The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 11 , Issue SupplementI
Showing 1-13 articles out of 13 articles from the selected issue
  • Norimitsu TAKAHASHI, Toshihito KADOTA, Shigeo KAWANO, Katsumi ISHIKAWA ...
    1986 Volume 11 Issue SupplementI Pages 1-16
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was examined for its oral, subcutaneous or intravenous acute toxicity using Slc: ICR mice, Crj: CD (Sprague-Dawley) rats and JW-NIBS rabbits of both sexes. The summarized results obtained are as follows: 1. A mode of manifestation of toxic effects was classified into immediate-type symptoms predominantly caused by the carrier and delayed-type symptoms predominantly caused by VP regardless of animal species and routes of administration, excluding the case of intravenous dosing to rabbits. 2. Referring to the delayed-type toxic signs, depilation, diarrhea and suppression of body weight increase were observed for mice and rats regardless of administration routes, and diarrhea was noted in rabbits by oral route. 3. Necropsy of three species of animals and histopathology on rabbits revealed thymic and splenic atrophy in mice and rats as well as thymic atrophy and inflammatory changes of intestine in rabbits dying by oral administration. 4. The drug-related cause of death for mice and rats seemed to be due to the cytocidal action of VP as an oncostatic drug, but the cause of death for rabbits by oral administration was considered to be somewhat different from that for mice and rats. 5. LD50 values (mg/kg) were as follows, showing oral toxicity in rabbits being rather potent as compared with that in mite or rats.
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  • Norimitsu TAKAHASHI, Toshihito KADOTA, Shigeo KAWANO, Keiko OHTA, Kats ...
    1986 Volume 11 Issue SupplementI Pages 17-49
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered orally to Crj: CD (Sprague-Dawley) rats of both sexes at dose levels of 3, 10, 30 and 100 mg/kg/day for one month with the object of examining its subacute toxicity and the reversibility of toxic effects. The summarized results obtained are as follows: 1. VP 30 mg/kg suppressed body weight increase and feed intake, and brought soft stool. VP 100 mg/kg decreased body weight and feed intake, and induced diarrhea, depilation and so forth. Furthermore, half of the animals at this dose level died showing systemic debility and emaciation. 2. VP 30 and 100 mg/kg predominantly decreased red blood cell count as well as white blood cell count accompanied with lowered lymphocyte fraction. 3. VP 10 mg/kg and higher lowered total serum protein content and serum alkaline phosphatade activity, and elevated A/G ratio. 4. VP 10 mg/kg and higher caused thymic atrophy and a decrease in testicular weight ; 30 and 100 mg/kg brought suppression of spermatogenesis ; and 100 mg/kg predominantly induced appearance of giant cells in epididymis, hypoplasia of bone marrow, ileocecitis, and atrophy of prostate, seminal vesicle and splenic germinalcenters. 5. Above-described changes excluding exacerbation of the findings on testis and epididymis were shown to be generally reversible. Based on these results, the no-effect dose level of VP under the present experimental condition was estimated to be 3 mg/kg/day against rats of both sexes.
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  • Norimitsu TAKAHASHI, Toshihito KADOTA, Shigeo KAWANO, Keiko OHTA, Kats ...
    1986 Volume 11 Issue SupplementI Pages 51-87
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered orally to Crj: CD (Sprague-Dawley) rats of both sexes at dose levels of 1, 3, 10 and 30 mg/kg/day for six months with the object of examining its chronic toxicity and the reversibility of toxic effects. The summarized results obtained are as follows: 1. VP 30 mg/kg suppressed body weight increase and feed intake, and brought transient diarrhea, anemia and depilation. Some animals receiving this dose died showing systemic debility, emaciation and ataxia. 2. VP 3 mg/kg and higher predominantly decreased red blood cell count as well as white blood cell count accompanied with lowered lymphocyte fraction. 3. VP 30 mg/kg lowered total serum protein content and elevated A/G ratio in males, and lowered serum alkaline phosphatase activity in females. 4. VP 10 and 30 mg/kg predominantly induced thymic atrophy, testicular atrophy with suppression of spermatogenesis and tubular atrophy, a decrease in epididymal weight, and splenic erythropoiesis. 5. Above-described changes excluding the findings on testis and epididymis in VP 30 mg/kg group were shown to be generally reversible. Based on these results, the non-effect dose level of VP under the present experimental condition was estimated to be 1 mg/kg/day against rats of both sexes.
