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PubMedDate not supplied

Issues related to the use of canines in toxicologic pathology--issues with pharmacokinetics and metabolism.

The dog is a commonly used animal model by virtue of its size, well-characterized physiology, and ease of handling. For these reasons and others, dogs are also useful in pharmacokinetic and metabolism studies during the development of both human and veterinary pharmaceutical products. In comparison with humans, or with other animals, dogs have some unique physiologic attributes that can affect the disposition of drugs. Species differences in gastrointestinal physiology, metabolism, renal function, and protein binding can affect the correlation of the pharmacokinetics and toxicology of dogs with those of other species. With the use of relevant examples, this article will provide an introduction to characteristics of dog physiology and their impact on pharmacokinetics, metabolism, drug disposition, toxicity, and dose selection.

Animals↗
PubMed1982

Patulin mycotoxicosis in the rat: toxicology, pathology and clinical pathology.

Patulin, a secondary metabolite produced by species of the genera Penicillium and Aspergillus, was administered to male Sprague-Dawley rats, weighing 50-60 g, by the oral, sc and ip routes. The 72-hr LD50 values (in mg/kg weight) were: oral, 55.0; sc, 11.0; ip, 10.0. Mortality was greatest 0-24 hr after administration by the oral and sc routes and 49-72 hr after ip dosing. Gross alterations consisted of gastric and intestinal hyperaemia and distention. Histopathological alterations consisted principally of ulceration and inflammation of the stomach. Patulin was administered orally to rats daily or every other day for 2 wk at doses of 50 or 75% of the oral LD50. Mortality in the treated groups was greater than in controls but was similar for all treated groups. No evidence of cumulative toxicity was found and the gross and histopathological alterations were similar to those found in the LD50 studies. Clinicopathological alterations included metabolic alkalosis with respiratory compensation, oliguria, decreased serum sodium, elevated blood glucose, reduced plasma protein and an elevated total leucocyte count which differential leucocyte counts indicated to be due to neutrophilia. The inflammatory alterations observed in the gastro-intestinal tract may be due to the irritant properties of patulin or to an alteration in the gastro-intestinal flora by the antibiotic activity of patulin.

Animals↗
PubMed1994

Endocrine considerations in toxicologic pathology.

Detection of xenobiotic-induced toxicity on the endocrine system is a very difficult task because of the close relationship that the endocrine system has with the neural and immune systems. This is further complicated when one is asked to extrapolate from lab animals to man. Knowledge across species of hormonal action, solubility, transportation, plasma half life, receptor location, type of mediator, rhythmicity and pattern of secretion, is essential. One hormone can exert various effects in different tissues, or one function can be regulated by several hormones or even many functions of one endocrine target tissue can be regulated by several hormones acting in concert. The endocrine toxic response is determined by the state of differentiation of the target site. Feedback mechanisms both positive and negative, should also be taken into consideration initially. Because the effects of hormones have wide-ranged ramifications, the toxic responses likewise encompass broad areas such as the regulation of energy availability, maintenance of the internal environmental, development, growth and reproduction. The initial step involves the ascertaining of interference with the general trophic and target gland function and the characterization of the primary toxic effect. Equally important is to calculate the dose which elicited this primary effect, taking into consideration the area under the curve of the target endocrine site. Adapting this step-by-step approach, the causality between a specific toxic dose and a specific toxic effect can be readily and reliably established across all lab animal species and man.

Animals↗
PubMed1984

Toxicologic, pathologic, and immunotoxic effects of 2,4-dichlorophenol in rats.

2,4-Dichlorophenol (DCP) is a drinking and waste-water contaminant formed by the spontaneous reaction of chlorine with phenols following chlorination of water for disinfection and deodorization. Rats were exposed to 0, 3, 30, or 300 ppm DCP in drinking water either in utero or for 12 wk postnatally following in utero exposure. Toxicity to DCP was assessed by organ and body weight changes, histopathology, and effects on reproduction and immunocompetence. Reproductive parameters measured included conception, litter size, pup birth weight, number stillborn, survival to weaning, and weaning weight. Immune parameters assessed were humoral immunity (antibody production) by an indirect enzyme-linked immunosorbent assay (ELISA), cell-mediated immunity by a delayed-type hypersensitivity response, and macrophage function by phagocytosis of radiolabeled blood cells. Rats that received the combined in utero and postnatal treatment with 300 ppm DCP had significantly increased liver and spleen weights, enhanced humoral immune responsiveness, and depressed cell-mediated immunity. Histopathologic changes were unremarkable in DCP-exposed rats, even in the presence of increased liver and spleen weights. The 6-wk-old progeny of DCP-treated dams had normal immune functions and showed no signs of DCP toxicity, other than increased spleen weights in the 300-ppm exposure group. The results indicate that (1) the immune system may be a sensitive target for chlorinated phenolic compounds, (2) DCP may exert different effects on separate major immune responses, and (3) unlike some other chlorinated phenols, DCP does not appear to alter reproductive performance in rats.

Animals↗
PubMed1973

Toxicological, pathological, and teratological studies in animals with cephradine.

Cephradine, a semisynthetic cephalosporin antibiotic, has a low order of oral and parenteral toxicity in animals. The oral LD(50) in mice and rats ranged from 5 to >8 g/kg, and the intraperitoneal LD(50) values in mice and rats were 0.7 to 1.5 g/kg and 4.0 g/kg, respectively. The intravenous LD(50) in mice ranged from 3.0 to 3.8 g/kg. In anesthetized dogs, intravenous doses of cephradine (40 and 120 mg/kg, given 45 min apart) had no effect on either the renal or cardiovascular systems. Single intramuscular injections (0.25 ml or 0.5 ml of a solution containing 125 to 235 mg of cephradine/ml) elicited no signs of either pain or local irritation in dogs, and only transient signs of slight-to-moderate irritation were observed in rabbits. In subacute toxicity studies, cephradine was administered for 4 weeks to rats (daily intraperitoneal doses of 160, 480, or 1,600 mg/kg) and dogs (daily intravenous doses of 80, 240, or 800 mg/kg); in addition, over a 2-week period, monkeys were given daily intravenous doses of 60, 180, or 600 mg/kg. No clinical, biochemical, gross, or micropathological changes due to cephradine were observed in these animals; especially notable was the absence of any signs of nephrotoxicity. In chronic toxicity studies, daily doses of cephradine were administered orally to rats (100 to 1,000 mg/kg), dogs (50 to 500 mg/kg), and monkeys (50 to 500 mg/kg) for 26, 26, and 13 weeks, respectively. Significant responses were observed only in rats, in which grossly enlarged, but histologically normal, ceca developed, a common finding in rodents dosed with antibiotics; in addition, there were increases in the relative and absolute weights of the adrenal glands. None of these effects was observed in rats that were necropsied 3 weeks after termination of dosage. In reproduction studies in mice and rats given either daily oral doses (100 or 300 mg/kg) or daily intraperitoneal doses (rats only; 80 or 320 mg/kg) of cephradine, no drug-related teratogenic changes in the offspring were observed.

Abnormalities, Drug-Induced↗