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At a recent workshop in Setubal (Portugal) principles were drafted to assess the suitability of (quantitative) structure-activity relationships ((Q)SARs) for assessing the hazards and risks of chemicals. In the present study we applied some of the Setubal principles to test the validity of three (Q)SAR expert systems and validate the results. These principles include a mechanistic basis, the availability of a training set and validation. ECOSAR, BIOWIN and DEREK for Windows have a mechanistic or empirical basis. ECOSAR has a training set for each QSAR. For half of the structural fragments the number of chemicals in the training set is > 4. Based on structural fragments and log Kow, ECOSAR uses linear regression to predict ecotoxicity. Validating ECOSAR for three 'valid' classes results in predictivity of a ≥ 64%. BIOWIN uses (non-)linear regressions to predict the probability of biodegradability based on fragments and molecular weight. It has a large training set and predicts non-ready biodegradability well. DEREK for Windows predictions are supported by a mechanistic rationale and literature references. The structural alerts in this program have been developed with a training set of positive and negative toxicity data. However, to support the prediction only a limited number of chemicals in the training set is presented to the user. DEREK for Windows predicts effects by 'if-then' reasoning. The program predicts best for mutagenicity and carcinogenicity. Each structural fragment in ECOSAR and DEREK for Windows needs to be evaluated and validated separately. [ABSTRACT FROM AUTHOR]

The BIOWIN biodegradation models were evaluated for their suitability for regulatory purposes. BIOWIN includes the linear and non-linear BIODEG and MITI models for estimating the probability of rapid aerobic biodegradation and an expert survey model for primary and ultimate biodegradation estimation. Experimental biodegradation data for 110 newly notified substances were compared with the estimations of the different models. The models were applied separately and in combinations to determine which model(s) showed the best performance. The results of this study were compared with the results of other validation studies and other biodegradation models. The BIOWIN models predict not-readily biodegradable substances with high accuracy in contrast to ready biodegradability. In view of the high environmental concern of persistent chemicals and in view of the large number of not-readily biodegradable chemicals compared to the readily ones, a model is preferred that gives a minimum of false positives without a corresponding high percentage false negatives. A combination of the BIOWIN models (BIOWIN2 or BIOWIN6) showed the highest predictive value for not-readily biodegradability. However, the highest score for overall predictivity with lowest percentage false predictions was achieved by applying BIOWIN3 (pass level 2.75) and BIOWIN6. [ABSTRACT FROM AUTHOR]

Environmental risk limits (ERLs) for individual congeners of polychlorinated biphenyls (PCB 77, 105, 118, 126, 153, 156, 157, and 169) are derived. After lipid normalization, toxicity data for birds, mammals, and aquatic organisms were converted to equivalent concentrations in soil or sediment organic carbon (OC). Accumulation in the food chain was taken into account. Field-derived data on the environmental fate of PCBs, e.g., biomagnification factors and biota-to-sediment accumulation factors, were used in the calculations. The variability in these data was incorporated by using probabilistic techniques. Parameters that are difficult to measure for these hydrophobic compounds, such as the bioconcentration factor or the sediment/water partition coefficient, were avoided where possible. Probability distributions for various species were combined per congener when statistically appropriate; ERLs were based on the fifth percentile of these combined distributions. Congener patterns occurring in various sediments and invertebrates in The Netherlands were used for determining a mixture ERL for non- and mono-ortho PCBs. The PCB 118 was selected as a guiding congener. If the concentration of PCB 118 is less than 5 Mu g/kg OC, Dutch ecosystems are assumed to be protected for effects of the whole mixture of non- and mono-ortho-substituted PCBs. Concentrations associated with adverse effects in field studies were comparable to concentrations that would result if all congeners would be present at the ERLlevel. [ABSTRACT FROM AUTHOR]

