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H Kamp,
V Strauss,
J Wiemer,
E Leibold,
T Walk,
W Mellert,
R Looser,
A Prokoudine,
E Fabian,
G Krennrich,
M Herold, B van Ravenzwaay
[show abstract]
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ABSTRACT: BASF has developed a rat plasma metabolomics data base (MetaMap(®)Tox) containing the metabolome of more than 500 chemicals, agrochemicals and drugs, for which the toxicity is well known, derived from 28 day repeated dose toxicity studies in rats. The quality/reproducibility of data was assessed by comparing the metabolome of 16 reference compounds tested at least twice under identical experimental conditions at three time points (d7, d14 and d28). Statistical correlation analysis showed that the repeated treatment induced very similar changes to the metabolome. For all repetitions the modes of action of the compounds were always correctly identified. Moreover, when compared against the metabolome of all compounds available in the MetaMap(®)Tox data base, the repetitions showed in most cases the highest degree of overall similarity with the metabolome of the original study. In addition, we also evaluated the robustness of our metabolomics technique, displayed by constancy of variability in control groups over time. Based on these results, it can be concluded, that metabolomics can reproducibly be applied during toxicological in vivo testing in rats under the conditions applied here.
Toxicology Letters 10/2012; · 3.23 Impact Factor
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H Kamp,
E Fabian,
S Groeters,
M Herold,
G Krennrich,
R Looser,
W Mattes,
W Mellert,
A Prokoudine,
P Ruiz-Noppinger,
V Strauss,
T Walk,
J Wiemer, B van Ravenzwaay
[show abstract]
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ABSTRACT: BASF and Metanomics have built-up the database MetaMap(®)-Tox containing rat plasma metabolome data for more than 500 reference compounds. Phenytoin was administered to five Wistar rats of both sexes at dietary dose levels of 600 and 2400 ppm over 28 days and metabolome analysis was performed on days 7, 14 and 28. Clinical pathology did not indicate clear evidence for liver toxicity, whereas liver histopathology revealed slight centrilobular hepatocellular hypertrophy. The metabolome analysis of phenytoin shows metabolome changes at both dose levels and the comparison with MetaMap-Tox indicated strong evidence for liver enzyme induction, as well as liver toxicity. Moreover, evidence for kidney and indirect thyroid effects were observed. This assessment was based on the metabolite changes induced, similarities to specific toxicity patterns and the whole metabolome correlation within MetaMap-Tox. As compared with the classical read-out, a more comprehensive picture of phenytoin's effects is obtained from the metabolome analysis, demonstrating the added value of metabolome data in preclinical/ toxicological studies.
Bioanalysis 09/2012; 4(18):2291-301. · 3.22 Impact Factor
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V Strauss,
W Mellert,
J Wiemer,
E Leibold,
H Kamp,
T Walk,
R Looser,
A Prokoudine,
E Fabian,
G Krennrich,
M Herold, B van Ravenzwaay
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ABSTRACT: Combination therapies with fibrates and statins are used to treat cardiovascular diseases, because of their synergistic effect on lowering plasma lipids. However, fatal side-effects like rhabdomyolysis followed by acute renal necrosis sometimes occur. To elucidate biochemical changes resulting from the interaction of fibrates and statins, doses of 100 mg/kg fenofibrate, 50mg/kg clofibrate, 70 mg/kg atorvastatin and 200 mg/kg pravastatin as well as combinations thereof were administered to Crl:Wi(Han) rats for 4 weeks. Plasma metabolome profile was measured on study days 7, 14 and 28. Upon study termination, clinical pathology parameters were measured. In a separate experiment plasmakinetic data were measured in male rats after 1 week of drug administration in monotherapy as well as in combinations. Lowering of blood lipid levels as well as toxicological effects, like liver cell degradation (statins) and anemia (fibrates) and distinct blood metabolite level alterations were observed in monotherapy. When fibrates and statins were co-administered metabolite profile interactions were generally underadditive or at the utmost additive according to the linear mixed effect model. However, more metabolite levels were significantly altered during combination therapy. New effects on the antioxidant status and the cardiovascular system were found which may be related to a development of rhabdomyolysis. Accumulation of drugs during the combination therapy was not observed.
