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  1. 1. OCCUPATIONAL CANCERS Jay Harper, MD, MPH 412-647-5323 [email_address]
  2. 2. Overview <ul><li>2 to 8 % of all cancers are thought to be due to occupational exposures (Doll & Peto) </li></ul><ul><li>Prevention is key </li></ul><ul><li>Environmental as well as occupational cancers </li></ul><ul><li>Multifactorial </li></ul>
  3. 3. History <ul><li>1775: Sir Percival Pott: scrotal cancer in chimney sweeps </li></ul><ul><li>1895: Bladder cancer: aromatic amines </li></ul><ul><li>1973: Lung cancer: bis-chloromethylether </li></ul><ul><li>1974: Liver angiosarcoma: vinyl chloride </li></ul>
  4. 4. Stages of Tumor Development <ul><li>Initiation </li></ul><ul><ul><li>Active mutation or damage to DNA </li></ul></ul><ul><ul><li>Single exposure may be sufficient (carcinogenic by themselves) </li></ul></ul><ul><ul><li>Action is irreversible </li></ul></ul><ul><ul><li>No apparent threshold </li></ul></ul><ul><ul><li>No morphologic changes in initiated cell </li></ul></ul><ul><ul><li>Dependency on metabolism and the cell cycle </li></ul></ul>
  5. 5. Stages of Tumor Development <ul><li>Promotion </li></ul><ul><ul><li>May speed cell production or suppress apoptosis </li></ul></ul><ul><ul><li>Causes morphologic changes </li></ul></ul><ul><ul><li>Modulation by environment and lifestyle </li></ul></ul><ul><ul><li>Probable threshold </li></ul></ul><ul><ul><li>Reversible </li></ul></ul>
  6. 6. Stages of Tumor Development <ul><li>Progression </li></ul><ul><ul><li>Additional changes necessary for the development of a malignant tumor </li></ul></ul><ul><ul><ul><li>Likely triggered by genetic events </li></ul></ul></ul><ul><ul><li>Development of invasiveness, metastasis, irreversible changes in genome </li></ul></ul><ul><ul><li>If no progression, then remains at benign stage such as papilloma, nodules or adenoma </li></ul></ul>
  7. 7. EPIDEMIOLOGIC STUDIES Criteria for Causality <ul><li>STRENGTH – magnitude of relative risk </li></ul><ul><li>CONSISTENCY – reported in multiple studies with different circumstances </li></ul><ul><li>BIOLOGICAL GRADIENT – dose-response validity </li></ul><ul><li>BIOLOGICAL PLAUSIBILITY – “makes sense’ </li></ul><ul><li>TEMPORALITY – cause precedes effect </li></ul>
  8. 8. EPIDEMIOLOGIC STUDIES <ul><li>Advantages </li></ul><ul><ul><li>Allows direct assessment in humans </li></ul></ul><ul><ul><li>May detect cancer cluster </li></ul></ul><ul><ul><li>Allows observation of cumulative effects of environmental and lifestyle factors affecting various stages </li></ul></ul><ul><ul><li>Allows estimates of relative risk </li></ul></ul>
  9. 9. EPIDEMIOLOGIC STUDIES <ul><li>Disadvantages </li></ul><ul><ul><li>Long latency periods </li></ul></ul><ul><ul><li>Limited to those materials used for many years </li></ul></ul><ul><ul><li>Retirement of workers </li></ul></ul><ul><ul><li>Difficulty with small risk: extrapolation beyond available data, poor-exposure record keeping, poor exposure recall, worker job transfers </li></ul></ul><ul><ul><li>Confounding risk factors cannot be controlled </li></ul></ul>
  10. 10. Animal Studies <ul><li>IARC requirements </li></ul><ul><li>Good qualitative predictor </li></ul><ul><li>Not-so-good quantitative predictor </li></ul><ul><li>Limitations </li></ul><ul><ul><li>High dose exposure is needed in order to detect significance </li></ul></ul><ul><ul><li>Different metabolism </li></ul></ul><ul><ul><li>Different routes of administration </li></ul></ul>
  11. 11. Short - Term Tests <ul><li>Provide evidence of mutagenicity </li></ul><ul><li>Ames test, sister-chromatin exchange, DNA repair </li></ul><ul><li>Quicker results, less expensive </li></ul><ul><li>Correlation of results with animals/humans imperfect </li></ul>
  12. 12. Molecular Biology <ul><li>Allows assessment of exposure and possible early health effects </li></ul><ul><li>Measure enzyme activity of the cytochrome p450 monooxygenase class </li></ul><ul><li>Measurement of DNA or protein adducts </li></ul><ul><li>Measurement of protein products in the urine </li></ul>
