Fate and transport of ten plant protection products of emerging concern in a coastal lagoon: Application and evaluation of a multimedia level III fugacity model.

Multimedia fugacity models are effective tools for studying the environmental behaviour and occurrence of contaminants of emerging concern (CECs) and assessing associated risks, especially when experimental data is limited. These models describe processes controlling chemical partitioning, transport, and reactions in environmental media using mathematical statements based on the concept of fugacity. To aid in identifying and prioritizing CECs for future local monitoring, we present here the application of a level III multimedia fugacity model assuming non-equilibrium between compartments and steady-state conditions. This model estimated predicted environmental concentrations (PECs), persistence, distribution, and transport of ten plant protection products (PPPs) in the Venice Lagoon, a complex coastal environment under high anthropogenic pressure. The model was evaluated through uncertainty and sensitivity analysis using the Monte Carlo approach and by comparing PECs with PPP concentrations measured during four sampling campaigns. Results showed good agreement with field data, with the highest concentrations in water and sediments estimated for glyphosate, followed by imidacloprid, metaflumizone, and triallate. The model indicated accumulation of all investigated PPPs in sediments. For most chemicals, advection outflow and degradation in the water column were the main removal mechanisms, while volatilization was significant only for oxadiazon and triallate. Sensitivity and uncertainty analysis revealed that degradation rates, organic carbon/water partitioning coefficients (KOC), and parameters describing air-water interactions had the strongest influence on the model's results, followed by inputs accounting for sediment sinking and resuspension. The lack of data on PPP degradation in brackish waters accounted for most of the uncertainty in model results. This work shows how a relatively simple multimedia model can offer new insights into the environmental behaviour of PPPs in a complex transitional waterbody such as the Venice lagoon, providing useful data for the identification of the CECs to be prioritised in future local monitoring efforts.

Analysing agricultural plant protection product concentrations in groundwater in Germany: Nationwide database with site and compound insights.

Pesticides from agricultural practices are among the most pressing reasons why groundwater sources do not reach the good chemical status standards as required by the European Water Framework directive. Complementary to previous federal pesticide reports, we analysed groundwater-monitoring data from 13 German Länder assembled in a database consisting of 26.192 groundwater measuring sites sampled between 1973 and 2021 of in total 521 parent compounds and metabolites. This study focuses on agricultural plant protection products. The monitored substance spectrum and site density developed over time and differs between Länder. More than 95 % of all samples lie below the respective (multiple) limits of quantification (LOQ). We thus report the frequency of exceedance above concentration thresholds, which allows to compare measurements temporally and spatially. Pesticide detections were found in all aquifer types, land uses and well screen depths. Most detections of higher concentrations were found in agricultural areas, at shallow screen depth in porous aquifers. Karst aquifers showed also a higher percentage of samples in higher concentration classes. Metabolites with high mobility and persistence were found in higher concentration ranges. Herbicides and metabolites thereof dominate the top 20 of pesticides that most frequently exceed 0.1 µg L-1. The ranking for 2010-2019 includes both authorised and banned compounds and their occurrence is discussed in the context of their mobility, persistence and underlying monitoring density. Yearly exceedance frequencies above 0.05, 0.1 µg L-1 and higher thresholds of metazachlor and its esa-metabolite, and national sales data of the parent compound did not show a temporal correlation in subsequent years. This study stresses the need for the harmonisation of heterogeneous pesticide data. Further, a characterisation of the groundwater data used to analyse pesticide occurrence in selected concentration ranges for relevant site factors and compound properties and provides a pesticide ranking based on exceedance frequencies is provided.

Contaminants of emerging concern in water and sediment of the Venice Lagoon, Italy.

