Open Access
Open access
Journal of Occupational Medicine and Toxicology, volume 20, issue 1, publication number 7

Cumulative risk assessment methodology applied to non-dietary exposures: developmental alterations in professional agricultural settings

Luca Tosti
, 
Martina Marazzini
, 
Mohammed Kanadil
, 
F Metruccio
Publication type: Journal Article
Publication date: 2025-02-28
scimago Q1
wos Q2
SJR: 0.868
CiteScore: 6.0
Impact factor: 2.9
ISSN: 17456673
Abstract

The safety assessment of combined exposure to xenobiotics has been an emerging topic for several years. Methodologies and approaches for cumulative risk assessment (CRA) are being developed primarily for the dietary risk assessment of pesticides, thus focusing only on consumer exposure. However, as highlighted in recent years, non-dietary exposures, such as those encountered by professionals in agricultural settings, may pose a significant risk due to their higher levels compared to dietary exposure. Despite this, existing methodologies for cumulative risk assessment (CRA) have not adequately addressed this critical aspect. In the EU, even if several legislations highlight the need to address the non-dietary CRA, no legal requirements are in place yet, therefore, there are no harmonized methodologies and approaches currently available. In a first step to fill this gap, this study is aimed at exploring CRA methodology applied to non-dietary exposure to pesticide in agricultural settings, specifically targeting operators, re-entry workers, and bystanders. The primary objective of the study was to verify the feasibility of an electronic register of plant protection treatments as data source for identifying and characterizing in field mixtures and consequently estimating cumulative non-dietary systemic exposure in real life. The relevant active substances selected for this investigation were those listed in foetal craniofacial alterations cumulative assessment groups (CAGs), established by the European Food Safety Authority (EFSA) for dietary CRA. Exposures to pesticides were estimated using European Union agreed mathematical models. The preliminary findings of this investigation effectively revealed the value of the register of treatments in assessing real-life plant protection products (PPP) usage in professional agricultural settings. In conclusion, the study provides encouraging insights into using the pesticide dietary CRA approach for non-dietary risk assessment in agricultural settings, underlining the necessity for further research and investigation of its feasibility for the evaluation of other acute effects but also for long-term effects related CAGs.

Found 13
By date By citations
Wiley
Specific effects on the thyroid relevant for performing a dietary cumulative risk assessment of pesticide residues: 2024 update
Crivellente F., Hernández‐Jerez A.F., Lanzoni A., Metruccio F., Mohimont L., Nikolopoulou D., Castoldi A.F.
EFSA Journal scimago Q1 wos Q2 Open Access , 
2024-03-26,  citations by CoLab: 7 ,  PDF, 
Wiley
Retrospective cumulative dietary risk assessment of craniofacial alterations by residues of pesticides
Anagnostopoulos C., Anastassiadou M., Castoldi A.F., Cavelier A., Coja T., Crivellente F., Dujardin B., Hart A., Hooghe W., Jarrah S., Machera K., Menegola E., Metruccio F., Sieke C., Mohimont L.
EFSA Journal scimago Q1 wos Q2 Open Access , 
2022-10-06,  citations by CoLab: 18 ,  PDF,  Abstract  
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.
Wiley
Guidance on the assessment of exposure of operators, workers, residents and bystanders in risk assessment of plant protection products
Charistou A., Coja T., Craig P., Hamey P., Martin S., Sanvido O., Chiusolo A., Colas M., Istace F.
EFSA Journal scimago Q1 wos Q2 Open Access , 
2022-01-18,  citations by CoLab: 45 ,  PDF,  Abstract  
This guidance is designed to assist risk assessors and applicants when quantifying potential non-dietary, systemic exposures as part of regulatory risk assessment for plant protection products (PPPs). It is based on the Scientific Opinion on 'Preparation of a Guidance Document on Pesticide Exposure Assessment for Workers, Operators, Residents and Bystanders' developed by the EFSA Panel on Plant Protection Products and their Residue (PPR) in 2010. Highlighting some inconsistencies between the approaches adopted by regulatory authorities, the PPR Panel proposed a number of changes to the practices in use (i.e. use of deterministic methods for individual PPPs; need to perform an acute risk assessment for PPPs that are acutely toxic; use of appropriate percentile for acute or longer term risk assessments). In the first version of the guidance, issued in 2014, several scenarios for outdoor uses were included, with an annexed calculator, as well as recommendations for further research. The guidance has been updated in 2021 with the inclusion of additional scenarios and revision of default values, on the basis of the evaluation of additional evidence. To support users in performing the assessment of exposure and risk, an online calculator, reflecting the guidance content, has been further developed.