Toxicology Letters 03/2012; 211(2):187-200. · 3.23 Impact Factor
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B van Ravenzwaay,
M Herold,
H Kamp,
M D Kapp,
E Fabian,
R Looser,
G Krennrich,
W Mellert,
A Prokoudine,
V Strauss,
T Walk,
J Wiemer
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ABSTRACT: BASF has developed a Metabolomics database (MetaMap(®) Tox) containing approximately 500 data rich chemicals, agrochemicals and drugs. This metabolome-database has been built based upon 28-day studies in rats (adapted to OECD 407 guideline) with blood sampling and metabolic profiling after 7, 14 and 28 days of test substance treatment. Numerous metabolome patterns have been established for different toxicological targets (liver, kidney, thyroid, testes, blood, nervous system and endocrine system) which are specific for different toxicological modes of action. With these patterns early detection of toxicological effects and the underlying mechanism can now be obtained from routine studies. Early recognition of toxicological mode of action will help to develop new compounds with a more favourable toxicological profile and will also help to reduce the number of animal studies necessary to do so. Thus this technology contributes to animal welfare by means of reduction through refinement (2R), but also has potential as a replacement method by analyzing samples from in vitro studies. With respect to the REACH legislation for which a large number of animal studies will need to be performed, one of the most promising methods to reduce the number of animal experiments is grouping of chemicals and read-across to those which are data rich. So far mostly chemical similarity or QSAR models are driving the selection process of chemical grouping. However, "omics" technologies such as metabolomics may help to optimize the chemical grouping process by providing biologically based criteria for toxicological equivalence. "From QSAR to QBAR" (quantitative biological activity relationship).
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 01/2012; 746(2):144-50. · 2.85 Impact Factor
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L Ma-Hock,
S Brill,
W Wohlleben,
P M A Farias,
C R Chaves,
D P L A Tenório,
A Fontes,
B S Santos,
R Landsiedel,
V Strauss,
S Treumann, B van Ravenzwaay
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ABSTRACT: Colloidal quantum dots (QD) show great promise as fluorescent markers. The QD used in this study were obtained in aqueous medium rather than the widely used colloidal QD. Both methodologies used for the production of QD are associated with the presence of heavy metals such as cadmium (Cd). Here we investigate the short-term inhalation toxicity of water-soluble core-shell CdS/Cd(OH)₂ QD. Male Wistar rats were head-nose exposed for 6 h/day on 5 days at the technically maximum concentration (0.52 mg Cd/m³). Histological examination was performed directly after the last exposure. Additional rats were used for Cd organ burden determinations. Clinical parameters in blood, bronchoalveolar lavage fluid and lung tissue were determined 3 days after the last exposure. To analyze the reversibility or progression of effects, the examinations were performed again after a recovery period of 3 weeks. The results of the study indicate that CdS/Cd(OH)₂ QD caused local neutrophil inflammation in the lungs that partially regressed after the 3-week recovery period. There was no evidence that QD were translocated to the central nervous system nor that a systemic acute phase response occurred.
Toxicology Letters 01/2012; 208(2):115-24. · 3.23 Impact Factor
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W Mellert,
M Kapp,
V Strauss,
J Wiemer,
H Kamp,
T Walk,
R Looser,
A Prokoudine,
E Fabian,
G Krennrich,
M Herold, B van Ravenzwaay
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ABSTRACT: Metabolite profiling (metabolomics) elucidates changes in biochemical pathways under various conditions, e.g., different nutrition scenarios or compound administration. BASF and metanomics have obtained plasma metabolic profiles of approximately 500 compounds (agrochemicals, chemicals and pharmaceuticals) from 28-day rat studies. With these profiles the establishment of a database (MetaMap(®)Tox) containing specific metabolic patterns associated with many toxicological modes of action was achieved. To evaluate confounding factors influencing metabolome patterns, the effect of fasting vs. non-fasting prior to blood sampling, the influence of high caloric diet and caloric restriction as well as the administration of corn oil and olive oil was studied for its influence on the metabolome. All mentioned treatments had distinct effects: triacylglycerol, phospholipids and their degradation product levels (fatty acids, glycerol, lysophosphatidylcholine) were often altered depending on the nutritional status. Also some amino acid and related compounds were changed. Some metabolites derived from food (e.g. alpha-tocopherol, ascorbic acid, beta-sitosterol, campesterol) were biomarkers related to food consumption, whereas others indicated a changed energy metabolism (e.g. hydroxybutyrate, pyruvate). Strikingly, there was a profound difference in the metabolite responses to diet restriction in male and female rats. Consequently, when evaluating the metabolic profile of a compound, the effect of nutritional status should be taken into account.
