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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)., (© 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

To use and implement an assessment scheme for the evaluation of endocrine disrupting properties of chemicals in ecotoxicology, the types of effect need to be agreed. Effects that merit further consideration in this context should fulfil the following three criteria: caused by an endocrine mode of action, be adverse, and be relevant at the population level to reflect the protection goal of ecotoxicological assessments. Thereafter, a comparison of effect values, regardless of the causative mechanisms, should be made, firstly to determine if endocrine toxicity generates the lowest endpoint within a taxon, and secondly if it is the lowest endpoint compared to that of other taxa living in the same compartment. These comparisons inform on two levels of specificity and determine if endocrine-mediated side-effects determine the ecotoxicological profile of a chemical. Various quantitative measures for the assessment of potency are also presented, which could assist in determining how to handle substances in the risk assessment when a regulatory concern is identified. Finally, derogation criteria should be defined for compounds that were designed as endocrine disruptors for non-vertebrates and those for which there is 'negligible exposure'. This paper discusses and provides proposals on how to apply these concepts for assessment of substances., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Amphibians are currently considered to be covered by pesticide Environmental Risk Assessment schemes by surrogacy assumptions of exposure and susceptibility based on typical laboratory test species such as fish, mammals, and birds. While multiple reviews have shown for this approach to be adequate in the case of aquatic stages, the same cannot be definitively stated for terrestrial stages. Concerns have risen that exposure of amphibians is likely to be highly influenced by dermal absorption, primarily due to the high permeability of their skin and the lack of a protective layer, such as fur or feathers. It is thus hypothesized that dermal uptake could be a significant route of exposure. Consequently, it is necessary to determine the relative importance of different exposure routes that might affect the integrated toxicity outcome for terrestrial amphibian life-stages. Here, a one-compartment Toxicokinetic model was derived and tested using a publicly available dataset containing relevant exposure and uptake information for juvenile anurans exposed to 13 different pesticides. Modelled body burdens were then compared to measured burdens for a total of 815 individuals. Overall, a good concordance between modelled and measured values was observed, with the predicted and measured body burdens differing by a factor of 2 on average (overall R2 of 0.80 and correlation coefficient of 0.89), suggesting good predictivity of the model. Accordingly, the model predicts realistic body burdens for a variety of frog and toad species, and overall, for anurans. As the model includes rehydration (implicit in the evaluated studies) but currently does not account for metabolism, it can be seen as a worst-case assessment. We suggest toxicokinetic models, such as the one here presented, could be used to characterize dermal exposure in amphibians, screen for pesticides of concern, and prioritize risk assessment efforts, whilst reducing the need for de novo vertebrate testing. [Display omitted] • A one compartment Toxicokinetic (TK) model is described for anurans. • The model allows to extrapolate body burdens after exposure to contaminated soil. • On average, model predictions deviated from measured data by a factor of 2. • Only in 1% of cases, estimates underestimated exposure by > 10x compared to measured data. • The model could be used to reduce the need de novo vertebrate testing. [ABSTRACT FROM AUTHOR]

An important goal in toxicology is the development of new ways to increase the speed, accuracy, and applicability of chemical hazard and risk assessment approaches. A promising route is the integration of in vitro assays with biological pathway information. We examined how the adverse outcome pathway (AOP) framework can be used to develop pathway‐based quantitative models useful for regulatory chemical safety assessment. By using AOPs as initial conceptual models and the AOP knowledge base as a source of data on key event relationships, different methods can be applied to develop computational quantitative AOP models (qAOPs) relevant for decision making. A qAOP model may not necessarily have the same structure as the AOP it is based on. Useful AOP modeling methods range from statistical, Bayesian networks, regression, and ordinary differential equations to individual‐based models and should be chosen according to the questions being asked and the data available. We discuss the need for toxicokinetic models to provide linkages between exposure and qAOPs, to extrapolate from in vitro to in vivo, and to extrapolate across species. Finally, we identify best practices for modeling and model building and the necessity for transparent and comprehensive documentation to gain confidence in the use of qAOP models and ultimately their use in regulatory applications. Environ Toxicol Chem 2019;38:1850–1865. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. [ABSTRACT FROM AUTHOR]

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.

