Correlation between renal damage including drug-induced nephropathy and its participation by monocytes and macrophages is reviewed.
Some population of monocytes and macrophages are important as antigen presenting cells in some species, and contributes principally to the development of humoral and cellular immunity. Monocytes and macrophages are also responsible for renal tissue reconstruction and repair through their secretive activity. Glomerular and tubular cells as well as interstitial fibroblasts are seemingly dependent upon the growth factors originating from monocytes and macrophages. A certain lapse of time of cell contact to monocytes and macrophages is supposed to be necessary for such renal cell proliferation. Interstitial fibrosisis, the endstage of renal parenchyma like global glomerular slerosis; final stage of glomerular injury, and monocytes and macrophages are seen correlating to its extension. The analysis of the mechamism toward interstitial fibrosis and scarring is also needed for the understanding of the preserva-tion of renal function.

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An integrated pathology and toxicology system network have been developed by the An-Pyo Center for use in toxicological studies. By utilizing UNIX workstations, this computer system offers high user interface with a multiwindow system and prompt response. Recording of microscopic findings is done simultaneously while evaluating observation of histopathological slides. Entry of histological findings is done by selecting words or phrases from multiple windows for organ and tissue specific findings, a general histological dictionary, an organ dictionary, a comment list, and cause of death section. Necropsy findings and clinical data, including hematology, clinical chemistry, and urinalysis data of individual animals can be displayed on screens. The system produces a variety of reporting and retrieval functions combined with statistical analyses. The network is equipped with a security system with personal entry codes and different levels of access for registered staff members and built in system of checks for correlating gross data with histopathological findings and incomplete entry of pathology information.

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Lesions induced in the respiratory organs of male F344 rats by methanol engine exhaust were studied histologically and electron-microscopically. Animals were exposed by the inhalation route to three concentrations of the exhaust for 8 hours/day, 7 days/week for 7, 14, 21, and 28 consecutive days. Histopathologically, lesions were found in the nasal cavity and the lungs from the 7 day time point. In the nasal cavity, hyperplasias/squamous cell metaplasias of the respiratory epithelium lining the naso-and/or maxillo-turbinate were observed in the high-concentration group (carbon monoxide: 94ppm, formaldehyde: 6.9ppm, methanol: 17.9ppm, nitrogen monoxide: 42.1ppm, nitrogen dioxide: 10.6ppm). The degree of severity of these lesions increased slightly with exposure-time and was dependent on concentration with an apparent threshold. In the lung, decrease or loss of cilia in the bronchial and/or bronchiolar epithelium was prominent in the high-concentration group. In addition, apical blebs of Clara cells on the terminal/respiratory bronchioli suffered reduction in the group. Under the scanning electron microscope, the main changes in the trachea/lungs were shortening and/or loss of cilia on the ciliated cells of the trachea, bronchi, and bronchioli. In the terminal/respiratory bronchiolar epithelium, Clara cells appeared roughly-and irregularly-shaped, with clumping of 2 to 3 cells, being hypertrophied. From these results, it was considered that the lesions in the nasal cavity were mainly caused by formalde-hyde while the lung lesions were induced by nitrogen dioxide. However, the possibility that other components in the exhaust might have exerted modifying potential could not be ruled out.

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3-Benzylsydnone-4-acetamide (BSA), mixed in the pellet feed or dissolved in drinking water, was given to Donryu rats of both sexes. In male rats fed diet containing 200 and 60 ppm BSA (30mg and 9mg daily in 15g of feed) for 15 weeks, hepatocellular carcinomas developed in 20 out of 21 (95.2%) and 2 out of 14 (14.3%) rats, respectively, in 71 weeks. None of 13 rats fed diet with 20 ppm (3mg/day) continuously for 104 weeks had liver tumors at sacrifice. Daily dose of 15.3mg/animal (60ppm in drinking water) of BSA to the male and 46.2mg (200ppm) to the female rats for 41 weeks induced hepatocellular carcinomas at the rate of 92.9% (13/14) and 66.7% (6/9), respectively, but none of 7 female rats ingesting 15.5mg/day (60ppm) of BSA had liver tumors, indicating that the male rats are more susceptible to BSA than the female in liver carcinogenesis. Hepatic tumors were multiple in almost all cases. Histologically they were well differentiated (most common) or poorly differentiated hepatocellular carcinomas, or cholangiocarcinomas (rare). From two hepatocellular carcinomas, ascitic and solid tumor cell lines were established by serial intraperitoneal transplantation. Initially BSA caused centrilobular necrosis of the liver, with elevated serum GPT activity, then appeared proliferating liver cell clusters from which adenomatous and neoplastic changes developed.

