Setting the stage for the review of the international estimate of short-term intake (IESTI) equation.

In the framework of setting Maximum Residue Limits (MRLs) for pesticides, both chronic and acute health risks to consumers arising from the long-term and short-term dietary exposure to pesticide residues have to be assessed. The current internationally harmonized approach for assessing the acute dietary exposure is based on deterministic methods for calculating the IESTI (International Estimate of Short-Term Intake). Recently, it became apparent that the IESTI approach needs a revision in the light of new scientific and political aspects. The main reasons that require this review were the lack of an international harmonization of the methodology which implies trade barriers as well as difficulties in risk communication concerning the public trust in regulatory systems. The most recent milestone in the scientific debate on a possible revision of the IESTI equation was an international scientific workshop held in Geneva in September 2015. The main objectives of this meeting were the re-evaluation, and where possible, the international harmonization of the input parameters for the IESTI equations as well as the equations themselves. The main recommendations from the workshop were (i) to replace the highest residue and supervised trials median residue with the maximum residue limit (MRL), (ii) to use a standard variability factor of three, (iii) to derive the P97.5 large portion value from the distribution of consumption values of dietary surveys expressed as kg food/kg bw/d, and (iv) to remove the commodity unit weight from the equations. In addition, the application of conversion factors and processing factors was addressed. On the initiative of the (World Health Organization) WHO Collaborating Centre on Chemical Food Safety at the National Institute for Public Health and the Environment (RIVM), the Netherlands, an international working group with members from the French Agency for Food, Environmental and Occupational Health and Safety, France (ANSES), Australian Pesticides and Veterinary Medicines Authority, Australia (APVMA), German Federal Institute for Risk Assessment, Germany (BfR), Chemical Regulation Division, the United Kingdom (CRD), European Food Safety Authority (EFSA), and RIVM, the Netherlands was formed after the IESTI workshop to conduct a comprehensive impact assessment of the proposed changes of the IESTI equations.

Impact of a proposed revision of the IESTI equation on the acute risk assessment conducted when setting maximum residue levels (MRLs) in the European Union (EU): A case study.

Proposals to update the methodology for the international estimated short-term intake (IESTI) equations were made during an international workshop held in Geneva in 2015. Changes to several parameters of the current four IESTI equations (cases 1, 2a, 2b, and 3) were proposed. In this study, the overall impact of these proposed changes on estimates of short-term exposure was studied using the large portion data available in the European Food Safety Authority PRIMo model and the residue data submitted in the framework of the European Maximum Residue Levels (MRL) review under Article 12 of Regulation (EC) No 396/2005. Evaluation of consumer exposure using the current and proposed equations resulted in substantial differences in the exposure estimates; however, there were no significant changes regarding the number of accepted MRLs. For the different IESTI cases, the median ratio of the new versus the current equation is 1.1 for case 1, 1.4 for case 2a, 0.75 for case 2b, and 1 for case 3. The impact, expressed as a shift in the IESTI distribution profile, indicated that the 95th percentile IESTI shifted from 50% of the acute reference dose (ARfD) with the current equations to 65% of the ARfD with the proposed equations. This IESTI increase resulted in the loss of 1.2% of the MRLs (37 out of 3110) tested within this study. At the same time, the proposed equations would have allowed 0.4% of the MRLs (14 out of 3110) that were rejected with the current equations to be accepted. The commodity groups that were most impacted by these modifications are solanacea (e.g., potato, eggplant), lettuces, pulses (dry), leafy brassica (e.g., kale, Chinese cabbage), and pome fruits. The active substances that were most affected were fluazifop-p-butyl, deltamethrin, and lambda-cyhalothrin.

Impact of proposed changes in IESTI equations for short-term dietary exposure to pesticides from Australian and Codex perspective.

