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Barium Chloride dihydrate (BaCl2.2H2O) was given for 92 days to B6C3F1 mice and Fischer 344/N rats in their drinking water at levels of 0, 125, 500, 1000, 2000, and 4000 ppm. The no-effect level for this study was 2000 ppm BaCl2.2H2O in the drinking water. At 4000 ppm, daily consumption for mice was 436 to 562 mg/kg barium, up to four times more chemical than rats. Mortality ranged from 60 to 70% in mice and from 10 to 30% in rats in the 4000 ppm groups. Deaths in mice were associated with a treatment-related renal toxicity. Renal lesions in rats were much less severe than in mice and did not contribute to the treatment-related deaths seen in the high dose group. Body weights of both species and sexes in the 4000 ppm groups were lower than controls at 92 days. Male and female rats in treated groups exhibited higher serum phosphorus than controls. Serum sodium, potassium, and calcium levels in rats were unchanged by barium treatment, as were hematological values. In both species at 4000 ppm, motor activity, grip strength, and thermal sensitivity were marginally affected. These effects were probably secondary changes resulting from BaCl2 toxicity observed at this dose level. In a mating trial, no anatomical effects on offspring of rats or mice were seen. Rats receiving 4000 ppm exhibited marginal reductions in pup weights. No effects were seen on reproductive indices.

Two hundred patients with chronic sinusitis were operated on using functional endoscopic sinus surgery (FESS) techniques. These patients were followed closely over 3 years. Patency of the endoscopic middle meatotomy was recorded using actuarial life-table methods. The overall patency rate of the endoscopic middle meatotomy was 93.55%, and the actuarial patency rate at 36 months was 87.47%. The presence of seasonal allergy with nasal polyps was the most important variable in predicting closure. Middle turbinectomy was the most important variable in predicting patency. Symptoms were evaluated by questionnaire at 1 year. Questionnaire data indicate that 96% of these patients are improved or asymptomatic.

Toxicology and carcinogenesis studies of furosemide, a widely used diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 14-day, 13-week and 2-year studies. Deaths occurred among rats and mice receiving diets containing 46,000 ppm furosemide in 14-day studies, and animals given diets containing lower concentrations lost weight. No deaths were seen in 13-week studies using top concentrations ranging from 10,000 to 20,000 ppm, but animals at higher concentrations had lower weight gains than controls. Nephrosis in rats and mice was the only significant compound-related lesion observed in the prechronic studies. In 2-year studies, rats received diets containing 0, 350 or 700 ppm furosemide and mice received diets containing 0, 700 or 1400 ppm furosemide. Survival of dosed and control rats of both sexes and male mice was similar; survival of high-dose female mice was lower than controls. Nephropathy was increased in male rats and in male and female mice. In female mice, increased malignant tumors of the mammary gland were associated with furosemide administration. In male rats, marginal increases in tubular cell neoplasms of the kidney and in meningiomas of the brain were observed in dosed animals, but these were not considered to be related clearly to exposure to furosemide.

Toxicology and carcinogenesis studies of hydrochlorothiazide, a benzothiadiazide diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 15-day, 13-week and 2-year studies. No rats died during the 15-day or 13-week studies at dietary concentrations of up to 50,000 ppm. Deaths of male mice in the top dose group in the 13-week study were likely to be related to chemical administration. In the prechronic studies, increased nephrosis and mineralization at the kidney corticomedullary junction were the primary toxic effects of hydrochlorothiazide observed in rats. In mice, chemical-related effects included nephrosis and calculi, inflammation and epithelial hyperplasia in the urinary bladder. In 2-year studies using dietary concentrations of 0, 250, 500 and 2000 ppm in rats and 0, 2500 and 5000 ppm in mice, survival of dosed and control groups of rats and mice was similar, as were body weights of mice. Dosed groups of male and female rats were uniformly lighter than controls (up to 25%) throughout the studies. Severe chronic renal disease with secondary parathyroid hyperplasia and fibrous osteodystrophy of the bone were attributed to chemical administration in rats. No neoplasms in rats or female mice or non-neoplastic lesions in mice were associated with hydrochlorothiazide. In high-dose male mice, liver neoplasms were increased but were not considered to be related to hydrochlorothiazide administration because of an unusually low incidence in the control group relative to historical controls.

