Developing a European network of analytical laboratories and government institutions to prevent poisoning of raptors.

Many cases of wildlife poisoning in Europe have been reported causing population declines, especially in raptors. Toxicovigilance and risk assessment studies are essential to reinforce the knowledge of the number of illegal poisoning cases and the substances involved in these crimes. Many researchers and projects in different institutions have suggested the creation of a network to improve communication and share information between European countries. This article presents the results of the Short-Term Scientific Mission titled "Developing a Network of Analytical Labs and Government Institutions" supported by the COST Action European Raptor Biomonitoring Facility (CA16224), which aims to initiate a network of veterinary forensic toxicology laboratories, in order to improve communication among laboratories to prevent wildlife poisoning, especially in raptors. For this purpose, a questionnaire was designed and sent by email to 119 laboratories in Europe. It contained 39 questions on different topics (e.g. laboratory activities, analytical information). A total of 29 responses were received. Most participant laboratories work on veterinary forensic toxicology research and external cases at the same time, which provides a robust overview of the actual situation in the field. Analytical techniques and data collection methods should be harmonised, and communication between laboratories is encouraged to create a more effective network. The present study established contact between laboratories as an initial step to create a European network and compiled basic data to identify strengths and weaknesses that will help harmonise methodologies across Europe and increase pan-European capacities.

Pharmacokinetics of low-dose methotrexate in horses.

This study aimed to investigate both the pharmacokinetic behavior and tolerance of methotrexate (MTX) in horses to design a specific dosing regimen as a new immunomodulatory drug for long-term treatment. To determine the primary plasma pharmacokinetic variables after single intravenous, subcutaneous or oral administration, six horses were administered 0.3 mg/kg MTX in a crossover design study. After a 10-week washout, MTX was administered subcutaneously to three of the six previously treated horses at a dose of 0.3 mg/kg once per week for 3 months. In both studies, MTX and metabolite concentrations were measured using LC-MS/MS. The absolute bioavailability of MTX was 73% following subcutaneous administration but less than 1% following oral administration. The plasma clearance was 1.54 ml min-1  kg-1 (extraction ratio = 2%). After 24 hr, plasma concentrations were below the LOQ. No adverse effects were noted except for a moderate reversible elevation in liver enzymes (GLDH). With regards to the main metabolites of MTX, very low concentrations of 7-hydroxy-MTX were found, whereas polyglutamated forms (mainly short chains) were found in red blood cells. A subcutaneous dose of 0.2 mg kg-1  week-1 may be safe and relevant in horses, although this has yet to be clinically confirmed.

Pharmacokinetics of low-dose methotrexate in healthy beagle dogs.

Methotrexate may be an alternative to ciclosporin in the treatment of canine atopic dermatitis (cAD) as suggested by recent data. The aim of the study was to investigate both the tolerance and the pharmacokinetic behavior of methotrexate (MTX) in plasma, following intravenous (i.v.), subcutaneous (s.c.) or oral (OR) administration over several weeks. Six healthy dogs were given oral MTX once a week, respectively, per dog at 2.5 mg/1 week, 5 mg/4 weeks, 7.5 mg/3 weeks, 10 mg/6 weeks and 12.5 mg/5 weeks. No clinically relevant abnormalities of laboratory parameters were noticed. A high inter-individual variation of MTX plasma concentration was observed with a suspicion of saturation phenomenon in absorption. To compare with other routes of administration, six healthy beagle dogs followed a crossover design study at 7.5 mg per dog MTX. The absolute bioavailability was 93% for SC injection and 30% for the oral route. The inter-individual variability was quite low following SC administration compared to oral route. Just as in human, given the substantial variability of oral absorption, clinicians cannot assume consistent oral bioavailability of MTX. Therefore, they may consider switching dogs to the SC route in case of absence of clinical response with a weekly oral dose.

Little field evidence of direct acute and short-term effects of current pesticides on the grey partridge.

