Critical analysis of biomonitoring endpoints for measuring exposure to polymeric diphenyl-methane-4,4'-diisocyanate (MDI) in rats: a comparison of markers of exposure and markers of effect.
The object of this study was to compare the relative sensitivity of markers of exposure and effects in the lung of rats exposed to polymeric diphenyl-methane-4,4'-diisocyanate (pMDI) aerosol. Rats were repeatedly exposed to 12.9 mg pMDI/m(3) (6 h/day, 5 days/week for 14 days; exposure was from days 0--17 followed by a post-exposure period to day 35). Markers of exposure were determined in bronchoalveolar lavage (BAL), blood (haemoglobin, plasma proteins), and urine on days 1, 4, 11, 18, 21, 28 and 35. Markers of effects were determined at the same time points and focused on changes in BAL constituents. In BAL, a maximum increase of total protein occurred following the first exposure and levelled off subsequently whilst BAL cell-related endpoints increased in a time-dependent manner. The kinetics of formation and elimination of adducts differed appreciably from one dosimeter to another. Whilst haemoglobin adducts were integrated by the cumulative exposures, the incremental yield of adduct formation appeared to be dependent on pulmonary as well as yet unknown erythrocyte-related factors. Plasma protein adducts attained a plateau after 1 week of exposure. MDI-related metabolite levels in urine did not show any time-dependent changes during the entire exposure period and declined rapidly during the post-exposure period. Thus, the kinetics of the fractional loading and clearance of pulmonary and extrapulmonary dosimeters did not parallel each other, nor was there a clear correlation with the markers of effects. In summary, it is concluded that biomonitoring is a powerful tool for the comparative dosimetry of well-defined exposure regimens. However, especially for irritant agents demonstrating portal-of-entry effects, markers related to 'total body burden' may not necessarily predict the absence or presence of local responses occurring within the target organ, namely the lung. In all compartments, dosimeters related to higher oligomers of MDI demonstrated low bioavailability, i.e. their recovery was appreciably lower than expected.
Pauluhn
Jürgen
J
Institute of Toxicology, Bayer AG, 42096 Wuppertal, Germany. juergen.pauluhn.jp@bayer-ag.de
D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001798:Blood Proteins / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004784:Environmental Monitoring / Q000379:methods*; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D017953:Isocyanates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011140:Polyurethanes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011506:Proteins / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors
D000485:Allergens; D015415:Biomarkers; D001798:Blood Proteins; D006454:Hemoglobins; D017953:Isocyanates; D011140:Polyurethanes; D011506:Proteins; C087867:polymeric 4,4'-diphenylmethane diisocyanate