Objective
To study in the workers exposed to 1,3-butadiene the interindividual variability in the production of haemoglobinbutadiene monoepoxide adducts.
To develop new methods to include in the biomonitoring analysis also adducts generated by butadiene-diepoxide.
The metabolism of 1,3-Butadiene (BD) involves the formation of the more toxic epoxides 1,2-epoxy-3-butene (BMO) and 1,2,3,4-diepoxybutane (DEB). Several drug-metabolising enzymes are involved in this metabolism, including cytochromes P450 2E1 and 2A6, in the formation of epoxides, and glutathione transferases M1 and T1, in the detoxification of the epoxides. The ratio between the activating and the deactivating enzymes are of great importance for the toxicity of BD. Since all the four enzymes mentioned above are polymorphic in humans, large interindividual differences in the formation of toxic metabolites of BD probably exist.
Since this wide interindividual variation of internal exposure and of biomarkers, like haemoglobin adduct, has already been demonstrated, butadiene exposure represent an interesting model situation to investigate the role of pharmacokinetic parameters for individual susceptibility.
In this respect the following studies are proposed, after having build up a cohort of workers exposed to butadiene and controls (environmental exposure), controlled for possibly confounding factors and well characterised as far the exposure is concerned:
1.Measure of mercapturic acid of BD, as indicator of internal dose, and of BMO in the blood;
2. Development of methods to analyse (a) plasma protein adducts of butadiene-monoepoxide, (b) plasma and haemoglobin adduct of butadiene-diepoxide.
3. Determining the genotype of polymorphic enzymes CYP2E1, CYP2A6 and glutathione transferases.
The levels of adducts determined and those of external and internal dose indicators will be correlated between them and with the activity of the above mentioned enzymes using appropriate methods for statistical analysis.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Coordinator
70124 Bari
Italy
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