The anatomical characteristics of the upper respiratory tract of various experimental animals and man are described. There are a number of differences and similarities macroscopically and microscopically between the species. Perhaps one of the most obvious examples of anatomical differences is in the structure of the turbinates. Some of the differences could affect deposition and clearance of particles in the nasal cavities. Effects of compounds in the nasal cavity, larynx, and trachea can differ depending on the cellular composition of the mucosa.

Abstract.Hepatoblastomas from B6C3F1 and BALB/c mice were examined by light and electron microscopy and by immunohistochemical reactions for alpha-fetoprotein, keratin, and vimentin. Tumors occurred in one group of a chronic bioassay for the interaction of diet, genetic strain, and the carcinogen, 2-acetylaminofluorene. Tumors had several populations (including epithelial and mesenchymal cells) in various stages of differentiation. Neoplastic epithelial cells had features of embryonal hepatocytes, such as sparse cytoplasmic organelles, absence of glycogen, abundant free ribosomes, occasional bile canaliculi, and peroxisome-like dense bodies. Embryonal fibroblast-like cells had pleomorphic and folded nuclei with prominent perinuclear chromatin and dispersed cytoplasmic organelles. Fibroblast-like cells were surrounded by bundles of collagen fibrils. Intermediate or transitional types of cells were seen. No tumor cells were immunoreactive for mouse alpha-fetoprotein (AFP) antibody, unlike those in hepatocellular adenomas or carcinomas. Epithelial and mesenchymal tumor cells contained intermediate filaments throughout the cytoplasm; some of these cells stained for keratin but not for vimentin. These findings suggest that mouse hepatoblastomas are derived from bipotential liver blastema cells and are composed of a mixture of several cell populations.Hepatoblastomas occur spontaneously and have been induced by chemical treatment in several strains of Distinctive histological features of these tumors, described by Turusov and colleagues in 1 973,42 included tumors diagnosed previously as hepatoblast~mas,~O poorly differentiated cholangiocarcinomas,29 cholangi~ma,~~ and an unusual tumor.4 We are not aware ofreports of hepatoblastomas in mice since 1973, except a case with squamous differentiati~n~~ and N-nitrosodiethylamine-induced hepatobla~tomas.~~ The existence of mouse hepatoblastoma in aged animals is still controversial, and its cell of origin is obs~u r e .~,~~The present study defines the detailed morphologic characteristics of this tumor by histological and ultrastructural observations together with immunohistochemistry for alpha-fetoprotein (AFT), keratin, and vimentin. Materials and Methods AnimalsMice used were part of a study conducted at the National Center for Toxicological Research (NCTR) to compare incStCrlfC3H/Nctr), raised at the NCTR. Diets were NIH-07 and AIN-76A, fed ad libitum. The carcinogen was 2-acetylaminofluorene (2-AAF) incorporated in the diets (Table 1). The study included 96 mice of each sex and strain at each dose group. Design for the AIN diet-and the NIH diet-fed groups were identical (Table 1). Animals were lulled after 24 months or when they became moribund by exsanguination under ether anesthesia.

Standard toxicological studies in dogs using high doses of vasodilators and positive inotropic/vasodilating agents give rise to a species-specific cardiotoxicity. The reason may be the extreme sensitivity of the dog to the pharmacological effects of these drugs; exaggerated pharmacodynamic effects and prolonged disturbance of homeostasis mechanisms often are responsible for the observed organ lesions. An assessment of the toxicological relevance and the risk for patients taking the drugs at therapeutic doses cannot be made without taking into account their pathomechanisms and the pathophysiological basis of the exceptional reaction patterns occurring in dogs. A large series of vasodilating and positive inotropic agents are presented, their pharmacological properties are described, and toxicological effects in dogs are compared. In view of the poor correlation between the distinct cardiac lesions induced in dogs and a lack of comparable toxicity in humans, it appears desirable to reassess the adequacy of the standard toxicological approaches for these substances.

The prostates of 1775 (614 control and 1161 experimental) 2-year-old F344 rats from 12 different carcinogen bioassays conducted by the Bioassay Program of the NCI and the NTP were evaluated histologically. The incidence of prostatic lesions including (atypical) hyperplastic foci, adenomas, and carcinomas was 6.8%. There was no difference in the type or incidence of the lesions between treated and untreated animals. Adenomas or carcinomas were found in 71 (4.0%) of the rats, primarily as incidental findings. The number of tumors and hyperplastic foci varied from laboratory to laboratory depending on the anatomical localization of the plane of the section. Most of the neoplasms were found in the ventrolateral lobes of the prostate (ventral prostate). When adequate sections were prepared of the ventral lobe, 10-20% of the prostates had these proliferative lesions. The lesions were usually small and originated in the epithelium of the alveoli and small ducts and were usually small and originated in the epithelium of the alveoli and small ducts and were not associated with the common inflammatory lesions of the rat prostate. Thin fibrous capsules were formed in a few of the larger tumors. Metastases were not observed but there was local invasion into alveoli, ducts and interstitial connective tissue. Evidence is presented that the atypical hyperplasias progress to adenoma and carcinoma. The F344 rat offers a potential model for the study of latent prostatic preneoplastic and neoplastic lesions.

