An eight-month-old, female, mixed-breed dog was presented with bilateral hind-limb paralysis that reportedly developed over a two-to-three week period and was not associated with trauma. Plain radiographs of the spinal column were unremarkable, and a myelogram outlined an intramedullary mass of the spinal cord at the first lumbar (L1) vertebra. A hemilaminectomy was performed, and a mass that was identified histologically as nephroblastoma was excised from the spinal cord. Following surgery, the dog became fully ambulatory, and at 22 months postsurgery she remains clinically normal. The diagnosis, treatment, progression, histogenesis, and pathology of canine nephroblastoma are discussed.

The rabbit is occasionally used for inhalation and intranasal safety assessment studies, but there are no detailed descriptions of the anatomy or histology of the rabbit nose. To address this deficit, the nasal cavities of thirty-two control adult rabbits were sectioned and examined to provide mapping of the main epithelial types and histological structures present within the cavity and turbinates. Four levels of the nasal cavity were prepared and examined using anatomic landmarks. Level I was sectioned immediately posterior to the incisors, Level II at the first palatal ridge, Level III immediately anterior to the first upper premolar teeth, and Level IV immediately anterior to the first upper molar. Level I was lined predominantly by squamous epithelium with small amounts of thick transitional epithelium, and examination is recommended only for studies involving test article administration via instillation. Level II was lined primarily with transitional and respiratory epithelia, whereas Levels III and IV were lined with respiratory and olfactory epithelia and often contained nasal-associated lymphoid tissue. The vomeronasal organs were evident only in Level II. The similarities and differences of these features are compared with those of other common laboratory species (rat, mouse, dog, and cynomolgus monkey) and man.

A study was conducted in which the early kinetics (4 hr to 96 hr) of an infection by Salmonella enteritidis in older white leghorn hens was examined, and a molt was induced through withholding feed to determine its effect on the progression of this infection. Molted and unmolted hens were orally infected with 5-10 x 10(6) S. enteritidis on day 4 of the feed removal. At 4, 24, 48, 72, and 96 hr postinfection, liver, spleen, ileum, colon, cecum, and feces were removed from six hens per group and sampled for the presence of the challenge organism. By 24 hr postinfection, S. enteritidis was most prevalent in the cecum and feces of unmolted hens, and this prevalence continued throughout the experimental period. In molted hens, however, S. enteritidis could be detected in a high percentage (90-100%) of colon, cecum, and feces samples at 24 to 96 hr postinfection and in 67% or more of ileum samples at 48 to 96 hr postinfection, indicating a much wider distribution of the S. enteritidis along the intestinal tract than in unmolted hens. The numbers of S. enteritidis recovered from these alimentary samples were also significantly higher in molted than unmolted hens. S. enteritidis could not be detected in livers or spleens of either treatment group at 4 or 24 hr postinfection. At 48, 72, and 96 hr postinfection, 50% or more of the livers and spleens in both the molted and unmolted hens were positive for the challenge organism, but significantly more S. enteritidis was recovered from the organs of the molted hens at these three sampling times.(ABSTRACT TRUNCATED AT 250 WORDS)

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The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project ( www.toxpath.org/inhand.asp ) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet ( http://www.goreni.org/ ). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple (“uncomplicated”) increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators.

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Squamous metaplasia is a nonspecific adaptive response to chronic irritation in the larynx and is often diagnosed as a test item-related change in rat inhalation studies. Investigating scientists are frequently asked to assess the adversity of laryngeal squamous metaplasia and to interpret its relevance to human risk. One factor in predicting relevance to human risk is the kinetics (degree and speed) of recovery following the cessation of exposure to the test item. Most reports describing recovery from squamous metaplasia in the rat larynx discuss the more severe end of the spectrum of metaplastic change (moderate to severe) and include relatively long (6 weeks or more) recovery periods. We conducted 2 studies to evaluate the toxicity and recovery from any potential effects of 4-(Chloro-2-methylphenoxy) butyric (MCPB) acid, a herbicide, when administered by inhalation to young male Sprague Dawley rats for 3 to 4 weeks. The studies resulted in minimal to moderate laryngeal squamous metaplasia for which we describe the kinetics of recovery over 1 to 4 weeks. We found that the microscopic change epithelial alteration, which is normally considered to be a precursor in the development of squamous metaplasia, can occur as a transitional stage between squamous and normal epithelium during recovery.