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Occupational Cancer: Untying the Gordion Knot of Work-Relatedness

Occupational Cancer: Untying the Gordion Knot of Work-Relatedness. Chris Martin, MD, MSc, FRCPC cmartin@hsc.wvu.edu Professor and Director, Institute of Occupational and Environmental Health West Virginia University School of Medicine. The Gordion Knot.

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Occupational Cancer: Untying the Gordion Knot of Work-Relatedness

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  1. Occupational Cancer: Untying the Gordion Knot of Work-Relatedness Chris Martin, MD, MSc, FRCPC cmartin@hsc.wvu.edu Professor and Director, Institute of Occupational and Environmental Health West Virginia University School of Medicine

  2. The Gordion Knot

  3. Bernardino RamazziniDe Morbis Artificum, 1700 “Every city in Italy has several religious communities of nuns, and you can seldom find a convent that does not harbor this accursed pest, cancer, within its walls. Now why is it that the breasts suffer for the derangements of the womb, whereas other parts of the body [uterus] do not suffer in this way? Now, these are not caused by suppression of the menses but rather, in my opinion, by their celibate life.”

  4. Outline 5 questions

  5. Outline • How much cancer is due to occupation?

  6. Outline • How much cancer is due to occupation? • How might an occupational exposure cause cancer?

  7. Outline • How much cancer is due to occupation? • How might an occupational exposure cause cancer? • What occupational exposures cause cancer?

  8. Outline • How much cancer is due to occupation? • How might an occupational exposure cause cancer? • What occupational exposures cause cancer? • When might a cancer be occupational?

  9. Outline • How much cancer is due to occupation? • How might an occupational exposure cause cancer? • What occupational exposures cause cancer? • When might a cancer be occupational? • What can be done?

  10. Cancer in Canada – 2012 estimates • 186,400 new cases of cancer (excluding 81,300 non-melanoma skin • 75,700 deaths • Second leading cause of death (Source: Canadian Cancer Society

  11. 1. How much cancer is due to occupation? • “Scientists have estimated that as may as 33% of all cancers are related to workplace exposures to carcinogens, (ref.: U. S. Civil Service Employees Association, 1998)”. Source: Health Canada http://www.hc-sc.gc.ca/ewh-semt/occup-travail/whmis-simdut/carcinogenesis-carcinogenese-eng.php

  12. 1. How much cancer is due to occupation? 30% Tobacco 30% Diet / Obesity / Physical inactivity 5% Family history 5% Biological agents 5% Perinatal effects / Growth 3% Alcohol 3% Reproductive factors 2% Radiation/sunlight 10% Unknown 100% Source: Cancer Care Ontario website http://www.cancercare.on.ca/index_statisticsAllSites.htm#fn4 citing Adami et al., 2001 and Colditz et al., 1996. Causes of Cancer Deaths in Developed Countries. 7% Occupation / Environment

  13. How many causes are there for any one outcome?

  14. A causal chain Latent Period Exposure 1 Disease Manifestation Induction period for exposure 2 Exposure 2 Disease Initiation

  15. 2. How might an occupational exposure cause cancer?

  16. Sources of information • Animal and in vitro studies • Human epidemiology, vast majority involve ionizing radiation exposure • Atomic bomb survivors in Japan • Life Span Study • http://www.rerf.or.jp/library/archives_e/lsstitle.html • Iatrogenic (mis)use • Examples: ankylosing spondylitis, tinea capitis, cancers

  17. Carcinogenesis • Fundamental event is alteration in DNA leading to unregulated cell growth – ‘single hit’ • Alteration must be stable and non-lethal • Humans have ~ 30 000 genes • 50 – 100 oncogenes • Mammalian origin • Specific genetic mutations associated with occupational cancers / exposures • tumor suppressor gene p53 and VCM (Smith SJ et al. Molecular epidemiology of p53 protein mutations in workers exposed to vinyl chloride.Am J Epidemiol. 1998 Feb 1;147(3):302-8).

  18. Mouse skin model

  19. Carcinogenesis Multi-stage model: • Initiation • Promotion • Progression

  20. Multi-stage Model of Carcinogenesis Initiation Promotion Progression

  21. Carcinogen Damages DNA No apparent threshold Single hit Not carcinogenic, unless preceded by initiation Epigenetic Threshold Prolonged exposure needed Initiator vs Promoter

  22. Types of carcinogens • “Incomplete” carcinogen requires a promoter • Example: bis (chloro-methyl) ether • “Complete” carcinogen both initiates and promotes • Example: cigarette smoke • “Co-carcinogen” enhances genotoxic effect of initiator when given at the same time • Example: ethanol and VCM

  23. No Threshold Model No threshold model drives regulatory climate for carcinogens. No threshold Risk Threshold Dose Threshold

  24. Regulating occupational carcinogens • Exposure limits will include safety or uncertainty factor • Usually 100 or 1,000 • Not based on science, but consensus • Exposures to known carcinogens require: • Justification • Optimization • Application of “ALARA” principle • Limitation (Source: International Commission on Radiological Protection at www.icrp.org)

  25. 3. What occupational exposures can cause cancer?