Direct lethal and sublethal effects of pesticides on farmland birds' populations are recurring questions and largely debated. In this context, we conducted an innovative study combining radiotelemetry, farmer surveys, residue analyses on carcasses and modelling to assess the unintentional effects of pesticides on terrestrial birds. We chose the grey partridge Perdix perdix as a case study because this typical bird of European cereal ecosystems is highly exposed to pesticides. In this paper we focused on acute and short-term impacts of pesticides on adult mortality during spring and summer in a one-substance approach (multiple exposure were not studied here) but for a large variety of active substances (a.s.) actually used in cultivated farmland of Northern France. The fate and the location of 529 partridges were monitored twice a day from early March to late August 2010 and 2011 on 12 sites (14,500 ha). Their daily potential exposure to 183 a.s. was determined by overlapping birds' habitat use and daily pesticide application data. Based on this procedure, we calculated mortality rates within 10 days following a potential exposure for 157 different a.s.. 5 a.s. were associated with a "10-day mortality rate" higher than 10% but a single one (thiacloprid) is reported to be highly toxic to birds. We recorded 261 mortalities among which 94 carcasses were in suitable condition for residue analyses. We detected at least one a.s in 39.4% of carcasses. However, only 2 mortality cases were attributed to poisoning (carbofuran). Furthermore, modelling results showed that these lethal pesticide-related poisonings decreased the population growth rate by less than 1%. In conclusion, we did not point out important direct acute and short-term effects of pesticides currently used by farmers during the breeding season on the grey partridge. This is discussed with regards to the complexity of potential effects in operational conditions.

VIGILANCE POISON: Illegal poisoning and lead intoxication are the main factors affecting avian scavenger survival in the Pyrenees (France).

A specific surveillance program has been set up to monitor avian scavenger populations in the French Pyrenean Mountains, hosting a high proportion of the French populations. The two main purposes of the study were to identify all causes of death and to investigate poisoning cases. All 170 birds found dead during the 7-year program were submitted to full necropsy, X-Ray, parasitological investigations and consistent analytical toxicology screenings (Cholinesterase inhibitors, anticoagulant rodenticides, organochlorine insecticides, Pb, Cd). Over the study period, 8 Bearded Vultures, 120 Griffon Vultures, 8 Egyptian Vultures and 34 Red kites were eventually collected. Mortality events were often multifactorial, but poisoning was by far the most common cause of death (24.1%), followed by trauma/fall (12%), bacterial diseases and starvation (8%) and electrocution (6%). Illicit use of banned pesticides was identified as a common cause of poisoning (53% of all poisoning cases) and lead poisoning was also identified as a significant toxicant issue (17% of all poisoning cases). Lead isotopic signature could be associated primarily with ammunition. Last, a positive association between trauma and lead contamination was detected, indicating that lead could be a significant contributor to different causes of death. These results urge for severe restrictions on the use of lead ammunition to prevent scavengers from detrimental exposure.

Wildlife ecotoxicology of plant protection products: knowns and unknowns about the impacts of currently used pesticides on terrestrial vertebrate biodiversity.

Agricultural practices are a major cause of the current loss of biodiversity. Among postwar agricultural intensification practices, the use of plant protection products (PPPs) might be one of the prominent drivers of the loss of wildlife diversity in agroecosystems. A collective scientific assessment was performed upon the request of the French Ministries responsible for the Environment, for Agriculture and for Research to review the impacts of PPPs on biodiversity and ecosystem services based on the scientific literature. While the effects of legacy banned PPPs on ecosystems and the underlying mechanisms are well documented, the impacts of current use pesticides (CUPs) on biodiversity have rarely been reviewed. Here, we provide an overview of the available knowledge related to the impacts of PPPs, including biopesticides, on terrestrial vertebrates (i.e. herptiles, birds including raptors, bats and small and large mammals). We focused essentially on CUPs and on endpoints at the subindividual, individual, population and community levels, which ultimately linked with effects on biodiversity. We address both direct toxic effects and indirect effects related to ecological processes and review the existing knowledge about wildlife exposure to PPPs. The effects of PPPs on ecological functions and ecosystem services are discussed, as are the aggravating or mitigating factors. Finally, a synthesis of knowns and unknowns is provided, and we identify priorities to fill gaps in knowledge and perspectives for research and wildlife conservation.

Regulatory framework for the assessment of the impacts of plant protection products on biodiversity: review of strengths and limits.

