Introduction to Radiation Health Late Effects — Cancer

Introduction to Radiation Health: Late Effects - Cancer Dr. Niel Wald

Radiobiological Effects • Non-Stochastic – Severity varies with dose – May have threshold (cataract, dermatitis) • Stochastic – Probability of occurrence in population varies with dose – No threshold (cancer, genetic damage) 227 -4

Intracellular Effects of Radiation 138 -A

Classification of Neoplasms Tissue Origin Benign Malignant 395 -4 Examples Epithelial Glandular Adenoma Adenocarcinoma Squamous and Transitional Polyp, papilloma Squamous cell carcinoma Transitional cell carcinoma Thyroid follicular adenoma Adenocarcinoma of lung Squamous papiloma of skin Squam. cell carcinoma skin Connective tissue Tissue type + suffix (-oma) Sarcoma Osteoma, Osteosarcoma, Hemangiosarcoma Hematopoietic & lymphoreticular Lymphoma Leukemia Large cell lymphoma Hodgkin’s disease Mylocytic leukemia Neural tissue Neuroma Neurofibroma Sarcoma Blastoma Glioblastoma multiforme Neurofibrosarcoma Mixed tissues of origin Teratoma Teratocarcinoma Teratoma of ovary Teratocarcinoma of testis

Basis for Tumor Dose: Response Estimates 175 -3

Tumor Growth Curve 395 -6

Scheme for Induction of Cancer by Environmental Carcinogens Normal Cells Initiator(s) (electrophilic, mutagenic) Chemical or Radiation Carcinogen Initiated Cells Promoter(s) Tumor Cells Clones Inactive Metabolites Gross Tumors Courtesy of Miller and Miller 395 -11

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395 -2

395 -3

Three germ layers and the tissues derived from them Embryonic origin Adult derivative Ectoderm Skin Brain Breast Sweat glands etc. Mesoderm Fibrous tissue (connective) Cartilage Bone Muscle etc. Endoderm Gut Liver Lung Pancreas etc. 666 -1

Histogenetic classification of benign tumors Normal tissue Glandular epithelium Surface epithelium Fibroblasts Cartilage Striated Muscle Smooth Muscle Blood Vessels Fat Bone Liver Resultant Benign tumor Adenoma Papilloma Fibroma Chondroma Rhabdomyoma Leiomyoma Hemangioma Lipoma Osteoma Hepatoma 642 -1

Histogenetic classification of malignant tumors Normal tissue Epithelium Connective tissue Bone Marrow Resultant Malignant tumor Carcinoma Sarcoma Leukemia More Specifically: Glandular epithelium Squamous epithelium Fibroblasts Cartilage Striated Muscle Smooth Muscle Endothelium Fat Bone Liver Adenocarcinoma Squamous carcinoma Fibrosarcoma Chondrosarcoma Rhabdomyosarcoma Leiomyosarcoma Angiosarcoma Liposarcoma Osteosarcoma Hepatocellular carcinoma 642 -2(1)

Histogenetic Classification of Malignant Tumors with Atypical Nomenclature: Normal tissue Skin- melanocytes Fibroblast/histiocyte Myeloid stem cells Plasma cells Lymphoid tissue Sympathetic neurones (neuroblasts) ? Endothelium Embryonal kidney Embryonal retina Gonad (male germ cells) Gonad (female germ cells) Germ cells Resultant Malignant tumor Malignant melanoma Malignant fibrous histiocytoma Myeloid leukemia Multiple myeloma Lymphoma/Hodgkin’s Dis. Neuroblastoma Kaposi’s sarcoma Nephroblastoma Retinoblastoma Seminoma Dysgerminoma Malignant teratoma 642 -2(2)