The ambitions for a circular economy are high and unambiguous, but day-to-day experience shows that the transition still has many difficulties to overcome. One of the current hurdles is the presence of hazardous substances in waste streams that enter or re-enter into the environment or the technosphere. The key question is: do we have the appropriate risk management tools to control any risks that might arise from the re-using and recycling of materials? We present some recent cases that illustrate current practice and complexity in the risk management of newly-formed circular economy chains. We also highlight how separate legal frameworks are still disconnected from each other in these cases, and how circular economy initiatives interlink with the European REACH regulation. Furthermore, we introduce a novel scheme describing how to decide whether a(n)(additional) risk assessment is necessary with regard to the re-use of materials containing hazardous substances. Finally, we present our initial views on new concepts for the fundamental integration of sustainability and safety aspects. These concepts should be the building blocks for the near future shifts in both policy frameworks and voluntary initiatives that support a sound circular economy transition., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endocrine systems, sexual behaviour and fertility and cardiovascular function. Therefore, concern about TH disruption (THD) has resulted in strategies being developed to identify THD chemicals (THDCs). Information on potential of chemicals causing THD is typically derived from animal studies. For the majority of chemicals, however, this information is either limited or unavailable. It is also unlikely that animal experiments will be performed for all THD relevant chemicals in the near future for ethical, financial and practical reasons. In addition, typical animal experiments often do not provide information on the mechanism of action of THDC, making it harder to extrapolate results across species. Relevant effects may not be identified in animal studies when the effects are delayed, life stage specific, not assessed by the experimental paradigm (e.g., behaviour) or only occur when an organism has to adapt to environmental factors by modulating TH levels. Therefore, in vitro and in silico alternatives to identify THDC and quantify their potency are needed. THDC have many potential mechanisms of action, including altered hormone production, transport, metabolism, receptor activation and disruption of several feed-back mechanisms. In vitro assays are available for many of these endpoints, and the application of modern '-omics' technologies, applicable for in vivo studies can help to reveal relevant and possibly new endpoints for inclusion in a targeted THDC in vitro test battery. Within the framework of the ASAT initiative (Assuring Safety without Animal Testing), an international group consisting of experts in the areas of thyroid endocrinology, toxicology of endocrine disruption, neurotoxicology, high-throughput screening, computational biology, and regulatory affairs has reviewed the state of science for (1) known mechanisms for THD plus examples of THDC; (2) in vitro THD tests currently available or under development related to these mechanisms; and (3) in silico methods for estimating the blood levels of THDC. Based on this scientific review, the panel has recommended a battery of test methods to be able to classify chemicals as of less or high concern for further hazard and risk assessment for THD. In addition, research gaps and needs are identified to be able to optimize and validate the targeted THD in vitro test battery for a mechanism-based strategy for a decision to opt out or to proceed with further testing for THD., (Published by Elsevier Ltd.)