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The effects of T-2 toxin on hepatocytes were investigated in vitro. Cultured mouse hepatocytes were treated with several doses of T-2 toxin (1, 10, and 100μg/ml) for 6 and 24 hr. There was no significant change in the release of GPT and LDH from cultured hepatocytes into medium. However, LPO contents in hepatocytes increased dose-dependently at 6 and 24 hr after T-2 toxin administration. A decrease in cell density in hepatocyte cultures due to atrophy and necrosis was conspicuous at 24 hrexposure to 100μg/ml of T-2 toxin. Electron microscopically, an increase of autosegrisomes was observed in hepatocytes at 24 hr-exposure to 1μg/ml of T-2 toxin. Apart from their severity, the nature of ultrastructural changes was common to hepatocytes exposed to 10 and 100μg/ml of T-2 toxin. Namely, degeneration of rER, deformation of mitochondria, and formation of autosegrisomes developed at 6hr and became more prominent at 24hr.

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Carbon tetrachloride (CCl₄) hepatotoxicity was studied in Mongolian gerbils in vivo and in vitro. After treating animals with 50μl/kg CCl₄, serum transaminase levels were remarkably elevated, and mild increase of triglycerides (TG) and decrease of total cholesterol (T-Chol) were seen in the liver showing slight perilobular zonal fatty degeneration. The fatty degeneration was significantly enhanced in animals fasted for 24 hr before CCl₄ treating. By phenobarbital (PB) pretreatment for 3 days, degenerated and necrotized hepatocytes were moderately increased in number without remarkable enhancement of fatty change in both fed and fasted animals. On the other hand, the primary culture of gerbil hepatocytes, which were exposed to 0.2 mM or more CCl₄ for 24hr, showed intracellular accumulation of TG and T-Chol with marked leakage of cellular lactic dehydrogenases (LDH) and glutamic oxaloacetic transaminases (GOT), resulting in severe vacuolar degeneration and necrosis. Pretreatment of the cell culture with 1 mM PB for 24hr caused more distinguished degeneration after exposure to 0.2 mM CCl₄, without intracellular lipid deposition nor enhanced enzyme leakage.

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The effects of ethanol on a liver tumor which was transplanted into athymic nude mice were investigated. The original liver tumor was obtained from a F344 rat, initiated with diethylnitrosamine (DEN), and subsequently administered 2-acetyl-aminofluorene (2-AAF), and established as a tumor line in rnu/rnu rats. Pieces of serially transplanted liver tumor were inoculated into 34 ICR nude, 5-week-old, mice. After one week, these were divided into two groups, one (Group 1) receiving a 0.2ml injection of ethanol in the transplanted and the afer (Group 2) given 0.2ml saline. Group 3, without the tumor transplanted was administered ethanol as a control. Subgroups of animals were killed at days 2, 5, 10, and 30. In group 1, at day 2 after the ethanol injection areas of tumor showed severe necrosis with crust formation. In contrast, those not receiving the ethanol injection demonstrated intact transplants. In group 1, necrotic portions were gradually absorbed and development of tumors was apparent by day 30, but the sizes of individual lesions were smaller than in the group given saline alone. Thus ethanol clearly inhibited the growth of transplanted liver tumor. The results suggest that ethanol injection might be effective as a treatment for hepatocellular neoplasms.

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Lung and kidney tumor induction was evaluated in hamsters and in 2 strains each of rats and mice given N-ethyl-N-hydroxyethylnitrosamine (EHEN) for 2 weeks in either the drinking water or mixed in the diet. Both male and female Wistar rats developed renal cell tumors, while hyperplastic tubules were the characteristic lesions observed in the kidneys of male F344 rats, male BALB/c, and A/J mice, and male Syrian golden hamsters. In contrast, lung adenomas and carcinomas were induced in both strains of mice but not in rats or hamsters. It thus appears that there are differences in susceptibilities between strains as well as between species in EHEN carcinogenicity.

