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

Abstract

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.

Analysis of biomarkers in rats and dogs exposed to polymeric methylenediphenyl diisocyanate (pMDI) and its glutathione adduct

“…The choice of strain was based on previous studies with this substance (Pauluhn, 2002a;Pauluhn and Lewalter, 2002;Pauluhn and Leng, 2003). At the commencement of the study, the rats were approximately 2-3 months old and their mean (±S.D.)…”

“…The average calculated exposure dose was 0.14 mg pMDI/kg bw. Atmospheres of pMDI aerosol were generated as described in previous studies (Pauluhn, 2002a;Pauluhn and Lewalter, 2002;Pauluhn and Leng, 2003). Briefly, under dynamic conditions using a digitally controlled Hamilton Microlab M pump and a modified Schlick-nozzle Type 970, form-S 3 (Schlick GmbH, Coburg, Germany).…”

“…A single oral and intraperitoneal dose was also included into the study. The rat was the chosen species based on previous inhalation and topical studies with pMDI and MDA (Pauluhn, 2002a;Pauluhn and Lewalter, 2002;Pauluhn and Leng, 2003).…”

Addendum to 4,4'‐Methylene diphenyl diisocyanate (inhalable fraction)[BAT Value Documentation, 2007]

“…The mechanism for sensitization by MDI has, however, still not been explained. In the rat, a half-life of 5.4 days could be found for the MDI protein adduct, which is twice as high as that for serum albumin in the same species (Pauluhn 2002). In humans, the half-life for serum albumin is 10 to 20 days (Margen and Tarver 1956).…”

“…A very small amount of MDI also binds to hemoglobin, so that MDI-Hb adducts are detectable in the erythrocytes of workers exposed to MDI (Schütze et al 1995;Sepai et al 1995) as well as in those of rats (Pauluhn 2002;Sabbioni et al 2000).…”