acropolis kick-off meeting
Utrecht, 7-8 June 2010
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
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
CONCLUSION
Available
evidence
is
that
interaction does not occur at
doses that are at or below the
No-Observable-Adverse-EffectLevel (NOAEL)
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 nonconazoles
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)
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano