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.

Risks of Plastic Debris: Unravelling Fact, Opinion, Perception, and Belief.

Researcher and media alarms have caused plastic debris to be perceived as a major threat to humans and animals. However, although the waste of plastic in the environment is clearly undesirable for aesthetic and economic reasons, the actual environmental risks of different plastics and their associated chemicals remain largely unknown. Here we show how a systematic assessment of adverse outcome pathways based on ecologically relevant metrics for exposure and effect can bring risk assessment within reach. Results of such an assessment will help to respond to the current public worry in a balanced way and allow policy makers to take measures for scientifically sound reasons.

Comparison of the mouse Embryonic Stem cell Test, the rat Whole Embryo Culture and the Zebrafish Embryotoxicity Test as alternative methods for developmental toxicity testing of six 1,2,4-triazoles.

The relatively high experimental animal use in developmental toxicity testing has stimulated the search for alternatives that are less animal intensive. Three widely studied alternative assays are the mouse Embryonic Stem cell Test (EST), the Zebrafish Embryotoxicity Test (ZET) and the rat postimplantation Whole Embryo Culture (WEC). The goal of this study was to determine their efficacy in assessing the relative developmental toxicity of six 1,2,4-triazole compounds,(1) flusilazole, hexaconazole, cyproconazole, triadimefon, myclobutanil and triticonazole. For this purpose, we analyzed effects and relative potencies of the compounds in and among the alternative assays and compared the findings to their known in vivo developmental toxicity. Triazoles are antifungal agents used in agriculture and medicine, some of which are known to induce craniofacial and limb abnormalities in rodents. The WEC showed a general pattern of teratogenic effects, typical of exposure to triazoles, mainly consisting of reduction and fusion of the first and second branchial arches, which are in accordance with the craniofacial malformations reported after in vivo exposure. In the EST all triazole compounds inhibited cardiomyocyte differentiation concentration-dependently. Overall, the ZET gave the best correlation with the relative in vivo developmental toxicities of the tested compounds, closely followed by the EST. The relative potencies observed in the WEC showed the lowest correlation with the in vivo developmental toxicity data. These differences in the efficacy between the test systems might be due to differences in compound kinetics, in developmental stages represented and in the relative complexity of the alternative assays.

Cumulative risk assessment of pesticide residues in food.

There is increasing need to address the potential risks of combined exposures to multiple residues from pesticides in the diet. The available evidence suggests that the main concern is from dose addition of those compounds that act by the same mode of action. The possibility of synergy needs to be addressed on a case-by-case basis, where there is a biologically plausible hypothesis that it may occur at the levels of residues occurring in the diet. Cumulative risk assessment is a resource-intense activity and hence a tiered approach to both toxicological evaluation and intake estimation is recommended, and the European Food Safety Authority (EFSA) has recently published such a proposal. Where assessments have already been undertaken by some other authority, full advantage should be taken of these, subject of course to considerations of quality and relevance. Inclusion of compounds in a cumulative assessment group (CAG) should be based on defined criteria, which allow for refinement in a tiered approach. These criteria should include chemical structure, mechanism of pesticidal action, target organ and toxic mode of action. A number of methods are available for cumulating toxicity. These are all inter-related, but some are mathematically more complex than others. The most useful methods, in increasing levels of complexity and refinement, are the hazard index, the reference point index, the Relative Potency Factor method and physiologically based toxicokinetic modelling, although this last method would only be considered should a highly refined assessment be necessary. Four possible exposure scenarios are of relevance for cumulative risk assessment, acute and chronic exposure in the context of maximum residue level (MRL)-setting, and in relation to exposures from the actual use patterns, respectively. Each can be addressed either deterministically or probabilistically. Strategies for dealing with residues below the limit of detection, limit of quantification or limit of reporting need to be agreed. A number of probabilistic models are available, but some of there are geographically constrained due to the underlying datasets used in their construction. Guidance on probabilistic modelling needs to be finalised. Cumulative risk assessments have been performed in a number of countries, on organophosphate insecticides alone (USA) or together with carbamates (UK, DK, NL), triazines, chloroacetanilides, carbamates alone (USA), and all pesticides (DE). All identifiable assumptions and uncertainties should be tabulated and evaluated, at least qualitatively. Those likely to have a major impact on the outcome of the assessment should be examined quantitatively. In cumulative risk assessment, it is necessary, as in other risk assessments, for risk managers to consider what level of risk would be considered "acceptable", for example what percentile of the population should be below the reference value. Criteria for prioritising CAGs for cumulative risk assessment include frequency of detection in monitoring programmes, high usage, high exposure relative to the reference value, large number of compounds (e.g. five or more) in a group.