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Archives of Toxicology (v.77, #1)
Children as a sensitive subgroup and their role in regulatory toxicology: DGPT workshop report by M. Schwenk; U. Gundert-Remy; G. Heinemeyer; K. Olejniczak; R. Stahlmann; W. Kaufmann; H. Bolt; H. Greim; E. von Keutz; H. Gelbke (pp. 2-6).
There is increasing discussion that children might be considered as a specific subgroup in public health regulations which could be more sensitive than the average "adult" human being. Differences between children and adults, with regard to susceptibility towards toxicants, may result from a combination of toxicokinetic, toxicodynamic and exposure factors. Kinetic factors are of importance mainly in the early postnatal period, largely as the result of immature elimination systems, i.e. metabolising enzymes and/or renal function. Specific vulnerability may prevail during several time periods, related to the development and maturation of organs (for example, brain, bone, endocrine system). For some substances, it has been shown that children at a specific age are less sensitive than adults. Specific exposures of toddlers to environmental chemicals may be high due to their moving behaviour and hand-to-mouth activities. Existing scenarios and models for exposure of children should be improved, in particular with respect to different ages. The outcome of model calculations must be verified by human biomonitoring analysis. At present, there is ongoing discussion of toxicological test models suitable to delineate human postnatal development. Experience with infant-orientated test systems is scarce (for example in developmental neurotoxicity). In general, tools for predicting toxicological sensitivity of children must be further improved. Regulators should also be aware that reduction of lifestyle-related toxic exposures such as smoking and drug abuse in children and adolescents is now an increasing public health problem in many countries.
Keywords: Children Neurotoxicity Risk assessment Test systems Human development
Children as a special population at risk – quinolones as an example for xenobiotics exhibiting skeletal toxicity by Ralf Stahlmann (pp. 7-11).
The sensitivity of the immature skeletal system during postnatal mammalian development was discussed during the workshop "Children as a Sensitive Subgroup and their Role in Regulatory Toxicology" (Schwenk et al. 2002, Arch Toxicol, in press). As a typical example of xenobiotics exhibiting this extraordinary type of toxicity, the quinolone-induced effects on cartilage, bone growth, and tendons were considered in depth. Animal experiments indicate that chondrotoxicity of quinolones can affect articular cartilage depending on the developmental stage. Results from studies with pipemidic acid in dogs at various developmental stages from 1 week old to 17 months old showed pronounced effects in the most sensitive age groups: 3- to 6-month-old dogs exhibited gait alterations and lameness, but signs of toxicity were not observed in 12- or 17-month-old dogs. Similarly, experiments performed in rats indicate that they exhibit the highest sensitivity for articular cartilage defects at a certain stage of development between 3 and 6 weeks postnatally; mature articular cartilage does not seem to be a target for quinolone-induced toxicity. Some very limited data indicate that in animals at an early developmental phase the epiphyseal growth plate can also be damaged by quinolones, and that these effects are associated with irreversible bone damage and growth inhibition. Another manifestation of toxic effects of quinolones on connective tissue structures are tendopathies. For this effect, it is not quite clear whether juveniles are more susceptible than adults because clinical and experimental data seem to point in different directions. Pathogenesis of both effects can probably be explained by the magnesium-chelating properties of these drugs, leading to a deficit of functionally available magnesium and, subsequently, to radical formation and irreversible connective tissue lesions. However, unequivocal explanations for the phase-dependency of the effects are lacking.
Keywords: Quinolones Skeletal system Developmental toxicity Children Magnesium
Alterations of metallothionein isomers in Hg0-exposed rat brain by A. Yasutake; M. Nagano; K. Hirayama (pp. 12-16).