The Daphnia 21 d reproduction test is considered as a comprehensive and decisive test in the OECD Conceptual Framework for testing and assessment of endocrine disrupting chemicals (EDCs). However, how to interpret results of the Daphnia 21 d reproduction test for identification, risk assessment and testing strategy of EDCs remains an unsolved issue. This study analysed a total number of 135 published studies encompassing 86 known EDCs and non-EDCs with different modes of action. Our results show that the majority of effects on apical endpoints (survival, molting, growth, time to reproductive maturity, brood size, the number of broods, and the total number of offspring) do not seem to be EDC-specific. In contrast, the endpoint sex ratio is likely specific to juvenile hormones and their mimics. Variability is quantified for three most reported endpoints survival, the total number of offspring and sex ratio. Quantification of the endpoint sensitivity shows that the sensitivity of the sex ratio is lower than that of the total number of offspring. The Daphnia 21 d reproduction test gives insufficient information to conclude if a substance is an EDC or not. EDCs that are potent in assays in vitro may not be potent in the Daphnia 21 d reproduction test. We conclude that the Daphnia 21 d reproduction test is important for deriving No Observed Effect Concentrations for risk assessment but may produce false negatives in identification of EDCs when used on its own. A targeted testing strategy for selection of species, tests, and endpoints is suggested for identifying EDCs., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In a fish testing strategy, positive results of the fish short term reproduction assay (FSTR), often trigger a definitive test like the fish sexual development test (FSDT) or the fish full life cycle test (FFLC), entailing ethical and economic problems. This study analysed 137 studies encompassing 35 chemicals with different modes of actions (MOAs). Variability is quantified for MOA endpoints vitellogenin (VTG) and secondary sex characteristics (SSCs) as well as for apical endpoints. Two MOA endpoints could indicate estrogenic, anti-estrogenic, androgenic, anti-androgenic and steroidogenesis activities. Great variability, however, has been observed for chemicals with anti-androgenic and steroidogenesis activities, suggesting that TG229/230 may not be sensitive enough to detect these types of chemicals and may produce false negatives. Changes in apical endpoints like fecundity are not limited to endocrine disrupting chemicals (EDCs). Non-EDCs could induce the similar effects on these apical endpoints. If elucidating MOA is needed, targeted in vitro MOA tests are suggested. Positive in vitro MOA results trigger a definitive test, which could be used for confirmation of the MOA in vivo and for deriving a no observed effect concentration (NOEC). Based on positive MOA results of TG229, a definitive test such as the FSDT or the FFLC is still needed, because the current TG229 has limitation on the derivation of a NOEC. An extended TG229 with more power to detect reproduction effects, as recently proposed in the OECD test guideline program, would improve the possibility to derive a NOEC and increase its usefulness in risk assessment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Currently, the laboratory-derived fish bioconcentration factor (BCF) serves as one of the primary data sources used to assess the potential for a chemical to bioaccumulate. Consequently, fish BCF values serve a central role in decision making and provide the basis for development of quantitative structure-property relationships (QSPRs) used to predict the bioaccumulation potential of untested compounds. However, practical guidance for critically reviewing experimental BCF studies is limited. This lack of transparent guidance hinders improvement in predictive models and can lead to uninformed chemical management decisions. To address this concern, a multiple-stakeholder workshop of experts from government, industry, and academia was convened by the International Life Sciences Institute Health and Environmental Sciences Institute to examine the data availability and quality issues associated with in vivo fish bioconcentration and bioaccumulation data. This paper provides guidance for evaluating key aspects of study design and conduct that must be considered when judging the reliability and adequacy of reported laboratory bioaccumulation data. Key criteria identified for judging study reliability include 1) clear specification of test substance and fish species investigated, 2) analysis of test substance in both fish tissue and exposure medium, 3) no significant adverse effects on exposed test fish, and 4) a reported test BCF that reflects steady-state conditions with unambiguous units. This guidance is then applied to 2 data-rich chemicals (anthracene and 2,3,7,8-tetrachlorodibenzo-p-dioxin) to illustrate the critical need for applying a systematic data quality assessment process. Use of these guidelines will foster development of more accurate QSPR models, improve the performance and reporting of future laboratory studies, and strengthen the technical basis for bioaccumulation assessment in chemicals management.

Bioavailability is increasingly recognised as the key issue linking increased levels of toxicants with actually occurring adverse effects in ecosystems, whilst taking the modifying effects of the abiotic components of the environment into account. Various factors may affect bioavailability in the field, and often these factors are time- and space-dependent. This is one of the main reasons why legislators have been reluctant in implementing bioavailability in risk assessment procedures. Over the last few years, however, considerable scientific progress has been made with regard to better understanding of chemical and ecological mechanisms responsible for rendering chemicals available for uptake and toxicity. As a consequence, legislators face the challenge to anticipate the scientific progress and to implement bioavailability in legislation. This paper discusses the possibilities of implementing various methodologies within a maximum period of time of three years.

Bioavailability is, to an increasing extent, recognised as the key issue linking the increased levels of toxicants to actually occurring adverse effects in ecosystems, whilst taking the modifying effects of the abiotic components of the environment into account. Various factors may affect bioavailability in the field, and these factors are often time and space dependent. This is one of the main reasons why legislators have been reluctant to implement bioavailability in risk assessment procedures. Over the last few years, however, considerable scientific progress has been made with regard to increasing our understanding of the chemical and ecological mechanisms responsible for rendering chemicals available for uptake and toxicity. As a consequence, legislators face the challenge of having to anticipate the scientific progress and to implement bioavailability in legislation. This contribution reports on the possibilities of implementing various methodologies within a maximum time period of three years.

