Wijnhoven, Susan W P; Hoogervorst, Esther M; Waard, Harm de; Horst, Gijsbertus T J van der; Steeg, Harry van (2007-01-03)
Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) are - except for the skin - not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.
Coleman, Kelly P; Grailer, Thomas P; McNamara, Lori R; Rollins, Beau L; Christiano, Nicholas J; Kandárová, Helena; De Jong, Wim H (2018-02-02)
A round robin study using reconstructed human epidermis (RhE) tissues was conducted to test medical device polymer extracts for skin irritation potential. Test samples were four irritant and three non-irritant medical device polymers. Five of these polymer samples were developed and two were obtained commercially. The three non-irritant samples were comprised of 100% 80A polyurethane, one-part silicone, and polyvinyl chloride (PVC). The polyurethane samples were made using a hot-melt process, while the silicone samples were created by mixing and casting. The PVC samples were commercially produced sheets. The four irritant samples were comprised of one-part silicone and 25% heptanoic acid (HA), two-part silicone and 15% sodium dodecyl sulfate (SDS), PVC and 4% Genapol® X-100, and PVC and 5.8% Genapol® X-080. The HA, SDS, and Genapol® X-100 samples were produced using the mixing and casting method, while the Genapol® X-080 sheet samples were obtained commercially. During development, irritant polymer samples were extracted using polar and non-polar solvents that were subsequently analyzed chemically. Samples with sufficient levels of extracted irritants were tested on RhE tissues to confirm their irritation potential. Polymers that passed this screening test were used in the round robin study described elsewhere in this special edition.
de With, G; Smetsers, R C G M; Slaper, H; de Jong, P (2018-01-04)
In the Netherlands considerable attention has been given to the exposure from thoron progeny in dwellings. For this purpose a nationwide survey on the thoron exhalation and thoron progeny concentration has been completed in 2015. Furthermore, extensive laboratory studies have been performed to measure activity concentrations and thoron exhalation rates from regular Dutch building materials. The purpose of this study is to demonstrate if the findings from both field experiments and laboratory results are consistent. For this reason measured properties of building materials and surface barriers, in-situ measurements on air ventilation and thoron(progeny) in dwellings as well as advanced computational modelling on indoor air and aerosol behaviour have been used. The results demonstrate that median and mean thoron progeny concentrations of 0.53 and 0.64 Bq·m-3 found in the survey are comparable with the mean concentration of 0.57 Bq·m-3 obtained from laboratory testing and calculation. Furthermore, upper thoron progeny concentrations from the survey and the calculations are with respectively 13 and 14 Bq·m-3 also in good agreement. Such elevated concentrations lead to an effective doses of around 4 mSv per year. The study also includes worst-case scenarios on the application of surface materials high on 232Th, and the expected reduction in thoron progeny when using mainstream mitigation measures.
Under the EU Directive 2004/28/EC, an environmental risk assessment of new veterinary medicinal products is required. Given the nature of risk assessment for new applications, there is a need to model exposure concentrations. Critical evaluations are essential to ensure that the use of models by regulators does not result in the propagation of misleading information. The empirical validations of soil exposure models, previously discussed in this journal, indicate that it is impossible to analyse the contribution of every model parameter to the variability in the predictions. In particular, the prediction of the slurry concentration is challenged by uncertainties concerning dilution, mixing and dissipation of residues. Surface water and groundwater models generated highly deviating results compared to the field results, questioning the usefulness of the available screening models. Animal husbandry, slurry handling and environmental conditions throughout Europe are considered in order to define realistic worst case scenarios, to be used in conjunction with distribution models for the environmental risk assessment of veterinary medicinal products at registration. Given the variability in manure management practice throughout Europe, a deterministic approach for the manure-to-soil model was selected. Both worst case and best case scenario were developed. Several modelling assumptions applied in the surface water exposure model for fish nursery effluent were validated against newly available data. Since the available data give no proof that a settling tank contributes to the removal of pesticides from waste water, it is recommended for risk assessment purposes to consider the contribution of the settling tank to removal of pesticides and medicines to be negligible. Surface water dilution factors may be considered to be rather small, a factor of 2, for low flow situations.
Oostrom, A J H H M van; Plokker, H W M; Asbeck, B S van; Rabelink, T J; Kessel, K P M van; Jansen, E H J M; Stehouwer, C D A; Cabezas, M Castro (2006-04-01)
We investigated whether pro-inflammatory aspects of the postprandial phase can be modulated by rosuvastatin in premature coronary artery disease (CAD) patients. Herefore standardized 8 h oral fat loading tests were performed off-treatment and after rosuvastatin 40 mg/d in 20 male CAD patients (50 +/- 4 years). The expression of leukocyte activation markers CD11a, CD11b, CD62L and CD66b was studied using flowcytometry. Migration of isolated neutrophils towards chemoattractants was determined in a fluorescence-based assay. Rosuvastatin did not affect baseline leukocyte counts nor the postprandial neutrophil increment (maximum mean increase +10% pre- and +14% post-treatment, P < 0.01 for each). Rosuvastatin reduced baseline platelets (from 266 +/- 78 to 225 +/- 74 x 10(9) cells/L, P < 0.001) and blunted the postprandial platelet count change (maximum mean increase +6%, P = 0.01, and 0%, respectively). The baseline expression of CD11a, CD11b and CD62L increased on most types of leukocytes by rosuvastatin, whereas the postprandial responses were unaffected. Pretreatment, postprandial neutrophil migration increased dose-dependently, but there were no postprandial changes after rosuvastatin. The latter effect was unrelated to changes in lipoprotein concentrations. In conclusion, in CAD patients postprandial pro-inflammatory and pro-coagulant changes can be modified by rosuvastatin. These apparently lipid-lowering independent effects may render protection against atherosclerosis.
