Cefic-lri Programme | European Chemical Industry Council

IRTA2-002-UUIR: Heterogeneity in Response to Iso-Cyanate Exposure in the Work Environment

Principal Investigator

Prof. Dr. Dirk Heederik
Institute for Risk Assessment Sciences
University of Utrecht
PO Box 80176
3508 TD Utrecht
The Netherlands
Tel +31 30 253 9480
Fax +31 30 253 5077


Dr. G. Doekes – IRAS – University Utrecht
Dr. R. Pieters – IRAS – University Utrecht
Dr. G. de Meer – IRAS – University Utrecht
Prof J. W. J. Lammers – Heart and Lung Institute – University Medical Centre – Utrecht
Dr L. Preller – TNO Chemistry – Zeist
Ms. A. Pronk – TNO Chemistry – Zeist
Dr. M. Raulf-Heimsoth – Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin


Di-isocyanates are in many countries a major cause of occupational asthma. However, few recent studies are available in which exposure to isocyanates has been measured and related to respiratory disease risk. Thus, information about exposure response relationships is extremely limited. This study comprises of a cross-sectional survey among approximately 600 isocyanate (IC) workers. All participants completed a questionnaire and blood was drawn for a serological analysis in which the presence of specific antibodies against di-isocyanates was established. In a second phase, a more detailed medical survey was conducted which included measurement of lung function, bronchial hyper-responsiveness and exhaled NO. Exposure to isocyanates was monitored in a large scale hygiene study in which 566 personal task based inhalation samples were collected. Personal exposure was estimated by combining results from task-based personal inhalation exposure assessment and task activity information to study associations with respiratory symptoms in 581 workers. The exposure measurements showed that hexamethylene diisocyanate (HDI) oligomers were dominant in frequency of occurrence and showed the highest exposure levels in different populations of spray painters. Many workers had respiratory symptoms, of which a considerable proportion was work-related. The prevalence of sensitization to isocyanates (specific IgE) was low (up to 4.2% in spray painters) suggesting that at most, specific IgE plays a role in a minority of individuals with symptoms. The prevalence of specific IgG was higher (2-50%) and strongly associated with exposure. Isolated peripheral blood mononuclear cells, from each individual included in the medical survey, were stimulated with isocyanates and MCP-1 development was measured. This test has been proposed as an alternative test to establish isocyanate sensitization. Only highly variable results were obtained, and no clear associations with exposure or disease endpoints have been observed.

Sensitization, symptoms and bronchial hyper-responsiveness were independently associated with estimated exposure. High exposed individuals also had a lower lung function. Associations found in this study indicate that isocyanate oligomers can induce respiratory health effects at levels commonly found in this industry. It is important to note that several of the endpoints seemed independently associated with exposure. The associations between symptoms bronchial hyper-responsiveness, and serological parameters, was clearly weaker that what is described for high molecular sensitizers. This might point to several independent responses as a result of exposure to isocyanates. Besides asthma chronic obstruction may also be involved. Bio-banked information will be used for further genetic studies in the framework of the EU multi-centre GABRIEL project on the genetics of asthma.

Related Publications

A Pronk, A Wisnewski, M Raulf-Heimsoth, L Preller, D Heederik, IM Wouters, G Doekes, A comparison of IgE and IgG ImmunoCAP® and enzyme immunoassays with various hexamethylene diisocyanate-albumin conjugates, submitted.

A Pronk, L Preller, G Doekes, I M Wouters, J Rooyackers, J-W Lammers, D Heederik, Bronchial hyperresponsiveness and lung function are associated with measured isocyanate exposure in spray painters, submitted.

A Pronk, L Preller, M Raulf-Heimsoth, IC Jonkers, JW Lammers, IM Wouters, G Doekes, AV Wisnewski, D Heederik, Respiratory symptoms, sensitization, and exposure response relationships in spray painters exposed to isocyanates, American Journal of Respiratory and Critical Care Medicine 2007, 176, 1090-1097.

A Pronk, Isocyanate exposure and respiratory health effects in the spray painting industry, Thesis, Utrecht University, Utrecht, November, 2007.

A Pronk, F Yu, J Vlaanderen, E Tielemans, L Preller, I Bobeldijk, JA Deddens, U Latza, X Baur, D Heederik, Dermal, inhalation, and internal exposure to 1,6-HDI and its oligomers in car body repair shop workers and industrial spray paintersOccupational & Environmental Medicine, 2006, 63, 624-631.

A Pronk, E Tielemans, G Skarping, I Bobeldijk, J van Hemmen, D Heederik, L Preller, Inhalation exposure to isocyanates of car body repair shop workers and industrial spray paintersAnnals of Occupational Hygiene 2006, 50, 1-14.


Timeline: August 2004 > January 2006

LRI funding: € 150 000

Cefic-Lri Programme Responsible Care

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