The role of bioassays in the evaluation of ecotoxicological aspects within the PEF/OEF protocols: The case of WWTPs.

The suitability evaluation of any industrial process should rely on economic, technical, social and, in particular, environmental aspects. The Commission Recommendation 2013/179/UE enables the improvement and the harmonization of the conventional evaluation of environmental footprints, such as LCA (Life Cycle Assessment), Carbon and Water Footprint, by suggesting the assessment of life cycle environmental performance of products and organisations (PEF, OEF). Novelty aspects reside in including new impact categories (namely, human toxicity cancer effects, human toxicity not-cancer effects and eco-toxicity). This paper presents an application of PEF/OEF protocol to the example case of an activated sludge wastewater treatment plant. Strengths and criticisms of this approach are discussed, by taking into consideration the possible final goal of the suitability assessment. Valuably, the adoption of bioassays (i.e., the input of their results in the models for calculating the life cycle environmental performance) for a more reliable evaluation of the impact on the ecosystem and human health is proposed.

Scientific principles for the identification of endocrine-disrupting chemicals: a consensus statement.

Endocrine disruption is a specific form of toxicity, where natural and/or anthropogenic chemicals, known as "endocrine disruptors" (EDs), trigger adverse health effects by disrupting the endogenous hormone system. There is need to harmonize guidance on the regulation of EDs, but this has been hampered by what appeared as a lack of consensus among scientists. This publication provides summary information about a consensus reached by a group of world-leading scientists that can serve as the basis for the development of ED criteria in relevant EU legislation. Twenty-three international scientists from different disciplines discussed principles and open questions on ED identification as outlined in a draft consensus paper at an expert meeting hosted by the German Federal Institute for Risk Assessment (BfR) in Berlin, Germany on 11-12 April 2016. Participants reached a consensus regarding scientific principles for the identification of EDs. The paper discusses the consensus reached on background, definition of an ED and related concepts, sources of uncertainty, scientific principles important for ED identification, and research needs. It highlights the difficulty in retrospectively reconstructing ED exposure, insufficient range of validated test systems for EDs, and some issues impacting on the evaluation of the risk from EDs, such as non-monotonic dose-response and thresholds, modes of action, and exposure assessment. This report provides the consensus statement on EDs agreed among all participating scientists. The meeting facilitated a productive debate and reduced a number of differences in views. It is expected that the consensus reached will serve as an important basis for the development of regulatory ED criteria.

Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz.

Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the "expected NOEL" was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose-response curve or effects at low levels.

A decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping).

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) 'Nano Task Force' proposes a Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) that consists of 3 tiers to assign nanomaterials to 4 main groups, to perform sub-grouping within the main groups and to determine and refine specific information needs. The DF4nanoGrouping covers all relevant aspects of a nanomaterial's life cycle and biological pathways, i.e. intrinsic material and system-dependent properties, biopersistence, uptake and biodistribution, cellular and apical toxic effects. Use (including manufacture), release and route of exposure are applied as 'qualifiers' within the DF4nanoGrouping to determine if, e.g. nanomaterials cannot be released from a product matrix, which may justify the waiving of testing. The four main groups encompass (1) soluble nanomaterials, (2) biopersistent high aspect ratio nanomaterials, (3) passive nanomaterials, and (4) active nanomaterials. The DF4nanoGrouping aims to group nanomaterials by their specific mode-of-action that results in an apical toxic effect. This is eventually directed by a nanomaterial's intrinsic properties. However, since the exact correlation of intrinsic material properties and apical toxic effect is not yet established, the DF4nanoGrouping uses the 'functionality' of nanomaterials for grouping rather than relying on intrinsic material properties alone. Such functionalities include system-dependent material properties (such as dissolution rate in biologically relevant media), bio-physical interactions, in vitro effects and release and exposure. The DF4nanoGrouping is a hazard and risk assessment tool that applies modern toxicology and contributes to the sustainable development of nanotechnological products. It ensures that no studies are performed that do not provide crucial data and therefore saves animals and resources.

