title: Development, validation and characterization of an analytical method for the quantification of hydrolysable urinary metabolites and plasma protein adducts of 2,4- and 2,6-toluene diisocyanate, 1,5-naphthalene diisocyanate and 4,4'-methylenediphenyl diisocyanate.
abstract: Occupational exposure to diisocyanates within the plastic industry causes irritation and disorders in the airway. The aim of this study was to develop, validate and characterize a method for the determination of 2,4-toluenediamine (2,4-TDA), 2,6-toluenediamine (2,6-TDA), 1,5-diaminonaphthalene (1,5-NDA) and 4,4'-methylenedianiline (4,4'-MDA) in hydrolysed urine and plasma, and to study the correlation between the plasma and urinary levels of these potential biomarkers of 2,4-toluene diisocyanate (2,4-TDI), 2,6-toluene diisocyanate (2,6-TDI), 1,5-naphthalene diisocyanate (1,5-NDI) and 4,4'-methylenediphenyl diisocyanate (4,4'-MDI), respectively. Samples were hydrolysed with 0.3 M NaOH at 100 degrees C for 24 h. The diamines were extracted, derivatized with pentafluoropropionic acid anhydride, and quantified by selected ion monitoring on gas chromatography-mass spectrometry. The repeatability and reproducibility of the method were 7-18% and 7-19%, respectively. Dialysis experiments showed that the metabolites of 2,4-TDI, 2,6-TDI, 1,5-NDI and 4,4'-MDI in plasma were exclusively protein adducts. No free diamines were found in urine, indicating that all diisocyanate-related metabolites were in a conjugated form. For each diisocyanate-related biomarker, there were strongly significant correlations (p<0.001) between individual levels of metabolites in plasma and urine, with Spearman's rank correlation coefficient (rs) values of 0.74-0.90. The methods presented here will be valuable for the development of biological monitoring methods for diisocyanates.
authors.affiliation: Department of Occupational and Environmental Medicine, Institute of Laboratory Medicine, University Hospital, Lund, Sweden. carl-johan.sennbro@ymed.lu.se
authors.forename: Carl Johan
authors.initials: CJ
authors.lastname: Sennbro
authors.forename: Christian H
authors.initials: CH
authors.lastname: Lindh
authors.forename: Håkan
authors.initials: H
authors.lastname: Tinnerberg
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gustavsson
authors.forename: Margareta
authors.initials: M
authors.lastname: Littorin
authors.forename: Hans
authors.initials: H
authors.lastname: Welinder
authors.forename: Bo A G
authors.initials: BA
authors.lastname: Jönsson
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000652:urine; D003959:Diamines / Q000097:blood / Q000652:urine; D005456:Fluorescent Dyes; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000032:analysis* / Q000378:metabolism; D006868:Hydrolysis; D017953:Isocyanates / Q000032:analysis* / Q000097:blood / Q000378:metabolism / Q000652:urine; D016273:Occupational Exposure / Q000032:analysis*; D010969:Plastics; D014051:Toluene 2,4-Diisocyanate / Q000097:blood / Q000652:urine; D001559:Benzhydryl Compounds
chemical_list: D015415:Biomarkers; D003959:Diamines; D005456:Fluorescent Dyes; D006841:Hydrocarbons, Aromatic; D017953:Isocyanates; D010969:Plastics; D014051:Toluene 2,4-Diisocyanate; C023446:1,5-naphthylene di-isocyanate; C026942:2,6-diisocyanatotoluene; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds