The basic knowledges for toxicologic pathology of the nasal cavity in rat and mouse, including methods of preparation of their tissue specimens, anatomical and histological features, spontaneous lesions, and toxic injuries induced by chemical substances are described. In our laboratory, the following three frontal _??_ection_??_ are examined regularly: i.e. at the level of the posterior edge of upper incisor teeth (level I), at the incisive papilla (level II), and at the level of the anterior edge of upper molar teeth (level III). The _??_pontaneous lesions found in F344 rat are rhinitis, eosinophilic change of epithelial cells, accumulation of foreign bodies in the nasal cavity, submucosal deposition of calcium, venous thrombosis, and respiratory epithelium metaplasia of the olfactory epithelium. Those seen in BDF I mouse are rhinitis. eosinophilic change of epithelial cells, and respiratory epithelium metaplasia of the olfactory epithelium and nasal glands. The toxic injuries of the nasal cavity caused by chemical compounds including fumigant, formaldehyde, vinyl chloride monomer, dimethylnitrosamine, and glycol ether solvent are demonstrated.

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Human pulmonary changes caused by various chemicals including oncostatics, and also of “oxygen lung” and radiation pneumonitis were mentioned in comparison with idiopathic interstitial pneumonia. Experimental “diffuse alveolar damage” induced by paraquat and hyperoxygen was referred. Chemicals induce as a rule interstitial pneumonia but many oncostatics cause intraalveolar as well as interalveolar fibrosis.

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Male ICR mice were exposed to 2 mmol/Kg body weight of naphthalene by single intraperitoneal injection. Treated mice were killed consecutively from 2 hours to 14 days after treatment. Tissues were examined for alterations of the bronchiolar epithelial cells by light and electron microscopes, and for amount of pulmonary cytochrome P-450 by ascorbate PES method.
Morphologically, naphthalene caused a remarkable increase in smooth-surfaced endoplasmic reticulum of the Clara cells within 4 hours after treatment and the subsequent lesions including the exfoliated ciliated cells. Foamy cell-like Clara cells were observed in the bronchiolar lumen from 6 to 24 hours followed by a pronounced increase in number of flat ciliated cells covering the denuded surface of the bronchiolar tree 48 hours after treatment. These lesions wer almost completely recovered 7 days after treatment.
The amount of pulmonary cytochrome P-450 increased promptly and reached up to the maximum level 4 hours after treatment, paralleling with the remarkable increase in smooth surfaced endoplasmic reticulum of the Clara cells. Thereafter, cytochrome P-450 showed a decrease in amount simultaneously with degeneration and desquamation of the Clara cells and reduced by 40% of control amount 24 hours after treatment. There results seem to show that the activity of cytochrome P-450 is closely related with smooth surfaced endoplasmic reticulum of the Clara cells, and naphthalene-induced pulmonary damage is mediated by cytochrome P-450.

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Liver cell necrosis was caused in beagle dogs, whose blood in amount of one to two percent of the bodyweight was removed almost everyday for 6 weeks and their hematocrit values were approximately 10% at necropsy time. When animals are in a severe anemic condition attributable to drug administration in toxicological studies, anemia should be considered as a causative factor of liver damage in addition to the possibility of the direct effect of chemicals on the liver.

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The carcinogenicity of commercial safflower yellow was examined in Fischer 344 rats of both sexes. Commercial safflower yellow was mixed in basal diet at levels of 0, 2.5 or 5.0%, and groups of 50 male and 50 female rats were administered each of these diets ad libitum. for 108wk. At final sacrifice no statistically significant differences between treated and control rats regarding mean body weight, or mortality, which was very low, were observed in either male or female. Many tumors developed in all groups including the controls and the organ distribution of neoplasms and their histological characterisitics did not differ significantly from those reported to occur spontaneously in this strain of rats. With the exception of C-cell adenomas of the thyroid gland which were increased in males receiving the 5.0% dose, no significant compound-related increases in tumor incidence over the corresponding control group were observed. Furthermore, such C-cell adenomas of the thyroid gland are frequent spontaneous tumors in F344 rats and the observed level was within the reported treatment-independent range. Moreover, no equivalent trend could be distinguished in the females. From these findings, it is concluded that commercial safflower yellow dose not induce tumors in F344 rats, when administered orally at doses of up to 5.0% mixed in basal diet for as long as 108wk.

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Immunohistochemical studies were performed on locally growing finger tip-sized tumors induced by the direct dusting of 1 mg 7. 12-dimethylben_??_(a) anthracene (DMBA) powder to the right inguinal mammary tissue of both female and male 30-day-old Sprague-Dawley rats. A variety of benign and malignant tumors of epithelial and/or mesenchymal origin were detected histologically in both sexes of rats. In tumor tissues, as well as in normal mammary glands, immunoreactivity with actin distinctly demonstrated the myoepithelial cells. Type IV collagen clearly separated the parenchymal cells from the surrounding mesenchymal cell_??_. Normal periductal/intralobular mesenchymal cells of the mammary tissues were found only to be vimentin positive, whereas some neoplastic mesenchymal cells were found to express actin. Desmin was found in a few neoplastic mesenchymal cell_??_. This revealed that neoplastic mesenchymal element_??_ were composed of fibroblast, myofibroblast, and muscular nature.

