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

Abstract 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 The Panel noted that the draft guidance could only be used by experienced users because there is no software tool that fully supports the work flow in the guidance document.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

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)

Guidance on the establishment of the residue definition for dietary risk assessment

EFSA has asked the Panel on Plant Protection Products and their Residues to prepare guidance on the establishment of the residue definition for dietary risk assessment. The residue definition for risk assessment is used by risk assessors to evaluate the potential risk of dietary intake of residues resulting from the application of a pesticide. This document guides the complex process of identifying the pertinent residue components that should be considered for dietary risk assessments of chemical active substances. Specifically, the document provides directions for determining the metabolites that require hazard identification and characterisation using scientific tools and methods ((quantitative) structure-activity relationship ((Q)SAR), read-across, threshold of toxicological concern (TTC)) and available data in combination, and for developing an appropriate testing strategy for these compounds. Further, for activities within the remit of the guidance document the terms 'potency' and 'toxicological burden' for consumers are defined and decision criteria established for the selection of the residue components that should be included in the residue definition for dietary risk assessment. In order to support the decision process it is recommended to make use of all information available, including mechanistic understanding, and to present detailed information on toxicity and exposure for every single metabolite and on the uncertainties connected to the proposed residue definition. The guidance document is complemented with three practical case studies demonstrating the applicability of the proposed decision scheme

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 parentdosed 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 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 \u2018General Unified Threshold models of Survival\u2019 (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 of the PPR Panelon 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 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