Scientific Opinion on the setting of health-based reference values for metabolites of the active substance terbuthylazine.

The EFSA Panel on Plant Protection Products and their Residues was requested to establish health-based reference values for groundwater metabolites (LM2, LM3, LM4, LM5 and LM6) of the active substance terbuthylazine based on the available evidence, unless the evidence was considered insufficient to do so. The request was accepted under the explicit circumstance that the reassessment would be made according to a different methodology than the routine methodology currently applied for the assessment of metabolites in groundwater. While for metabolites LM2, LM4 and LM5, it was concluded that the reference values for terbuthylazine are applicable, substance-specific reference values could not be derived for metabolites LM3 and LM6. The applied threshold of toxicological concern (TTC) approach has shown that metabolites LM3 and LM6 are of potential concern for consumer health, since at least one representative groundwater leaching scenario results in exposure above the relevant threshold. Moreover, other sources of exposure to LM3 and LM6 could not be excluded with certainty. It is therefore recommended to address the specific toxicities of metabolites LM3 and LM6.

Probabilistic dietary risk assessment of pesticide residues in foods for the German population based on food monitoring data from 2009 to 2014.

Dietary risks for the German population owing to pesticide residues in foods were assessed based on food monitoring data, consumption surveys for children and adults and compound specific toxicological reference values or general thresholds of toxicological concern. A tiered probabilistic modelling was conducted to screen 700 pesticides for significant long- and short-term dietary exposures. Especially for the short-term dietary exposure, the probabilistic methodology used allows simultaneous consideration of the complete daily consumption, whereas most regulatory bodies still rely on single commodity approaches. After screening, refined exposure assessments were conducted for 19 compounds under consideration of conversion factors for toxicologically relevant metabolites, processing information, experimentally derived variability factors and the edible portion for each food item. In total, for 693 compounds the dietary exposure was unlikely to present a chronic or acute public health concern for the German population. In contrast, the refined assessments indicate that the short-term dietary exposure for chlorpyrifos and the cumulative short-term dietary exposure for dimethoate and omethoate may present a public health concern. For copper, owing to exposure assessment limitations, as well as for dimethylvinphos, halfenprox and tricyclazole, which exceeded the thresholds of toxicological concern, the dietary risk assessment remained inconclusive.

Scientific Opinion on the state of the science on pesticide risk assessment for amphibians and reptiles.

Following a request from EFSA, the Panel on Plant Protection Products and their Residues developed an opinion on the science to support the potential development of a risk assessment scheme of plant protection products for amphibians and reptiles. The coverage of the risk to amphibians and reptiles by current risk assessments for other vertebrate groups was investigated. Available test methods and exposure models were reviewed with regard to their applicability to amphibians and reptiles. Proposals were made for specific protection goals aiming to protect important ecosystem services and taking into consideration the regulatory framework and existing protection goals for other vertebrates. Uncertainties, knowledge gaps and research needs were highlighted.

Scientific opinion on pesticides in foods for infants and young children.

Following a request from the European Commission, the EFSA Panel on Plant Protection Products and their Residues (PPR Panel) prepared a scientific opinion to provide a comprehensive evaluation of pesticide residues in foods for infants and young children. In its approach to develop this scientific opinion, the EFSA PPR Panel took into account, among the others, (i) the relevant opinions of the Scientific Committee for Food setting a default maximum residue level (MRL) of 0.01 mg/kg for pesticide residues in foods for infants and young children; (ii) the recommendations provided by EFSA Scientific Committee in a guidance on risk assessment of substances present in food intended for infants below 16 weeks of age; (iii) the knowledge on organ/system development in infants and young children. For infants below 16 weeks of age, the EFSA PPR Panel concluded that pesticide residues at the default MRL of 0.01 mg/kg for food for infants and young children are not likely to result in an unacceptable exposure for active substances for which a health-based guidance value (HBGV) of 0.0026 mg/kg body weight (bw) per day or higher applies. Lower MRLs are recommended for active substances with HBGVs below this value. For infants above 16 weeks of age and young children, the established approach for setting HBGVs is considered appropriate. For infants below 16 weeks of age the approach may not be appropriate and the application of the EFSA guidance on risk assessment of substances present in food intended for infants below 16 weeks of age is recommended. The contribution of conventional food to the total exposure to pesticide residues is much higher than that from foods intended for infants and young children. Because of the increased intake of conventional food by young children, these have the highest exposure to pesticide residues, whereas infants 3-6 months of age generally have lower exposure. The impact of cumulative exposure to pesticide residues on infants and young children is not different from the general population and the EFSA cumulative risk assessment methodology is also applicable to these age groups. Residue definitions established under Regulation (EC) No 396/2005 are in general considered appropriate also for foods for infants and young children. However, based on a tier 1 analysis of the hydrolysis potential of pesticides simulating processing, the particular appropriateness of existing residue definitions for monitoring to cover processed food, both intended for infants and young children as well as conventional food, is questionable.

