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The influence of sodium chloride on chemical carcinogenesis of the gastroduodenal tract was examined in male outbred Wistar rats exposed to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water (100 mg/liter) for 20 weeks. Sodium chloride given concomitantly with MNNG during the first 20 weeks of the experiment increased both the incidence and the size of tumors at 40 weeks. However, sodium chloride given after MNNG during the second 20 weeks of the experiment did not enhance tumor development. This study indicates that, although sodium chloride given with MNNG enhances tumor development, sodium chloride does not promote gastric carcinogenesis.

Transmission electron microscopic studies of precancerous and cancerous lesions in the pancreas of hamsters induced by N-nitrosobis(2-oxopropyl)amine (BOP) are presented. BOP was injected subcutaneously once weekly for 10 weeks and hamsters were sacrificed every 5 weeks after initiation of the experiment. The ultrastructural findings indicated that serial changes occurred in the epithelium of the pancreatic duct. The epithelial cells became cuboidal and showed increased secretions at 5 weeks. Probably precancerous cells with prominent nucleoli and irregular rough endoplasmic reticulum were found in the main duct at 10 weeks. At 15 weeks, pancreatic tumors forming a duct arrangement were seen, in good accord with the histological appearance. Well differentiated adenocarcinoma cells showing a tubular pattern had oval nuclei with granular chromatin. Poorly developed rough endoplasmic reticulum was irregularly distributed throughout the cytoplasm and the cell surface was covered with microvilli. Poorly differentiated adenocarcinoma showed poor gland formation and had distorted nuclei with prominent nucleoli. These cells were loosely joined. Mitochondria and rough endoplasmic reticulum were poorly developed, and the tumor cells were devoid of secretory granules. The most characteristic and common change of the precancerous and cancerous lesions in this experiment was the appearance of numerous microvilli on the luminal surface and loss of cytodifferentiation. These findings were obviously different from those of normal epithelial cells or those seen in inflammation. The findings in this study confirm that the pancreatic carcinoma induced by N-nitrosobis(2-oxopropyl)amine in Syrian hamsters is of duct cell origin. No evidence of acinar cells was obtained.

Spontaneous tumors of the nervous system and associated organs and/or tissues in 346 male and 346 female F344/DuCrj rats and 200 male and 177 female Slc:Wistar rats were examined. The main neurogenic tumors observed were gliomas and neurinomas, which were detected in both strains of rats. Out of 7 gliomas, 6 were found in the brain and 1 in the spinal cord, and out of 4 neurinomas, 2 were in the trigeminal nerves and the other 2 were in the spinal nerves. In addition, other types of tumors (2 granular cell tumors in the brain, 1 pinealoma, 3 ganglioneuromas in the adrenal gland, 1 undifferentiated carcinoma in the nasal cavity and 1 chordoma in the posterior neck region) were observed.

Spontaneous tumors in 296 male and 297 female F-34/DuCrj rats used as control groups in six carcinogenicity tests were tabulated and evaluated. In males the most frequent tumors were testicular interstitial cell tumors, followed by mammary fibromas and fibroadenomas, mononuclear cell leukemias, pheochromocytomas, C-cell adenomas of the thyroid, pituitary adenomas, preputial adenomas, neoplastic nodules of the liver, and lung adenomas. In contrast, in females pituitary adenomas, uterine endometrial stromal polyps, mammary fibroadenomas, mononuclear cell leukemias and C-cell adenomas were the most common. Various other tumors of almost all other organs and/or tissues were found, although their incidences were low. Variability in the rates of incidence in some tumors was observed in different control groups.

The threshold level of minimum carcinogenic dose of N-ethyl-N-nitrosourea (ENU) and the effect of dose on organ specificity were examined by continuous oral administration to both sexes of F344 rats of low doses of ENU at four concentrations (0.3, 1, 3 and 10 ppm) in the drinking water. ENU at 10 ppm selectively induced neurogenic tumors and tumors of the digestive tract, including duodenal tumors. Even at lower doses it enhanced the spontaneous development of some other tumors. A high dose of ENU (400 ppm) was previously found to induce duodenal tumors selectively. These results indicate that the organ specificity of ENU is influenced by the dose and that ENU has multi-potent carcinogenic activity in many organs and/or tissues. In this study, some specific tumors, such as those of the nervous system and digestive tract, seemed to require a minimum carcinogenic level of ENU (10 ppm) for their appearance. However, it seems that ENU is carcinogenic at much lower dose levels than 10 ppm because ENU enhanced the spontaneous development of some other tumors in many experimental groups. The so-called virtually safe doses inducing these specific tumors at a risk level of 10(-6) were calculated.

The effect of potassium bromate, a food additive, was examined in male F-344 rats based on two-stage renal carcinogenesis with N-ethyl-N-hydroxyethylnitrosamine (EHEN) as an initiator. Average numbers of dysplastic foci and renal cell tumors were significantly increased in rats given potassium bromate after initiation with EHEN. It was concluded that potassium bromate has an enhancing effect on renal tumorigenesis.