This study investigates for the first time the contamination of water and sediment of the Venice Lagoon by twenty Contaminants of Emerging Concern (CECs): three hormones, six pharmaceutical compounds (diclofenac and five antibiotics, three of which are macrolides), nine pesticides (methiocarb, oxadiazon, metaflumizone, triallate, and five neonicotinoids), one antioxidant (BHT), and one UV filter (EHMC). Water and sediment samples were collected in seven sites in four seasons, with the aim of investigating the occurrence, distribution, and possible emission sources of the selected CECs in the studied transitional environment. The most frequently detected contaminants in water were neonicotinoid insecticides (with a frequency of quantification of single contaminants ranging from 73% to 92%), and EHMC (detected in the 77% of samples), followed by BHT (42%), diclofenac (39%), and clarithromycin (35%). In sediment the highest quantification frequencies were those of BHT (54%), estrogens (ranging from 35% to 65%), and azithromycin (46%). Although this baseline study does not highlight seasonal or spatial trends, results suggested that two of the major emission sources of CECs in the Venice Lagoon could be tributary rivers from its drainage basin and treated wastewater, due to the limited removal rates of some CECs in WWTPs. These preliminary results call for further investigations to better map priority emission sources and improve the understanding of CECs environmental behavior, with the final aim of drawing up a site-specific Watch List of CECs for the Venice Lagoon and support the design of more comprehensive monitoring plans in the future.

Ambient air concentrations of plant protection products: Data collection for the combined air concentration database and associated risk assessment.

CropLife Europe collected literature values from monitoring studies measuring air concentrations of Plant Protection Products (PPPs) that may be inhaled by humans located in rural areas but not immediately adjacent to PPP applications. The resulting "Combined Air Concentration Database" (CACD) was used to determine whether air concentrations of PPPs reported by the French "Agency for Food, Environmental and Occupational Health & Safety" (ANSES) are consistent with those measured by others to increase confidence in values of exposure to humans. The results were put into risk assessment context. Results show that 25-90% of samples do not contain measurable PPP concentrations. Measured respirable fractions were below EU default air concentrations used for risk assessment for resident exposure by the European Food Safety Authority. All measured exposures in the CACD were also below established toxicological endpoints, even when considering the highest maximum average reported concentrations and very conservative inhalation rates. The highest recorded air concentration was for prosulfocarb (0.696 µg/m³ measured over 48 h) which is below the EFSA default limit of 1 µg/m³ for low volatility substances. In conclusion, based on the CACD, measured air concentrations of PPPs are significantly lower than EFSA default limits and relevant toxicological reference values.

Proposals for new transfer coefficient (TC) values for worker re-entry activities in grape vineyards.

New transfer coefficient (TC) values were derived for vineyard workers handling treated grapevines during harvesting and crop maintenance activities. Re-entry exposure and dislodgeable foliar residue (DFR) studies were performed in Europe, covering hand harvesting, pruning/training, pruning/tying and pruning/shoot lifting. Foliar applications of fungicides (iprovalicarb, dimethomorph, dithianon, pyrimethanil and fenbuconazole) were made and 73 workers at 16 sites were monitored over one working day. Exposure was measured on inner and outer dosimeters, face/neck wipes and hand washes. In concurrent DFR studies, leaf punches were taken at each site during the time of worker re-entry. Potential exposure values correlated well with DFR values. TC values were derived for various re-entry activities for potential and actual exposure, with and without gloves. The harvesting task resulted in lower TC values than the other crop maintenance tasks. Additional TC values reflecting the use of protective gloves can be derived from the results. The TC values are much lower than current European Food Safety Authority (EFSA) default values. This project addresses a data gap identified by EFSA for specific EU TC values to permit more realistic and reliable re-entry worker exposure estimates for grapes.

Development and validation of a simple and efficient method for the analysis of commercial formulations containing clopyralid, picloram and aminopyralid as active ingredients.