The placing of plant protection products (PPPs) on the market in the European Union is governed by numerous regulations. These regulations are among the most stringent in the world, however they have been the subject of criticisms especially because of the decline in biodiversity. The objectives of this work were to review (1) the functioning and actors involved in the PPP framework processes, (2) the construction of the environmental risk assessment focused on biodiversity, and (3) the suggested ways to respond to the identified limits. Both literature from social sciences and ecotoxicology were examined. Despite the protective nature of the European regulation on PPPs, the very imperfect consideration of biodiversity in the evaluation process was underlined. The main limits are the multiplicity of applicable rules, the routinization of the evaluation procedures, the lack of consideration of social data, and the lack of independence of the evaluation. Strengths of the regulation are the decision to integrate a systemic approach in the evaluation of PPPs, the development of modeling tools, and the phytopharmacovigilance systems. The avenues for improvement concern the realism of the risk assessment (species used, cocktail effects…), a greater transparency and independence in the conduct of evaluations, and the opening of the evaluation and decision-making processes to actors such as beekeepers or NGOs. Truly interdisciplinary reflections crossing the functioning of the living world, its alteration by PPPs, and how these elements question the users of PPPs would allow to specify social actions, public policies, and their regulation to better protect biodiversity.

Wildlife ecological risk assessment in the 21st century: Promising technologies to assess toxicological effects.

Despite advances in toxicity testing and the development of new approach methodologies (NAMs) for hazard assessment, the ecological risk assessment (ERA) framework for terrestrial wildlife (i.e., air-breathing amphibians, reptiles, birds, and mammals) has remained unchanged for decades. While survival, growth, and reproductive endpoints derived from whole-animal toxicity tests are central to hazard assessment, nonstandard measures of biological effects at multiple levels of biological organization (e.g., molecular, cellular, tissue, organ, organism, population, community, ecosystem) have the potential to enhance the relevance of prospective and retrospective wildlife ERAs. Other factors (e.g., indirect effects of contaminants on food supplies and infectious disease processes) are influenced by toxicants at individual, population, and community levels, and need to be factored into chemically based risk assessments to enhance the "eco" component of ERAs. Regulatory and logistical challenges often relegate such nonstandard endpoints and indirect effects to postregistration evaluations of pesticides and industrial chemicals and contaminated site evaluations. While NAMs are being developed, to date, their applications in ERAs focused on wildlife have been limited. No single magic tool or model will address all uncertainties in hazard assessment. Modernizing wildlife ERAs will likely entail combinations of laboratory- and field-derived data at multiple levels of biological organization, knowledge collection solutions (e.g., systematic review, adverse outcome pathway frameworks), and inferential methods that facilitate integrations and risk estimations focused on species, populations, interspecific extrapolations, and ecosystem services modeling, with less dependence on whole-animal data and simple hazard ratios. Integr Environ Assess Manag 2024;20:725-748. © 2023 His Majesty the King in Right of Canada and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Reproduced with the permission of the Minister of Environment and Climate Change Canada. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Toxicological effects assessment for wildlife in the 21st century: Review of current methods and recommendations for a path forward.

Model species (e.g., granivorous gamebirds, waterfowl, passerines, domesticated rodents) have been used for decades in guideline laboratory tests to generate survival, growth, and reproductive data for prospective ecological risk assessments (ERAs) for birds and mammals, while officially adopted risk assessment schemes for amphibians and reptiles do not exist. There are recognized shortcomings of current in vivo methods as well as uncertainty around the extent to which species with different life histories (e.g., terrestrial amphibians, reptiles, bats) than these commonly used models are protected by existing ERA frameworks. Approaches other than validating additional animal models for testing are being developed, but the incorporation of such new approach methodologies (NAMs) into risk assessment frameworks will require robust validations against in vivo responses. This takes time, and the ability to extrapolate findings from nonanimal studies to organism- and population-level effects in terrestrial wildlife remains weak. Failure to adequately anticipate and predict hazards could have economic and potentially even legal consequences for regulators and product registrants. In order to be able to use fewer animals or replace them altogether in the long term, vertebrate use and whole organism data will be needed to provide data for NAM validation in the short term. Therefore, it is worth investing resources for potential updates to existing standard test guidelines used in the laboratory as well as addressing the need for clear guidance on the conduct of field studies. Herein, we review the potential for improving standard in vivo test methods and for advancing the use of field studies in wildlife risk assessment, as these tools will be needed in the foreseeable future. Integr Environ Assess Manag 2024;20:699-724. © 2023 His Majesty the King in Right of Canada and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Reproduced with the permission of the Minister of Environment and Climate Change Canada. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

A prospective study on clinical signs, management, outcomes, and delayed neurologic sequelae due to metaldehyde poisoning in 26 dogs.

