Toxicology and carcinogenesis studies of pentachlorophenol in rats.

Pentachlorophenol (PCP) has been used as an herbicide, algaecide, defoliant, wood preservative, germicide, fungicide, and molluscicide. A 28-day toxicity study of PCP in F344/N rats of both sexes was conducted to select dose levels for a carcinogenicity study. Groups of 10 male and 10 female rats were given 0, 200, 400, 800, 1600, or 3200 ppm PCP in feed for 28 days. The incidences of minimal to mild hepatocyte degeneration in males and females exposed to 400 ppm or greater and the incidences of centrilobular hepatocyte hypertrophy in the 3200-ppm groups were increased. For carcinogenicity studies, groups of 50 male and 50 female F344/N rats were fed diets containing 200, 400, or 600 PCP for 2 years. A stop-exposure group of 60 male and 60 female rats received 1000 ppm of PCP in feed for 52 weeks and control feed thereafter for the remainder of the 2-year studies; 10 male and 10 female rats were evaluated at 7 months. Survival of 600-ppm males was significantly greater than that of the controls; survival of all other exposed groups was similar to that of the control groups. Mean body weights of the 400- and 600-ppm groups were generally less than those of the controls throughout the studies. There was no evidence of carcinogenic activity of PCP in male or female rats fed diets containing 200, 400, or 600 ppm for 2 years. Stop-exposure study males and females regained a transitory body weight reduction by the end of the 2 year study, and males had better survival than the controls. At a 7-month interim evaluation, the incidences of centrilobular hypertrophy in stop-exposure males and females exceeded those in the controls. At 2 years, malignant mesothelioma originating from the tunica vaginalis was present in 9 1000-ppm males and 1 control male (p = 0.014). Nasal squamous cell carcinomas were present in five 1000-ppm males and 1 control male. This incidence was not significantly increased but exceeded the historical control range (0-4%). Based on the increased incidences of mesotheliomas and nasal tumors, there was some evidence of carcinogenic activity of PCP in male rats given a diet containing 1000 ppm for 1 year followed by control diet for 1 year. There was no evidence of PCP carcinogenic activity in stop-exposure female rats.

Hematological effects in F344 rats and B6C3F1 mice during the 13-week gavage toxicity study of methylene blue trihydrate.

Methylene blue trihydrate is used widely as a dye and therapeutic agent. Methylene blue was administered by gavage to 30 animals/sex/dose group in a 0.5% aqueous methylcellulose suspension at doses of 0, 25, 50, 100, and 200 mg/kg. Blood samples from 10 animals/sex/dose group were collected at the end of study weeks 1, 6, and 13. Methylene blue treatment resulted in methemoglobin formation and oxidative damage to red blood cells, leading to a regenerative anemia and a variety of tissue and biochemical changes secondary to erythrocyte injury. An early change was a dose-related increase in methemoglobin, where the response of rats and mice was similar in magnitude. Mice appeared to be more sensitive than rats to the formation of Heinz bodies and the development of anemia that was characterized by a decrease in hemoglobin, hematocrit, and erythrocyte count. Splenomegaly was apparent in all treated mice and in the 100 mg/kg (males only) and 200 mg/kg rats at necropsy. There was a dose-related increase in absolute and relative spleen weight for both species. Microscopic examination revealed increased splenic hematopoiesis in all mice treatment groups and in rats at the 50 mg/kg dose level and above. Splenic congestion and bone marrow hyperplasia were also observed in these rat-dose groups. Mice at the higher doses showed hematopoiesis in the liver and accumulation of hemosiderin in Kupffer cells. These gross and microscopic findings are consistent with the development of hemolytic anemia. A dose-related increase in the reticulocyte count during study weeks 6 and 13 suggested a compensatory response to anemia.

Comparative carcinogenicity in Sprague-Dawley rats of the polychlorinated biphenyl mixtures Aroclors 1016, 1242, 1254, and 1260.