Scientific Opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) effect models for regulatory risk assessment of pesticides for aquatic organisms.

Following a request from EFSA, the Panel on Plant Protection Products and their Residues (PPR) developed an opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) models and their use in prospective environmental risk assessment (ERA) for pesticides and aquatic organisms. TKTD models are species- and compound-specific and can be used to predict (sub)lethal effects of pesticides under untested (time-variable) exposure conditions. Three different types of TKTD models are described, viz., (i) the 'General Unified Threshold models of Survival' (GUTS), (ii) those based on the Dynamic Energy Budget theory (DEBtox models), and (iii) models for primary producers. All these TKTD models follow the principle that the processes influencing internal exposure of an organism, (TK), are separated from the processes that lead to damage and effects/mortality (TD). GUTS models can be used to predict survival rate under untested exposure conditions. DEBtox models explore the effects on growth and reproduction of toxicants over time, even over the entire life cycle. TKTD model for primary producers and pesticides have been developed for algae, Lemna and Myriophyllum. For all TKTD model calibration, both toxicity data on standard test species and/or additional species can be used. For validation, substance and species-specific data sets from independent refined-exposure experiments are required. Based on the current state of the art (e.g. lack of documented and evaluated examples), the DEBtox modelling approach is currently limited to research applications. However, its great potential for future use in prospective ERA for pesticides is recognised. The GUTS model and the Lemna model are considered ready to be used in risk assessment.

Scientific Opinion about the Guidance of the Chemical Regulation Directorate (UK) on how aged sorption studies for pesticides should be conducted, analysed and used in regulatory assessments.

The EFSA Panel on Plant Protection Products and their Residues reviewed the guidance on how aged sorption studies for pesticides should be conducted, analysed and used in regulatory assessment. The inclusion of aged sorption is a higher tier in the groundwater leaching assessment. The Panel based its review on a test with three substances taken from a data set provided by the European Crop Protection Association. Particular points of attention were the quality of the data provided, the proposed fitting procedure of aged sorption experiments and the proposed method for combining results obtained from aged sorption studies and lower-tier studies on degradation and adsorption. Aged sorption was a relevant process in all cases studied. The test revealed that the guidance could generally be well applied and resulted in robust and plausible results. The Panel considers the guidance suitable for use in the groundwater leaching assessment after the recommendations in this Scientific Opinion have been implemented, with the exception of the use of field data to derive aged sorption parameters. The Panel noted that the draft guidance could only be used by experienced users because there is no software tool that fully supports the work flow in the guidance document. It is therefore recommended that a user-friendly software tool be developed. Aged sorption lowered the predicted concentration in groundwater. However, because aged sorption experiments may be conducted in different soils than lower-tier degradation and adsorption experiments, it cannot be guaranteed that the higher tier predicts lower concentrations than the lower tier, while lower tiers should be more conservative than higher tiers. To mitigate this problem, the Panel recommends using all available higher- and lower-tier data in the leaching assessment. The Panel further recommends that aged sorption parameters for metabolites be derived only from metabolite-dosed studies. The formation fraction can be derived from parent-dosed degradation studies, provided that the parent and metabolite are fitted with the best-fit model, which is the double first-order in parallel model in the case of aged sorption.

Scientific Opinion of the PPR Panel on the follow-up of the findings of the External Scientific Report 'Literature review of epidemiological studies linking exposure to pesticides and health effects'.

In 2013, EFSA published a comprehensive systematic review of epidemiological studies published from 2006 to 2012 investigating the association between pesticide exposure and many health outcomes. Despite the considerable amount of epidemiological information available, the quality of much of this evidence was rather low and many limitations likely affect the results so firm conclusions cannot be drawn. Studies that do not meet the 'recognised standards' mentioned in the Regulation (EU) No 1107/2009 are thus not suited for risk assessment. In this Scientific Opinion, the EFSA Panel on Plant Protection Products and their residues (PPR Panel) was requested to assess the methodological limitations of pesticide epidemiology studies and found that poor exposure characterisation primarily defined the major limitation. Frequent use of case-control studies as opposed to prospective studies was considered another limitation. Inadequate definition or deficiencies in health outcomes need to be avoided and reporting of findings could be improved in some cases. The PPR Panel proposed recommendations on how to improve the quality and reliability of pesticide epidemiology studies to overcome these limitations and to facilitate an appropriate use for risk assessment. The Panel recommended the conduct of systematic reviews and meta-analysis, where appropriate, of pesticide observational studies as useful methodology to understand the potential hazards of pesticides, exposure scenarios and methods for assessing exposure, exposure-response characterisation and risk characterisation. Finally, the PPR Panel proposed a methodological approach to integrate and weight multiple lines of evidence, including epidemiological data, for pesticide risk assessment. Biological plausibility can contribute to establishing causation.