  26. International Agency for Research on Cancer (IARC) • Part of the World Health Organization (WHO) • http://www.iarc.fr

  27. International Agency for Research on Cancer (IARC) • Standardized evaluations of the strength of the evidence for carcinogenicity • Evaluations of 953 agents in 100 monographs (published as of September 2012) • ‘agent’ may be chemical, mixture, biological agent, industry, etc. • Data summaries and evaluations available online

  28. IARC Evaluation • Review: 1. laboratory experiments 2. human epidemiology • Grade evidence for each as sufficient, limited or inadequate • Consider other data (pathology, genetics, structure-activity relationships etc.) • Provide overall evaluation

  29. 1. Laboratory Experiments • In vivo (animal) studies • For IARC, may be only species • In vitro studies • Ames’ test

  30. IARC Overall Evaluation

  31. IARC Overall Evaluation • With 953 agents evaluated, which group is the largest? • Carcinogenic • A. Probably carcinogenic B. Possibly carcinogenic 3. Not classifiable 4. Probably NOT carcinogenic

  32. IARC Overall Evaluation • With 953 agents evaluated, which group is the largest? • Carcinogenic • A. Probably carcinogenic B. Possibly carcinogenic 3. Not classifiable (508) 4. Probably NOT carcinogenic

  33. IARC Overall Evaluation • With 953 agents evaluated, which group is the smallest? • Carcinogenic • A. Probably carcinogenic B. Possibly carcinogenic 3. Not classifiable 4. Probably NOT carcinogenic

  34. Caprolactam • Used in nylon fiber production

  35. IARC Overall Evaluation • Carcinogenic (108) • A. Probably carcinogenic (64) B. Possibly carcinogenic (272) • Not classifiable (508) • Probably NOT carcinogenic (1)

  36. Alcoholic beverages Arsenic Asbestos Benzene Benzidine Beryllium Bis-chloromethylether Chromium VI Coal tars Hepatitis B,C virus Nickel Polynuclear aromatic hydrocarbons (PAHs) Rubber industry Silica Sulfuric acid mist X and γ radiation Vinyl chloride Wood dust Some IARC Group 1 Carcinogens

  37. IARC Evaluations • Note: strength of evidence for any one agent may vary depending site, overall evaluation reflects strongest evidence. Example: Asbestos is a Group 1 carcinogen, but evidence for lung cancer, mesothelioma is greater than for GI, laryngeal malignancies • Evaluation says nothing about potency. • Not without controversy.

  38. Carcinogens and Canadian OSH Regulations • WHMIS (Workplace Hazardous Materials Information System) relies on IARC as well as American Conference of Governmental Industrial Hygienists (ACGIH) when designating a substance as a carcinogen. • Class D by WHMIS

  39. 4. When might a cancer be due to an occupational exposure?

  40. Occupations with well-documented increased rates of cancers

  41. Occupations with well-documented increased rates of cancers

  42. When might a cancer be occupational? • When you see an unusual cancer.

  43. Mesothelioma • Malignancy of pleura, peritoneum tunica vaginalis, ovary • Incurable, very poor prognosis (months) • Increasing incidence (~300 per year in Canada) • Associated with asbestos exposure in about 80% of cases • Recall: long latency • May follow seemingly trivial exposure • No association with smoking

  44. Angiosarcoma of the Liver Among Polyvinyl ChlorideWorkers – Kentucky (MMWR 1974;23:49-50)

  45. Angiosarcoma of the liver and vinyl chloride monomer • 4 cases identified between September 1967 and December 1973 • All were employed in polyvinyl chloride polymerization section of a plant near Louisville, Kentucky employing 270 people • General population rate at that time = 25 cases per year in US • One of the classic case clusters in occupational medicine • Associated with vinyl chloride monomer exposure • Highly reactive gas

  46. Occupational cancers • However, the vast majority of occupational cancers are the same as those observed in general population • Leukemia, lung, bladder

  47. When might a cancer be occupational? • When you see an unusual cancer. • When you see an increased frequency of a cancer.

  48. The first recognized occupational cancer (1775).

  49. The most recently recognized occupational cancer? • IARC, October, 2007: Shift-work that involves circadian disruption is probably carcinogenic to humans (Group 2A) • Monograph 98, 2010 Painting, Firefighting, and Shiftwork

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