A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens

Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E₂). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E₂ and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment

Laten we Irak onze ISIS-gangers maar ophangen?

In Irak zijn deze week zes Franse ISIS-leden veroordeeld tot de dood door ophanging. De Europese landen laten Irak en vooral de Syrische Koerden zitten met westerse ISIS-strijders, én met de vrouwen en kinderen. Dat kan op den duur gevaarlijk zijn, zeggen deskundigen.Security and Global Affair

Symbolic Model Checking for Dynamic Epistemic Logic

Dynamic Epistemic Logic (DEL) can model complex information scenarios in a way that appeals to logicians. However, existing DEL implementations are ad-hoc, so we do not know how the framework really performs. For this purpose, we want to hook up with the best available model-checking and SAT techniques in computational logic. We do this by first providing a bridge: a new faithful representation of DEL models as so-called knowledge structures that allow for symbolic model checking. Next, we show that we can now solve well-known benchmark problems in epistemic scenarios much faster than with existing DEL methods. Finally, we show that our method is not just a matter of implementation, but that it raises significant issues about logical representation and update

Prediction of carcinogenic potential of chemicals using repeated-dose (13-week) toxicity data

AbstractSub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study

Comparison of clastogen-induced gene expression profiles in wild-type and DNA repair-deficient Rad54/Rad54B cells

Background: Previously we found that Rad54/Rad54B cells are more sensitive towards mitomycin C (MMC) as compared to wild-type (WT) cells. This difference in sensitivity was absent upon exposure to other clastogens like bleomycin (BLM) and g-radiation. In order to get further insight into possible underlying mechanisms, gene expression changes in WT and Rad54/Rad54B MEFs (mouse embryonic fibroblasts) after exposure to the clastogens MMC and BLM were investigated. Exposures of these cells to mutagens (N-ac-AAF and ENU) and vehicle were taken as controls. Results: Most exposures resulted in an induction of DNA damage signaling and apoptosis genes and a reduced expression of cell division genes in cells of both genotypes. As expected, responses to N-ac-AAF were very similar in both genotypes. ENU exposure did not lead to significant gene expression changes in cells of both genotypes, presumably due to its short half-life. Gene expression responses to clastogens, however, showed a genotype-dependent effect for BLM and MMC. MMC treated Rad54/Rad54B MEFs showed no induction of p53-signaling, DNA damage response and apoptosis as seen for all the other treatments. Conclusion: These data support our finding that different types of clastogens exist and that responses to these types depend on the DNA repair status of the cells.Toxicogenomics and risk assessmen

Benzo(a)pyrene induces similar gene expression changes in testis of DNA repair proficient and deficient mice

<p>Abstract</p> <p>Background</p> <p>Benzo [a]pyrene (B[a]P) exposure induces DNA adducts at all stages of spermatogenesis and in testis, and removal of these lesions is less efficient in nucleotide excision repair deficient <it>Xpc</it>^-/-mice than in wild type mice. In this study, we investigated by using microarray technology whether compromised DNA repair in <it>Xpc</it>^-/-mice may lead to a transcriptional reaction of the testis to cope with increased levels of B[a]P induced DNA damage.</p> <p>Results</p> <p>Two-Way ANOVA revealed only 4 genes differentially expressed between wild type and <it>Xpc</it>^-/-mice, and 984 genes between testes of B[a]P treated and untreated mice irrespective of the mouse genotype. However, the level in which these B[a]P regulated genes are expressed differs between Wt and <it>Xpc</it>^-/-mice (p = 0.000000141), and were predominantly involved in the regulation of cell cycle, translation, chromatin structure and spermatogenesis, indicating a general stress response. In addition, analysis of cell cycle phase dependent gene expression revealed that expression of genes involved in G1-S and G2-M phase arrest was increased after B[a]P exposure in both genotypes. A slightly higher induction of average gene expression was observed at the G2-M checkpoint in <it>Xpc</it>^-/-mice, but this did not reach statistical significance (P = 0.086). Other processes that were expected to have changed by exposure, like apoptosis and DNA repair, were not found to be modulated at the level of gene expression.</p> <p>Conclusion</p> <p>Gene expression in testis of untreated <it>Xpc</it>^-/-and wild type mice were very similar, with only 4 genes differentially expressed. Exposure to benzo(a)pyrene affected the expression of genes that are involved in cell cycle regulation in both genotypes, indicating that the presence of unrepaired DNA damage in testis blocks cell proliferation to protect DNA integrity in both DNA repair proficient and deficient animals.</p

Partner notification and partner treatment for chlamydia: Attitude and practice of general practitioners in the Netherlands; a landscape analysis

Background: Chlamydia prevalence remains high despite scaling-up control efforts. Transmission is not effectively interrupted without partner notification (PN) and (timely) partner treatment (PT). In the Netherlands, The follow-up of partners is not standardized and may depend on GPs' time and priorities. We investigated current practice and attitude of GPs towards PN and PT to determine the potential for Patient-Initiated Partner Treatment, which is legally not supported yet. Methods: Multiple data-sources were combined for a landscape analysis. Quantitative data on (potential) PT were obtained from prescriptions in the national pharmacy register (2004-2014) and electronic patient data from NIVEL-Primary Care Database (PCD) and from STI consultations in a subgroup of sentinel practices therein. Furthermore, we collected information on current practice via two short questionnaires at a national GP conference and obtained insight into GPs' attitudes towards PN/PT in a vignette study among GPs partaking in NIVEL-PCD. Results: Prescription data showed Azithromycin double dosages in 1-2% of cases in the pharmacy register (37.000 per year); probable chlamydia-specific repeated prescriptions or double dosages of other antibiotics in NIVEL-PCD (115/1078) could not be interpreted as PT for chlamydia with certainty. STI consultation data revealed direct PT in 6/100 cases, via partner prescription or double doses. In the questionnaires the large majority of GPs (>95% of 1411) reported to discuss PN of current and ex-partner(s) with chlamydia patients. Direct PT was indicated as most common method by 4% of 271 GPs overall and by 12% for partners registered in the same practice. Usually, GPs leave further steps to the patients (83%), advising patients to tell partners to get tested (56%) or treated (28%). In the vignette study, 16-20% of 268 GPs indicated willingness to provide direct PT, depending on patient/partner profile, more (24-45%) if patients would have the chance to notify their partner first. Conclusion: GPs in the Netherlands already treat some partners of chlamydia cases directly, especially partners registered in the same practice. Follow-up of partner notification and treatment in general practice needs more attention. GPs may be open to implement PIPT more often, provided there are clear guidelines to arrange this legally and practically