Dose- and time-response studies of sodium o-phenylphenate urinary bladder carcinogenicity in rats.

Dose- and time-response studies of urinary bladder carcinogenesis due to orally administered sodium o-phenylphenate (OPP-Na) were performed using 5-week-old male Fischer 344 rats given diets containing 0 (control), 2500, 5000, 10,000, 15,000 or 20,000 ppm OPP-Na for 104 weeks and fed basal diets until 112 weeks (experiment 1). In addition, rats received diets containing 20,000 ppm OPP-Na for 0 (control), 12, 24, 52 or 104 weeks and were killed at week 112 (experiment 2). In experiment 1, the transitional cell carcinoma (TCC) was the major tumor type in the urinary bladder, and the dose-response curve was steep with many tumors occurring at the high doses of 15,000 and 20,000 ppm. The virtually safe dose at a risk level of 10(-6) for TCCs and papillomas was estimated to be 144 ppm by the Weibull model, a high value similar to that for sodium saccharin. In experiment 2, a few TCCs developed after 24 weeks of treatment, but the time-response curve was also steep with the majority of lesions occurring after longer exposure periods. Based on the observed steepness in dose- and time-responses, any implied cancer risk of OPP-Na at the low doses of interest to man must be considered to be very small.

Subchronic toxicity study of gallic acid by oral administration in F344 rats.

Subchronic toxicity of gallic acid (GA) was investigated in F344 rats by feeding diet containing 0, 0.2, 0.6, 1.7 and 5% GA for 13 weeks. Each group consisted of 10 rats of each sex. Toxicological parameters included clinical signs, body weight, food consumption, hematology, blood biochemistry, organ weights and histopathological assessment. Body weight gain in the 5% GA-treated animals of both sexes from week 1 to the end of the experiment was significantly lower than that of the untreated controls. Toxic effects following administration of 0.6% or more in males and 5% in females included reduction of hemoglobin concentration, hematocrit and red blood cell counts and increase in reticulocytes. Histopathologically, extramedullary hematopoiesis, hemosiderin deposition and congestion appeared in the spleens of 5% GA-treated animals, suggesting development of hemolytic anemia. In addition, centrilobular liver cell hypertrophy, reflected in increase in liver weight, was observed in animals of both sexes from 1.7%. In the kidney, Berlin blue-negative brown pigment deposition in the proximal tubular epithelium was observed at 5% GA. However, the severity of these pathological changes was weak. Based on the present toxicology data, 0.2% was determined to be a no-observed-adverse-effect level (NOAEL) in rats. This level was translated into 119 and 128 mg/kg/day, respectively for male and female rats.

Toxic effects of benzyl and allyl isothiocyanates and benzyl-isoform specific metabolites in the urinary bladder after a single intravesical application to rats.

Allyl isothiocyanate (AITC) is known to be weakly carcinogenic, whereas benzyl isothiocyanate (BITC) has been suggested to exert carcinogenicity toward the rat urinary bladder. To elucidate direct toxic effects of isothiocyanates (ITCs), BITC, AITC, or BITC-metabolites conjugated either with glutathione, cysteinylglycine, cysteine, or mercapturic acid were intravesically instilled into female F344 rats. Exposure to AITC and BITC at 2.8 mg/kg body weight, and the same mol quantity (37 micromol/kg) of BITC-metabolites was for 2 h. Nineteen hours thereafter, the animals were intravenously administered 5-bromo-2'-deoxyuridine (BrdU) and killed 1 h later. BITC caused more profound toxic damage than AITC. Among the BITC-metabolites, cytotoxicity was evident with intermediate glutathione or cysteinylglycine conjugates, whereas the mercapturic acid, considered to be the major final urinary metabolite, exerted little effects. BrdU labeling was essentially dependent on the degree of cytotoxic potential of each compound. Considering the previous study results demonstrating the generation of free BITC from metabolites in urine, the present results support the idea that cytotoxic activity of orally administered ITCs is derived from free forms cleaved from conjugated metabolite(s) in urine.

Assessment of renal toxicity by analysis of regeneration of tubular epithelium in rats given low-dose cadmium chloride or cadmium-polluted rice for 22 months.