Background: Metaldehyde poisoning in dogs is well known and described issue. Several studies focused on the incidence, epidemiological features, and clinical and pathological findings associated with this intoxication. However, there are no prospective studies of metaldehyde poisoning and late-onset seizures. Aims: To prospectively describe clinical signs, therapeutic management, outcomes, and delayed-onset seizures due to metaldehyde poisoning in dogs. Methods: A 15-month prospective study on dogs with a diagnosis of metaldehyde poisoning, either via phone call to the animal poison control center or analysis at the toxicology laboratory in Lyon, France. Clinical signs, therapeutic management and outcomes, and the late onset of seizures were assessed for at least 3 years. Results: Twenty-six dogs were enrolled in the study. The most prevalent clinical signs were ataxia (18 dogs), convulsions (17), hypersalivation (15), and tremors (15). Treatment was symptomatic (e.g., activated charcoal, emetic therapy, and intravenous fluids) with anticonvulsant therapy (mainly diazepam). The overall survival rate was 81% (21/26 dogs). All dogs that received active charcoal (11/11) or emetic therapy (4/4) survived. Twelve of 17 dogs had convulsions and survived; 9 were followed up for at least 3 years after poisoning, and none had any other seizure episode or neurological sequelae. Conclusion: This prospective study describes clinical signs, therapeutic management and outcome of metaldehyde poisoning in dogs, and late-onset neurologic sequelae. None of the nine cases that were followed for 3 years developed neurological signs after metaldehyde poisoning. Therefore, long-term antiepileptic therapy is not indicated.

Afoxolaner (NexGard®) in pet snakes for the treatment and control of Ophionyssus natricis (Mesostigmata: Macronyssidae).

BACKGROUND: Ophionyssus natricis is the main species of mite that infests captive reptiles. High infestations may result in the host experiencing general discomfort and deleterious effects, even death. Moreover, O. natricis is an important vector of reptile vector-borne diseases and is considered to be the putative vector of the Reptarenavirus, the causal agent of the inclusion body disease. Despite the cosmopolitan distribution of O. natricis in captive reptiles, treatment options are limited. The aim of the present study was to assess the efficacy of afoxolaner (NexGard®; Boehringer Ingelheim, Ingelheim, Germany) in heavily infested, privately owned snakes, evaluate the prevalence of mites and drug availability in the plasma of treated snakes (pharmacokinetics) and perform a clinical examination of animals. METHODS: The study was conducted in two snake breeding facilities, where many snakes were infested with mites. Each animal was clinically examined and weighed, and mite infestations were assessed on the animals and in their enclosures (environment). Animals were treated with a dose of 2.5 mg afoxolaner per kilogram body weight (2.5 mg/kg) administered orally. All animals were examined pre-treatment (T0) and at various time points post-treatment (T1, 6 h; T2, 24 h; T3, 14 days; T4, 28 days). The collected mites were morphologically identified at the species level and the species identity also confirmed molecularly. RESULTS: Overall, 81 snakes from the two participating facilities (i.e. 70 from site 1 and 11 from site 2) were screened, and 31 (38.3%) snakes were found to have at least one mite. All mites were identified morphologically and molecularly as O. natricis. Lampropeltis was the genus of snakes with highest number of infested individuals. Mites were found to be alive on snakes at T1, but at T2 only dead mites were observed, and at T3 and T4 mites were no longer present on the animals or in their environment. No side effects were observed in the treated snakes. CONCLUSIONS: A single oral administration of afoxolaner at 2.5 mg/kg was a safe treatment for snakes and 100% effective for the eradication of natural O. natricis infestation without the need to treat the environment of the snake.

Statement of the Scientific Panel on Plant Protection Products and their Residues (PPR Panel) on the design and conduct of groundwater monitoring studies supporting groundwater exposure assessments of pesticides.

