Curtis D. Port

Chronic Exposure to Nitrogen Dioxide

Squirrel monkeys continuously exposed to 1 ppm of nitrogen dioxide (NO2) for 493 days were challenged five times with monkey-adapted influenza A/PR/8/34 virus. All monkeys exposed to NO2 produced serum neutralization antibody within 21 days after virus infection, whereas only one control monkey exposed to filtered air showed comparable response. The differences observed in hemagglutination-inhibition antibody titers, body temperatures, respiratory functions, body weights, and hematological values between the experimental and control monkeys were not significant. Histopathologic examination of lung tissues indicated slight emphysema and thickened bronchial and bronchiolar epithelium only in monkeys exposed to NO2 and challenged with the influenza virus. Transmission election microscopic examination did not disclose any ultrastructural changes that could be attributed to the experimental exposures.

Toxicologic Evaluation of Streptozotocin (NSC 85998) in Mice, Dogs and Monkeys

Single intravenous doses of CDF1 mice, and single and five daily intravenous treatment schedules in beagle dogs and rhesus monkeys were used to evaluate the toxicity of Streptozotocin (SZN). The major target organs in the three species were liver, kidney, lymphoid tissue and pancreatic islet beta cells. Moderate bone marrow depression and gastrointestinal toxicity were observed in the large animal species after lethal doses. Monkeys were less sensitive than the dog to the hepatotoxic effects of SZN and clinical signs of liver dysfunction were more severe in dogs after multiple doses. Microscopic lesions in the renal proximal convoluted tubules were present in the three species; these lesions appeared to be irreversible for dogs. The toxic effect on the endocrine pancreas was manifest by hyperglycemia, glucosuria, islet atrophy and beta cell degranulation. Multiple dose regimens were less toxic than single doses in dogs and monkeys in terms of the total dose received.

Surface Morphology of Tracheal Epithelium in Vitamin A Deficiency and Reversal

Vitamin A, which maintains cellular differentiation of epithelial tissues, also has an effect on metaplastic and neoplastic lesions in the respiratory tract. The surface morphology of hamster tracheal epithelium during vitamin A deficiency and during reversal upon the administration of vitamin A was studied by scanning electron microscopy. Focal squamous metaplasia of the tracheal epithelium, confined upon the upper two thirds of the ventral surface of the trachea, occurs in vitamin A deficiency. Synchronous differentiation of the epithelium with sloughing of the existing surface occurs after reversal of the deficient state. This change is rapid, occurring within 4 days of the administration of vitamin A. The SEM enabled documentation of extent distribution and surface changes in vitamin A deficiency and reversal.

Role of Particles in Respiratory Carcinogenesis Bioassay

In animal models of lung cancer induction, metallic dust particles have been used to increase the lung retention of carcinogens and enhance tumor development. The influence of the physical characteristics of the carcinogen-dust combination on lung tumor induction was investigated in a Syrian hamster model where benzopyrene(BP)-ferric oxide suspensions were given by intratracheal instillation.

Large-Volume Intratracheal Instillation of Particulate Suspensions to Hamsters

A technique has been developed that permits the intratracheal instillation of volumes as large as 1.5 ml into the respiratory tract of young adult Syrian golden hamsters. 2 factors are of unique importance for the success of this technique: 1. the use of halothane anesthesia that permits total recovery in as little as 2 minutes, and 2. the use of an intratracheal speculum that seals at the larynx and prevents loss of suspension from the lungs. Suspensions consisting of 2% (w/v) ferric oxide, or benzo(a)pyrene-ferric oxide, in 0.5% gelatin-saline have been instilled with a technique mortality rate of less than 5%. Histopathological examination of the lungs at 4 weeks revealed no significant changes related to the technique. Distribution of a suspension containing black ink was uniform when volumes larger than 1 ml were instilled; smaller volumes were less well distributed. Examination of the gastrointestinal tract within 5 hours after instillation showed that no significant loss of ink suspension from the lungs had occurred. Additional studies are in progress to determine the tumorigenic potential of benzo(a)pyrene-ferric oxide when administered in 2 doses, 7 days apart, of 1.5 ml each (total dose = 30 mg BaP) to the same amount of carcinogen administered in 10 or more doses of 0.25 ml at weekly intervals.

The Mongolian gerbil as a model for chronic lead toxicity

Abstract The long term administration of lead acetate in the diet of Mongolian gerbils results in a chronic progressive nephropathy with tubular degeneration, interstitial fibrosis and intranuclear inclusions; in addition, microcytic hypochromic anaemia with red cell destruction and deposition of lipofuscin and hemosiderin in the liver also occurs. These histological findings were confirmed by scanning and transmission electron microscopy. The development of a chronic nephropathy accompanied by haematological changes following long term administration of lead in the diet suggests that the gerbil may be a useful animal model to study chronic lead poisoning in man.

Effect of particle size distribution on hexamethylmelamine toxicity in rats.

Single oral dose toxicities of six hexamethylmelamine samples with different particle size distributions were evaluated in Osborne-Mendel rats. The calculated LD50 values for the 6 samples were 1706 to 2150 mg/kg )10,236 to 12,900 mg/m2). The two samples with median particle size less than 40 micron were more toxic than the other 4 samples. Among the latter samples, severity of toxic effects was not correlated with particle size. Leukocytes, lymphocytes, platelets and body weight showed dose-related decreases for all samples. Particle size appeared to have a minimal effect on these variables. The drug produced toxic effects on rapidly proliferating tissues: lymphoid, hematopoietic and germinal epithelium. At lethal doses, microscopic lesions were lymphoid tissue hypoplasia, bone marrow hypoplasia with elevated myeloid:erythroid ratios and spermatogenic arrest. The major target organs at nonlethal doses were bone marrow and germ cells, with germinal epithelium showing the most severe lesions.

Influenza-Virus-Induced Hyperplasia of the Respiratory Tract of the Hamster

Hamster-adapted A/PR/8 influenza virus infection followed by a secondary insult consisting of 0.25 ml of 0.5% gelatin-saline instilled directly into the trachea causes epithelial hyperplasia of both the trachea and lung. The extent of the response is related to, and dependent upon, the time interval between virus infection and gelatin-saline administration; the optimal time interval is between 12 and 18 hr. The presence of hyperplasia was measured by 3H-thymidine incorporation. Hyperplasia of the trachea is first apparent 3 days after virus infection, peaks at the fourth day, and is no longer present by the twentieth day. Hyperplasia in the lung begins 4 days after virus infection, peaks at the sixth day, and is undetectable by the twentieth day. Additional studies are in progress to determine the effect of virus-induced hyperplasia on benzo(a)pyrene-ferric oxide initiated respiratory carcinogenesis.