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  • Norimitsu TAKAHASHI, Toshihito KADOTA, Shigeo KAWANO, Keiko OHTA, Kats ...
    1986 Volume 11 Issue SupplementI Pages 89-122
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered intravenously to Crj : CD (Sprague-Dawley) rats of both sexes at dose levels of 0.15, 0.50, 1.5 and 4.5 mg/kg/day for one month with the object of examining its subacute toxicity and the reversibility of toxic effects. For the purpose of comparison, vincristine (abbr. to VCR) was administered in the same manner at dose levels of 0.04 and 0.08 mg/kg/day. The summarized results obtained are as follows: 1. VP 0.50 mg/kg and higher sur)pressed body weight increase and food intake dose-responsively. VP 4.5 mg/kg brought depilation and anemia, and some of male animals receiving this dose died showing systemic debility, emaciation and ataxia. 2. VP 0.50 mg/kg and higher decreased white blood cell count accompanied with lowered lymphocyte fraction, and 1.5 and 4.5 mg/kg predominantly decreased red blood cell count. 3. VP 1.5 and 4.5 mg/kg lowered total serum protein content and serum alkaline phosphatase activity, and elevated A/G ratio. 4. VP 0.50 mg/kg and higher predominantly decreased testicular weight, and l.5 and 4.5 mg/kg predominantly brought thymic atrophy, hypoplasia of bone marrow and testicular atrophy with suppression of spermatogenesis and tubular atrophy. VP 4.5 mg/kg induced atrophy of germinal centers and hemosiderosis in spleen, and epididymal atrophy with decrease of sperms in number and appearance of giant cells. 5. Above-described changes excluding the findings on testis and epididymis were generally reversible. 6. Most of the findings for a reference drug, VCR, were similar to those for VP, and their severities brought by VP 1.5 and 4.5 mg/kg were comparable to those by VCR 0.04 and 0.08 mg/kg, respectively. Based on these results, the non-effect dose level of VP under the present experimental condition wad estimated to be 0.15 mg/kg/day against rats of both sexes.
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  • Norimitsu TAKAHASHI, Toshihito KADOTA, Shigeo KAWANO, Keiko OHTA, Hiro ...
    1986 Volume 11 Issue SupplementI Pages 123-161
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered intravenously to Crj: CD (Sprague-Dawley) rats of both sexes at dose levels of 0.05, 0.15, 0.5 and 1.5 mg/kg/day for three months with the object of examining its toxicity and the reversibility of toxic effects. For the purpose of comparison, vincristine (abbr. to VCR) was administered in the same manner at a dose level of 0.02 mg/kg/day. The summarized results obtained are as follows: 1. VP 1. 5 mg/kg brought anemia as well as suppression of body weight increase and food intake, and 0.5 and l.5 mg/kg increased water consumption. However, no drug-related deaths occurred. 2. VP 0.5 and l.5 mg/kg predominantly decreased red blood cell count and white blood cell count accompanied with lowered lymphocyte fraction which was agreeable to the findings on bone marrow. VP 1.5 mg/kg increased platelet count. 3. VP 1.5 mg/kg lowered total serum protein content and elevated A/G ratio. 4. VP 0.15 mg/kg and higher decreased testicular weight; 0.5 and 1.5 mg/kg brought thymic atrophy, suppression of spermatogenesis, tubular atrophy and hydropic change in testis. VP 1.5 mg/kg induced decrease of sperms in number and appearance of giant cells in epididymis. 5. Above-described changes excluding the findings on testis and epididymis were shown to be generally reversible. 6. Most of the findings for a reference drug, VCR, were qualitatively comparable to those for VP. Based on these results, the non-effect dose level of VP under the present experimental condition was estimated to be 0.05 mg/kg/day against male rats and 0.15 mg/kg/day against female rats.
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  • Norimitsu TAKAHASHI, Shigeo KAWANO, Hisashi KOHMURA, Katsumi ISHIKAWA
    1986 Volume 11 Issue SupplementI Pages 163-176
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, and VP-protein conjugates were examined for their antigenic properties using male Hartley guinea pigs. The results of systemic anaphylaxis test, passive cutaneous anaphylaxis test, passive hemagglutination test and Schultz-Dale reaction revealed that VP possessed neither antigenic nor haptenic properties. The dose levels of VP employed in the present experiment were confirmed not to suppress immune reactions.
