The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 29 , Issue 5
December
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  • Naruto TOMIYAMA, Makio TAKEDA, Momiko WATANABE, Hiroko KOBAYASHI, Taka ...
    2004 Volume 29 Issue 5 Pages 505-516
    Published: 2004
    Released: February 24, 2005
    JOURNALS FREE ACCESS
    We previously demonstrated a good correlation between the increased relative liver weight caused by DDT and the area under the concentration-time curve (AUC) of DDT or the total DDT (T-DDT) in plasma and liver of rats in a 7-day repeated dose study at 1000 ppm. To confirm the reliability of AUC for predicting toxic responses at different dose levels, we conducted a further 28-day repeated dose study of p,p'-DDT in male F344 rats at dietary levels of 50, 160, and 500 ppm. Concentrations of DDT and its metabolites in plasma, brain, liver, and fat for each dose group were measured at various time intervals during the study. The concentrations of DDT and T-DDT in plasma and liver were compared with their AUCs in relation to hepatotoxic responses including increased relative liver weight, microsomal enzyme induction (CYP2B1), and inhibition of gap junctional intercellular communication. The coefficient (R2) values of each toxic response in correlation with AUCs were generally much higher than those with concentrations at any dose levels, although the R2 values vary considerably among toxic parameters. These results have confirmed that the AUC of DDT or T-DDT in plasma or liver is a reliable marker for predicting hepatotoxicity caused by DDT in repeated dose studies.
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  • Kazunori GOTO, Keiji KOIZUMI, Hitoshi TAKAORI, Yoshinobu FUJII, Yuko F ...
    2004 Volume 29 Issue 5 Pages 517-534
    Published: 2004
    Released: February 24, 2005
    JOURNALS FREE ACCESS
    Flutamide, when administered subcutaneously to female rats at doses of 3, 10, or 30 mg/kg/day during late pregnancy (gestational days 16-21), significantly and dose-dependently decreased anogenital distance (AGD) of the male offspring in each dose group compared to controls. Significant delays in preputial separation were found in males at a dose of 30 mg/kg, but body weight gain was not inhibited. Cryptorchidism and absence of the prostate gland and seminal vesicles were found in males at doses ≥ 10 mg/kg, and testicular hypoplasia at a dose of 30 mg/kg. Hypospadias was noted in all dose groups and vaginal pouches at doses of ≥10 mg/kg. The effects on the accessory reproductive organs were severe, although the effects on the testes themselves were mild. However, those effects appeared to become more pronounced with growth, as evaluated on Days 30 and 42 and Weeks 16 to 18. Most of these affected animals displayed cryptorchidism. Male offspring exposed to flutamide in utero showed impairments of sexual behavior as adults in a dose-related manner. Number and frequency of mounts with intromissions was markedly decreased in all treated groups as compared to controls. At 10 mg/kg, no mounting with ejaculation was observed, and at a dose of 30 mg/kg, no mounting with intromission or ejaculation was observed. These changes in sexual behavior were closely associated with abnormalities of the external genitalia. Animals with hypospadias did not display mounts with ejaculation. However, F1 males that copulated at a dose of 3 mg/kg had a normal reproductive function. Histological examination of the reproductive organs revealed degeneration of the seminiferous tubules, hypospermatogenesis, and hypoplasia and inflammation of the seminal vesicles and prostate. Serum levels of FSH, LH, and testosterone in these animals were comparable between control and all dose groups. Therefore, the male reproductive dysfunction seen in the present study could not be attributed to abnormal sex hormone levels during maturation, but to possible demasculinization of the brain and progressively delayed dysmorphorogy of the male genitalia caused by fetal exposure to flutamide.
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  • Akihiko HIROSE, Ryuichi HASEGAWA, Akiyoshi NISHIKAWA, Mika TAKAHASHI, ...
    2004 Volume 29 Issue 5 Pages 535-539
    Published: 2004
    Released: February 24, 2005
    JOURNALS FREE ACCESS
    The revision of the Japanese drinking water quality guidelines was established in May 2003. The WHO drinking water quality guidelines for the 3rd edition were also revised and the draft has been open to the public since last year. Most guideline values of each chemical in both Japan and WHO were quite similar; however, there are different overt values for three chemicals. In this short communication, we describe them and discuss the reason for taking the different toxicity endpoints and derivation method for these three chemicals, di(2-ethylhexyl) phthalate, toluene and vinyl chloride.
