radiation exposures – Radiation hormesis: what do the data Indicate? • Non-ionizing Radiation – Sources of exposure – Epidemiological studies of RF fields • Risk Communication, Risk Perception and Risk Decision Making McLaughlin Centre for Population Health Risk Assessment The Next Generation Risk Science McLaughlin Centre for Population Health Risk Assessment Next Generation Risk Assessment McLaughlin Centre for Population Health Risk Assessment Three Cornerstones • New paradigm for toxicity testing (TT21C), based on perturbation of toxicity pathways • Advanced risk assessment methodologies, including those addressed in Science and Decisions • Population health approach: multiple health determinants and multiple interventions McLaughlin Centre for Population Health Risk Assessment Key Characteristics of Human Carcinogens McLaughlin Centre for Population Health Risk Assessment What can we learn about human cancer based on 50 years of cancer research? McLaughlin Centre for Population Health Risk Assessment IARC Scientific Publication No. 165 • Twenty chapters prepared by workshop participants (9 on concordance and 11 on mechanisms) • Five chapters by McLaughlin Centre investigators • Consensus statement from workshop participants McLaughlin Centre for Population Health Risk Assessment Group 1 Radiation Agents in Volumes 100A-F, 105, 106, 107 and 109 Radiation well-studied in humans and animals McLaughlin Centre for Population Health Risk Assessment Key Characteristics of 86 Group-1 Agents by Type of Agent McLaughlinRadiation Centre for agents Population have aHealth distinct Risk profile Assessment of key characteristics Exposure to Ionizing Radiation McLaughlin Centre for Population Health Risk Assessment Exposure to Ionizing Radiation in the United States McLaughlin Centre for Population Health Risk Assessment https://www.epa.gov/radiation/radiation-sources-and-doses Computed Tomography Effective dose Examination (mSv) Head CT 2 Chest CT 7 Abdomen CT 8 Pelvis CT 6 Coronary artery calcification CT 3 Coronary CT angiogram 16 C. H. McCollough, J. T. Bushberg, J. G. Fletcher, and L. J. Eckel. Answers to Common Questions About the Use and Safety of CT Scans. Mayo.Clin.Proc. 90 (10):1380-1392, 2015. McLaughlin Centre for Population Health Risk Assessment “Answers to Common Questions About the Use of CT Scans” 1. How is radiation dose in CT quantified? 2. How much radiation does CT use? 3. How much radiation is dangerous? 4. Is there any direct evidence that CT scans cause cancer? 5. Are estimates of how many people exposed to CT will die of radiation-induced cancer accurate? 6. Children are much more sensitive to radiation than are adults: is it appropriate to use examinations like CT in children? 7. What is being done to lower radiation exposures and why? 8. Why do the doses provided in radiation reports vary so much? 9. At what point does the cumulative dose from repeated examinations become dangerous? Should previous examinations be considered when ordering new examinations? 10.Should I order examinations that use lower doses of radiation (such as chest radiographs) or nonionizing radiation (such as ultrasound and magnetic resonance imaging) rather than CT scans? 11.What important points should I consider discussing with patients concerned about radiation exposure? McLaughlin Centre for Population Health Risk Assessment C. H. McCollough et al. Mayo.Clin.Proc. 90 (10):1380-1392, 2015. “Is there any direct evidence that CT scans cause cancer?” “ . .McLaughlin increased cancerCentre forrisk Population after low- Healthdose radiation Risk Assessment exposure from CT scans in young patients.” Occupational Radiation Exposure McLaughlin Centre for Population Health Risk Assessment National Dose Registry of Canada • 206, 620 workers (105,456 males and 101,164 females) monitored between 1951 and 1983 • Average cumulative dose 6.3 mSv • Mortality follow-up 1951-1987 • 5,426 deaths; 1,632 cancer deaths McLaughlin Centre for Population Health Risk Assessment ERR/Sv for males McLaughlin Centre for Population Health Assessment Risk National Dose Registry of Canada • 191,333 workers (95,643 males and 95,690 females) monitored between 1969 and 1983 • Cancer incidence data for the period 1969-1988 • 3,737 cancer cases McLaughlin Centre for Population Health Risk Assessment 40 30 20 for malesfor Sv 10 ERR/ 0 McLaughlin Centre for Population Health Risk Assessment • 42,175 dental workers (9,051 males and 33,124 females) • Study period 1951-1987 for mortality and 1969-1987 for cancer incidence • 558 deaths from all