A critical appraisal of existing concepts for the grouping of nanomaterials.

The grouping of substances serves to streamline testing for regulatory purposes. General grouping approaches for chemicals have been implemented in, e.g., the EU chemicals regulation. While specific regulatory frameworks for the grouping of nanomaterials are unavailable, this topic is addressed in different publications, and preliminary guidance is provided in the context of substance-related legislation or the occupational setting. The European Centre for Ecotoxicology and Toxicology of Chemicals Task Force on the Grouping of Nanomaterials reviewed available concepts for the grouping of nanomaterials for human health risk assessment. In their broad conceptual design, the evaluated approaches are consistent or complement each other. All go beyond the determination of mere structure-activity relationships and are founded on different aspects of the nanomaterial life cycle. These include the NM's material properties and biophysical interactions, specific types of use and exposure, uptake and kinetics, and possible early and apical biological effects. None of the evaluated grouping concepts fully take into account all of these aspects. Subsequent work of the Task Force will aim at combining the available concepts into a comprehensive 'multiple perspective' framework for the grouping of nanomaterials that will address all of the mentioned aspects of their life cycles.

Are we in the dark ages of environmental toxicology?

Environmental toxicity is judged to be in a "dark ages" period due to longstanding limitations in the implementation of the simple conceptual model that is the basis of current aquatic toxicity testing protocols. Fortunately, the environmental regulatory revolution of the last half-century is not substantially compromised as development of past regulatory guidance was designed to deal with limited amounts of relatively poor quality toxicity data. However, as regulatory objectives have substantially increased in breadth and depth, aquatic toxicity data derived with old testing methods are no longer adequate. In the near-term explicit model description and routine assumption validation should be mandatory. Updated testing methods could provide some improvements in toxicological data quality. A thorough reevaluation of toxicity testing objectives and methods resulting in substantially revised standard testing methods, plus a comprehensive scheme for classification of modes/mechanisms of toxic action, should be the long-term objective.

Worldwide regulatory guidance values for surface soil exposure to noncarcinogenic polycyclic aromatic hydrocarbons.

Regulatory guidance values are used worldwide to control residential exposures to surface soil contamination. A total of 1791 values used in 39 nations to control exposures to eight polycyclic aromatic hydrocarbons (PAH) not normally considered to be carcinogenic (acenaphthene, acenaphthylene, anthracene, benzo(g,h,i)perylene, fluroanthene, fluorene, phenanthrene and pyrene) are examined. The guidance values vary over 5.8 to 8.3 orders of magnitude and have distributions that strongly resemble distributions of lognormal random variables. Where the U.S. Environmental Protection Agency (USEPA) has provided values, they fall near the upper end of the distributions and appear to exert influence on values from other U.S. jurisdictions. Approximately 84% of all U.S. values fall above a median PAH value. Uncertainty bounds approximated from the USEPA risk model encompass 28% of the regulatory values and these are predominantly from U.S. jurisdictions. An unusually high degree of toxicology data uncertainty for these PAH appears to be a significant factor influencing variability. The USEPA assigns its highest toxicology uncertainty factor value of 3000 to these components.

Worldwide regulatory guidance values for surface soil exposure to carcinogenic or mutagenic polycyclic aromatic hydrocarbons.

Regulatory guidance values are used worldwide to control residential exposure to surface soil contamination. A total of 1,991 values used in 44 United Nations member states plus 4 territories or administrative regions to control exposure to seven polycyclic aromatic hydrocarbons (PAH) generally considered to be carcinogenic or mutagenic (benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, dibenzo(a,h)anthracene, chrysene and indeno(1,2,3-c,d)pyrene) are examined. The distributions of these values vary over 6.3-7.2 orders of magnitude and resemble the distributions of lognormal random variables. The U.S. Environmental Protection Agency (USEPA) values fall near the low end of these distributions and exert a modest influence on the values from other U.S. jurisdictions. On average, 17 additional jurisdictions use USEPA values and 21% of all guidance values fall within uncertainty bounds approximated from the USEPA risk model. An average of 62% of U.S. guidance values fall below the median value, but this varies from 43% for chrysene to 70% for dibenz(a,h)anthracene and benzo(a)pyrene. Although the magnitudes of guidance values differ, the ratios of values often reflect the relationships implied by benzo(a)pyrene Toxicity Equivalency Factors (TEFs). This influence is strongest in RGVs from U.S. jurisdictions.

