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PubMed1980

Morphology of the neoplasms of the thyroid gland in Fischer 344 rats treated with 4,4'-methylene-bis-(N,N-dimethyl)-benzenamine.

Follicular neoplasms of the thyroid gland developed in 79 of 200 Fischer 344 rats of both sexes, fed either 0.0375% or 0.075% 4,4'-methylene-bis-(N,N-dimethyl)-benzenamine (MDBA) mixed with the diet. Hyperplastic changes in the follicular epithelium occurred in 12 rats fed the higher concentration of this chemical. One of 40 control rats had a follicular carcinoma of the thyroid gland.

Adenocarcinoma↗
PubMed1992

EPR and 1H and 13C dynamic nuclear polarization studies of a molecularly doped polymer: bisphenol A polycarbonate doped with trianisylamine and trianisylaminium perchlorate.

We have investigated the EPR and DNP behavior of a molecularly doped polymer modeling those used to transport electronic charge in electrophotography. The EPR spectra show no evidence of the superexchange reported for a closely related system based on tri-p-tolylamine. The difference may be due to larger charge-transfer matrix elements in the latter system. An unambiguous interpretation of the observed 1H DNP was rendered difficult by the unanticipated asymmetry of the EPR spectra. We report extensive data on the "three-spin" effect evident in the DNP-enhanced 13C NMR spectra, and comment on its potential for characterizing polymer interfaces.

Aniline Compounds↗
PubMed2006

Analysis of biomarkers in rats and dogs exposed to polymeric methylenediphenyl diisocyanate (pMDI) and its glutathione adduct.

Hemoglobin adducts (Hb-MDX) of monomeric methylenediphenyl diisocyanate (MDI) are often interpreted as indirect evidence of hydrolysis of the diisocyanate moiety to the respective amine (diphenylmethane-4,4'-diamine, 4,4'-MDA) which constitutes the rationale of using this biomarker as an internal dosimeter of exposure to putatively formed MDA. In contrast, more recently published data suggest that following inhalation the high concentration of glutathione (GSH) present in lungs favor an adduct formation with GSH and/or peptides/proteins rather than hydrolysis. The focus of this study was to test this alternate hypothesis, viz. whether Hb-MDX can also be formed by the GSH bis-adduct of monomeric MDI. The synthesized mMDI-GSH bis-adduct was administered to rats by single intratracheal instillation. Additional groups were dosed by gavage and intraperitoneal injection. Biomarkers of exposure were determined in blood (plasma protein and hemoglobin adducts) and urine after harsh alkaline and acid hydrolysis, respectively. Data from previous single inhalation exposure studies with aerosols of MDI and 4,4'-MDA in rats served as reference. As to whether N-acetylation plays any modifying role to yield these mMDI-specific biomarkers was addressed in similarly head-only exposed dogs, a species with no appreciable N-acetylation capacity whereas rats are strong N-acetylators. The results obtained suggest that biomarkers in blood from controlled exposures above current workplace standards of mMDI appear not to be suitable for reliable assessments of past exposures. The biomarkers typically used to assess past exposures to MDI were also identified following exposure to the MDI-GSH bis-adduct. Their yield was low but quite similar for MDI aerosol and the MDI-GSH bis-adduct, whilst that of MDA was distinctively higher. The findings of this study are supportive of a conceptual pathway that the MDI-derived biomarkers of exposure are formed through MDI-GSH adducts rather than MDA. Data from dogs support the findings from rats and show that N-acetylation does not appear to be an essential modifying factor. It is concluded that the yield of MDI-related markers of exposure is relatively low and dependent on the exposure dose (and route). MDA originating from hydrolyzed serum protein or hemoglobin appear to be confounded by false-positive background levels which are surmised to be associated with the method of hydrolysis. The determination of urinary biomarkers might be a useful tool to identify recent exposures (by any route). Due methodological uncertainties associated with the harsh hydrolysis of biological specimens may be reduced substantially when using incremental pre- to post-shift changes rather than relying solely on absolute data.