Endocrine screening assays not only provide mechanistic information on the potential of a substance to interact with the endocrine system, but also data potentially relevant for risk assessment. However, these screening assays have a number of limitations that should be considered before the direct use of such data for risk assessment purposes. This paper discusses the limitations that should be considered for both human and environmental risk assessment. A proposal is made to provide an objective and transparent process in order to consider which endpoint(s) might be incorporated into a risk assessment, and when more definitive studies may be of value. The proposal is complemented with an easy-to-follow flowchart to aid industry scientists and regulators when evaluating the relevance of these data. Such an approach is necessary to ensure the appropriate use of screening data to further our understanding of the eco/toxicological profile of substances undergoing screening. [ABSTRACT FROM AUTHOR]

The relative sensitivity of amphibians to chemicals in the environment, including plant protection product active substances, is the subject of ongoing scientific debate. The objective of this study was to compare systematically the relative sensitivity of amphibians and fish to chemicals. Acute and chronic toxicity data were obtained from the U.S. Environmental Protection Agency (U.S. EPA) ECOTOX database and were supplemented with data from the scientific and regulatory literature. The overall outcome is that fish and amphibian toxicity data are highly correlated and that fish are more sensitive (both acute and chronic) than amphibians. In terms of acute sensitivity, amphibians were between 10- and 100-fold more sensitive than fish for only four of 55 chemicals and more than 100-fold more sensitive for only two chemicals. However, a detailed inspection of these cases showed a similar acute sensitivity of fish and amphibians. Chronic toxicity data for fish were available for 52 chemicals. Amphibians were between 10- and 100-fold more sensitive than fish for only two substances (carbaryl and dexamethasone) and greater than 100-fold more sensitive for only a single chemical (sodium perchlorate). The comparison for carbaryl was subsequently determined to be unreliable and that for sodium perchlorate is a potential artifact of the exposure medium. Only a substance such as dexamethasone, which interferes with a specific aspect of amphibian metamorphosis, might not be detected using fish tests. However, several other compounds known to influence amphibian metamorphosis were included in the analysis, and these did not affect amphibians disproportionately. These analyses suggest that additional amphibian testing is not necessary during chemical risk assessment. Environ. Toxicol. Chem. 2013;32:984-994. © 2013 SETAC [ABSTRACT FROM AUTHOR]

There is generally a lack of saltwater ecotoxicity data for risk assessment purposes, leaving an unknown margin of uncertainty in saltwater assessments that utilize surrogate freshwater data. Consequently, a need for sound scientific advice on the suitability of using freshwater data to extrapolate to saltwater effects exists. Here we use species sensitivity distributions to determine if freshwater datasets are adequately protective of saltwater species assemblages for 21 chemical substances. For ammonia and the metal compounds among these data, freshwater data were generally protective because freshwater organisms tended to be more sensitive. In contrast, for pesticide and narcotic compounds, saltwater species tended to be more sensitive and a suitable uncertainty factor would need to be applied to surrogate freshwater data. Biological and physicochemical factors contribute to such differences in freshwater and saltwater species sensitivities, but the species compositions of datasets used are also important. [ABSTRACT FROM AUTHOR]

The use of the water-accommodated fraction (WAF) approach for the preparation of exposure systems of complex substances such as petroleum products has been a standard way to perform aquatic toxicity tests on these substances for over 30 years. In this Commentary, we briefly describe the historical development, rationale, and guidance for the use and reporting of the WAF approach to assess complex substances. We then discuss two case studies, with coal tar pitch and kerosene/jet fuel, which illustrate challenges from regulatory authorities in Europe and the United States when using the WAF approach. We describe how the WAF approach is the only currently known method for testing the toxicity of the whole of a complex substance, even when some of its constituents remain unknown; it accounts for differences in the solubility of the constituents within a complex substance; and use of loading rates to describe any toxic effects is a unifying concept that allows direct comparison with releases of readily soluble substances in hazard assessment and chemical classification. [ABSTRACT FROM AUTHOR]

Abstract: Ecotoxicity testing of pesticide active ingredients and formulated plant protection products (PPPs) prior to their commercial use is required by authorities around the world. Such studies are important for the conduct of risk assessments to protect wildlife and the environment, but they should only be conducted when their use is scientifically justified. One test of questionable scientific merit is the chronic fish toxicity test when conducted with formulated PPPs, which is a potential requirement under European legislation: chronic exposure to the formulated product per se rarely occurs in the environment and therefore it is generally not possible to use the data from chronic formulation studies in a meaningful risk assessment. A recent survey of European crop protection companies to explore the scientific merits and regulatory drivers for chronic fish toxicity studies has shown that current practice in deciding on the need for chronic fish toxicity testing of formulated PPPs varies substantially between companies. The most commonly cited reason for conducting such studies was solely to meet regulatory requirements. We conclude that chronic formulation testing is rarely if ever scientifically justified, and recommend that the forthcoming revision of the EU Aquatic Toxicology Guidance Document takes account of this by including a requirement that justification must be provided for conducting the test, rather than the current situation where the onus is on the registrant to provide a justification for not conducting the test. [ABSTRACT FROM AUTHOR]