In 2015 a scientific workshop was held in Geneva, where updating the four equations for estimating the short-term dietary exposure (International Estimated Short Term Intake, IESTI) to pesticides was suggested. The impact of these proposed changes on the exposure was studied by using residue data and large portion consumption data from Codex and Australia. For the Codex data, the exposure increased by a median factor of 2.5 per commodity when changing to the proposed IESTI equations. The increase in exposure was highest for bulked and blended food commodities (case 3 equations), followed by medium-sized food commodities (case 2a equations) and small- and large-sized food commodities (case 1 and case 2b equations). For the Australian data, out of 184 maximum residue limit (MRL) large portion combinations showing acute exposures below the acute reference dose (ARfD) with the current IESTI equations, 23 exceeded the ARfD with the proposed IESTI equations (12%). The percentage exceeding the ARfD was higher for the Australian MRL large portion combinations (12% of 184) than for those of Codex (1.3% of 8,366). However, the percentage MRL loss in the Australian dataset may not be representative of all pesticide MRLs since it concerns six pesticides only, specifically selected to elucidate the potential effects of the use of the proposed IESTI equations. For the Codex data, the increase in exposure using the proposed equations resulted in a small increased loss of 2.6% of the 1,110 MRLs estimated by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR): 1.4% of the MRLs were already not acceptable with the current equations, 4.0% of the MRLs were not acceptable with the newly proposed equations. Our study revealed that case 3 commodities may be impacted more by the proposed changes than other commodities. This substantiates one of the conclusions of the Geneva workshop to gather information on bulking and blending practices in order to refine MRL setting and dietary risk assessment for case 3 commodities where possible.

Effect of individual parameter changes on the outcome of the estimated short-term dietary exposure to pesticides.

In 2015 a scientific workshop was held in Geneva, where updating the International Estimate of Short-Term Intake (IESTI) equations was suggested. This paper studies the effects of the proposed changes in residue inputs, large portions, variability factors and unit weights on the overall short-term dietary exposure estimate. Depending on the IESTI case equation, a median increase in estimated overall exposure by a factor of 1.0-6.8 was observed when the current IESTI equations are replaced by the proposed IESTI equations. The highest increase in the estimated exposure arises from the replacement of the median residue (STMR) by the maximum residue limit (MRL) for bulked and blended commodities (case 3 equations). The change in large portion parameter does not have a significant impact on the estimated exposure. The use of large portions derived from the general population covering all age groups and bodyweights should be avoided when large portions are not expressed on an individual bodyweight basis. Replacement of the highest residue (HR) by the MRL and removal of the unit weight each increase the estimated exposure for small-, medium- and large-sized commodities (case 1, case 2a or case 2b equations). However, within the EU framework lowering of the variability factor from 7 or 5 to 3 counterbalances the effect of changes in other parameters, resulting in an estimated overall exposure change for the EU situation of a factor of 0.87-1.7 and 0.6-1.4 for IESTI case 2a and case 2b equations, respectively.

Proportionality principle revisited - relationship between application rates and pesticide residue concentrations in food commodities.

BACKGROUND: The proportionality principle has been broadly used for over 10 years in regulatory assessments of pesticide residues. It allows extrapolation of supervised field trial data conducted at lower or higher application rates compared to the use pattern under evaluation by adjustment of measured concentrations, assuming direct proportionality between the rates applied and the resulting residues. This work revisits the principle idea by using supervised residue trials sets conducted under identical conditions but with deviating application rates. Four different statistical methods were used to investigate the relationship between application rates and residue concentrations and to draw conclusions on the statistical significance of the direct proportionality assumed. RESULTS: Based on over 5000 individual trial results, the assumption of direct proportionality was not confirmed to be statistically significant (P > 0.05) using three models: direct comparison of application rates and residue concentrations ratios and two linear log-log regression models correlating application rate and residue concentration or only residue concentrations per se. In addition, a fourth model analysed deviations between expected concentrations following direct proportional adjustment and measured residue values from corresponding field trials. In 56% of all cases, the deviation was larger than ±25%, which represents the tolerance usually accepted for the selection of supervised field trials in regulatory assessments. CONCLUSION: Overall, the assumption of direct proportionality between application rates and resulting residue concentrations of pesticides was not statistically significant. Although the proportionality approach is highly pragmatic in regulatory practice, its use should be considered carefully on a case-by-case basis. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Long-term dietary exposure to copper in the population in Germany - Results from the BfR MEAL study.

