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Among endocrine disruption, interference with the thyroid hormone (TH) regulation is of increasing concern. Respective compounds encode through their structural features both the potential for TH disruption, and the bioavailability mitigating the toxicological effect. The aim of this study is to provide a substructure-based screening-level QSAR (quantitative structure-activity relationship) that discriminates bioavailable TH disruptors from not bioavailable counterparts, covering both direct and indirect (retinoid- and AhR-mediated) modes of action. The QSAR has been derived from literature data for 1642 compounds, and takes into account Lipinski's rule-of-five and the brain/blood partition coefficient Kbrain/blood. For its validation, an external test set of 145 substances has been used. For 1787 compounds meeting the model application domain, the model yields only one false negative. The discussion addresses the mechanistic meaning of the bioavailability triggers molecular weight, H-bond donor and acceptor, hydrophobicity (log Kow), and the physicochemical properties underlying log Kbrain/blood. The model may serve as bioavailability-screening step within a decision support system for the predictive assessment of chemicals regarding their potential to disrupt thyroid hormone function in a direct or indirect manner.

The octanol/air partition coefficient Koa is important for assessing the bioconcentration of airborne xenobiotics in foliage and in air-breathing organisms. Moreover, Koa informs about compound partitioning to aerosols and indoor dust, and complements the octanol/water partition coefficient Kow and the air/water partition coefficient Kaw for multimedia fate modeling. Experimental log Koa at 25 °C has been collected from literature for 2161 compounds with molecular weights from 16 to 959 Da. The curated data set covers 18.2 log units (from −1.0 to 17.2). A newly developed fragment model for predicting log Koa from molecular structure outperforms COSMOtherm, EPI-Suite KOAWIN, OPERA, and linear solvation energy relationships (LSERs) regarding the root-mean-squared error (rms) and the maximum negative and positive errors (mne and mpe) (rms: 0.57 vs 0.86 vs 1.09 vs 1.19 vs 1.05–1.53, mne: −2.55 vs −3.95 vs −7.51 vs −7.54 vs (−5.63) – (−7.34), mpe: 2.91 vs 5.97 vs 7.54 vs 4.24 vs 6.89–10.2 log units). The prediction capability, statistical robustness, and sound mechanistic basis are demonstrated through initial separation into a training and prediction set (80:20%), mutual leave-50%-out validation, and target value scrambling in terms of temporarily wrong compound-Koa allocations. The new general-purpose model is implemented in a fully automatized form in the ChemProp software available to the public. Regarding Koa indirectly determined through Kow and Kaw, a new approach is developed to convert from wet to dry octanol, enabling higher consistency in experimental (and thus also predicted) Koa.

Knowledge of exposure to a wide range of chemicals, and the spatio-temporal variability thereof, is urgently needed in the context of protecting and restoring aquatic ecosystems. This paper discusses a computational material flow analysis to predict the occurrence of thousands of man-made organic chemicals on a European scale, based on a novel temporally and spatially resolved modelling framework. The goal was to increase understanding of pressures by emerging chemicals and to complement surface water monitoring data. The ambition was to provide a first step towards a real-life mixture exposure situation accounting for as many chemicals as possible. Comparison of simulated concentrations and chemical monitoring data for 226 substance/basin combinations showed that the simulated concentrations were accurate on average. For 65% and 90% of substance/basin combinations the error was within one and two orders of magnitude respectively. An analysis of the relative importance of uncertainties revealed that inaccuracies in use volume or use type information contributed most to the error for individual substances. To resolve this, we suggest better registration of use types of industrial chemicals, investigation of presence/absence of industrial chemicals in wastewater and runoff samples and more scientific information exchange.

Knowledge of exposure to a wide range of chemicals, and the spatio-temporal variability thereof, is urgently needed in the context of protecting and restoring aquatic ecosystems. This paper discusses a computational material flow analysis to predict the occurrence of thousands of man-made organic chemicals on a European scale, based on a novel temporally and spatially resolved modelling framework. The goal was to increase understanding of pressures by emerging chemicals and to complement surface water monitoring data. The ambition was to provide a first step towards a “real-life” mixture exposure situation accounting for as many chemicals as possible. Comparison of simulated concentrations and chemical monitoring data for 226 substance/basin combinations showed that the simulated concentrations were accurate on average. For 65% and 90% of substance/basin combinations the error was within one and two orders of magnitude respectively. An analysis of the relative importance of uncertainties revealed that inaccuracies in use volume or use type information contributed most to the error for individual substances. To resolve this, we suggest better registration of use types of industrial chemicals, investigation of presence/absence of industrial chemicals in wastewater and runoff samples and more scientific information exchange.

