Jack Pepys ( ) Father of Occupational Asthma Professor of Clinical Immunology ( ) Cardiothoracic Institute, Brompton Hospital

Achievements in research in occupational asthma

Western red cedar (Thuja plicata) Toluene diisocyanates

Bronchial biopsy during LAR in a patient with RCA Cells expressing activation markers in bronchial biopsies of patients with RCA, atopic asthma and normals

Reactive airways dysfunction syndrome: persistent asthma syndrome after high- level irritant exposure Brooks et al. Chest 1985;88:

Classification of Occupational asthma Immunologic (with latency) Nonimmunologic (without latency) RADS or irritant- induced asthma HMW compounds Laboratory animals Flour, detergent enzymes IgE-dependentIgE-independent LMW compounds Diisocyanates Red cedar Colophony Chlorine, acetic acid, acids, formalin, spray paints, isocyanates, metam sodium, bleaching agents

Development of diagnostic methods 1713 Ramazzini “What is your occupation?” 1832 Thackrah “…the scientific treatment of a malady requires a knowledge of its nature, and the nature is imperfectly understood without knowledge of the cause” Measurement of airflow obstruction by a “pulmometer” – early version of spirometer 1952 Colldahl BPT using common allergens 1963 Gelfand BPT using LMW agents

1969 Pepys Simulated work exposure testing - safe and reproducible TDI - application of polyurethane varnish without and with TDI activator Development of diagnostic methods Types of asthmatic reaction

Development of diagnostic methods Malo et al - closed circuit for exposure tests, providing a steady level of exposure Flour

Serial monitoring of PEF in the diagnosis of OA Burge, Eur Respir J 1982

Use of induced sputum and measurement of exhaled nitric oxide in the diagnosis of OA Eosinophils in sputum before and during late asthmatic reaction Exhaled nitric acid before and at 6 hr after methacholine challenge; before, 6 and 24 hrs after plicatic acid challenge in patients who had a positive late reaction

Natural history: Follow up studies of OA patients after removal from exposure Agent N Duration of FU (yrs) Symptomatic (%) Year Red cedar Red cedar Colophony Snow crab Snow crab Isocyanates 50 > Isocyanates Various 28 4 –

Diagnosis > Ceased exposure PC 20 Years since diagnosis PC 20 of patients with red cedar asthma

Macrophages Lymphocytes Neutrophils Eosinophils Epithelial Cells Degenerated Cells Cellular content of BAL of patients with red cedar asthma on follow up * * Chan-Yeung et al. Clinical Allergy 1988

Year in programme % Sensitization Occupational rhinoconjunctivitis Occupational asthma Prospective study of apprentices of animal facilities (n = 417) Gautrin et al AJRCCM: 2001

Determinants of sensitization and OA in apprentices exposed to laboratory animals Determinants OR (95% CI) Sensitization Atopy 2.2 ( ) Resp symptoms during pollen season 5.2 ( ) > 53 hours of exposure to rodents 2.5 ( ) Occupational asthma Atopy to pets 4.1 ( ) PC 20 <32 mg/ml 2.5 ( ) High FEV ( ) Gautrin et al ERJ 2002

Malo 2003 Natural History of Occupational Asthma

Prevalence of occupational asthma by types of agent AgentsPrevalence (%) Platinum refinery54 (South Africa) Colophony22 (UK) Various isocyanates20 (Canada) Isocyanates (production)8.3 (US) Spiramycin19 (Canada) Western red cedar 5.0 (Canada)

Attributable risk (AR) of work exposure for asthma by source of data AR Population-based studies 15 (2-20) Medical practice data 9 (2-33) Surveillance or registry data 4 (2-17) Medicolegal data 5 (3-8) Overall Median 10 (2-45) Blanc and Toren 1999

Exposure-response relationships SubstanceLowest effective dose Flour1-2.4 mg/m 3 Fungal amylase0.25 ng/m 3 Red cedar dust 1 mg/m 3 Natural rubber latex0.6 ng/m 3 Cow dander1-29 ug/g dust Rat urine0.1 – 68 u/m 3 Acid anhydride - TMA0.82 mg/m 3 Isocyanates5-10 ppb Baur et al. Clin Exp Allergy 1998

Genetic factors in occupational asthma

Accepted claims for diisocyanate-induced and other types of OA in Ontario, Tarlo and Liss 2002 Annual incidence of incident reports and allergy clinic visits of hospital staff relating to perceived NRL allergy Prevention of OA

Structure of the occupational agent Some agents are potent respiratory sensitizers: HMW – those with enzymatic activity eg. detergent enzymes LMW compounds – those with N=C=O eg. isocyanates