Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi...

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



The state of the art in EUThe state of the art in EU

(EFSA PPR Panel Opinions)(EFSA PPR Panel Opinions)



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



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



Types of combined actionsTypes of combined actions

Simple similar action

Simple dissimilar action

Interaction

Stronger than expected effect

Weaker than expected effect



Available evidence is that

interaction does not occur at

doses that are at or below the

No-Observable-Adverse-Effect-

Level (NOAEL)

CONCLUSIONCONCLUSION



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)



The problemThe problem

Definition of the Cumulative Assessment

Groups



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



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



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



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)



CUMULATIVE CUMULATIVE

ASSESSMENT ASSESSMENT GROUP GROUP

VSVS

COMMONCOMMON

MODE/MECHANISM OF ACTIONMODE/MECHANISM OF ACTION GROUPGROUP



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



In vitro approachesIn vitro approaches

CONAZOLES (UMIL)

NEUROTOXICANTS (IRAS)

(pyrethroids

carbamates

organophosphates)



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



In vivo tests

RRR Approach

Verification of the correctness of the in

vitro approach



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)



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)



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)

Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi...

Documents

Transcript of Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria Azienda Ospedaliera Luigi...