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Archives of Toxicology (v.75, #3)
No Title by A. Esquifino; R. Seara; E. Fernández-Rey; A. Lafuente (pp. 127-133).
This work examines changes of gamma aminobutyric acid (GABA) and taurine contents in the hypothalamus, striatum and prefrontal cortex of the rat after an alternate schedule of cadmium administration. Age-associated changes were also evaluated, of those before puberty and after adult age. In control rats GABA content decreased with age in the median eminence and in anterior, mediobasal and posterior hypothalamus, prefrontal cortex and the striatum. Taurine content showed similar results with the exception of mediobasal hypothalamus and striatum, where no changes were detected. In pubertal rats treated with cadmium from 30 to 60 days of life, GABA content significantly decreased in all brain regions except in the striatum. When cadmium was administered from day 60 to 90 of life, GABA content was significantly changed in prefrontal cortex only compared with the age matched controls. Taurine content showed similar results in pubertal rats, with the exception of the median eminence and the mediobasal hypothalamus, neither of which showed a change. However, when cadmium was administered to rats from day 60 to 90 of life, taurine content only changed in prefrontal cortex compared with the age matched controls. These results suggest that cadmium differentially affects GABA and taurine contents within the hypothalamus, median eminence, striatum and prefrontal cortex as a function of age.
Keywords: Cadmium GABA Taurine
No Title by Ivan D. Dobrev; Melvin E. Andersen; Raymond S. Yang (pp. 134-144).
The volatile organic solvents trichloroethylene (TCE), tetrachloroethylene (perchloroethylene, PERC), and 1,1,1-trichloroethane (methylchloroform, MC) are widely distributed environmental pollutants and common contaminants of many chemical waste sites. To investigate the mode of pharmacokinetic interactions among TCE, PERC, and MC and to calculate defined "interaction thresholds", gas-uptake experiments were performed using a closed-chamber exposure system. In each experiment, two rats (Fischer 344, male, 8–9 weeks old) were exposed to different initial concentrations of TCE, PERC, and MC, applied singly or as a mixture, and their concentration in the gas phase of the chamber was monitored over a period of 6 h. A physiologically based pharmacokinetic (PBPK) model was developed to test multiple mechanisms of inhibitory interactions, i.e., competitive, non-competitive, or uncompetitive. All mixture exposure data were accurately described by a system of equations in which a PBPK model was provided for each chemical and each was regarded as an inhibitor of the others' metabolism. Sensitivity-analysis techniques were used to investigate the impact of key parameters on model output and optimize experimental design. Model simulations indicated that, among these three chemicals, the inhibition was competitive. The PBPK model was extended to assess occupationally relevant exposures at or below the current threshold-limit values (TLVs). Based on 10% elevation in TCE blood levels as a criterion for significant interaction and assuming TCE exposure is set at TLV of 50 ppm, the calculated interaction thresholds for PERC and MC were 25 and 135 ppm, respectively. TLV exposures to binary TCE/PERC mixture were below the 10% significance level. The interaction threshold for TCE and MC co-exposure would be reached at 50 and 175 ppm, respectively. Such interactive PBPK models should be of value in risk assessment of occupational and environmental exposure to solvent mixtures.
Keywords: Trichloroethylene Tetrachloroethylene Methylchloroform Chemical mixtures PBPK modeling Gas uptake Sensitivity analysis Metabolic interaction
No Title by T. Schettgen; T. Weiss; J. Angerer (pp. 145-149).
Phenmedipham [methyl-3-(3-methylphenylcarbamoyloxy)carbamate] is used as a herbicide, especially in the growing of sugar beet and strawberries. During metabolism of the substance in rats, the two carbamate moieties of phenmedipham are cleaved and the metabolites methyl-N-(3-hydroxyphenyl)-carbamate, m-aminophenol and hydroxyacetanilide are formed. These compounds and their conjugates are excreted in urine. Additionally, it has been suggested that m-toluidine is formed during metabolism. For the first time it has been possible to detect this metabolite in the urine of workers after agricultural use of phenmedipham. The concentrations of m-toluidine in urine were significantly higher in persons occupationally exposed than in controls. The median values for each group were 0.36 µg/l and 0.16 µg/l, respectively. This means that persons not exposed to phenmedipham also excrete m-toluidine, possibly as a result of the uptake of pesticides like phenmedipham from the diet.
Keywords: Phenmedipham Pesticides Biomonitoring Urine m-Toluidine Aromatic amines
No Title by Elke Röhrdanz; Gabriele Schmuck; Sandra Ohler; Quynh-Hoa Tran-Thi; Regine Kahl (pp. 150-158).
Oxidative stress has been causally linked to a variety of neurodegenerative diseases. To clarify the role of the antioxidant enzyme (AOE) system in oxidative brain damage primary cultures of rat astroglial cells were exposed to hydrogen peroxide (H2O2). Expression of AOEs and several parameters for cell viability and functionality were measured. In our experiments astrocytes responded to low concentrations of H2O2 exposure with a pronounced generation of ROS which ran parallel with induction of lipid peroxidation. This distinct oxidative stress was not reflected in cell viability or functionality parameters measured. Cytotoxicity, a decrease in glutathione content of astrocytes, and impairment of mitochondrial functions became obvious only for higher concentrations of H2O2. After H2O2 exposure catalase, manganese superoxide dismutase, and glutathione peroxidase expression levels were found to be increased, whereas copper/zinc superoxide dismutase mRNA expression was not affected. These data indicate that the AOE system of astrocytes can be directly regulated by oxidative stress and may thus contribute to protection of cells against oxidative insults.