A comprehensive chronic toxicity and carcinogenicity study was conducted on a series of Aroclors (1016, 1242, 1254, and 1260). Each Aroclor was assessed at multiple dietary concentrations, ranging from 25 to 200 ppm, for 24 months in male and female Sprague-Dawley rats. Liver toxicity was indicated by elevated serum enzyme activity (AST, ALT, and GGT), elevated serum cholesterol concentration, decreases in hematologic parameters (RBC, Hb, and Hct), hepatocellular hypertrophy, an increased incidence of altered hepatocellular foci, and an increased incidence of hepatocellular neoplasms (primarily adenomas). Liver toxicity was distinctly more severe in females than in males. The incidence of hepatocellular neoplasms was highly sex-dependent (females >> males), differed between Aroclor mixtures and, for females, increased with dose and followed the general incidence pattern of Aroclor 1254 > Aroclor 1260 approximately Aroclor 1242 > Aroclor 1016. A significant response (p < 0.05) in males was seen only for the high dose of Aroclor 1260. A small increase in the incidence of thyroid gland follicular cell adenomas was noted in males for Aroclors 1242, 1254, and 1260, with the incidence being uniform across dose groups and Aroclor mixtures. For females, increased survival relative to controls was observed for all Aroclor treatment groups. A significantly decreased trend in the incidence of mammary gland neoplasms compared to control was also noted for females receiving Aroclors 1242, 1254, and 1260.

Histopathologic evidence for parvovirus infection in dogs.

Two dogs kenneled at a commercial establishment died of a disease manifested as severe hemorrhagic diarrhea. Histopathologic findings in both dogs bore a striking resemblance to those typical of feline infectious enteritis. Viral particles resembling members of the Parvoviridae family were observed in the contents of the small intestine of one of the dogs. The disease was similar to the recently recognized canine gastroenteritis associated with a parvovirus-like agent.

An endemic focus of Trypanosoma cruzi infection in a subhuman primate research colony.

Leishmanial forms of Trypanosoma cruzi with multifocal pseudocysts were identified in a deceased adult female rhesus monkey (Macaca mulatta) that had been maintained in an outdoor primate colony in southern Texas. Subsequent clinical investigation of the remainder of the colony identified 20 additional monkeys seropositive for T cruzi. Concurrent epizootiologic surveys confirmed the presence of sylvatic reservoirs and triatomine vectors of T cruzi infection and identified a natural T cruzi transmission cycle. Veterinarians associated with the research colony were informed of the potential for further T cruzi transmission and appropriate insect vector and reservoir animal control programs were implemented..

The pathoparasitology of the alimentary tract and pancreas of nonhuman primates: a review.

A review of the literature concerning the gross and histologic lesions associated with protozoal and metazoal parasitism in the alimentary tract and pancreas of nonhuman primates is presented. In addition, the natural history, morphology, life cycle, methods for diagnosis, and potential for zoonotic disease are reviewed briefly for each parasite discussed. The parasite species reviewed in detail are those most common or most likely to produce lesions in the alimentary tract and pancreas of the nonhuman primate host. All parasites, both pathogenic and nonpathogenic, in each major group (protozoa: flagellates, sarcodines, sporozoans, neosporans, and ciliates; and metazoa: trematodes, cestodes, nematodes, acanthocephalans, and pentastomids) that have been reported in the nonhuman primate alimentary tract and pancreas are presented in tables.

The pathoparasitology of the alimentary tract and pancreas of nonhuman primates: a review.

A review of the literature concerning the gross and histologic lesions associated with protozoal and metazoal parasitism in the alimentary tract and pancreas of nonhuman primates is presented. In addition, the natural history, morphology, life cycle, methods for diagnosis, and potential for zoonotic disease are reviewed briefly for each parasite discussed. The parasite species reviewed in detail are those most common or most likely to produce lesions in the alimentary tract and pancreas of the nonhuman primate host. All parasites, both pathogenic and nonpathogenic, in each major group (protozoa: flagellates, sarcodines, sporozoans, neosporans, and ciliates; and metazoa: trematodes, cestodes, nematodes, acanthocephalans, and pentastomids) that have been reported in the nonhuman primate alimentary tract and pancreas are presented in tables.

Severe polyarthritis in a rhesus monkey: suggested Mycoplasma etiology.

A female juvenile rhesus monkey experienced a 3-wk period of vague lameness and limb disuse, followed by a severe attack of acute polyarthritis resulting in marked radiographic changes. The acute condition lasted about 3 wk and was followed by a chronic but active condition lasting another 13 mo until the animal was killed. Although a causative organism was not isolated, serologic and clinical laboratory data and histopathologic results were presented which suggest a diagnosis of mycoplasma polyarthritis.

Endometrial stromal tumor in a chimpanzee.

A 25-year-old female chimpanzee with disseminated tuberculosis also had two uterine tumors. One a typical leiomyoma and the other, which occluded the uterine lumen, was composed of cells resembling normal endometrial stroma in its proliferative phase. It was diagnosed as an endometrial stromal tumor and was similar to that which occurs in the human female. This is the first report of this lesion in a nonhuman primate.

