Summary The recent advent of microphysiological systems – microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro – is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agriculture, food, ecosystems or cosmetics, thus, replacing laboratory animal models used currently. Thirty-five experts from academia, industry and regulatory bodies present here the results of an intensive workshop (held in June 2015, Berlin, Germany). They review the status quo of microphysiological systems available today against industry needs, and assess the broad variety of approaches with fit-for-purpose potential in the drug development cycle. Feasible technical solutions to reach the next levels of human biology in vitro are proposed. Furthermore, key organ-on-a-chip case studies, as well as various national and international programs are highlighted. Finally, a roadmap into the future is outlined, to allow for more predictive and regulatory-accepted substance testing on a global scale.

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Challenges to improve toxicological risk assessment to meet the demands of the EU chemical's legislation, REACH, and the EU 7th Amendment of the Cosmetics Directive have accelerated the development of non-animal based methods. Unfortunately, uncertainties remain surrounding the power of alternative methods such as in vitro assays to predict in vivo dose-response relationships, which impedes their use in regulatory toxicology. One issue reviewed here, is the lack of a well-defined dose metric for use in concentration-effect relationships obtained from in vitro cell assays. Traditionally, the nominal concentration has been used to define in vitro concentration-effect relationships. However, chemicals may differentially and non-specifically bind to medium constituents, well plate plastic and cells. They may also evaporate, degrade or be metabolized over the exposure period at different rates. Studies have shown that these processes may reduce the bioavailable and biologically effective dose of test chemicals in in vitro assays to levels far below their nominal concentration. This subsequently hampers the interpretation of in vitro data to predict and compare the true toxic potency of test chemicals. Therefore, this review discusses a number of dose metrics and their dependency on in vitro assay setup. Recommendations are given on when to consider alternative dose metrics instead of nominal concentrations, in order to reduce effect concentration variability between in vitro assays and between in vitro and in vivo assays in toxicology.

It is generally known that there are compounds present in the aquatic environment that can disturb endocrine processes, for example via interaction with the endogenous hormone receptors. Most research so far has focused on compounds that bind to the estrogen and/or androgen receptor, but ligands for other hormone receptors might also be present. In this study, a newly completed panel of human cell derived CALUX reporter gene bioassays was utilized to test water extracts for estrogen (ER), as well as androgen (AR), progesterone (PR), and glucocorticoid (GR) receptor mediated transactivation activity. Effluents from industry, hospital, and municipal sewage treatment plants, as well as tap water and different sources of surface water were tested. The CALUX reporter gene panel showed high sensitivity and specificity to known agonists, enabling discrimination between different receptor based endocrine responses present in the aquatic environment. Our results clearly showed the presence of agonistic activity on the ER, as well as on the AR, PR, and GR in the raw and wastewater and surface water extracts. However, no hormone receptor-mediated transactivation was detected in the drinking water or in the blank water. The levels of estrogenic activity were 0.2-0.5 ng E2-equiv/L for surface water and 0.4-1.0 ng E2-equiv/L for municipal effluents, which was consistent with previous studies. Surprisingly, the other hormonal activities were found to be present in similar or much higher levels. Most notably, glucocorticoid-like activity was detected in all samples, at surprisingly high levels ranging from 0.39-1.3 ng Dex-equiv/L in surface water and 11-243 ng Dex-equiv/L in effluents. When regarding the fact that dexamethasone in the GR CALUX bioassay is a factor 12 more potent than the natural hormone cortisol, results expressed as cortisol equivalents would range up to 2900 ng cortisol equiv/L. Further studies are needed to establish the identity of the active compounds and to understand the significance of the level of activities with regard to human and ecotoxicological risks.

Titanium dioxide (TiO 2 ) is commonly applied to enhance the white colour and brightness of food products. TiO 2 is also used as white pigment in other products such as toothpaste. A small fraction of the pigment is known to be present as nanoparticles (NPs). Recent studies with TiO 2 NPs indicate that these particles can have toxic effects. In this paper, we aimed to estimate the oral intake of TiO 2 and its NPs from food, food supplements and toothpaste in the Dutch population aged 2 to over 70 years by combining data on food consumption and supplement intake with concentrations of Ti and TiO 2 NPs in food products and supplements. For children aged 2-6 years, additional intake via ingestion of toothpaste was estimated. The mean longterm intake to TiO 2 ranges from 0.06 mg/kg bw/day in elderly (70+), 0.17 mg/kg bw/day for 7-69-year-old people, to 0.67 mg/kg bw/day in children (2-6 year old). The estimated mean intake of TiO 2 NPs ranges from 0.19 mg/kg bw/day in elderly, 0.55 mg/kg bw/day for 7-69-yearold people, to 2.16 mg/kg bw/day in young children. Ninety-fifth percentile (P95) values are 0.74, 1.61 and 4.16 mg/kg bw/day, respectively. The products contributing most to the TiO 2 intake are toothpaste (in young children only), candy, coffee creamer, fine bakery wares and sauces. In a separate publication, the results are used to evaluate whether the presence of TiO 2 NPs in these products can pose a human health risk.

