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The toxicity and ecotoxicity of pesticide active ingredients are evaluated by a number of standardized test methods using vertebrate animals. These standard test methods are required under various regulatory programs for the registration of pesticides. Over the past two decades, additional test methods have been developed with endpoints that are responsive to endocrine activity and subsequent adverse effects. This article examines the available test methods and their endpoints that are relevant to an assessment of endocrine‐disrupting properties of pesticides. Furthermore, the article highlights how weight‐of‐evidence approaches should be applied to determine whether an adverse response in (eco)toxicity tests is caused by an endocrine mechanism of action. The large number of endpoints in the current testing paradigms for pesticides make it unlikely that endocrine activity and adversity is being overlooked. Integr Environ Assess Manag 2023;19:1089–1109. © 2023 Bayer CropScience and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Key Points: Current testing paradigms for pesticides include numerous endpoints addressing endocrine activity and adversity.A weight‐of‐evidence evaluation of test results is essential to assessing potential endocrine activity and/or adverse effects resulting from endocrine activity.The large number of endpoints in the current testing paradigms for pesticides make it unlikely that endocrine activity and adversity is being overlooked. [ABSTRACT FROM AUTHOR]

In order to protect European Union (EU) drinking water resources from chemical contamination, criteria for identifying persistent, mobile, and toxic (PMT) chemicals and very persistent and very mobile (vPvM) chemicals under the EU REACH Regulation were proposed by the German Environment Agency (Umweltbundesamt—UBA). Additionally, new hazard classes for PMT and vPvM substances in the revised EU classification, labeling, and packaging (CLP Regulation) are intended. Therefore, a reliable approach in the identification of potential drinking water resource contaminants is needed. The scientific basis of the property‐based PMT/vPvM criteria, focusing on mobility, which dictates the migration of chemical drinking water sources, was evaluated, and a critical analysis of the deviation of sorption metrics from simple behavior was carried out. Based on our evaluation, a Koc may be used for nonionic substances on a screening level only, requiring a higher tier assessment. It is considered inappropriate for hydrophilic and ionizable chemicals, particularly for soils with low organic carbon contents. The nonextractable residue formation is complex and not well understood but remains significant in limiting the mobility of chemicals through soils and sediments. In order to inform the EU commission's work on the introduction of new hazard classes for PMT and vPvM substances into the European legislation, the derivation of a tiered approach is proposed, which utilizes the weight of evidence available, with adoption of appropriate higher tier models commensurate with the nature of the substance and the data available. Integr Environ Assess Manag 2023;19:775–791. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Key Points: A Koc may be used for nonionic substances on a screening level only, requiring a higher tier assessment.The log Koc is considered inappropriate for hydrophilic and ionizable chemicals, particularly for soils with low organic carbon contents.Therefore, for the introduction of new hazard classes for PMT/vPvM substances into CLP, the derivation of a tiered approach is proposed, which utilizes the weight of evidence available, with adoption of appropriate higher tier models commensurate the nature of the substance and the data available. [ABSTRACT FROM AUTHOR]

Many regulations are beginning to explicitly require investigation of a chemical's endocrine‐disrupting properties as a part of the safety assessment process for substances already on or about to be placed on the market. Different jurisdictions are applying distinct approaches. However, all share a common theme requiring testing for endocrine activity and adverse effects, typically involving in vitro and in vivo assays on selected endocrine pathways. For ecotoxicological evaluation, in vivo assays can be performed across various animal species, including mammals, amphibians, and fish. Results indicating activity (i.e., that a test substance may interact with the endocrine system) from in vivo screens usually trigger further higher‐tier in vivo assays. Higher‐tier assays provide data on adverse effects on relevant endpoints over more extensive parts of the organism's life cycle. Both in vivo screening and higher‐tier assays are animal‐ and resource‐intensive and can be technically challenging to conduct. Testing large numbers of chemicals will inevitably result in the use of large numbers of animals, contradicting stipulations set out within many regulatory frameworks that animal studies be conducted as a last resort. Improved strategies are urgently required. In February 2020, the UK's National Centre for the 3Rs and the Health and Environmental Sciences Institute hosted a workshop ("Investigating Endocrine Disrupting Properties in Fish and Amphibians: Opportunities to Apply the 3Rs"). Over 50 delegates attended from North America and Europe, across academia, laboratories, and consultancies, regulatory agencies, and industry. Challenges and opportunities in applying refinement and reduction approaches within the current animal test guidelines were discussed, and utilization of replacement and/or new approach methodologies, including in silico, in vitro, and embryo models, was explored. Efforts and activities needed to enable application of 3Rs approaches in practice were also identified. This article provides an overview of the workshop discussions and sets priority areas for follow‐up. Integr Environ Assess Manag 2022;18:442–458. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). KEY POINTS: In vivo screening and higher‐tier assays to evaluate a chemical's potential endocrine‐disrupting properties and potential impacts on ecosystems are animal‐ and resource‐intensive and can be technically challenging to conduct.There has been much recent work to develop new approach methodologies (NAMs)—in silico and in vitro approaches—that can be applied in this space.An understanding of the opportunities and challenges with the current in vivo approaches, coupled with the ongoing efforts to expand the development, use, and application of NAMs, will help focus short‐ and long‐term goals.International, multisector science‐based activities provide the framework to improve ecological safety as it relates to compounds with endocrine‐disrupting properties. [ABSTRACT FROM AUTHOR]