Keywords: Catalase Superoxide dismutase Glutathione peroxidase Hydrogen peroxide Astrocytes
No Title by V. Feron; B. Kittel; C. Kuper; H. Ernst; S. Rittinghausen; H. Muhle; W. Koch; A. Gamer; A. Mallett; H. Hoffmann (pp. 159-175).
Two independent bioassays are available which have examined the potential carcinogenicity of monomeric and polymeric methylene diphenyl diisocyanate (MDI) following long-term inhalation exposure in rats. Thesestudies are not directly comparable, however, due to differences in design and conduct of the in-life phase, and differences in nomenclature used for some of the histopathological findings. This paper presents a definitive overview ofthe pulmonary toxicity of MDI developed following a thorough review of both investigations. As part of this process, the test materials and the designs of the studies were compared, and an in-depth review of lung lesions was conducted by an independent reviewing pathologist.This included the re-examination of the original lung slides, supported by an analysis of the exposure regimens, the results of which were used to develop an accurate profile of the doses received by the animals in the two studies. Histopathological findings were then combined with this information to give an overall dose-response curve for both studies as a whole. The range of total inhalation exposures to MDI was calculated as 559, 1972, 2881, 6001, 17,575 and 17,728 mgh/m3. Major pulmonary effects included increased lung weights together with bronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis which occurred consistently in both studies, indicating a very similar qualitative response of the lungs to polymeric and monomeric MDI. The quantitative response of the lung was clearly dose-related in each study, and when the studies were considered as a whole a reasonable overall dose-response relationship was apparent for major lung lesions. Lung tumours (in low incidences) only occurred at the highest dose level in both studies (17,575 and 17,728 mgh/m3). For inflammatory and other non-neoplastic pulmonary changes, the lowest dose examined (559 mgh/m3) was regarded as a no-observed-adverse-effect-level for both polymeric and monomeric MDI. It was concluded that the results of the two studies could be combined to serve as a basis for human risk assessment of MDI.
Keywords: Methylene diphenyl diisocyanate (MDI) Inhalation Combined long-term rat bioassays Pulmonary effects
No Title by ; ; ; ; ; ; ; (pp. 176-183).
Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus ochraceus as well as other moulds. This mycotoxin contaminates animal feed and food. OTA is immunosuppressive, genotoxic, teratogenic, carcinogenic and is nephrotoxic in all animal species studied so far. OTA inhibits protein synthesis and induces lipid peroxidation. Since it seems impossible to avoid completely contamination of foodstuffs by toxigenic fungi, it is necessary to investigate the possible ways of limiting such toxicity. An attempt to prevent OTA-induced nephrotoxic and genotoxic effects, mainly the karyomegaly, has been made in vivo using aspartame (L-aspartyl-L-phenylalanine methyl ester), a structural analogue of both OTA and phenylalanine. Aspartame (25 mg/kg body weight) prevented most of the nephrotoxic effects induced by OTA (289 µg/kg body weight). It also showed some utility in preventing morphological and histological damage, mainly the karyomegaly. The protective effects of aspartame on OTA-induced nephrotoxicity could be based on several mechanisms related to competitive binding to plasma proteins, to transport or tissue distribution in the kidney or to the elimination of the toxin in the urine.
Keywords: Ochratoxin A Nephrotoxicity Karyomegaly Prevention Aspartame
No Title by Hong-Tai Chang; Jong-Khing Huang; Jue-Long Wang; Jin-Shiung Cheng; Kam-Chung Lee; Yuk-Keung Lo; Muh-Chiou Lin; Kwong-Yui Tang; Chung-Ren Jan (pp. 184-188).
This study examined the effect of tamoxifen, an anti-breast cancer drug, on Ca2+ handling in bladder female transitional cancer cells. Changes in cytosolic free Ca2+ levels were recorded by using the Ca2+-sensitive dye fura-2. In a dose-dependent manner, tamoxifen induced intracellular free Ca2+ concentrations ([Ca2+]i) increases between 5 and 20 µM with an EC50 of 10 µM. External Ca2+ removal reduced the response by 60±6%. Addition of 3 mM Ca2+ caused a [Ca2+]i increase after pretreatment with 10 µM tamoxifen in Ca2+-free medium. In Ca2+-free medium, pretreatment with 10 µM tamoxifen abolished the [Ca2+]i increase induced by 1 µM thapsigargin, an endoplasmic reticulum Ca2+ pump inhibitor. Conversely, pretreatment with 1 µM thapsigargin prevented tamoxifen from releasing more Ca2+. Inhibition of phospholipase C-dependent inositol 1,4,5-tris-phosphate formation with 2 µM U73122 did not alter 10 µM tamoxifen-induced Ca2+ release. The [Ca2+]i increase induced by 5 µM tamoxifen was not altered by 10 µM La3+, nifedipine, verapamil, and diltiazem. Collectively, it was found that tamoxifen increased [Ca2+]i in bladder cancer cells by releasing Ca2+ from the endoplasmic reticulum Ca2+ stores in a manner independent of phospholipase C activity, and by inducing Ca2+ entry from external medium.
Keywords: Bladder cell carcinoma BFTC cells Ca2+ signaling Fura-2 Tamoxifen