Liquid chromatography plays a pivotal role in evaluating pesticide formulations as it enables the determination of multiple active substances in plant protection products. An adaptable separation technique has been developed, enabling the qualitative and quantitative analysis of clopyralid, picloram, and aminopyralid within pesticide formulations in line with SANCO/3030/99 rev. 5 guidelines. This article offers an insight into the validation procedure encompassing key aspects such as selectivity, linearity, accuracy, precision, and recovery. It places emphasis on critical stages, including sample preparation, chromatographic separation, detection, quantification, and data analysis. The active ingredients are separated using chromatography with isocratic elution, utilizing a mobile phase consisting of a mixture of water, acetonitrile, and acetic acid in a specific ratio (83:15:2 v/v/v). This separation is carried out on a YMC-Pack ODS-AQ column (250 mm x 4.6 mm, 5 µm) at a flow rate of 1.5 mL/min. The method's validation parameters have produced satisfactory outcomes. The recovery rates for each individual compound were found to be in the range of 98.6% to 101.0%. Precision, as indicated by the relative standard deviation (%RSD), was lower than the values predicted by the modified Horwitz equation. Furthermore, the correlation coefficients assessing the linearity of the response exceeded 0.99.

Moving past neonicotinoids and honeybees: A systematic review of existing research on other insecticides and bees.

Synthetic pesticides (e.g. herbicides, fungicides and insecticides) are used widely in agriculture to protect crops from pests, weeds and disease. However, their use also comes with a range of environmental concerns. One key concern is the effect of insecticides on non-target organisms such as bees, who provide pollination services for crops and wild plants. This systematic literature review quantifies the existing research on bees and insecticides broadly, and then focuses more specifically on non-neonicotinoid insecticides and non-honeybees. We find that articles on honeybees (Apis sp.) and insecticides account for 80% of all research, with all other bees combined making up 20%. Neonicotinoids were studied in 34% of articles across all bees and were the most widely studied insecticide class for non-honeybees overall, with almost three times as many studies than the second most studied class. Of non-neonicotinoid insecticide classes and non-honeybees, the most studied were pyrethroids and organophosphates followed by carbamates, and the most widely represented bee taxa were bumblebees (Bombus), followed by leaf-cutter bees (Megachile) and mason bees (Osmia). Research has taken place across several countries, with the highest numbers of articles from Brazil and the US, and with notable gaps from countries in Asia, Africa and Oceania. Mortality was the most studied effect type, while sub-lethal effects such as on behaviour were less studied. Few studies tested how the effect of insecticides were influenced by multiple pressures, such as climate change and co-occurring pesticides (cocktail effects). As anthropogenic pressures do not occur in isolation, we suggest that future research also addresses these knowledge gaps. Given the changing global patterns in insecticide use, and the increasing inclusion of both non-honeybees and sub-lethal effects in pesticide risk assessment, there is a need for expanding research beyond its current state to ensure a strong scientific evidence base for the development of risk assessment and associated policy.

Non-disclosure of developmental neurotoxicity studies obstructs the safety assessment of pesticides in the European Union.

BACKGROUND: In the European Union (EU), the safety assessment of plant protection products relies to a large extent on toxicity studies commissioned by the companies producing them. By law, all performed studies must be included in the dossier submitted to authorities when applying for approval or renewal of the active substance. METHODS: For one type of toxicity, i.e. developmental neurotoxicity (DNT), we evaluated if studies submitted to the U.S. Environmental Protection Agency (EPA) had also been disclosed to EU authorities. RESULTS: We identified 35 DNT studies submitted to the U.S. EPA and with the corresponding EU dossiers available. Of these, 9 DNT studies (26%) were not disclosed by the pesticide company to EU authorities. For 7 of these studies, we have identified an actual or potential regulatory impact. CONCLUSIONS: We conclude that (1) non-disclosure of DNT studies to EU authorities, in spite of clear legal requirements, seems to be a recurring phenomenon, (2) the non-disclosure may introduce a bias in the regulatory risk assessment, and (3) without full access to all performed toxicity studies, there can be no reliable safety evaluation of pesticides by EU authorities. We suggest that EU authorities should cross-check their data sets with their counterparts in other jurisdictions. In addition, applications for pesticide approval should be cross-checked against lists of studies performed at test facilities operating under Good Laboratory Practice (GLP), to ensure that all studies have been submitted to authorities. Furthermore, rules should be amended so that future studies should be commissioned by authorities rather than companies. This ensures the authorities' knowledge of existing studies and prevents the economic interest of the company from influencing the design, performance, reporting and dissemination of studies. The rules or practices should also be revised to ensure that non-disclosure of toxicity studies carries a significant legal risk for pesticide companies.

