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

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

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  • 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. 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. 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. “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. AsbestosSerpentine Amphibole (curly) (needle-like) Chrysotile Amosite Crocidolite Anthophyllite Actinolite Tremolite
  • 6. The 3 Main Commercial Fibers Chrysotile** Amosite Crocidolite
  • 7. Chrysotile
  • 8. Crocidolite
  • 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. 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. 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. Jeffrey Mine, Asbestos, Quebec
  • 13. Asbestos Consumption Today
  • 14. The ‘Magic Mineral’ World’s Fair 1939
  • 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. Toxicity Recognized• 1900s – asbestosis described in UK• 1960 – Wagner’s publication describing mesothelioma in those exposed to asbestos in South Africa
  • 17. Wittenoom CrocidoliteWestern Australia mining townUntil 1966, 6500 men and 500 women Courtesy of Dr. Bruce Robinson, Univ of Perth, Australia
  • 18. Asbestos: Commercial
  • 19. Asbestos: Used in Cigarette Filters 1952-1956
  • 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. In place Asbestos:Exposed Asbestos-cement
  • 22. Asbestos in Buildings: ’50s-’80s
  • 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. • 1,000 tons of asbestos released• Asbestos at increased levels in settled surface dust
  • 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. Vermiculite Shipped around Country Center for Asbestos Related Disease; www.libbyasbestos.org
  • 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. Mesothelioma Increases withResidential Proximity to Naturally- occurring Asbestos Am J Resp Crit Care Med 172(8):1019-1025, 2003
  • 29. Asbestiform Fibers• Discovered due to mesothelioma clusters – Cappadocia, Turkey – erionite – Biancavilla, Italy – fluoro-edenite
  • 30. Erionite in Turkey
  • 31. Why are Asbestos and Asbestiform Fibers Toxic?• Due to both chemistry and shape• Field of ‘fiber toxicology’
  • 32. Toxicity: Chemistry• Iron – generation of ROS (Fenton)• Surface adsorption of proteins• Nonreactivity – permanence in body
  • 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. Mesothelial Cells Exposed to Crocidolite
  • 35. Toxicity in vitro Requires Internalization Am J Respir Cell Mol Biol 23(3):371-8, 2000
  • 36. Asbestos Fibers Damage Chromosomes Am J Pathol 126:343-349, 1987
  • 37. Normal Upper Lobe of Rat Lung Courtesy Dr. Arnold Brody, Tulane Univ Medical School
  • 38. Asbestos Intercepted at the1st Bronchoalveolar Duct Junction (After 1hr of inhalation exposure) Courtesy Dr. Arnold Brody, Tulane Univ Medical School
  • 39. After 5 Hours..Courtesy Dr. Arnold Brody, Tulane Univ Medical School
  • 40. Bronchovascular Bundle/Intralobar Septae: Provide Access to Pleural Space J Appl Physiol. 1990 Jun;68(6):2623-30
  • 41. From Alveolus to Visceral to Parietal Pleura Parietal Visceral
  • 42. Pleural Lymphatics Outlined by Carbon Rib Intercostal space Courtesy of Kurt Albertine, Univ of Utah
  • 43. Lymphatic Stomata in the Parietal Pleura J Thorac Cardiovasc Surg 2000;120:437-447
  • 44. Is there evidence in humans? “Black Spots” Am J Respir Crit Care Med 153:444-449, 1996
  • 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. “Black Spots” nearly Universal in Urban Dwellers Am J Surg Pathol 26(9):1198-1206, 2002 2
  • 47. “Black Spots” do not Overlap with Pleural Plaques Black Spots Pleural Plaques Am J Surg Pathol 26(9):1198-1206, 2002 2
  • 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. Mr. DJ, 57 years old
  • 50. CT scan:“pleural plaques, calcified and non- calcified”
  • 51. After chest pain for 14 months:
  • 52. Other Asbestos-related Pleural Changes
  • 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. 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. 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. 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. Carbon Nanotubes: The New Fiber on the Block• Carbon, not silica, crystalline fiber – Have high tensile strength – Nonreactive
  • 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. 1 day 7 days Carbon Nanotubes No Short (1-5 um) Long(15-50 um) Am J Pathol. 178(6): 2587–2600, 2011.
  • 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. 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. 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. Thank you!Questions?

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