Animal poisoning in Europe, part 3: wildlife

This review article is the third in a series on animal poisoning in Europe and represents a collation of published and non-published wildlife poisoning data from Belgium, France, Greece, Italy and Spain over the last 10 years. Birds, particularly waterfowl and raptors, were more commonly reported as victims of poisoning than wild mammals. In addition to specific but important toxicological disasters, deliberate primary or secondary poisonings are of concern to all countries. Metals (particularly lead arising from sporting/hunting activities) and pesticides (mainly anticholinesterases and anticoagulants) are frequent causes of poisoning, and often have fatal consequences. A more unified and consistent approach throughout European countries to improve the reporting and the analytical confirmation of wildlife poisoning would help to reduce the number of cases of malicious or negligent animal poisoning

Strategies to improve the regulatory assessment of Developmental Neurotoxicity (DNT) using in vitro methods

Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing. Since at the regulatory level, systematic testing of DNT is not a standard requirement within the EU or USA chemical legislation safety assessment, DNT testing is only performed in higher tiered testing triggered based on chemical structure activity relationships or evidence of neurotoxicity in systemic acute or repeated dose toxicity studies. However, these triggers are rarely used and, in addition, do not always serve as reliable indicators of DNT, as they are generally based on observations in adult rodents. Therefore, there is a pressing need for developing alternative methodologies that can reliably support identification of DNT triggers, and more rapidly and cost-effectively support the identification and characterization of chemicals with DNT potential. We propose to incorporate mechanistic knowledge and data derived from in vitro studies to support various regulatory applications including: (a) the identification of potential DNT triggers, (b) initial chemical screening and prioritization, (c) hazard identification and characterization, (d) chemical biological grouping, and (e) assessment of exposure to chemical mixtures. Ideally, currently available cellular neuronal/glial models derived from human induced pluripotent stem cells (hiPSCs) should be used as they allow evaluation of chemical impacts on key neurodevelopmental processes, by reproducing different windows of exposure during human brain development. A battery of DNT in vitro test methods derived from hiPSCs could generate valuable mechanistic data, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential.JRC.F.3-Chemicals Safety and Alternative Method

Animal poisoning in Europe, part 1: farm livestock and poultry

The lack of a reference Veterinary Poison Control Centre for the European Union (EU) means that clinicians find it difficult to obtain information on poisoning episodes. This three-part review collates published and unpublished data obtained from Belgium, France, Greece, Italy and Spain over the last decade in order to provide a broader toxicoepidemiological perspective. The first article critically evaluates the national situation in the five European countries and concludes that information for livestock and poultry is limited and fragmentary compared to other animal groups. The analysis has revealed that clinical cases of poisoning are only occasionally studied in depth and that cattle are the species most frequently reported. Several plants and mycotoxins, a few pesticides and metals, together with contaminants of industrial origin, such as dioxins, are responsible for most of the recorded cases

Animal poisoning in Europe, part 2: companion animals

This is the second in a series of three review articles on animal poisoning in Europe and focuses on cases in pet animals and horses in five European countries (Belgium, France, Greece, Italy and Spain) reported over the last decade. In the participating countries, dogs were the most commonly poisoned species, particularly younger animals. The majority of cases in companion animals resulted from exposure to insecticides, although rodenticides (especially anticoagulants and strychnine) posed a significant risk. In all five countries, horses and cats appeared to be more susceptible to plant toxins. Intoxications with herbicides, metals, household products and drugs for veterinary and human use were reported sporadically. The review demonstrates the importance of increased awareness so as to minimise poisoning episodes and emphasises the need to establish a European system for the recording of poisoning data

International regulatory and scientific effort for improved developmental neurotoxicity testing

