Disease relevance of 4,4'-METHYLENEBIS(2-CHLOROANILINE)

• In animal studies, MDA has induced thyroid and liver neoplasms while exposure to MOCA resulted in a variety of tumors including those of the liver, mammary gland and bladder [1].
• The tissue distribution kinetics and elimination of 4,4'-methylene bis(2-chloroaniline) (MBOCA) in rats was studied after a single dose of [14C]MBOCA (0.49 mg/kg body weight, i.v.). The highest concentrations of radioactivity were in the small intestine, liver, adipose, lung, kidney, skin, and adrenals [2].
• One MOCA dog, sacrificed after 8.3 years on test was found to have a papillary transitional cell carcinoma of the urinary bladder [3].
• The hepatocellular carcinoma incidence in rats fed a protein-deficient diet with 500 ppm MOCA was 18 percent, whereas in rats fed a protein-adequate diet with the same MOCA concentration this incidence was only 4 percent [4].
• Of four MOCA dogs sacrificed after 9.0 years on test, three were found to have papillary transitional cell carcinomas of the urinary bladder and one had a combined transitional cell carcinoma and adenocarcinoma of the urethra [3].

High impact information on 4,4'-METHYLENEBIS(2-CHLOROANILINE)

• These data indicate that specific inducible and constitutive cytochromes P-450 are involved in the metabolic activation and detoxification of the carcinogens ABP and MOCA [5].
• 4-Aminobiphenyl and 4,4'-methylenebis-2-chloroaniline were both weakly genotoxic, but no clear correlation was seen with acetylator phenotype [6].
• Neoplastic transformation and DNA-binding of 4,4'-methylenebis(2-chloroaniline) in SV40-immortalized human uroepithelial cell lines [7].
• Thus, the aim of this study was to detect and quantify DNA adducts in the urinary bladder of dogs exposed to MOCA and thereby provide data that could be useful for risk assessment after human exposure to MOCA [8].
• 4,4'-Methylenebis(2-chloroaniline) (MOCA) has considerable human occupational exposure and it induces urinary bladder tumors in the dog, a species that has been often used as a model for aromatic amine-induced urinary bladder carcinogenesis in humans [8].

Biological context of 4,4'-METHYLENEBIS(2-CHLOROANILINE)

• Anti-P450 3A4 inhibited (up to 80% of) the microsomal transformation of MOCA to a product genotoxic as judged by bacterial SOS response [9].
• Initial studies using the 14C-ring-labeled MOCA showed that 24 hr after a single IP dosage to rats (3.74 mumole/kg), 0.08% of the administered dose was adducted to the Hb, and base hydrolysis liberated 38% of the bound radioactivity [10].
• Hydroxylation of 4,4'-methylenebis(2-chloroaniline) by canine, guinea pig, and rat liver microsomes [11].
• MOCA exposure caused a dose-dependent inhibition of natural immune activities (i.e. natural killer, NK and natural P815 killer, NPK) and mitogen-stimulated proliferation of T- and B-lymphocytes, with 50% inhibition (IC50) of splenic-cell activities occurring at 145, 85, 21 and 31 microM, respectively [12].
• Kinetics of tissue distribution and elimination of 4,4'-methylene bis(2-chloroaniline) in rats [2].

Anatomical context of 4,4'-METHYLENEBIS(2-CHLOROANILINE)

• Human liver microsomes were fractionated and MOCA N-oxidation activity was monitored through the procedure [9].
• N-Hydroxylation of MOCA occurred at a rate of 335 +/- 119 pmol/min/mg rat microsomal protein (n = 3) versus 230 or 765 (n = 2) with microsomes from humans; the product was identified by isotopic dilution for both species [13].
• MOCA-DNA adducts have also been detected in vivo in treated rats and in exfoliated urothelium of a worker accidentally exposed to MOCA [8].
• Beagle dogs were treated with single and multiple doses of MOCA and DNA adduct levels were determined in liver and bladder epithelium [8].
• Mean MN frequencies were higher in urothelial cells and lymphocytes of MOCA workers (14.27 +/- 0.56 and 13.25 +/- 0.48 MN/1000 cells) than in controls (6.90 +/- 0.18 and 9.24 +/- 0.29 MN/1000 cells) [14].

Associations of 4,4'-METHYLENEBIS(2-CHLOROANILINE) with other chemical compounds

• In vitro effects of MOCA and dapsone on rat hepatic and splenic immune cells [12].
• Of the two mouse micronucleus-negative rat carcinogens, acrylonitrile was positive in rat bone marrow and 4,4'-methylene bis(2-chloroaniline) was negative in both rat bone marrow and peripheral blood [15].
• Lung microsomes also demonstrated high peroxidative activation of ABP, benzidine, 4,4'-methylene-bis(2-chloroaniline), 2-aminofluorene, and 2-naphthylamine [16].
• Suggested changes to guidelines for health surveillance of MOCA-exposed workers in Australia include a reduction in acceptable levels of urinary MOCA to below 15 mumol/mol creatinine [14].
• Simultaneous determination of 2,4- and 2,6-diisocyanatotoluene (TDI) and 3,3'-dichloro-4,4'-diaminodiphenylmethane (MOCA) in air [17].

Gene context of 4,4'-METHYLENEBIS(2-CHLOROANILINE)

• It is therefore of interest to identify the human cytochrome P450 (P450) enzymes involved in MOCA N-oxidation, the primary reaction involved in the formation of an electrophilic product [9].
• Induction of ornithine decarboxylase activity by 4,4'-methylene bis(2-chloroaniline) in the rat [18].
• In addition, prophylactic cranial irradiation was administered concurrently with thoracic irradiation to 194 patients receiving CAML-HC, VCAM, or MOCA [19].
• METHODS: Urinary MOCA markers were measured in urine samples collected at the end of the workshifts [20].

Analytical, diagnostic and therapeutic context of 4,4'-METHYLENEBIS(2-CHLOROANILINE)

• This highly specific and sensitive method for measuring urinary 4,4'-methylenebis(2-chloroaniline) (MBOCA) involves liquid chromatography with electrochemical detection [21].
• Three adducts, with the same retention times on HPLC, were present after i.p. injection of the N-acetyl derivative of MOCA tritiated in the benzene rings [22].
• Determination of 4,4'-methylenebis(2-chloroaniline) in urine using capillary gas chromatography and negative ion chemical ionization mass spectrometry [23].
• After dermal administration of MOCA the major portion of the dose, 86.2%, remained at the application site throughout the study [24].
• The effect of multiple oral administration of MOCA, a suspect human carcinogen, was studied in the adult male rat [25].

References