“Toxic Relationship to the Pleura: Update and Future Concerns” by V. Courtney Broaddus, MD

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“Toxic Relationship to the Pleura: Update and Future Concerns” by V. Courtney Broaddus, MD

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“Toxic Relationship to the Pleura: Update and Future Concerns” by V. Courtney Broaddus, MD

  1. 1. Asbestos and its Toxic Relationship to the Pleura: Update and Future Concerns V. Courtney Broaddus, MD San Francisco General Hospital University of California, San Francisco
  2. 2. Outline for this talk• What is asbestos? Asbestiform?• How are we currently exposed?• What is so toxic about these fibers?• Why do they target the parietal pleura?• What is the future concern?
  3. 3. Asbestos• Asbestos – regulatory and commercial term for 6 naturally silicate crystalline fibers – Resistant to heat, fire, chemicals – Strong & flexible enough to be woven into cloth – Resistant to electrical current – High tensile strength
  4. 4. “asbestinon” means unquenchable• Mined for at least 2000 years• Historical notes – Marco Polo given clothes that would not burn from a stone with “threads” – Napkins cleaned by throwing into a fire – Perpetual wicks – Shrouds for funeral pyres Scientific American July 1997; 70-75.
  5. 5. AsbestosSerpentine Amphibole (curly) (needle-like) Chrysotile Amosite Crocidolite Anthophyllite Actinolite Tremolite
  6. 6. The 3 Main Commercial Fibers Chrysotile** Amosite Crocidolite
  7. 7. Chrysotile
  8. 8. Crocidolite
  9. 9. Brief History• Mining grew rapidly in late 1800s during the Industrial Revolution• Mining peaked in 1975; in 25 countries• Largest mine, the Jeffrey mine in Asbestos, Quebec• Major exporters are Russia (#1) and Canada (#2)
  10. 10. Current Status Worldwide• Banned in more than 30 countries – – European Union, Argentina, Egypt, Australia• USA has no ban – EPA ban in 1988, overturned in 1991 – restricted but still in use (brakes, roofing, gaskets)• Use shifting to developing countries with limited regulation
  11. 11. Legal Status in US• Asbestos claims represent the longest, largest tort in US history – >700,000 claimants; >8400 defendants• Many large producers declared bankruptcy and set up trusts
  12. 12. Jeffrey Mine, Asbestos, Quebec
  13. 13. Asbestos Consumption Today
  14. 14. The ‘Magic Mineral’ World’s Fair 1939
  15. 15. Asbestos Exposure Before ‘80’s• Heaviest exposure – Primary – miners, insulators, shipyard workers, sprayers – Secondhand – family members• Everyday products – Christmas snow (“flocking”), hair dryers, toothpaste• Contaminant in vermiculite (Libby MT)
  16. 16. Toxicity Recognized• 1900s – asbestosis described in UK• 1960 – Wagner’s publication describing mesothelioma in those exposed to asbestos in South Africa
  17. 17. Wittenoom CrocidoliteWestern Australia mining townUntil 1966, 6500 men and 500 women Courtesy of Dr. Bruce Robinson, Univ of Perth, Australia
  18. 18. Asbestos: Commercial
  19. 19. Asbestos: Used in Cigarette Filters 1952-1956
  20. 20. Current Sources of Exposure in US: A New Era of Low Dose Exposure• “In place” – Extensively used in construction, 20% of buildings – Can be disturbed by renovations, demolition• Naturally occurring – Asbestos in CA, ND, VA – Asbestiform fibers • Erionite – Turkey • Fluoro-edenite - Italy
  21. 21. In place Asbestos:Exposed Asbestos-cement
  22. 22. Asbestos in Buildings: ’50s-’80s
  23. 23. Changing Pattern of Mesothelioma in Australia Building/ 200 Construction Cases of WorkersMesothelioma 100 Wittenoom workers 1970- 1980- 1990- 2000- 1979 1989 1999 2009 AW Musk et al. AACR, 2012
  24. 24. • 1,000 tons of asbestos released• Asbestos at increased levels in settled surface dust
  25. 25. Asbestos as Contaminant• Libby, MT – Vermiculite used for home insulation, garden soils – Contaminated with tremolite • “Zonolite” – major source for vermiculite from 1919-1990
  26. 26. Vermiculite Shipped around Country Center for Asbestos Related Disease; www.libbyasbestos.org
  27. 27. Agency for Toxic Substances & Disease Registry, CDC A Phase 1 site where Libby vermiculite was likely processed until 1990 Easthampton, MA Zonolite Company
  28. 28. Mesothelioma Increases withResidential Proximity to Naturally- occurring Asbestos Am J Resp Crit Care Med 172(8):1019-1025, 2003
  29. 29. Asbestiform Fibers• Discovered due to mesothelioma clusters – Cappadocia, Turkey – erionite – Biancavilla, Italy – fluoro-edenite
  30. 30. Erionite in Turkey
  31. 31. Why are Asbestos and Asbestiform Fibers Toxic?• Due to both chemistry and shape• Field of ‘fiber toxicology’
  32. 32. Toxicity: Chemistry• Iron – generation of ROS (Fenton)• Surface adsorption of proteins• Nonreactivity – permanence in body
  33. 33. Toxicity: Fiber Shape• Damages cells when internalized – In macrophages, ‘frustrated phagocytosis” – In mesothelial cells, • interferes with mitotic spindle • delivers ROS to the nucleus• Penetrates deep into lung (beyond ciliary clearance)• Accumulates in parietal pleura
  34. 34. Mesothelial Cells Exposed to Crocidolite
  35. 35. Toxicity in vitro Requires Internalization Am J Respir Cell Mol Biol 23(3):371-8, 2000
  36. 36. Asbestos Fibers Damage Chromosomes Am J Pathol 126:343-349, 1987
  37. 37. Normal Upper Lobe of Rat Lung Courtesy Dr. Arnold Brody, Tulane Univ Medical School
  38. 38. Asbestos Intercepted at the1st Bronchoalveolar Duct Junction (After 1hr of inhalation exposure) Courtesy Dr. Arnold Brody, Tulane Univ Medical School
  39. 39. After 5 Hours..Courtesy Dr. Arnold Brody, Tulane Univ Medical School
  40. 40. Bronchovascular Bundle/Intralobar Septae: Provide Access to Pleural Space J Appl Physiol. 1990 Jun;68(6):2623-30
  41. 41. From Alveolus to Visceral to Parietal Pleura Parietal Visceral
  42. 42. Pleural Lymphatics Outlined by Carbon Rib Intercostal space Courtesy of Kurt Albertine, Univ of Utah
  43. 43. Lymphatic Stomata in the Parietal Pleura J Thorac Cardiovasc Surg 2000;120:437-447
  44. 44. Is there evidence in humans? “Black Spots” Am J Respir Crit Care Med 153:444-449, 1996
  45. 45. Deposition is not Uniform: “Black Spots” 4.1 fibers/g0.5 fibers/g Am J Respir Crit Care Med 153:444-449, 1996
  46. 46. “Black Spots” nearly Universal in Urban Dwellers Am J Surg Pathol 26(9):1198-1206, 2002 2
  47. 47. “Black Spots” do not Overlap with Pleural Plaques Black Spots Pleural Plaques Am J Surg Pathol 26(9):1198-1206, 2002 2
  48. 48. Why does Asbestos Target the Parietal Pleura?• Inhaled asbestos fibers deposit in the lung at bifurcations – Translocate alone or in macrophages – Move across the visceral pleura• Move with pleural liquid to lymphatics – Lodge and accumulate at the stomata• Decades go by…
  49. 49. Mr. DJ, 57 years old
  50. 50. CT scan:“pleural plaques, calcified and non- calcified”
  51. 51. After chest pain for 14 months:
  52. 52. Other Asbestos-related Pleural Changes
  53. 53. Clinical Presentation• Pleural effusion and/or chest wall pain• Male > female; increasingly in younger ages – Occupational – carpenter, plumbers, insulation, electrician – Non-occupational – home repair, summer jobs
  54. 54. Diagnosis• Problems with pleomorphic morphology – Distinguishing from reactive mesothelium – Distinguishing from other tumors• Usually need tissue for a panel of immunohistochemical stains – Different issues for epithelioid versus sarcomatous types
  55. 55. Treatment: Chemotherapy• Responses < 20%• Improvement with Pemetrexed + addition of anti- Cisplatin metabolites – Response 41% vs 17% – Survival 12 months compared to 9 months Cisplatin alone• Surgery for cytoreduction Vogelzang NJ et al. J Clin Oncol 2003
  56. 56. Future Aids to Early Diagnosis• Mesothelin as serum or effusion marker – Surface molecule – Soluble mesothelin • Elevated in serum • Parallels tumor size • Can predate diagnosis• Other biomarkers – osteopontin Robinson BW et al. Lancet 362: 1612, 2003
  57. 57. Carbon Nanotubes: The New Fiber on the Block• Carbon, not silica, crystalline fiber – Have high tensile strength – Nonreactive
  58. 58. Toxicity Profile of Carbon Nanotubes• Act similarly to asbestos – In vitro – DNA damage, chromosomal damage – In vivo – can translocate to pleura • Pleural reaction dependent on length• ? Biopersistence
  59. 59. 1 day 7 days Carbon Nanotubes No Short (1-5 um) Long(15-50 um) Am J Pathol. 178(6): 2587–2600, 2011.
  60. 60. Conclusions• Asbestos is still with us as ‘in place’, naturally occurring and as contaminant – Fibers accumulate at parietal pleural “black spots” and persist for decades• Low level exposure is still of concern – Be alert to sources of exposure – Be alert to changing epidemiology of mesothelioma• Carbon nanotubes may have similar toxicity
  61. 61. Thanks to those who shared images and input:• Bruce Robinson, Univ of Perth, Australia• Agnes Kane, Brown Univ• Marie-Claude Jaurand, INSERM, Paris• Brooke Mossman, Univ of VT• Kurt Albertine, Univ of Utah• Arnold Brody, Tulane Univ Med School• Bill Musk, Univ of Perth, Australia• Linda Reinstein, ADAO
  62. 62. Thanks to my colleagues and collaborators:• Raphael Bueno, Brigham & Women’s• David Sugarbaker, Brigham & Women’s• Jeanine Wiener-Kronish, MD MGH• Norman Staub, UCSF• Michael Matthay, UCSF
  63. 63. Thank you!Questions?

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