Using mode of action information to improve regulatory decision-making: an ECETOC/ILSI RF/HESI workshop overview.

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), the International Life Sciences Institute (ILSI) Research Foundation (RF), and the ILSI Health and Environmental Sciences Institute (HESI) hosted a workshop in November 2009 to review current practice in the application of mode of action (MOA) considerations in chemical risk assessment. The aim was to provide a rationale for a more general, but flexible approach and to propose steps to facilitate broader uptake and use of the MOA concept. There was consensus amongst the workshop participants that it will require substantial effort and cooperation from the multiple disciplines involved to embrace a common, consistent, and transparent approach. Setting up a repository of accepted MOAs and associated guidance concerning appropriate data to support specific MOAs for critical effects would facilitate categorization of chemicals and allow predictions of toxicity outcomes by read-across. This should in future contribute to the reduction of toxicity testing in animals. The workshop participants also acknowledged the value and importance of human data and the importance of integrating information from biological pathway analyses into current MOA/human relevance frameworks.

Science based guidance for the assessment of endocrine disrupting properties of chemicals.

The European legislation on plant protection products (Regulation (EC) No. 1107/2009) and biocides (Directive 98/8/EC), as well as the regulation concerning chemicals (Regulation (EC) No. 1907/2006 'REACH') only support the marketing and use of chemical products on the basis that they do not induce endocrine disruption in humans or non-target species. However, there is currently no agreed guidance on how to identify and evaluate endocrine activity and disruption. Consequently, an ECETOC task force was formed to provide scientific criteria that may be used within the context of these three legislative documents. Specific scientific criteria for the determination of endocrine disrupting properties that integrate information from both regulatory (eco)toxicity studies and mechanistic/screening studies are proposed. These criteria combine the nature of the adverse effects detected in studies which give concern for endocrine toxicity with an understanding of the mode of action of toxicity so that adverse effects can be explained scientifically. The criteria developed are presented in the form of flow charts for assessing relevant effects for both humans and wildlife species. In addition, since not all chemicals with endocrine disrupting properties are of equal hazard, assessment of potency is also proposed to discriminate chemicals of high concern from those of lower concern. The guidance presented in this paper includes refinements made to an initial proposal following discussion of the criteria at a workshop of invited regulatory, academic and industry scientists.

Rationale and decision rules behind the ECETOC NanoApp to support registration of sets of similar nanoforms within REACH.

New registration requirements for nanomaterials under REACH consider the possibility to form 'sets of similar nanoforms' for a joined human health and environmental hazard, exposure and risk assessment. We developed a tool to create and justify sets of similar nanoforms and to ensure that each of the nanoforms is sufficiently similar to all other nanoforms. The decision logic is following the ECHA guidance in a transparent and evidence-based manner. For each two nanoforms the properties under consideration are compared and corresponding thresholds for maximal differences are proposed. In tier1, similarity is assessed based on intrinsic properties that mostly correspond to those required for nanoform identification under REACH: composition, impurities/additives, size, crystallinity, shape and surface treatment. Moreover, potential differences in the agglomeration/aggregation state resulting from different production processes are considered. If nanoforms were not sufficiently similar based on tier1 criteria, additional data from functional assays are required in tier2. In rare cases, additional short-term in vivo rodent data could be required in a third tier. Data required by tier 2 are triggered by the intrinsic properties in the first tier that did not match the similarity criteria. Most often this will be data on dissolution and surface reactivity followed by in vitro toxicity, dispersion stability, dustiness. Out of several nanoforms given by the user, the tool concludes which nanoforms could be justified to be in the same set and which nanoforms are outside. It defines the boundaries of sets of similar nanoforms and generates a justification for the REACH registration.