Previously we found that exposure to mercury vapor effectively induced brain metallothionein (MT) in rats. Here, using FPLC-gel chromatography, we examined time-dependent alterations in the MT isomers, MT-I/II and MT-III, following 3 weeks of exposure. Rats were exposed to mercury vapor at 8.3 mg/m3 for 15 h in total over 5 consecutive days. Total MT levels in rat cerebrum and cerebellum increased by 65% and 155%, respectively, 24 h after the final exposure. The increased levels in both tissues remained unchanged for at least 2 weeks after termination of exposure. Interestingly, most MT in control rat cerebrum and cerebellum was accounted for by MT-III, with MT-I/II being less than 10%. Through mercury vapor exposure, MT-I/II was quickly induced to a significant extent in both tissues, reaching a level comparable to that of MT-III. The induction rate of MT-I/II in the cerebellum was somewhat higher than in the cerebrum. Chromatograms showed that the MT-I/II thus induced began to decline at an early stage in both tissues. In the cerebrum, the amount of MT-I/II on day 22 was about 30% of the maximum level on day 1. On the other hand, the induction of MT-III was not that dramatic, but it did become evident, at least in the latter stage, when MT-I/II had begun to decrease. Thus, though the induction rate of MT-III was not as high as MT-I/II, it was sustained throughout the experimental period.
Keywords: Metallothionein Brain Rat Mercury vapor Gel chromatography
Effect of methylmercury on histamine release from rat mast cells by Elizabeth E. Graevskaya; Akira Yasutake; Ryoji Aramaki; Andrew B. Rubin (pp. 17-21).
Methylmercury chloride (MeHgCl) is well known as a significant environmental hazard, particularly as a modulator of the immune system. As it is acknowledged that the critical effector cells in the host response participating in various biological responses are mast cells, we tried to define the possible contribution of mast cells in the development of methylmercury-evoked effects. We investigated the effects of methylmercury on the rat mast cell degranulation induced by non-immunological stimuli (the selective liberator of histamine, compound 48/80, and calcium ionophore A23187) both in vivo and in vitro. Using the cells prepared from methylmercury-intoxicated rats through a 5-day treatment of MeHgCl (10 mg/kg/day), we observed the suppression of calcium ionophore A23187- and 48/80-induced histamine release, which was enhanced with time after treatment. Similar suppression was observed in the ionophore-stimulated release, when cells were prepared from rat with a single treatment of MeHgCl (20 mg/kg). It should be noted that when cells from the control rat were pre-incubated with methylmercury in vitro at a 10–8 M concentration for 10 min, A23187 and compound 48/80-stimulated histamine release was significantly enhanced. However, when the pre-incubation period was prolonged to 30 min, the release was suppressed. An increase in the methylmercury concentration to 10–6 M also suppressed the histamine release. These results show that methylmercury treatment can modify mast cell function depending on concentration and time, and might provide an insight into the role of mast cells in the development of methylmercury-stimulated effects.
Keywords: Mast cells Methylmercury Histamine release Rats
Standardized extracts of flavonoids increase the viability of PC12 cells treated with hydrogen peroxide: effects on oxidative injury by Lubica Horáková; Anke Licht; Grit Sandig; Manuela Jakstadt; Zdena Duracková; Tilman Grune (pp. 22-29).
Oxidative stress plays an important role in cell death associated with many diseases. In the present study, concentration-dependence of hydrogen peroxide on rat pheochromocytoma (PC12) cell viability was studied. Preventive effects of antioxidants on the viability of these cells treated with 2 mM hydrogen peroxide were compared. Trolox and Stobadine, as chain-breaking antioxidants were studied in comparison with standardized extracts of flavonoids of Ginkgo biloba and Pycnogenol, known as agents effective in several diseases. All antioxidants increased the viability of hydrogen peroxide-treated PC12 cells. Flavonoid extracts were more effective than Trolox and Stobadine. Antioxidants were most effective if present after the oxidative treatment. As expected, the preloading with antioxidants was without effect on cell viability. Correlations between viability increase induced by antioxidants, and content of oxidation products of proteins and lipids were studied at concentrations of antioxidants mostly effective in preventing cell death: Trolox (10 µM), Stobadine (30 µM), Ginkgo biloba (160 µg/ml), Pycnogenol (100 µg/ml). In these concentrations, antioxidants did not statistically significantly decrease the content of protein carbonyls, with exception of Stobadine, which had no effect. Ginkgo biloba, Trolox and Stobadine intensively decreased the content of malondialdehyde, a product of lipid peroxidation. Pycnogenol was without any preventive effect. Concentrations of antioxidants with a large effect on viability of PC12 cells were not effective in preventing oxygen radical-induced injury of proteins. Antioxidants prevented the oxidative injury of lipids more effectively than that of proteins.