Assessing the risk of induction of skin sensitization to plant protection products: A quantitative approach.

Exposure to skin sensitizers is common and regulated in many industry sectors. For cosmetics, a risk-based approach has been implemented, focused on preventing the induction of sensitization. First, a No Expected Sensitization Induction Level (NESIL) is derived, then modified by Sensitization Assessment Factors (SAFs) to derive an Acceptable Exposure Level (AEL). The AEL is used in risk assessment, being compared with an estimated exposure dose, specific to the exposure scenario. Since in Europe there is increased concern regarding exposure towards potentially sensitizing pesticides via spray drift, we explore how existing practice can be modified to allow Quantitative Risk Assessment (QRA) of pesticides for bystanders and residents. NESIL derivation by the Local Lymph Node Assay (LLNA), the globally required in vivo assay for this endpoint, is reviewed alongside consideration of appropriate SAFs. Using a case study, the principle that the NESIL in µg/cm2 can be derived by multiplying LLNA EC3% figure by a factor of 250 is adopted. The NESIL is then reduced by an overall SAF of 25 to establish an exposure level below which there is minimal bystander and resident risk. Whilst this paper focuses on European risk assessment and management, the approach is generic and universally applicable.

Quantitative risk assessment of skin sensitising pesticides: Clinical and toxicological considerations.

Like many other consumer and occupational products, pesticide formulations may contain active ingredients or co-formulants which have the potential to cause skin sensitisation. Currently, there is little evidence they do, but that could just reflect lack of clinical investigation. Consequently, it is necessary to carry out a safety evaluation process, quantifying risks so that they can be properly managed. A workshop on this topic in 2022 discussed how best to undertake quantitative risk assessment (QRA) for pesticide products, including learning from the experience of industries, notably cosmetics, that already undertake such a process routinely. It also addressed ways to remedy the matter of clinical investigation, even if only to demonstrate the absence of a problem. Workshop participants concluded that QRA for skin sensitisers in pesticide formulations was possible, but required careful justification of any safety factors applied, as well as improvements to the estimation of skin exposure. The need for regulations to stay abreast of the science was also noted. Ultimately, the success of any risk assessment/management for skin sensitisers must be judged by the clinical picture. Accordingly, the workshop participants encouraged the development of more active skin health monitoring amongst groups most exposed to the products.

A comparison between field measurements of vapour concentrations of plant protection products and predictions by the BROWSE model.

A database of field measurements of air concentrations of pesticide active ingredients has previously been compiled by CropLife Europe with an aim to revise the default air concentration values and assumptions applied in assessing vapour exposure in the risk assessment of bystanders and residents. The BROWSE model, released in 2014, which is a regulatory risk assessment model that includes the exposure of residents and bystanders has a component relating to post-application vapour inhalation. Predictions of concentration deduced from exposures obtained using the BROWSE model were compared with field measurements of 24-h and 7-day average concentrations. The methodology for obtaining concentration estimates from the BROWSE model is described, and the criteria for including field studies in the comparison are given. The field data were adjusted to account for differences between the field experiment and the BROWSE scenario using factors derived from a separate plume dispersion model. This showed that BROWSE provides a satisfactory level of conservatism in determining potential exposures of residents and bystanders to vapour and could be a reliable alternative to replace the current EFSA approach for predicting vapour inhalation exposures for pesticides where no compound-specific data are available.

High-throughput screening and quantitative analysis of hidden ingredients in plant protection products by GC-MS/MS.