Mechanisms of Cell Death 642 -3

Cell Death (necrosis and apoptosis) 642 -4

Maturation Arrest 642 -6

Metastasis Formation 666 -2

Metastasis Formation 666 -3

Cancer Development 395 -16

General Properties of Initiating Agents & Promoting Agents Initiating Agents* 1. 2. 3. 4. 5. 6. 7. 8. Carcinogenic by themselves. Activity strictly determined by molecular structure. Generally active in more than one tissue. No detectable threshold dose; action is cumulative and irreversible. Most require metabolic activation and covalently bind to macromolecules. Most are mutagens. More active in proliferating tissues. Induce rapid shift in the biological potential of the cells (a single exposure is often sufficient to initiate). Promoting Agents 1. 2. 3. 4. 5. 6. 7. Not carcinogenic alone; must be given after initiating agent to exert effect. Activity strictly determined by molecular structure. Action of individual exposures is reversible and not cumulative. Repeated exposures are required. Metabolism or macromolecular binding may not be required. Not mutagenic but may enhance the expression of induced mutations. Usually induce proliferation in target tissue (although proliferation alone is not a sufficient promoting stimulus). Induced changes are progressive; stable intermediate stages may be observed prior to overt malignancy. *defined in a broad sense as agents that can both initiate cancer in limited dosages and induce cancer in higher dosages or in states of increased host susceptibility 395 -15

Properties of Oncogenes and Tumor Supressor Genes Property Oncogenes Tumor Supressor Genes One Two Function of mutation Gain of function (“dominant”) Loss of function (“recessive”) Germline inheritance No Yes Somatic mutations Yes Mutational events involved in cancer Effects on growth control Activate cell proliferation Negatively regulate growthpromoting genes Effects of gene transfection Transform partly abnormal fibroblasts (e. g. , NIH 3 T 3) Supress malignant phenotype in malignant cells Genetic alterations Point mutations, gene rearrangements, amplification Deletions, point mutations * From Rudden, 1995 b, with permission. 666 -9

International Leukemia Incidence 666 -4

Alternative Radiation Dose-Response Curves 227 -5

Cancer Summary • Tissues vary considerably with respect to their sensitivity to cancer induction. • The major sites of solid tumors induced by whole-body exposure to radiation are the breast, thyroid, lung and digestive organs. • Age, both at the time of exposure and diagnosis, is a very important variable relating to cancer induction. • The latency period (time from exposure to tumor detection) is frequently very long, i. e. years to decades. • Interaction between host and environmental factors (i. e. , hormonal influences, exposure to other carcinogenic agents) may play a significant role in tumor induction. • Nearly all the tissues in the body are susceptible to tumor induction. • The dose-response relationships for many animal model systems are qualitatively similar to those for human tumor induction. However, direct quantitative risk extrapolation from animals to man would be inappropriate 395 -28

Radiation Cancer Risk Estimation 341 -2

Radiation-induced Cancer Risk 227 -6

Absolute Risk Model 220 -4

Relative Risk Model 220 -5

Dose-response Interpolation Curves 227 -1

Radiation Dose: Slope Relationships Dose Range Low Intermediate High Very High Rads 0 to ~ 20 to 250 ~ 250 to 400 > ~ 400 Low LET D: R Curve Range Straight Increasing Slope Max. to 0 Slope Remainder 227 -2

Radiation Dose Rate Ranges Dose-Rate Range Low Intermediate High Rads 5 per year or less Between low and high ~ 200 - 250 in minutes to 12 hours 227 -3

Hiroshima Dose: Distance Relationship 92 -I

ABCC Shielding History Floor Plan 93 -C

A-Bomb Leukemia Cases by Year 100 -C

A-Bomb Leukemia by Type and Dose 96 -B

A-Bomb Leukemia Dose-Response Curves 302 -5

A-Bomb Exposure Age vs. Leukemia Risk 220 -2

The quadratic risk coefficient ( ) has increased, whereas the linear low-dose risk coefficient ( ) has decreased, suggesting that currently accepted standards for low-level gamma exposures are not in need of revision on the basis of changes in data from Japan. Risk Coefficients for Leukemia Mortality Risk Coefficient 10 rad Induced Effect Leukemia (Cases/106/year/rad) 100 rad “New” BEIR (1980) 0. 8 0. 98 2. 7 1. 8 Source: Adapted from Straume and Dobson (1981). Reproduced from Health Physics, Vol. 44 by permission of the Health Physics Society 303 -4

The observed and expected numbers of Ankylosing Spondylitis deaths due to leukemia and aplastic anemia, 1935 - 54 study series Number of Deaths Disease Group Sex Minimum expected Maximum expected Observed Leukemia M. F. 1. 25 0. 19 2. 06 0. 34 22 0 M. And F. 1. 44 2. 40 22 M. F. 0. 12 0. 03 0. 20 0. 05 10 1 (International List Code no. 204) Aplastic anemia (International List Code no. 292 -4) M. And F. 0. 15 0. 25 11 Significance of difference between observed and maximum expected number of deaths: Leukemia: P < 0. 000001 Aplastic anemia: P < 0. 000001 104 -E

