Transplantation studies on induced and spontaneous nodules from B6C3F1 mouse liver.

The present research was designed to assess the potential for progressive growth of hyperplastic, adenomatous, and carcinomatous mouse liver lesions grafted into syngeneic hosts and to determine the effect of treatment type, donor age, and metastatic potential on this parameter. Lesions were obtained from male B6/C3F1 mice fed on an open formula (NIH-007) diet or the same diet mixed with a chlorinated hydrocarbon pesticide (3,5-dichloro-(N-1,1-dimethyl-2-propyl)benzamide) (DcB). Animals were killed at 18 or 24 months of age. Hosts for transplanting were killed at 8 months, or when grafts reached 2 cm in diameter. Lesions diagnosed as nonmalignant (hyperplastic or benign) were more likely to grow after transplantation if obtained after 24 months, rather than after 18 months (0.025 less than p less than 0.05). There was a close correlation between donor lesion morphology and ability to grow in a recipient mouse (p less than 0.0005; 36% of the hyperplastic, 32% of the adenomatous and 79%, of the malignant lesions grew). The majority of lesions retained the morphologic appearance of the donor lesions. Transplanted lesions from control mice were more likely to grow than were those from DCB-treated mice (0.01 less than p less than 0.025). This correlation was particularly strong for hyperplastic nodules. Metastatic capability in the donor animals correlated positively with both growth potential (p less than 0.01) and growth rate (p less than 0.05) in recipient mice. These findings suggest that progression toward autonomous growth may occur both within the original host and during a prolonged transplantation period, making data interpretation difficult. Lesion morphology alone may not be adequate for assessing capacity for autonomous growth. Other factors, such as evidence of metastasis or local invasion in the primary host, may be required to make more meaningful diagnosis.

Dietary nutrients and contaminants in laboratory animal experimentation.

Analyses for selected components in random samples of natural product diets for experimental rodents revealed significant variations in content of nutrients and contaminants in various lots of feed. Modification of the diet and contamination with any of several toxicants appreciably affected the responses of experimental animals to specific drugs or chemicals under test, which could cause biased interpretation of results. Therefore, continuous monitoring of laboratory animals' diets and maintenance of quality control are necessary. For example, low magnesium concentrations may affect the kidney; excessive calcium concentration may influence absorption and utilization of zinc; excesses of vitamins A and D are highly toxic; deficiency or excess of selenium affects biological systems; and poor protein quality may provide inadequate or imbalanced amino acids and thereby influence structure and function of animal systems in experimental studies. Important contaminants are the mycotoxins (particularly aflatoxin), heavy metals (lead, mercury, cadmium, arsenic), nitrates and nitrosamine (N-dimethylnitrosamine), chlorinated hydrocarbons, and polychlorinated biphenyls.

Toxicological evaluation of Norpace after intravenous administration to rat and dog.

Norpace (disopyramide phosphate) is a drug for treating cardiac arrhythmias. It has been evaluated for potential toxicological effects in albino rats and Beagle dogs, to provide safety support for clinical studies involving intravenous infusion. The compound was dissolved in Sodium Chloride for Injection, U.S.P. and administered daily by continuous intravenous infusion to groups of rats and dogs. Dose levels to 4.95 mg/kg/h for 14 and 28 consecutive days, respectively were employed. Rats received the formulation for 6--12 h daily; dogs were infused for 6 h daily. Conventional physical, cardiovascular, hematology, clinical chemistry and postmortem gross and microscopic examinations were performed. No compound-related changes were observed in the physical examinations (including ophthalmic), blood pressure (rat), ECG (dog), body weight, or clinical lab parameters evaluated; Food consumption was unontinuous restraining procedure employed during infusions reduced food consumption in all dogs, however, Postmortem examination did not reveal any lesions unique to treated animals. Some dogs exhibited intravenous fibrin thrombi at the site of injection. Organizing blood clots were occasionally present in the thoracic cavity of the rat. These findings were considered related to the infusion technique employed, rather than the drug administered. It was concluded that daily intravenous infusions of Norpace at doses up to 4.65 mg/kg/h to rats and dogs for 14 and 28 consecutive rays respectively, cause no biologically meaningful detrimental effects.

Ocular effects of oral contraceptives. I. Studies in the dog.

The administration of two oral contraceptives to female dogs for 5 years did not produce ocular lesions. Corneal and lenticular opacities occurred with equal frequency in control and treated groups, and fundic lesions, including papilledema, venous dilatation, and venous or arterial retinal thrombosis, were not produced by doses of Enovid-E or Ovulen 1, 10, and 25 times the human dose.

Effect of oral contraceptives on the mammary glands of Rhesus monkeys: a preliminary report.

PIP: To determine the relationship of oral contraceptive use and breast cancer, 96 rhesus monkeys were administered either Enovid-E (2.5 mg norethynodrel and .1 mg mestranol) or Ovulen (1 mg ethynodiol diacetate and .1 mg mestranol) cyclically for 5 years at doses of 1, 10 and 50 times the human dose. The animals' progress was compared with a control group of 32 monkeys. General physical and mammary gland examinations were conducted before treatment and monthly thereafter. During the 5 year study period none of the treated animals demonstrated clinical evidence of mammary gland lesions, no deaths from breast malignancy occurred, and no palpable breast nodules were found.^ieng