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  • Norimitsu TAKAHASHI, Shuichi KAI, Hisashi KOHMURA, Katsumi ISHIKAWA, K ...
    1986 Volume 11 Issue SupplementI Pages 177-194
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered orally to male Crj: CD (Sprague-Dawley) rats for 64 days and to female rats of the same strain for 15 days prior to mating at dose levels of l, 3 and l0 mg/kg /day. These animals were then mated under the consecutive administration of this drug and the females confirmed to be copulated were further dosed from day 0 through 7 of gestation. The summarized results obtained are as follows: 1. VP 10 mg/kg suppressed the body weight increase in females from day 8 of pre-mating through day 20 of gestation, but did not affect the body weight in males. 2. VP 10 mg/kg decreased the organ weights of testes, epididymides and thymus in males and induced atrophy of these organs macroscopically, but did not affect their reproductive performances. 3. As for fetuses, VP 10 mg/kg elevated the mortality and induced anophthalmia, microphthalmia and dilated lateral ventricles, as well as suppressed their growth and the ossification processes of sternums, sacral and coccygeal vertebrae, metacarpus, thoracic vertebrae and pubis. Based on these results, the no-effect dose level of VP under the present experimental condition was estimated to be 3 mg/kg/day against parent rats of both sexes and their offspring.
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  • Norimitsu TAKAHASHI, Shuichi KAI, Hisashi KOHMURA, Katsumi ISHIKAWA, K ...
    1986 Volume 11 Issue SupplementI Pages 195-225
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered orally to pregnant Crj: CD (Sprague-Dawley) rats from day 7 through 17 of gestation at dose levels of 1, 3 and 10 mg/kg/day. The summarized results obtained are as follows: 1. VP 10 mg/kg suppressed the maternal body weight increase from day 12 through 20 of gestation. 2. VP 10 mg/kg brought the inhibition of fetal growth accompanied by the lowered values in body weight and body length. Furthermore, the elevated incidences of skeletal anomalies and unossified 5th and 6th sternums, as well as retarded ossification of thoracic vertebrae were also noted in this dose level. 3. VP 10 mg/kg induced anophthalmia, microphthalmia and dilated lateral ventricles in fetuses (F1), as well as unilateral anophthalmia in offspring (F1). 4. VP 10 mg/kg increased the days required for opening of eyelids and descending of testes in offspring (F1), but failed to affect their learning ability, motility, motor activity or emotional development. 5. VP 10 mg/kg suppressed the growth of genital organs in Fl rats of both sexes, but failed to affect their reproductive ability or gestation period. 6. As for F2 newborns derived from Fl rats whose dams had ever received VP 10 mg/kg during the period of fetal organogenesis, the number of implantations and survivors as well as birth indexes lowered due to changes in these items restricted to a few litters. Based on these results, the no-effect dose level of VP under the present experimental condition was estimated to be 3 mg/kg/day against dams and their offspring.
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  • Norimitsu TAKAHASHI, Shuichi KAI, Hisashi KOHMURA, Katsumi ISHIKAWA, K ...
    1986 Volume 11 Issue SupplementI Pages 227-239
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered orally to pregnant JW-NIBS rabbits from day 6 through 18 of gestation at dose levels of 0.3, 1, 3 and 10 mg/kg/day. The summarized results obtained are as follows: 1. VP 3 and l0 mg/kg elevated the maternal mortality dose-responsively. 2. VP 3 mg/kg and lower doses failed to affect the fetal growth and ossification processes, and did not induce drug-dependent external and visceral anomalies as well as skeletal variations and anomalies. Based on these results, the no-effect dose levels of VP under, the present experimental condition were estimated to be l mg/kg/day against dams and 3 mg/kg/day against fetuses.
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  • Norimitsu TAKAHASHI, Shuichi KAI, Hisashi KOHMURA, Katsumi ISHIKAWA, K ...
