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

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. Asbestos
Serpentine 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 Crocidolite
Western Australia mining town
Until 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 Workers
Mesothelioma
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 with
Residential 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

32. Why are Asbestos and Asbestiform
Fibers Toxic?
• Due to both chemistry and shape
• Field of ‘fiber toxicology’

33. Toxicity: Chemistry
• Iron – generation of ROS (Fenton)
• Surface adsorption of proteins
• Nonreactivity – permanence in body

34. 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

35. Mesothelial Cells Exposed to
Crocidolite

36. Toxicity in vitro Requires
Internalization
Am J Respir Cell Mol Biol 23(3):371-8, 2000

37. Asbestos Fibers Damage
Chromosomes
Am J Pathol 126:343-349, 1987

38. Normal Upper Lobe of Rat Lung
Courtesy Dr. Arnold Brody, Tulane Univ Medical School

39. Asbestos Intercepted at the
1st Bronchoalveolar Duct Junction
(After 1hr of inhalation exposure)
Courtesy Dr. Arnold Brody, Tulane Univ Medical School

40. After 5 Hours..
Courtesy Dr. Arnold Brody, Tulane Univ Medical School

41. Bronchovascular Bundle/Intralobar Septae:
Provide Access to Pleural Space
J Appl Physiol. 1990 Jun;68(6):2623-30

42. From Alveolus to Visceral to Parietal
Pleura
Parietal Visceral

43. Pleural Lymphatics Outlined by
Carbon
Rib
Intercostal
space
Courtesy of Kurt Albertine, Univ of Utah

44. Lymphatic Stomata in the Parietal
Pleura
J Thorac Cardiovasc Surg 2000;120:437-447

45. Is there evidence in humans?
“Black Spots”
Am J Respir Crit Care Med 153:444-449, 1996

46. Deposition is not Uniform:
“Black Spots” 4.1 fibers/g
0.5 fibers/g
Am J Respir Crit Care Med 153:444-449, 1996

47. “Black Spots” nearly Universal
in Urban Dwellers
Am J Surg Pathol 26(9):1198-1206, 2002
2

48. “Black Spots” do not Overlap
with Pleural Plaques
Black Spots Pleural Plaques
Am J Surg Pathol 26(9):1198-1206, 2002
2

49. 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…

50. Mr. DJ, 57 years old

51. CT scan:
“pleural plaques, calcified and non-
calcified”

52. After chest pain for 14 months:

53. Other Asbestos-related Pleural
Changes

54. 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

55. 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

56. 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

57. 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

58. Carbon Nanotubes:
The New Fiber on the Block
• Carbon, not silica, crystalline fiber
– Have high tensile strength
– Nonreactive

59. 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

60. 1 day 7 days
Carbon
Nanotubes
No
Short
(1-5 um)
Long
(15-50 um) Am J Pathol. 178(6):
2587–2600, 2011.

61. 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

62. 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

63. 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

64. Thank you!
Questions?