Groundwater monitoring is the highest tier in the leaching assessment of plant protection products in the EU. The European Commission requested EFSA for a review by the PPR Panel of the scientific paper of Gimsing et al. (2019) on the design and conduct of groundwater monitoring studies. The Panel concludes that this paper provides many recommendations; however, specific guidance on how to design, conduct and evaluate groundwater monitoring studies for regulatory purposes is missing. The Panel notes that there is no agreed specific protection goal (SPG) at EU level. Also, the SPG has not yet been operationalised in an agreed exposure assessment goal (ExAG). The ExAG describes which groundwater needs to be protected, where and when. Because the design and interpretation of monitoring studies depends on the ExAG, development of harmonised guidance is not yet possible. The development of an agreed ExAG must therefore be given priority. A central question in the design and interpretation of groundwater monitoring studies is that of groundwater vulnerability. Applicants must demonstrate that the selected monitoring sites represent realistic worst-case conditions as specified in the ExAG. Guidance and models are needed to support this step. A prerequisite for the regulatory use of monitoring data is the availability of complete data on the use history of the products containing the respective active substances. Applicants must further demonstrate that monitoring wells are hydrologically connected to the fields where the active substance has been applied. Modelling in combination with (pseudo)tracer experiments would be the preferred option. The Panel concludes that well-conducted monitoring studies provide more realistic exposure assessments and can therefore overrule results from lower tier studies. Groundwater monitoring studies involve a high workload for both regulators and applicants. Standardised procedures and monitoring networks could help to reduce this workload.

Impacts of neonicotinoids on biodiversity: a critical review.

Neonicotinoids are the most widely used class of insecticides in the world, but they have raised numerous concerns regarding their effects on biodiversity. Thus, the objective of this work was to do a critical review of the contamination of the environment (soil, water, air, biota) by neonicotinoids (acetamiprid, clothianidin, imidacloprid, thiacloprid, thiamethoxam) and of their impacts on terrestrial and aquatic biodiversity. Neonicotinoids are very frequently detected in soils and in freshwater, and they are also found in the air. They have only been recently monitored in coastal and marine environments, but some studies already reported the presence of imidacloprid and thiamethoxam in transitional or semi-enclosed ecosystems (lagoons, bays, and estuaries). The contamination of the environment leads to the exposure and to the contamination of non-target organisms and to negative effects on biodiversity. Direct impacts of neonicotinoids are mainly reported on terrestrial invertebrates (e.g., pollinators, natural enemies, earthworms) and vertebrates (e.g., birds) and on aquatic invertebrates (e.g., arthropods). Impacts on aquatic vertebrate populations and communities, as well as on microorganisms, are less documented. In addition to their toxicity to directly exposed organisms, neonicotinoid induce indirect effects via trophic cascades as demonstrated in several species (terrestrial and aquatic invertebrates). However, more data are needed to reach firmer conclusions and to get a clearer picture of such indirect effects. Finally, we identified specific knowledge gaps that need to be filled to better understand the effects of neonicotinoids on terrestrial, freshwater, and marine organisms, as well as on ecosystem services associated with these biotas.

Development of adverse outcome pathways relevant for the identification of substances having endocrine disruption properties Uterine adenocarcinoma as adverse outcome.

Development of adverse outcome pathways (AOPs) for uterine adenocarcinoma can provide a practical tool to implement the EFSA-ECHA Guidance (2018) for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. AOPs can give indications about the strength of the relationship between an adverse outcome (intended as a human health outcome) and chemicals (pesticides but not only) affecting the pathways. In this scientific opinion, the PPR Panel explored the development of AOPs for uterine adenocarcinoma. An evidence-based approach methodology was applied, and literature reviews were produced using a structured framework assuring transparency, objectivity, and comprehensiveness. Several AOPs were developed; these converged to a common critical node, that is increased estradiol availability in the uterus followed by estrogen receptor activation in the endometrium; therefore, a putative AOP network was considered. An uncertainty analysis and a probabilistic quantification of the weight of evidence have been carried out via expert knowledge elicitation for each set of MIEs/KEs/KERs included in individual AOPs. The collected data on the AOP network were evaluated qualitatively, whereas a quantitative uncertainty analysis for weight of the AOP network certainty has not been performed. Recommendations are provided, including exploring further the uncertainties identified in the AOPs and putative AOP network; further methodological developments for quantifying the certainty of the KERs and of the overall AOPs and AOP network; and investigating of NAMs applications in the context of some of the MIEs/KEs currently part of the putative AOP network developed.