    1986 Volume 11 Issue SupplementI Pages 241-261
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered orally to female Crj: CD (Sprague-Dawley) rats from day 17 of gestation through postpartum day 20 at dose levels of 1, 3 and 10 mg/kg/day. The summarized results obtained are as follows: 1. VP 10 mg/kg induced thymic atrophy in dams. 2. VP failed to affect the parturition of dams. 3. VP 10 mg/kg lowered the viability of newborns (F1) on postpartum day 3 and increased the days required for descending of testes, but failed to affect the growth of genital organs, learing ability, motility, motor activity or emotional development. 4. VP 10 mg/kg brought a transient suppression of body weight increase in pregnant F1 rats, but failed to affect their reproductive ability and parturition. 5. F2 newborns derived from F1 rats whose dams had ever received VP during the prenatal and lactation periods showed no changes in observation items at birth. 6. Long-term rearing F1 rats derived from VP-treated dams manifested no delayed toxicity including carcinogenicity. Based on these results, the no-effect dose level of VP under the present experimental condition was estimated to be 3 mg/kg/day against dams and their offspring.
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  • Norimitsu TAKAHASHI, Shuichi KAI, Hisashi KOHMURA, Katsumi ISHIKAWA, T ...
    1986 Volume 11 Issue SupplementI Pages 263-279
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered intravenously to male Crj : CD (Sprague-Dawley) rats for 61 days and to female rats of the same strain for 14 days prior to mating at dose levels of 0.05, 0.2 and 0.8 mg/kg/day. These animals were then mated under the consecutive administration of this drug and the females confirmed to be copulated were further dosed from day 0 through 7 of gestation. The summarized results obtained are as follows: 1. Body weight increases were suppressed at the dose level of VP 0.8 mg/kg in male s and females. 2. VP 0.2 and 0.8 mg/kg decreased the thymic weight and 0.8 mg/kg decreased testicular and epididymal weight in males showing macroscopic atrophy of these organs, but these doses failed to affect the reproductive ability and so on in parent rats. 3. As for fetuses, VP 0.8 mg/kg elevated the mortality, decreased the number of survivors and suppressed their growth. Furthermore, this dose raised the incidences of anophthalmia, microphthalmia, dilated lateral ventricles and unossified 5th and 6th sternums, as well as brought retarded ossification of sternums, cervical vertebrae, sacral and coccygeal vertebrae, metacarpus and thoracic vertebrae. Based on these results, the no-effect dose levels of VP under the present experimental condition were estimated to be 0.05 mg/kg/day against parent rats of both sexes and 0.2 mg/kg/day against their offspring.
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  • Norimitsu TAKAHASHI, Shuichi KAI, Hisashi KOHMURA, Katsumi ISHIKAWA, K ...
    1986 Volume 11 Issue SupplementI Pages 281-300
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered intravenously to female Crj: CD (Sprague-Dawley) rats from day 17 of gestation through postpartum day 20 at dose levels of 0.05, 0.2 and 0.8 mg/kg/day. The summarized results obtained are as follows: 1. VP 0.2 and 0.8 mg/kg suppressed the body weight increase and brought thymic atrophy in dams. 2. VP failed to affect the states of birth of newborns (F1). 3. In F1 offspring, VP 0.8 mg/kg increased the days required for testicular descending and vaginal opening, and suppressed the body weight increase, but failed to affect the growth of genital organs, reproductive ability, learing ability, motility, motor activity or emotional development. 4. F2 newborns derived from F1 rats whose dams had ever received VP during the prenatal and lactation periods showed no changes in observation items at birth. Based on these results, the no-effect dose level of VP under the present experimental condition was estimated to be 0.05 mg/kg/day against dams and 0.2 mg /kg/day against their offspring.
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  • Hiroshi NAKANOMYO, Masaki HIRAOKA, Mayumi SHIRAYA
    1986 Volume 11 Issue SupplementI Pages 301-310
    Published: April 25, 1986
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Mutagenicities of Etoposide (VP 16-213) and Teniposide (VM-26), podophyllotoxin derivatives with antitumor activity, were studied by Rec-assay, Salmonella/microsome reverse mutation assay (Ames' test) and Micronucleus test. In the Rec-assay, both Etoposide and Teniposide showed positive results on B. subtilis H17 rec+ and M45 rec-. They also induced the revertants of S. typhimurium TA 98, TA 1537 and TA 1538, but not of S. typhimurium TA 100, TA 1535 or E. coli WP2 uvrA in the Reverse mutation test. The results were not influenced by the addition of S-9 Mix. In the Micronucleus test, Etoposide and Teniposide induced significantly micronucleated polychromatic erythrocytes of the bone marrow cells in mice; 3.3-4.3% at the doses of 0.75-6 mg/kg and 4.0-6.1% at 0.5-4 mg/kg, respectively. These results indicate that Etoposide and Teniposide are both mutagenic.
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