title: Concentration-dependence of biomarkers of exposure of methylenediphenyl-diisocyanate following acute inhalation exposure of rats.
abstract: Rats were nose-only exposed for 6 h to polymeric methylenediphenyl-diisocyanate (pMDI). Concentrations varied from 0.12 to 12.7 mg/m(3) using a highly respirable aerosol. In regard to the concentration of the monomeric fraction of MDI contained in pMDI, the lowest concentration was in the range of the current workplace limit of MDI which is 0.05 mg/m(3). Biomarkers of exposure were determined in hydrolyzed urine (collection started after cessation of exposure for approximately 18 h; acid hydrolysis) and hydrolyzed hemoglobin (collection of blood approximately 20 h after cessation of exposure; alkaline hydrolysis). The determination revealed two-order of magnitudes higher yields of the biomarkers in urine when compared to hemoglobin. The concentration of analytes from the respective biological matrix was highly correlated with the airborne concentration of pMDI whilst their yields exhibited a reciprocal relationship to the airborne concentration of pMDI. A linear relationship could only be demonstrated by using a logarithmic transformation of data. With respect to the amount of 4,4'-methylenediphenyldianiline creatinine (MDA/g creatinine) in hydrolyzed urine of rats at an exposure level similar to the current workplace concentration of MDI, this marker of exposure was approximately 10-times lower in rats than predicted for humans. This suggests that the extrapolation of animal data to man as well as from one exposure regimen to another, without taking into consideration the different deposition/retention patterns of vapors (<or=0.05 mg/m(3)) or aerosols of MDI, might be error prone. In summary, taking into account previous and current experimental evidence, these data substantiate further that the formation of MDI-related biomarkers appear to be governed by spontaneously occurring, scavenging reactions at the portal-of-entry. Comparison of MDI with its corresponding amine support that the analytes determined stem from conjugated MDI rather than in vivo hydrolyzed MDI.
authors.affiliation: Department of Toxicology, BAYER HealthCare, Building no 514, 42096, Wuppertal, Germany. juergen.pauluhn.jp@bayer-ag.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
authors.forename: Gabriele
authors.initials: G
authors.lastname: Leng
mesh_terms: D000280:Administration, Inhalation; D000814:Aniline Compounds / Q000097:blood*; D000818:Animals; D015415:Biomarkers / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004784:Environmental Monitoring / Q000379:methods; D006454:Hemoglobins / Q000378:metabolism; D019570:Inhalation Exposure; D007509:Irritants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D017953:Isocyanates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008176:Lung Volume Measurements; D008297:Male; D011140:Polyurethanes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D001559:Benzhydryl Compounds
chemical_list: D000814:Aniline Compounds; D015415:Biomarkers; D006454:Hemoglobins; D007509:Irritants; D017953:Isocyanates; D011140:Polyurethanes; C087867:polymeric 4,4'-diphenylmethane diisocyanate; C009505:4,4'-diaminodiphenylmethane; D001559:Benzhydryl Compounds