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Chemicals that are persistent in the environment,mobile in the aquatic environment and toxic may be critical for the quality of raw waters. In the present study, a list of 167 REACHregistered substances were assessed with respect to their intrinsic substance properties persistence in the aquatic environment (Paq),mobility in the aquatic environment (M) and toxicity (T) usingmodified criteria earlier defined by Kalberlah et al. (2014).This was done by comprehensive manual research of all relevant information and data in all available data sources including mathematical models.Additionally, the substances were assessed and ranked with respect to their potential for environmental emissions based on the evaluation approach developed by Schulze et al. (2018).The present study provides a consolidated list of substances assessed according to the above criteria, including 8 substances assessed as PaqMT substances and 21 substances assessed as PaqMsubstances with suspected T. Further 105 suspected PaqMT substances were identified.Consequently, a total of 134 substances based on suspected PaqMT properties combined with expected environmental emissions are recommended to the German Environment Agency (UBA) for further investigation and scientific and  regulatory scrutiny.However, this result may not be suitable to indicate the need for regulatory measures.The study identified considerable data gaps (especially for experimental data) that in many cases hampered the assessment of the criteria, especially for Mand T.Manufacturers, importers and downstream users of substances should strive to obtain and report data of better quality in order to carry out a more accurate assessment. Further, the results of this project will support the ongoing discussion to define PMT criteria under REACH.Stoffe, die persistent in der Umwelt,mobil im Wasserkreislauf und toxisch sind, könnten die Qualität der Rohwässer zur Trinkwassergewinnung gefährden. Im Rahmen des vorliegenden Vorhabens

Surface water concentrations of 54 pharmaceuticals were predicted for seven major Swedish rivers and the Stockholm City area basins using the STREAM-EU model. These surface water concentrations were used to predict the ecotoxicological impact resulting from the exposure of aquatic organisms to this mixture of 54 pharmaceuticals. STREAM-EU model results indicated that <10 substances were present at median annual water concentrations greater than 10 ng/L with highest concentrations occurring mostly in the more densely populated area of the capital city, Stockholm. There was considerable spatial and temporal variability in the model predictions (1–3 orders of magnitude) due to natural variability (e.g. hydrology, temperature), variations in emissions and uncertainty sources. Local mixture ecotoxicological pressures based on acute EC50 data as well as on chronic NOEC data, expressed as multi-substance potentially affected fraction of species (msPAF), were quantified in 114 separate locations in the waterbodies. It was estimated that 5% of the exposed aquatic species would experience exposure at or above their acute EC50 concentrations (so-called acute hazardous concentration for 5% of species, or aHC5) at only 7% of the locations analyzed (8 out of 114 locations). For the evaluation based on chronic NOEC concentrations, the chronic HC5 (cHC5) is exceeded at 27% of the locations. The acute mixture toxic pressure was estimated to be predominantly caused by only three substances in all waterbodies: Furosemide, Tramadol and Ibuprofen. A similar evaluation of chronic toxic pressure evaluation logically demonstrates that more substances play a significant role in causing a higher chronic toxic pressure at more sites as compared to the acute toxic pressure evaluation. In addition to the three substances contributing most to acute effects, the chronic effects are predominantly caused by another five substances: paracetamol, diclofenac, ethinylestradiol, erythromycin and