Toxicology Letters 09/2011; 207(2):173-81. · 3.23 Impact Factor
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B van Ravenzwaay,
G Coelho-Palermo Cunha,
V Strauss,
J Wiemer,
E Leibold,
H Kamp,
T Walk,
W Mellert,
R Looser,
A Prokoudine,
E Fabian,
G Krennrich,
M Herold
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ABSTRACT: Metabolite profiles (metabolomics) of plasma samples of Wistar rats dosed with di(2-ethylhexyl)phthalate (DEHP - 3000ppm) and dibutylphthalate (DBP - 150, 1000 and 7000ppm) were individually determined in 28 days dietary studies. In addition, profiles of combined exposure to 3000ppm DEHP and either 150, 1000 or 7000ppm DBP were determined. High dose levels induced more profound metabolite changes in males than in females for both compounds. At 150ppm DBP (NOEL for toxicity) there were very few (<false positives rate), inconsistent changes, demonstrating a metabolomic NOEL. A part of the total metabolite profile was consistent with a pattern of changes indicative of peroxisome proliferation, confirmed by increased cyanide-insensitive Palmitoyl-CoA oxidation. Simultaneous administration of 3000ppm DEHP and 150ppm DBP did not result in relevant changes when compared to the metabolite profile of 3000ppm DEHP alone. Co-administration of 1000ppm DBP induced marginal additional changes relative to the profile of 3000ppm DEHP alone. Simultaneous exposure to high dose levels of DEHP and DBP resulted in a profile that was significantly different compared to the individual compounds. A quantitative statistical analysis of the data revealed that the effect of combined treatment on the metabolites was less than additive.
Toxicology Letters 10/2010; 198(2):159-70. · 3.23 Impact Factor
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ABSTRACT: Besides other modes of action, endocrine disruptors may interact with hormone receptors thereby modifying the physiological function of endogenous hormones. In the present study, we report the results obtained with yeast based assays to detect the (anti-)estrogenic potential (YES) and the (anti-)androgenic potential (YAS) of 105 substances. The results show very high reproducibility and good concordance with literature data of in vivo and/or in vitro studies: the overall true positive rate, true negative rate and accuracy of the assays were 78%, 95%, and 87% (estrogen agonism), and 70%, 97%, and 90% (estrogen antagonism), 88%, 96%, and 95% (androgen agonism) and 81%, 88%, and 85% (androgen antagonism). Furthermore, the performance of the YES assay has been compared to the HeLa based transcriptional activation assay using 20 compounds. The overall true positive rate, true negative rate, and accuracy obtained for the 20 compounds were 100%, 88%, and 95% (mammalian cell based HeLa assay) and 92%, 86%, and 90% (yeast based YES assay). Taken together, the YES and YAS are robust systems, easy to handle and satisfying the requirements for screening systems that can be applied in programs including the US Environmental Protection Agency's Endocrine Disruptor Screening Program.