Scientific Opinion addressing the state of the science on risk assessment of plant protection products for in-soil organisms.

Following a request from EFSA, the Panel on Plant Protection Products and their Residues developed an opinion on the science behind the risk assessment of plant protection products for in-soil organisms. The current risk assessment scheme is reviewed, taking into account new regulatory frameworks and scientific developments. Proposals are made for specific protection goals for in-soil organisms being key drivers for relevant ecosystem services in agricultural landscapes such as nutrient cycling, soil structure, pest control and biodiversity. Considering the time-scales and biological processes related to the dispersal of the majority of in-soil organisms compared to terrestrial non-target arthropods living above soil, the Panel proposes that in-soil environmental risk assessments are made at in- and off-field scale considering field boundary levels. A new testing strategy which takes into account the relevant exposure routes for in-soil organisms and the potential direct and indirect effects is proposed. In order to address species recovery and long-term impacts of PPPs, the use of population models is also proposed.

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia.

In 2013, EFSA published a literature review on epidemiological studies linking exposure to pesticides and human health outcome. As a follow up, the EFSA Panel on Plant Protection Products and their residues (PPR Panel) was requested to investigate the plausible involvement of pesticide exposure as a risk factor for Parkinson's disease (PD) and childhood leukaemia (CHL). A systematic literature review on PD and CHL and mode of actions for pesticides was published by EFSA in 2016 and used as background documentation. The Panel used the Adverse Outcome Pathway (AOP) conceptual framework to define the biological plausibility in relation to epidemiological studies by means of identification of specific symptoms of the diseases as AO. The AOP combines multiple information and provides knowledge of biological pathways, highlights species differences and similarities, identifies research needs and supports regulatory decisions. In this context, the AOP approach could help in organising the available experimental knowledge to assess biological plausibility by describing the link between a molecular initiating event (MIE) and the AO through a series of biologically plausible and essential key events (KEs). As the AOP is chemically agnostic, tool chemical compounds were selected to empirically support the response and temporal concordance of the key event relationships (KERs). Three qualitative and one putative AOP were developed by the Panel using the results obtained. The Panel supports the use of the AOP framework to scientifically and transparently explore the biological plausibility of the association between pesticide exposure and human health outcomes, identify data gaps, define a tailored testing strategy and suggests an AOP's informed Integrated Approach for Testing and Assessment (IATA).

Comparison of the Avalon Dual-Lumen Cannula with Conventional Cannulation Technique for Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: Comparison of two kinds of cannulation (double-lumen cannula [DLC, Avalon Elite Bicaval Dual Lumen Catheter] and conventional cannulation with two cannulas) for venovenous extracorporeal membrane oxygenation (ECMO) therapy in terms of effectiveness, usage complexity, and costs. METHODS: Retrospective case series of 17 patients who received venovenous ECMO therapy due to acute respiratory distress syndrome (ARDS) between January 2010 and March 2012. Nine patients were treated with the DLC and eight patients with conventional cannulation. We analyzed the outcome data, ECMO values, respirator settings, blood gas values, realized prone positioning, and costs, and compared both methods. RESULTS: Both kinds of cannulation are efficient regarding oxygenation and decarboxylation. There is no significant difference in mortality, hospitalization time (intensive care unit [ICU] and hospital) and complications during ECMO therapy between both groups. Cannula implantation is much more complex in the DLC group and requires more experience in TEE (transesophageal echocardiography) diagnostics and cannulation technique. In addition, the costs for the Avalon (MAQUET Cardiopulmonary AG, Germany) cannula are significantly higher than for conventional cannulation. Furthermore, prone positioning could be easier achieved in the DLC group. CONCLUSION: In summary, double-lumen cannulation allows sufficient gas exchange with more effort (material, technical, and physicians' experience) and higher costs but better mobilization possibilities (particularly prone position) and potential avoidance of deep sedation and mechanical ventilation. From the current point of view, the DLC should be reserved for special cases.

Generation of multi-millijoule red-shifted pulses for seeding stimulated Raman backscattering amplifiers.

