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Archives of Toxicology (v.75, #1)

No Title by Horst Spielmann; Ulrich Gerbracht (pp. 1-21).

Data on 172 pesticides (fungicides, herbicides, insecticides and other pesticides) submitted for regulatory purposes during the past 40 years to the German Federal Institute for the Health Protection of Consumers and Veterinary Medicine (BgVV) were analysed to determine whether chronic studies in dogs (52/104 weeks) provide essential additional specific toxicological compared with subchronic (13 weeks) or subacute (4 weeks) studies in the same species. Comparison of the lowest observed effect levels (LOELs) in dogs revealed no significant differences between subchronic and chronic studies but a significant difference between subacute studies and subchronic or chronic studies. Moreover, there was a significant correlation between the LOELs determined in subchronic studies and those determined in chronic studies in dogs (r=0.78–0.84). The distribution of target organ toxicity determined in chronic studies in dogs was not significantly different from the distribution determined in subchronic studies, except for effects on the spleen in studies on herbicides which were only observed in chronic studies and in combined subchronic/chronic studies, but never in subchronic studies. Organ-specific effects that were observed in chronic studies but not in subchronic studies were found in 30 of 55 studies on fungicides, in 25 of 44 on herbicides, in 17 of 38 on insecticides and in 10 of 16 on other pesticides. Compared with 26-week studies, additional organ-specific toxic effects were found in three of five, in three of four, in one of three and in one of one 52/104-week studies on fungicides, of herbicides, of insecticides and other pesticides, respectively. The organ-specific effects that were seen only in the chronic dog studies were evaluated according to their severity, e.g. significant damage to organs versus changes in enzyme activities that do not affect organ function or histology. Such effects were not considered to be specific for dogs in chronic studies if similar effects were also found in chronic studies in rodents (rat or mouse). In 15 of 141 studies in dogs serious side effects were observed in chronic studies that were not observed in subchronic studies. Furthermore, for 9 of 172 pesticides significant new effects were seen in 52/104-week studies when compared with 4- or 13-week studies and in 7 of 141 52/104-week studies when compared with 13-week studies. Analysis of the severity of organ-specific toxic effects of pesticides revealed that chronic long-term studies (52/104 weeks) in dogs do not provide specific additional information to 26-week studies in the same species.

Keywords: Pesticides Regulatory testing Chronic toxicity studies Dog Interspecies comparison

No Title by F.X. Reichl; J. Durner; K.H. Kunzelmann; R. Hickel; W. Spahl; W.R. Hume; G.W.H Moes; K. Kehe; U. Walther; W. Forth (pp. 22-27).

The excretion of the dental composite component triethylene glycol dimethacrylate (TEGDMA) in feces and urine in vivo and, using the pendular perfusion technique with segments of jejunum and colon, the biliary and enteric excretion in situ were investigated in anesthetized guinea pigs. In the in situ experiments guinea pigs (n=4) received TEGDMA (0.02 mmol/kg body weight labelled with a tracer dose ¹⁴C-TEGDMA 0.7 kBq/g body weight) injected into the jugular vein. In the in vivo experiments guinea pigs (n=4) received TEGDMA (+¹⁴C-TEGDMA; same dose as above) via a gastric tube. Urine and feces were collected for 24 h. In the in situ experiments organs were removed from the guinea pigs 60 min after the beginning of the experiment, and the ¹⁴C radioactivity measured. During the 60-min perfusion period the calculated amount of ¹⁴C radioactivity excreted into the total jejunum and colon was 0.9±0.2% and 1.9±0.1% of the dose administered, respectively (means±SEM). Of the ¹⁴C-TEGDMA dose, 3.7±0.2% was found in the bile. A significantly (P<0.05) higher bile/blood concentration ratio was found 10 min after injection of TEGDMA as compared with the ratios at 20 to 60 min. The following ¹⁴C activities (percent of the dose) per total organ were found in guinea pigs (in situ experiment; means±SEM): 6.9±1.7 (muscle), 3.9±0.5 (kidney), 3.3±0.1 (skin), 1.4±0.1 (blood), and 1.2±0.1 (liver). The ¹⁴C activity in all other organs was <0.4%. The total ¹⁴C recovery in all organs tested was 17.5±1.8%. Over 24 h the amounts of ¹⁴C activity excreted in the feces and urine were 0.5±0.1% and 14.7±1.8% of the dose administered, respectively (means±SEM). The following ¹⁴C activities (percent of the dose) per total organ or contents of organs were found (means±SEM): 1.4±0.3 (liver), 0.8±0.3 (muscle), 0.5±0.1 (skin), and 0.5±0.1 (contents of cecum). The ¹⁴C activity in all other organs was <0.2%. The total ¹⁴C recovery in all organs tested was 3.9±0.9%. In a second series of in vivo experiments exhaled air from the animals was captured during the 24-h experimental period. Of the administered dose, 61.9±4.6% of the ¹⁴C (means±SEM; n=4) was exhaled as ¹⁴C-carbon dioxide. The results indicate a rapid clearance of ¹⁴C-TEGDMA and/or ¹⁴C-TEGDMA metabolite(s) from the organism and exhalation is the major route of elimination.

Keywords: 14C-TEGDMA Clearance Blood Urine Guinea pig

No Title by Wen-Cheng Chang; Yuan-Chih Lee; Chuen-Lan Liu; Jeng-Dong Hsu; Hsue-Chun Wang; Chang-Che Chen; Chau-Jong Wang (pp. 28-35).

Epidemiological evidence suggests that smoking is a major cause of human lung cancer. However, the mechanism by which cigarette smoke induces the cancer remains unestablished. To evaluate the effects of cigarette smoke on the expression of inducible nitric oxide synthase (iNOS), nuclear protooncogenes and related mitogen-activated protein kinases (MAPKs) in rat lung tissue, a histopathological study of the effects of gas-phase cigarette smoke on rat lung tissue were carried out. The terminal bronchioles were found to be infiltrated predominantly by lymphocytes in the peribronchiolar region and a mild to moderate degree of emphysema was noted in the alveolar spaces. The terminal bronchioles also showed marked lipid peroxidation, dilatation, and peribronchiolar fibrosis. Immunohistochemical evaluation showed that the expression of iNOS, NF-κB, MAPKs (MEK1, ERK2), phosphotyrosine protein and c-fos was increased in the terminal bronchioles but protein kinase C (PKC), MEKK-1, c-jun, p38 and c-myc showed no change. These results provide evidence to suggest that exposure to cigarette smoke results in oxidant stress which leads to the stimulation of iNOS and c-fos together with the induction of protein tyrosine phosphorylation and MEK1/ERK2 which in turn may promote lung pathogenesis.

Keywords: Cigarette smoke c-Fos NF-κB Mitogen-activated protein kinases Inducible nitric oxide synthase Protein tyrosine phosphorylation

No Title by Renate Thiel; Stefanie Metzner; Christine Gericke; Ute Rahm; Ralf Stahlmann (pp. 36-41).

During therapy with fluoroquinolones adverse CNS reactions such as dizziness, light-headedness, insomnia or sleepiness are observed in up to 20% of patients. Using a device developed at our institute for the simultaneous registration of the activity of rats housed in single cages, we have investigated the effects of trovafloxacin, fleroxacin or ofloxacin on the locomotor activity of juvenile and adult rats (11 per group) after oral administration of 600 mg/kg for 5 consecutive days. The effects were most pronounced after fleroxacin, which induced a reduction in activity to 36±9% (mean±SD) of the values measured in juvenile rats before treatment and to 60±21% (mean±SD) in adult rats. HPLC analysis of the plasma concentrations in juvenile rats showed that the concentrations of trovafloxacin were considerably lower than those of the other fluoroquinolones that had been studied previously in our laboratory: the peak concentration of trovafloxacin was 14±2.9 mg/l (mean±SD) after a single dose of 600 mg/kg in juvenile rats. Overall, we showed that the locomotor activities of juvenile and adult rats were significantly depressed during treatment with fluoroquinolones. The effects were more pronounced in juveniles. Monitoring of the locomotor activity of rats is a suitable approach to study CNS effects of fluoroquinolones in animals, but pharmacokinetics have to be taken into account.

Keywords: Fluoroquinolones Neurotoxicity Behaviour Pharmacokinetics Rats

No Title by Osamu Takahashi; Shinshi Oishi (pp. 42-51).

Male F344/DuCrj (Fischer) rats were given bisphenol A (BPA) in the diet at levels of 0 (control), 0.25, 0.50 and 1.00%, equivalent to 0, 235, 466 and 950 mg/kg per day, respectively, for 44 days. Body weight gains were depressed dose-dependently in BPA-treated rats, and those of 0.50 and 1.00% groups were significant. Testis and epididymis weights were not significantly decreased. Both absolute and relative weights of dorsolateral prostate and preputial glands were reduced in a dose-related fashion. Absolute weights of seminal vesicles and hypophysis were also decreased. Histopathologically, seminiferous tubule degeneration and loss of elongated spermatids were observed, the severity being related to BPA dose. The disorganization, distortion and degeneration of late spermatids, and the atrophy of seminiferous tubules were found even in the 0.25% BPA group. Serum testosterone concentrations were not decreased in BPA-treated groups. These results indicate that BPA even at a level of 0.25% (235 mg/kg per day) is clearly toxic to male reproductive organs.