Toxicology in Vitro 10/2010; 24(7):2030-40. · 2.78 Impact Factor
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B. van Ravenzwaay,
G. C. Cunha,
E. Fabian,
M. Herold,
H. Kamp,
G. Krennrich,
A. Krotzky,
E. Leibold,
R. Looser,
W. Mellert,
A. Prokoudine,
V. Strauss,
R. Trethewey,
T. Walk,
J. Wiemer
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ABSTRACT: The use of metabolite profiling techniques (metabonomics or metabolomics) in toxicology is a relatively new branch of this
science. Due to their unique biochemical properties, cancer cells should, in principle, be an ideal field of application for
metabolite profiling. However, due to technical and study design limitations there are only a few reliably metabolite profiles
for human tumors. This chapter provides examples for the recognition of metabolic changes in animals induced by exposure to
(carcinogenic) chemicals. In two major projects (COMET and MetaMapTox), data bases have been developed which are sufficiently
large to evaluate the full potential of metabolite profiling in toxicology and cancer research. In both projects blood and
urine were used as matrices which can be easily obtained with minimally-invasive methods. Based on a high degree of standardization
and a large-scale controlled data collection, consistent patterns of metabolite changes have been identified which are associated
with different toxicological modes of action, some of which are known to enhance tumor development in rodents.
04/2010: pages 141-166;
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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.
Xenobiotica 01/2010; 40(1):72-82. · 1.79 Impact Factor
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V Strauss,
J Wiemer,
E Leibold,
H Kamp,
T Walk,
W Mellert,
R Looser,
A Prokoudine,
E Fabian,
G Krennrich,
M Herold, B van Ravenzwaay
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ABSTRACT: The impact of the strain on the metabolite profile of plasma samples in rats dosed with 2500 ppm 2-methyl-4-chlorophenoxyacetic acid (MCPA acid) or 45 mg/kg bw/day 4-chloro-3-nitroaniline (4C3N) for 4 weeks was evaluated. Four different strains were used: two Wistar strains (Crl:WI(Han), Han:RCC:WIST(SPF)), one Sprague-Dawley (Crl:CD) and one Fisher strain (F-344/Crl). The metabolite profiles in the plasma were measured by LC-MS and GC-MS. The profound changes of the metabolite values induced by the MCPA acid treatment outweighed slight deviations caused by physiological variations between the different rat strains. The metabolome changes of the MCPA acid in all strains could be related to toxicological "mode of action" patterns (peroxisome proliferator, renal organic anionic transporter inhibition) with Crl:WI(Han) rats as reference strain. 4C3N administration led to extravascular hemolytic anemia with a small number of metabolome changes, which were strain dependent. The metabolome pattern associated with "hemolytic anemia" established with the reference strain (Crl:Wi(Han)) was not sufficiently similar in other strains. Thus, comparable metabolome profiles were obtained in different rat strains for a compound inducing profound metabolite changes. For a compound with a weak profile the results were more variable and appeared to be strain dependent.
Toxicology Letters 09/2009; 191(1):88-95. · 3.23 Impact Factor
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ABSTRACT: Uvinul T 150, a UVB absorber, was administered (concentration 5%) in a vehicle to the skin of hairless albino mice before ultraviolet radiation (UVR) exposure for 5 days per week in a photocarcinogenicity study. Uvinul T 150 prolonged the latency period to 50% skin tumor incidence (controls: 21-22 weeks; Uvinul T 150: 36 weeks in males and 31 weeks in females). When Uvinul T 150 was applied in an alternating-exposure procedure (3 days/week before and 2 days/week after UVR), the inhibition of photocarcinogenesis was less marked (latency period 28-30 weeks). The vehicle formulation had no effect (latency period 20-21 weeks). The sensitivity of the test system was demonstrated by a positive control (8-methoxy-psoralene). Although UVB absorption was shown to inhibit photocarcinogenesis, the results also suggest that UVA radiation makes a contribution to skin tumor formation.
