A 90-day drinking water toxicity study in rats of the environmental contaminant ammonium perchlorate.

Perchlorate (ClO(4)(-)), the dissociated anion of perchlorate salts such as ammonium, potassium, and sodium perchlorate, has been recently recognized as a persistent and pervasive contaminant of drinking water supplies in a number of metropolitan areas. Perchlorate is of concern because of uncertainties in the toxicological database available to address the potential human health effects of low-level exposure. The purpose of this study was to evaluate the subchronic toxicity of perchlorate when administered to Sprague-Dawley rats as ammonium perchlorate (AP) for 14 or 90 days. The study consisted of an untreated control group and five treatment groups that received continuous exposure to AP via the drinking water at dosage levels of 0.01, 0.05, 0.2, 1.0, and 10.0 mg/kg/day. The study design included a nontreatment recovery period of 30 days to evaluate the reversibility of any AP-induced effects at the 0.05, 1.0, and 10.0 mg/kg/day levels. The study also investigated the potential effects of AP on male sperm parameters, female estrous cyclicity, bone marrow micronucleus formation, and serum hormone levels, i.e., triiodothyronine (T(3)), thyroxine (T(4)), and thyroid stimulating hormone (TSH). No toxicologically meaningful differences were observed between the control and AP-treated groups with respect to survival, clinical observations, body weights, food consumption, water consumption, ophthalmology, hematology, clinical chemistry, estrous cycling, sperm parameters, or bone marrow micronucleus formation. A target organ effect was produced by AP in the thyroids of male and female rats at the 10 mg/kg/day level after 14 and 90 days of exposure. The effect was characterized by significantly increased thyroid weights and thyroid histopathology consisting primarily of follicular cell hypertrophy with microfollicle formation and colloid depletion. These changes were reversible after a nontreatment recovery period of 30 days. Statistically significant changes in TSH and thyroid hormones were observed at all AP dosage levels tested; however, no thyroid organ weight or histopathological effects were observed at AP dosage levels < or = 1.0 mg/kg/day. In the absence of thyroid organ weight and histopathological effects, the toxicological significance of TSH and thyroid hormone changes at AP dosage levels < or = 1.0 mg/kg/day remains to be determined.

Influence of dietary protein, fat, and fiber on growth, blood chemistry, and tumor incidences in Fischer 344 rats.

Composition of diets may influence growth, diseases, tumor rates, and responses to chemical treatment. For two years, Fischer 344 rats were fed the NIH-07 open-formula nonpurified diet (approximately 23% protein, approximately 5% fat, and approximately 3.5% fiber) and nonpurified experimental diets (NTP-90, NTP-91, and NTP-92) containing lower protein and higher fat and fiber (14.6-15.3% protein, 7.2-8.5% fat, and 9.4-14% fiber) than the NIH-07 diet. Rats were evaluated for growth patterns, survival, hematology, serum chemistry, nephropathy, and tumor incidences. Growth patterns were similar in rats fed the experimental diets and in those fed the NIH-07 diet. However, in rats fed the experimental diets, the adult body weights were significantly (6-9%) lower and the survival at 110 weeks of age was significantly higher (15-20%) than in rats fed the NIH-07 diet. Lower protein content of experimental diets decreased the severity of nephropathy. Higher fat content of experimental diets appears to have decreased the incidence or delayed the development of leukemia and associated mortality in males. Higher fiber content of experimental diets appears to have delayed the development of mammary tumors and associated mortality in females. Higher fat and/or fiber of the experimental diets decreased the incidence of pheochromocytomas in males. The lower protein and higher fat and fiber contents of the experimental diets decreased the spontaneous tumor burden in two-year studies. These studies indicate that diets for rats in long-term studies could be modified to decrease the severity of nephropathy and to decrease/delay the development of spontaneous tumors.

U.S. military working dogs with Vietnam service: definition and characteristics of the cohort.

We verified and corrected inaccuracies in descriptive profile information on military working dogs (MWDs) that died from 1965 to 1980 and were reported in the Armed Forces Institute of Pathology Registry of Veterinary Pathology. Using other available military records, we determined which dogs served in Vietnam. Identified were 3,895 MWDs with a unique identity tattoo that served in Vietnam, of which 2,389 served exclusively with U.S. military forces and died in Vietnam. Another 479 Vietnam veteran MWDs completed their service elsewhere. This overall effort resulted in signalment corrections, generally age at death, in 21% of the Registry MWD accessions during the study period. The improved definition and characterization of the Vietnam cohort will lead to greater precision in epidemiologic investigations of the health effects from the Vietnam experience in U.S. military working dogs.

