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 systems of operational military aircraft. Maintenance of missiles and aircraft may result in accidental human exposure to high concentrations for 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 high concentration of N2H4 for repeated short exposures and to investigate 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 Syrian 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 exposures. Rodents were euthanized 24 hr after exposures 1 and 10 and 24 to 30 months poststudy initiation. Significant reductions in body weight were observed in N2H4-treated rodents compared to controls during the exposure interval. No hydrazine-induced mortality was detected. Histopathologic 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, squamous metaplasia of the transitional epithelium. Minimal to mild rhinitis resulted from N2H4 exposures. Apoptosis was observed in olfactory and squamous metaplastic transitional epithelium. Lesions occurred at sites reportedly having high air-flow and generally appeared to be more severe in the anterior portion of the nose. By 24 months, the squamous metaplastic transitional epithelium reverted back to normal-appearing transitional epithelium. By 24+ months, low incidences (sexes combined) of hyperplasia (5/194, 2.6%) and neoplasia (11/194, 5.7%) were detected, principally in the transitional epithelium of the 750 ppm 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 hamsters. The location and type of N2H4-induced proliferative lesions were 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: hyperplasia 15.5% vs 2.6% and polypoid adenoma 44.6% vs 5.2%). The product (CD) of concentration + time was the same (750 ppm hours) for the high-dose groups for both studies, but the duration of exposure was 150 x longer and the concentration was 150 x lower in the chronic study.(ABSTRACT TRUNCATED AT 400 WORDS)

Reproductive toxicity screen of ammonium dinitramide administered in the drinking water of Sprague-Dawley rats.

The Department of Defense is currently considering replacing ammonium perchlorate with ammonium dinitramide (ADN), a class 1.1 explosive oxidizer to be used in solid rocket propellant mixtures and explosives. This study was intended to evaluate the potential of ADN to produce alterations in paternal fertility, maternal pregnancy and lactation, and growth and development of offspring. Male and female rats received drinking water containing 0.0, 0.2, 1.0, or 2.0 g ADN/liter throughout the study. Mating occurred following 14 days of treatment. All dams, one-half the males, and representative pups were maintained for a total of 90 days of treatment. No mortality occurred in parental animals during the study. Treatment with ADN resulted in no adverse effects on mating; 92-100% of the animals mated. No treatment-related effects were seen in parental animals clinically or histopathologically. Adverse treatment-related effects were noted in maternal and paternal fertility indices, gestational indices, and live birth indices in both the mid- and high-dose groups. Litter sizes in the mid- and high-dose groups were significantly smaller than those of the low-dose and control groups. Mean pup weights showed no statistically significant differences between ADN-treated pups and controls. Gross and histopathological examination of the animals failed to identify the cause for the decrease in litter production in the mid- and high-dose dams. This study indicates that ADN is a reproductive toxicant. The no-observable-effect level (NOEL) is 29 mg/kg/day, the median dose of the low level female rats.

The effects of JP-8 jet fuel on male Sprague-Dawley rats after a 90-day exposure by oral gavage.

The U.S. Air Force is converting from JP-4 jet fuel to the less volatile JP-8 jet fuel, which is similar to commercial Jet Fuel A. Our previous 90-day inhalation study with JP-8 vapor, using F-344 rats and C57BL/6 mice, resulted in no treatment-related adverse effects other than alpha 2-microglobulin nephropathy in male rats (Mattie et al., 1991). In the present study, male rats were dosed with neat JP-8 (0, 750, 1500, 3000 mg/kg) daily by gavage for 90 days in an effort to characterize the kidney lesion and assess further any additional adverse effects associated with prolonged oral exposure to this fuel. Results of this study revealed a significant dose-dependent decrease in body weights of rats exposed to JP-8. Male rat-specific alpha 2-microglobulin nephropathy was observed by histopathologic examination. A number of significant changes were also seen in blood and urine that were not dose-dependent. Additional treatment-related effects were a gastritis and a perianal dermatitis. Although there were no histopathological or weight changes in the livers of exposed rats, there was an increase in the liver enzymes AST and ALT. The elevated enzymes did not increase with increasing dose of JP-8.

