1. Non-RADS Irritant Asthma Paul K. Henneberger, MPH, ScD Division of Respiratory Disease Studies National Institute For Occupational Safety & Health Centers for Disease Control and Prevention 3 rd Jack Pepys Workshop Saturday, May 19, 2007 Montreal, Quebec The findings and conclusions in this presentation have not been formally disseminated by the National Institute for Occupational Safety and Health and should not be construed to represent any agency determination or policy.

2. Outline Selected questions from 2 nd Pepys Workshop statement Background: findings before last Workshop Examples of findings since last Workshop Can we answer selected questions from the 2 nd Workshop? Questions for discussion today

3. Selected questions and goals from the 2 nd Pepys Workshop: Irritant-induced Asthma 43. Are underlying host factors more important in the response to low-level irritant exposures than to massive accidental exposures? 33. Biological markers to identify the effects of irritants on the expression of asthma are needed

4. Background: Irritants, atopy, and asthma Preller 1996 study of pig farmers –Atopy associated with non-allergenic quaternary ammonium compounds (QACs) –Symptoms consistent with asthma were associated with atopy + exposure to QACs Brooks 1998: Pre-existing allergic/atopic status and/or pre-existing asthma were significant contributors to not-so-sudden, irritant-induced asthma

5. Background: Biomarkers studied by Bernard & colleagues Isolated pneumoproteins in serum and used as indicators of lung epithelium damage and permeability SP-A and SP-B: Alveolar surfactant associated proteins A and B CC-16: –Antioxidant 16 kDa cell protein –Small anti-inflammatory protein secreted by non-ciliated bronchiolar Clara cells

6. Study by Bernard & colleagues: Carbonnelle 2002 Studied children and adults who attended indoor chlorinated pool Exposure to chlorine by-products including nitrogen trichloride (NCl 3 ) Findings: –Increases in SP-A and SP-B associated with cumulated pool attendance –Little change in CC-16 levels Conclude: Exposure impacted deep lung

7. Examples of findings since the 2 nd Jack Pepys Workshop 1.Asthma associated with low-level irritants 2.Asthma associated with low-level irritants only in atopic subjects 3.Low-level irritants acting in combination with other agents 4.Biomarkers of irritant exposure

8. Asthma-irritant association Medina-Ramon 2005: asthma associated with bleach use in cleaners Nickmilder & Bernard 2007 –From the International Study of Asthma and Allergies in Childhood (ISAAC) –Subjects: children 13-14 yrs old –For each additional chlorinated pool per 10 5 inhabitants, increase of 2.7% (95% CI 1.9%-3.5%) for ever-asthma

9. Asthma-irritant association: European Community Respiratory Health Survey (ECRHS) farmers Smit 2007 used ECRHS data Hay fever (OR=2.1, 95% CI 1.0-4.4) but not asthma (OR=1.7, 95% CI 0.7-3.9) associated with use of QACs

10. Asthma-irritant association only in atopic subjects: Indoor pools Bernard 2006 study of pool attendance on among 341 children 10-13 yrs old Asthma associated with cumulated pool attendance (CPA) only if child also atopic (total IgE>100 kIU/L) OR=1.8 (95% CI 1.1-2.7) for each 100 hour increase in CPA for atopics

11. QACs as adjuvants without respiratory exposure Larsen 2004 exposed mice by subcutaneous injections to ovalbumin and quaternary ammonium compounds (QACs) Observed IgE adjuvant effect of certain QACs and combinations of QACs

12. Biomarkers: Indoor pool attendance Lagerkvist 2004 –Children who regularly attended indoor pools had significantly lower CC-16 levels –Might be due to Clara cell damage or dysfunction Carraro 2006 –Children who regularly attended pools 1 to 2 hours/week did not have increase in fractional exhaled nitric oxide, suggesting a lack of eosinophilic airway inflammation

13. Can we answer selected questions from the 2 nd Pepys Workshop? 43. Are underlying host factors more important in the response to low-level irritant exposures than to massive accidental exposures? Host factors modified the effect of low-level irritant exposures in some studies 33. Biological markers to identify the effects of irritants on the expression of asthma are needed Biological markers for effects of irritants continue to be explored

14. Questions How do the following risk factors for work-related asthma interact? Work-related irritant exposures Biomarkers (e.g., of epithelial damage) Atopy Work-related allergen exposures Sensitization to workplace allergens Non-work exposures (ambient air pollution, at home)

15. Questions What proportion of work-related asthma is due to low-level irritant exposure: a)alone? b)in the presence of atopy? c)combined with allergen exposure?

16. Questions How do we better understand the combination and temporal sequence of potential risk factors for asthma? Where should we go with biomarkers for irritants? Which ones? How to use?