Albumin adducts, hemoglobin adducts and urinary metabolites in workers exposed to 4,4′-methylenediphenyl diisocyanate

Abstract

4,4'-Methylenediphenyl diisocyanate (MDI) is the most widely used isocyanate in the manufacture of polyurethanes. MDI has been implicated as one of the major causes of occupational asthma. Hydrolysis of MDI can yield 4,4'-methylenedianiline (MDA), which is a suspected human carcinogen. Thus the need to monitor occupational exposure to MDI is of great significance. The use of air monitors alone has been found to be insufficient and there is a need for sensitive markers of recent and long-term exposure. We obtained biological samples from a group of 20 workers exposed to MDI vapor during the manufacture of polyurethane products. The air levels of MDI in the factory were measured using personal, work room and work station monitors. In most cases the levels were below detection limits. The blood and urine samples were analyzed for the presence of adducts and metabolites using GC-MS methods. Urinary base-extractable metabolites were found above control levels in 15 of the 20 workers and ranged from 0.035 to 0.83 pmol MDA/ml. The level of the acetylated metabolite N'-acetyl-4,4'-methylenedianiline (AcMDA) ranged from 0.13 to 7.61 pmol/ml. The amount of MDA released after acid hydrolysis was on average 6.5 times higher than the amount of free MDA and AcMDA present in urine. MDA was detected as a hemoglobin (Hb) adduct in all of the 20 subjects. The level ranged from 70 to 710 fmol/g Hb. In one individual the Hb adduct of AcMDA was detected. This is the first time a Hb adduct of AcMDA has been detected after occupational exposure to MDI. This is a further piece of evidence for the biological availability of the suspected human carcinogen MDA from in vivo hydrolysis of MDI. Plasma albumin conjugates of MDI can cause the onset of respiratory disorders in both man and animal models. Thus we investigated the presence of plasma protein adducts. The plasma MDA levels ranged from 0.25 to 5.4 pmol/ml. Up to 120 fmol/mg were found to be covalently bound to albumin.

Hexamethylendiisocyanat, 2,4‐Toluylendiisocyanat, 2,6‐Toluylendiisocyanat, Isophorondiisocyanat und Diphenylmethan‐4,4′‐diisocyanat – Bestimmung von Hexamethylendiamin, 2,4‐Toluylendiamin, 2,6‐Toluylendiamin, Isophorondiamin und 4,4′‐Diaminodiphenylmethan in Urin mittels Gaschromatographie‐Massenspektrometrie [Biomonitoring Methods in German language, 2017]

“…Die Halbwertszeit der TDI-Addukt-Fragmente in Plasma ist deutlich länger und wird mit 10 und 21 Tagen angegeben [Lind et al 1996[Lind et al , 1997. Nach MDI-Belastung wurde eine bis zu vierstündige Halbwertszeit für die Ausscheidung der MDI-Addukt-Fragmente im Urin beschrieben [Schütze et al 1995;Sepai et al 1995]. Die mittlere Halbwertszeit für die HDI-Addukt-Fragmente im Urin beträgt 2,5 h [Brorson et al 1990;Greim 1996;Tinnerberg et al 1995] und für die IPDI-Addukt-Fragmente im Urin 2,8 h [Tinnerberg et al 1995].…”

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

“…Most of the MDI is eliminated as conjugate and with the urine. After hydrolysis of the urine, the MDI conjugates can be detected as MDA (Schütze et al 1995;Sepai et al 1995).…”

“…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).…”

Review of the occupational exposure to isocyanates: Mechanisms of action

“…Incidentally, it is known that TDI can be easily to be hydrolyzed, and changed to toluene diamine (TDA), although Sabbioni et al 11) also concluded that conjugation is the predominant reaction after TDI exposure in rats, and that TDA is not a primary in vivo reaction product under the conditions they tested. In rats, hemoglobin (Hb) adducts were found to correlate with the administered dose of either MDA (4,4'-methylenedianiline) or MDI [11][12][13] .…”