  13. 13. Regulatory Issues <ul><li>If there is sufficient evidence of carcinogenicity, then corrective action is taken, even if uncertainty exists </li></ul><ul><li>Limited evidence should be stimulus for more research </li></ul><ul><li>Risk assessment is crucial to best public policy </li></ul>
  14. 14. Agencies <ul><li>IARC : International Agency for Research on Cancer </li></ul><ul><li>ACGIH : American Conference of Governmental Industrial Hygienists </li></ul><ul><li>NTP : US Public Health Service National Toxicology Program </li></ul><ul><li>NIOSH : National Institute for Occupational Safety and Health </li></ul>
  15. 15. IARC <ul><li>Group 1 – carcinogenic to humans </li></ul><ul><li>Group 2 </li></ul><ul><ul><li>2A – probably carcinogenic to humans </li></ul></ul><ul><ul><li>2B – possibly carcinogenic to humans </li></ul></ul><ul><li>Group 3 – not classifiable </li></ul><ul><li>Group 4 – probably not carcinogenic to humans </li></ul>
  16. 16. Known Human Occupational Lung Cancers <ul><li>Arsenic </li></ul><ul><li>Asbestos </li></ul><ul><li>Beryllium </li></ul><ul><li>Cadmium </li></ul><ul><li>Chloromethyl ethers </li></ul><ul><li>Chromium </li></ul><ul><li>Coal-related products </li></ul><ul><li>Mustard gas </li></ul><ul><li>Nickel </li></ul><ul><li>Radon </li></ul><ul><li>Vinyl chlorine </li></ul>
  17. 17. Lung Cancer - Asbestos <ul><li>Chrysotile is the most common form of asbestos (Other forms are amosite, crocidolite, tremolite) </li></ul><ul><li>Asbestos affects parenchyma and pleura of lungs </li></ul><ul><li>Can cause cancer of larynx, GI tract (stomach) as well as lung </li></ul><ul><li>Long latency </li></ul><ul><li>Synergism with smoking </li></ul>
  18. 18. Asbestos - Mesothelioma <ul><li>Uncommon </li></ul><ul><li>No evidence for direct relationship </li></ul><ul><li>Dose – response relationship exists, although no threshold theorized </li></ul><ul><li>No interaction with smoking </li></ul><ul><li>All fiber types may cause mesothelioma </li></ul><ul><ul><li>Crocidolite (long, thin fiber) is the most potent type </li></ul></ul>
  19. 19. Lung Cancer - Chloromethyl ether <ul><li>Chloromethyl methyl ether (CMME) and Bis (chloromethyl) ether (BCME) </li></ul><ul><li>BCME more potent then CMME </li></ul><ul><li>Oat cell type </li></ul><ul><li>Intermediate product used in ion-exchange resins, bactericides, pesticides and solvents </li></ul>
  20. 20. Lung Cancer - Chromium <ul><li>Hexavalent (+6) form is carcinogenic; other forms are not </li></ul><ul><li>Also causes perforated nasal septum </li></ul><ul><li>Used as hardening agent in metallic compounds </li></ul>
  21. 21. Lung Cancer - Arsenic <ul><li>May cause skin cancer, as well as lung cancer </li></ul><ul><li>Synergistic with smoking </li></ul><ul><ul><li>Between additive and multiplicative </li></ul></ul><ul><li>Most often seen in upper lobes </li></ul><ul><li>Copper smelting and pesticide production </li></ul><ul><li>Found in natural and man-made sources </li></ul><ul><ul><li>Seafood source is non-toxic </li></ul></ul><ul><ul><li>Toxic in Fowler’s solution (used for eczema/psoriasis) and pesticides (vineyard workers) </li></ul></ul>
  22. 22. Lung Cancer - Nickel <ul><li>Associated with lung, nasal and laryngeal cancers </li></ul><ul><li>Nickel mining and refining </li></ul><ul><li>Soluble forms are more potent </li></ul><ul><li>Squamous cell most common type </li></ul><ul><li>Good housekeeping is especially important for reducing occupational exposure </li></ul>
  23. 23. Lung Cancer - Coal-related products <ul><li>PAH – Polyaromatic Hydrocarbon </li></ul><ul><li>Known carcinogens are benz(a)anthracene and 7,12 dimethylbenzanthracene </li></ul><ul><li>Lung cancer is seen in coke-oven workers; scrotal cancer in chimney sweeps </li></ul><ul><li>PAH’s are formed through incomplete combustion of coal, tar, coke and oil </li></ul><ul><li>PAH’s found in coal gasification facilities, gas and coke works, iron and steel foundries, petroleum distillates and diesel exhaust. </li></ul>
  24. 24. Lung Cancer - Mustard Gas <ul><li>Bis (beta-chloroethyl) sulfide </li></ul><ul><li>Poisonous gas used in WWI </li></ul><ul><li>Causes squamous cell lung CA </li></ul><ul><li>Excess lung cancers seen in Japanese and German workers manufacturing mustard gas </li></ul>