Elsevier
An adverse outcome pathway on the disruption of retinoic acid metabolism leading to developmental craniofacial defects
Menegola E., Veltman C.H., Battistoni M., Di Renzo F., Moretto A., Metruccio F., Beronius A., Zilliacus J., Kyriakopoulou K., Spyropoulou A., Machera K., van der Ven L.T., Luijten M.
Toxicology scimago Q1 wos Q1 , 
2021-06-26,  citations by CoLab: 18 ,  Abstract  
Adverse outcome pathway (AOP) is a conceptual framework that links a molecular initiating event (MIE) via intermediate key events (KEs) with adverse effects (adverse outcomes, AO) relevant for risk assessment, through defined KE relationships (KERs). The aim of the present work is to describe a linear AOP, supported by experimental data, for skeletal craniofacial defects as the AO. This AO was selected in view of its relative high incidence in humans and the suspected relation to chemical exposure. We focused on inhibition of CYP26, a retinoic acid (RA) metabolizing enzyme, as MIE, based on robust previously published data. Conazoles were selected as representative stressors. Intermediate KEs are RA disbalance, aberrant HOX gene expression, disrupted specification, migration, and differentiation of neural crest cells, and branchial arch dysmorphology. We described the biological basis of the postulated events and conducted weight of evidence (WoE) assessments. The biological plausibility and the overall empirical evidence were assessed as high and moderate, respectively, the latter taking into consideration the moderate evidence for concordance of dose-response and temporal relationships. Finally, the essentiality assessment of the KEs, considered as high, supported the robustness of the presented AOP. This AOP, which appears of relevance to humans, thus contributes to mechanistic underpinning of selected test methods, thereby supporting their application in integrated new approach test methodologies and strategies and application in a regulatory context.
Wiley
Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals
More S.J., Bampidis V., Benford D., Bennekou S.H., Bragard C., Halldorsson T.I., Hernández‐Jerez A.F., Koutsoumanis K., Naegeli H., Schlatter J.R., Silano V., Nielsen S.S., Schrenk D., Turck D., Younes M., et. al.
EFSA Journal scimago Q1 wos Q2 Open Access , 
2019-03-25,  citations by CoLab: 257 ,  PDF,  Abstract  
This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. The framework is based on the risk assessment steps (problem formulation, exposure assessment, hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture approaches and component-based approaches. Specific considerations are given to component-based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended.
Wiley
Guidance on dermal absorption
Buist H., Craig P., Dewhurst I., Hougaard Bennekou S., Kneuer C., Machera K., Pieper C., Court Marques D., Guillot G., Ruffo F., Chiusolo A.
EFSA Journal scimago Q1 wos Q2 Open Access , 
2017-06-30,  citations by CoLab: 87 ,  PDF,  Abstract  
This guidance on the assessment of dermal absorption has been developed to assist notifiers, users of test facilities and Member State authorities on critical aspects related to the setting of dermal absorption values to be used in risk assessments of active substances in Plant Protection Products (PPPs). It is based on the 'scientific opinion on the science behind the revision of the guidance document on dermal absorption' issued in 2011 by the EFSA Panel on Plant Protection Products and their Residues (PPR). The guidance refers to the EFSA PPR opinion in many instances. In addition, the first version of this guidance, issued in 2012 by the EFSA PPR Panel, has been revised in 2017 on the basis of new available data on human in vitro dermal absorption for PPPs and wherever clarifications were needed. Basic details of experimental design, available in the respective test guidelines and accompanying guidance for the conduct of studies, have not been addressed but recommendations specific to performing and interpreting dermal absorption studies with PPPs are given. Issues discussed include a brief description of the skin and its properties affecting dermal absorption. To facilitate use of the guidance, flow charts are included. Guidance is also provided, for example, when there are no data on dermal absorption for the product under evaluation. Elements for a tiered approach are presented including use of default values, data on closely related products, in vitro studies with human skin (regarded to provide the best estimate), data from experimental animals (rats) in vitro and in vivo, and the so called 'triple pack' approach. Various elements of study design and reporting that reduce experimental variation and aid consistent interpretation are presented. A proposal for reporting data for assessment reports is also provided. The issue of nanoparticles in PPPs is not addressed. Data from volunteer studies have not been discussed since their use is not allowed in EU for risk assessment of PPPs.
