ONCOGENIC POTENTIAL OF INHALED HYDRAZINE IN THE NOSE OF RATS AND HAMSTERS AFTER 1 OR 10 1-HR EXPOSURES

Hydrazine (N2H4) is used as a fuel for missiles and standby power syst ems of operational military aircraft. Maintenance of missiles and airc raft may result in accidental human exposure to high concentrations fo r brief periods of time. The purposes of this study were to assess the oncogenic potential of N2H4 in rats and male hamsters exposed to a hi gh concentration of N2H4 for repeated short exposures and to investiga te the relationships of acute and subchronic effects of N2H4 to nasal tumorigenesis. In Phase 1 (acute and subchronic) and Phase 2 (lifetime ) experiments, groups of male and female Fischer 344 rats and male Syr ian golden hamsters were exposed by inhalation to 0, 75 (Phase 2 only) , or 750 ppm N2H4 for 1 (acute) or 10 (subchronic) 1-hr weekly exposur es. Rodents were euthanized 24 hr after exposures 1 and 10 and 24 to 3 0 months poststudy initiation. Significant reductions in body weight w ere observed in N2H4-treated rodents compared to controls during the e xposure interval. No hydrazine-induced mortality was detected. Histopa thologic examination after the acute and subchronic exposures revealed degeneration and necrosis of transitional, respiratory, and olfactory epithelia in the anterior nose and, in rats exposed subchronically, s quamous metaplasia of the transitional epithelium. Minimal to mild rhi nitis resulted from N2H4 exposures. Apoptosis was observed in olfactor y and squamous metaplastic transitional epithelium. Lesions occurred a t sites reportedly having high air-flow and generally appeared to be m ore severe in the anterior portion of the nose. By 24 months, the squa mous metaplastic transitional epithelium reverted back to normal-appea ring transitional epithelium. By 24+ months, low incidences (sexes com bined) of hyperplasia (5/194, 2.6%) and neoplasia sia (11/194, 5.7%) w ere detected, principally in the transitional epithelium of the 750 pp m N2H4-treated rats. A similar incidence of hyperplasia (2/94, 2%) and neoplasia (5/94, 5.3%) was detected in the high-exposure group of ham sters. The location and type of N2H4-induced proliferative lesions wer e similar to those reported in a chronic N2H4-exposure study (5.0 ppm X 6 hr/day x 5 days/week for 1 year) conducted in our laboratory, but the chronic study had much higher incidences (rats, sexes combined: hy perplasia 15.5% vs 2.6% and polypoid adenoma 44.6% vs 5.2%). The produ ct (CD) of concentration x time was the same (7500 ppm hours) for the high-dose groups for both studies, but the duration of exposure was 15 0x longer and the concentration was 150x lower in the chronic study. T hese comparisons suggest that the duration of exposure is a more signi ficant factor than concentration in N2H4-induced nasal tumorigenesis. (C) 1995 Society of Toxicology.