A model for risk assessment was built for simultaneous, congener-specific PCB bioaccumulation from sediment to fish to otters (Lutra lutra). Toxic equivalence factors (TEFs) were used to sum individual congeners in otters to a toxic equivalent concentration (TEQ) relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Microbial dechlorination and burial in sediments and bioaccumulation are modeled to predict time trends of PCB concentrations in otters. Effects of accumulated PCBs on otters were assessed for vitamin A metabolism and reproduction, taking model uncertainty into account. Three locations in The Netherlands were modeled with PCB levels in sediment of 1 to 171 pg TEQ/g organic carbon (OC). Almost 100% reduction in litter size was predicted for the most polluted area in 1996. Due to large associated uncertainty, a period of 25 to 80 years may be needed for recovery of otter vitamin A levels and litter size at this site. Calculated median sediment quality criteria (SQC) range between 1 and 12 pg TEQ/g OC, depending on the chosen effect criterion. Uncertainty in calculated effects and SQCs is substantial and is mainly caused by uncertainty in PCB congener 126 accumulation.

In previous studies, the risk of toxicant accumulation in food chains was used to calculate quality criteria for surface water and soil. A simple algorithm was used to calculate maximum permissable concentrations [MPC = no-observed-effect concentration/bioconcentration factor(NOEC/BCF)]. These studies were limited to simple food chains. This study presents a method to calculate MPCs for more complex food webs of predators. The previous method is expanded. First, toxicity data (NOECs) for several compounds were corrected for differences between laboratory animals and animals in the wild. Second, for each compound, it was assumed these NOECs were a sample of a log-logistic distribution of mammalian and avian NOECs. Third, bioaccumulation factors (BAFs) for major food items of predators were collected and were assumed to derive from different log-logistic distributions of BAFs. Fourth, MPCs for each compound were calculated using Monte Carlo sampling from NOEC and BAF distributions. An uncertainty analysis for cadmium was performed to identify the most uncertain parameters of the model. Model analysis indicated that most of the prediction uncertainty of the model can be ascribed to uncertainty of species sensitivity as expressed by NOECs. A very small proportion of model uncertainty is contributed by BAFs from food webs. Correction factors for the conversion of NOECs from laboratory conditions to the field have some influence on the final value of MPC5, but the total prediction uncertainty of the MPC is quite large. It is concluded that the uncertainty in species sensitivity is quite large. To avoid unethical toxicity testing with mammalian or avian predators, it cannot be avoided to use this uncertainty in the method proposed to calculate MPC distributions. The fifth percentile of the MPC is suggested as a safe value for top predators.

A simplified food web with three trophic levels is designed: plants and invertebrates at the first, small birds and mammals at the second, and birds and beasts of prey at the third trophic level. Exposure of top predators via separate food chains is analyzed. However, most top predator species are exposed via more than one food chain (food web). Therefore, a species-specific approach is followed too, for which four bird of prey species and two beast of prey species with different food choices are selected: sparrow hawk, kestrel, barn owl, little owl, badger, and weasel. The most critical food chains for secondary poisoning of top predators are soil --> worm/insect --> bird --> bird of prey for dichlorodiphenyltrichloroethane (DDT), and soil --> worm --> bird/mammal --> bird of prey for cadmium (Cd). The risk for the selected top predator species is much lower than the risk based on these critical food chains because the critical food chains constitute a minor part of their food webs. Species feeding on birds (sparrow hawk) and small carnivorous mammals (barn owl) are exposed to DDT and Cd to a much higher extent than species mainly feeding on small herbivorous mammals (kestrel and weasel). It is recommended to include exposure via the pathways soil --> worm/insect --> bird/mammal --> top predator in procedures for derivation of environmental quality objectives for persistent and highly lipophilic compounds.