Hidden ingredients in plant protection products (PPPs) threaten public health, food trade, and the environment. In this study, we developed a high-throughput screening method of 639 hidden ingredients in PPPs using GC-MS/MS in multiple reaction monitoring mode. Results showed that the qualitative criteria of retention time (tR) shift and uncertainty of qualifier to quantifier ratio in the commercially available Shimadzu Smart Pesticides Database were set at < 0.17 min and < 30%, respectively, which could be used to tentatively identify compounds without standards. The limits of quantification were 0.01-0.05 mg/kg. A wide linear range of 10-1000 µg/L was observed with R2 ≥ 0.975. Recoveries from three types of PPP formulations were 62.08%- 126.3%, with relative standard deviations < 15.7%. Finally, this method was applied to screen and quantify hidden ingredients in 91 plant protection products (PPPs) samples collected from online sales in China. Only one hidden ingredient, dimethomorph (1.6 g/kg), was detected in the polyoxin formulation (15% wettable powder). The results will be helpful in assessing the potential risks of hidden ingredients in PPPs.

Pesticides in Agricultural Soils: Major Findings from Various Monitoring Campaigns in Switzerland.

Synthetic pesticides are widely applied in modern agriculture, where they are used against diseases, pests, and weeds to secure crop yield and quality. However, their intensive application has led to widespread contamination of the environment, including soils. Due to their inherent toxicity, they might pose a risk to soil health by causing harm to non-target organisms and disrupting ecosystem services in both agricultural and other exposed soils. Following the Swiss National Action Plan on the reduction of pesticide risks, Agroscope has conducted several soil monitoring studies that are briefly presented here. All of them resort to different multi-residue trace analytical approaches to simultaneously quantify up to about 150 modern pesticides by either accelerated solvent, or Quick, Easy, Cheap, Efficient, Rugged, Safe (QuEChERS) extraction, followed by separation and detection with liquid chromatography-triple quadrupole mass spectrometry. While partly still in progress, our investigations led to the following major findings this far: Multiple pesticides are commonly present in soils, with individual concentrations in agricultural soils often reaching up to a few tens of µg/kg. Pesticide occurrence and concentrations in agricultural soils primarily depend on land use, land use history and cultivated crops. Pesticides can prevail much longer than predicted by their half-lives, and were found in soils even decades after conversion from conventional to organic farming. Corresponding residual fractions can be in the order of a few percent of the originally applied amounts. We further found negative associations of pesticide residues with the abundance of beneficial soil life, underpinning their potential risk to the fertility of agricultural soils. Traces of pesticides are also detected in soils to which they were never applied, indicating contamination, e.g., via spray drift or atmospheric deposition. These results confirm the general notion of both scientists and legislators that prospective risk assessments (RA; as executed during registration and use authorization) should be confirmed and adjusted by retrospective RA (e.g., by environmental monitoring studies of currently used compounds) to jointly lead to an overall reduced environmental risk of pesticides.

Early Assessment of Biodegradability of Small Molecules to Support the Chemical Design in Agro & Pharma R&D.

The use of agrochemical and pharmaceutical active ingredients is essential in our modern society. Given the increased concern and awareness of the potential risks of some chemicals, there is a growing need to align with 'green chemistry' and 'safe and sustainable by design' principles and thus to evaluate the hazards of agrochemical and pharmaceutical active ingredients in early stages of R&D. We give an overview of the current challenges and opportunities to assess the principle of biodegradability in the environment. Development of new medium/high-throughput methodologies, combining predictive tools and wet-lab experimentation are essential to design biodegradable chemicals early in the active ingredient discovery and selection process.

LAMP for in-field quantitative assessments of airborne grapevine downy mildew inoculum.