The adverse outcome pathway (AOP) concept was developed to describe the linkage of events starting with chemical exposure to an apical effect, across levels of biological organization. In an AOP, the MIE is causally related to the AO through a series of key events (KEs) linked by key-event relationships (KERs). [Extracted from the article]

The European Commission intends to protect vertebrate wildlife populations by regulating plant protection product (PPP) active substances that have endocrine‐disrupting properties with a hazard‐based approach. In this paper we consider how the Commission's hazard‐based regulation and accompanying guidance can be operationalized to ensure that a technically robust process is used to distinguish between substances with adverse population‐level effects and those for which it can be demonstrated that adverse effects observed (typically in the laboratory) do not translate into adverse effects at the population level. Our approach is to use population models within the adverse outcome pathway framework to link the nonlinear relationship between adverse effects at the individual and population levels in the following way: (1) use specific protection goals for focal wildlife populations within an ecosystem services framework; (2) model the effects of changes in population‐related inputs on focal species populations with individual‐based population models to determine thresholds between negligible and nonnegligible (i.e., adverse) population‐level effects; (3) compare these thresholds with the relevant endpoints from laboratory toxicity tests to determine whether they are likely to be exceeded at hazard‐based limits or the maximum tolerated dose/concentration from the experimental studies. If the population threshold is not exceeded, then the substance should not be classified as an endocrine disruptor with population‐relevant adversity unless there are other lines of evidence within a weight‐of‐evidence approach to challenge this. We believe this approach is scientifically robust and still addresses the political and legal requirement for a hazard‐based assessment. Integr Environ Assess Manag 2019;15:278–291. © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC) Key Points: In this paper we consider how the European Commission's hazard‐based Plant Protection Product Regulation can be operationalized to distinguish between substances with adverse population‐level effects and those for which observed adverse effects do not translate into adverse population‐level effects.Our approach is to use population models within the adverse outcome pathways framework to link the nonlinear relationship between adverse effects at the individual and population levels.Only if the population threshold is exceeded should the active substance be classified as an endocrine disruptor with population‐relevant adversity, unless this classification is challenged by other lines of evidence (e.g., from field studies) within a weight‐of‐evidence approach.We believe this approach is scientifically robust and addresses the political and legal requirement for a hazard‐based assessment. [ABSTRACT FROM AUTHOR]

Globally, chemical hazard and risk assessments rely on the results of vertebrate toxicity tests. Interspecies correlation estimation models for aquatic species have been developed from data collected for whole organisms through standardized toxicity tests, with reported test methods, exposure durations, and endpoints. [Extracted from the article]

The article explores several factors to consider in determining laboratory studies' population relevance in assessing wildlife population stability as a protection goal in exotoxicology. Topics include the need to ensure the stability of wildlife populations, the use of laboratory studies in ecological risk assessment, and the population relevance of an endpoint. Also discussed are the developments in predictive ecotoxicology and adverse outcome pathways.

ABSTRACT Regulatory policies in many parts of the world recognize either the utility of or the mandate that all available studies be considered in environmental or ecological hazard and risk assessment (ERA) of chemicals, including studies from the peer-reviewed literature. Consequently, a vast array of different studies and data types need to be considered. The first steps in the evaluation process involve determining whether the study is relevant to the ERA and sufficiently reliable. Relevance evaluation is typically performed using existing guidance but involves application of 'expert judgment' by risk assessors. In the present paper, we review published guidance for relevance evaluation and, on the basis of the practical experience within the group of authors, we identify additional aspects and further develop already proposed aspects that should be considered when conducting a relevance assessment for ecotoxicological studies. From a regulatory point of view, the overarching key aspect of relevance concerns the ability to directly or indirectly use the study in ERA with the purpose of addressing specific protection goals and ultimately regulatory decision making. Because ERA schemes are based on the appropriate linking of exposure and effect estimates, important features of ecotoxicological studies relate to exposure relevance and biological relevance. Exposure relevance addresses the representativeness of the test substance, environmental exposure media, and exposure regime. Biological relevance deals with the environmental significance of the test organism and the endpoints selected, the ecological realism of the test conditions simulated in the study, as well as a mechanistic link of treatment-related effects for endpoints to the protection goal identified in the ERA. In addition, uncertainties associated with relevance should be considered in the assessment. A systematic and transparent assessment of relevance is needed for regulatory decision making. The relevance aspects also need to be considered by scientists when designing, performing, and reporting ecotoxicological studies to facilitate their use in ERA. Integr Environ Assess Manag 2017;13:652-663. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC) [ABSTRACT FROM AUTHOR]

