摘要:

AbstractBemitradine (SC‐33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2‐year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg−1for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5–15% in the female and 10–12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg−1females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms.The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC‐36741; desethylbemitradine) were tested and found to be non‐genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics,in vivomouse micronucleus and mouse lymphoma TK+/− (bemitradine only) assays.Finally, in an altered hepatic foci (Y‐glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital.We concluded that bemitradine (which has been dropped from development) is a non‐genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemi

ISSN:0260-437X    

DOI:10.1002/jat.2550120303

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractBrown bullheads were given a single intraperitoneal dose of 0, 5, 25 or 125 mg kg−1benzo[a]pyrene (BaP), a carcinogenic polycyclic aromatic hydrocarbon, and evaluated over 18 months. Flow cytometric analyses of hepatocyte DNA content indicated an increase in DNA synthesis in BaP‐exposed fish prior to day 14 post‐exposure. Thereafter, all flow cytometric variables returned to initial levels. Histopathological evaluation of livers from fish sampled at 18 months revealed significant differences among treatments in the amount of hepatic macrophage ceroid pigmentation and basophilic staining intensity. No neoplasms or changes in blood cell DNA content were detected. Significant morphometric variations existed among fish, but differences between sexes overshadowed differences attributable to dose. Flow cytometry yielded no evidence of long‐term DNA alterations from a single exposure to BaP; however, the differences detected by DNA analysis shortly after the toxic event suggest that flow cytometric cell cycle analysis may be useful for documenting continuing ex

ISSN:0260-437X    

DOI:10.1002/jat.2550120304

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractPregnant Wistar rats were given butyl benzyl phthalate (BBP) at a dose of 2.0% in the diet on days 0–20, days 0–11 or days 11–20 of pregnancy. Food consumption and body weight gain were decreased in pregnant rats given BBP. Pre‐implantation loss in the BBP‐treated groups was comparable to that in the control and pair‐fed groups. All dams given BBP on days 0–20 or days 0–11 exhibited complete resorption of all the implanted embryos. No increase in post‐implantation loss was found in pregnant rats given BBP on days 11–20. Marked teratogenicity was detected in fetuses of the dams given BBP on days 11–20. Cleft palate and fusion of the sternebrae were predominantly observed. Seventy‐two of the 134 fetuses had a cleft palate. The incidence of malformations in this group was significantly and markedly higher than that in the control and pair‐fed groups. In conclusion, the administration of BBP during the first and second half of pregnancy produced embryolethality and ter

ISSN:0260-437X    

DOI:10.1002/jat.2550120305

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractPalytoxin, in concentrations as low as 100 fM, caused contractions of porcine coronary artery rings. Palytoxin concentrations of10 nM palytoxin for 1–2 h reduced contractions to potassium 18 h later to 61% of the expected contraction and abolished those to palytoxin administered later. Both 10 and 100 nM palytoxin depleted potassium from coronary artery rings. Verapamil (10 μM) prevented potassium depletion by 10 nM palytoxin, but neither 10 μM verapamil nor 1 μM nifedipine prevented potassium depletion in rings exposed to 100 nM palytoxin. Thus, the contractile action and the potassium depleting action of palytoxin on the porcine coronary artery involve mobilization of nifedipine‐ and verapamil‐sensitive calcium. Verapamil‐ and nifedipine‐sensitive calcium was not required for depletion of potassium by the highest PTX concentration (100

ISSN:0260-437X    

DOI:10.1002/jat.2550120306

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe tannin content of over‐the‐counter Indian tea, of green coffee beans and of the roasted coffee beans prepared from the same green beans was determined with a radial diffusion ‐ protein precipitation technique and with a spectrophotometric method. The green beans contained 6.6 ± 0.6 mg g−1weight tannic acid equivalents as found by protein precipitation (n= 5, ± SD) or 6.8 ± 2.3 mg g−1by spectrophotometry. The same figures for roasted beans were 18 ± 1.7 and 17 ± 2.7 mg g−1, respectively. Tea contained 37 ± 2.6 mg g−1weight tannic acid equivalents as analysed by spectrophotometry and 24 ± 2.8 mg g−1by the protein precipitation technique. The latter finding may show that the biological reactivity of tannins is variable, although no major changes in the tannin‐precipitated albumin occurred as shown by electrophoretic analysis. Both methods provide an easy analysis of the reportedly ca

ISSN:0260-437X    

DOI:10.1002/jat.2550120307

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe lethalities of pure methanol and pure ethanol were compared to two mixtures of ethanol/methanol with the following percentages (95/5% and 65/35% v/v). This study was conducted to simulate situations of human exposure to denaturated alcohol (by 5% methanol) or adulterated alcohol (by 35% methanol). Four groups of female adult virgin albino rats were treated with the four mixtures. A fifth group was used as a vehicle control. Graded oral doses were given to eight animals per dose. Lethality over 24 h was used as an endpoint. The LD50was calculated for each of the four treatments on a molar basis. A dose‐response function for each mixture was plotted of percentage lethality vs. mmol kg−1equivalent to the given ml kg−1dose. Results showed a significantly different LD50estimates (P<0.03) for the four mixtures. The order of lethal toxicity was as follows: 95/5% methanol/ethanol, pure methanol, pure ethanol then 65/35% methanol/ethanol. Slope comparisons indicated two pairs: 65/35% ethanol/methanol and pure ethanol yielding a steep slope, and 95/5% ethanol/methanol and pure methanol yielding a shallow slope. These data indicated that the acute lethality of ethanol/methanol mixtures is a complex unpredictable function. This toxicity presumably depends in a complicated way on the differences in the effective molecular weights of the two alcohols in each of the mix

