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Amsterdam-Zuidoost, Netherlands

Lewin G.,Fraunhofer Institute for Toxicology and Experimental Medicine | Escher S.E.,Fraunhofer Institute for Toxicology and Experimental Medicine | van der Burg B.,BioDetection Systems BV | Simetska N.,Fraunhofer Institute for Toxicology and Experimental Medicine | Mangelsdorf I.,Fraunhofer Institute for Toxicology and Experimental Medicine
Reproductive Toxicology

Studies on reproductive toxicity need high numbers of test animals. Therefore, we investigated whether chemical structural features (SF) in combination with in vitro data on specific adverse outcome pathways (AOPs) may be used for predicting reproductive toxicity of untested chemicals. Using the OECD Toolbox and expert judgment, we identified 89 structure groups for 275 chemicals for which the results of prenatal developmental toxicity or multigeneration studies were present in the Fraunhofer database on Fertility and Developmental Toxicity in experimental animals (FeDTex) database. Likewise, we evaluated 220 chemicals which had been tested in reporter gene assays on endocrine ((anti)estrogenic and (anti)androgenic) properties in the CALUX® test battery. There was a large spread of effect levels for substances within the chemical structure groups for both, in vivo and in vitro results. The groups of highest concern (diphenyl derivatives, planar conjugated systems with fused rings, phenols and organophosphates) correlated quite well, however, between the in vivo and in vitro data on estrogenic activity. For the 56 chemicals represented in both databases, lowest effect doses in vivo correlated well with the estrogenic activity in vitro. These results suggest that a panel of assays covering relevant AOPs and data on metabolism and toxicokinetics may allow prediction of relative reproductive or development toxicity potency within the identified chemical structure groups. © 2014 Elsevier Inc. Source

Becker R.A.,American Chemistry Council | Ankley G.T.,U.S. Environmental Protection Agency | Edwards S.W.,U.S. Environmental Protection Agency | Kennedy S.W.,Environment Canada | And 8 more authors.
Regulatory Toxicology and Pharmacology

Systematic consideration of scientific support is a critical element in developing and, ultimately, using adverse outcome pathways (AOPs) for various regulatory applications. Though weight of evidence (WoE) analysis has been proposed as a basis for assessment of the maturity and level of confidence in an AOP, methodologies and tools are still being formalized. The Organization for Economic Co-operation and Development (OECD) Users' Handbook Supplement to the Guidance Document for Developing and Assessing AOPs (OECD 2014a; hereafter referred to as the OECD AOP Handbook) provides tailored Bradford-Hill (BH) considerations for systematic assessment of confidence in a given AOP. These considerations include (1) biological plausibility and (2) empirical support (dose-response, temporality, and incidence) for Key Event Relationships (KERs), and (3) essentiality of key events (KEs). Here, we test the application of these tailored BH considerations and the guidance outlined in the OECD AOP Handbook using a number of case examples to increase experience in more transparently documenting rationales for assigned levels of confidence to KEs and KERs, and to promote consistency in evaluation within and across AOPs. The major lessons learned from experience are documented, and taken together with the case examples, should contribute to better common understanding of the nature and form of documentation required to increase confidence in the application of AOPs for specific uses. Based on the tailored BH considerations and defining questions, a prototype quantitative model for assessing the WoE of an AOP using tools of multi-criteria decision analysis (MCDA) is described. The applicability of the approach is also demonstrated using the case example aromatase inhibition leading to reproductive dysfunction in fish. Following the acquisition of additional experience in the development and assessment of AOPs, further refinement of parameterization of the model through expert elicitation is recommended. Overall, the application of quantitative WoE approaches hold promise to enhance the rigor, transparency and reproducibility for AOP WoE determinations and may play an important role in delineating areas where research would have the greatest impact on improving the overall confidence in the AOP. © 2015 The Authors. Source

Meijer L.,University of Groningen | Martijn A.,University of Groningen | Melessen J.,University of Groningen | Brouwer A.,BioDetection Systems BV | And 3 more authors.
Human Reproduction