In 2013 the Organisation for Economic Co‐operation and Development (OECD) test guideline (236) for fish embryo acute toxicity (FET) was adopted. It determines the acute toxicity of chemicals to embryonic fish. Previous studies show a good correlation of FET with the standard acute fish toxicity (AFT) test; however, the potential of the FET test to predict AFT, which is required by the Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) regulation (EC 1907/2006) and the Classification, Labelling and Packaging (CLP) Regulation (EC 1272/2008), has not yet been fully clarified. In 2015 the European Chemicals Agency (ECHA) requested that a consultant perform a scientific analysis of the applicability of FET to predict AFT. The purpose was to compare the toxicity of substances to fish embryos and to adult fish, and to investigate whether certain factors (e.g., physicochemical properties, modes of action, or chemical structures) could be used to define the applicability boundaries of the FET test. Given the limited data availability, the analysis focused on organic substances. The present critical review summarizes the main findings and discusses regulatory application of the FET test under REACH. Given some limitations (e.g., neurotoxic mode of action) and/or remaining uncertainties (e.g., deviation of some narcotic substances), it has been found that the FET test alone is currently not sufficient to meet the essential information on AFT as required by the REACH regulation. However, the test may be used within weight‐of‐evidence approaches together with other independent, relevant, and reliable sources of information. The present review also discusses further research needs that may overcome the remaining uncertainties and help to increase acceptance of FET as a replacement for AFT in the future. For example, an increase in the availability of data generated according to OECD test guideline 236 may provide evidence of a higher predictive power of

The development and implementation of safe-by-design strategies is key for the safe development of future generations of nanotechnology enabled products. The safety testing of the huge variety of nanomaterials that can be synthetized is unfeasible due to time and cost constraints. Computational modeling facilitates the implementation of alternative testing strategies in a time and cost effective way. The development of predictive nanotoxicology models requires the use of high quality experimental data on the structure, physicochemical properties and bioactivity of nanomaterials. The FP7 Project MODERN has developed and evaluated the main components of a computational framework for the evaluation of the environmental and health impacts of nanoparticles. This chapter describes each of the elements of the framework including aspects related to data generation, management and integration; development of nanodescriptors; establishment of nanostructure-activity relationships; identification of nanoparticle categories; hazard ranking and risk assessment.

Aquatic bioconcentration factors (BCFs) are critical in PBT (persistent, bioaccumulative, toxic) and risk assessment of chemicals. High costs and use of more than 100 fish per standard BCF study (OECD 305) call for alternative methods to replace as much in vivo testing as possible. The BCF waiving scheme is a screening tool combining QSAR classifications based on physicochemical properties related to the distribution (hydrophobicity, ionisation), persistence (biodegradability, hydrolysis), solubility and volatility (Henry's law constant) of substances in water bodies and aquatic biota to predict substances with low aquatic bioaccumulation (nonB, BCF < 2000).The BCF waiving scheme was developed with a dataset of reliable BCFs for 998 compounds and externally validated with another 181 substances. It performs with 100% sensitivity (no false negatives), > 50% efficacy (waiving potential), and complies with the OECD principles for valid QSARs. The chemical applicability domain of the BCF waiving scheme is given by the structures of the training set, with some compound classes explicitly excluded like organometallics, poly- and perfluorinated compounds, aromatic triphenylphosphates, surfactants. The prediction confidence of the BCF waiving scheme is based on applicability domain compliance, consensus modelling, and the structural similarity with known nonB and B/vB substances.Compounds classified as nonB by the BCF waiving scheme are candidates for waiving of BCF in vivo testing on fish due to low concern with regard to the B criterion. The BCF waiving scheme supports the 3Rs with a possible reduction of > 50% of BCF in vivo testing on fish. If the target chemical is outside the applicability domain of the BCF waiving scheme or not classified as nonB, further assessments with in silico, in vitro or in vivo methods are necessary to either confirm or reject bioaccumulative behaviour.

An exposure assessment for multiple pharmaceuticals in Swedish surface waters was made using the STREAM-EU model. Results indicate that Metformin (27 ton/y), Paracetamol (6.9 ton/y) and Ibuprofen (2.33 ton/y) were the drugs with higher amounts reaching the Baltic Sea in 2011. 35 of the studied substances had more than 1 kg/y of predicted flush to the sea. Exposure potential given by the ratio amount of the drug exported to the sea/amount emitted to the environment was higher than 50% for 7 drugs (Piperacillin, Lorazepam, Metformin, Hydroxycarbamide, Hydrochlorothiazide, Furosemide and Cetirizine), implying that a high proportion of them will reach the sea, and below 10% for 27 drugs, implying high catchment attenuation. Exposure potentials were found to be dependent of persistency and hydrophobicity of the drugs. Chemicals with Log D > 2 had exposure potentials <10% regardless of their persistence. Chemicals with Log D  <  −2 had exposure potentials >35% with higher ratios typically achieved for longer half-lives. For Stockholm urban area, 17 of the 54 pharmaceuticals studied had calculated concentrations higher than 10 ng/L. Model agreement with monitored values had an r2 = 0.62 for predicted concentrations and an r2 = 0.95 for predicted disposed amounts to sea.