Keywords: Oxidative stress PC 12 cells Ginkgo biloba Pycnogenol Protein carbonyls
Cytometric determination of novel organotellurium compound toxicity in a promyelocytic (HL-60) cell line by Brian L. Sailer; Nathan Liles; Sarah Dickerson; Thomas G. Chasteen (pp. 30-36).
The increasing use of tellurium compounds in organic synthesis, industrial applications, and as a possible component in pesticides means that its introduction into the environment will increase in the future. Therefore, knowledge of the relative toxicity and mode of toxic action of tellurium-containing compounds is important. The studies detailed here used three model compounds: diphenyl ditelluride, 3,3′-diaminodiphenyl ditelluride, and 4,4′-diisopropyldiphenyl ditelluride. Experiments with human promyelocytic (line HL-60) cells indicate that all of the organotellurium compounds induce an apoptotic form of cell death. The induction of apoptosis occurs in a time- and dose-dependent manner as assayed by three different analytical methods: fluorescence microscopy, gel electrophoresis, and flow cytometry. Apoptotic cells were evident as early as 2 h following treatment with 1×10–6 M concentrations of the compounds. Based on these results, future care should be afforded these compounds in laboratory as well as industrial settings.
Keywords: Organotellurium compounds Apoptosis Cytotoxicity Flow cytometry Fluorescence microscopy
Association between head and neck cancer and microsomal epoxide hydrolase genotypes by Matthias Wenghoefer; Beate Pesch; Volker Harth; Peter Broede; Stefan Fronhoffs; Olfert Landt; Thomas Brüning; Josef Abel; Hermann M. Bolt; Claus Herberhold; Hans Vetter; Yon-Dschun Ko (pp. 37-41).
Tobacco-associated carcinogens are catalyzed by microsomal epoxide hydrolase (mEH). Combinations of the Y113H and H139R polymorphic EPHX1 variants have been assumed to alter the enzyme activity and thus the risk of squamous cell head and neck cancer (SCCHN). Based on in vitro data, a putative low, medium and high mEH activity has been associated with combinations of these genotypes, and the respective activity categories have been frequently used in the estimation of risks for smoking-related cancers. We investigated the SCCHN risk for EPHX1 genotypes among 280 cases and 289 controls. We could not detect main effects of the EPHX1 genotypes, but a smaller risk of the 139HR genotype in smokers (odds ratio, OR, 0.57; 95% confidence interval, CI, 0.34–0.95). We could not confirm an increase of the SCCHN risk for genotype combinations according to a putative medium and high enzyme activity (OR 1.28, 95% CI 0.84–1.96; OR 0.98, 95% CI 0.58–1.64, respectively), but a significant heterogeneity of the estimated risks for the singular genotypes within these categories among smokers (P=0.02). Further, p53 mutations among smoking cases were less frequent in the group with a putative high enzyme activity, although insignificant due to small numbers (OR 0.54, 95% CI 0.13–2.17). This supports uncertainties in categorizing genotypes with respect to limited enzyme activity data, especially when taken from in vitro experiments.
Keywords: Head and neck cancer Microsomal epoxide hydrolase p53 Gene Polymorphisms Smoking
Hibiscus protocatechuic acid inhibits lipopolysaccharide-induced rat hepatic damage by W.-L. Lin; Y.-J. Hsieh; F.-P. Chou; C.-J. Wang; M.-T. Cheng; T.-H. Tseng (pp. 42-47).
