In order to help clarify the biological and predicitive significance of phenotypically altered bepatocellular foci (AHF) for liver neoplasia. qualitative and quantitative evaluations of AHF followed by stereological analysis were performed on standard hematoxylin and eosin-stained liver sections from control and treated Fischer 344 (F344) rats of both sexes. The rats were used in conventional 2-year carcinogenicity studies of 7 chemical agents: 1-amino-2, 4-dibromoanthraquinone (ADBAQ), C.I. Acid Red 114, methyl carbamate, 4-hydroxyacetanilide, epinephrine hydrochloride, dimethoxane, and talc. The first three chemicals were clearly hepatocarcinogenic while the latter four were not. Liver samples were collected at 6, 9, 12, 15, 18, and/or 24 months on study.
1. Control rats: Although AHF had a broad spectrum of morphological features, they could be classified into the following 5 types using previously published criteria: basophilic, eosinophilic, clear, vacuolated, and mixed cell AHF. Approximately 50% of the animals had AHF at 6 months, and the incidence reached nearly 100% at 15 months in both sexes. Stereological analysis revealed that the number, size and volume fraction of AHF increased with age in both sexes and the changes were most evident for basophilic and clear cell AHF. The number of basophilic AHF was significantly greater in females than in males while clear cell AHF were more numerous in males. This sex difference was observed at each time point. Mean number of AHF including all types in males and females at 24 months was 547 and 460 per cubic centimeter of liver, respectively. Despite the high incidence of AHF in control rats, the incidence of hepatocellular neoplasms is low. The implication is that most AHF do not progress to neoplasia in control F344 rats.
2. Rats treated with hepatocarcinogens: The morphological variability of AHF was much greater than in the controls and unique types of basophilic and/or eosinophilic AHF were found in addition to the common (typical in control rats) types of AHF. The unique AHF showed a morphological spectrum and sequential changes suggesting they could develop into hepatocellular neoplasms. There were dose and time-dependent increases in stereological parameters of number, size, and volume fraction for the unique AHF as well as commonly occurring clear, vacuolated, and mixed cell AHF. Consistent stereological changes were not found for commonly occurring basophilic and eosinophilic AHF. These results indicate that hepatocarcinogens may induce unique types of AHF and also cause quantitative increases in some types of commonly occurring AHF such as clear, vacuolated and mixed cell types.
3. Rats treated with non-hepatocarcinogens: The morphological variability of AHF was the same as that in the controls. There were no increases in stereological measurements of AHF although some quantitative changes in the number of AHF were noted.

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Acute toxicity of Streptozotocin (SZ) was examined in 3-month-old APA hamsters at dose levels of 0 (C). 20 (T1), 40 (T2), and 60mg/kg b.w. (T3-group). In T3-group, depression of body weight gain was recorded and a death occurred to one male 3 days after administration. Changes in blood chemical and urinary parameters suggestive of the existence of functional disorders in the liver and kidney were observed in male of T2-and T3-groups and in females of T3-group. In these groups, prominent elevation of blood glucose level was also recorded. Histopathological changes were mainly observed in the liver (fatty change and decrease of glycogen granules in hepatocytes). pancreas (atrophy and degeneration of beta cells with decrease of insulin granules). lymphoid organs (depression of lymphocytes), and kidney (fatty change in proximal tubule epithelium and necrosis in distal tubule epithelium). Most of these changes were detected in males of T2-and T3-groups and in females of T3group, but renal lesions were found only in T3-group. On the other hand, similar but far less severe changes were noticed in males of T3-group of Std: golden hamsters employed as a control strain.

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The mechanisms by which human recombinant Cu-Zn superoxide dismutase prevents cultured rat hepatocytes from tert-butylhydroperoxide (TBHP) cytotoxicity were investigated. Both liposome-encapsulated human recombinant Cu-Zn superoxide dismutase (LSOD) and free (not liposome-encapsulated) human recombinant Cu-Zn superoxide dismutase (FSOD) were uptaken by cultured rat hepatocytes and prevented TBHP-induced cell killing dose-dependently. The 50%-effective final concentrations of FSOD for its cytoprotection and cellular internalization were approximately 9-and 6-fold higher than those of LSOD, respectively. Whereas the pretreatment of cultured rat hepatocytes with each of 5 different blockers of the endocytosis abolished both cellular uptake and cytoprotection of FSOD, the same treatment did not affect those of LSOD. The present results indicate that LSOD prevents TBHP-induced killing of cultured rat hepatocytes more efficiently than dose FSOD and suggest that the endocytosis-independent mechanism by which cultured rat hepatocytes uptake LSOD participates in the cytoprotection of such an enzyme.

