Reduced blood clearance and increased urinary excretion of N-nitrosodimethylamine in patas monkeys exposed to ethanol or isopropyl alcohol.

Low concentrations of N-nitrosodimethylamine are metabolized in rodent and human liver by cytochrome P450IIE1, an activity competitively inhibitable by ethanol. In rodents coadministration of ethanol with N-nitrosodimethylamine results in increased tumorigenicity in extrahepatic organs, probably as a result of reduced hepatic clearance. To test this concept in a primate, the effects of ethanol cotreatment on the pharmacokinetics of N-nitrosodimethylamine were measured in male patas monkeys. Ethanol, 1.2 g/kg given p.o. before i.v. N-nitrosodimethylamine (1 mg/kg) or concurrently with an intragastric dose resulted in a 10-50-fold increase in the area under the blood concentration versus time curves and a 4-13-fold increase in mean residence times for N-nitrosodimethylamine. Isopropyl alcohol, 3.2 g/kg 24 h before N-nitrosodimethylamine, also increased these parameters 7-10-fold; this effect was associated with persistence of isopropyl alcohol and its metabolic product acetone, both IIE1 inhibitors, in the blood. While no N-nitrosodimethylamine was detected in expired air, trace amounts were found in urine. Ethanol and isopropyl alcohol pretreatment increased the maximum urinary N-nitrosodimethylamine concentration 15-50-fold and the percentage of the dose excreted in the urine by 100-800-fold. Thus ethanol and isopropyl alcohol greatly increase systemic exposure of extrahepatic organs to N-nitrosodimethylamine in a primate.

Potential occupational exposure associated with parenteral administration of N-nitrosodiethylamine to Macaca mulatta: evidence of post-injection release to the atmosphere.

In order to assess the exposure of workers administering N-nitrosodiethylamine (NDEA) parenterally to Macaca mulatta, air samples were drawn through Thermosorb/N cartridges. Samples were analysed by gas chromatography-thermal energy analysis; the limit of detection was 0.02 micrograms/m3. Significant amounts of NDEA were found in those samples taken in the animal holding room. The NDEA recovered may be accounted for by its expiration by the animals (the contribution from excreta and leakage from the injection site is probably minor). On the basis of the total amount of NDEA administered (840 mg during the first experiment and 250 mg in the second) and the rate at which the animal holding room was ventilated, and assuming that the samples were representative, we estimate that 0.9% of the NDEA administered was released to the atmosphere in 5 h in the first experiment and that 2.7% and 0.8% were released in the first and second 24-h periods, respectively, in the second experiment. It should be noted that this potential source of exposure may be significant not only for workers but also for control or other experimental animals housed in the same room.

Identification of 1-hydroxypyrene as a major metabolite of pyrene in pig urine.

1-Hydroxypyrene is a major metabolite of pyrene given orally to pigs. A method for isolating the metabolite from urine is described, utilizing C18-adsorbent cartridges, h.p.l.c. separation, and fluorescence detection. Unconjugated 1-hydroxypyrene can be detected in the urine of pigs following oral administration of as little as 1 mg pyrene. Identity of the 1-hydroxypyrene was confirmed by u.v.-absorption and fluorescence spectrometry, mass spectrometry, and by comparison with the retention time characteristic of synthetic 1-hydroxypyrene.