Vitamin A acetate: a behavioral teratology study in rats.

We evaluated the effects of maternal administration of vitamin A acetate on pup development and behavior. Vitamin A acetate was administered by oral gavage to pregnant rats (N = 10/treatment) on gestation days 6-19 at doses of 25,000, 50,000 or 100,000 I.U./kg/day. Male and female pups from dams that received 100,000 I.U./kg/day showed a significantly reduced live birth index but few external abnormalities. Twenty-four and 48 hour survival indices were also significantly reduced. The mean pup body weight gain at 100,000 I.U./kg/day was significantly reduced at days 1-3, 3-7 and 21-42. Pinna detachment and eye opening were significantly delayed in all male pups and in female pups from the 50,000 and 100,000 I.U./kg/day groups. Incisor eruption was significantly delayed in male and female pups from the 25,000 and 50,000 I.U./kg/day groups. The following showed no treatment effects: dam mean weight change, length of gestation, total litter size, surface righting, cliff avoidance, negative geotaxis, swimming development, open field activity and discriminatory learning.

Experimentally induced malignant hypertension in beagle dogs.

The pathology of malignant hypertension in dogs induced either purposely or inadvertently by the Goldblatt procedure has not been previously reported. Malignant hypertension was experimentally produced in beagle dogs by a modified Goldblatt procedure; in a single surgical procedure, one kidney was removed and the blood flow to the remaining kidney was reduced by 50%. A sudden onset of severe clinical signs developed within one to three weeks after surgery. The dogs were markedly depressed or in shock, were vomiting, and had either bloody feces or bloody diarrhea. Hematologic changes compatible with a diagnosis of microangiopathic hemolytic anemia consisted of hemolysis, thrombocytopenia, and the presence of burr cells and schistocytes. Some dogs had neutrophilia and slight to moderate increases in blood urea nitrogen and creatinine. At necropsy, there were gross hemorrhages in the heart, brain, urinary bladder, and gastrointestinal tract. Histologic findings consisted of multifocal parenchymal hemorrhage, fibrinoid necrosis of arterioles, medial smooth muscle hyperplasia, adventitial fibroplasia and mononuclear cell infiltrates, and microthrombi. The vascular clamp most likely protected the kidney from the systemic hypertension since the remaining kidney was largely not remarkable by light or electron microscopy. The dog appears to be a good model to study the pathology of malignant hypertension and microangiopathic hemolytic anemia.

Evaluation of a direct blood pressure measurement technique for canine toxicity studies.

Repeated direct puncture of the central ear (intermediate auricular) artery to obtain mean arterial blood pressure in control and hypertensive dogs was evaluated. Unilateral nephrectomy and partial constriction of the contralateral renal artery were performed on four dogs to create hypertension. Ear artery blood pressure measurements and electrocardiograms were recorded twice pretest and after surgery at Weeks 1, 2, 4, 6, 8, 9, 10, and 11 on control (n = 6) and hypertensive (n = 4) dogs. Mean ear arterial blood pressures from the hypertensive dogs were significantly increased from Weeks 2 to 11. Indwelling omocervical artery catheters were implanted in both control and hypertensive dogs at Week 8. Mean omocervical artery blood pressures from hypertensive dogs were significantly increased at Weeks 8 through 11. Mean omocervical artery pressures were only significantly increased over mean ear artery pressures at Week 8 for control dogs and at Week 10 for hypertensive dogs. Nonspecific electrocardiographic changes in the ST-T segment and U waves occurred with greater frequency in hypertensive dogs than in control dogs. Hypertensive dogs developed subendothelial proliferation in the renal artery and aorta, and a proliferative vasculopathy in the heart and lungs. This ear artery technique was used successfully in two canine toxicity studies of different ICI pharmaceutical compounds. The ear artery method for measuring mean arterial blood pressure is suitable for canine toxicity studies and is a reasonably accurate measurement of systemic pressure.

A computerized data management system for behavioral teratology studies.

A computerized system was designed for behavioral teratology studies to (1) generate preprinted data recording/submission forms, (2) calculate testing dates, (3) generate a daily activity schedule for testing, and (4) update established data sets for access by data entry personnel. The computer-generated forms are used to record data from the following behavioral/developmental tests for rats: pup weights, pinna detachment, surface righting, cliff avoidance, incisor eruption, eye opening, negative geotaxis, olfactory discrimination, swimming development, open field, swimming maze and operant visual discrimination learning. Three behavioral teratology studies have been conducted in our laboratory using this computerized system. The human error rates in these studies were 0.26, 0.34 and 0.46 percent, respectively. The advantages of this system include: (1) computer-calculated test dates; (2) elimination of manual data transcription; (3) more consistent data recording and scoring conditions; (4) better scheduling control; and (5) faster data entry and statistical analysis.

Immune mechanisms in byssinosis.

The pathogenesis of byssinosis has been attributed to several different immunopathologic mechanisms, including a type III (immune complex) pulmonary injury. To further examine this type III theory, sera (Monday preshift) from 59 cotton textile workers were examined by gel diffusion and counterimmunoelectrophoresis for precipitating antibodies to aqueous extracts of cotton bract, carpels, stems, leaves, immature cotton bract, carpels, stems, leaves, immature cotton lint, and cardroom cotton dust. Sera were also collected from 35 nonexposed normal volunteers and examined similarly. No true precipitating antibodies to these extracts could be detected in any of the control or worker serum samples. The aqueous extracts of cardroom cotton dust and cotton stems were found to contain naturally occurring components that precipitated (in agarose gel) beta-lipoprotein and gamma-globulins (mostly IgG) in a nonimmunologic manner. Sera from normal human controls and cotton textile workers all produced identical patterns of reaction with these two extracts. Treatment of these extracts with polyvinylpolypyrrolidone, a specific insoluble adsorbent for polyphenolic tannins, eliminated this pseudoimmune reaction. Although the role this pseudoimmune reaction may play in the pathogenesis of byssinosis is still unknown, it demonstrates the problems associated with laboratory-based investigations of the immunologic aspects of byssinosis.

Acute experimental pulmonary responses to cardroom cotton dust.

Laboratory rabbits were exposed for 60 min to aerosols of dry cardroom cotton dust 4 days/wk (Tuesday through Friday) for 15 consecutive weeks. As a parameter of pulmonary pathophysiology, arterial blood gases were monitored with time after challenge. Post-exposure blood gas analyses at 1 hr showed progressive decreases in arterial oxygen tension, with concommitant increases in arterial carbon dioxide tension and the alveolar-arterial oxygen gradient. These responses appeared to result from acute reversible airway obstruction which caused unequal gas distribution and ventilation-perfusion inequalities. When a group of proven responder rabbits was challenged with cardroom cotton dust which was first treated in a manner which paralleled the preparation of medical grade cotton, only minor decreases in arterial oxygen tension were observed. The data suggest that some, as yet undefined, agent(s) which was removed by the treatment was responsible for inciting the observed pathophysiology.