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The present report concerns the inhibitory effect of dietary restriction on the age-associated pathologic changes destined to occur in Fisher (F-344) rats.
A total of 360 rats of both sexes were divided into 3 groups consisting 60 males and 60 females each. Rats of the first group were fed a standard commercial diet CRF-1 ad libitum. The second, daily restricted group was given about 8gm and 12gm of diet daily (approximately 67% of ad libitum intake) in females and males, respectively. The third, intermittent feeding group was fed twice a week for a total amount of 67% of ad libitum intake (28gm for females and 41gm for males each time). Ten animals of each group were necropsied after one year and the remaining 50 animals of each group were maintained for two years.
Twelve females and 15 males in the ad libitum feeding group, 7 females and 10 males in the daily restricted group, and 10 females and 6 males in the intermittent feeding group died during the experimental period. Body weight was decreased approximately 52% to 63% in both food restricted groups relative to the ad libitum feeding group. The occurrence of tumors, i.e., pituitary tumors, mononuclear cell leukemia, testicular interstitial tumors, and breast tumors, was significantly suppressed in these food restricted groups relative to the ad libitum feeding group. Non-neoplastic lesions, such as chronic nephropathy and myocardiopathy were markedly reduced in food restricted groups. As the most noticeable laboratory finding, a marked reduction of plasma lipid peroxide level was noted in the food restricted groups.

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The relationship between the alterations of different pulmonary drug metabolizing systems and the selective damages of Clara cells in ddY mice caused by bromobenzene treatment was investigated in order to elucidate the mechanism of bromobenzene-induced pneumotoxicity. Pulmonary drug metabolizing systems showed different responses to oral administration of bromobenzene (5 mmole/kg body weight) in mice at 8 and 24 hours. The time-dependent decrease of coumarin hydroxylase activity was the severest compared to other drug metabolizing enzymes. Bromobenzene treatment caused selective damages of the Clara cells without influencing the ciliated bronchiolar cells and alveolar type II cells, and the degrees of Clara cell damage became severer with time. These results suggest that the degradation of pulmonary coumarin hydroxylase is closely related to the selective damage of Clara cells induced by bromobenzene, and this enzyme contributes to the occurrence of bromobenzene-induced Clara cell damages.

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Ultrastructural observations by scanning electron microscope (SEM) of pre- or neoplastic tracheal lesions in Syrian golden hamsters induced by diethylnitrosamine (DEN) were investigated. Twenty five, six-week-old, male Syrian golden hamsters were injected subcutaneously twice a week for 12 weeks with 18mg/kg body weight of DEN. Six hamsters were injected only vehicle and served as control. At weeks 2, 4, 8, 12, and 16, 5 hamsters of DEN treated group were sacrificed. At weeks 2, 8, and 12, hamsters of vehicle control group were also sacrificed. Sequential changes of tracheal tumors were investigated by ultrastructural and histopathological observations. At week 2, a focal loss of cilia from surface cells of the trachea of DEN treated hamster were already detected by SEM. At week 4, decilinated changes of the surface became more markedly, and at week 8, various kinds of preneoplastic and neoplastic changes were observed in trachea of DEN treated hamster. Those changes could be detected by microscopy as well as SEM. By week 16, papillary tumors were found in all animals treated with DEN. No changes were observed in trachea of control animals. These results showed that scanning observations can detect the very early lesions of trachea and it is a very useful method especially for detecting the changes of tracheal lesions on hamster tracheal carcinogenesis.

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Renal carcinomas were induced by N-ethyl-N-hydroxyethylnitrosamine (EHEN) followed by trisodium nitrilotriacetate monohydrate (NTA) in Wistar rats. In these rats, various parameters which are clinically used as tumor markers were examined. Renal tumors developed in 6 (37.5%) of 16 rats treated with EHEN alone and in 14 (82.4%) of 17 rats treated with EHEN and subsequently with NTA. When various parameters were compared between these two groups and the control group, RBC, Hb Al-P, LDH, BUN, Cr, and Ca in the former two groups differed significantly from those values of the untreated controls. In the EHEN-treated rats (Group 1 and 2), erythropoietin (EP) was higher in the tumor-bearing group than in the tumor-free group (p<0.025), although no other significant difference was observed. As compared to the untreated controls, tumor-bearing rats showed significant elevation in RBC (p<0.005). Cr (p<0.005), and EP (p<0.05) and significant reduction in Hb (p<0.005). Al-P (p<0.005), and LDH (p<0.05). Therefore, the significant difference in RBC, Hb, Al-P, LDH, and Cr seems to be attributable to the effect of EHEN and NTA. These results suggest that EP is specifically elevated in rats with renal tumor.

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The basic structure of rat incisors and the process of enamel formation are reviewed, and the drug-induced lesions of rat incisors are discribed.
The rodent incisors grow, calcify and erupt continuously throughout the life of the animal, and show in one longitudinal section the complete life cycle of tooth development from inception to maturity. Therefore it is a valuable biologic indicator which reflects and records, during its development, the metabolic status of the animal. Drug-induced lesions in developing enamel of incisors are white discoloration of enamel surface, degeneration, necrosis, and atrophy of ameloblasts and/or papillary cells, disturbance of pigmentation, and hypocalcification of enamel. These changes correlate with the stage of enamel formation. The advantage of using rat incisors for toxicity studies is stressed.

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