- To develop improved ways of monitoring exposure to isocyanates
- To examine the role of genetic polymorphism in isocyanate-metabolizing enzymes indetermining individual susceptibility to developing bronchial asthma
- To develop biomarkers (protein, haemoglobin, DNA adducts, cytogenetic changes) which can be used in assessing the relative hazards to allergic, mutagenic and/or carcinogenic diseases after exposure to isocyanates.
Isocyanates (with the general chemical formula R-(N=C=O)n are highly reactive industrial chemicals, widely used and produced by European chemical industries. Their principal use is in the manufacture of polyurethane foams, elastomers, adhesives, paints, and coatings. Workers who are exposed to isocyanates have a risk of developing chronic airway disorder, especially bronchial asthma. The incidence of occupational asthma in isocyanate exposed workers depends on the degree of exposure, and 5 -10 % of the exposed workers are affected. Isocyanates can react with proteins and form immunogenic protein complexes causing allergenic responses. Isocyanates can also react with water to form corresponding amines. Acetylated (di)amines are found in urine after occupational exposure to (di)isocyanates. Aromatic amines may also react with proteins and with DNA, after having been oxidised by the proper cytochrome P450 isozyme(s) and acetylated by N-acetyl transferase(s). Oxidation and conjugation reactions can thus play a role in determining the availability of activated amine metabolites. About 50% of Caucasians are slow N-acetylators, which could be an important determinant of individual responses to isocyanate exposure. It is unclear, however, to what extent the observed respiratory effects of isocyanates are caused by the parent compound, or by conjugates formed upon reaction with biological molecules. Isocyanates can also react with glutathione. Two glutathione S-transferases (GSTs), important enzymes in the conjugation of a number of electrophilic substances, are polymorphic. A large proportion of Caucasians lack both alleles of one or both of the GST genes. It is to be examined whether people with a slow N-acetylation associated genotype or with homozygous deletion of one or both of the GST genes have an increased susceptibility for diisocyanate-induced asthma.
One difficulty in measuring exposure to allergenic chemicals, such as isocyanates, is that the relevant exposure is often low and sometimes only of short duration. Adduct-formation with plasma proteins and with haemoglobin would allow integration of the dose over time, providing a better average of the daily exposure, and the ability to detect exposure some time after its occurrence.