Background Prenatal exposure to endocrine disruptors, like organohalogen compounds (OHCs), might be responsible for the increased aberrations in human male sexual development (hypospadias, cryptorchidism, testicular cancer and fall in sperm count) observed over the past decades. This development is established during fetal life, and reflected in sex hormone levels, testes volume and penile length post-partum. The present study investigates the correlation between prenatal OHC levels and male sexual development outcomes.Methods AND RESULTSLevels of eight neutral [2,2′-bis-(4-chlorophenyl)-1,1′- dichloroethene (4,4′-DDE), 2,2′,4,4′,5,5′- hexachlorobiphenyl, 2,2′,4,4′-tetrabromodiphenyl ether (BDE)-47,-99,-100,-153,-154 and 1,2,5,6,9,10-hexabromocyclododecane, HBCDD] and four phenolic [(pentachlorophenol (PCP), 4OH-CB-107 (4-hydroxy-2,3,3′, 4′,5-pentachlorobiphenyl),-146 and-187)] OHCs were determined in 55 maternal serum samples taken at 35 weeks of pregnancy. Eight sex development-related hormones [testosterone, free testosterone, sex hormone-binding globulin (SHBG); LH, FSH, estradiol (E2), free E2 (FE2) and inhibin B (InhB)] were determined in their sons at 3 months of age, and testes volume and penile length at 3 and 18 months of age. The following prenatal OHC levels correlated significantly with sex hormone levels: PCP with SHBG and InhB (ρ 0.30 and-0.43, respectively), 4OH-CB-107 with testosterone (ρ 0.31) and BDE-154 with FE2, E2 and InhB (ρ 0.49, 0.54 and 0.34, respectively). BDE-154 levels correlated positively with testes volume at 18 months of age (ρ 0.34). Conclusions Prenatal OHC exposure is correlated with aspects of sexual development outcome in boys up to 18 months of age. © 2012 The Author. Source

Schriks M.,KWR Watercycle Research Institute | van der Linden S.C.,BioDetection Systems BV | Stoks P.G.M.,Association of Rhine Waterworks RIWA | van der Burg B.,BioDetection Systems BV | And 4 more authors.

Considering the important role that surface waters serve for drinking water production, it is important to know if these resources are under the impact of contaminants. Apart from environmental pollutants such as pesticides, compounds such as (xeno)estrogens have received al lot of research attention and several large monitoring campaigns have been carried out to assess estrogenic contamination in the aquatic environment. The introduction of novel in vitro bioassays enables researchers to study if - and to what extent - water bodies are under the impact of less-studied (synthetic) hormone active compounds. The aim of the present study was to carry out an assessment on the presence and extent of glucocorticogenic activity in Dutch surface waters that serve as sources for drinking water production. The results show glucocorticogenic activity in the range of Source

Wang S.,Wageningen University | Rijk J.C.W.,Wageningen University | Besselink H.T.,BioDetection Systems BV | Houtman R.,PamGene International B.V. | And 4 more authors.
Toxicological Sciences

In the present study, a previously established integrated testing strategy (ITS) for in vitro estrogenicity testing was extended with additional in vitro assays in order to broaden its sensitivity to different modes of action resulting in apparent estrogenicity, i.e., other than estrogen receptor (ER) binding. To this end, an extra set of 10 estrogenic compounds with modes of action in part different from ER binding, were tested in the previously defined ITS, consisting of a yeast estrogen reporter gene assay, an U2OS ERα CALUX reporter gene assay and a cell-free coregulator binding assay. Two androgen reporter gene assays and the enhanced H295R steroidogenesis assay were added to that previous defined ITS. These assays had added value, as several estrogenic model compounds also elicited clear and potent antiandrogenic properties and in addition also showed effects on steroidogenesis that might potentiate their apparent estrogenic effects in vivo. Adding these assays, examining mechanisms of action for estrogenicity apart from ERα binding, gives a more complete and comprehensive assessment of the ability of test compounds to interfere with endocrine signaling. It was concluded that the extended ITS will go beyond in vivo estrogenicity testing by the uterotrophic assay, thereby contributing to the 3R-principles. © The Author 2014. Source

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