Spondylitis: Leukemia Dose-Response 104 -G

Spondylitis: Leukemia Latency Postexposure 104 -F

Incidence of Death from Leukemia in Physicians Occupation Time Place Total Deaths Leukemia Deaths Incidence Radiologist Non-radiologist All Physicians 1929 -43 1933 -42 USA USA 175 50, 160 26, 788 8 221 143 4. 57% 0. 44% 0. 53 % Radiologist 1938 -42 USA 95 5 Ratio of Incidences Radiologists: All Physicians General Population Incidence 5. 3 % March 10. 3: 1 0. 39% 10. 6: 1 All Specialists All Physicians Radiologist Non-radiologist All Physicians Radiologist 1938 -42 1944 -48 1947 -51 1949 -58 1897 -56 Radiologist Non-radiologist Radiologist 1938 -42 1952 -55 USA USA G. Brit. Eire USA USA 2, 029 12, 419 124 15, 637 11, 481 296 23, 393 463 19 62 6 113 133 11 221 3 0. 94 % 0. 50 % 4. 84 % 0. 72 % 1. 2 % 3. 71 % 0. 77 % 0. 65 % 205 34, 626 8 158 3. 9 % 0. 44 % 3. 57 % 1952 -55 1930 -54 USA USA 1. 00 % 3. 65 % 2. 33 % 0. 63 % Henshaw and Hawkins Dublin and Spiegelman March 6. 7: 1 0. 52% Peller and Pick Cronkite 4. 8: 1 Court-Brown Ulrich 3. 6: 1 Non-radiologist Radiologist Non-radiologist with Xray Non-radiologist without X-ray Reference 0. 39% (1950) Melville in Schwartz and Upton Warren 104 -D

Risk of Leukemia in various Diseases and Conditionsa, b Group Identical twin of leukemic twin Irradiation-treated polycythemia vera Blood syndrome Hiroshima survivors who were within 1, 000 meters of the hypocenterc Down’s Syndrome Irradiation-treated patients with ankylosing spondylitis Siblings of leukemic children Children exposedd to pelvimetry in utero (gestational exposure) U. S. white children < 15 years of age Approximate Risk 1/3 1/6 1/8 Increased Risk Over Control Population Occurrence 1, 000 500 375 Weeks to months 10 -15 years < 30 years of age 1/60 1/95 50 30 Average 12 years < 10 years of age 1/270 1/720 10 4 15 years To 10 years 1/2, 000 1/2, 800 1. 5 1 < 10 years To 10 years a Risk of leukemia in various groups with specific epidemiologic and pathologic characteristics in populations followed for 10 -30 years. b Leukemia cases/106 c risk (lifetime): Mortality increment from single exposure to 1 rad is 15 -25 persons or ~ 1/50, 000. Free in air doses (rads): gamma rays > 500 rads; neutrons > 60 rads Source: Modified from Miller (1970; from Brent (1980) 303 -5

Leukemia Risk Adults Children Percent increase in risk/ rem 2 to 3 5 to 10 Absolute risk (cases/ 106/ rad) 1 to 2 2 to 3 96 -I

A-Bomb: Mortality Relative Risks 173 -1

A-Bomb: Cancer Relative Risks 173 -2

A-Bomb: Cancer Dose-Response 173 -3

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Thyroid Cancer Risk Associated with I-131 Exposure from Chernobyl Estimated Thyroid Dose from I-131 (Gy) < 0. 30 -0. 99 1. 0+ RR Cases Population Controls 64 88 26 15 17 4 2. 1 (1. 7 -5. 8) Cases Medical Controls 64 84 26 19 17 4 2. 6 (1. 4 -4. 8) Adapted from Astakhova et al. , 1998 668 -5

Observed and Expected Neoplasms by Site in Hiroshima and Nagasaki Residents Exposed to 1 -9 rad (1950 -1974) Hiroshima SITES Leukemia Thyroid Female Breast Trachea, Bronchus, Lung Digestive Organs, Peritonium Stomach Esophagus Cervix Uteri, Uterus Overy, Tube, Ligament Bladder, Urinary Prostate Nagasaki OBS. EXP. OBS / EXP 4 17 22 49 318 197 9 66 3 9 7 10. 1 21. 4 28. 8 52. 2 319. 5 204. 2 15. 5 60. 9 6. 9 16. 2 11. 1 0. 4 0. 8 0. 9 1. 0 0. 6 1. 1 0. 4 0. 6 OBS. EXP. OBS / EXP 5 12 9 20 125 75 5 34 1 3 3 5. 8 13. 1 12. 7 19. 8 125. 7 75. 2 7. 9 29. 0 1. 5 4. 7 3. 4 0. 9 0. 7 1. 0 0. 6 1. 2 0. 7 0. 6 0. 9 175 -16