Toxicity assessment and public policies: an urgent need for research.

The new European regulation on chemicals triggers a huge number of new testing. However, more than 2 years after the enforcement of this policy, toxicity assessment and risk assessment are still using single species tests that deliver little information. As it is often the case, the link between science and policy seems to be disrupted. However, policy makers need more than ever information on the fate and effects of chemicals on living systems. Without relevant knowledge for decision making, the application of the precautionary principle is the only reasonable way to manage risks. It is necessary to develop new risk assessment strategies using the last innovations from biology: the omics tools, ecology, ecosystem modeling, chemistry, and computing. This article highlights some of the recent trends in ecotoxicology and calls for a new research strategy. This strategy implies research to be funded by its users.

[Toxicogenomics in hazard assessment of chemicals]. / Toksykogenomika w ocenie zagrozen substancji chemicznych.

Recent changes in the European legislation of chemicals suggest an urgent need for introduction of novel, alternative methods for testing chemical substances. Such possibility is offered by toxicogenomics--a scientific discipline combining knowledge from the field of toxicology, i.e., a science investigating the properties of toxic agents and the negative effects these agents exert on health and environment, with genomics, i.e., a science investigating the structure and function of genomes. New research strategies within the field of toxicology (transcriptomics, proteomics, metabolomics) offer conditions to assess the hazards associated with the effects of chemicals with both established and suspected toxic potentials.

Key Opportunities to Replace, Reduce, and Refine Regulatory Fish Acute Toxicity Tests.

Fish acute toxicity tests are conducted as part of regulatory hazard identification and risk-assessment packages for industrial chemicals and plant protection products. The aim of these tests is to determine the concentration which would be lethal to 50% of the animals treated. These tests are therefore associated with suffering in the test animals, and Organisation for Economic Co-operation and Development test guideline 203 (fish, acute toxicity) studies are the most widely conducted regulatory vertebrate ecotoxicology tests for prospective chemical safety assessment. There is great scope to apply the 3Rs principles-the reduction, refinement, and replacement of animals-in this area of testing. An expert ecotoxicology working group, led by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research, including members from government, academia, and industry, reviewed global fish acute test data requirements for the major chemical sectors. The present study highlights ongoing initiatives and provides an overview of the key challenges and opportunities associated with replacing, reducing, and/or refining fish acute toxicity studies-without compromising environmental protection. Environ Toxicol Chem 2020;39:2076-2089. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Critical Review of Read-Across Potential in Testing for Endocrine-Related Effects in Vertebrate Ecological Receptors.

Recent regulatory testing programs have been designed to evaluate whether a chemical has the potential to interact with the endocrine system and could cause adverse effects. Some endocrine pathways are highly conserved among vertebrates, providing a potential to extrapolate data generated for one vertebrate taxonomic group to others (i.e., biological read-across). To assess the potential for biological read-across, we reviewed tools and approaches that support species extrapolation for fish, amphibians, birds, and reptiles. For each of the estrogen, androgen, thyroid, and steroidogenesis (EATS) pathways, we considered the pathway conservation across species and the responses of endocrine-sensitive endpoints. The available data show a high degree of confidence in the conservation of the hypothalamus-pituitary-gonadal axis between fish and mammals and the hypothalamus-pituitary-thyroid axis between amphibians and mammals. Comparatively, there is less empirical evidence for the conservation of other EATS pathways between other taxonomic groups, but this may be due to limited data. Although more information on sensitive pathways and endpoints would be useful, current developments in the use of molecular target sequencing similarity tools and thoughtful application of the adverse outcome pathway concept show promise for further advancement of read-across approaches for testing EATS pathways in vertebrate ecological receptors. Environ Toxicol Chem 2020;39:739-753. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

The stereoisomerism of second generation anticoagulant rodenticides: a way to improve this class of molecules to meet the requirements of society?