Hibiscus protocatechuic acid (PCA), a phenolic compound found in the dried flowers of Hibiscus sabdariffa L. (Malvaceae), was demonstrated to have an antioxidant effect in vitro and in vivo, and an antitumor property in our previous study. In the present study, we used lipopolysaccharide (LPS, an endotoxin) to induce rat liver inducible nitric oxide synthase (iNOS), and found that pretreatment with PCA decreased the liver iNOS and the serum total nitrite induced by LPS. Our investigation showed that pretreatment of rats with PCA (0.2 and 0.5 mmol/kg dosed by gavage) for 5 days significantly decreased the serum levels of the hepatic enzyme markers alanine- and aspartate aminotransferase (ALT, alanine aminotransferase; AST, aspartate aminotransferase) induced by the 6-h treatment with LPS (i.p.; 5 mg/kg). Histopathological evaluation of the rat livers revealed that PCA reduced the incidence of liver lesions induced by LPS, including neutrophil infiltration, congestion, and liver cell swelling induced by LPS in rats. We conclude that PCA, an antioxidant, presents an inhibitory potential on iNOS and hepatic damage induced by LPS.
Keywords: Hibiscus protocatechuic acid Lipopolysaccharide Inducible nitric oxide synthase
Developmental toxicity of pyrethroids
by Bala Y. Muhammad; Richard D. Verschoyle; David E. Ray (pp. 48-49).
Thimerosal induces micronuclei in the cytochalasin B block micronucleus test with human lymphocytes by Götz A. Westphal; Soha Asgari; Thomas G. Schulz; Jürgen Bünger; Michael Müller; Ernst Hallier (pp. 50-55).
Thimerosal is a widely used preservative in health care products, especially in vaccines. Due to possible adverse health effects, investigations on its metabolism and toxicity are urgently needed. An in vivo study on chronic toxicity of thimerosal in rats was inconclusive and reports on genotoxic effects in various in vitro systems were contradictory. Therefore, we reinvestigated thimerosal in the cytochalasin B block micronucleus test. Glutathione S-transferases were proposed to be involved in the detoxification of thimerosal or its decomposition products. Since the outcome of genotoxicity studies can be dependent on the metabolic competence of the cells used, we were additionally interested whether polymorphisms of glutathione S-transferases (GSTM1, GSTT1, or GSTP1) may influence the results of the micronucleus test with primary human lymphocytes. Blood samples of six healthy donors of different glutathione S-transferase genotypes were included in the study. At least two independent experiments were performed for each blood donor. Significant induction of micronuclei was seen at concentrations between 0.05–0.5 µg/ml in 14 out of 16 experiments. Thus, genotoxic effects were seen even at concentrations which can occur at the injection site. Toxicity and toxicity-related elevation of micronuclei was seen at and above 0.6 µg/ml thimerosal. Marked individual and intraindividual variations in the in vitro response to thimerosal among the different blood donors occurred. However, there was no association observed with any of the glutathione S-transferase polymorphism investigated. In conclusion, thimerosal is genotoxic in the cytochalasin B block micronucleus test with human lymphocytes. These data raise some concern on the widespread use of thimerosal.
Keywords: Thimerosal Cytokinesis-block micronucleus assay Glutathione S-transferase
A re-assessment of styrene-induced clastogenicity in mice in a subacute inhalation study by Günter Engelhardt; Armin Gamer; Pavel Vodicka; Ivo Bárta; Hans-Dieter Hoffmann; Gauke Veenstra (pp. 56-61).
To date, a number of in vivo cytogenetic assays have studied the clastogenicity (chromosome aberrations, micronuclei formation) in bone marrow of rodents exposed to styrene by various routes. The majority of all these cytogenetic experiments yielded negative findings (Scott and Preston, Mutat Res 318:175–203, 1994). Recently published data from a micronucleus test in mice exposed via inhalation for up to 21 days showed some positive response, but was not fully conclusive (Vodicka et al., Chem Biol Interact 137:213–227, 2001). Since this exposure regimen has considerable relevance for workplace exposure, the present study was performed to further elucidate these findings. NMRI mice were exposed by whole body inhalation to styrene concentrations of 750 mg/m3 and 1,500 mg/m3 for 1, 3, 7, 14 and 21 consecutive days (6 h/day). Animals were killed directly after exposure and bone marrow was sampled for analysis of micronucleus induction. Under the experimental conditions used in the present investigation, there was no evidence of clastogenicity at any concentration or exposure interval.
Keywords: Styrene Micronucleus assay Clastogenicity Inhalation