Comparison of the toxicity of citral in F344 rats and B6C3F1 mice when administrated by microencapsulation in feed or by corn-oil gavage.

A study of the potential effects of microencapsulation on the toxicity of citral was conducted in 14-day continuous feeding studies with both sexes of F344 rats and B6C3F1 mice. Toxicity by the feeding route was compared with that from bolus doses of the neat chemical in corn oil administrated by gavage. Both sexes of rats and mice were given diet containing 0, 0.63, 1.25, 2.5, 5 and 10% citral microcapsules. These feed formulations were equivalent to daily doses of 0, 142, 285, 570, 1140 and 2280 mg citral/kg body weight for rats and 0, 534, 1068, 2137, 4275 and 8550 mg citral/kg body weight for mice. The daily gavage doses were 0, 570, 1140 and 2280 mg citral/kg body weight for both sexes of rats, and 0, 534, 1068 and 2137 mg citral/kg body weight for both sexes of mice. Citral microcapsules administered in the diet did not cause mortality in mice or rats. Toxicity was confined to decreases in body weight at the 10% concentration in mice, at the 5 and 10% concentrations in rats, and decreases in absolute weights of the liver, kidney and spleen at the 10% concentration in rats. The only histopathological change observed was minimal to mild hyperplasia and/or squamous metaplasia of the respiratory epithelium in the anterior portion of the nasal passages of rats fed 5 or 10% citral microcapsules. By contrast, citral gavage caused mortality in five out of five male and female mice at 2137 mg/kg body weight, and in two out of five male mice at 1068 mg/kg body weight. There were dose-related increases in absolute liver weights of male and female mice. Cytoplasmic vacuolization of hepatocytes occurred in all female mice gavaged with 1068 and 2137 mg citral/kg body weight, and in male mice from the 2137 mg/kg dose group. Necrosis, ulceration and/or acute inflammation of the forestomach occurred in the high-dose mice of both sexes. Inflammation and/or hyperplasia of the forestomach occurred in about half of the male and female mice dosed with 1068 mg citral/kg. Citral gavage at doses that were equivalent to up to 10% in the diet (2280 mg/kg body weight) did not cause toxicity in rats, except for minimal hyperplasia of the squamous epithelium of the forestomach in high-dose males.(ABSTRACT TRUNCATED AT 400 WORDS)

Early tissue reaction to textured breast implant surfaces.

Capsular contracture around breast implants with smooth surfaces continues to be an unpredictable complication. Some surgeons believe that silicone implants covered with porous polyurethane foam have a lowered potential to contract. These textured implants are not as biocompatible as silicone. Recently, silicone implants with textured surfaces have been introduced with the hope that the incidence of unacceptable implant contracture will be reduced. Using a rat implant model, the tissue reaction to textured implant surfaces was assessed. The implant surfaces evaluated were Silastic II, Siltex, MISTI, Biocell, Silastic MSI, and Même. Disks of each implant material were implanted under the dorsal skin of rats for a period of 28 days. Each implant with its surrounding tissue was excised, processed for histological analysis, and assessed for the tissue's response to the implant with particular emphasis on the formation of a continuous collagen capsule. The results indicated that the magnitude of surface texturing influenced the development of a complete capsule. Implant surfaces with a texture of less than 150 microns in height or depth (Silastic II, Siltex, and MISTI) resulted in the formation of complete capsules. An implant (Biocell) with irregular texturing (200-350 microns) produced an organized capsule over most of its surface with localized interruptions of the capsule at the sites of its deepest cavities. Implant surfaces with texturing that exceeded 350 microns in height or depth (Silastic MSI and Même) resulted in inhibition of the formation of a continuous capsule during this 28-day study.

An epizootic of measles in captive silvered leaf-monkeys (Presbytis cristatus) in Malaysia.

