Toxicological risk assessment of plant protection products (PPP) is currently carried out with the principal input from regulatory toxicology studies following OECD test guidelines, with little input from epidemiological data. An EFSA-commissioned systematic review of pesticide epidemiological studies (Ntzani et al. in Literature review on epidemiological studies linking exposure to pesticides and health effects. EFSA supporting publication 2013:EN-497, 2013) revealed statistically significant associations, among others, between pesticide exposures, and Parkinson’s disease and childhood leukemia. Thereafter, EFSA launched a project with a mandate for the plant protection products and their residues (PPR) Panel to set the ground for the use of epidemiological data in the risk assessment of pesticides, as requested by Regulation (EC) 1107/2009. The project culminated with the publication of two EFSA’s scientific opinions on the potential contribution of experimental investigations and epidemiological studies in PPP risk assessment and with the scientific conference held on 20 November 2017, in Parma, Italy. The application of modern methodologies in exposure assessment, toxicology and epidemiology would improve the pesticide risk assessment process and support a mechanistic shift for the integration of these three disciplines under a novel paradigm in risk assessment. The application of the adverse outcome pathway (AOP) conceptual framework to this approach would contribute to gain insight into the biological plausibility of a hazard identified in epidemiological or experimental studies and would inform an Integrated Approach to Testing and Assessment (IATA) within a regulatory context.
This is a preview of subscription content, log in to check access.
Buy single article
Instant unlimited access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Andreotti G, Koutros S, Hofmann JN, Sandler DP, Lubin JH, Lynch CF, Lerro CC, De Roos AJ, Parks CG, Alavanja MC, Silverman DT, Beane Freeman LE (2018) Glyphosate use and cancer incidence in the agricultural health study. J Natl Cancer Inst 110:509–516
Bal-Price A, Meek MEB (2017) Adverse outcome pathways: application to enhance mechanistic understanding of neurotoxicity. Pharmacol Ther 179:84–95. https://doi.org/10.1016/j.pharmthera.2017.05.006
Bal-Price A, Lein PJ, Keil KP, Sethi S, Shafer T, Barenys M, Fritsche E, Sachana M, Meek ME (2017) Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity. Neurotoxicology 59:240–255. https://doi.org/10.1016/j.neuro.2016.05.010
Bal-Price A, Leist M, Schildknecht S, Tschudi-Monnet F, Paini A, Terron A (2018a) Adverse outcome pathway on inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits. OECD Series on Adverse Outcome Pathways, No. 7, OECD Publishing, Paris. https://doi.org/10.1787/b46c3c00-en
Bal-Price A, Leist M, Schildknecht S, Tschudi-Monnet F, Paini A, Terron A (2018b) Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits (AOP 3). Draft version under review. https://aopwiki.org/aops/3. Accessed 02 Dec 2018
Bhat VS, Meek MEB, Valcke M, English C, Boobis A, Brown R (2017) Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance. Crit Rev Toxicol 47(9):729–749. https://doi.org/10.1080/10408444.2017.1303818
Choi J, Polcher A, Joas A (2016) Systematic literature review on Parkinson’s disease and Childhood Leukaemia and mode of actions for pesticides. EFSA Supporting Publications 19 January 2016. https://doi.org/10.2903/sp.efsa.2016.EN-955
Delrue N, Sachana M, Sakuratani Y, Gourmelon A, Leinala E, Diderich R (2016) The adverse outcome pathway concept: a basis for developing regulatory decision-making tools. Altern Lab Anim 44(5):417–429
Edwards SW, Tan YM, Villeneuve DL, Meek ME, McQueen CA (2016) Adverse outcome pathways-organizing toxicological information to improve decision making. J Pharmacol Exp Ther 356(1):170–181. https://doi.org/10.1124/jpet.115.228239
EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues), Ockleford C, Adriaanse P, Berny P, Brock T, Duquesne S, Grilli S, Hernandez-Jerez AF, Bennekou SH, Klein M, Kuhl T, Laskowski R, Machera K, Pelkonen O, Pieper S, Smith R, Stemmer M, Sundh I, Teodorovic I, Tiktak A, Topping CJ, Wolterink G, Angeli K, Fritsche E, Hernandez-Jerez AF, Leist M, Mantovani A, Menendez P, Pelkonen O, Price A, Viviani B, Chiusolo A, Ruffo F, Terron A, Bennekou SH (2017a) Scientific Opinion on the investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson’s disease and childhood leukaemia. EFSA J 15(3):4691. https://doi.org/10.2903/j.efsa.2017.4691 (325 pp)
EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues), Ockleford C, Adriaanse P, Berny P, Brock T, Duquesne S, Grilli S, Hougaard S, Klein M, Kuhl T, Laskowski R, Machera K, Pelkonen O, Pieper S, Smith R, Stemmer M, Sundh I, Teodorovic I, Tiktak A, Topping CJ, Wolterink G, Bottai M, Halldorsson T, Hamey P, Rambourg M-O, Tzoulaki I, Marques DC, Crivellente F, Deluyker H, Hernandez-Jerez AF (2017b) Scientific opinion of the PPR panel on the follow-up of the findings of the External Scientific Report “Literature review of epidemiological studies linking exposure to pesticides and health effects”. EFSA J 15(10):5007. https://doi.org/10.2903/j.efsa.2017.5007 (101 pp)
Fritsche E, Crofton KM, Hernandez AF, Hougaard Bennekou S, Leist M, Bal-Price A, Reaves E, Wilks MF, Terron A, Solecki R, Sachana M, Gourmelon A (2017) OECD/EFSA workshop on developmental neurotoxicity (DNT): the use of non-animal test methods for regulatory purposes. Altex 34(2):311–315. https://doi.org/10.14573/altex.1701171
Goodman M, Naiman DQ, LaKind JS (2018) Systematic review of the literature on triclosan and health outcomes in humans. Crit Rev Toxicol 48(1):1–51. https://doi.org/10.1080/10408444.2017.1350138
Hernandez AF, Menendez P (2016) Linking pesticide exposure with pediatric leukemia: potential underlying mechanisms. Int J Mol Sci 17(4):461. https://doi.org/10.3390/ijms17040461
Hernandez AF, Tsatsakis AM (2017) Human exposure to chemical mixtures: challenges for the integration of toxicology with epidemiology data in risk assessment. Food Chem Toxicol 103:188–193. https://doi.org/10.1016/j.fct.2017.03.012
LaKind JS, Sobus JR, Goodman M, Barr DB, Först P, Albertini RJ, Arbuckle TE, Schoeters G, Tan YM, Teeguarden J, Tornero-Velez R, Weisel CP (2014) A proposal for assessing study quality: biomonitoring, environmental epidemiology, and short-lived chemicals (BEES-C) instrument. Environ Int 73:195–207. https://doi.org/10.1016/j.envint.2014.07.011
LaKind JA, Idri F, Naiman DQ, Verner MA (2019) Biomonitoring and nonpersistent chemicals—understanding and addressing variability and exposure misclassification. Curr Environ Health Rep. https://doi.org/10.1007/s40572-019-0227-2
Meek ME, Palermo CM, Bachman AN, North CM, Jeffrey Lewis R (2014) Mode of action human relevance (species concordance) framework: evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. J Appl Toxicol 34(6):595–606. https://doi.org/10.1002/jat.2984
Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, PRISMA-P Group (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 1(4):1. https://doi.org/10.1186/2046-4053-4-1
Ntzani EE, Chondrogiorgi M, Ntritsos G, Evangelou E, Tzoulaki I (2013) Literature review on epidemiological studies linking exposure to pesticides and health effects. EFSA supporting publication 2013:EN-497, 159 pp
Pelkonen O, Terron A, Hernandez AF, Menendez P, Bennekou SH, EFSA WG EPI1 Members (2017) Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research. Arch Toxicol 91(8):2763–2780. https://doi.org/10.1007/s00204-017-1986-x