Acetanilides↗
PubMed1989

Genotoxicity and effects on rat liver drug-metabolizing enzymes by possible substitutes for 4,4'-methylene bis(2-chloroaniline).

The mutagenic properties of Ethacure 300, Cyanacure and Polacure 740M, all possible substitutes for the industrial carcinogen, 4,4'-methylene bis(2-chloroaniline), have been determined in Salmonella typhimurium strains TA100, TA98, TA1535 and TA1537. These data have been compared with the effects of these chemicals on ethoxyresorufin O-deethylase (EROD) activity and aldrin epoxidase (AE) activity in rat liver. Ethacure 300 was clearly positive in both TA100 and TA98 bacterial strains, while Cyanacure was positive only in TA100. Polacure 740M was negative in all strains. Ethacure 300 caused a 28-fold induction of EROD while Cyanacure caused a doubling. Polacure 740M was without effect. Neither Ethacure 300 nor Cyanacure affected AE, while Polacure 740M caused an increase at only the lower dose tested. Thus there was excellent correlation between mutagenicity and EROD induction. A similar correlation was noted for six other structurally related compounds giving support to the contention that the ability of a chemical to induce EROD bears some relationship to its carcinogenic potential.

4-Aminobenzoic Acid↗
PubMed1981

Inhibitory effect of 4,4'-diaminodiphenylmethane on liver, kidney and bladder carcinogenesis in rats ingesting N-ethyl-N-hydroxyethylnitrosamine or N-butyl-N-(4-hydroxybutyl) nitros-amine.

The effects of 4,4' -diaminodiphenylmethane (DDPM) administration in the "post-initiation" stage of liver, kidney and bladder carcinogenesis were examined in male F344 rats. In experiment 1, rats were given drinking water containing 0.1% N-ethyl-N-hydroxyethyl-nitrosamine for 2 weeks than diet containing 0.1% DDPM for 32 weeks. In week 3, the right kidney was removed. The incidence of hepatocellular carcinoma was significantly less in rats given DDPM than in controls. DDPM decreased the incidence and average number/cm2 of neoplastic nodules and renal cell tumors of the kidney. In experiment II, rats were given 0.01% N-butyl-N-(4-hydroxybutyl)nitrosamine for 4 weeks and then 0.1% DDPM for 34 weeks kin their drinking water. DDPM inhibited the induction of papillomas in the bladder. These results indicate that DDPM administration in the "post-initiation" stage inhibited liver, kidney and bladder carcinogenesis in rats.

Aniline Compounds↗
PubMed2003

Lack of carcinogenic risk in the prostate with transplacental and lactational exposure to bisphenol A in rats.

The current study was designed to examine the modulating effects of bisphenol A (BPA) on prostate cancer risk in male offspring exposed transplacentally and lactationally. BPA was administered to F344 female rats by gavage at 0, 0.05, 7.5, 30, 120 mg/kg/day during pregnancy and lactation periods. When F1 males reached 5 weeks old, they were given 10 subcutaneous injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) or corn oil vehicle and rats were then sacrificed under ether anesthesia at week 60. There were no observable effects on the accessory sex organ weights of male offspring. Transplacental and lactational exposure to BPA did not affect the incidences of preneoplastic and neoplastic lesions in the accessory sex organs (prostate and seminal vesicle) of F1 rats and did not induce any proliferating lesions without DMAB. Our data suggest that maternal exposure to BPA during the period of pregnancy and lactation does not affect the risk of prostate carcinogenesis in male offspring.

Administration, Oral↗
PubMed1989

Metabolic oxidation of the carcinogens 4-aminobiphenyl and 4,4'-methylene-bis(2-chloroaniline) by human hepatic microsomes and by purified rat hepatic cytochrome P-450 monooxygenases.

