Benoit Nemery, MD, PhD Lung Toxicology Research Unit Occupational Medicine and Pneumology

1. TTS 2006, Kemer-Antalya, 21.04.2006, Round TablePROBLEMS RELATED WITH PNEUMOCONIOSESRecent developments in lung disease caused by mineral dusts Benoit Nemery, MD, PhD Lung Toxicology Research Unit Occupational Medicine and Pneumology K.U.Leuven – Belgium ben.nemery@med.kuleuven.be

2. Effects of exposure to particles • Effects depend on • Dose and site of deposition + clearance • Type of particles • Mechanism of action

3. vair +++ impaction > 5 µm ++ mucociliary escalator sedimentation 1 - 5 µm + Lymph node diffusion < 0.2 µm slow clearance 0 Pleura Particle deposition & clearance

4. toxicallergiccancer rhinitis rhinitis sino-nasal ca. sinusitis sinusitis tracheo- bronchitis asthma COPD broncho- bronchiolitis bronchiolitis pulmonary ca. pneumonitis alveolitis/ pneumoconiosis pneumonitis emphysema fibrosis pleuritis/plaques mesothelioma Pleura

5. Type of particles • Inorganic (mineral) particles • Organic particles • pesticides, therapeutic agents, ... • Particles of biological origin

6. Mineral dusts • Si • coal • fibres (incl. asbestos) • metallic dusts • combustion (fly ash) • other mineral dusts (acids, bases, salts) • PNOC “Particulates Not Otherwise Classified” [“inert dusts”, “nuisance dusts”]

7. Pneumoconiosis • Fibrotic disease of the lung parenchyma (focal or diffuse) caused by accumulation of mineral dust or fibres • silicosis • asbestosis • coal worker’s pneumoconiosis • other pneumoconioses • talcosis • ...

8. Mineral pneumoconioses “intrinsic” toxicity ? x Susceptibility Cumulative Dose

9. Silicosis • Caused by free crystalline SiO2 (quartz, …) • mining, quarrying, tunnelling • stone cutting, polishing, cleaning • sandblasting • abrasive & scouring powders • foundries • ceramics, refractory bricks, enamels • construction, demolition

10. t° “no” silicosis SiO2 • SiO2 = silicon dioxide (“silica”) • free silica: SiO2 • crystalline: quartz, cristobalite, tridymite silicosis • amorphous : diatomite (Kieselgur), vitreous SiO2 • combined silica: silicates SiO2 + cations (Na, Mg, Al, …) or anions (F, Cl) e.g. talc = Mg3Si4O10(OH)2, kaolin = Al2O3SiO2H2O often: contamination by free SiO2 (+ to +++) X

11. OH. Fubini B, Hubbard A. Free Rad Biol Med, 2003, 34, 1507-16 Freshly fractured > aged silica

12. Fubini B, Hubbard A. Free Rad Biol Med, 2003, 34, 1507-16 → OH.

13. Fubini B, Hubbard A. Free Rad Biol Med, 2003, 34, 1507-16

14. Acute silicosis • Alveolar proteinosis, silico-lipoproteinosis • intense exposure to very fine & freshly fractured silica particles (sandblasting, silica flour) • within weeks to months • diffuse ground glass appearance • DIP, PAS positive material in alveoli, few or no silicotic nodules • typical BAL liquid (milky) DD endogenous lipoid pneumonia • poor prognosis (whole-lung lavage?)

15. Silicosis • Chronic simple silicosis • discrete silicotic hyaline nodules in lung • little or no functional consequences • may progress, sometimes rapidly (“accelerated silicosis”), even after cessation of exposure, to • Complicated silicosis (Progressive Massive Fibrosis = PMF) • confluent noduli (> 1 cm) • often + emphysematous changes • evolution to cor pulmonale

16. Silicosis • Involvement of hilar/mediastinal lymph nodes • enlargement + egg shell calcifications • may be early (sole) manifestation of silicosis • DD other causes of hilar lymphadenopathy (sarcoidosis, lymphoma, …) • possible pathogenic role in PMF (impaired lung clearance) • possible complications: broncholithiasis, broncho-oesophageal fistula, left laryngeal palsy

18. Mediastinoscopy: lymph node

19. Complications of silicosis • Tuberculosis • Bronchopulmonary cancer (IARC group 1) • Autoimmune disease • Systemic sclerosis ((Erasmus syndrome)) • Rheumatoid arthritis ((Caplan syndrome)) • Lupus erythematosus • Renal disease ! Also without pulmonary silicosis

20. Talc • Mg3Si4O10(OH)2 + varying proportions of impurities, incl. quartz & tremolite • talc pneumoconiosis • talco-silicosis, talco-asbestosis • talcosis: interstitial lung disease, possibly with granulomas

21. Case (B.L.) • Female, 62 y, nonsmoker, housewife • diagnosis of sarcoidosis (?) but: open lung biopsy: crystals in areas of fibrosis • worked from 14-18 y in factory making rubber hoses; operator of machine injecting talc Gysbrechts et al. ERJ, 1998, 11, 1412-5