Rhomberg LR, Goodman JE, Bailey LA, Prueitt RL, Beck NB, Bevan C, Honeycutt M, Kaminski NE, Paoli G, Pottenger LH, Scherer RW, Wise KC, Becker RA (2013) A survey of frameworks for best practices in weight-of-evidence analyses. Crit Rev Toxicol 43(9):753–784. https://doi.org/10.3109/10408444.2013.832727
Sakuratani Y, Horie M, Leinala E (2018) Integrated approaches to testing and assessment: OECD activities on the development and use of adverse outcome pathways and case studies. Basic Clin Pharmacol Toxicol 123(Suppl 5):20–28. https://doi.org/10.1111/bcpt.12955
SAPEA, Science Advice for Policy by European Academies (2018) Improving authorisation processes for plant protection products in Europe: a scientific perspective on the potential risks to human health. SAPEA, Berlin. https://doi.org/10.26356/plantprotectionproducts
Scientific Advice Mechanism (SAM) (2018) EU authorisation processes of plant protection products from a scientific point of view. Scientific Advice Mechanism (SAM), Brussels. https://doi.org/10.2777/238919 (KI-04-17-354-EN-N). ISBN 978-92-79-67735-9
Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, PRISMA-P Group (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2(350):g7647. https://doi.org/10.1136/bmj.g7647
Terron A, Bal-Price A, Paini A, Monnet-Tschudi F, Bennekou SH, EFSA WG EPI1 Members, Leist M, Schildknecht S (2018) An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition. Arch Toxicol 92(1):41–82. https://doi.org/10.1007/s00204-017-2133-4
US-EPA (United States Environmental Protection Agency) (2016) Office of pesticide programs’ framework for incorporating human epidemiologic & incident data in risk assessments for pesticides December 28, 2016. https://www3.epa.gov/pesticides/EPA-HQ-OPP-2008-0316-DRAFT-0075.pdf. Accessed 28 Sept 2018
Vineis P, Chadeau-Hyam M, Gmuender H, Gulliver J, Herceg Z, Kleinjans J, Kogevinas M, Kyrtopoulos S, Nieuwenhuijsen M, Phillips DH, Probst-Hensch N, Scalbert A, Vermeulen R, Wild CP (2017) EXPOsOMICS Consortium. The exposome in practice: design of the EXPOsOMICS project. Int J Hyg Environ Health 220:142–151
Vinken M (2018) Taking adverse outcome pathways to the next level. Toxicol In Vitro 50:A1–A2. https://doi.org/10.1016/j.tiv.2018.03.017
Viviani B (2016) Adverse Outcome Pathway: Redox-cycling of a chemical initiated by electrons released by the mitochondrial respiratory chain leading to parkinsonian motor deficits. Toxicol Let 259S:S62
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This report is based on plenary talks and extensive discussions at the EFSA Scientific conference on the use of epidemiological findings in regulatory pesticide risk assessment on 21 November, 2017, in Parma, Italy. The speakers were Federica Crivellente (EFSA), Susanne Hougaard Bennekou (Danish EPA, EFSA PPR Panel), Bette Meek (University of Ottawa), Antonio Hernandez Jerez (University of Granada, EFSA PPR Panel), David Miller (US-EPA), Karin Angeli (ANSES), Laura Beane Freeman (US NCI), Judy Lakind (LaKind Associates), Marie-Odile Rambourg (ANSES), Manolis Kogevinas (ISGlobal), Carol Burns (ECPA), and Martin Dermine (PAN Europe). The speakers and discussants are thanked for their contributions during the meeting; however, report authors are responsible for views and recommendations expressed in this report (see the EFSA site: https://www.efsa.europa.eu/en/events/event/171121-0).
About this article
Cite this article
Pelkonen, O., Bennekou, S.H., Crivellente, F. et al. Integration of epidemiological findings with mechanistic evidence in regulatory pesticide risk assessment: EFSA experiences. Arch Toxicol 93, 1779–1788 (2019). https://doi.org/10.1007/s00204-019-02467-w
- Plant protection products
- Risk assessment
- Adverse outcome pathway (AOP)
- Integrated Approach to Testing and Assessment (IATA)