Intestinal polyposis associated with oxyurid parasites in a chimpanzee (Pan troglodytes).

A 40-year-old male chimpanzee had multiple intestinal polyps associated with immature male oxyurid parasites. The gross and histologic characteristics of these lesions were identical to those produced by Nochtia nochti in the stomach and esophagus of Old World primates. It was theorized that the lesions resulted from hypersensitivity to oxyurid infection in an aberrant host.

Mycotic infections of the alimentary tract of nonhuman primates: a review.

Lesions of candidiasis, mucormycosis (phycomycosis), entomophthoramycosis, geotrichosis, cryptococcosis, paracoccidioidomycosis and coccidioidomycosis have been reported in the alimentary tract of nonhuman primates. Candidiasis and mucormycosis were reported most often. Both Old and New World monkeys and great apes are susceptible; infection is rare in prosimians. Ulcers and necrosis of the mucosa of the alimentary tract are the principal gross lesions. A granulomatous inflammatory process occurs in which the fungi are visible histologically on hematoxylin and eosin (HE)-stained sections, but they are seen and characterized better when stained with periodic acid-Schiff (PAS) or Gomori methenamine silver (GMS) techniques. Cultural or immunofluorescence studies, or both, are necessary for specific identification of the fungi. Immunosuppression is suggested as a predisposing factor in certain mycotic diseases.

Spontaneous occurrence of Angiostrongylus costaricensis in marmosets (Saguinus mystax).

Two marmosets imported from Iquitos, Peru, were found to be infected with Angiostrongylus costaricensis. Both animals had large solitary granulomas involving the wall and adjacent mesentery of the small intestine. Histopathologic examination showed the adult nematodes in the lumina of the mesenteric arteries that coursed through these granulomas. The inflammatory reaction was associated with numerous degenerating eggs and larvae. This is the first report of this parasite in nonhuman primates and extends its geographic range to Peru. In addition, in one animal, Dipetalonema sp were seen free in the abdominal cavity, and pleroceroid larvae (spargana) were in the loose connective tissue of the left axilla. This animal also had microgranulomas associated with eggs and larvae of Angiostrongylus in the kidney, liver, lung, and heart.

Mycotic infections of the alimentary tract of nonhuman primates: a review.

Lesions of candidiasis, mucormycosis (phycomycosis), entomophthoramycosis, geotrichosis, cryptococcosis, paracoccidioidomycosis and coccidioidomycosis have been reported in the alimentary tract of nonhuman primates. Candidiasis and mucormycosis were reported most often. Both Old and New World monkeys and great apes are susceptible; infection is rare in prosimians. Ulcers and necrosis of the mucosa of the alimentary tract are the principal gross lesions. A granulomatous inflammatory process occurs in which the fungi are visible histologically on hematoxylin and eosin (HE)-stained sections, but they are seen and characterized better when stained with periodic acid-Schiff (PAS) or Gomori methenamine silver (GMS) techniques. Cultural or immunofluorescence studies, or both, are necessary for specific identification of the fungi. Immunosuppression is suggested as a predisposing factor in certain mycotic diseases.

Pharmacological and toxicological evaluation of orally administered pyridostigmine in dogs.

Pyridostigmine bromide, a reversible cholinesterase inhibitor, was administered orally (capsule gavage) to beagle dogs (10-15 months of age) of both sexes once daily at 5, 10, or 20 mg/kg for 14 days; every 8 hr at 2 or 5 mg/kg for 28 days; or every 8 hr at 0.05, 0.5, or 2 mg/kg for 3 months as part of its preclinical safety assessment. A small portion of the dogs receiving pyridostigmine for 3 months were allowed an untreated recovery period of an additional 3 months. Daily doses of 10 or 20 mg/kg were lethal to some of the dogs when given for up to 14 days and caused severe intestinal distress, including diarrhea, emesis, and reddened feces in all animals. The cause of death was intestinal intussusception. Signs of systemic toxicity apparent at these doses included hypersalivation and tremors. Similar but less severe effects were produced by 5 mg/kg per day; plasma cholinesterase activities were inhibited by all three doses in a dose-related manner. Signs of toxicity in the 28-day and 3-month studies were generally limited to the gastrointestinal tract and included diarrhea or soft stools and reddened or mucoid-containing stools; these signs appeared to reverse upon discontinuation of the drug. A single dog at 2 mg/kg every 8 hr developed an apparent intussusception. There were no pathological changes in clinical chemistry, hematology, or urinalysis parameters associated with doses of 0.05, 0.5, or 2 mg/kg every 8 hr for up to 3 months, nor were any drug-related lesions observed upon gross necropsy and microscopic evaluation of the major tissues and organs. Red blood cell (RBC) acetylcholinesterase (AChE) activities in the 3-month study were inhibited by approximately 10, 50, and 70% in the 0.05, 0.5, and 2 mg/kg every 8-hr dose groups, respectively, and these degrees of inhibition were maintained throughout the period of treatment. These data suggest that prolonged oral administration of pyridostigmine at doses sufficient to cause profound and sustained inhibition of RBC AChE activity (i.e., as high as 70%) cause mainly local, gastrointestinal distress related to altered intestinal motility. At the extreme, this can be manifested as a life-threatening intestinal intussusception. Systemic anticholinesterase effects (other than enzyme inhibition) were observed only at doses of 2 mg/kg and greater, while local (gastrointestinal) effects and inhibition of RBC AChE were observed at doses as low as 0.05 mg/kg.