causes and 656 incident cases of cancer McLaughlin Centre for Population Health Risk Assessment Average annual exposure to Canadian dental workers has decreased markedly in recent decades McLaughlin Centre for Population Health Risk Assessment Radiation Hormesis McLaughlin Centre for Population Health Risk Assessment DRCA: Database of Radiogenic Caner in Animals McLaughlin Centre for Population Health Risk Assessment Characteristics of the Database A comprehensive database Distribution of Datasets by Radiation Type contains data from 262 X-rays, 154 Alpha, 143 experiments: - 800 datasets on the incidence of Beta, 80 specific tumours; - 87,982 exposed animals; Neutrons, 250 Gamma, 173 - 37,111 control animals. Distribution of Datasets by Animal Species Distribution of datasets by mode of radiation administration Hamster, 2 Inhalation, 86 Dog, 119 Injestion , 12 Injection, 120 Rat, 102 Instillation, 3 Mouse, 577 External, 579 McLaughlin Centre for Population Health Risk Assessment Examples of Dose-Response with No Evidence of an Effect or a Decrease in Cancer Incidence at Low Doses No cancers in control and exposed animals; Deringer et al 1955 No apparent effect; Maisin et al 1988 .4 1 .38 .36 .34 Proportion of animals with tumors with animals of Proportion Proportion of animals with tumors with animals of Proportion -1 .32 0 .2 .4 .6 .8 1 0 .2 .4 .6 .8 1 Dose (Gy) Dose (Gy) U-shaped dose-response: Ulrich et al 1979 J-shaped dose-response; Covelli et al 1988 .02 .007 .015 .0065 .01 .006 .005 0 .0055 Proportion of animals with tumors with animals of Proportion Proportion of animals with tumors with animals of Proportion .005 -.005 0 .5 1 1.5 2 0 .2 .4 .6 Dose (Gy) Dose (Gy) McLaughlin Centre for Population Health Risk Assessment Examples of Dose-Response with Some Evidence of a Radiation Effect at Low Doses Cancer incidence increases with increasing dose; Ulrich et al 1984 Inverse U-shape; Benjamin et al 1998 .35 .035 .03 .3 .025 .25 .02 .2 .015 Proportion of animals with tumors with animals of Proportion Proportion of animals with tumors with animals of Proportion .01 .15 0 .05 .1 .15 .2 0 .2 .4 .6 .8 Dose (Gy) Dose (Gy) McLaughlin Centre for Population Health Risk Assessment Numbers of Datasets with Various Dose- Response Shapes Type of dose-response Number of datasets (%) U-shape 245 J-shape 98 No apparent effect 127 No cancers in exposed and control animals 42 Total with no evidence of an effect or a decrease in 512 (64%) cancer incidence at low doses Increase in cancer incidence with dose 214 Inverse U-shaped 74 Total with some evidence of a radiation effect at low 288 (36%) doses Total 800 (100%) McLaughlin Centre for Population Health Risk Assessment Meta-analysis of the DRCA: What is the Empirical Evidence for Radiation Hormesis? McLaughlin Centre for Population Health Risk Assessment Defining a U-Shaped Dose-response Relationship (Hunt-Bowman Quadratic Model Below NOEL) 2.0 1.6 Estimated high NOEL 1.2 0.8 U-Shaped Zone 0.4 Disease Response Disease Background Response 0.0 0 2 4 6 8 10 12 Dose McLaughlin Centre for Population Health Risk Assessment Examine Empirical Evidence for Hormesis Under the hypothesis of hormesis, an excess of decreased tumour responses at low doses would be expected: the DRCA provides an opportunity to compare the observed number of decreases and increases in tumour response at low doses McLaughlin Centre for Population Health Risk Assessment Compare Increases and Decreases in Risk at Low Doses McLaughlinSimilar Centre results for Populationfor A: Alpha; Health B: Risk Beta; Assessment C: Gamma; and E: X-ray Conclusions from Meta-analysis • The meta-analysis of this large database of radiation tumourigenesis experiments in animals provides limited evidence of hormesis • This finding should not be interpreted as providing strong evidence against the hypothesis of radiation hormesis, since the power to detect a hormetic effect in the currently available animal carcinogenicity literature is limited by the moderately small number of studies with data points in the low dose range McLaughlin Centre for Population Health Risk Assessment Occupational Exposure to Radon McLaughlin Centre for Population Health Risk Assessment Modeling Lung Cancer Risks in Colorado Uranium Miners Exposed to Radon S. H. Moolgavkar, G. Luebeck, D. Krewski, and J. M. Zielinski. Radon, cigarette smoke, and lung cancer: a reanalysis of the Colorado plateau uranium miners' data. Epidemiology 4:204-217, 1993. McLaughlin Centre for Population Health Risk
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