ISSN:0260-437X    

DOI:10.1002/jat.2550120308

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractCytogenetic analyses were conducted on bone marrow and pulmonary lavage cells from rats that received repeated inhalation exposures to formaldehyde. Male Sprague‐Dawley rats were exposed to 0, 0.5, 3, or 15 ppm formaldehyde for 6 h per day, 5 days per week, for 1 and 8 weeks. There was no significant increase in chromosomal abnormalities in the bone marrow cells of formaldehyde‐exposed rats relative to controls. There was a statistically significant increase in chromosomal aberrations in the pulmonary lavage cells from rats that inhaled 15 ppm. There were 7.6 and 9.2% of the scored pulmonary lavage cells that had aberrations following 1 and 8 weeks, respectively, of 15 ppm formaldehyde exposure (with control levels of 3.5 and 4.8%, respectively). The predominant damage seen was chromatid breaks. These findings indicate that marginal but statistically significant genotoxic effects could be detected locally in lung alveolar macrophages, but not distally in bone marrow, following repeated formaldehyde exposures only at a high concentration that is carcinogenic to rats. The biological significance of this effect is uncertain since formaldehyde is not considered to be a lung carcinogen in r

ISSN:0260-437X    

DOI:10.1002/jat.2550120309

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractPregnant Sprague‐Dawley rats were intraperitoneally injected with physiological saline solution (vehicle) or cadmium chloride (CdCl2) at 2.5 mg kg−1body wt. on days 8, 10, 12 and 14 of gestation. Offspring were examined for renal alkaline phosphatase activity (ALP) on postnatal days (PND) 3 and 12, and for kidney metallothionein (MTh) and for liver, kidney and entire gastrointestinal tract109Cd content at birth and on PND 3 and 12. No effects were observed on neonatal survival or on body, liver and kidney weights of pups up to PND 12. Newborns born and fed by mothers exposed to CdCl2during pregnancy exhibited a significant decrease in ALP activity on PND 3. Conversely, no significant changes were observed in newborns lactatcd by surrogate non‐treated mothers. Renal MTh increased with age but was not influenced by maternal treatment. Traces of109Cd were present in the liver at birth (5–7 ng). Thereafter,109Cd was mainly found in the gastrointestinal tract of newborns lactated by their biological mothers (610–690 ng on PND 12), with a marginal uptake in the liver (10–12 ng on PND 12).109Cd was not detectable in the kidneys at any age (<4 ng).These results show that prenatal exposure to Cd cannot be the sole aetiological agent in the induction of the subtle and transitory changes in renal biochemistry observed in offspring born and fed by female rats intraperitoneally injected with 2.5 mg CdCl2kg−1body wt. on days 8, 10, 12 and 14 of gestation. The resofts also contradict the role of a direct effect

ISSN:0260-437X    

DOI:10.1002/jat.2550120310

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractPrevious studies have demonstrated the importance of substitution at the 3‐ and 5‐positions of the phenyl ring inN‐phenylsuccinimides for the production of nephrotoxicarrts in this series of compounds. The purpose of this study was to determine if the electronic nature of the 3,5‐substituents is an important determinant for nephrotoxic potential. Male Fischer 344 rats (four rats per group) were administered a single intraperitoneal injection of a succinimide (0.4 or 1.0 mmol kg−1) or vehicle, and the renal function was monitored for 48 h. OnlyN‐(3,5‐dichlorophenyl)succinimide (0.4 or 1.0 mmol kg−1) induced marked changes in renal function. Urine volume, BUN concentration and proteinuria were increased followingN‐(3,5‐dinitrophenyl)succinimide (1.0 mmol kg−1) treatment but other renal parameters and renal morphology were unchanged in this treatment group. These results indicate that the presence of halogen atoms atthe 3‐ and 5‐positioiis of the phenyl nag inN‐phenylsuccinimides is more important for nephrotoxic potential than the presence of non‐halogen substituents. The reason why halogen substitution is an important determinant forN‐phenylsuccin

ISSN:0260-437X    

DOI:10.1002/jat.2550120311

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe local lymph node assay (LLNA) assesses the sensitizing activity of chemicals by measurement of primary lymphocyte proliferation in lymph nodes draining the site of application. In this final inter‐laboratory stady the consistency of LLNA results between laboratories and with guinea pig maximization test (GPMT) data was examined under ‘field’ conditions. Nine chemicals were evaluated independently by each laboratory according to guidelines for test concentration and vehicle selection developed during previous validation studks to ensure assay optimization. Equivalent predictions of sensitization potential were obtained by all laboratories for eight chemicals. Five of seven chemicals identified as sensitizers in the GPMT were correctly identified in the LLNA—four by all laboratories and 1 (4‐chloroaniline) by one laboratory only—although in this latter case, two other laboratories obtained clear dose responses, suggestive of sensitization. The LLNA identified correctly those chemicals predicted to be extreme or strong sensitizers in the GPMT. The remaining two chemicals were non‐sensitizers in the guinea pig and failed to elicit positive proliferative responses in the LLNA. These data demonstrate that sensitivity and reliability of the LLNA is retained when chemicals are evaluated independently, and that it provides a reliable pre‐screen for the identification of chemicals with significant sensitiz

ISSN:0260-437X    

DOI:10.1002/jat.2550120312

出版商:John Wiley&Sons, Ltd.    

年代:1992

数据来源: WILEY