Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano WP4: Cumulative Assessment Group refinement strategies Angelo Moretto Department of Occupational Health, Università di Milano International Centre for Pesticides (ICPS), Azienda Ospedaliera Luigi Sacco, Milano acropolis kick-off meeting Utrecht, 7-8 June 2010

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano The state of the art in EU (EFSA PPR Panel Opinions)

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Opinion of the Scientific Panel on Plant Protection Products and their Residues to evaluate the suitability of existing methodologies and, if appropriate, the identification of new approaches to asses cumulative and synergistic risks from pesticides to human health with a view to set MRLs for those pesticides in the frame of Regulation (EC) 396/2005 The EFSA Journal (2008) 704, 1-84

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano 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 The EFSA Journal(2009); 7(9)1167

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Types of combined actions Simple similar action Simple dissimilar action Interaction Stronger than expected effect Weaker than expected effect

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Available evidence is that interaction does not occur at doses that are at or below the No-Observable-Adverse-Effect- Level (NOAEL) CONCLUSION

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Only dose additivity seems to be a priority in risk assessment i.e.only exposure to substances sharing a common MOA need to be cumulated (if exposure derives from residues in food)

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano The problem Definition of the Cumulative Assessment Groups

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano 1.Preliminary grouping based on: Structural similarity Mechanism of pesticidal action General mechanism of mammalian toxicity A particular toxic effect

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano 2.Refinement of the preliminary grouping by detailed evaluation of available toxicology data Substances not causing a common (i.e. concordant in both site and nature) toxic effect are eliminated

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano 3.Determination of the MOA by which each substance causes a common toxic effect Refine groupings by excluding substances that cause a common toxic effect by a different MOA

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Issues on definition CAG Refinement might not be Feasible (lack of information) Necessary (e.g. too time-consuming vs expected outcome) Care is needed on definition of common mode of action (e.g.: anti-androgens and estrogen-like)

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano CUMULATIVE ASSESSMENT GROUP VS COMMON MODE/MECHANISM OF ACTION GROUP

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Objective of WP4 Refinement of CAG In vitro approaches Use of PBPK modelling Existing models Development of a modelling strategy

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano In vitro approaches CONAZOLES (UMIL) NEUROTOXICANTS (IRAS) (pyrethroids carbamates organophosphates)

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Conazoles Teratogenic effects (basis for EFSA PPR Panel opinion on triazoles) Rat embryos Treatment with single conazoles (both teratogenic and non-teratogenic) Treatment with mixtures of conazoles (as above) Treatment with compounds, not conazoles, causing the same teratogenic effects Treatment with mixtures of conazoles and non- conazoles

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano In vivo tests RRR Approach Verification of the correctness of the in vitro approach

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Neurotoxicants Measurements of several parameters in vitro after treatment with a single compound Measurements as above after multiple compounds Development of a predictive model(s)

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano PBPK Modelling Review of available models Development of models from experimental studies Application of models to exposure data (conazoles) Application of models to existing dietary and biomarker data (chlorpyrifos)

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi Sacco - Milano Review of the literature and available data Use of in vitro data to Refine CAG Identify deviations from dose-additivity Evaluation of uncertainties in the refinement of CAG (in collaboration with WP5)