Analysis of markers of exposure to polymeric methylene-diphenyl diisocyanate (pMDI) in rats: a comparison of dermal and inhalation routes of exposure.
Rats received polymeric methylenediphenyl-diisocyanate (pMDI) or a mixture of methylenediphenyl-4,4'-diamine (4,4'-MDA) and amino-di(aminophenylmethylene)-benzene (3-core MDA) by single inhalation or dermal exposure. The ratio of 4,4'-MDA and 3-core MDA used in this study mirrored that of 4,4'-MDI and 3-core MDI present in pMDI. The yields of the corresponding markers of exposure in hydrolyzed blood (Hb-adducts) and urine were determined. For the inhalation exposure, rats were acutely exposed for a duration of 6 h to 3.7 mg pMDI/m3 and 2.7 mg MDA/m3, respectively. Furthermore, C x t products of approximately 1200 mg pMDI/m3 x h were examined, ranging from 3 h x 6.2 mg/m3, 1.5 h x 12.7 mg/m3, 45-min x 25.1 mg/m3, and 23-min x 58.1 mg/m3. Additional groups of rats received equimolar doses of pMDI and MDA by epicutaneous exposure, i.e., 100 mg pMDI/kg bw, equivalent to approximately 50 mg 4,4'-MDI/kg bw and 34 mg 3-core MDI/kg bw or 79 mg MDA-mixture/kg bw, equivalent to 46 mg 4,4'-MDA/kg bw and 33 mg 3-core-MDA/kg bw. The biomarkers measured in this study suggest that the kind and yield of biomarkers are dependent on the route of exposure and differ markedly for MDI and MDA. This isocyanate appears to undergo reactions specific to the site of first contact (e.g., formation of adducts, conjugates and/or polyureas), suggesting that these markers of 'total body burden' can neither predict the local dose at that site nor does it provide any means to identify the route receiving the most critical dose. Similarly, it appears that the formation of biomarkers is governed by reactions requiring an intact isocyanate group rather than hydrolysis. In contrast, for MDA this type of portal-of-entry specificity was not observed. Moreover, trace amounts of diamines available to dermal contact, with respect to the isocyanate, may cause false-positive readings. Thus, in spite of the recognized advantages of biomonitoring to identify cryptic exposures not readily detected by conventional analytical sampling procedures, in regard to pMDI this technique appears to be potentially biased to overestimate exposure, i.e., results obtained from integrating dosimeters of exposure need to be verified by adequate air monitoring.
Pauluhn
Jürgen
J
Department of Toxicology, BAYER AG, Wuppertal, Germany. juergen.pauluhn.jp@bayer-ag.de
Lewalter
Jürgen
J
D000279:Administration, Cutaneous; D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D005189:False Positive Reactions; D017953:Isocyanates / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism; D008297:Male; D011140:Polyurethanes / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000485:Allergens; D015415:Biomarkers; D017953:Isocyanates; D011140:Polyurethanes; C087867:polymeric 4,4'-diphenylmethane diisocyanate