Continuous administration of either 400 ppm or 100 ppm 1-propyl-1-nitrosourea (PNU) in drinking water to Syrian golden hamsters, from 11 weeks of age, induced tumors of the spleen, forestomach, duodenum, and vagina. The tumor incidences in the spleen were 33 of the 36 males (91.7%) and 34 of the 37 females (91.9%) in the 400 ppm group and 32 of the 40 males (80%) and 26 of the 34 females (76.5%) in the 100 ppm group. In addition, tumors were induced in the forestomach and duodenum of both sexes and in the vagina in females. Histologically, the tumors were classified as hemangioendotheliomas of the spleen, squamous cell papillomas and carcinomas of the forestomach, adenocarcinomas of the duodenum, and squamous cell papillomas and carcinomas of the vagina. Compared to results previously reported in rats, the present results reveal a remarkable species difference in the organ specificity of PNU.

Sodium chloride, saccharin sodium, phenobarbital sodium and aspirin were tested for tumor-promoting activity in the glandular stomach of rats after initiation with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) coupled with administration of a high salt diet. Male outbred Wistar rats were given MNNG in the drinking water (100 mg/liter) for 8 weeks, and during this period they were fed on diet supplemented with 10% sodium chloride. Thereafter, they were divided into 5 groups and fed on the basal diet or one of various diets supplemented with 10% sodium chloride, 5% saccharin, 0.05% phenobarbital or 1% aspirin until the end of the experiment. All animals were killed at the 40th experimental week for necropsy and histological examination. The incidence of adenocarcinoma was increased in the group given sodium chloride following initiation by MNNG and sodium chloride as compared with the group given MNNG and sodium chloride initiation only, but not significantly. However, the incidence of preneoplastic hyperplasia was significantly increased in this group. Saccharin also enhanced the development of adenocarcinomas of the glandular stomach. The results indicated that dietary administration of sodium chloride or saccharin after MNNG tends to promote tumor development. Phenobarbital or aspirin did not enhance tumor development, aspirin in fact rather showing a tendency to decrease the tumor incidence.

The carcinogenicity of fish meal pyrolysate was examined in noninbred Syrian golden hamsters of both sexes. Hamsters were given a diet containing 5%, 10%, 20% or 40% fish meal pyrolysate for 102 weeks in Experiment 1, and 10% or 20% fish meal pyrolysate for 112 weeks in Experiment 2. Hamsters in control groups in both experiments were fed a normal basal diet. Various tumors were found in both experimental and corresponding control groups, but there was no significant difference in the incidence of any tumors between the experimental and control groups. Thus, the fish meal pyrolysate tested was not carcinogenic to Syrian golden hamsters under these conditions. In male hamsters the severity and incidence of fatty degeneration of the liver and chronic nephropathy tended to correlate with the concentration of fish meal pyrolysate in the diet. With females, however, the correlation was not so clear. In neither sex did the presence of atrial thrombosis or systemic amyloidosis appear to be dependent on the dietary concentration of fish meal pyrolysate.

Changes of amylase activity and isozymic pattern in the serum, urine, ascites, pancreas and parotid gland of hamsters during pancreatic carcinogenesis induced by N-nitrosobis (2-oxopropyl) amine (BOP) were examined. During the early stage of pancreatic carcinogenesis, amylase activity in the urine was greatly increased and the pancreatic type of isozyme increased in the serum and urine, but in the terminal stage, the activity decreased and the isozymic pattern reverted to normal. These alterations of amylase could be due to focal pancreatitis around dysplastic ductules and small carcinoma lesions causing leakage of pancreatic juice. This phenomenon may be of value in diagnosis of the early stage of pancreatic cancer.

Thiram was added at levels of 0.1 and 0.05% to the diet of F-344 rats for 2 years. The results indicated that thiram significantly reduced the incidence of spontaneous leukemia, and also tended to reduce the incidences of pituitary and thyroid tumors.

The morphological and biochemical characteristics of a transplantable tumor line of rat gastric carcinoma (SG2B), that developed in a Wistar strain rat after treatment with N-methyl-N'-nitro-N-nitrosoguanidine and then 4-nitro-quinoline 1-oxide were examined at the 60th passage. The tumor was serially transplanted into newborn rats by subcutaneous and intraperitoneal routes and has been passed through 60 transplant generations over a 4-year period. The tumors appeared to be well-differentiated tubular adenocarcinomas throughout successive passages, and at each generation transplants were almost identical to the original gastric adenocarcinoma as judged by light and electron microscopic observation. Ultrastructurally, the neoplastic cell contained abundant free ribosomes and exhibited few mucin granules. The microville on the apical cell surface were short and irregularly spaced. Electrophoresis showed that pepsinogens (Pg) 3 and 4 were present but no Pg 1 was detectable at the 60th passage, as was the case in the tissue at the 2nd and 5th passages. The pepsinogen content of the tissue at the 60th passage was similar to that at the 5th passage. The tumor tissue has thus retained the morphological and biochemical character of a pyloric gland type tumor for a long time (over 4 years) during serial transplantation.