Pesticide residues are frequently found in water bodies and may threaten freshwater ecosystems and biodiversity. In addition to runoff or leaching from treated agricultural fields, pesticides may enter streams via effluents from wastewater treatment plants (WWTPs). We compared the pesticide toxicity in terms of log maximum Toxic Unit (log mTU) of sampling sites in small agricultural streams of Germany with and without WWTPs in the upstream catchments. We found an approximately half log unit higher pesticide toxicity for sampling sites with WWTPs (p < 0.001). Compared to fungicides and insecticides, herbicides contributed most to the total pesticide toxicity in streams with WWTPs. A few compounds (diuron, terbuthylazin, isoproturon, terbutryn and Metazachlor) dominated the herbicide toxicity. Pesticide toxicity was not correlated with upstream distance to WWTP (Spearman's rank correlation, rho = − 0.11, p > 0.05) suggesting that other context variables are more important to explain WWTP-driven pesticide toxicity. Our results suggest that WWTPs contribute to pesticide toxicity in German streams.

The acute fish toxicity (AFT, OECD TG 203) is required to provide information on the acute toxicity of chemicals for environmental hazards and risk assessment. It is conducted as part of the registration of (industrial) chemicals under European regulations as well as other regulations. To reduce the number of tests on animals, the REACH Regulation promotes alternative methods for the hazard assessment of substances. For example, testing according to OECD Technical Guideline 236 (fish embryo acute toxicity test (FET)) has been suggested as one of the alternative methods to toxicity testing in adult fish. The aim of this study was to assess the capacity of the FET test in predicting acute fish toxicity and to define the applicability domain of the FET test for regulatory purposes. The existing fish embryo data (acute - 96h LC50) were compared to data on adult fish toxicity (acute - 96h LC50) and the limits of applicability investigated by analysis of the relation of the results with respect to physicochemical parameters, structural domains, excess toxicities (i.e. the ratio of predicted baseline toxicity LC50 versus observed acute LC50, also called toxic ratio).

The majority of repeated dose toxicity studies are available for the oral route. For risk assessment, however, data are needed from the relevant exposure route, i.e. inhalation or dermal. Instead of conducting additional animal studies, route-to-route (R2R) extrapolation may be performed. To explore uncertainties associated with this approach, we derived extrapolation factors (EF) based on no/lowest effect levels (NOELs/LOELs) in the Fraunhofer RepDose® database.For R2R extrapolation oral-to-inhalation 246 study pairs on 110 chemicals were analyzed. Systemic effects triggered the LOELs in the underlying inhalation studies in 49.2%, local effects in 21.9% and both local and systemic effects in 30.9% of the data pairs. For systemic effects in inhalation studies an EF of 2.2 (95% confidence interval: 1.2–3.1) was derived, for local effects, the EF was 4.4 (95% confidence interval: 2.0–8.6), and the EF without distinguishing local or systemic effects (any EF) was 3.2 (95%, confidence interval: 1.7–5.0). Calculation with LOELs instead of NOELs, exposure duration and intrinsic properties of the chemical (toxicity or physicochemical properties) did not influence the EF significantly.For R2R extrapolation oral-to-dermal 46 study pairs on 28 chemicals were analyzed. An overall EF of 0.4 (95%, confidence interval: 0.2–0.9) was obtained. Here, we found a significant difference of EFs for low and high toxic chemicals.Overall, we conclude that reliable systemic NOELs/LOELs can be obtained for inhalation studies via R2R extrapolation from oral studies. Based on the data for any EF we propose to use an EF of 3, which covers also the uncertainty that unexpected local effects may occur in an inhalation study. For the dermal route, our dataset was too small to allow general conclusions, but the results so far do suggest that the current ECHA guidance is conservative when assuming that dermal absorption is as high as oral absorption.

