Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion.

The hepatic metabolism of arylamine bladder carcinogens to N-hydroxy arylamine N-glucuronides, their excretion in the urine, and their subsequent acidic hydrolysis to highly carcinogenic and reactive N-hydroxy arylamines have been proposed as essential steps in arylamine-induced urinary bladder carcinogenesis. In this study, alteration of urinary pH, inhibition of metabolic sulfation, and blockage of biliary disposition were shown to profoundly affect the urinary excretion of the probable ultimate bladder carcinogen, N-hydroxy-2-naphthylamine (N-HO-2-NA) and its N-glucuronide conjugate. The normal pH of rat urine (6.7) was altered to 5.7 or 7.7 by administration of NH4Cl or NaHCO3 in the drinking water. Subsequent treatment with either 2-naphthylamine (2-NA) or 2-nitronaphthalene (2-NN) resulted in increased urinary levels of free N-HO-2-NA (relative to its N-glucuronide) in acidic urines and decreased relative amounts of free N-HO-2-NA in alkaline urines. In addition, 2-NN yielded 5--10-fold greater levels of urinary N-HO-2-NA and its N-glucuronide than rats given 2-NA; and 2-NA was not detected as a urinary metabolite of 2-NN. Some 12 additional metabolites of 2-NA and 2-NN were also found. Of these, 2-amino-1-naphthol and its sulfate and glucuronide conjugates were quantitated. From these data, 2-NA and 2-NN appear to share common metabolic pathways which yield free N-HO-2-NA as a putative ultimate urinary bladder carcinogen. Pentachlorophenol, a known inhibitor of hepatic sulfotransferases, was shown to cause a 2--3-fold increase in the urinary levels of N-HO-2-NA N-glucuronide and N-HO-2-NA from 2-NA-treated rats. Similarly, inhibition of the biliary excretion of 2-NA by bile duct ligation resulted in a 6-fold increase in total urinary N-HO-2-NfA. Furthermore, analyses of bile revealed that substantial amounts of N-HO-2-NA N-glucuronide, but not free N-HO-2-NA, were present. The role of urinary versus biliary excretion of N-hydroxy arylamines in relation to bladder and colon carcinogenesis is discussed.

Dephenylation of N-phenyl-2-naphthylamine in dogs and its possible oncogenic implications.

N-Dephenylation of N-phenyl-2-naphthylamine (PBNA) is strictly limited in dogs, and a 5 mg/kg dose gives 0-10 microng of urinary 2-naphthylamine (BNA), which does not appear to undergo further metabolism. Neither 2-naphthylhydroxylamine (BNHA) nor 2-amino-1-naphthylsulphate were detected in the urine of treated animals. Urinary output of BNA varies markedly between dogs, and at different times in the same animal. The extent of PBNA N-dephenylation is unaltered by chronic administration. Calculations based on Druckery and Küpfmüller's equation (1948) and present data indicate that, for dogs to form BNA tumours through exposure to a relatively high dose-level of PBNA, the period of daily dosing would occupy, or even exceed, the normal life-span. The carcinogenic risk of PBNA to human subjects is discussed.

Excretion of 35S-Tobias acid (2-naphthylamino, 1-sulphonic acid) by the rat after oral and intravenous administration.

Urinary and faecal excretion of radioactivity after either an intravenous or oral (1 mg/kg) dose of 35S-labelled Tobias acid (2-naphthylamino, 1-sulphonic acid), a dyestuff intermediate structurally similar to the powerful carcinogen 2-naphthylamine, was studied in rats. The Tobias acid was eliminated from the body within 24 hours of administration, almost exclusively through the urine. TLC-chromatography of faecal extracts and urine did not disclose the presence of excreted products other than unchanged Tobias acid and the search for inorganic 35SO4 in the urine by BaCl2 precipitation was negative. There was significant absorption from the gastrointestinal tract, but neither cleavage of the sulphonic group nor other biotransformation by the intestinal flora was apparent under the test condition. There was no evidence that the sulphonic group of Tobias acid is cleaved in the body to a significant extent to give 2-naphthylamine. This information should help in the evaluation of the occupational hazard potential of Tobias acid.

4-aminobiphenyl, 2-naphthylamine, and analogs: analytical properties and trace analysis in five substrates.

Methods for monitoring trace levels of 4-aminobiphenyl, 2-naphthylamine, and their hydrochloride salts in waste water, microbiological growth media, potable water, human urine, and mouse blood utilizing spectrophotofluorometry (SPF) are described. The salient elements of the methods are extraction of the residues as the free amine with benzene, rapid cleanup on an alumina column, and quantification of the free amine in methanol via SPF. Potable water solutions of the salts are diluted with 0.01 N aqueous HCL and quantified directly by SPF. Ancillary analytical information concerning gas chromatography of the free amines, partitioning properties of the compounds between solvent pairs, their solubility and stability in water, and thin-layer chromatographic data is presented. The compositions of various admixtures of 1- and 2-naphthylamine or their salts were determined by using SPF with calculations based on simultaneous equations.