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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.

A 13-week subchronic oral toxicity study of phaffia colour was performed in both sexes of F344 rats by feeding of CRF-1 powder diet containing 0, 0.2, 0.6, 1.7 and 5%. Rats were randomly divided into 5 groups, each consisting of 10 males and 10 females. No animals died during the administration period. There were no treatment-related changes in body weight gain, hematological and blood biochemical examination. No treatment-related histopathological changes were also observed in any dosed groups. These findings indicate that the treatment of 5% phaffia colour in diet for 13 weeks does not cause any toxicological changes in rats.

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.

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.

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.

A 13-week subchronic oral toxicity study of ammonium sulfate was performed in both sexes of F344 rats by feeding them a CRF-1 powder diet containing concentrations of 0%, 0.38%, 0.75%, 1.5%, and 3.0% of the substance. Rats were randomly divided into 5 groups each consisting of 10 males and 10 females. Male animals in the 3% group exhibited diarrhea during the administration period. No changes indicating obvious ammonium sulfate toxicity were observed in the body weights, organ weights, hematological, serum biochemical, or histopathological examinations. Based on these results, the NOEL (no-observed-effect level) of ammonium sulfate for F344 rats was judged to be 1.5% in males (886 mg/kg/day) and 3% in females (1975 mg/kg/day), and the MTD (maximally tolerated dose) for 2-year carcinogenicity studies in F344 rats was concluded to be 3.0% or more in the diet.

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.