Results and conclusions of the National Toxicology Program's rodent carcinogenicity studies with sodium fluoride.

The US National Toxicology Program (NTP) has conducted toxicity and carcinogenicity studies with sodium fluoride administered in the drinking water to F344/N rats and B6C3F1 mice. The drinking water concentrations used in the 2-year studies were 0, 25, 100, or 175 ppm sodium fluoride (equivalent to 0, 11, 45 or 79 ppm fluoride). Survival and weight gains of rats and mice were not affected by fluoride treatment. Animals receiving sodium fluoride developed effects typical of dental fluorosis, and female rats given 175 ppm had increased osteosclerosis. There were no increases in neoplasms in female rats or in male or female mice that were attributed to sodium fluoride administration. There was equivocal evidence of carcinogenic activity of sodium fluoride in male rats based on the occurrence of a small number of osteosarcomas in treated animals.

Segmental replacement of the ureter using Sparks' mandrils. An experimental study.

Segmental ureteral replacement with free autogenous fibroelastic Dacron tube grafts in three dogs was unsuccessful during preliminary trials. However, a proliferation of urothelium, smooth muscle, and blood vessels throughout the length of the grafts was demonstrated, providing an encouraging potential for further investigations. Technical refinements are suggested that may provide for improved success with experimental ureteral replacement.

Neurotoxicity and carcinogenicity of N-methylolacrylamide in F344 rats and B6C3F1 mice.

Toxicology and carcinogenicity studies of N-methylolacrylamide were conducted by administering the chemical by gavage in water to both sexes of F344/N rats and B6C3F1 mice 5 times per week for 16 d, 13 wk, or 2 yr. In 16-d studies, rats receiving doses of 200 mg/kg or higher and mice receiving 400 mg/kg died. In 13-wk studies, all rats given 100 mg/kg or higher doses died. Rats receiving 50 mg/kg or higher doses developed hindlimb ataxia progressing to paralysis. In neurobehavioral assessments, decreased forelimb and hindlimb grip strength occurred in rats at doses as low as 12.5 mg/kg. Landing footspread was also increased in dosed rats compared to controls. Axon filament and myelin sheath degeneration in the spinal cord and/or peripheral nerves occurred in rats receiving doses of 25 mg/kg or higher. Necrosis in the granular cell layer of the cerebellum was seen in rats given 200 mg/kg. Mice receiving 200 mg/kg in 13-wk studies died. Decreased grip strength was noted in mice at doses as low as 25 mg/kg, and rotarod performance was also affected by N-methylolacrylamide administration, but no neuropathology was seen microscopically. Testicular weights were decreased at doses as low as 12.5 mg/kg, and hepatocellular necrosis, thymic lymphocyte necrosis, and hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were seen in mice that died (200 mg/kg). In 2-yr studies, survival and weight gains in male and female rats receiving doses of 6 or 12 mg/kg/d were minimally affected. No biologically important clinical signs or neoplastic or nonneoplastic lesions were attributed to N-methylolacrylamide administration to rats, suggesting that higher doses could have been tolerated. In mice, survival was not different between dosed and control groups (0, 25, or 50 mg/kg/d). Body weights were higher by as much as 25% in dosed compared to control groups. No compound-related clinical signs were observed, but increases in neoplasms of the harderian gland, liver, and lung were clearly related to chemical administration in both sexes of mice. Benign granulosa-cell neoplasms of the ovary were also increased in dosed female mice.