ABSTRACT Endocrine-disrupting substances (EDS) may have certain biological effects including delayed effects, multigenerational effects, and may display nonmonotonic dose-response (NMDR) relationships that require careful consideration when determining environmental hazards. Endocrine disrupting substances can have specific and profound effects when exposure occurs during sensitive windows of the life cycle (development, reproduction). This creates the potential for delayed effects that manifest when exposure has ceased, possibly in a different life stage. This potential underscores the need for testing in appropriate (sensitive) life stages and full life cycle designs. Such tests are available in the Organisation for Economic Co-operation and Development (OECD) tool box and should be used to derive endpoints that can be considered protective of all life stages. Similarly, the potential for effects to be manifest in subsequent generations (multigenerational effects) has also been raised as a potential issue in the derivation of appropriate endpoints for EDS. However, multigenerational studies showing increasing sensitivity of successive generations are uncommon. Indeed this is reflected in the design of new higher tier tests to assess endocrine active substances (EAS) that move to extended one-generation designs and away from multi-generational studies. The occurrence of NMDRs is also considered a limiting factor for reliable risk assessment of EDS. Evidence to date indicates NMDRs are more prevalent in in vitro and mechanistic data, not often translating to adverse apical endpoints that would be used in risk assessment. A series of steps to evaluate NMDRs in the context of endocrine hazard and risk assessment procedures is presented. If careful consideration of delayed, multigenerational effects and NMDRs is made, it is feasible to assess environmental endocrine hazards and derive robust apical endpoints for risk assessment procedures ensuring a high level of environmental protection. Integr Environ Assess Manag 2017;13:293-301. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC) [ABSTRACT FROM AUTHOR]

ABSTRACT The ecotoxicity testing of chemicals for prospective environmental safety assessment is an area in which a high number of vertebrates are used across a variety of industry sectors. Refining, reducing, and replacing the use of animals such as fish, birds, and amphibians for this purpose addresses the ethical concerns and the increasing legislative requirements to consider alternative test methods. Members of the UK-based National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) Ecotoxicology Working Group, consisting of representatives from academia, government organizations, and industry, have worked together over the past 6 y to provide evidence bases to support and advance the application of the 3Rs in regulatory ecotoxicity testing. The group recently held a workshop to identify the areas of testing, demands, and drivers that will have an impact on the future of animal use in regulatory ecotoxicology. As a result of these discussions, we have developed a pragmatic approach to prioritize and realistically address key opportunity areas, to enable progress toward the vision of a reduced reliance on the use of animals in this area of testing. This paper summarizes the findings of this exercise and proposes a pragmatic strategy toward our key long-term goals-the incorporation of reliable alternatives to whole-organism testing into regulations and guidance, and a culture shift toward reduced reliance on vertebrate toxicity testing in routine environmental safety assessment. Integr Environ Assess Manag 2016;12:417-421. © 2015 SETAC [ABSTRACT FROM AUTHOR]

The article discusses the examination of chemicals as disruptors to the endocrine glands. Topics discussed include the regulations on plant protection, the change in endocrine function, the practical experiments for endocrine disruptors, and the significance of separating generalized stress endocrine response from direct endocrine interaction.

The article focuses on a research related to reduction in number of fish in bioconcentraion testing and identification of the related barriers. Topics discussed include bioconcentration tests being conducted according to Organization for Economic Co-operation and Development (OECD) guideline, use of 1-concentration approach for the research and amendment of OECD guideline permitting for testing of 1 concentration and guidelines of the U.S. Environmental Protection Agency.

The article offers information on assessment of endocrine disruption effects in vertebrates. Topics discussed include development of a regulation to identify the endocrine- disrupting properties of plant protection products (PPPs) by European Commission; hazard-based risks associated with plants involves restriction of safe products; and impact of PPPs on vertebrates physiology.