We have detailed two distinct mechanisms whereby membranes are damaged in the context of lethal cell injury. The first results from the insertion of proteins into the phospholipid bilayer. This is the mechanism by which viruses, both those that are directly and indirectly cytopathic, kill cells. It is suspected that there is at least one situation, the killing of thymocytes by glucocorticoids, in which the programed death of cells is the consequence of the insertion of a protein into the membrane.
The second mechanism is the loss of the unsaturated fatty acids of membrane phospholipids, an event that occurs as a result of either their peroxidative decomposition or the activation of a membrane-bound phospholipase. In each case, the loss of unsaturated fatty acids increases the molecular order of the membrane. As a result, there is the appearance of lateral domains of differing fluidity, the interfaces between which are believed to be sites of increased membrane permeability.

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The effect of long-term exercise on the onset and progression of age-related pathological changes in male and female Wistar rats was studied. Male and female Wistar rats immediately after weaning were assigned to a voluntary wheel running group. Two year exercise reduced the body weight gains of both sexes and improved the survival curves in males.
Histopathologically, the exercise was more effective than freely eating sedentary control in the reduction of chronic nephropathy and anterior adenoma of pituitary, which are major fatal age-related changes in rats. The exercised rats showed low incidences of skeletal muscle fibrosis and mammary tumors. These results suggested that voluntary exercise for 2 years reduced the occurrence of age-related changes, and these effects were related with suppression of body weight gains.

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To investigate the damage of cerebellar granule cells in thiophene poisoning, spontaneously hypertensive rats were subcutaneously given thiophene for variable dose and administered period. Urine test revealed ketonuria, proteinuria, and hemoglobulinuria at the first treatment and then appeared ruffled hair, inactivity, and weight loss in the rats. Thereafter clinical signs were swing of trunk, convulsion, kangaroo-like jumping, etc. by order. At the acute stage, the cerebellar lesions displayed demarcated degeneration characteristic with edema that is composed of infarction, and were localized extensively in the rostral folia and/or focally in the caudal folia. The valley and lateral side in each folium were more severely damaged than the hill. These lesions were replaced by gliosis and/or microcyst on long survival. Dose of 0.15ml/time was optimal for the proposal induced cerebellar lesion under the continued administration for 4-6 days. It is concluded that thiophene causes vascular damage and granule cell degeneration in the rostral cerebellar cortex where is supplied by the superior cerebellar artery.

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Histopathological, histometrical and ultrastructural changes in protective effects of recombinant human Cu, Zn-superoxide dismutase (SOD) against diffuse alveolar damage (DAD) of the male rats induced by paraquat were studied. The animals were given a single intraperitoneal injection of 25mg/kg body weight of paraquat, followed by a single intraperitoneal injection of 46, 000U/kg body weight of SOD at 1 and 7 hour after paraquat injection for SOD group. In contrast an equal volume of saline was injected instead of SOD for the control group. Difference in results between SOD and control groups was early and late phase effects. In the early phase effects, pulmonary congestion was suppressed from 2 hours after paraquat injection and edematous swelling of type I alveolar epithelia was significant even 24 hours after paraquat injection in the SOD group. In the late phase effects, proliferative changes of alveolar epithelium and interstitium in the SOD group were decreased. From these results, it is supposed that 1) paraquat-induced DAD is alleviated by SOD treatment which results in a scavenger of the superoxide radical and suppression of secondary inflammation by paraquat injection, and 2) SOD treatment may be an effective treatment for paraquat toxicity.

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Hepatomas were induced in Nagase analbuminemic rats (NARs) by administration of 3'-methyl-4-diaminoazobenzene (3'-Me-DAB), and the correlation between the change in the population of albumin-positive (Alb⁺) hepatocytes and the area of placental form of glutathione-S-transferase (GST-P) positive foci, an index of preneoplastic foci, was investigated immunohistochemically. The population of Alb⁺ hepatocytes increased with prolongation in the period of 3'-Me-DAB administration, and this increase was highest in animals without cancer, reaching about twice that in non-cancerous areas of the liver of cancer-bearing animals. This difference occurred because GST-P positive foci contained few Alb⁺ hepatocytes, which were numerous in non-cancerous areas of the liver in cancer bearing cases. An inverse correlation was also found between the percentage occupancy of GST-P positive foci and the densiry of Alb⁺ hepatocytes. This inverse relationship between GST-P positive foci and Alb⁺ hepatocytes was confirmed by studies on partially hepatectomized animals. We inferred from these results that the influence of carcinogens on the albumin gene may be mediated by a different mechanism from that for inducing carcinogenesis.