The German Total Diet Study (BfR MEAL Study) measured copper in 356 foods. In 105 of these foods copper was determined separately for conventionally and organically pooled samples. Mammalian liver, nuts, oilseeds, cocoa powder and chia seeds contained the highest copper levels. Organically produced foods tended to have higher levels compared to conventionally produced foods. Children's copper exposure was between 0.04 mg/kg body weight per day (mg/kg bw/day) and 0.07 mg/kg bw/day (median). High exposure (95th percentile) ranged between 0.07 mg/kg bw/day and 0.11 mg/kg bw/day. Adult's exposure ranged between 0.02 mg/kg bw/day (median) and 0.04 mg/kg bw/day (95th percentile). Grains and grain-based products were main contributors for all age groups. Copper intake was about 10% higher in a scenario where consumers select the organically produced variants. Children's median and high exposure was above the acceptable daily intake (ADI) of 0.07 mg/kg bw/day set by the European Food Safety Authority (EFSA). However, according to EFSA's evaluation this is not of concern due to higher requirement related to growth. For adults, frequent consumers of mammalian liver exceeded the ADI in median and 95th percentile. Intake of copper-containing dietary supplements may also lead to exceedance of the ADI in all age groups.

Retrospective cumulative dietary risk assessment of craniofacial alterations by residues of pesticides.

EFSA established cumulative assessment groups and conducted retrospective cumulative risk assessments for two types of craniofacial alterations (alterations due to abnormal skeletal development, head soft tissue alterations and brain neural tube defects) for 14 European populations of women in childbearing age. Cumulative acute exposure calculations were performed by probabilistic modelling using monitoring data collected by Member States in 2017, 2018 and 2019. A rigorous uncertainty analysis was performed using expert knowledge elicitation. Considering all sources of uncertainty, their dependencies and differences between populations, it was concluded with varying degrees of certainty that the MOET resulting from cumulative exposure is above 100 for the two types of craniofacial alterations. The threshold for regulatory consideration established by risk managers is therefore not exceeded. Considering the severity of the effects under consideration, it was also assessed whether the MOET is above 500. This was the case with varying levels of certainty for the head soft tissue alterations and brain neural tube defects. However, for the alterations due to abnormal skeletal development, it was found about as likely as not that the MOET is above 500 in most populations. For two populations, it was even found more likely that the MOET is below 500. These results were discussed in the light of the conservatism of the methodological approach.

Identification of a pesticide exposure based market basket suitable for cumulative dietary risk assessments and food monitoring programmes.

Consideration of cumulative dietary risks is a requirement in the European legislation for setting maximum residue levels for pesticides. Current cumulative exposure assessment methodologies strongly rely on representative occurrence data from food monitoring programmes. This study provides a sensitivity analysis, utilising (i) European consumption data expressed as raw agricultural commodity (RAC) equivalents from 23 different countries as published by the European Food Safety Authority and (ii) all maximum residue levels established for pesticides under European Regulation (EC) No 396/2005. Based on two different degrees of conservatism, market baskets consisting of 16 or 41 RACs, respectively, were identified, covering the majority of the total chronic and acute daily exposure. The coverage of the exposure by these market baskets was tested by comparison of cumulative probabilistic exposure assessments for the German population using all food commodities and those using the reduced sets. It was demonstrated that ≥85% of the total chronic exposure is already covered by 16 RACs, while 41 RACs are required to reach a similarly satisfying coverage of the total acute exposure. Results from this study support resource efficient modelling of complex cumulative assessment scenarios and may help to improve the design of food monitoring programmes with respect to a more efficient assessment of potential consumer risks.

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.