The anatomical characteristics of the upper respiratory tract of various experimental animals and man are described. There are a number of differences and similarities macroscopically and microscopically between the species. Perhaps one of the most obvious examples of anatomical differences is in the structure of the turbinates. Some of the differences could affect deposition and clearance of particles in the nasal cavities. Effects of compounds in the nasal cavity, larynx, and trachea can differ depending on the cellular composition of the mucosa.

We have recently demonstrated that the dihydropyridine-derivative B859-35 has a selective chemotherapeutic effect on experimentally induced neuroendocrine lung tumors in hamsters. These tumors resembled human atypical lung carcinoids morphologically and expressed mammalian bombesin, calcitonin and neuron-specific enolase. In the hamster model, B859-35 had no antiproliferative effect on pulmonary adenomas of Clara cell origin. In this study, we have tested the antiproliferative effects of B859-35 and of the Ca(2+)-channel blocker Verapamil in vitro on three human lung cancer cell lines. The neuroendocrine cell line NCI-H727 is derived from a lung carcinoid and expresses mammalian bombesin and calcitonin. Two non-neuroendocrine cell lines are derived from peripheral pulmonary adenocarcinomas, with line NCI-H322 expressing features of Clara cells while line NCI-H358 expresses features of alveolar type II cells. B859-35 was a potent antiproliferative agent in the neuroendocrine line NCI-H727 at concentrations as low as 0.001 pM, while it inhibited cell proliferation in the two other cell lines at concentrations of 100 nM and above. Verapamil inhibited cell proliferation in the neuroendocrine line NCI-H727 at concentrations of 1 nM and above.

Abstract. Of 60,048 aging F344 rats, 28 had ganglioneuromas of the adrenal gland. The rats were between 58 and 122 weeks old; 25 of them between 93 and 122 weeks when the tumors were found. The neoplasms were composed of large or small typical ganglion cells with a large pale nucleus and a prominent, often eccentric, nucleolus. The ganglion cells usually were distributed throughout the medullary tumor and surrounded by various numbers of supporting cells, including Schwann's cell types, and capsular or satellite cells. Often there was no clear-cut border between ganglion cells and neoplastic pheochromocytes. Electron microscopy of re-embedded tissues showed neurosecretory granules and cytoplasmic areas with an extensive rough endoplasmic reticulum (Nissl substance) in the ganglion cells and axons. The Schwann's cells were surrounded by a basement membrane and formed long cytoplasmic extensions around the axons. Almost all ganglioneuromas were associated with neoplastic pheochromocytes which usually were located at the edge of the tumors.Tumors of neurogenic origin (neuroblastoma, ganglioneuroblastoma, ganglioneuroma) are the most common solid abdominal neoplasms found in children [1,2,5,12,16,22,23]. Forty percent of them arise in the adrenal medulla [6]. We do not presently have a model system for studying the pathogenesis of these tumors in animals. None of the known cancer-inducing agents has produced a significant number of tumors of this type in the abdominal cavity of experimental animals, nor do they often occur spontaneously in untreated animals [7][8][9][10]19,20].Histological data on more than 60,000 F344 rats had accumulated from past bioassays. From these, we reviewed the morphology of 28 ganglioneuromas diagnosed histologically from adrenal gland tumors of F344 rats. The tumor samples were retrieved from the bioassay experiments conducted in the NCI Carcinogenesis Testing Program from 1972 to 1979 [13], and included material from chemically treated and untreated (control) rats. Materials and MethodsThe rats had been obtained when 6 weeks old from commercial suppliers and studied for 2 years [9]. Necropsies were done on all animals found dead and on those that were moribund 614

The carcinogenic effects of diisopropanolinitrosamine (DIPN) were tested in Sprague-Dawley rats and were then compared with results produced earlier by the same substance in Syrian hamsters. In addition to the similarities, several differences were noted; for example, DIPN caused pancreatic tumors in all the hamsters, but only 1 pancreatic tumor was observed among the 150 rats. Administration of DIPN to rats led to the development of neoplasms in the nasal and paranasal cavities, lungs, thyroid gland, esophagus, liver, and kidneys. The highest tumor incidence in rats was in the nasal cavities. Almost all the pulmonary neoplasms were malignant and were usually squamous cell carcinomas. We found a 15.4-50% incidence of malignant tumors of the thyroid gland; we also noted that thyroid neoplasms occurred at almost the same rate (36.4-50%) in the groups given 1/5, 1/10, and 1/20 the median lethal dose.