Main conclusions and perspectives from the collective scientific assessment of the effects of plant protection products on biodiversity and ecosystem services along the land-sea continuum in France and French overseas territories.

Preservation of biodiversity and ecosystem services is critical for sustainable development and human well-being. However, an unprecedented erosion of biodiversity is observed and the use of plant protection products (PPP) has been identified as one of its main causes. In this context, at the request of the French Ministries responsible for the Environment, for Agriculture and for Research, a panel of 46 scientific experts ran a nearly 2-year-long (2020-2022) collective scientific assessment (CSA) of international scientific knowledge relating to the impacts of PPP on biodiversity and ecosystem services. The scope of this CSA covered the terrestrial, atmospheric, freshwater, and marine environments (with the exception of groundwater) in their continuity from the site of PPP application to the ocean, in France and French overseas territories, based on international knowledge produced on or transposable to this type of context (climate, PPP used, biodiversity present, etc.). Here, we provide a brief summary of the CSA's main conclusions, which were drawn from about 4500 international publications. Our analysis finds that PPP contaminate all environmental matrices, including biota, and cause direct and indirect ecotoxicological effects that unequivocally contribute to the decline of certain biological groups and alter certain ecosystem functions and services. Levers for action to limit PPP-driven pollution and effects on environmental compartments include local measures from plot to landscape scales and regulatory improvements. However, there are still significant gaps in knowledge regarding environmental contamination by PPPs and its effect on biodiversity and ecosystem functions and services. Perspectives and research needs are proposed to address these gaps.

Adaptation of a real-time PCR method for the detection and quantification of pathogenic leptospires in environmental water.

Leptospirosis is a major zoonotic disease that affects humans and animals in all continents, in both rural and urban areas. In Europe, metropolitan France is the most affected country, with about 300 human cases declared per year. In France, although leptospirosis is now mostly considered as a recreational disease related to freshwater areas, isolation of pathogenic leptospires from environmental water samples still remains difficult. It thus seemed important to set up an efficient method to detect and quantify these bacteria in this environment. We determined a DNA extraction method suitable for freshwater samples and adapted a real-time quantitative PCR based on the detection of the LipL32 gene using the SYBR green chemistry. The method developed is specific for pathogenic Leptospira. It permits the detection of all the pathogenic strains tested and none of the saprophytic strains. Quantification is possible between 10 and 10(7) bacteria/mL, and therefore, the method represents a tool that could be integrated into future public health surveillance programs for recreational freshwater areas.

Tissue concentrations of pesticides, PCBs and metals among ospreys, Pandion haliaetus, collected in France.

In this study, osprey (Pandion haliaetus) tissues collected in France were used for contaminants analyses by a non-invasive approach. 53 pesticides (organochlorine, organophosphate, carbamate, pyrethroids, herbicides, anticoagulant rodenticides), 13 PCBs, and 5 metals (mercury, lead, cadmium, copper and arsenic) were quantified in liver of 14 individual samples. PCBs and mercury were frequent (mean 0.5 mg/kg, range < d.l.-2.6 mg/kg and mean 3.4 mg/kg, range < d.l.-16.3 mg/kg wet weight, respectively). Inter-individual variations in contaminant diversity and amounts were noticed. Immediate conservation of the species in the country does not seem to be threatened by global contamination.

Are severe adverse events commonly observed in dogs during cancer chemotherapy? A retrospective study on 155 dogs.