Skin pharmacology and physiology 05/2009; 22(3):166-76. · 2.92 Impact Factor
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ABSTRACT: Systemic and respiratory tract (RT) toxicity of triethanolamine (TEA) was assessed in a 28-day nose-only inhalation study in Wistar rats (10animals/sex, concentrations: 0, 20, 100, 500mg/m3; 5 days/week, 6h/day). In two nose-only 90-day inhalation studies, with similar exposure design, Wistar rats were exposed to 0, 15, 150, 400mg/m3 diethanolamine (DEA) (DEA Study 1:13animals/sex, general subchronic study) and to 0, 1.5, 3, 8mg/m3 (DEA Study 2:10animals/sex) to specifically investigate respiratory tract toxicity. Only DEA induced systemic toxicity at or above 150mg/m3 (body and organ weight changes, clinical- and histo-pathological changes indicative for mild blood, liver, kidney and testicular effects). Neurotoxicity was not observed for both substances. Exposure to both substances resulted in laryngeal epithelial changes starting from 3mg/m3 for DEA (reversible metaplasia at the base of the epiglottis, inflammation at higher concentrations extending into the trachea) or from 20mg/m3 for TEA (focal inflammation, starting in single male animals). TEA appears to be less potent with respect to systemic toxicity and RT irritancy than DEA. The 90-day no adverse effect concentration" (NOAEC) for changes due to TEA exposure in the respiratory tract was 4.7mg/m3 derived by extrapolation from the NOAEC of the 28day study.
Food and Chemical Toxicology 07/2008; 46(6):2173-83. · 3.00 Impact Factor
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ABSTRACT: Administration of an iron-deficient diet to Wistar rats resulted within 14 days in reduced serum iron concentrations, a microcytic hypochromic anemia, characteristic for impaired hemoglobin synthesis, and an increase of duodenal epithelial cell proliferation. After 5 weeks of iron deficiency, hypochromic microcytic anemia and a clear increase of duodenum weight but no pronounced effects on cell proliferation was observed. Increased duodenum weights corresponded to significant increases in mucosal area, indicating a diffuse, simple mucosal hyperplasia. The sequence of events following iron depletion thus appears to be: (1) reduced serum iron levels, (2) induction of hypochromic microcytic anemia, (3) increased duodenal epithelial cell proliferation, and (4) increased duodenal weight (increased mucosal area). Iron deficiency anemia was rapidly reversible after a 2-week recovery period. However, increased duodenum weights were still noted at that time. Intramuscular iron supplementation in animals fed with iron-deficient diet maintained body iron levels not below normal values, and neither anemia nor increased duodenum cell proliferation were detected after 14 days. A 5-week iron supplementation period resulted in slightly increased serum iron values, and slightly decreased duodenal epithelial cell proliferation. Thus, increased duodenum mucosal hyperplasia was shown to be secondary to depletion of body iron and anemia and reflects an attempt to increase iron absorption to counteract iron deficiency.
Toxicology Letters 05/2008; 177(3):156-67. · 3.23 Impact Factor
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ABSTRACT: Effects of common anaesthetics such as ether, methoxyflurane, isoflurane, carbon dioxide (at 100%, 80% or 60% admixed with O(2)) on toxicity and clinical pathology parameters in rats were investigated. Ether, methoxyflurane and 100% CO(2) induced toxicity in some animals. Erythrocyte, haemoglobin and haematocrit were reduced in females by 100% CO(2), methoxyflurane and isoflurane. Glucose was increased by 60% CO(2), 80% CO(2), ether, isoflurane and methoxyflurane in males. Chloride was reduced by isoflurane and all CO(2) concentrations in females. Serum proteins were reduced by isoflurane and methoxyflurane. Sodium, inorganic phosphate, calcium and magnesium were reduced by methoxyflurane and isoflurane, but increased by all CO(2) concentrations. Potassium was reduced by ether, methoxyflurane or isoflurane. Triiodothyronine and thyroxine were reduced by all anaesthetics. Prolactin was reduced by methoxyflurane, but raised by ether and isoflurane. Erythrocyte cholinesterase (E-ChE) activity is markedly reduced (20-40%) after anaesthesia with all CO(2) concentrations in both sexes. E-ChE was unaffected by ether, methoxyflurane, or isoflurane. Serum and brain cholinesterase activities were not affected. E-ChE inhibition correlated with decreased blood pH, suggesting that this was caused by acidosis. This is of practical relevance in the risk assessment of cholinesterase inhibitors. Conclusions: Clinical pathology data were affected by all anaesthetics. CO(2)/O(2) (80%/20%) and isoflurane are the most suitable anaesthetics. If E-ChE activity is to be determined, isoflurane is the anaesthetic of choice.