Wolfs, Marion; Jong, Nynke de; Ocké, Marga C; Verhagen, Hans; Monique Verschuren, W M (2006-10-01)
Postlaunch monitoring of functional foods can encompass monitoring of effectiveness under conditions of customary use. To this end, the effectiveness of phytosterol/-stanol enriched margarine consumption in free-living conditions was investigated with data from the Dutch "Doetinchem cohort study". In total, 4,505 subjects (aged 26-70 years) were examined in 1994-1998 and re-examined during 1999-2003. A general and a food frequency questionnaire and non-fasting blood samples for total and HDL cholesterol determination were obtained. Subjects were stratified into phytosterol/-stanol enriched margarine users (n = 84) and non-users (n = 4,421) based on the re-examination data, as these margarines were available on the Dutch market from 1999 onwards. Mean spontaneous daily use (g +/- SD) of phytosterol-containing margarine (n = 71) was 15 +/- 8 and of phytostanol-containing margarine (n = 13) 9+/-6. After five years, total blood cholesterol had increased with 0.26 mmol/l in non-users while it had not significantly changed in users. The difference in total blood cholesterol change in users versus non-users was -0.30 mmol/l (p < 0.001). The beneficial effect of the phytosterol/-stanol enriched margarine, used under customary conditions can be characterized as a stabilization of cholesterol levels. This is the first report finding a modest beneficial effect on blood cholesterol level under customary conditions thereby partly confirming findings from clinical trials.
Luijten, Mirjam; Speksnijder, Ewoud N; Alphen, Niels van; Westerman, Anja; Heisterkamp, Siem H; Benthem, Jan van; Kreijl, Coen F van; Beems, Rudolf B; Steeg, Harrym van (2006-04-11)
Chronic use of phenacetin-containing analgesics has been associated with the development of renal cancer. To establish genotoxicity as a possible cause for the carcinogenic effect of phenacetin, we exposed wild type and DNA repair deficient Xpa-/- and Xpa-/-/Trp53+/- mice (further referred as Xpa and Xpa/p53 mice, respectively), carrying a reporter lacZ gene, to 0.75% (w/w) phenacetin mixed in feed. Xpa mice completely lack the nucleotide excision repair pathway, and as such they are sensitive to some classes of genotoxic compounds. Phenacetin exposure induced a significant increase of lacZ mutations in the kidney of both Xpa and Xpa/p53 mice. A minor response was found in liver, whereas no lacZ mutation induction was observed in the spleen of these animals. Interestingly, the observed phenacetin-induced mutant frequencies were higher in male than those found in female mice. This gender difference is probably due to a difference in metabolic rate. Phenacetin-induced mutations mainly consisted of point mutations rather than deletions. The mutational spectra in the kidney of treated WT and Xpa mice were quite similar. Taken together, these results demonstrate that the human carcinogen phenacetin acts as a weak genotoxic agent in an in vivo mouse model system.
Fritsche, Ellen; Grandjean, Philippe; Crofton, Kevin M; Aschner, Michael; Goldberg, Alan; Heinonen, Tuula; Hessel, Ellen V S; Hogberg, Helena; Bennekou, Susanne Hougaard; Lein, Pamela J; et al. (2018-02-12)
This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes.
Vredenbregt, M J; Blok-Tip, L; Hoogerbrugge, Ronald; Barends, D M; Kaste, D de (2006-03-03)
We describe a near-infrared spectroscopy (NIRS) method for fast-screening Viagra tablets, counterfeit Viagra tablets, and imitations of Viagra. The method can (1) check the homogeneity of a batch; (2) distinguish counterfeits and imitations from authentic Viagra; (3) screen for the presence of sildenafil citrate, the pharmacologically active substance in Viagra, irrespectively of the excipients present; (4) and detect whether similar samples have been previously analysed. We applied the method to 103 samples with a diversity of appearance, chemical composition, and origin. Other analytical methods confirmed the positive screening results for sildenafil citrate and the presence of other pharmacological active substances. The NIRS screening indicated the absence of sildenafil citrate in the presence of another pharmacological substance for only 2 samples, where the reference methods showed the presence of sildenafil citrate in addition to that of clomifene citrate. Otherwise, the method gave no false positive or negative results. The NIRS screening method is very fast and reliable for detecting counterfeits and imitations, and it correctly predicts the presence or absence of sildenafil citrate in 98% of the samples.
Smith, Noel H; Kremer, Kristin; Inwald, Jacqueline; Dale, James; Driscoll, Jeffrey R; Gordon, Stephen V; Soolingen, Dick van; Hewinson, R Glyn; Smith, John Maynard (2006-03-21)
A phylogeny of the Mycobacterium tuberculosis complex has recently shown that the animal-adapted strains are found in a single lineage marked by the deletion of chromosomal region 9 (RD9) [Brosch et al., 2002. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc. Natl Acad. Sci. USA 99 (6), 3684-3689]. We have obtained the spoligotype patterns of the RD9 deleted strains used to generate this new evolutionary scenario and we show that the presence of spoligotype spacers 3, 9, 16, 39, and 40-43 is phylogenetically informative in this lineage. We have used the phylogenetically informative spoligotype spacers to screen a database of spoligotype patterns and have identified further members of a group of strains apparently host-adapted to antelopes. The presence of the spoligotype spacers is congruent with the phylogeny generated by chromosomal deletions, suggesting that recombination is rare or absent between strains of this lineage. The phylogenetically informative spacers, in concert with the previously identified single nucleotide mutations and chromosomal deletions, can be used to identify a series of clades in the RD9 deleted lineage each with a separate host preference. Finally, we discuss the application of the ecotype concept to this series of clades and suggest that the M. tuberculosis complex may best be described as a series of host-adapted ecotypes.
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