The presence of aromatic amines in the environment has been in the focus of research, as many of these compounds are known or suspected mutagens and carcinogens. To facilitate the detection of aromatic amines in complex environmental samples by LC-high resolution mass spectrometry, an on-line-post-column and a pre-column derivatization method to label (in an ideal case) all aromatic amines was evaluated by applying different derivatization reagents. 4-Fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was found to be the most promising labeling reagent due to its high reactivity with both primary and secondary amines and its low signal in positive mode electrospray ionization (ESI+). Post-column on-line derivatization did not result in sufficient signal intensities of derivatives. With pre-column derivatization most of the selected aromatic amines resulted in a derivative that shows common fragments of diagnostic value. The selectivity of NBD-F was studied in depth with a data set of 220 compounds with different functional groups showing that also aliphatic amines and some thiols yield a derivative. The developed method was successfully applied to wastewater effluent samples and several derivatives were confirmed by diagnostic neutral losses.

Environmental quality monitoring of water resources is challenged with providing the basis for safeguarding the environment against adverse biological effects from exposure to anthropogenic chemicals originating from diffuse and point sources. Although current regulatory efforts focus on monitoring and assessing a few legacy chemicals, many more anthropogenic chemicals are and will become detected in aquatic resources as a result of progress in analytical techniques. Assessing this type of exposure information based on available standard approaches from prospective risk assessment for single chemicals inevitably leads to indication of risk in most surface water bodies. As an alternative to generic assessment approaches, effect-based monitoring approaches are suggested. This offers the advantage of reducing uncertainties of effect extrapolation and additionally accounts for mixture effects. To become a credible complement to chemical monitoring information, however, a better understanding of the capabilities and gaps of available effect-based tools is needed. The authors therefore undertook to 1) compile organic contaminants detected in freshwater monitoring studies, 2) provide a synopsis of the mode of action knowledge available for the detected compounds, 3) perform a hazard ranking to identify priority mixtures, and 4) reflect on the challenges to make bioassays fit for effect-based monitoring. The present Focus article shows that chemical occurrence in European freshwaters seems to be highly variable in composition and relative abundancies. Further, although the present mode of action knowledge remains limited, the authors already see the need for batteries of effect-based tools if a more comprehensive coverage of prevailing effect qualities for mixtures is to be targeted. Finally, they suggest a list of organic compounds that could serve as a reference list for effect-based tool validation studies.

The present study is motivated by the increasing demand to consider internal partitioning into tissues instead of exposure concentrations for the environmental toxicity assessment. To this end, physiologically based pharmacokinetic (PBPK) models can be applied. We evaluated the variation in accuracy of PBPK model outcomes depending on tissue constituents modeled as sorptive phases and chemical distribution tendencies addressed by molecular descriptors. The model performance was examined using data from 150 experiments for 28 chemicals collected from US EPA databases. The simplest PBPK model is based on the “Kow-lipid content” approach as being traditional for environmental toxicology. The most elaborated one considers five biological sorptive phases (polar and non-polar lipids, water, albumin and the remaining proteins) and makes use of LSER (linear solvation energy relationship) parameters to describe the compound partitioning behavior. The “Kow-lipid content”-based PBPK model shows more than one order of magnitude difference in predicted and measured values for 37% of the studied exposure experiments while for the most elaborated model this happens only for 7%. It is shown that further improvements could be achieved by introducing corrections for metabolic biotransformation and compound transmission hindrance through a cellular membrane. The analysis of the interface distribution tendencies shows that polar tissue constituents, namely water, polar lipids and proteins, play an important role in the accumulation behavior of polar compounds with H-bond donating functional groups. For compounds without H-bond donating fragments preferable accumulation phases are storage lipids and water depending on compound polarity.

The threshold of toxicological concern (TTC) of a compound represents an exposure value below which the associated human health risk is considered negligible. As such, this approach offers assessing the risk of potential toxicants when little or no toxicological information is available. For the inhalation repeated-dose TTC, the goal was to derive structural alerts that discriminate between high- and low-toxic compounds. A further aim was to identify physicochemical parameters related to the inhalation-specific bioavailability of the compounds, and to explore their use as predictors of high vs low toxicity. 296 compounds with subacute, subchronic and chronic inhalation toxicity NOEC (no-observed effect concentration) values were subdivided into three almost equal-sized high-, medium- and low-toxic (HTox, MTox, LTox) potency classes. Whereas the derived 14 HTox and 7 LTox structural alerts yield an only moderate discrimination between these three groups, the high-toxic vs low-toxic mis-classification is very low: LTox-predicted compounds are not HTox to 97.5%, and HTox-predicted compounds not LTox to 88.6%. The probability of a compound being HTox vs LTox is triggered further by physicochemical properties encoding the tendency to evaporate from blood. The new structural alerts may aid in the predictive inhalation toxicity assessment of compounds as well as in designing low-toxicity chemicals, and provide a rationale for the chemistry underlying the toxicological outcome that can also be used for scoping targeted experimental studies.