Food and Chemical Toxicology 10/2007; 45(9):1709-18. · 3.00 Impact Factor
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ABSTRACT: The perchlorate discharge assay (PDA) is potentially of high diagnostic value to distinguish between direct and indirect thyroid toxicity mechanisms, provided that standard treatment times are established and positive controls yield reproducible results. Therefore the PDA was evaluated after 2 and/or 4 weeks of treatment with positive control compounds in rats. Phenobarbital, Aroclor 1254 and beta-naphthoflavone (indirect toxic mechanism) enhanced thyroidal radioiodide accumulation, and the administration of potassium perchlorate had no effect on thyroid: blood (125)I ratio. Phenobarbital caused follicular cell hypertrophy and hyperplasia in the thyroid and centrilobular hypertrophy in the liver, without effects on serum triiodotyronine (T(3)), thyroxine (T(4)) levels. Thyroid-stimulating hormone (TSH) levels were moderately increased. Propylthiouracil (direct toxic mechanism) caused severe thyroid follicular cell hypertrophy and hyperplasia, reduced serum T(3) and T(4) levels and increased serum TSH levels, and reduced thyroidal radioiodide accumulation; perchlorate administration significantly reduced thyroid: blood (125)I ratio, demonstrating an iodide organification block. Potassium iodide (direct toxic mechanism) virtually blocked thyroidal radioiodide accumulation, without significant effects on serum T(3), T(4), and TSH levels and a microscopic correlate for higher thyroid weights. Thus, positive controls yielded reproducible results and we conclude that both the 2- and 4-week PDA is suitable to distinguish between direct and indirect thyroid toxicity mechanisms.
Regulatory Toxicology and Pharmacology 09/2007; 48(3):270-8. · 2.43 Impact Factor
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ABSTRACT: To ensure the product safety of nanomaterials, BASF has initiated an extensive program to study the potential inhalation toxicity of nanosize particles. As preparation work for upcoming inhalation studies, the following manufactured nanomaterials have been evaluated for their behavior in an exposure system designed for inhalation toxicity studies: titanium dioxide, carbon black, Aerosil R104, Aerosil R106, aluminum oxide, copper(II) oxide, amorphous silicon dioxide, zinc oxide, and zirconium(IV) oxide. As the physicochemical properties and the complex nature of ultrafine aerosols may substantially influence the toxic potential, the particle size, specific surface area, zeta potential, and morphology of each of the materials were determined. Aerosols of each material were generated using a dry powder aerosol generator and by nebulization of particle suspensions. The mass concentration of the particles in the inhalation atmosphere was determined gravimetrically and the particle size was determined using a cascade impactor, an optical particle counter, and a scanning mobility particle sizer. The dispersion techniques used generated fine aerosols with particle size distributions in the respiratory range. However, as a result of the significant agglomeration of nanoparticles in the test materials evaluated, no more than a few mass percent of the materials were present as single nanoparticles (i.e., < 100 nm). Considering the number, a greater percentage of nanoparticles was present. Based on the obtained results and experience with the equipment, a technical setup for inhalation studies with nanomaterials is proposed. Furthermore, a stepwise testing approach is recommended that also could reduce the number of animals used in testing.
Inhalation Toxicology 08/2007; 19(10):833-48. · 1.92 Impact Factor
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ABSTRACT: Will metabolomics have a greater chance of success in toxicology and biomarker assessment than genomics and proteomics? Metabolomics has the advantage that (1) it analyses the last step in a series of changes following a toxic insult, (2) many of the metabolites have a known function and (3) changes are detectable in blood. If the analysis of a great number of individual organs can be replaced by one matrix then this will provide significant advantages (less invasive method, no need to kill animals, time course analysis possible). We have chosen to perform the analysis of blood metabolites in such a way as to minimize the risk of artifacts and to have a high number of known metabolites. We have also reduced the amount of variation in the biological system as well as during analysis. In a series of proof of concept studies it could be demonstrated that (1) the metabolome of control animals was stable of a period of nearly 1 year, with a remarkable differentiation between males and females, (2) a dose response relationship in metabolome changes was induced by phenobarbital and that (3) different modes of action could be distinguished by blood metabolome analysis. To investigate the potential of metabolomics to find biomarkers or specific patterns of change we have analyzed the blood metabolome of rats treated with HPPD inhibitors, a novel class of herbicides. The results demonstrated that a single metabolite, tyrosine, can be used as a biomarker. In addition to tyrosine we also found a specific pattern of change that involved nine metabolites. Though the extent of change was less than for tyrosine the consistent change of these metabolites is diagnostic for this (toxicological) mode of action.
