3 epoxy-resin hardeners, 4,4'-diaminodiphenyl ether (DDE), 4,4'-diaminodiphenylmethane (DDM), and 4,4'-diaminodiphenylsulfone (DDS), and their N-acetyl and N,N'-diacetyl derivatives were examined for their mutagenicity using Salmonella typhimurium TA98 and TA100 as the tester stains and an S9 mix containing a rat-liver 9000 X g supernatant fraction as the metabolic activation system. DDE and DDM were mutagenic towards TA98 and TA100 in the presence of S9 mix while DDS exhibited no significant mutagenic activity towards these tester strains. These epoxy-resin hardeners were metabolized in vivo and their N-acetyl and N,N'-diacetyl metabolites were found in the urine. Among these acetyl metabolites, only N-acetyl-DDE was found to be mutagenic towards TA98 and TA100 in the presence of S9 mix. None of these acetyl metabolites exhibited significant mutagenic activity towards these tester strains in the absence of S9 mix.
"N-acetyl-MDA is a major metabolite in urine samples of workers exposed to MDA (Robert et al., 1995; Schutze et al., 1995) or to MDI (Sepai et al., 1995; Dalene et al., 1996). Both the N-acetyl and the N,N'diacetyl-MDA metabolites have been identified in urine following administration of MDA (Tanaka et al., 1985) or MDI (Gledhill et al., 2005) to rats. Whereas N-acetyl-MDA represents more than half of all MDA metabolites in human urine in MDA-exposed workers, the N,N'diacetyl-MDA metabolite represents less than 3%. "
[Show abstract][Hide abstract] ABSTRACT: 4,4'-Methylenedianiline (MDA) is widely used in the manufacturing of polyurethane foam, epoxy resins, and polymers. Exposure to MDA induces liver damage in humans and rats. MDA undergoes N-acetylation catalyzed by N-acetyltransferase 1 (NAT1) and 2 (NAT2) in the liver. Both human and rat NAT2 are polymorphic, and human NAT2 genetic polymorphism modifies the frequency and/or severity of drug and xenobiotic toxicity in human populations. Recombinant expression of rat Nats in Escherichia coli showed that MDA was acetylated by both recombinant rat Nat1 and Nat2 and was catalyzed at substantially higher rates by rapid acetylator Nat2 compared with slow acetylator Nat2. Rapid acetylator F344 rat liver cytosols catalyzed the N-acetylation of MDA at significantly higher rates than those from slow acetylator Wistar-Kyoto (WKY) inbred rats. To test the effect of NAT2 genetic polymorphism on hepatotoxicity from acute MDA exposure, we compared hepatotoxicity in rapid (F344) and slow (WKY) Nat2 acetylator inbred rats that were administered MDA. Based on the results of dose-response studies ranging up to 150 mg/kg MDA administered by intragastric gavage, the effect of a moderately hepatotoxic dose (37.5 mg/kg) was compared in rapid versus slow acetylator rats. Plasma alanine transaminase enzyme activities were approximately 5-fold higher (p < 0.05) in rapid versus slow acetylator rats after MDA treatment, and necrotizing hepatitis with portal damage consisting of bile ductular necrosis, portal expansion, and inflammation was clearly more prominent. These results suggest that acetylator phenotype is an important factor for susceptibility toward MDA hepatotoxicity.
Journal of Pharmacology and Experimental Therapeutics 01/2006; 316(1):289-94. DOI:10.1124/jpet.105.093302 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A new specific and sensitive method has been used to monitor workers from five different factories where 4,4'-diaminodiphenylmethane (methylene dianiline) (DDM) was being used. The isolation and identification of an N-acetyl conjugate of DDM, a major metabolite of DDM found in human urine, is reported for the first time. The use of this biological monitoring method will allow the assessment of the absorption of DDM and help in monitoring improvements in work practices, particularly where exposure may occur through pathways other than inhalation.
British journal of industrial medicine 10/1986; 43(9):620-5. DOI:10.1136/oem.43.9.620
[Show abstract][Hide abstract] ABSTRACT: A sensitive and specific gas chromatographic/mass spectrometric assay is described for the determination of N-acetyl 4,4'-methylene dianiline (N-acetyl MDA) and N-acetyl 4,4'-methylene-bis(2-chloroaniline) (N-acetyl MbOCA) in urine. The method is based on the solvent extraction of the compounds together with deuterium-labelled internal standards, the compounds being separated and detected by capillary gas chromatography/mass spectrometry as their pentafluoropropyl derivatives. The method has been applied to the detection of N-acetyl MbOCA and N-acetyl MDA in the urine of workers occupationally exposed to MbOCA and MDA. The results show that whilst N-acetyl MbOCA is a relatively minor urinary metabolite a significant proportion of MDA is excreted as the N-acetylated compound.
Biomedical & environmental mass spectrometry 09/1988; 17(3):161-7. DOI:10.1002/bms.1200170303
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