Proposals for new spray drift exposure values in orchards and vineyards for residents and bystanders.

In the EU, predicted exposure to spray drift for residents and bystanders from applications in orchards and vineyards is based on data from one study published in 1987, where one downwind distance (8 m) was considered. CropLife Europe conducted sixteen new GLP compliant studies in 4 EU countries, 8 in orchards, 8 in vineyards with early and late season applications, using adult and child mannequins located 5, 10 and 15 m downwind from the last row to measure dermal and inhalation exposures. The resulting "Bystander Resident Orchard Vineyard (BROV)" database comprises 288 observations and offers a more comprehensive option for exposure prediction. There were differences between adult and child, crop type, leaf cover and distance from the sprayer, supporting the derivation of mean, median, 75th and 95th percentile exposures for each subset. Exposures did not generally correlate with wind speed, wind direction, sprayer type, spray quality, spray concentration or amount applied. Dermal and inhalation exposure were lower in vineyards than in orchards and further analysis is required to understand why.

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.

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.

Practical guidance to evaluate in vitro dermal absorption studies for pesticide registration: An industry perspective.

While there are some regulatory assessment criteria available on how to generally evaluate dermal absorption (DA) studies for risk assessment purposes, practical guidance and examples are lacking. The current manuscript highlights the challenges in interpretating data from in vitro assays and proposes holistic data-based assessment strategies from an industry perspective. Inflexible decision criteria may be inadequate for real data and may lead to irrelevant DA estimates. We recommend the use of mean values for reasonably conservative DA estimates from in vitro studies. In cases where additional conservatism is needed, e.g., due to non-robust data and acute exposure scenarios, the upper 95% confidence interval of the mean may be appropriate. It is critical to review the data for potential outliers and we provide some example cases and strategies to identify aberrant responses. Some regional regulatory authorities require the evaluation of stratum corneum (SC) residue, but here, as a very simple pro-rata approach, we propose to review whether the predicted post 24-h absorption flux exceeds the predicted elimination flux by desquamation because otherwise it is not possible for the SC residue to contribute to systemic dose. Overall, the adjustment of DA estimates due to mass balance (normalization) is not recommended.

Measured air concentrations of pesticides for the estimation of exposure to vapour in European risk assessments.

There is an identified need to revise the default air concentration values and assumptions applied in assessing vapour exposure in the risk assessment of bystanders and residents to plant protection products. To address this, we evaluated inhalation exposure via vapour using previously unpublished data from 29 field and wind tunnel studies. The database comprises 35 trials with 11 active ingredients covering a wide range of scenarios with respect to vapour pressure, crops, application rates and European regions. Of the 961 individual measurements, 634 were below the Limit of Detection (LOD), 282 were between the LOD and Limit of Quantification (LOQ) and only 45 (4.7%) were quantifiable. Ten individual non-normalized samples exceeded 0.1 µg/m³. Of the 81 first-day measurements after the application, 36 were

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.

An OECD TG 428 study ring trial with 14C-Caffeine demonstrating repeatability and robustness of the dermal absorption in vitro method.

The dermal absorption potential of 14C-Caffeine applied as a 4 mg/mL concentration (10 µL/cm2 finite dose) was investigated in six laboratories under Good Laboratory Practice conditions using an OECD TG 428-compliant in vitro assay with flow-through cells and split-thickness human skin. Potential sources of variation were reduced by a standardized protocol, test item and skin source. Particularly, skin samples from same donors were distributed over two repeats and between labs in a non-random, stratified design. Very similar recovery was achieved in the various assay compartments between laboratories, repeats and donors, demonstrating that the assay can be robustly and reliably performed. The absorption in one laboratory was 5-fold higher than in the others. This did not clearly correlate with skin integrity parameters but might be associated with an accidental COVID-19 pandemic-related interruption in sample shipment. It is possible that other factors may affect dermal absorption variation not routinely assessed or considered in the current method. The mean receptor fluid recovery, potential absorption (recovery in receptor fluid and skin except tape strips 1 and 2) and mass balance of caffeine was 6.99%, 7.14% and 99.13%, respectively, across all and 3.87%, 3.96% and 99.00% in the subset of five laboratories.

Review of air concentrations of pesticides for estimating exposure to vapour in European risk assessments.

In current European non-dietary risk assessment for bystanders and residents, one of the plant protection product exposure pathways to be addressed is vapour inhalation. At present, active ingredients are grouped according to vapour pressure and assigned corresponding values. Risk assessments are driven by only two default air concentration values. Sampling is inconsistent, background data are sparse and many factors having an impact on air concentrations are not considered. Within the changing regulatory landscape over the last 20 years, criteria for volatility grouping and consequently for vapour exposure estimation have been applied heterogeneously. Here we review the background data currently used in the exposure assessment guidance to demonstrate the arbitrary nature of derived air concentration values and their inconsistent application in exposure assessment. In doing so we discuss air concentration from a risk assessment perspective and how active ingredients are grouped according to vapour pressure. We examine the database which at present forms the basis for predicting inhalation exposure to PPPs, particularly the two concentration levels driving risk assessments, and we discuss several other factors having an impact on air concentration. In conclusion, we recommend an urgent revision of the default air concentration values and assumptions applied in assessing vapour exposure.

Dose Setting for Dermal Absorption Studies on Dried Foliar Residues.

Currently, the standard approach to estimate systemic exposure of workers after contact with dried pesticide residues on crops during re-entry activities relies on using the highest identified dermal absorption value for aqueous spray dilutions. However, recent dermal absorption studies with dried residues and their respective in-use dilutions have shown that this is likely to significantly overestimate their dermal penetration potential and, thus, predicted systemic exposure. The choice of appropriate dose levels for these dermal absorption studies has not been defined. Moreover, actual skin loading during re-entry tasks may differ significantly from that achieved by applying a fixed volume of an aqueous dilution, which is the standard practice in generic dermal absorption studies. To address this, we propose an approach to dose setting for dried residue studies within the current European risk assessment framework. Skin loading for studies can be calculated from the existing exposure algorithms and by taking appropriate body surface areas into account. Thus, skin loading in studies will vary depending on the exact nature and duration of the task and the region of the body exposed, reflecting actual exposure scenarios.

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.

Dermal absorption study OECD TG 428 mass balance recommendations based on the EFSA database.

The European Food Safety Authority (EFSA) guidance (EFSA, 2017) for dermal absorption (DA) studies recommends stringent mass balance (MB) limits of 95-105%. EFSA suggested that test material can be lost after penetration and requires that for chemicals with <5% absorption the non-recovered material must be added to the absorbed dose if MB is <95%. This has huge consequences for low absorption pesticides. Indeed, one third of the MBs in the EFSA DA database are outside the refined criteria. This is also true for DA data generated by Cosmetics Europe (Gregoire et al., 2019), indicating that this criterion is often not achieved even when using highly standardized protocols. While EFSA hypothesizes that modern analytical and pipetting techniques would enable to achieve this criterion, no scientific basis was provided. We describe how protocol procedures impact MB and evaluate the EFSA DA database to demonstrate that MB is subject to random variation. Generic application of "the addition rule" skews the measured data and increases the DA estimate, which results in unnecessary risk assessment failure. In conclusion, "missing material" is just a random negative deviation to the nominal dose. We propose a data-driven MB criterion of 90-110%, fully in line with OECD recommendations.