  25. 25. Lung Cancer - Radon <ul><li>“ Wasting disease of the mountains” seen in miners by Agricola and Paracelsus </li></ul><ul><li>Radon daughter products </li></ul><ul><li>Cigarette smoking acts synergistically with radon </li></ul><ul><li>Lifetime dose in certain dwellings is concern </li></ul>
  26. 26. Prevention of Occupational Lung Cancer <ul><li>Primary prevention is important </li></ul><ul><ul><li>Smoking cessation </li></ul></ul><ul><li>Secondary prevention (medical monitoring) </li></ul><ul><ul><li>OSHA mandates monitoring for asbestos, acrylonitrile, arsenic, silica, and vinyl chloride </li></ul></ul><ul><ul><li>NIOSH recommends monitoring for beryllium, carbon black, chromium VI, coal tar products, inorganic nickel and coal gasification </li></ul></ul><ul><ul><li>Chemopreventive agents </li></ul></ul>
  27. 27. Upper Respiratory Cancers <ul><li>Sino-nasal </li></ul><ul><ul><li>Nickel, wood dust, chromium , cutting oils, mustard gas </li></ul></ul><ul><li>Laryngeal </li></ul><ul><ul><li>Asbestos, nickel, mustard gas, cutting oils </li></ul></ul>
  28. 28. Hematologic Cancers <ul><li>Risk Factors </li></ul><ul><ul><li>Ionizing radiation </li></ul></ul><ul><ul><li>Benzene </li></ul></ul><ul><ul><li>Agricultural work </li></ul></ul><ul><ul><li>Cytotoxic drugs </li></ul></ul>
  29. 29. Hematologic Cancer - Ionizing Radiation <ul><li>Studies from atomic blasts from WWII </li></ul><ul><li>Associated with all leukemia types except CLL </li></ul><ul><li>ALARA (as low as reasonably achievable) </li></ul>
  30. 30. Hematologic Cancer - Benzene <ul><li>Associated with pancytopenia and AML </li></ul><ul><li>Industrial rubber workers, refinery workers, chemical workers (soaps, dyes, cosmetics, perfumes), explosives industry </li></ul><ul><li>Safe exposure level unknown </li></ul>
  31. 31. Hematologic Cancer - Agricultural Exposure <ul><li>Farmers </li></ul><ul><li>Multiple etiologies, including pesticides and herbicides </li></ul><ul><li>Leukemia, Multiple Myeloma, Hodgkin’s Disease and Non-Hodgkin’s Lymphoma </li></ul>
  32. 32. Hematologic Cancer - Medical Exposures <ul><li>Anti-neoplastic drugs </li></ul><ul><li>Ethylene oxide </li></ul><ul><li>Radiation </li></ul>
  33. 33. Bladder Cancer <ul><li>Especially dye/pigments and tire/rubber mfg. </li></ul><ul><li>Up to 20% of bladder CA related to occupation </li></ul><ul><li>Kidney concentrates toxin; prolonged exposure in bladder </li></ul><ul><li>Benzidene </li></ul><ul><li>2-Naphylamine </li></ul><ul><li>4-Nitrobiphenyl </li></ul><ul><li>4,4-methylene-bis-(2-chloroaniline) or MOCA </li></ul><ul><li>4,4-methylene dianiline or MDA </li></ul>
  34. 34. Bladder Cancer Screening <ul><li>Hematuria – high risk populations only </li></ul><ul><li>Urine cytology </li></ul><ul><li>Newer areas of detection: quantitative fluorescence image analysis (QFIA) and DNA flow cytometry. </li></ul><ul><li>Sensitivity/specificity issues </li></ul>
  35. 35. Bladder Cancer Screening <ul><li>NIOSH recommendations </li></ul><ul><ul><li>Screening for bladder cancer should be viewed as a research endeavor whose benefits are not yet delineated </li></ul></ul><ul><ul><li>Screening techniques are evolving; it would be wise to bank serum and urine samples </li></ul></ul><ul><ul><li>Natural history of bladder CA is unclear, thus the value of detecting superficial versus invasive lesions is unclear </li></ul></ul>
  36. 36. GI Tract <ul><li>Gastric </li></ul><ul><ul><li>Asbestos, wood dust, rubber industry </li></ul></ul><ul><li>Colon </li></ul><ul><ul><li>Sedentary work is risk factor </li></ul></ul><ul><ul><li>Asbestos and rubber industry suspected </li></ul></ul><ul><ul><li>Screening (Digital Rectal Exam vs. stool guiac vs. sigmoidoscopy) </li></ul></ul>
  37. 37. GI Tract - Liver <ul><li>Hepatitis B&C, alcohol, aflatoxins </li></ul><ul><li>Asbestos suspected </li></ul><ul><li>Solvents associated with hepatic fibrosis </li></ul><ul><li>Hepatic Angiosarcoma </li></ul><ul><ul><li>Vinyl chloride </li></ul></ul><ul><ul><li>Thorotrast </li></ul></ul><ul><ul><li>Arsenic </li></ul></ul>
  38. 38. Skin Cancer <ul><li>Ionizing radiation </li></ul><ul><li>Arsenic </li></ul><ul><li>Polycyclic aromatic hydrocarbons </li></ul><ul><li>UV radiation </li></ul>