Metabolic N-oxidation and ring-oxidation of carcinogenic arylamines by hepatic cytochromes P-450 are generally regarded as critical activation and detoxification pathways, respectively. Two arylamines with known human exposure, 4-aminobiphenyl (ABP) and 4,4'-methylene-bis(2-chloroaniline) (MOCA), have been examined as substrates for 10 different purified rat hepatic cytochromes P-450 and for human liver microsomal preparations from 22 individuals. Metabolites were analyzed by high-performance liquid chromatography and flow scintillation techniques. As reported for certain other carcinogenic arylamines, the isosafrole-inducible isozyme, P-450ISF-G, had the highest catalytic activity for ABP N-oxidation (13.6 nmol/min/nmol P-450), but P-450BNF-B, P-450UT-A, P-450UT-F, and P-450PB-B also showed appreciable activity. Ring-oxidation of ABP occurred only to a minor extent. In contrast, N-oxidation of MOCA was preferentially catalyzed by the phenobarbital-inducible enzymes, P-450PB-B and P-450PB-D (9.0 and 6.6 nmol/min/nmol P-450, respectively). MOCA ring-oxidation and methylene carbon oxidation showed varied cytochrome P-450 selectivity and accounted for 14 to 79% of total oxidation products. There was a 44-fold variation in rates of ABP N-oxidation in the 22 human liver microsomal preparations, while rates of N-oxidation of MOCA varied only 8-fold. Ring/methylene carbon-oxidation of MOCA accounted for 6-19% of total oxidation products in the case of the human microsomal preparations, whereas ring-oxidation of ABP accounted for less than 7% of total oxidation. In addition, there was a strong correlation (R = 0.90) between rates of ABP N-oxidation and phenacetin O-deethylation, which is considered a human genetic polymorphism. Moreover, both the ABP N-oxidation and phenacetin O-deethylation activities of human liver microsomes showed a good correlation (R = 0.72) with the levels of cytochrome P-450 immunochemically related to rat P-450ISF-G. 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. Therefore, individual profiles of cytochromes P-450, affected by both environmental and genetic factors, may be significant determinants of individual susceptibility to arylamine carcinogenesis.

Aminobiphenyl Compounds↗
PubMed1977

Effect of various factors on the induction of liver tumors in animals by quinoline.

Tumorigenic effect of a diet containing quinoline on the liver of various animals and the synergistic or antagonistic effect by other chemicals on quinoline hepatocarcinogenesis in rats were examined. It was concluded that 4,4'-diaminodiphenylmethane (0.1%) and 3-methylcholanthrene (0.0067%) had a significant inhibitory effect on liver carcinogenesis due to quinoline in rats, but 1-naphthyl isothiocyanate (0.06%) and p-hydroxypropiophenone (1.0%) had no inhibitory effect in the present observations. Transmission electron-microscopic study demonstrated the fine structure of vascular tumors induced by quinoline. On the other hand, it was found that quinoline induced liver tumors in both sexes of mice and rats but not in hamsters or guinea pigs. Male rats were more susceptible than females to the tumorigenic action of quinoline, and mice showed the least susceptibility. Histological changes in the liver of rats or mice induced by quinoline were clasified as hemangioendotheliomas or hemangiosarcomas and hepatocellular carcinomas. Several rats treated with quinoline had hemangiosarcomatous metastatic foci in the lung.

1-Naphthylisothiocyanate↗
PubMed1983

Role of the acetylation polymorphism in determining susceptibility of cultured rabbit hepatocytes to DNA damage by aromatic amines.

In humans and rabbits, differences in the rate of N-acetylation of aromatic amines are under polymorphic genetic control. Individuals are classified as either rapid or slow acetylators. In the current study, the relationship between acetylator phenotype and susceptibility to the genotoxicities of benzidine, 4-aminobiphenyl, 4,4'-methylenebis-2-chloroaniline, and 2-naphthylamine was investigated. Cultured hepatocytes isolated from rapid and slow acetylator rabbits were exposed to a dose range of the aromatic amines, and genotoxicity was determined by the autoradiographic measurement of DNA repair synthesis. Hepatocytes from rapid acetylator rabbits were more susceptible to the genotoxic effect of benzidine than were cells from slow acetylators. 4-Aminobiphenyl and 4,4'-methylenebis-2-chloroaniline were both weakly genotoxic, but no clear correlation was seen with acetylator phenotype. No genotoxicity was observed with 2-naphthylamine. These results thus demonstrate that differences in acetylation rates can affect the genotoxicity of benzidine. This study provides further evidence for the role of the genetically determined acetylator polymorphism in determining susceptibility to the effects of certain aromatic amine carcinogens. Since the acetylator polymorphism is a human trait, a similar susceptibility may be displayed in humans.