22. 100 µm 5 µm Case (B.L.) “impure talc” Gysbrechts et al., 1998

23. Coal dust • “Coal worker’s pneumoconiosis” (CWP) • distinct from silicosis “coal macule” ≠ silicotic nodule but often + free crystalline silica → “anthracosilicosis” • many similarities between silicosis and CWP • clinical course • radiology (simple / PMF) • pulmonary function (→ emphysema) • risk of TB

24. Asbestosis • Fibrosis of the lung parenchyma • High cumulative exposure (> 25 fibre.years) • Rare

25. Asbestos-induced lesions Past exposure Specificity • asbestosis +++ + • bronchopulmonary cancer ++? - • pleural effusion ++ - • diffuse pleural thickening ++ -/+ • rounded atelectasis ++ + • pleural plaques + +++ • malignant mesothelioma + +++

26. Other pneumoconioses • siderosis & welders’ pneumoconiosis • dental technician’s pneumoconiosis • aluminium • “aluminosis” is rare and controversial • granulomatous reactions (DD sarcoidosis) • Sn (stannosis), Ba (barytosis) • Ce (rare earths) • SiC (carborundum)

27. Mixed-dust pneumoconioses Honma K. et al. Proposed criteria for mixed-dust pneumoconiosis: definition, descriptions, and guidelines for pathologic diagnosis and clinical correlation. Human Pathology, 2004, 35, 1515-23 • Dust macules, with or without silicotic nodules + history of exposure to “mixed” dusts (= crystalline SiO2 + nonfibrous silicates)

28. Mixed-dust pneumoconioses Honma K. et al. Hum Pathol, 2004, 35, 1515-23 • Exclusion of other well-defined pneumoconiosis (silicosis, asbestosis, CWP; welder’s pneumoconiosis, silicate pneumoconiosis, carborundum pneumoconiosis, corundum pneumoconiosis; berylliosis, hard metal disease) • Metal miners, quarry workers, foundry workers, pottery and ceramic workers, stonemasons • Mainly irregular opacities

29. Honma K. et al. Hum Pathol, 2004, 35, 1515-23 Dust macules Silicotic nodule

30. Honma K. et al. Hum Pathol, 2004, 35, 1515-23 Mixed dust fibrosis

31. Honma K. et al. Hum Pathol, 2004, 35, 1515-23 Mixed dust fibrosis

32. Honma K. et al. Hum Pathol, 2004, 35, 1515-23 Mixed dust fibrosis

33. Indium-Tin Oxide (ITO) Homma S. et al. Pulmonary fibrosis in an individual occupationally exposed to inhaled indium-tin oxide. ERJ 2005, 25, 200-4 • Man, 30 y, light smoker (3 cig/d for 3 y) • Exposure for 4 y to ITO dust • Manufacture of flat-panel displays (LCD, plasma screen) • Dry cough and exertional dyspnoea; normal PFT • Chest x-ray: reticulonodular shadows (right upper f)

34. Indium-Tin Oxide (ITO) Homma S. et al. ERJ 2005, 25, 200-4 • CT

35. Homma S. et al. ERJ 2005, 25, 200-4 • VATS

36. Electron probe X-ray microanalysis + SEM with EDX In 61%, Sn 4% In Homma S. et al. ERJ 2005, 25, 200-4

37. Metallic dusts • Some metals (Be, Co) may cause interstitial lung disease without obvious relation to cumulative dust exposure ( other mineral pneumoconioses) • difficult differential diagnosis with other ILD (“idiopathic pulmonary fibrosis”, “sarcoidosis”) • genetic predisposition, immunological sensitisation, poor defense against free-radicals?

38. low “intrinsic” toxicity immune sensitization or “idiosyncrasy” x “Low” Dose Susceptibility ILD due to “hypersensitivity”

39. low “intrinsic” toxicity x immune sensitization “Low” Dose Susceptibility ILD due to “hypersensitivity”

40. Beryllium lung disease • Be used in (light) alloys (aerospace, electronics, dental, …), ceramics, nuclear weapons, … • granulomatous lung disease (= sarcoidosis) • cellular immune response to Be (diagnosis: Be Lymphocyte Proliferation Test) • high susceptibility if HLA-DPß1 glu69 • other metals: Zr, Al, Ti?

41. low “intrinsic” toxicity x “idiosyncrasy” “Low” Dose Susceptibility ILD due to “hypersensitivity”

42. Hard metal / cobalt • sintered hard metal: WC (90%) + Co(5-10%) + … diamond tools: microdiamonds + Co • used for machining, cutting, drilling, polishing, …

43. HARD METAL Cobalt News 96/4

44. DIAMOND TOOLS Hoge Raad voor Diamant Cobalt News 93/2

45. Hard metal / cobalt lung • in workers making or repairing hard metal tools or using diamond tools • giant cell interstitial pneumonitis (GIP) diffuse fibrosis • mechanism? • also “cobalt-asthma” in Co workers

46. F - 24 y - NS diamond polisher TLC 49% pred DLco 27% pred 1991 1986

47. GIP - cobalt lung BAL E.K. Verbeken

48. Thank you for your attention ben.nemery@med.kuleuven.be