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The dose-dependent promoting effect of phenobarbital (PB) on rat 2-stage hepatocar-cinogenesis was investigated. Male F344 rats were given 600, 300, 150, 75 or 38ppm PB solutions ad libitum as their drinking water for 39 weeks following initiation with a single intraperitoneal injection of diethylnitrosamine (DEN) (100mg/kg). At week 40, the incidences of hepatic tumors were increased significantly in the DEN+PB groups given 300ppm and 600ppm PB, as compared to that in the DEN group. Linear dose-response curves for numbers and sizes of enzyme altered foci (γ-GTP or GST-P positive foci) were observed in all DEN+PB groups. Numbers and sizes of foci were increased even in the DEN+PB group given the lowest PB, as compared to that in the group given DEN only, while being not significant. Therefore, second experiment was done using a larger range of PB doses. Rats were given 1, 200, 300, 75, 16, 4 or 1ppm PB solutions in the same manner to the first experiment. The incidence of hepatic tumors was increased clearly in the DEN+PB groups given 300ppm PB or above, as compared to that in the group given DEN only. Linear dose-response curves for numbers and sizes of enzyme-altered hepatic foci were obtained in the dose range 16ppm-1, 200ppm PB, and numbers and/or sizes of enzyme-altered foci increased significantly in the DEN+PB groups given 300ppm PB or above. The minimum promoting dose level of PB for enzyme-altered foci, calculated from dose-response curves by the Logit model, was 15-23ppm. These results indicate that the calculated level was evident at low dose, while dose-dependence was demonstrated over a large range. The incidence of hepatic tumors, and numbers and sizes of foci decreased slightly in animals given the lowest dose (1ppm) of PB, as compared to those in animals receiving DEN only.

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Effects of various chemicals on the development of urinary bladder tumors in mouse treated with N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) were examined, Male C3H/He mice received 0.05% BBN in drinking water for 8 weeks, and were subsequently treated with basal diet containing trisodium nitrilotriacetate monohydrate (Na₃NTA·H₂O), nitrilotriacetic acid (H₃NTA), sodium saccharin, and DL-tryptophan for 12 weeks. DL-tryptophan tended to induce a more significant increase in neoplastic and dysplastic lesions of the urinary bladder as compared to Na₃NTA·H₂O, H₃NTA and sodium saccharin. These data showed that DL-tryptophan was more effective than Na₃NTA·H₂O, H₃NTA and sodium saccharin with regard to promoting potential on the development of urinary bladder tumors in mouse treated with BBN.

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The present investigation was conducted to examine the effects of combination chemotherapy including Cyclophosphamide (CPM), THP-adriamycin (THP), and Cisplatin (CDDP) (CTP regimen) on the development of urinary bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in rats compared with CPM, adriamycin (ADM), and CDDP (CAP regimen). One hundred fiftyone male F344 rats were divided into 7 groups: Group 1 (BBN treatment alone), Group 2 (BBN treatment followed by CAP), Group 3 (BBN treatment followed by CTP), Group 4 (CAP without BBN treatment), Group 5 (CTP without BBN treatment), Group 6 (saline treatment alone), and Group 7 (untreated controls). All rats were sacrified 24 weeks after the beginning of the experiment. Bladder carcinoma was observed only in Groups 1 through 3. The incidence of carcinoma did not significantly differ between any two of these three groups, 29/30 (97%) for Group 1, 16/18 (89%) for Group 2, and 25/29 (86%) for Group 3. The grade and stage of the carcinoma were not suppressed by either treatment. The mean number of tumors was significantly lower in Group 3 than those in Group 1 (P<0.01) and in Group 2 (P<0.05). Renal changes were most marked and both CTP and CAP treatment groups showed proliferation of renal tubules and appearance of giant cells. No cardiotoxicity was observed in Group 5 although changes such as myocardiac fibrosis were observed in Group 4. These results suggest that THP is useful in the combination chemotherapy for invasive bladder cancer.