Dipentylnitrosamine (DPN), administered in the diet at a concentration of 2,000 ppm to Fischer-344 rats, produced hepatomas in 27% of both males and females within 8 weeks. Bile-duct carcinomas were also produced. All animals also showed liver nodular hyperplasia and bile-duct cell proliferation. Feeding DPN at 1,500 ppm produced hepatomas or bile-duct carcinomas in 7% of the males and varying degrees of nodular hyperplasia and duct cell proliferation after 8 weeks of feeding. The total cumulative dose after feeding 2,000 ppm DPN was of the order of 7,700 mg/kg body weight in males and 8,200 mg/kg in females. There was a 28% weight decrement in animals feed 2,000 ppm DPN when compared to controls but no mortality. DPN carcinogenicity was enhanced when DPN was combined with a liver carcinogen, cycasin (fed as cycad not flour, equivalent to 160 ppm cycasin). No effect on DPN carcinogenicity was found in rats fed DPN and lasiocarpine, another known liver carcinogen with antimitotic activity. Neither was there any effect of DPN carcinogenicity in rats fed DPN and N-butyl-N-(4-hydroxybutyl) nitrosamine or N-methyl-N'-nitro-N-nitrosoguanidine. In contrast, the trisodium salt of nitrilotriacetic acid reduced the hepatocarcinogenic action of DPN. The enhancement of DPN carcinogenicity with cycasin is compatible with the hypothesis that DPN-induced liver cell populations (hyperplastic nodules) can resist the cytotoxic effect of cycasin and differentiate rapidly towards hepatomas, while other areas of the liver are suppressed.

Scientists at the National Toxicology Program are studying the toxicologic properties of 8-methoxypsoralen (8-MOP) with and without 320-400 nm UV (UVA). The combination of psoralen and UVA is a promising treatment for psoriasis. In this study, 8-MOP was administered to male and female Fischer 344 rats without subsequent UVA exposure for the determination of toxic effects of the psoralen alone. The drug (in corn oil) was administered by gavage 5 days/week for 90 days at doses of 0, 25, 50, 100, 200, and 400 mg/kg. The effects of toxicity were seen primarily in the 200- and 400-mg/kg dose groups, which included mortality, decreased body weight gain, and dose-related increases in liver:body ratios. On histopathology, target organ toxicity was seen in the liver, testes, and adrenals. In this study, relatively high doses of 8-MOP were tolerated in comparison to the dose of psoralen used in combination therapy clinically.

The bone marrow colony-forming unit (CFU) technique of Till and McCulloch was employed to test the radioprotective effect of AET, anoxia, urethan on marrow cells irradiated in vivo. For AET and anoxia, a dose-reduction factor of 1.9 to 2.1 was found. Since the marrow cells were assayed for CFU content immediately after irradiation of the donor, the observed effect can be interpreted as a "true" radiation dose reduction. By contrast, urethan injection did not increase the survival of marrow CFU assayed immediately after whole-body x-irradiation. However, both urethan and AET afforded radioprotection of endogenous CFU content of spleen and bone marrow, but not of endogenous spleen colony count. It is concluded that the mechanism of radioprotection by urethan is fundamentally different from that of AET or anoxia.

Combined treatment of mice with urethane (a nucleic acid antagonist and mitotic inhibitor) plus sublethal x-radiation (500 rad) suppresses the homograft response to a degree considerably greater than that observed with this dose of x-rays alone. Thus, LAF(1) mice receiving two injections of urethane plus 500 rad of x-radiation prior to grafting retained C(3)H mouse skin grafts for periods up to 60 days, with a mean graft survival time of 40 days, as compared with 18 days for mice exposed to 500 rad only.

Adult mice subjected to thymectomy or sham thymectomy received lethal irradiation and subsequent protective infusion of syngeneic bone marrow. Thirty days later they received allogeneic and xenogeneic skin grafts. Donors of the xenogeneic grafts were rats. The thymectomized mice rejected the grafts of rat skin only slightly later than the controls did; in contrast, the time of retention of allogeneic grafts was significantly longer in the thymectomized mice.

Adult mice [CBA/J (H-2(k))], which received either a single sublethal dose of x-radiation (500 rad) or urethan plus 500 rad, were given intravenous injections of C3H/HeJ (H-2(k)) spleen or bone marrow cells (18 to 42 x 10(6) cells per mouse) or both, for 3 days. C3H/HeJ tail-skin homografts were retained (over 130 days) by these mice, whereas BALB/cJ (H-2(d)) homografts all were rejected within 33 days. Similarly irradiated or urethan-treated controls (or controls treated with a combination of both), which did not receive C3H cells, rejected both homografts. Specific homograft tolerance is induced in adult mice by this procedure.

Adult thymectomized, irradiated mice restored with syngeneic bone marrow exhibit an accelerated response toward second-set skin homografts, although the response to the primary grafts is impaired. Such mice have a long-lasting impairment (up to 223 days) of the primary response to allogeneic grafts (but not to xenogeneic grafts) and show the greatest deficiency of response toward grafts sharing the same H2 locus as the host. Thymectomy in the adult mouse is ineffective in altering a state of homograft sensitivity induced prior to irradiation.