An epizootic of measles occurred in a group of 31 silvered leaf-monkeys (Presbytis cristatus) that had been in captivity for 4-12 months. Twenty-four of the monkeys exhibited a maculopapular rash that persisted for 6-9 days. A serous to mucopurulent nasal discharge and conjunctivitis were seen in some animals. Eight monkeys died during the epizootic; however, their deaths could not be directly attributed to measles. Serum samples from the surviving monkeys collected 1-2 months prior to, and 5 weeks after, the epizootic were examined by the complement-fixation and hemagglutination-inhibition tests for antibodies to measles virus. The preepizootic complement-fixation titers were all less than 1:4 and hemagglutination-inhibition titers, less than 1:10. The postepizootic complement-fixation titers in 21 of 23 surviving monkeys ranged from 1:8 to 1:128, and hemagglutination-inhibition titers in 22 of 23 monkeys ranged from 1:40 to 1:80 or greater.

Stylostome formation by Leptotrombidium mites (Acari: Trombiculidae).

The modes of stylostome formation by larvae (chiggers) of Leptotrombidium intermedium, L. fletcheri, L. arenicola, and L. deliense in parasitized mouse skin were studied histologically in relation to their capacity to transmit Rickettsia tsutsugamushi. Three types of stylostome formation were recognized among the different species: the epidermal stylostome formed by the larva of L. intermedium; the mesenchymal stylostome formed by the larva of L. fletcheri; and, the mixed stylostome formed by the larva of both L. arenicola and L. deliense. Dermal inflammations related to the three types of stylostomes were histologically defined. The possible importance of stylostome characteristics to the transmission of rickettsial organisms is discussed.

Platelet migration inhibtion as an indicator of immunologically mediated target cell injury in canine ehrlichiosis.

A platelet migration inhibition test was devised to determine the presence of antiplatelet activity in serum collected from experimentally produced and natural cases of canine ehrlichiosis. The maximum platelet migration inhibition effect was observed during the acute phase of the disease and before the appearance of specific humoral antibody, measured by the indirect fluorescent-antibody test. Platelet migration inhibition may be one of the earliest events leading to pancytopenia. In most cases, sera positive for humoral antibodies also were positive for platelet migration inhibition, although no direct correlation was evident between the serological titer and the degree of platelet migration inhibition. Inoculation of dogs with uninfected canine blood did not induce the production of inhibition factor or antibody activity, which precluded a histocompatibility response to the cellular elements in the inoculum. Scanning electron microscopy indicated that the platelet inhibition factor interfered with platelet migration by inhibiting pseudopod formation. Affected platelets became rounded and showed evidence of clumping and leakage.

Pathogenesis of infection with Rickettsia rickettsii in the dog: a disease model for Rocky Mountain spotted fever.

Dogs inoculated with Rickettsia rickettsii developed a clinical syndrome ranging in severity from a mild febrile exanthema to death within six days after inoculation. The severity of the disease appeared to be dose-related, and the signs were comparable to R. rickettsii infection in humans on a clinical and hematological basis. Dogs were rickettsemic for 10 to 14 days after infection. In most animals the level of rickettsemia was greater than or equal to 10(2.5) guinea pig intraperitoneal 50% infectious doses (GPID50). Infected dogs responded serologically as determined by indirect fluorescent antibody methods and were protected when challenged six to 12 months later with 10(7.0) GPID50 of the homologous strain of R. rickettsii. The monocyte culture technique was successfully used for the detection of rickettsemia, and the results compared favorably with those obtained by the guinea pig inoculation method of isolation.

Studies on the pathogenesis of Rickettsia rickettsii in the dog: clinical and clinicopathologic changes of experimental infection.

Beagle dogs inoculated with the agent of Rocky Mountain spotted fever, Rickettsia rickettsii, developed a clinical syndrome that extended from febrile exanthema to death and appeared to be dose related. Infected dogs were anorectic and lethargic and developed cutaneous lesions characteristic of Rocky Mountain spotted fever, including petechia, ecchymosis, edema, and necrosis. Hematologic changes after inoculation included anemia, leukopenia proceeding to leukocytosis, and thrombocytopenia. Changes in blood chemistry values included increases in serum alkaline phosphatase and cholesterol, and hyponatremia and hypochloremia. The prominent histopathologic change was necrotizing vasculitis. The canine disease is comparable with human Rocky Mountain spotted fever on a clinical, hematologic, biochemical, and pathologic basis, and may provide a model system for this disease in man. The results suggest the dog may be involved in the epidemiology of R rickettsii infections.