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High dose (500mg/kg) and low dose (300mg/kg) of 2, 5-hexanedione were orally administered to female Sprague-Dawley rats for 4 and 8 weeks, respectively, and the influence of these treatments on the nerve tissue was examined hisologically and ultrastructurally. Abnormal gait was observed in the high dose group at the 4th week of treatment, but no neurological signs could be detected in the low dose group during 8 weeks of treatment. In the histopathological examination, the brain of animals belonging to the high dose group showed edema and necrosis in the thalamus and vacuolation in the oerebellar and vestibular nuclei. Small foci of hemorrhage were rarely observed in the thalamus. In the low dose group, the histopathological changes were characterized by axonal swelling in the cerebellar white matter, fasciculus gracilis of the cervical cord, and peripheral nerves. The swollen axons contained numerous neurofilaments with disorganized arrangement. Edema and necrosis in the thalamus or vacuolar change in the cerebellar and vestibular nuclei were not detected in the low dose group. These results indicated that the abnormal gait in the high dose group could be ascribed to the changes in the thalamus or in the cerebellar and vestibular nuclei.

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Clofibrate, one of hypolipidemic compounds, has been shown as a hepatocarcinogen in rats. In the present experiment, effects of clofibrate given in the promotion stage on liver, gallbladder, pancreas, lung, and kidney carcinogenesis were investigated in male Syrian golden hamsters. After subcutaneous administration of BHP at a dose of 500 mg/kg body weight once a week for 5 weeks, hamsters were maintained on diet containing 0.25% or 0.5% clofibrate for 30 weeks. The hepato-promoting activity of clofibrate was indicated by multiplicity of liver lesions including hyperplastic nodules and hepatocellular carcinomas, and it was greater in hamsters given 0.25% clofibrate than in those receiving 0.5% clofibrate. Peroxisome proliferation was observed in the hepatocytes of hamster given 0.5% clofibrate for 13 weeks under the electron microscope. Inhibitry effect of clofibrate was demonstrated in the development of pancreatic duct adenocarcinoma and lung neoplasms, including adenoma and adenocarcinoma. Hypolipidemic status shown in the serum of hamsters given clofibrate might be involved in the inhibitory effect on pancreas and lung carcinogenesis. Clofibrate did not affect gall- bladder and kidney carcinogenesis. These results indicated that clofibrate modulated liver, pancreas, and lung carcinogenesis in hamsters.

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The effects of partial cystetomy, unilateral ureteric ligation, and transurethral injection of physiological saline on the induction of DNA synthesis in urinary bladder epithelium were studied in a total of 130 male F344 rats. DNA synthesis was evaluated by autoradiography and by immunohistochemical detection of bromodeoxyuridine labeled cells. DNA synthesis began to increase 12 hours after each treatment and reached a maximum at 24 to 48 hours with a mean labeling index of 15.8% (partial cystectomy; 48hrs), 1.9% (unilateral ureteric ligation; 24 hrs), 2.5% (1 injection of physiological saline; 24 hrs), and 5.2% (2 times injections of physiological saline; 36 hrs). The proliferative activity of bladder epithelial cells returned to normal 2 weeks after partial cystectomy, and 1 week after unilateral ureteric ligation or physiological saline injection.

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Papillary necrosis associated with moderate to marked calcification in the renal papilla was incidentally observed in rats simultaneously or subsequently treated with two or more chemicals. In the gastric carcinogenesis model utilizing N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and NaCl as an 8-week-initiation treatment, the lesions in the renal papilla were selectively induced in rats subsequently administered 0.1% ehthoxyquin (EQ) in the diet for 32 weeks. EQ alone also induced the lesions, but the incidence and grade of the necrosis and calcification were much less than in the pretreated group. The additional experiment revealed that the combined pretreatment with MNNG and NaCl is important for induction of the lesions by EQ. In another experiment in which rats were simultaneously administered butylated hydroxyanisole (BHA) and retinyl acetate (RA) for 52 weeks, BHA enhanced the renal papillary lesions induced by RA. BHA alone did not induce the histopathological changes in the kidney. and the effect was dose-dependent for both BHA and RA.

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Effects of nephrotoxic agents on rat hepato- and renal-carcinogenesis were examined histopathologically. Groups of male F344 rats were given a single intragastric administration of 400 mg/kg bw chloroform, 48 h after the treatment they were given 0.1% N-ethyl-N-hydroxyethylnitrosamine (EHEN) in drinking water for 2 weeks. One week after the withdrawal of EHEN treatment, 20 rats each were treated with 0.75% diphenylamine (DPA), 0.25% acetaminophen (AAP), 0.25% N-(3, 5-dichlorophenyl) succinimide (NDPS), 0.1% furocemide (FRM) in basal diet or basal diet alone for 31 weeks. Unilateral nephrectomy was carried out one week after the treatment with chemicals. Animals were killed for autopsy beginning 34 weeks after the treatment with EHEN.
Histologically, the incidences of altered foci, neoplastic nodule, and hepatocellular carcinoma in the groups treated with DPA, AAP, NDPS or FRM were not significantly different from those of the controls. The incidence of microadenoma of the kidney in the group treated with DPA was significantly higher (P<0.01) than the control, but not different in other groups. The incidence of renal cell tumor was not modified by the additional treatment with nephrotoxic chemicals. These nephrotoxic chemicals did not induce any pathological changes in the liver and kidney at these dose levels employed in this experiment, except NDPS which induced mild interestitial nephritis. These results indicate that DPA has an enhancing effect on the renal carcinogenesis without inducing toxic changes in the kidney.

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