Showing papers by "Franz Oesch published in 2010"

Gene toxicity studies on titanium dioxide and zinc oxide nanomaterials used for UV-protection in cosmetic formulations

Abstract: Titanium dioxide and zinc oxide nanomaterials, used as UV protecting agents in sunscreens, were investigated for their potential genotoxicity in in vitro and in vivo test systems. Since standard OECD test methods are designed for soluble materials and genotoxicity testing for nanomaterials is still under revision, a battery of standard tests was used, covering different endpoints. Additionally, a procedure to disperse the nanomaterials in the test media and careful characterization of the dispersed test item was added to the testing methods. No genotoxicity was observed in vitro (Ames' Salmonella gene mutation test and V79 micronucleus chromosome mutation test) or in vivo (mouse bone marrow micronucleus test and Comet DNA damage assay in lung cells from rats exposed by inhalation). These results add to the still limited data base on genotoxicity test results with nanomaterials and provide congruent results of a battery of standard OECD test methods applied to nanomaterials.

In vitro mammalian metabolism of the mitosis inhibitor zoxamide and the relationship to its in vitro toxicity.

Abstract: The in vitro mammalian metabolism of the fungicide zoxamide is related to its in vitro mammalian toxicity. After incubation of zoxamide with rat liver microsomes leading to practically 100% metabolism (mostly hydroxylated zoxamide), the cytotoxicity (methyl thiazole tetrazolium (MTT) test) and the mitosis-inhibiting potential (shown by cell count and by cell cycle analysis) for V79 were not distinguishable from those of zoxamide, demonstrating that the hydroxylation of zoxamide did not change the cytotoxicity or mitosis-inhibiting potential as determined by these assays. After incubation of zoxamide with rat liver S9 predominantly leading to conjugation with glutathione, and after incubation of zoxamide with rat liver slices predominantly leading to the glucuronide of the hydroxylated zoxamide, these activities were eliminated demonstrating that the glutathione conjugate and the glucuronide had lost the activities in these assays due either to no intrinsic potential of these conjugates or to their inability to penetrate the plasma membrane of mammalian cells. It is concluded that the metabolic hydroxylation of zoxamide did not change its activity in the assays used for investigating its influence on cell proliferation, cell cycle and cytotoxicity, while the formation of conjugates with glutathione or glucuronic acid led to the apparent loss of these activities. Thus, with zoxamide as a prototype, it was shown that, in principle, mammalian metabolism and its relationship to mammalian detoxication of fungicidal mitosis inhibitors may be reasonably anticipated from in vitro studies. In addition, the results provide a rational for the observed absence of typically mitosis inhibition-associated toxicities of zoxamide in mammals in vivo.

Stem cells in chemical carcinogenesis.

Abstract: The advanced course was held on behalf of ECNIS, aEuropean Network of Excellence (NoE). In ECNIS—Environmental Cancer, Nutrition and Individual Suscepti-bility—twenty-four different European partners are orga-nized in 15 work packages, thereby bringing togethermultidisciplinary expertise. The goal of ECNIS is tointegrate and stimulate cancer research by fostering inter-actions between epidemiologists, molecular genetics,biochemists and molecular toxicologists. The most importantinstruments to achieve science integration are scientificmeetings, such as workshops and advanced courses, jointtraining programmes, stimulation and support of scientificcooperations, exchange of researchers, shared laboratoryfacilities and generation of platforms and databases. Cur-rent knowledge, gaps, open questions and future challengesin cancer research are summarized, discussed and finallydisseminated in several review articles as well as meetingreports. Further information on ECNIS is available athttp://www.ecnis.org.The main focus of ECNIS is the identification anddevelopment of both, biomarkers of exposure and bioin-dicators of disease to analyze the potential protectiveeffects of nutritional components as well as impact ofindividual susceptibility factors on environmental cancerrisk. To achieve this goal, it is necessary to understand themolecular mechanisms of chemical carcinogenesis.Therefore, a task of ECNIS work package 10 ‘‘Mechanisticresearch to support cancer hazard and risk assessment’’coordinated by Franz Oesch (Mainz) is to elucidate andcommunicate molecular mechanisms of chemical carcino-gens to improve risk assessment (see also Oesch et al.2008). Although it is known that chemical carcinogenesisis a multistep process which typically involves activationof a pro-carcinogen to a genotoxic agent, induction of DNAdamage and mutations, clonal expansion of initiated cellsgiving rise to a tumour, followed by further mutations andprogression to a malignant cancer, this view is much toosimplistic and many aspects are still unclear. These includethe nature of dose–response relationships, especiallyextrapolation to low doses, effects of mixtures, gender-,species- and age-dependent determinants, individual sus-ceptibility factors, such as polymorphisms of genes andinfluence of circadian rhythms in chemical carcinogenesis.One important matter of debate is the nature of the cellstargeted by a chemical carcinogen or tumour promotor.Already in the nineteenth century, pathologists havehypothesized that tumours may originate from stem cells.