doses that were toxic to the dams. Reproductive effects (ovarian and testicular atrophy, endometrial inflammation, endometrial cysts, and aspermatogenesis) were observed in hamsters and mice exposed by inhalation to hydrazine at 1–5 ppm (Vernot et al. 1985) and UDMH at 0.05 ppm (Haun et al. 1984).
A number of animal studies have reported increases in the incidence of cancers after exposure to hydrazines (reviewed in ATSDR 1997; IARC 1999b; NRC 1996, 2000). Studies of hamsters exposed to UDMH by subcutaneous injection have had both positive findings (Ernst et al. 1987) and negative findings (Jeong and Kamino 1993). Oral exposures (by gavage or in drinking water) to UDMH or hydrazine (administered as hydrazine sulfate or isonicotinic acid hydrazide), however, have produced increased tumor rates (particularly of respiratory or hepatic tissues) in multiple strains of mice, rats, and hamsters (Bhide et al. 1976; Biancifiori 1970; Biancifiori et al. 1964, 1966; Bosan et al. 1987; Maru and Bhide 1982; Roe et al. 1967; Severi and Biancifiori 1968; Steinhoff and Mohr 1988; Toth 1969).
Inhalation exposure, which would be most relevant to the Gulf War experience, has been less intensively investigated but also produced positive findings. Year-long exposure of rats and hamsters to hydrazine at 0.05, 0.25, 1.0, or 5.0 ppm for 6 hr/day, 5 days/wk followed by at least a year of observation before sacrifice led to dose-dependent increases in the incidence of lesions of the nasal epithelium (Vernot et al. 1985). Mice had slight increases in the incidence of lung adenomas in the high-dose group, but the small groups of dogs (four males and four females per dose level) showed no consistent response (Vernot et al. 1985). Inhalation exposure of rats and mice to UDMH was associated with leukemia and tumors of the lung, nasal passages, bone, pancreas, pituitary, blood vessels, liver, and thyroid (Haun et al. 1984). Chronic inhalation of MMH was not found to be carcinogenic in rats or dogs, but it did produce lung, nasal, and liver tumors in mice and nasal, renal, and adrenal tumors in hamsters (Kinkead et al. 1985).
Hydrazine and UDMH have been shown to be genotoxic in both in vivo and in vitro tests (reviewed in ATSDR 1997). Hydrazine and UDMH are alkylating agents and produced DNA damage in in vivo assays but had negative results in in vivo assays of unscheduled DNA synthesis, dominant lethal mutation, and gene mutation. Hydrazine and UDMH had positive results in gene-mutation assays in Salmonella typhimurium and Escherichia coli with and without activation and in Photobacterium leiognathi without activation. Mammalian cell assays had positive results for DNA alkylation, transformation, sister chromatid exchange, and unscheduled DNA synthesis without activation, and for gene mutation with and without activation.
Amyloidosis of the kidneys was observed in hamsters exposed to hydrazine by inhalation at 0.25 ppm for 6 hr/day, 5 days/wk for 1 year but not in rats, mice, or dogs experiencing the same treatment regimen (Vernot et al. 1985). No renal effects were observed in dogs exposed to UDMH by inhalation at 25 ppm (Rinehart et al. 1960) or in mice given hydrazine orally at 9.5 mg/kg/day (Steinhoff et al. 1990).
Case studies have suggested that exposure to hydrazine or hydrazine derivatives is associated with systemic lupus erythematosus or a similar syndrome (Durant and Harris 1980) (Pereyo 1986), but the data are too sparse to support conclusions about an association. In addition, decreased T helper-cell counts observed in mice given UDMH by injection at 75