Titanium dioxide white pigment consists of particles of various sizes, from which a fraction is in the nano range (5100 nm). It is applied in food as additive E 171 as well as in other products, such as food supplements and toothpaste. Here, we assessed whether a human health risk can be expected from oral ingestion of these titanium dioxide nanoparticles (TiO 2 NPs), based on currently available information. Human health risks were assessed using two different approaches: Approach 1, based on intake, i.e. external doses, and Approach 2, based on internal organ concentrations using a kinetic model in order to account for accumulation over time (the preferred approach). Results showed that with Approach 1, a human health risk is not expected for effects in liver and spleen, but a human health risk cannot be excluded for effects on the ovaries. When based on organ concentrations by including the toxicokinetics of TiO 2 NPs (Approach 2), a potential risk for liver, ovaries and testes is found. This difference between the two approaches shows the importance of including toxicokinetic information. The currently estimated risk can be influenced by factors such as absorption, form of TiO 2 , particle fraction, particle size and physico-chemical properties in relation to toxicity, among others. Analysis of actual particle concentrations in human organs, as well as organ concentrations and effects in liver and the reproductive system after chronic exposure to well-characterized TiO 2 (NPs) in animals are recommended to refine this assessment.

Toxicological relevance of emerging contaminants for drinking water quality Schriks, M.; Heringa, M.B.; van der Kooij, M.M.E.; de Voogt, W.P.; van Wezel, A.P. General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 02 Apr 2019This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. IntroductionDue to anthropogenic activities, freshwater systems worldwide are confronted with thousands of compounds. In the European Union, for example, there are more than 100 000 registered chemicals (EINECS), of which 30 000-70 000 are in daily use. About 300 million tons of synthetic compounds annually used in industrial and consumer products, partially find their way to natural waters (Schwarzenbach et al., 2006). A major contribution to chemical contamination originates from wastewater discharges that impact surface water quality with incompletely removed organic contaminants (Kolpin et al., 2004;Snyder et al., 2001). Additional contamination comes from diffuse agricultural activities, in which over 140 million tons of fertilizers and several million tons of pesticides are applied each year, and from atmospheric deposition. Such contamination can become an increasing problem for drinking water supplies, especially since the European REACH legislation may drive producers to develop newly designed less lipophilic/bioaccumulative chemicals that will be inherently more difficult to remove by traditional drinking water treatment techniques. Author's personal copy Recently, Loos et al. (2009) presented an EU-wide monitoring study on 35 organic compounds in European river waters in concentrations up to 40 mg/L. In addition, we have shown the occurrence of emerging polar contaminants, such as benzotriazoles and metabolites of illicit drugs (e.g. benzoylecgonine, desalkylflurazepam and 9-carbonic acid-d-9-THC) in groundwaters and surface waters in the Netherlands Van Leerdam et al., 2009).Many of these emerging contaminants raise consid...

BackgroundTitanium dioxide (TiO2) is produced at high volumes and applied in many consumer and food products. Recent toxicokinetic modelling indicated the potential of TiO2 to accumulate in human liver and spleen upon daily oral exposure, which is not routinely investigated in chronic animal studies. A health risk from nanosized TiO2 particle consumption could not be excluded then.ResultsHere we show the first quantification of both total titanium (Ti) and TiO2 particles in 15 post-mortem human livers and spleens. These low-level analyses were enabled by the use of fully validated (single particle) inductively coupled plasma high resolution mass spectrometry ((sp)ICP-HRMS) detection methods for total Ti and TiO2 particles. The presence of TiO2 in the particles in tissues was confirmed by Scanning Electron Microscopy with energy dispersive X-ray spectrometry.ConclusionsThese results prove that TiO2 particles are present in human liver and spleen, with ≥24% of nanosize (< 100 nm). The levels are below the doses regarded as safe in animals, but half are above the dose that is deemed safe for liver damage in humans when taking into account several commonly applied uncertainty factors. With these new and unique human data, we remain with the conclusion that health risks due to oral exposure to TiO2 cannot be excluded.Electronic supplementary materialThe online version of this article (10.1186/s12989-018-0251-7) contains supplementary material, which is available to authorized users.