To determine whether low-dose oral administration of cadmium (Cd) induces renal toxicity, six groups of female Sprague-Dawley rats were fed a diet containing low amounts of CdCl2 or Cd-polluted rice at concentrations up to 40 ppm, and were killed after 12, 18, and 22 months (experiment 1). In addition to the determination of cortical Cd levels and histopathological assessment of kidneys, labeling indices (LIs) for proliferating cell nuclear antigen (PCNA) in the renal cortical tubular epithelium of Cd-treated rats were determined as a measure of regenerative activity. For comparison, the kidneys of rats given diets containing small to large amounts of CdCl2 up to 600 ppm for 4 months were similarly examined (experiment 2). Animals in experiment 1 demonstrated spontaneous chronic nephropathy and fluctuation in the tubular PCNA LI, but these findings were not correlated with renal Cd levels at 22 months. PCNA LI on the other hand, appeared to be linked to the severity of chronic nephropathy. In experiment 2, levels of CdCl2 of 200 ppm or more clearly induced degeneration and apoptosis of proximal tubules with high correlations between renal Cd levels, PCNA LI, and the severity of tubular degeneration. The results demonstrated that, in contrast to high-dose Cd administration, treatment with 40 ppm or less for 22 months did not influence tubular regeneration as a component of nonspecific chronic nephropathy, suggesting that long-term oral administration of low levels of Cd does not injure renal tubules in female rats.

[A 90-day repeated dose toxicity study of madder color in F344 rats: a preliminary study for chronic toxicity and carcinogenicity studies].

A 90-day toxicity study of madder color was performed in F344 rats by feeding the pellet diet containing 0, 0.6, 1.2, 2.5 and 5.0% of test substance to clarify its toxic potential and to determine the dose levels for the following chronic toxicity/carcinogenicity studies. Body weight gain and food consumption were dose-dependently decreased at 1.2% or more in males and at 2.5% or more in females throughout the experimental period. All animals were survived until the end of experiment and subjected to autopsy. Hematologically, the following parameters were fluctuated in relation to the treatment: decreases in the red blood cells, hemoglobin, and hematocrit in females at 2.5% or more; increase of platelets in males at 2.5% or more, and in females at 5%; increase in white blood cells in males at 5%. Serum protein parameters were also affected by the treatment in males at 1.2% or more and in females at all doses. Increase in the serum calcium level was observed in males at 2.5% or more and in females at 5%. Serum inorganic phosphorus level was also increased in males at 1.2% or more and in females at 2.5% or more. At autopsy, both absolute and relative kidney weights of females increased dose-dependently at 0.6% or more. Relative liver weight in females also increased at 1.2% or more. Histopathologically, microvesicular vacuolar degeneration of proximal tubules was observed in the kidney of both sexes (males at 1.2% or more; females at 0.6% or more). In addition, mononuclear cell infiltration (both sexes) and hyaline casts and tubular regeneration (male) appeared in the kidney at 5%. In the female liver, focal liver cell necrosis associated with mononuclear cell infiltration was evident at 5%. The results demonstrate the toxic effects of madder color on the liver (in females at 5%) and kidney (in males at 1.2% or more; in females at 0.6% or more) of F344 rats when treated orally for 90 days. In addition, toxicities in hematopoietic system and/or bone would probably be appeared when rats are treated with 1.2% or more of madder color for long-term over 90 days. NOAEL was determined to be 0.6% in males, but could not be determined in females under the condition of this study. Based on the results of this study, the dose levels for subsequent chronic toxicity and carcinogenicity studies were determined to be 0.2, 1.0 and 5.0%, and 2.5 and 5.0%, respectively.

[A 13-week subchronic toxicity study of chitin in F344 rats].

A subchronic toxicity study of chitin, a natural structural component of crustacean shells, was performed in F344 rats by feeding of the powdered diet containing 5%, 1.7%, 0.6%, 0.2%, and 0% concentrations of the substance. Each group consisted of 10 males and 10 females. All animals survived until the end of the experiment. There were no changes indicating obvious toxicity of chitin in the clinical signs, body weight, food intake, hematology, serum biochemistry, or histopathological findings, except a slight decrease in body weight gain in the 5% chitin-treated males. Although the mechanism is unclear, the suppression of body weight gain may be due to the slight decrease in caloric content of the food in the 5% chitin-treated animals, a change unrelated to toxicity. Thus, there was no obvious toxicity of chitin in F344 rats at concentrations up to 5% in the diet for 13 weeks.