Toxicology Letters 08/2007; 172(1-2):21-8. · 3.23 Impact Factor
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ABSTRACT: Pulmonary irritant threshold concentrations of two hexamethylene-1,6-diisocyanate (HDI)-based prepolymers (I: polymeric emulsfier modified and II: oligomeric allophanate modified) were determined in acute inhalation studies according to TRGS 430 (Dangerous Substances Technical Rule, isocyanates, Germany), based on benchmark extrapolation of bronchoalveolar lavage fluid (BALF) total protein. It was also investigated if the method is robust enough to be transferred to an independent laboratory. Five male Wistar rats per group were exposed nose-only to the test substances as liquid aerosols to concentrations of 0, 0.5, 3, 15 mg/m(3) for both test substances with an additional test group at 50 mg/m(3) for test substance I. The duration of the exposure was 6h, followed by serial sacrifices 1 day, 3 days and 7 days post exposure. BALF was analyzed for biochemical and cytological markers indicative for injury of the bronchoalveolar region. The exposure of rats to test substance I and II caused dose depended lung irritation with BALF total protein concentration being the most sensitive indicator of pulmonary effects. The extrapolated no observed adverse effect level of test substance I was 1.1 mg/m(3) and that of test substance II 2.3 mg/m(3). The acute pulmonary irritant threshold concentrations were found to be similar to those reported by [Pauluhn, J., 2004. Pulmonary irritant potency of polyisocyanate aerosols in rats: comparative assessment of irritant threshold concentrations by bronchoalveolar lavage. J. Appl. Toxicol. 24, 231-247] for HDI-homopolymers and other HDI-based polyisocyanates, and were at least 30 times higher than the MAK (occupational exposure limit) value for the HDI monomer (0.035 mg/m(3)). Thus the EBW (exposure assessment value) for these two HDI-based prepolymers can be established at 10x MAK, i.e. at 0.35 mg/m(3).
Food and Chemical Toxicology 03/2007; 45(2):237-43. · 3.00 Impact Factor
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ABSTRACT: Microfine metallic oxides such as titanium dioxide or zinc oxide have been found to be highly protective against harmful UV rays. Because their long-term use could potentially lead to health effects if significant amounts of these microfine metallic oxides would be absorbed through the skin, the in vitro absorption of microfine zinc oxide and titanium oxide in cosmetic formulations through porcine skin was investigated. In the experiments with a microfine zinc oxide formulation, the mean total recoveries of Zn were in the range from 102% to 107% of the total Zn applied. Virtually the total amount of applied Zn was recovered in the first five tape strips. The amounts of Zn found in the skin membrane and the receptor fluid were comparable in untreated, vehicle treated or test substance treated skin preparations. The absorption-time plots from diffusion cells treated with the vehicle did not differ from those treated with the ZnO containing formulation. In the experiments with microfine titanium dioxide formulations T-Lite SF-S and T-Lite SF, mean total recoveries of Ti ranged from 98% to 100% and 86% to 93% of the total Ti applied, respectively. Virtually the total amount of applied Ti could be removed from the skin surface by washing. The amounts of titanium found in the tape strips and skin preparations were in the order of the analytical determination limit. No Ti was found in the receptor fluid at any sampling time. The results show that neither zinc or titanium ions nor microfine zinc oxide or titanium dioxide particles were able to penetrate porcine stratum corneum. Therefore, from the absence of internal exposure we conclude that their use in sunscreens does not pose a health risk.
Toxicology in Vitro 05/2006; 20(3):301-7. · 2.78 Impact Factor