Radiation Field for Newborn Thymus Therapy 108 -E

Tumors After Newborn Thymus Irradiation Type of Neoplasm Anterior + Posterior Untreated Siblings Observed Expected Observed Malignant Thyroid carcinoma Leukemia Hodgkin’s disease Salivary gland tumor Breast carcinoma Brain tumor Benign Thyroid adenoma Osteochondroma Breast adenoma Expected 23 14. 50 0. 31 3. 21 0. 80 0. 15 0. 40 2. 48 --3. 10 7. 22 --- 14 3 0 1 31 15 9 1 2. 21 0. 06 0. 43 0. 16 0. 03 0. 05 0. 28 --0. 60 1. 26 --- 14 0 2 1 1 0 2 32 3 3 7 108 -I

Bikini A-Bomb. Test Fallout 109 -G

Thyroid Nodules (1981)* After Bikini A-BOMB test Group age 1954 No. Est. thyroid Dose (rads) Rongelap 1 yr 2 -10 > 10 6 16 45 > 1, 500 (? ) 800 -1500 387 4 13 6 66. 7 81. 2 13. 3 0 1 3 0 6. 2 6. 6 Ailingnae < 10 > 10 7 12 275 -450 140 2 4 28. 6 33. 3 0 0 Utirik < 10 > 10 64 100 60 -90 53 5 12 7. 8 12. 0 1 2 1. 6 2. 0 Matched Controls < 10 > 10 229 371 6 29 2. 6 7. 8 2 3 0. 9 0. 8 Total Nodules No. % Carcinoma No. % * Prevalence has not been corrected for control levels. The carcinoma prevalence is probably low, since all unoperated nodule cases were considered benign for this table. Occult carcinomas were not included as carcinomas. 109 -H

Post-Chernobyl Accident Fallout 668 -4

Thyroid Cancer Post-Chernobyl Accident 668 -10

Thyroid Nodules Post-Bikini Test Fallout 258 -4

Absolute Risk of Thyroid Abnormalities After Exposure to Radiation Type of Abnormality and Population Surveyed Thyroid nodularity Children Adults Thyroid cancer Children Adults Hypothyroidism “Low dose” - children “High dose” - adults Thyroid nodularity in children Thyroid cancer in children Hypothyroidism in adults Mean Dose or Dose Range (rem) for which Data Were Available Absolute Risk Internal Irradiation (131 I) 9, 000 0. 23 8, 755 0. 11 Statistical Risk Range 0 to 0. 52 0. 06 to 0. 15 9, 000 8, 755 0. 06 0. 05 0 to 0. 16 0. 038 to 0. 066 < 10 to 1, 900 2, 500 to 20, 000 4. 9 4. 4 3. 9 to 22. 9 2. 8 to 7. 6 External Irradiation 0 to 1, 500 1, 640 12. 3 4. 2 10. 2 4 to 45 0. 9 to 17. 3 0 to 25 221 -3

Thyroid Cancer Dose-Response 304 -5

Thyroid Cancer after External Irradiation Series A-bomb, age < 30 c (> 50 rads) A-Bomb, age > 30 c (> 50 rads) Thymus x-ray (Rochester) Tonsil x-ray (M. Reese) Head/ Neck x-ray (Cinn. ) Tinea (Israel, NYC) a U, Type of control No. a persons group Mean dose (rads) Obs. Exp. Abs. riskb 4, 377 U ~ 130 26 2, 8 3. 4 2, 782 2, 651 2, 578 1, 266 13, 060 U S, P --D D, S, U ~ 130 138 ~ 780 ~ 290 ~9 6 30 181 16 23 2. 6 0. 7 ~2 ~ 0, 4 6, 8 0. 3 3. 5 ~ 3. 6 ~ 1. 7 ~ 6. 3 unexposed group; S, siblings; D, same-disease control; P, general population control b Absolute risk = excess cancers/ 106 PY-rad c From Prentice et al. , with permission 304 -6