The Organisation for Economic Co-operation and Development (OECD) coordinates international efforts to enhance developmental neurotoxicity (DNT) testing. In most regulatory sectors, including the ones dealing with pesticides and industrial chemicals registration, historical use of the in vivo DNT test guideline has been limited. Current challenges include a lack of DNT data for a number of chemicals, lack of mechanistic information, and difficulty in interpreting results. A series of workshops in the last decade has paved the way for a consensus among stakeholders that there is need for a DNT testing battery that relies on in vitro methods and is complemented by alternative species assays. Preferably, a battery of in vitro and alternative assays should be anchored towards mechanistic relevance for applying an integrated approach for testing and assessment (IATA) framework. Specific activities have been initiated to facilitate this OECD project: the collation of available DNT in vitro methods and their scoring for readiness; the selection of these methods to form a DNT testing battery; the generation of a reference set of chemicals that will be tested using the battery; the case studies exemplifying how DNT in vitro data can be interpreted; and the development of an OECD guidance document. This manuscript highlights these international efforts and activities.JRC.F.3-Chemicals Safety and Alternative Method

t4 Workshop Report Recommendation on test readiness criteria for new approach methods in toxicology: exemplified for developmental neurotoxicity

Multiple non animal-based test methods have never been formally validated. In order to use such new approach methods (NAM) in a regulatory context, a process and criteria to define the readiness of the NAM would be useful. The field of neurodevelopmental toxicity (DNT) testing has been chosen here to exemplify the application of readiness criteria. The number of chemicals not tested, and the testing cost per chemical are overwhelming for DNT. Thus, there is a need for low-cost, high-throughput NAM approaches, to obtain initial information on potential hazard, and to allow prioritization for further testing. We give here a background on the regulatory and scientific status of DNT testing, to show that different types of test readiness levels are required, depending on the intended use of the data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAM with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggested that several assays reached high readiness levels. Therefore, suggestions were made on how DNT NAM may be assembled to an integrated approach to testing and assessment (IATA). In parallel, an overview of the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision was presented on how further NAM development may be guided by knowledge of signaling pathways necessary for normal brain development, DNT pathophysiology, and relevant adverse outcome pathways.JRC.F.3-Chemicals Safety and Alternative Method

Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes.

This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes.JRC.F.3-Chemicals Safety and Alternative Method

Finding Synergies for 3Rs – Toxicokinetics and Read-Across: Report from an EPAA Partners’ Forum

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners’ Forum Toxicokinetics and Read-Across to provide an overview on research activities to develop in vitro toxicokinetics methods and physiologically-based kinetic (PBK) models and to find synergies to enhance use of toxicokinetic data to strengthen read-across. In certain sectors, PBK modelling is being used for risk assessment, but less so in others. An important hurdle to PBK modelling is a lack of toxicokinetic data. Preferably, toxicokinetic data should be generated using in vitro and in silico tools and anchored towards human relevance. Specific activities were identified to facilitate the use of in vitro and in silico toxicokinetic data to support read-across: The collation of available tools indicating the parameters and applicability domains covered; endpoint-specific guidance on toxicokinetic parameters required for read-across; case studies exemplifying how toxicokinetics data help support read-across. Activities to enhance the scientific robustness of read-across include the further user-friendly combination of read-across tools; and formal guidance by the authorities specifying the minimum information requirements to justify read-across for a given toxicity endpoint. The EPAA was invited to continue dissemination activities and to explore possibilities to create a database of toxicokinetic tools that assist risk assessment.JRC.F.3-Chemicals Safety and Alternative Method

Finding Synergies for 3Rs – Toxicokinetics and Read-Across: Report from an EPAA Partners’ Forum

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners’ Forum Toxicokinetics and Read-Across to provide an overview on research activities to develop in vitro toxicokinetics methods and physiologically-based kinetic (PBK) models and to find synergies to enhance use of toxicokinetic data to strengthen read-across. In certain sectors, PBK modelling is being used for risk assessment, but less so in others. An important hurdle to PBK modelling is a lack of toxicokinetic data. Preferably, toxicokinetic data should be generated using in vitro and in silico tools and anchored towards human relevance. Specific activities were identified to facilitate the use of in vitro and in silico toxicokinetic data to support read-across: The collation of available tools indicating the parameters and applicability domains covered; endpoint-specific guidance on toxicokinetic parameters required for read-across; case studies exemplifying how toxicokinetics data help support read-across. Activities to enhance the scientific robustness of read-across include the further user-friendly combination of read-across tools; and formal guidance by the authorities specifying the minimum information requirements to justify read-across for a given toxicity endpoint. The EPAA was invited to continue dissemination activities and to explore possibilities to create a database of toxicokinetic tools that assist risk assessment.JRC.F.3-Chemicals Safety and Alternative Method