2-Naphthylamine↗
PubMed1980

Combined action of hepatotoxic substances and increased environmental temperature on the liver of rats.

Male albino rats were orally treated in a single dose with 40 mg allyl alcohol/kg or 50 mg 4,4'-methylenedianilline/kg, or 100 mg 1,1,2,2-tetrachloroethane/kg, or 400 mg carbon tetrachloride/kg, or 800 mg chloroforme/kg, immediately after-wards exposed to increased temperature (35 degrees C, 50% RH, 4 h), and examined 20--22 hours later. Under these conditions, only carbon tetrachloride led to a more intensified changes manifesting themselves in changes of the serum enzymes LAP, ALAT, and GLDH, as well as in liver histology. The liver lesions, caused by the substances mentioned, reacted to an additional thermal strain in a comparable manner as the LD50-values determined under identical exposure conditions. The temperature-dependent enhancement of the carbon tetrachloride hepatotoxicity is ascribed to an intensification of liver peroxidation processes due to increased core temperature.

1-Propanol↗
PubMedDate not supplied

[The correction of the liver detoxifying function with phenobarbital and ziksorin before and after ischemia].

Rat experiments have shown preliminary administration of phenobarbital and zixoryn (before ischemia) fails to prevent the hepatic monoxygenase system from ischemic lesion, followed by profound destructive changes in the liver, though the functional activity of the microsomal system remained high. Phenobarbital and zixoryn induction of monooxygenases in the postischemic period contributed to the complete restoration of the levels of microsomal cytochromes and the metabolic activity of xenobiotics in the liver just in its early periods. It is concluded that it is advisable to use the inductors in the postischemic restorative period to correct the detoxifying function of the liver.

Aminopyrine↗
PubMed2002

Determination of modafinil, modafinil acid and modafinil sulfone in human plasma utilizing liquid-liquid extraction and high-performance liquid chromatography.

An assay was developed to determine concentrations of modafinil (dl-2-[(diphenylmethyl)sulfinyl]acetamide; Provigil) and its two major circulating metabolites, modafinil acid and modafinil sulfone, in human plasma. The assay utilized liquid-liquid extraction of the analytes and an internal standard, (phenylthio)acetic acid, from plasma into a mixture of hexane-dichloromethane-glacial acetic acid (55:45:2, v/v). The analytes were resolved isocratically on a narrow-bore phenyl column at a mobile phase flow-rate of 0.3 ml/min and were monitored by UV detection at 235 nm. The method reported herein reduces the required sample volume of previously reported methods from 1.00 to 0.200 ml of plasma while lowering the limit of quantification (LOQ). The linear range of the assay was from 0.100 to 20.0 microg/ml for each of the three compounds.

Benzhydryl Compounds↗
PubMed1975

Alkylation by secondary alcohols III: Fusion of medicinal sulfanilamides with benzhydrol.

The fusion of certain sulfanilamides with benzhydrol in the presence of anhydrous zinc chloride affords several different products, depending primarily on the temperature at which the reaction is carried out. With sulfanilamide itself, three different products were isolated at 100, 160, and 180 degrees. A sequence of steps is suggested to account for the three products, one of which involves an intramolecular rearrangement of a benzhydryl moiety. The fusion of benzhydrol with p-toludine gives 2,6-dibenzhydrylaniline and not the N,N-dibenzhydryl derivative as previously reported.

Alcohols↗