A subchronic oral toxicity study of dokudami extract, distilled with ethanol from the leaves of dokudami (Houttuynia cordata Thunb.), was conducted. Groups of 10 male and 10 female F344/DuCrj rats were fed dokudami extract at dietary levels of 0, 0.5, 1.5 and 5.0% for 13 weeks. There were no treatment-related adverse effects on body weight, food and water consumption, or on ophthalmology, hematology and urinalysis data. The serum BUN level was significantly increased in the 5.0% female group and remarkable elevation in absolute and relative kidney weights was also found in both sexes receiving 5.0% of dokudami extract. Furthermore, on histopathological assessment, marked mineralization at the cortico-medullary junction of the kidney was observed in the 1.5 and 5.0% female groups and the 5.0% male group. No treatment-related histopathological changes in any other organs/tissues were observed in either sex given 5.0% dokudami extract. Thus, the No-Observed-Adverse-Effect-Level (NOAEL) for dokudami extract was judged to be a dietary level of 1.5% (999 mg/kg body weight/day) for males and 0.5% (350 mg/kg body weight/day) for females under the present experimental conditions.

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4-Nonylphenol (4-NP), a compound of concern as an estrogenic xenobiotic, was assessed for its ability to modify prostate carcinogenesis in male offspring exposed prenatally and neonatally. 4-NP was administered to F344 female rats by gavage at a dose of 0, 0.1, 10 or 100 mg/kg during pregnancy and the lactation period. A slight suppression of maternal body weight gain and prolongation of the gestation period were observed at a 4-NP dose of 100 mg/kg. At this dose, a slight decrease in the mean number of newborn (live + stillborn), and a slight increase in the mean number of stillborn with an increase in the male ratio were observed, suggesting a lethality, presumably in females, although all data were not statistically significant. Male offspring received 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) by gavage at a dose of 100 mg/kg once a week from 5 weeks of age for 19 weeks and all surviving animals were sacrificed at the age of 65 weeks. There was no variation in growth rates among the treated groups. Histopathological examination did not reveal any differences in tumor morphology or incidence in the prostate. We concluded that gestational and lactational exposure to 4-NP does not modify susceptibility of male offspring to a food-derived prostate carcinogen, PhIP at a later stage.

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It has often been observed that chemical-induced initial insult is no longer detected in examinations after additional consecutive treatments, suggesting that the target organs acquire resistance to chemical toxicity. In this study, we examined whether acquired resistance to toxicity would be observed after repeated treatments of a toxic dose of bromobenzene (BB). In Experiment 1, F344 male rats were intraperitoneally given BB at a dosage of 150 mg/kg/day. Based on the serum AST level 20 h after the first treatment, the rats were divided into 2 groups, Groups 2 and 3, which consisted of rats with elevated AST and rats without remarkable changes in AST activity, respectively. Subsequently, the rats were subjected to the same BB treatment regimen for 4 or 9 consecutive days. The control group (Group 1) was administered with the vehicle. The AST activity of Group 2 showed no remarkable changes from Day 3, indicating an acquired resistance to BB hepatotoxicity. Measurements of drug-metabolizing enzymes in Group 2 demonstrated a reduction in CYP contents and activities, and a strong induction of GST, which contributed to the resistance. The aminotransferase activities in Group 3, however, showed no changes throughout the dosing periods. In Experiment 2, the rats with the same BB treatment regimen as Experiment 1 were administered intraperitoneally with a single dosage of BB of 300 mg/kg. Although a higher dosing of BB caused hepatic injury in all three groups, the degree of injury in the two groups with BB treatment was much slighter than that in the control (vehicle + BB). These results indicate that not only Group 2 but also Group 3 acquired resistance to BB hepatotoxicity after repeated treatments. The exposure levels of BB in the two groups were lower than those of the control. Thus, changes in the drug-metabolizing reaction related to the metabolism and detoxification of BB contributed to the resistance to BB hepatotoxicity.

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A subcutaneous mass was found in a 15-month-old male beagle dog. It grew to 6 cm in diameter, and then reduced gradually to 4 cm. Histopathologically, the mass was well circumscribed but uncapsulated and comprised of hypocellular hyalinized fibrosclerotic tissue and a variable inflammatory infiltrate, which was composed chiefly of the lymphocyte. The characteristic findings of this nodular lesion were remarkably similar to those of calcifying fibrous pseudotumor (CFP) in human, but lacking in calcification in this case. To establish the disease entity for this kind of fibrous pseudotumor in dogs, additional case reports are required.

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To investigate the endocrine-mediated effects of neonatal administration of the weak estrogenic compounds, bisphenol A, nonylphenol and genistein, were subcutaneously injected with these compounds at doses of 0.1, 1, and 10 μg/rat/day for 5 days starting on postnatal day 1. Rats were autopsied at 47-50 days. Positive control groups were given diethylstilbestrol (DES) at the same dose levels as the other chemicals. The ano-genital distance, age of vaginal opening and preputial separation, and estrus cyclicity for all living offspring were examined. No abnormalities by the injection of nonylphenol and genistein were detected in this study. In the BPA groups, ano-genital distance in the females in the 1 and 10 μg BPA groups was shorter than in the control group, and the ventral prostate weight was higher in the 10 μg BPA group than in the control group. On the other hand, in the DES groups, delayed preputial separation occurred later in the 0.1 and 1 μg groups than in the control group, and in the 10 μg groups, preputial separation was not completed. Also the estrous stage persisted in female of all DES groups. Underdevelopment of the seminal vesicle and prostate were observed in males of the 1 and 10 μg DES groups, and fewer ovarian corpus lutea, ovarian follicular cysts, and uterine glands, as well as increased uterine epithelial height and squamous metaplasia of the epithelium in the uterus were observed in females of all DES groups. We concluded that the findings observed in the weak estrogenic compound groups were not toxicologically relevant changes and that the present data provide valuable information for the neonatal exposure assay using weak estrogenic compounds.

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