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Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
WP4: WP4: Cumulative Assessment Cumulative Assessment
Group refinement Group refinement strategiesstrategies
Angelo MorettoDepartment 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 EUThe state of the art in EU
(EFSA PPR Panel Opinions)(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, 1-84The 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)1167The EFSA Journal(2009); 7(9)1167
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
Types of combined actionsTypes 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)
CONCLUSIONCONCLUSION
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 problemThe problem
Definition of the Cumulative Assessment
Groups
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
1.1. Preliminary grouping based on: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 CAGIssues 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 CUMULATIVE
ASSESSMENT ASSESSMENT GROUP GROUP
VSVS
COMMONCOMMON
MODE/MECHANISM OF ACTIONMODE/MECHANISM OF ACTION GROUPGROUP
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
Objective of WP4 Objective of WP4 “Refinement of CAG”“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 approachesIn vitro approaches
CONAZOLES (UMIL)
NEUROTOXICANTS (IRAS)
(pyrethroids
carbamates
organophosphates)
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
ConazolesConazoles
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
NeurotoxicantsNeurotoxicants
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 ModellingPBPK 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 Review of the literature and available datadata
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)