Biomonitoring of workers exposed to 4,4'-methylenedianiline or 4,4'-methylenediphenyl diisocyanate

Abstract

4,4'-Methylenedianiline (MDA) and 4,4'-methylenediphenyl diisocyanate (MDI) are important intermediates in the production of polyurethanes. In order to biomonitor people exposed to low levels of MDA or MDI we have developed sensitive methods to measure hemoglobin (Hb) adducts and urine metabolites. Adducts and metabolites from 33 workers exposed to MDA and 27 workers exposed to MDI were analyzed by gas chromatography-mass spectrometry after hydrolysis, extraction and derivatization with heptafluorobutyric anhydride. Hb adducts of MDA were detected in 31 out of the 33 MDA workers and both MDA and N-acetyl-MDA (AcMDA) were found in 20 of these individuals. The detection limit for MDA was 20 fmol and for AcMDA 100 fmol/sample, which correspond to an absolute detection limit of approximately 1 fmol MDA and 5 fmol AcMDA, respectively. In the urine of workers exposed to MDA both MDA and AcMDA were found in all samples, with the exception of five where only MDA was detected. Acid hydrolysis of the urine samples yielded an approximately 3-fold higher concentration of MDA than the sum of MDA and AcMDA found after base hydrolysis. MDA but not AcMDA found in urine and in Hb correlate well, except for three outliers. In one workers the Hb adduct level of MDA was very low compared to the urine levels. Two workers had very high levels of MDA as Hb adducts but very low levels as urine metabolites. The former case indicates that the workers were recently exposed to higher levels of MDA. The latter case suggests a relatively low recent exposure. The air levels of MDA, monitored using personal air monitors, were below the detection limit. It was possible, however, to determine exposure to MDA for all workers with the methods presented in this publication. Workers exposed exclusively to MDI were studied. Exposure levels, as monitored using personal air samplers, were below the detection limit of 3 micrograms/m3, with the exception of three individuals. In 10 of the MDI workers, hydrolyzable Hb adducts of MDA (57-219 fmol/g Hb) were found. Except for four subjects, the presence of MDA (0.007-0.14 nmol/l) and AcMDA (0.08-3 nmol/l) was detected in all urine samples after base treatment. Following acid hydrolysis of the urine, higher levels of MDA (0.7-10 nmol/l) were found than the sum of free MDA and AcMDA. According to the present data, it was possible to detect exposure to MDI in a greater number of individuals by analyzing urinary metabolites than by measuring Hb adducts or air monitoring.

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].…”

“…So konnten Persson et al [1993] TDA im Urin von Arbeitern nachweisen, die gegenüber TDI-Konzentrationen im Bereich von 0,4-4 µg/m 3 exponiert waren. Entsprechend ließ sich MDA im Urin MDI-exponierter Arbeiter bestimmen, bei denen die Ergebnisse der Luftmessungen unterhalb der jeweiligen Nachweisgrenze von 20-30 µg/m 3 lagen [Kääriä et al 2001 b;Schütze et al 1995].…”

4,4′‐Methylene diphenyl diisocyanate (MDI) [101‐68‐8] and “polymeric” MDI (PMDI) [9016‐87‐9] [MAK Value Documentation, 2008]

“…Exposure to MDI can be demonstrated by determining MDA in hydrolysed urine or hydrolysed protein (plasma, erythrocytes) Kääriä et al 2001;Schütze et al 1995;Sennbro et al 2006;Skarping et al 1994Skarping et al , 1995Skarping et al , 1996. Hydrolysis is necessary to dissolve the binding of MDI to biological materials, for example protein.…”

Albumin adducts and urinary metabolites resulting from occupational exposure to 1,5-naphthalene diisocyanate

“…The urinary levels of the corresponding aromatic amines obtained after acid hydrolysis were determined for MDI [19,20,29,30], TDI [31] and NDI [32][33][34]. Hemoglobin adducts of MDI were found in humans [19] and in rats [35]. 1,5-Naphthalenediamine (NDA) was found in plasma after base hydrolysis [32].…”