AIMS: Cheap, rapid tools for measuring emissions of Plasmopara viticola sporangia directly in the field are required to protect grapevines efficiently and sustainably against downy mildew. To this end, we adapted an existing loop-mediated isothermal amplification (LAMP) protocol based on ITS2 sequences, coupled with a rotating-arm sampler and simple cell lysis, for the in-field measurement of airborne sporangia of P. viticola. METHODS AND RESULTS: We estimated the sensitivity and specificity of the molecular reaction with an unpurified DNA template in controlled conditions, using the droplet digital PCR (ddPCR) as a reference. We show that the LAMP lower limit of quantification is 3.3 sporangia.m-3 air sampled. Cell lysis in KOH solution was less efficient than CTAB for DNA extraction, but the repeatability of the method was good. We tested this protocol directly in a plot at Chateau Dillon (Blanquefort, France) in which we monitored P. viticola sporangia concentrations from March to October 2020 (88 samples which revealed concentrations ranging from 0 to 243 sporangia.m-3 ). There was a significant quantitative correlation (R2  = 0.52) between ddPCR and LAMP results. CONCLUSION: LAMP analysis of an unpurified DNA matrix is a simple and reliable method for in-field estimations of the concentration of airborne P. viticola sporangia. SIGNIFICANCE AND IMPACT OF THE STUDY: This study constitutes a first step towards the development of a regional grapevine downy mildew monitoring network in the vineyards of Bordeaux.

A new conceptional model for deriving average dermal absorption estimates from studies with multiple tested concentrations for non-dietary risk assessment of pesticides.

Dermal absorption values are used to translate external dermal exposure into potential systemic exposure for non-dietary risk assessment of pesticides. While the Environmental Protection Agency of the United States of America (US EPA) derives a common dermal absorption factor for active substances covering all related products, the European Food Safety Authority (EFSA) requests specific product-based estimates for individual concentrations covering the intended use rates. The latter poses challenges, because it disconnects exposure dose from applied dose in absorption studies, which may not be suitable in scenarios where concentration is not relevant. We analyzed the EFSA dermal absorption database, collected 33 human in vitro studies from CropLife Europe (CLE) companies, where ≥3 in-use dilution concentrations were tested, and 15 dermal absorption triple pack datasets. This shows that absolute dermal absorption correlates with absolute applied dose on a decadic logarithm-scale, which is concordant with the toxicological axiom that risk is driven by exposure dose. This method is radically different from the current European approach focused on concentrations and offers new insights into the relationship of internal and external exposure doses when utilizing data from in vitro studies. A single average dermal absorption value can be simply derived from studies with multiple tested concentrations, by calculating the y-intercept of a linear model on a decadic logarithm scale while assuming a slope of 1. This simplifies risk assessment and frees resources to explore exposure refinements. It also serves as a basis to harmonize dermal absorption estimation globally for use in exposure-driven risk assessments.

Automated Mobile Hot Mist Generator: A Quest for Effectiveness in Fruit Horticulture.

The study relates to the use of automated plant protection systems in agriculture. The article presents a proprietary automated mobile platform with an aerosol generator of hot mist. Furthermore, the cause of the loss of a chemical preparation in the spraying of plant protection products on the tree crown was determined in the course of field research. A statistical analysis of the results of experiment was carried out and the effect of droplet size on leaf coating density was determined. The manuscript presents a diagram of the degree of penetration of the working solution as it drops into the crown of the tree, as well as a cross-sectional graph of the permeability of the spray from the projection of the fruit tree crown. The most effective modes of operation of the automated mobile platform for spraying plant protection products with a mist generator aggregate were established. Analysis of the results shows that the device meets the spraying requirements of the procedure for spraying plant protection products. The novelty of this research lies in the optimal modes identified by movement of the developed automated mobile platform and the parameters of plant treatment with protective equipment when using a hot mist generator. The following mode parameters were established: the speed of the automated platform was 3.4 km/h, the distance to the crown of the tree was 1.34 m, and the flow rate of the working fluid was 44.1 L/h. Average fuel consumption was 2.5 L/h. Effective aerosol penetration reduced the amount of working fluid used by up to 50 times.

Characterization of the composition of plant protection products in different formulation types employing suspect screening and unknown approaches.