Use of 59Fe for sheep erythrocyte kinetic studies.

Erythrocyte (RBC) survival time as determined by in vivo 59Fe-labeled RBC in 6 adult sheep was 111.7 (SEM +/- 8.4) days. The plasma clearance (T/2) of 59Fe was 148 (+/- 17.3) minutes and the maximum RBC uptake of 59Fe was 52.4% (+/- 3.6%). Plasma iron turnover rate was 0.356 (+/- 0.016) mg/kg/24 hours, and RBC iron turnover rate was 0.186 (+/- 0.016) mg/kg/24 hours. Blood volume measurement was 53.5 (+/- 3.9) ml/kg of body weight.

Electron microscope study of experimental enteric infection in neonatal dogs with a canine coronavirus.

Neonatal dogs, inoculated orally with coronavirus 1-71, grown in canine kidney cell cultures, developed diarrhea and a severe enteritis characterized by atrophy of the villi, changes in the enterocytes, and accelerated epithelial cell loss. Electron microscopy of the mucosal epithelium, 4 days after challenge, showed that the virus penetrated into the enterocytes between microvilli, possibly by pinocytotic mechanism. In the enterocytes, virions were most often enclosed, singly or in groups, in cytoplasmic vesicles. They were less frequently found in the cisternae of the Golgi apparatus, the endoplasmic reticulum, or in the dilated perinuclear space and only rarely, free in the cytoplasm. Virions replicated by budding only on the smooth.membranes of the cytoplasmic vesicles. The infected cells showed a variety of cytopathic effects, some nonspecific, such as disruption of the microvilli, loss of density of the cytoplasm, presence of lipid inclusions, alteration of mitochondria, and dilation of the endoplasmic reticulum and Golgi cisternae and of the perinuclear space. Other cytopathic effects, characteristic of the coronavirus infection, consisted of formation of dense filamentous structures and of membrane-bound bodies. Progeny virions appeared to discharge into the gut lumen through the disrupted cell membranes of infected enterocytes still in situ or following their premature shedding.

Oral infection of mammals with Sarcocystis fusiformis bradyzoites from cattle and sporocysts from dogs and coyotes.

Individual sporocysts containing 4 sporozoites were shed in the feces of dogs, foxes, and raccoons after ingestion of bovine tissue infected with Sarcocystis fusiformis bradyzoites. No sporocysts were shed by cats, monkeys, swine, skunks, ferrets, rats, guinea pigs, or rabbits after ingestion of similar bovine tissue. The shedding of sporocysts by dogs that had ingested tissue from a bovine experimentally infected with sporocysts from coyotes indicated that both canids were definitive hosts for the same species of Sarcocystis. After oral inoculation wtih sporocysts from dogs previously fed infected bovine heart, a calf became infected; but sheep, swine, rats, mice, rabbits, and monkeys did not. These results show the narrow specificity of the asexual stages of this parasite for the bovine intermediate host and the wider, though still restricted, host range of the sexual stages of this parasite for coyotes, dogs, foxes, and raccoons, the definitive hosts.

Ultrastructural observations on Ehrlichia equi organisms in equine granulocytes.

The ultrastructure of the etiological agent of equine ehrlichiosis, Ehrlichia equi, was studied in equine peripheral leukocytes. The organisms occurred within membrane-lined cytoplasmic vacuoles of neutrophils and eosinophils. Ovoid, round, and rod-shaped profiles were observed. From 1 to 33 organisms were present in a thin-section profile of a cytoplasmic vacuole. Many cells contained multiple organism-containing vacuoles. The organisms had a cell wall and plasma membrane, and internally they consisted of electron-dense and lucid areas. A great variation in size was observed. The morphological features were most consistent with agents of the genus Ehrlichia.

Airsacculitis in the baboon.

A baboon (Papio anubis) that had been given opiate compounds through an indwelling catheter developed mucopurulent airsacculitis. After a prolonged course, the infection was eventually controlled by medical and surgical means. Air-sac involvement, though rarely reported in nonhuman primates, appeared frequently in the group of baboons to which this subject belonged--all of which were being treated experimentally with opiates. Proposed explanations for this unusual incidence included the propensity of opiates to induce a histamine response, almost continuous contamination of pathogenic bacteria in the indwelling catheters, and a suggested anatomic predisposition of the baboon larynx to drain secretions into the air sac.