The efficient generation of redshifted pulses from chirped femtosecond joule level Bessel beam pulses in gases is studied. The redshift spans from a few 100 cm⁻¹ to several 1000 cm⁻¹ corresponding to a shift of 50-500 nm for Nd:glass laser systems. The generated pulses have an almost perfect Gaussian beam profile insensitive of the pump beam profile, and are much shorter than the pump pulses. The highest measured energy is as high as 30 mJ, which is significantly higher than possible with solid state nonlinear frequency shifters.

Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions.

The advent of new testing systems and "omics"-technologies has left regulatory toxicology facing one of the biggest challenges for decades. That is the question whether and how these methods can be used for regulatory purposes. The new methods undoubtedly enable regulators to address important open questions of toxicology such as species-specific toxicity, mixture toxicity, low-dose effects, endocrine effects or nanotoxicology, while promising faster and more efficient toxicity testing with the use of less animals. Consequently, the respective assays, methods and testing strategies are subject of several research programs worldwide. On the other hand, the practical application of such tests for regulatory purposes is a matter of ongoing debate. This document summarizes key aspects of this debate in the light of the European "regulatory status quo", while elucidating new perspectives for regulatory toxicity testing.

Test of time dilation using stored Li+ ions as clocks at relativistic speed.

We present the concluding result from an Ives-Stilwell-type time dilation experiment using 7Li+ ions confined at a velocity of ß=v/c=0.338 in the storage ring ESR at Darmstadt. A Λ-type three-level system within the hyperfine structure of the 7Li+3S1 →3P2 line is driven by two laser beams aligned parallel and antiparallel relative to the ion beam. The lasers' Doppler shifted frequencies required for resonance are measured with an accuracy of <4×10(-9) using optical-optical double resonance spectroscopy. This allows us to verify the special relativity relation between the time dilation factor γ and the velocity ß, γ√1-ß2=1 to within ±2.3×10(-9) at this velocity. The result, which is singled out by a high boost velocity ß, is also interpreted within Lorentz invariance violating test theories.

Regional brain atrophy in mouse models of neuronal ceroid lipofuscinosis: a new rostrocaudal perspective.

The neuronal ceroid lipofuscinoses (Batten disease) are collectively the most common inherited neurodegenerative disorder of childhood. Mouse models of neuronal ceroid lipofuscinosis represent a powerful resource for investigating the underlying disease mechanisms, which remain poorly understood. Here we present a new rostrocaudal analysis of regional brain volume rather than focusing on central nervous system structures that can be affected. This has revealed an earlier onset of regional atrophy than was suspected in infantile neuronal ceroid lipofuscinosis (or CLN1 disease, infantile), with a greater involvement of rostral structures. We have also provided the first description of regional atrophy in severely affected mice with the juvenile variant (CLN3 disease, juvenile). These data reveal new perspectives on how the central nervous system is affected in these disorders, which have implications for judging the efficacy of therapeutic strategies in preclinical studies.

Immune cells perturb axons and impair neuronal survival in a mouse model of infantile neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses are fatal neurodegenerative disorders in which the visual system is affected early in disease progression. A typical accompanying feature is neuroinflammation, the pathogenic impact of which is presently obscure. Here we investigated the role of inflammatory cells in palmitoyl protein thioesterase 1-deficient (Ppt1(-/-)) mice, a model of infantile neuronal ceroid lipofuscinosis (CLN1 disease, infantile), predominantly focusing on the visual system. We detected an early infiltration of CD8+ T-lymphocytes and observed activation of microglia/macrophage-like cells. To analyse the pathogenic impact of lymphocytes, we crossbred Ppt1(-/-) mice with mutants lacking lymphocytes (Rag1(-/-)), and scored axonal transport, axonal perturbation and neuronal survival. This lack of lymphocytes led to a significant amelioration of disease phenotypes, not only in the retino-tectal system, but also in other regions of the central nervous system. Finally, reconstitution experiments revealed a crucial role of CD8+ T-lymphocytes in pathogenesis. Our study provides novel pathomechanistic insights that may be crucial for developing treatment strategies.

Recurrent left atrial and left ventricular thrombosis due to heparin-induced thrombocytopenia: case report and short review.

The combination of heparin-induced thrombocytopenia (HIT) II, left ventricular failure with extracorporeal membrane oxygenation (ECMO) therapy, and recurrent left ventricular thrombosis is rare and predicts a poor outcome. In this case, HIT II occurred after an ischemic cardiogenic shock. We initiated ECMO and intra-aortic balloon pump therapy during coronary artery bypass grafting and ventricular thrombectomy. Despite continued therapeutic therapy with heparin and later argatroban, the patient developed solid and recurrent thrombotic masses in the left atrium and left ventricle.