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  • Jong-Sung LEE, Jong-Il PARK, Sun-Hee KIM, Sun-Hee PARK, Seong-kwi KANG ...
    2004 Volume 29 Issue 5 Pages 541-553
    Published: 2004
    Released: February 24, 2005
    JOURNALS FREE ACCESS
    Single- and 13-week repeated-dose toxicities of Geranti Bio-Ge Yeast®, organic germanium fortified yeasts, were investigated in rats. Both sexes of Sprague-Dawley rats were orally administered once at a dose of 2,000 mg/kg in single-dose toxicity or daily for 13 weeks at doses of 500, 1,000 or 2,000 mg/kg in repeated-dose toxicity tests. In single-dose toxicity test to determine dose levels in repeated-dose toxicity study, the body weight gain was suppressed at 2,000 mg/kg, although no death, clinical signs and pathological findings related to the treatment were observed. In repeated-dose toxicity test, there were no clinical signs in animals administered up to 2,000 mg/kg, except one rat died due to a gavage error. In addition, no significant changes in feed consumption and body weight gain were obtained during the treatment period, in spite of week-to-week fluctuation of water consumption. There were no considerable changes in ophthalmoscopy, urinalysis, hematology and serum biochemistry, except a significant decrease in albumin/globulin ratio in males treated with 1,000 mg/kg. In contrast, a significant increase in relative heart weight was observed in both male and female rats treated with a high dose (2,000 mg/kg) of Geranti Bio-Ge Yeast®. In microscopic examination, mild lesions were found sporadically in both control and treatment groups in a dose-independent manner. In spite of some alterations in water consumption, serum biochemistry and organ weights, such effects were not considered to include toxicopathological significance, based on the lack of dose-dependency, consistent time-course and gender relationship. Taken together, it is suggested that no observed adverse effect level (NOAEL) of Geranti Bio-Ge Yeast® is considered to be over 2,000 mg/kg in rats, and that long-term oral intake in humans might not exert adverse effects.
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  • Jong-Sung LEE, Jong-Il PARK, Sun-Hee KIM, Hye-Young LEE, Zai-Zhi HWANG ...
    2004 Volume 29 Issue 5 Pages 555-569
    Published: 2004
    Released: February 24, 2005
    JOURNALS FREE ACCESS
    Single- and 13-week repeated-dose toxicities of Geranti Bio-Ge Yeast®, organic germanium fortified yeasts, were investigated in dogs. Both sexes of Beagle dogs were orally administered once at a dose of 2,000 mg/kg in single-dose toxicity or daily for 13 weeks at doses of 500, 1,000 or 2,000 mg/kg in repeated-dose toxicity tests. In single-dose toxicity test, no animal dead, moribund, or showing clinical signs or changes in body weight gain was found. In repeated-dose toxicity study, there were no considerable changes in ophthalmoscopy and urinalysis. Several alterations were observed in electrocardiography, hematology and blood biochemistry, including heart rate, R-R interval, QT correcting, reticulocytes, activated partial thromboplastin time and albumin/globulin ratio in only male dogs, but not in females, administered with Geranti Bio-Ge Yeast® in a dose-independent manner. In gross findings, several cases of abnormal findings were observed in both control and treatment groups, showing diffuse dark brown to black discoloration of liver, in a dose-independent manner. In microscopic examination, mild lesions, including cholestasis and inflammatory cell foci in liver, kidneys and prostate, were found sporadically in both control and treatment groups. In spite of some alterations in electrocardiography, hematology, blood biochemistry, gross and microscopic findings, such effects were not considered to include toxicopathological significance, based on the marginal changes within normal ranges and lack of dose-dependency, consistent time-course and gender relationship. Taken together, it is suggested that no observed adverse effect level (NOAEL) of Geranti Bio-Ge Yeast® is considered to be 2,000 mg/kg in dogs, and that long-term treatment in clinical trials might not exert adverse effects.
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