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In order to investigate whether goitrogens and liver enzyme-inducers modify the tumorigenesis in the liver or lung, 6-week old male F344 rats were given single subcutaneous injection of DHPN, and starting one week later received water containing goitrogens, namely sulfadimethoxine (SDM), propylthiouracil (PTU) and potassium thiocyanate (KSCN), or an enzyme-inducer, phenobarbital (PB), for 19 weeks ad libitum. Although the number of GST-P positive foci in the liver was significantly increased in the PB group as compared to the control group, there were no significant fluctuations in the SDM, PTU and PB groups. With respect to the lung, it is suggested that SDM, KSCN and PB may enhance the lung tumorigenesis, since the multiplicities of hyperplasias of alveolar epithelia were increased in groups treated with these compounds.

Liver tumor-promoting effects of anthelminthic agents, febantel (Feb), fenbendazole (Fen) or oxfendazole (Oxf), were investigated in a rodent 2-stage carcinogenesis model. Five-week-old male F344 rats were initiated with or without diethylnitrosamine (DEN) and one week later given diet containing Fen (3600, 1800, 600, 200 or 70 ppm), Feb (2000, 1000, 500 or 100 ppm) or Oxf (500, 250, 100 or 10 ppm) for 8 weeks. Induction of CYP1A1/2 was observed in treated groups of DEN + Feb and DEN + Oxf groups, and its induction was most marked in DEN + Oxf groups. CYP2B1 and CYP4AI were also induced in these treated groups. The number or area of Cx32 positive spots per hepatocyte was significantly decreased in treated groups except for DEN + Oxf 100 ppm group, as compared to DEN alone group. GST-P positive foci was significantly increased in DEN + Fen groups treated with 1800 ppm or more, DEN + Feb groups treated with 1000 ppm Feb or more and DEN + Oxf groups treated with 250 ppm Oxf or more. These results suggest that these three compounds have liver tumor promotion effects and the promoting action in Oxf is most strong among them.

In order to characterize the toxicity of iron lactate, a 26-week feeding study was performed in male and female F344 rats. Animals were divided into 2 groups, and given diet containing iron lactate at concentration of 0 or 2%. No animals died during the administration period. Body weight gain was suppressed in both sexes of the 2% group compared with the 0% group. Hematologically, anemia was observed in male of the 2% group. Serum alkaline phosphatase decreased in both sexes of the 2% group. The spleen weight of both sexes and kidney weight of females were higher in the 2% group than in the 0% group. Lipid peroxide increased not only in the liver and the kidney homogenates of treated males and females, but also in the serum of treated females. Histopathologically, iron deposition was observed in the liver, the kidney and the spleen of treated males and females, and in the intestine of treated females. The present results indicate that the iron lactate administration caused iron deposition in the liver and the other several organs, resulting in lipid peroxidation in these organs.

To clarify whether bromodichloromethane (BDCM)-induced cholangiofibrosis progresses to cholangiocarcinoma, further morphological examinations were performed on the livers obtained from our previous experiment. The livers of Wistar rats fed diet containing 2200, 550, 140 or 0 ppm of microencapsulated BDCM up to 24 months were examined at months 6, 12, 18, and 24. The liver sections were stained with H-E, PAS and Azan, and were subjected to immunostaining using antiproliferating cell nuclear antigen (PCNA) monoclonal antibody for determination of the PCNA labeling index of bile duct epithelia, as well as silver staining for nucleolar organizer regions (AgNORs). At month 6, the severity of hyperplasia of atypical bile duct epithelia in the 2200 ppm group was marked, their PCNA labeling index being highest (68.5). The number of bile ducts gradually decreased, and the severity of fibrosis became more marked, with prolongation of the treatment. The PCNA labeling index in hyperplastic bile ducts in this group also decreased to 31.5 at month 24. The number of AgNORs in the nuclei of bile duct epithelia in the 2200 ppm group was highest at month 6, but decreased thereafter. The present study suggests that the possibility of the progression from cholangiofibrosis to neoplastic lesions is extremelly low.

A 13-week subchronic oral toxicity study of isopropyl p-hydroxybenzoate was performed in both sexes of F344 rats. CRF-1 diet containing 0, 0.25, 1.25, 2.5 or 5% isopropyl p-hydroxybenzoate was fed to 5 randomly constituted groups of animals, each consisting of 10 males and 10 females, to determine appropriate dose levels for a subsequent 2-year carcinogenicity study. No animals died during the administration period. Significant suppression of body weight gain was observed in males of the 2.5% and 5% isopropyl p-hydroxybenzoate groups, and in females of the groups treated with 1.25% or above as compared with the control group. Serum biochemistry evaluations revealed increases in gamma-GTP and total cholesterol in male groups treated with 2.5% or more and increases in gamma-GTP, ALP and BUN in female groups treated with 1.25% or more, as compared to the controls. Histopathologically, centrilobular hepatocellular swelling was observed in males treated with 2.5% or more and in females of the 5% group. In the affected populations, hepatocytes filled with small vacuoles, possibly of lipid native, were sometimes found. An increased severity of intracytoplasmic eosinophilic globule formation in the renal proximal tubular epithelia of males of the 5% group was noted. Based on these results, a dietary concentration of 1% in males or 0.5% in females was concluded to be a suitable maximum tolerable dose (MTD) of this chemical for a 2-year carcinogenicity study in rats.

Acute oral toxicity test of glutaraldehyde (GA) was carried out in young (5-6W) and old (57-60W) Wistar/ST rats. Experiment 1: Various doses of GA were administered by gavage. After 30 minutes, the rats showed abnormal gait, then took an abdominal or lateral position after 4 hours. Gross erosion, discoloration and thickening of the glandular stomach mucosa and hyperemia of the liver, intestine and lung were observed in the dead rats. The LD50 values were 283 mg/kg for young rats and 141 mg/kg for old rats. Experiment 2: One half of the LD50 doses (140 mg/kg and 70 mg/kg of GA) were administered to young and old rats by gavage, respectively. Both groups showed a similar toxicity. Organ weights were not changed. In gross findings, erosion, discoloration and thickening of the glandular stomach mucosa were observed on day 1-7, but these damages were recovered by day 14. Histopathologically, atrophy, degeneration, necrosis, hemorrhage, edema and cell infiltration of the glandular stomach mucosa were found on day 1. Recovery from these changes was observed from day 3. Changes in several serum enzyme activities were observed on day 1-3. Therefore, susceptibility to the acute toxic effect of GA was higher in old rats than in young rats. However, no apparent differences were observed in the toxic profiles by GA between young and old rats.

Tris(2-chloroethyl)phosphate (TCEP), a widely used flame retardant, was tested for its skin chronic toxicity/carcinogenicity using female Slc: ddY mice. TCEP (5 and 50%) dissolved in ethanol was applied to the shaved skin twice a week for 79 weeks. The control group received ethanol under similar condition. In addition, 5 animals in each group were killed at 6 and 12 months and used for the chronic toxicity study. In body weight, food consumption and survival rate, there was no significant difference between the control and treated groups. Spleen weight was decreased in the 50% group. No significant difference in the incidence of tumors and other non-neoplastic lesions of the skin and other organs was found between the control and treated groups. The results indicate that under the conditions of the present study, TCEP has no carcinogenicity and toxicity for the skin.