Second generation anticoagulant rodenticides (SGAR) are generally highly efficient for rodent management even towards warfarin-resistant rodents. Nevertheless, because of their long tissue-persistence, they are very associated with non-target exposure of wildlife and have been identified as 'Candidates for Substitution' by the European Union's competent authority. A promising way to reduce ecotoxicity issues associated to SGAR could be the improvement of SGAR based on their stereoisomery, and due to this improvement, positioning about SGAR might be reconsidered. © 2018 Society of Chemical Industry.

Predictive models in ecotoxicology: Bridging the gap between scientific progress and regulatory applicability-Remarks and research needs.

This paper concludes a special series of 7 articles (4 on toxicokinetic-toxicodynamic [TK-TD] models and 3 on quantitative structure-activity relationship [QSAR] models) published in previous issues of Integrated Environmental Assessment and Management (IEAM). The present paper summarizes the special series articles and highlights their contribution to the topic of increasing the regulatory applicability of effect models. For both TK-TD and QSAR approaches, we then describe the main research needs. The use of TK-TD models for describing sublethal effects must be better developed, particularly through the improvement of the dynamic energy budget (DEBtox) approach. The potential of TK-TD models for moving from lower (molecular) to higher (population) hierarchical levels is highlighted as a promising research line. Some relevant issues to improve the acceptance of QSAR models at the regulatory level are also described, such as increased transparency of the performance assessment and of the modeling algorithms, model documentation, relevance of the chosen target for regulatory needs, and improved mechanistic interpretability. Integr Environ Assess Manag 2019;00:000-000. © 2019 SETAC.

Prioritization of substances for national ambient monitoring of sediment in Switzerland.

In Switzerland, surface waters are protected by the Swiss Water Protection Ordinance (OEaux; OFEV 1998), which stipulates that the water quality shall be such that the water, suspended matter, and sediments contain no persistent synthetic substances to ensure the protection of aquatic life. Local agencies are in charge of water quality monitoring, using a set of validated methods. Several lists of priority substances have been developed for aquatic microcontaminants for surface water monitoring but not for sediments. Some local agencies have established sediment monitoring programs, but to date, there exists no harmonized methodology for sediment quality assessment in Switzerland. Within the main goal of developing and providing methodologies for monitoring sediment quality in Switzerland, a screening was performed to help prioritize sediment-relevant microcontaminants. The screening approach was largely based on the NORMAN (network of reference laboratories, research centers, and related organizations for monitoring emerging environmental substances) system and was carried out in four steps: (1) identification of candidate substances, (2) selection of sediment relevant substances, (3) classification of substances into different categories based on identified data gaps and envisaged actions, and (4) ranking within each action category. This paper describes the methodology used in the prioritization process for sediment-relevant substances and provides recommendations for monitoring strategies in Switzerland.

Parameters for assessing the aquatic environmental impact of cosmetic products.

The cosmetic industry's growing concern about the impact of its supply chain on the environment, sustainability of raw materials, and biodiversity increases the need to ensure that the final product has a lower environmental impact. The objective of this review is to summarize and compare the information available from international organizations and legislation regarding the main criteria used to assess raw materials for aquatic toxicity, as well as the most suitable alternative methods for obtaining assessment parameters. Using the literature available in databases, a review of the scientific literature and international legislation, this work discusses and compares the parameters established by international organizations such as the Environmental Protection Agency (EPA) and Cradle to Cradle (C2C), as well as European legislation, namely, European Regulation 1272/2008, for assessing environmental impact. Defining the ecotoxicity parameters of the main classes of raw materials in rinse-off cosmetic products can enable the development of products that are more environmentally sustainable, prioritizing substances with less environmental impact.