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Of 164 dogs used in routine toxicity studies, seven male and three female Beagle dogs 6 to 17 months of age were found to have spontaneous proliferation of pancreatic endocrine cells. The changes consisted of various combinations of irregular-shaped islets, the budding of endocrine cells from ductal epithelia, beta cell nesidioblastosis composed of a few beta cells, focal adenomatous proliferation of endocrine cells, and prominent ductulo-insular complexes. The proliferated endocrine cells were slightly enlarged containing numerous minute granules in their cytoplasm and were interspersed with ductular cells. Immunocytochemically, a moderate increase was seen in beta and delta cells, and pancreatic polypeptide cells were frequently observed in the nesidioblastic lesions, suggesting that nesidioblastosis might have occurred as a regenerative change stimulated by the destruction of exocrine tissue.

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Effects of testosterone(17α-methyl testosterone) on the serum concentration of TSH(thyroid stimulating hormone) and on the development of thyroid tumors were studied in castrated rats pretreated with N-bis(2-hydroxypropyl) nitrosamine(DHPN). In addition, the dose dependency of testosterone on serum TSH concentration was assessed in castrated animals. The incidences of thyroid tumors induced by DHPN were 69% in non-castrated rats, 40% in castrated rats, 85% in castrated rats treated with 300 ppm testosterone diet, 21% in castrated rats treated with 1500 ppm testosterone diet, 20% and 6% in non-castrated rats treated with 300 ppm or 1500 ppm testosterone diet, respectively. The mean serum TSH concentration in castrated rats treated with DHPN and 1500 ppm testosterone diet showed a tendency of higher than the other group values, but not significantly, and the incidences of thyroid tumors did not demonstrate any clear relation to serum TSH concentration values. The serum TSH concentrations were 2.86±1.86 ng/ml in non-castrated rats and 2.80±0.16, 2.57±0.21, 2.43±0.92, 2.10±0.59, 3.09±1.03, 2.73±0.80 and 3.58±0.16 ng/ml in castrated rats fed on diets containing 0, 100, 300, 600, 900, 1200 and 1500 ppm testosterone, respectively. A dose dependent influence of testosterone on mean seminal vesicle and prostate weights but not on serum TSH concentration as well as thyroid weights was observed. The results, thus, suggest that higher concentration of testosterone without higher concentration of TSH inhibits the development of thyroid tumors in rats treated with DHPN.

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Female ACI and Donryu rats were given 40, 20 or 10ppm solutions of N-methyl-N-nitrosourethane (MNUR) continuously in the drinking water. The resulting incidences of tumors were nearly 100% in all groups, animals of both strains showing dose-dependent mean survival times. In both strains of rats, the main target organs were restricted to the upper digestive tract and no strain differences between ACI and Donryu rats were found. Upper digestive tract tumors were found most frequently in the forestomach, followed by the esophagus and oral cavity and/or pharynx. Histologically, they were all squamous cell papillomas or carcinomas.
The organotropism of MNUR is compared with those of other N-alkyl-N-nitrosourethanes and also N-alkyl-N-nitrosoureas which have chemical structures analogous to N-alkyl-N-nitrosourethanes.

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The effect of prolactin (PRL) on gastric tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in 5-week-old F344: JCR rats. A pituitary gland from female rats of same age was implanted into a spleen of male with silicone capsule containing estrone. One month after implantation, 100mg/l of MNNG were given for 6 months. Animals were sacrificed one year after the MNNG administration. The incidence of gastric tumors was 8/31 (26%) and 3/23 (13%) with or without the implantation, respectively. Serum PRL level but not growth hormone was increased in the group implanted with the pituitary gland. There was no correlationship between gastric tumors and level of PRL.

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