Springer Nature
A new model for the prediction of agricultural operator exposure during professional application of plant protection products in outdoor crops
Großkopf C., Mielke H., Westphal D., Erdtmann-Vourliotis M., Hamey P., Bouneb F., Rautmann D., Stauber F., Wicke H., Maasfeld W., Salazar J.D., Chester G., Martin S.
Journal fur Verbraucherschutz und Lebensmittelsicherheit scimago Q3 wos Q4 , 
2013-08-13,  citations by CoLab: 37 ,  Abstract  
A new predictive model for the estimation of agricultural operator exposure has been developed on the basis of new exposure data to improve the current agricultural operator exposure and risk assessment in the EU. The new operator exposure model represents current application techniques and practices in EU Member States (MS) and is applicable for national or zonal authorisation of plant protection products as well as for approval of active substances in plant protection products (PPP) supporting a stepwise risk assessment. 34 unpublished exposure studies conducted between 1994 and 2009 were evaluated for the new model. To ensure a very high quality of data the studies had to meet a set of quality criteria, e.g. GLP conformity or compliance with OECD guidance. Exposure data and supplementary information on the trials were used for a statistical analysis of exposure factors. The statistical analyses resulted in six validated models for typical outdoor scenarios of pesticide mixing/loading and application. As a major factor contributing to the exposure of operators, the amount of active substance used per day was identified. Other parameters such as formulation type, droplet size, presence of a cabin or density of the canopy were selected as factors for sub-scenarios. For two scenarios the corresponding datasets were too small to identify reliable exposure factors; instead the relevant percentiles of the exposure distribution were used. The whole project report on the development of the new model (including the underlying study data) and the corresponding exposure calculators will be published at the BfR website ( http://www.bfr.bund.de ) after confirmation of the model by EU MS.
Wiley
Scientific Opinion on the identification of pesticides to be included in cumulative assessment groups on the basis of their toxicological profile
EFSA Journal scimago Q1 wos Q2 Open Access , 
2013-07-01,  citations by CoLab: 93 ,  PDF,  Abstract  
The European Food Safety Authority asked the Panel on Plant Protection Products and their Residues to develop an Opinion on the identification of pesticides to be included in cumulative assessment groups (CAGs) on the basis of their toxicological profile. In 2008, the PPR Panel adopted an Opinion on the suitability of existing methodologies for cumulative risk assessment of pesticides and a tiered approach was proposed, which was applied to a selected group of triazole pesticides in 2009. The present Opinion suggests a methodology for grouping of pesticides based on phenomenological effects and provides CAGs for the thyroid and nervous system. This approach can be applied even when the underlying biochemical events mediating the effects are not understood, and is based on a standardised and thorough review of Draft Assessment Reports (DARs) supporting the approval of all pesticides in Europe, and on recommendations from the European Commission. Pesticidal active substances exhibiting neurotoxic properties were allocated to CAGs for acute effects on motor, sensory and autonomic divisions of the nervous system and neurochemical endpoints. Chronic effects across the same divisions/endpoints and neuropathological effects were collated. Active substances having adverse effects on the thyroid system were allocated to CAGs for effects either on C-cells/the calcitonin system or on follicular cells/the T3/T4 system. The PPR Panel notes that the resulting groups encompass many pesticides and also that individual pesticides could appear in several groups and therefore the data entries for performing cumulative risk assessment (CRA) are of considerable magnitude. Although some CAGs contain a large number of pesticides, little indication of cumulative risk may be inferred from the size of CAGs per se. The PPR Panel recommends that the methodology is implemented for all major organ/systems but the approach used should be considered specific for pesticides.
Elsevier
Stage-dependent abnormalities induced by the fungicide triadimefon in the mouse☆
Di Renzo F., Broccia M.L., Giavini E., Menegola E.
