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General Toxicity (general + toxicity)
Selected AbstractsStructure,activity relationships for the mutagenicity and carcinogenicity of simple and ,-, unsaturated aldehydesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2003Romualdo Benigni Abstract Aldehydes are important industrial compounds that are used for the synthesis of chemicals and pharmaceuticals and as solvents, food additives, and disinfectants. Because of their reactivity, aldehydes are able to interact with electron-rich biological macromolecules and adverse health effects have been reported, including general toxicity, allergenic reactions, mutagenicity, and carcinogenicity. The cost, time, and number of animals necessary to adequately screen these chemicals places serious limitations on the number of aldehydes whose health potential can be studied and points to the need of using alternative methods for assessing, at least in a preliminary way, the risks associated with the use of aldehydes. A method of choice is the study of quantitative structure,activity relationships (QSARs). In the present work, we present QSAR models for the mutagenicity and carcinogenicity of simple aldehydes and ,-, unsaturated aldehydes. The models point to the role of electrophilicity, bulkiness, and hydrophobicity in the genotoxic activity of the aldehydes and lend themselves to the prediction of the activity of other untested chemicals of the same class. Environ. Mol. Mutagen. 42:136,143, 2003. © 2003 Wiley-Liss, Inc. [source] Evaluation of the rodent micronucleus assay by a 28-day treatment protocol: Summary of the 13th Collaborative Study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Environmental Mutagen Society of Japan (JEMS),Mammalian Mutagenicity Study Group (MMS)ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2001Shuichi Hamada Abstract To examine whether micronucleus tests can be incorporated into general toxicology assays, we performed micronucleus tests applying the treatment protocols typically used in such assays. In this 13th Collaborative Study of the CSGMT, both rats and mice were tested, although rats were used in the majority of the studies. Fifteen mutagens were tested in rats, mainly by oral (p.o.) administration. Micronucleus induction was evaluated 2, 3, and 4 days, and 1, 2, 3, and 28 days after the beginning of the treatment in the peripheral blood, and at 28 days in the bone marrow. Of the 15 chemicals that induced micronuclei in rats in short-term assays, two chemicals (1,2-dimethylhydrazine·2HCl and mitomycin C) were negative in all our experiments, possibly because of insufficient dose levels. The remaining 13 were positive within the estimated dose range of a general toxicology assay, suggesting the possibility of integrating the micronucleus assay into general toxicology assays. Three patterns were observed in micronucleus induction during the period of repeated treatment: (1) gradual increases in micronucleus frequency with sequential doses, (2) a peak at 3,5 days followed by gradual decreases in micronucleus frequency with sequential doses, and (3) a rapid increase in micronucleus frequency followed by a plateau. We evaluated factors that might have been involved in those patterns, such as the spleen function, target organ exposure, extramedullary hematopoiesis, hypothermia, and hypoxia. Another factor we considered was dosage. Because the dosages employed in a general toxicity assay are usually lower than those used in short-term micronucleus assays, this discrepancy was considered the greatest potential problem for integrating the micronucleus assay into general toxicology assays. Our results indicate that the integration of the micronucleus assay into a 28-day toxicological assay is feasible. To serve this purpose, blood samples collected 4 days after the beginning of treatment and blood and bone marrow samples collected at autopsy should be examined. Furthermore, although it is recognized that mice may be suitable for performing independent micronucleus assays, we propose that rats can provide biologically important and relevant information regarding potential chemical mutagens that can be evaluated under conditions used in the conduct of general toxicology studies. Environ. Mol. Mutagen. 37:93,110, 2001 © 2001 Wiley-Liss, Inc. [source] RAT in vivo models of taxanes' peripheral neurotoxicity following chronic intravenous administrationJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2004A Canta The "taxanes" family includes some widely used antineoplastic agents, such as paclitaxel and docetaxel. Treatment with these microtubule-stabilizing drugs is often associated with neurotoxicity, a potentially severe side effect limiting the clinical utility of these agents. To study the pathogenesis of taxanes' neurotoxicity and to compare it to the effect of new agents, the availability of reliable in vivo models is warranted. In this study we developed chronic iv models for the assessment of "taxanes" peripheral neurotoxicity. Forty-eight adult Wistar rats were divided into six groups of 8 animals each and treated as follows: paclitaxel or docetaxel at doses of 5, 10, 12.5 mg/kg 1q7d × 4 via a chronic jugular vein implant. The evaluation was based on the assessment of body weight and survival as a measure of general tolerability, and on the measurement of tail nerve conduction velocity, a neurophysiological method previously used in animal models of toxic peripheral neuropathies. The results were compared with those obtained in untreated or vehicle-treated control rats. A clear dose-dependent effect was evident both on general toxicity, and on neurophysiological changes measured at the end of the treatment (untreated controls = 41,9 m/sec, vehicle = 40,3 m/sec; paclitaxel 5 mg/kg = 32,5 m/sec, 10 mg/kg = 28,5 m/sec, 12.5 m/kg = 27,4 m/sec; docetaxel 5 mg/kg = 33,6 m/sec, 10 mg/kg = 27,8 m/sec, 12.5 mg/kg = 27,0 m/sec), demonstrating the usefulness of this new model system to investigate peripheral neurotoxicity mediated by taxanes, and potentially other drugs, under chronic treatment schedules. [source] Statins can modulate effectiveness of antitumor therapeutic modalitiesMEDICINAL RESEARCH REVIEWS, Issue 1 2010Marek Jakobisiak Abstract Despite significant, frequently very strong, antiproliferative and tumoricidal effects of statins demonstrated in vitro, their antitumor effects in animal models are modest, and their efficacy in clinical trials has not been proven. As such, statins seem unlikely to be ever regarded as antitumor agents. However, statins are regularly taken by many elderly cancer patients for the prevention of cardiovascular events. Owing to their pleiotropic effects in normal and tumor cells, statins interact in various ways with many antitumor treatment modalities, either potentiating or diminishing their effectiveness. Elucidation of these interactions might affect the choice of treatment to be planned in cancer patients as some combinations might be contraindicated, whereas others might elicit potentiated antitumor effects but at a cost of increased general toxicity. Some other combinations might induce either comparable or even stronger antitumor effects, but with a beneficial concomitant reduction of specific side effects. Most of the studies reviewed in this article have been carried in vitro or in experimental tumor models, but clinical relevance of the findings is also discussed. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 1, 102,135, 2010 [source] First Exposure in Man: Toxicological ConsiderationsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2000Per Spindler Recommendations on the type and extent of preclinical safety studies that should be conducted prior to first dose in man have been developed by the International Conference on Harmonisation, and the European Committee for Proprietary Medicinal Products. These recommendations include studies designed to characterise local tolerance and general toxicity of the drug candidate as well as its genotoxic potential and ability to interfere with reproduction. For trials which can be categorised as low dose PK screening trials and trials with products where rodent and non-rodent (primarily dog) models do not show any biological response (e.g. some biotechnology-derived hormones and cytokines) other testing paradigms should be used. The present recommendations for preclinical testing have had an important impact on the documented impressive safety record of phase I clinical trials. In this spirit we extend our warmest and sincerest thanks to Professor Jens S. Schou for his long and deep engagement in European and International harmonisation of preclinical test recommendations. His efforts have had a substantial impact on the present testing recommendations, which are of obvious benefit to the safety of the patient. [source] | ||||||||||