Keywords: Bisphenol A Testis Epididymis Seminal vesicle Prostate gland Preputial gland Hypophysis Testosterone Rats

No Title by Michael J. Iatropoulos; Alan M. Jeffrey; Gerhard Schlüter; Harald G. Enzmann; Gary M. Williams (pp. 52-58).

Alternative bioassays of mannitol (MAN) and caprolactam (CAP) were conducted in transgenic p53-deficient mice. Also, to assess the sensitivity of the transgenic mice to a model DNA-reactive carcinogen, the hepatic effects of diethylnitrosamine (DEN) were compared in the wild type background strain of mouse and in the transgenic derivative. Fifty-one male wild type strain C57BL/6 mice p53 (+/+), 8 weeks old, and 51 heterozygous p53 (+/-) C57BL/6 Tac-[KO]Trp53 N5 mice, 8 weeks old, were allocated to six experimental groups as follows: groups 1 (wild type +/+) and 2 (p53 +/-) served as room controls, groups 3 (+/+) and 4 (+/-) were exposed orally (gavage) to 50 µmol/kg body weight DEN weekly for a total of ten doses during the first 10 weeks of the study, group 5 (+/-) was exposed to 15,000 ppm CAP in the diet for up to 26 weeks, and group 6 (+/-) was exposed to 50,000 ppm MAN in the diet for up to 26 weeks. After 10 weeks, liver from control and DEN-exposed mice was used for O ⁴-ethylthymidine (O ⁴-EtT) DNA adduct analysis by the immunoslot blot method. The cell replicating fraction (RF) in the liver was determined by quantification of the percentage of immunohistochemically stained hepatocytes positive for proliferating cell nuclear antigen. No significant or consistent body or liver weight changes were present in any of the treatment groups. No consistent and pertinent changes in RF values were present in any of the treatment groups. None of the tested substances produced neoplasms of any type in p53 (+/-) mice. DEN induced comparable levels of O ⁴-EtT adducts in the liver in both wild type and p53 +/- genotypes, but no morphologic changes were evident in the livers of either genotype. The lack of response to DEN, in spite of formation of DNA adducts, may reflect the resistance to hepatocarcinogenesis of the background C57BL/6 strain of the transgenic, and calls into question the general sensitivity of this transgenic for detection of carcinogenic effects.

Keywords: Transgenic p53-deficient mice Carcinogenicity bioassay Diethylnitrosamine Hepatocarcinogenesis

No Title by Güngör Kanbak; Fahrettin Akyüz; Mine İnal (pp. 59-61).

The aim of this study was to observe ethanol-induced membrane injury and to investigate the protective effect of betaine against chronic ethanol toxicity. Rats were divided into three groups: control group (n=8), ethanol (8 g/kg per day) group (n=8) and ethanol plus betaine (0.5% w/v) group (n=8). Cholesterol concentrations (P<0.05) and the cholesterol/phospholipid (C/PL) molar ratio (P<0.01) were significantly increased in the erythrocyte membranes of ethanol-treated rats compared with those of the control group. Cholesterol (P<0.05) and the C/PL ratio (P<0.01) were decreased to control group levels after betaine administration. The activities of Ca²⁺-Mg²⁺ ATPase and Na⁺-K⁺ ATPase were lower than those of the control group (both P<0.001), but the activities of these enzyme were increased in the betaine treatment group (P<0.05). Our findings show that chronic ethanol consumption may affect membrane functions and betaine administration may be a useful agent for the treatment of chronic ethanol toxicity.

Keywords: Ethanol Betaine Na+-K+ ATPase Ca2+-Mg2+ ATPase Membrane lipids

No Title by Winfried Kessler; Wanwiwa Phokha; György A. Csanády; Johannes G. Filser (pp. 62-64).

We measured the background levels of di(2-ethylhexyl) phthalate (DEHP) and its hydrolytic metabolite mono(2-ethylhexyl) phthalate (MEHP) in blood from naive female Sprague-Dawley rats and in de-ionized charcoal-purified water using an analytical procedure that is based on sample treatment with acetonitrile, n-hexane extraction and analysis by gas chromatography. In blood, blank values of 91.3±34.7 µg DEHP/l (n=31) and 30.1±13.1 µg MEHP/l (n=20) were obtained, and in water, values of 91.6±44.2 µg DEHP/l (n=26) and 26.7±10.4 µg MEHP/l (n=15) were found. Since there is no difference between the background valves obtained from blood of naive rats and water, we conclude that DEHP and MEHP result from contamination during the analytical procedure.

Keywords: Di(2-ethylhexyl) phthalate Mono(2-ethylhexyl) phthalate Rat Blood

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Archives of Toxicology (v.75, #1)