Non-RADS Irritant Asthma

Paul K. Henneberger, MPH, ScDDivision of Respiratory Disease Studies

National Institute For Occupational Safety & HealthCenters for Disease Control and Prevention

3rd Jack Pepys WorkshopSaturday, 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.

Outline

• Selected questions from 2nd Pepys Workshop statement

• Background: findings before last Workshop• Examples of findings since last Workshop • Can we answer selected questions from the

2nd Workshop?• Questions for discussion today

Selected questions and goals from the 2nd 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

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

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

Study by Bernard & colleagues: Carbonnelle 2002

• Studied children and adults who attended indoor chlorinated pool

• Exposure to chlorine by-products including nitrogen trichloride (NCl3)

• Findings:– Increases in SP-A and SP-B associated with

cumulated pool attendance– Little change in CC-16 levels

• Conclude: Exposure impacted deep lung

Examples of findings since the 2nd 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

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

105 inhabitants, increase of 2.7% (95% CI 1.9%-3.5%) for ever-asthma

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

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

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

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

Can we answer selected questions from the 2nd 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

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)

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?

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?