Breast Cancer Post-TB Fluoroscopy 305 -7

Post-A-Bomb Breast Cancer 305 -4

Breast Cancer after TB Fluoroscopy 305 -6

Lung Cancer: Czech Miners 306 -7

Lung Cancer: US Uranium Miners 113 -F

Histologic Classification of Lung Cancer I. Squamous cell carcinomas II. Small cell carcinomas 1. 2. 3. Fusiform cell type (intermediate) Polygonal cell type “ “ Lymphocyte-like type (oat cell)Intermediate III. Adenocarcinomas IV. Large cell carcinomas 260 -2

Lung Cancer and Age in Miners Age at Start of Mining Excess Rate and 95% Confidence Limits (10 -6 WLM-1) Under 30 140 (100 - 180) 30 to 39 230 (160 - 300) Over 40 370 (280 - 460) All 230 (155 - 305) 145 -10

Thorotrast Distribution 23 yrs. Post-injection 110 - I

Liver Cancer in Thorotrast Patients Surviving at least 10 years After Intravascular Injection Country and Year of Last Followup Germany, 1977 Denmark, 1977 Portugal, 1974 Total No. Cases Liver Cancer Traced Patients Surviving at Least 10 Yr Person-Years at Risk from 10 Yr After Injection to Death or Last Contact 176 50 75 301 1, 733 646 667 3, 046 28, 424 12, 274 12, 673 a 53, 371 The fraction of the Portuguese patients surviving at least 10 yr and their average time to death or last contact were considered similar to those documented for the Danish patients. In both countries, suspected brain diseases were the main reason for the intravascular injection of Thorotrast (80% in Portugal and nearly 100% in Denmark). a 223 -1

Causes of Death Among the 1, 120 Traced Individuals Who Received Thorotrast and were Followed-up Until March 30, 1966 Causes of Death (Only the Basic Cause of Death Was Considered) Total number of deaths which could have been due to a possible thorotrast side-effect A. Local Granulomata B. Hemangioendotheliomata C. Malignant tumor on the edge of granulomata D. Other malignant tumors E. Leukemias F. Aplastic anemias G. “Purpuras” H. Liver fibrosis I. Other possible fatal ‘consequences” Deaths, due to causes which could not be due to thorotrast Unknown cause of death Total deaths during the period Number of Deaths Number Total Percent 101 13. 77% 9 27 5 23 9 6 2 17 3 591 80. 63% 41* 733 5. 59% * Some of these cases are still under investigation and will probably be classified eventually in other diagnoses Usual Time Interval Between Administration & Death (in Yrs. ) --15 y. or more 25 y. or more 15 - 20 y. or more 17 y. 18 y. 19 y. 15 - 20 y. or more ----- 110 -C

Thorotrast Patients: Liver Tumors and Dose Rate 307 -4

Liver Cancer Summary Excess Risk Cases/ 106/ Yr/ RAD High LET Low LET 13. 0 0. 7 223 -3

Cancer in Radium Dial Painters 308 -8

Dial Painters’ Radium Burden and Cancer 115 -E

Dial Painters’ Skeletal Dose and Bone Cancer 224 -1

Cancer Rate Per Million Persons Per RAD of Exposure Incidence (Unscear ‘ 77) Thyroid Breast (F) Leukemia Lung Bone Other Fatalities (ICRP ‘ 77) 100 20 -50 2 -5 2 -15 5 50 20 20 5 50 175 -17

492 -3

Comparison of Lifetime Excess Cancer risk Estimates from BEIR III and BIER V Reports Continuous Lifetime Exposure, 1 m. Gy/y (deaths per 100, 000) Instantaneous Exposure, 0. 1 Gy (deaths per 100, 000) Males Leukemia BIER IIIa BIER V Ratio BIER V / BIER III Nonleukemia BIER III Additive risk model Relative risk model BIERV Ratio BIER V / BIER III a Females Males Females 15. 9 70 12. 1 60 27. 4 110 18. 6 80 4. 4 5. 0 4. 3 24. 6 42. 4 42. 1 65. 2 92. 9 450 118. 5 540 192 660 213 730 4. 8 - 18. 3 4. 6 - 12. 7 3. 4 - 15. 7 3. 4 - 11. 2 based on Table V-16, page 203 and Table V-19, page 206 492 -4