Reproductive Toxicology scimago Q2 wos Q2 , 
2011-02-01,  citations by CoLab: 13 ,  Abstract  
Aim of this work is the study of abnormalities induced by the triazole triadimefon (FON) administered to pregnant mice at E8, E9, E10, E11 or E12. Pregnant CD-1 mouse were gavaged with FON 500 mg/kg at the selected stages and sacrificed at term and fetuses morphologically examined and processed for visceral and skeletal analysis. Administration of FON on E8, E10-E12 resulted in fetuses with cleft palate (E8 39% and E12 24% representing the peak of sensitivity, in E8 fetuses associated to severe skull basis abnormalities). Other cranial malformations (fusions abnormalities or agenesis of bones) were observed in E8-E10 groups (E8 the most sensitive with 96% of malformed fetuses). Cardiovascular abnormalities were observed in a stage dependent manner at E8-E10 (22.2, 3.8, 7.8%). As far as craniofacial malformation is concerned, we propose that FON acts on two different stages, involved in early and late craniofacial formation.
Wiley
Scientific Opinion on Risk Assessment for a Selected Group of Pesticides from the Triazole Group to Test Possible Methodologies to Assess Cumulative Effects from Exposure through Food from these Pesticides on Human Health
EFSA Journal scimago Q1 wos Q2 Open Access , 
2009-09-01,  citations by CoLab: 71 ,  PDF, 
Springer Nature
Guidance for Exposure and Risk Evaluation for Bystanders and Residents exposed to Plant Protection Products during and after Application
Martin S., Westphal D., Erdtmann-Vourliotis M., Dechet F., Schulze-Rosario C., Stauber F., Wicke H., Chester G.
Journal fur Verbraucherschutz und Lebensmittelsicherheit scimago Q3 wos Q4 , 
2008-08-04,  citations by CoLab: 36 ,  Abstract  
Plant protection products are applied in agriculture and horticulture in areas that may be accessible to the public. This means that individuals might be exposed who are not actively involved in the application of these products. The individual may be temporarily located in the vicinity of the application (the so-called ‘bystander’) or working or living in the vicinity of the application (the so-called ‘resident’). In this guidance paper scenarios for the evaluation of exposure associated with plant protection product application for bystanders and for residents (including children) are described.
SAGE
Developmental and Reproduction Toxicology—A Practical Approach, Second Edition Edited by Ronald D. Hood Publisher: CRC Press, Taylor & Francis Group. 2006. ISBN: 0 8493-1254-X. 1149 pages. Price: $179.95.
Kapp R.W.
International Journal of Toxicology scimago Q3 wos Q4 , 
2007-01-01,  citations by CoLab: 1 , 
Taylor & Francis
EUROPOEM, A Predictive Occupational Exposure Database for Registration Purposes of Pesticides
Van Hemmen J.J.
Applied Occupational and Environmental Hygiene , 
2001-01-01,  citations by CoLab: 36 ,  Abstract  
For registration of agricultural pesticides, the risks for humans, animals, and the environment must be determined. The risk assessment is based on an appraisal of the levels of exposure and the hazards of the active substance(s) in the plant protection product, that is, the agricultural pesticide. Funded by the European Commission (AIR3 CT93-1370), the EUROPOEM database has been developed by a group of experts, representing governments, industry, and academia. The currently available exposure database reflects exposure to operators (mixer/loaders and applicators). The EUROPOEM approach is based on a harmonized protocol for conduct of field studies of operator exposure (presently published as an Organization for Economic Cooperation and Development [OECD] Guidance Document) and a tiered approach to exposure and risk assessment. The database is constructed from exposure data obtained in representative field studies. These field studies are considered according to criteria reflecting the quality of documentation, study design, adequate methodology, number of replicates, and QA/QC elements, for use of the inhalation and dermal exposure data. The resulting exposure data were combined according to comparable use scenarios. From the resulting databases typical surrogate potential exposure values have been obtained, which are determined by their use for either acute or chronic health effects, and the size of the database. For large databases (over 50-100 data points), from many different field studies (10 or more), the 75th percentile is taken if the exposure is considered leading to chronic effects. For smaller databases, a more conservative 90th percentile is taken as surrogate value, or none at all for very small databases (15-20 or less data points from 3 or less different field studies). The choice for the 75th percentile is based on the assumed or observed lognormal distribution of the exposure data, as being the most relevant typical value for long-term effects, since the 75th percentile of log-normal distributions is nominally very similar to a calculated arithmetic mean (AM). The AM, as such however, is irrelevant for log-normal distributions.

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