BACKGROUND: Plant protection products (PPPs) are used extensively in agriculture to control crops. These PPPs, which may be found in different types of formulations, are composed of a designated pesticide (active principle) and other inactive ingredients as co-formulants. They perform specific functions in the formulation, as solvents, preservatives or antifreeze agents, among others. RESULTS: A research technique based on ultra-high-performance liquid chromatography (UHPLC) coupled to a Quadrupole-Orbitrap mass analyzer was successfully applied to characterize the composition of six different PPPs in terms of the presence of co-formulants and types of formulations: emulsifiable concentrate (EC), emulsion in water (EW), suspension concentrate and water-dispersible granule. These PPPs (FLINT MAX, MASSOCUR 12.5 EC, IMPACT EVO, TOPAS, LATINO and IMPALA STAR) had antifungal activity, containing one triazole compound as active principle (tebuconazole, penconazole, myclobutanil, flutriafol or fenbuconazole, respectively). Non-targeted approaches, applying suspect and unknown analysis, were carried out and ten compounds were identified as potential co-formulants. Six (glyceryl monostearate, 1-monopalmitin, dimethyl sulfoxide, N,N-dimethyldecanamide, hexaethylene glycol and 1,2-benzisothiazol-3(2H)-one) were confirmed by injecting analytical standards. Finally, these compounds were quantified in the PPPs. CONCLUSION: The current study allowed for detecting co-formulants in a wide range of concentrations, between 0.04 (dimethyl sulfoxide) and 19.00 g L-1 (glyceryl monostearate), highlighting the feasibility of the proposed analytical methodology. Moreover, notable differences among the types of formulations of PPPs were achieved, revealing that EC and EW were the formulations that contained the largest number of co-formulants (four out of six detected compounds). © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro.

Currently, the authorisation process for plant protection products (PPPs) relies on the testing of acute and topological toxicity only. Contrastingly, the evaluation of active substances includes a more comprehensive set of toxicity studies. Nevertheless, mixture effects of active ingredients and co-formulants may result in increased toxicity. Therefore, we investigated effects of surface active co-formulants on the toxicity of two PPPs focussing on qualitative and quantitative toxicokinetic effects on absorption and secretion. The respective products are based on the active substances abamectin and fluroxypyr-meptyl and were tested for cytotoxicity in the presence or absence of the corresponding surfactants and co-formulants using Caco-2 cells. In addition, the effect of co-formulants on increased cellular permeation was quantified using LC-MS/MS, while potential kinetic mixture effects were addressed by fluorescence anisotropy measurements and ATPase assays. The results show that surface active co-formulants significantly increase the cytotoxicity of the investigated PPPs, leading to more than additive mixture effects. Moreover, analytical investigations show higher efflux ratios of both active substances and the metabolite fluroxypyr upon combination with certain concentrations of the surfactants. The results further point to a significant and concentration-dependent inhibition of Pgp transporters by most of the surfactants as well as to increased membrane fluidity. Altogether, these findings strongly support the hypothesis that surfactants contribute to increased cytotoxicity of PPPs and do so by increasing the bioavailability of the respective active substances.

Compounded conservatism in European re-entry worker risk assessment of pesticides.

We review the risk parameters and drivers in the current European Union (EU) worker risk assessment for pesticides, for example considering crop maintenance, crop inspection or harvesting activities, and show that the current approach is very conservative due to multiple worst-case default assumptions. As a case study, we compare generic exposure model estimates with measured worker re-entry exposure values which shows that external cumulative exposure is overpredicted by about 50-fold on average. For this exercise, data from 16 good laboratory practice (GLP)-compliant worker exposure studies in 6 crops were evaluated with a total number of 184 workers. As generic overprediction does not allow efficient risk management or realistic risk communication, we investigate how external exposure can be better predicted within the generic model, and outline options for possible improvements in the current methodology. We show that simply using averages achieves more meaningful exposure estimates, while still being conservative, with an average exposure overprediction of about 9-fold. Overall, EU risk assessment includes several numerically unaccounted "hidden safety factors", which means that workers are well protected; but simultaneously risk assessments are biased towards failing due to compounded conservatism. This should be considered for further global or regional guidance developments and performing more exposure-relevant risk assessment.