Reproductive toxicity screen of 1,3,5-trinitrobenzene administered in the diet of Sprague-Dawley rats.

Several Army installations targeted for restoration have measurable quantities of 1,3,5-trinitrobenzene (TNB) in the soil and groundwater. As part of the process of developing environmental and health effects criteria for restoration, a modified Screening Information Data Set (SIDS) reproductive study was performed. Male and female Sprague-Dawley rats received a diet containing approximately 30, 150, or 300 mg TNB/kg diet. Mating occurred following 14 days of treatment. All dams, one-half the males, and representative pups were maintained for a total of 90 days of treatment. No mortality occurred during the study; however, a decrease in mean body weights was noted in both sexes of high-dose rats. A dose-related effect was noted in measurements of sperm function/activity. Sperm depletion and degeneration of the seminiferous tubules were noted histopathologically. Methemoglobinemia and splenic hemosiderosis were common findings in the high- and mid-dose levels of both sexes at necropsy. No adverse effects were noted in mating or fertility indices. No significant treatment-related differences were found in length of gestation, sex ratio, gestation index, or mean number of pups per litter.

Anatomic and physiologic characterization of the WF/PmWp-"fz" (fuzzy) rat.

The WF/PmWp-"fz" rat is an inbred strain of hypotrichotic rat derived from a Wistar Furth colony. This strain, also known as the "fuzzy rat," has been used for dermal toxicity research; however, little is known about its longevity and age-related physiologic and pathologic changes. Presented are basic anatomic and physiologic parameters, collected for each sex at five ages, including hematologic and clinical biochemical profiles, organ and body weights, and a characterization of gross and histopathologic findings.

General toxicity and reproductive screen of liquid propellant XM46 administered in the drinking water of Sprague-Dawley rats.

Liquid propellant XM46 is being considered as a replacement for solid propellants, both as part of a regenerative injection gun system and as a working fluid in an electrothermal gun system. The XM46 formulation contains hydroxylammonium nitrate, triethanolammonium nitrate, and water. Male and female Sprague-Dawley rats received XM46 in drinking water containing 2.0, 1.0, 0.2, or 0.0 g XM46/liter throughout a 90-day study. Mating occurred following 14 days of treatment. One-half the male rats per group were necropsied after 28 days of treatment; the remaining males and all dams were necropsied following 90 days of treatment. No mortality occurred in any of the parental animals during the study. The study did not demonstrate any adverse effects on reproduction or litter parameters. Hemolytic anemia and methemoglobinemia were common in both sexes of rats. Splenomegaly was found in both sexes; in male rats as early as 28 days. Exposures via drinking water containing XM46 for 90 days did not result in any decrease in reproductive performance in male or female rats, but it did result in clinical signs of hemolytic anemia at doses as low as 17 mg/kg/day.

Hepatotoxicity in guinea pigs following acute inhalation exposure to 1,1-dichloro-2,2,2-trifluoroethane.

Groups of 10 male Hartley guinea pigs were exposed to 3.0, 2.0, 1.0, or 0.1% (v/v) 1,1-Dichloro-2,2,2-trifluoroethane (HCFC-123) or 1.0% (v/v) halothane by inhalation for 4 hr. A sixth group of 10 guinea pigs received only air. All animals were sacrificed 48 hr postexposure. Gross and histopathologic examination of the liver, heart, and kidney and routine hematology and clinical chemistry analyses [including isocitrate dehydrogenase (ICDH)] were done on all guinea pigs. Lesions related to HCFC-123 and halothane exposure were limited to the liver and included centrolobular vacuolar (fatty) change, multifocal random degeneration and necrosis, and centrolobular degeneration and necrosis. These lesions were observed in 90-100% of the exposed animals and were absent in the air-only controls. There was significant individual animal variation in susceptibility to both HCFC-123 and halothane, resulting in a spectrum of histologic lesions and clinical chemistry values within each exposure group. Alanine aminotransferase, aspartate aminotransferase, and ICDH were the most significant predictors of hepatocellular damage. Similarities in the response between halothane and HCFC-123 in this guinea pig model suggests that humans susceptible to halothane-induced hepatitis may be susceptible to HCFC-123 by a common mechanism of toxicity.