Knowledge about tautomer forms of a structure is important since, e.g., a property prediction for a molecule can yield to different results which depend on the individual tautomer. Tautomers are isomers that can be transformed to each other through chemical equilibrium reactions. In this paper the first exact Branch-and-Bound (B&B) algorithm to calculate tautomer structures is proposed. The algorithm is complete in the sense of tautomerism and generates all possible tautomers of a structure according to the tautomer definition, it is initialized with. To be efficient, the algorithm takes advantage of symmetric and formation properties. Some restrictions are used to enable an early pruning of some branches of the B&B tree. This is important, since a simple enumeration strategy would lead to number of candidate tautomers that is exponentially increasing with the number of hydrogen atoms and their attachment sites. The proposed implementation of the B&B algorithm covers the majority of the prototropic tautomer cases, but can be adapted to other kinds of tautomerism too. Furthermore, a computer processable definition of tautomerism is given in the form of the moving hydrogen atom problem.

The fish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, but concerns have been raised for its predictivity given that a few compounds have been shown to exhibit a weak acute toxicity in the fish embryo. In order to better define the applicability domain and improve the predictive capacity of the fish embryo test, we performed a systematic analysis of existing fish embryo and acute fish toxicity data. A correlation analysis of a total of 153 compounds identified 28 compounds with a weaker or no toxicity in the fish embryo test. Eleven of these compounds exhibited a neurotoxic mode of action. We selected a subset of eight compounds with weaker or no embryo toxicity (cyanazine, picloram, aldicarb, azinphos-methyl, dieldrin, diquat dibromide, endosulfan, and esfenvalerate) to study toxicokinetics and a neurotoxic mode of action as potential reasons for the deviating fish embryo toxicity. Published fish embryo LC50 values were confirmed by experimental analysis of zebrafish embryo LC50 according to OECD guideline 236. Except for diquat dibromide, internal concentration analysis did not indicate a potential relation of the low sensitivity of fish embryos to a limited uptake of the compounds. Analysis of locomotor activity of diquat dibromide and the neurotoxic compounds in 98 hpf embryos (exposed for 96 h) indicated a specific effect on behavior (embryonic movement) for the neurotoxic compounds. The EC50s of behavior for neurotoxic compounds were close to the acute fish toxicity LC50. Our data provided the first evidence that the applicability domain of the fish embryo test (LC50s determination) may exclude neurotoxic compounds. However, neurotoxic compounds could be identified by changes in embryonic locomotion. Although a quantitative prediction of acute fish toxicity LC50 using behavioral assays in fish embryos may not yet be possible, the identification of neurotoxicity could trigger the conduction of a conventional fish acu

The vision of a sustainable and safe use of chemicals to protect human health, preserve the environment and maintain the ecosystem requires innovative and more holistic approaches to risk assessment (RA) in order to better inform decision making. Integrated risk assessment (IRA) has been proposed as a solution to current scientific, societal and policy needs. It is defined as the mutual exploitation of environmental risk assessment (ERA) for human health risk assessment (HHRA) and vice versa in order to coherently and more efficiently characterize an overall risk to humans and the environment for better informing the risk analysis process. Extrapolating between species which are relevant for HHRA and ERA requires a detailed understanding of pathways of toxicity/modes of action (MoA) for the various toxicological endpoints. Significant scientific advances, changes in chemical legislation, and increasing environmental consciousness have created a favourable scientific and regulatory environment to develop and promote the concept and vision of IRA. An initial proof of concept is needed to foster the incorporation of IRA approaches into different chemical sectorial regulations and demonstrate their reliability for regulatory purposes. More familiarity and confidence with IRA will ultimately contribute to an overall reduction in in vivo toxicity testing requirements. However, significant progress will only be made if long-term support for MoA-related research is secured. In the short term, further exchange and harmonization of RA terminology, models and methodologies across chemical categories and regulatory agencies will support these efforts. Since societal values, public perceptions and cultural factors are of increasing importance for the acceptance of risk analysis and successful implementation of risk mitigation measures, the integration of socio-economic analysis and socio-behavioural considerations into the risk analysis process may help to produce a more effecti