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Apparently normal urinary bladder of beagle dogs of both sexes were examined histopathologically. Materials were obtained from fifty autopsied aged beagle dogs and six autopsied young beagle dogs. Changes of urinary bladder epithelium were classified into five types: Brunn's nest, squamous metaplasia, lymphocytic infiltration, epithelial hyperplasia, and atypia. Brunn's nests in aged dogs were found at all ages and in both sexes. Squamous metaplasia in aged dogs was found in 25.0% of males and 50.0% of females. Scattered lymphocytic infiltration in aged dogs could be observed in 18.0% of both sexes. Epithelial hyperplasia and atypia in aged dogs were found in 82.0% and 28.0% of cases, respectively; however, no difference between sexes was found. Sites of predilection for Brunn's nests were the trigone and anterior wall; however, those for other types of lesion were not found. As for young dogs, Brunn's nests were found in 66.7% of both sexes, and sites of predilection were the trigone and anterior wall; the other lesions were not observed. These chronic changes of urinary bladder epithelium in aged beagle dogs should be considered in the studies of bladder carcinogenesis and natural history of bladder tumor in dogs.

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Scanning electron microscopic observation of the organ of Corti was conducted in kanamycin (KM)-treated beagle dogs, which were subjected to time lapse recording of auditory brainstem response (ABR). KM was administered subcutaneously 5 times per week to 4 beagle dogs at doses of 250 and 500mg/kg for 3-6 weeks (a total dose of 4, 750 to 7, 000 mg/kg). The animals were subjected to pathological examination when definite changes in ABR appeared. Severity of morphological changes were closely related with the degree of the ABR change and histopathological renal lesion. In the animals with slightly decreased amplitude of wave I of ABR also exhibited only a slight renal lesion. The organ of Corti, however, showed essentially a normal structure in these animals. In the animal manifesting moderate ABR change, renal lesion was moderate and the change of the hair cell in the organ of Corti was slight. The animal with such severe auditory disturbance as flattened ABR waveform showed a severe renal lesion and almost complete damages of the hair cells in the organ of Corti. In the present observation, the characteristics of KM-induced lesion in the organ of Corti in dogs are essentially the same with in other species. In addition, the examination of hearing ability could be done as an item during the course of routine long-term repeated dose study using dogs.

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The pancreas and liver of SZ-induced diabetic mice were histopathologically examined up to 4 weeks after the intraperitoneal injection of SZ (200mg/kg). In the pancreas, degeneration of islet, β cells associated with insulitis was prominent in the early stage while a decrease in the size of the islet became predominant in the later stage. On the other hand, scattered minimal foci of hepatocellular necrosis and moderate mononuclear cell infiltration in the portal area were the main hepatic changes in the early stage. In the later stage, prominent hypertrophy of hepatocytes due to an increase in intracytoplasmic acidophilic granules was conspicuous. In coincidence with the light microscopic findings, the most characteristic ultrastructural hepatocellular alteration in the later stage was a marked increase in number of swollen mitochondria. In these hepatocytes, depletion of glycogen granules and rough endoplasmic reticula were also observed.

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Renal changes in mice daily treated with low doses of ochratoxin A (OA; 50-400μg/kg) for up to 4 weeks were investigated by electron microscope. Except the mice treated with 50μg/kg of OA for 4 weeks, all treated mice showed the following changes in the epithelial cells of Henle's loop: (1) degeneration of mitochondria, (2) increment of endoplasmic reticula, and (3) increase in the number and size of lysosomes and myelin figures.

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A case of histiocytic sarcoma developed primarily in the epididymis of B6C3F1 mouse at 109 weeks old was reported. Metastases were observed in the liver and adipose tissue of the abdominal cavity. Tumor cells showed atypism, pleomorphism and active erythrophagocytosis. Touton type giant cells, which were PAS positive after diastase digestion, were seen in the tumor. Electronmicroscopically, the tumor cells had many slender processes forming interdigitation with the adjacent cells. However, no junctional complex or basal lamina was observed in the tumor cells. Tubular autolysozomes in the cytoplasm were characteristic feature of tumor cells of the present case. The vacuoles containing finger print membranes similar to the structures observed in human eosinophilic granuloma of the bone were found in some of the tumor cells. The structures similar to Birbeck's granule of the T-zone histiocyte were also observed.
This case seems to be the first report on histiocytic sarcoma developed in the epididymis of B6C3F1 mice. Since fibrohistiocytic proliferative lesion developed in the epididymis of B6C3F1 mice. Since fibrohistiocytic proliferative lesions were known to develop occasionally in the epididymis of B6C3F1 mice, differential diagnosis from this proliferative lesions is important. Further immunohistological analysis for elucidating the origin and pathogenesis of this neoplastic lesion will be needed.

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