Overall prevalence of severe adverse events (sAE) has been poorly studied in veterinary medicine and peer-reviewed studies mostly focused on a single protocol, making it difficult to have a general overview. The aim of this retrospective study was to assess the frequency and risk factors of sAE secondary to various protocols of chemotherapy in dogs. Medical records of 155 dogs receiving chemotherapy between January 2013 and December 2018 were reviewed. Adverse events (AE) were graded according to Veterinary Comparative Oncology Group-common terminology criteria for AE (VCOG-CTCAE) grading system. Statistical analyses were performed to determine whether demographic, cancer type and chemotherapy protocol were associated with development of sAE and their consequences. AE were reported at least once in 124 (80%) dogs and sAE were observed in 50 (32.3%) dogs. Among them, 23 (14.8%) had gastro-intestinal and 31 (20.0%) had myelotoxic events. sAE led to hospitalisation in 37 (23.9%) dogs, to chemotherapy arrest in 12 (7.7%) dogs and to euthanasia or death in 9 (5.8%) dogs. Haematopoietic tumours were statistically associated with a higher frequency of sAE (p = .004), gastrointestinal sAE (p = .009) and hospitalisation (p = .004). A body weight over 10 kg was associated with less haematological sAE (p < .001). The use of a multi-agent protocol was highlighted as a risk factor for sAE (p = .038) and haematological sAE (p < .001). sAE following chemotherapy and leading to hospitalisation, chemo arrest or death were relatively common. A special attention during chemotherapy follow-up should be given to small dogs and those receiving multi-agent protocol or treated for haematopoietic tumours.

A meta-analysis of ecotoxicological models used for plant protection product risk assessment before their placing on the market.

Before their placing on the market, the safety of plant protection products (PPP) towards both human and animal health, and the environment has to be assessed using experimental and modelling approaches. Models are crucial tools for PPP risk assessment and some even help to avoid animal testing. This review investigated the use of modelling approaches in the ecotoxicology section of PPP active substance assessment reports prepared by the authorities and opened to consultation from 2011 to 2021 in the European Union. Seven categories of models (Structure-Activity, ToxicoKinetic, ToxicoKinetic-ToxicoDynamic, Species Sensitivity Distribution, population, community, and mixture) were searched for into the reports of 317 active substances. At least one model category was found for 44 % of the investigated active substances. The most detected models were Species Sensitivity Distribution, Structure-Activity and ToxicoKinetic for 27, 21 and 15 % of the active substances, respectively. The use of modelling was of particular importance for conventional active substances such as sulfonylurea or carbamates contrary to microorganisms and plant derived substances. This review also highlighted a strong imbalance in model usage among the biological groups considered in the European Regulation (EC) No 1107/2009. For example, models were more often used for aquatic than for terrestrial organisms (e.g., birds, mammals). Finally, a gap between the set of models used in reports and those existing in the literature was observed highlighting the need for the implementation of more sophisticated models into PPP regulation.

Statement on the active substance flupyradifurone.

Flupyradifurone is a novel butenolide insecticide, first approved as an active substance for use in plant protection products by Commission Implementing Regulation (EU) 2015/2084. Following concerns that this substance may pose high risks to humans and the environment, the French authorities, in November 2020, asked the Commission to restrict its uses under Article 69 of Regulation (EC) No 1107/2009. To support this request, competent Authorities from France cited a series of literature papers investigating its hazards and/or exposure to humans and the environment. In addition, in June 2020, the Dutch Authorities notified the Commission, under Article 56 of Regulation (EC) No 1107/2009, of new information on flupyradifurone on the wild bee species Megachile rotundata. This notification is also referred to in the French notification on flupyradifurone. Consequently, the EFSA PPR Panel was mandated to quantify the likelihood of this body of evidence constituting proof of serious risks to humans or the environment. Therefore, the EFSA PPR Panel evaluated the likelihood of these studies indicating new or higher hazards and exposure to humans and the environment compared to previous EU assessments. A stepwise methodology was designed, including: (i) the initial screening; (ii) data extraction and critical appraisal based on the principles of OHAT/NTP; (iii) weight of evidence, including consideration of the previous EU assessments; (iv) uncertainty analysis, followed, whenever relevant, by an expert knowledge elicitation process. For the human health, only one study was considered relevant for the genotoxic potential of flupyradifurone in vitro. These data did not provide sufficient information to overrule the EU assessment, as in vivo studies already addressed the genotoxic potential of flupyradifurone. Environment: All available data investigated hazards in bee species. For honey bees, the likelihood of the new data indicating higher hazards than the previous EU assessment was considered low or moderate, with some uncertainties. However, among solitary bee species - which were not addressed in the previous EU assessment - there was evidence that Megachile rotundata may be disproportionately sensitive to flupyradifurone. This sensitivity, which may partially be explained by the low bodyweight of this species, was mechanistically linked to inadequate bodily metabolisation processes.