ACROPOLIS 1st Project Meeting with the SAB
Milano, 31 March 2011
The relevance and uselfulness
of in vitro studies in refining
Cumulative Assessment
Groups (WP4)
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
In vitro approaches
 CONAZOLES
(UMIL)
 NEUROTOXICANTS
(IRAS)
(Organochlorines
conazoles
pyrethroids
carbamates
organophosphates)
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
RRR Approach
Verification of the correctness of the in
vitro approach as the only in vivo test(s)
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
In vitro tests allow for:
Testing many compounds to identify a common
hazard
Testing many doses to establish an accurate doseresponse curve
Testing many mixture combinations to establish
additivity, synergy, antagonism
Testing unrelated chemicals
Measurements of several relevant parameters, if
needed
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
In vitro approach
Consequently, the number of in vivo
tests:
 can be reduced
 focused on relevant combinations
 conducted with doses relevant to derive
Reference Values
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
In vitro – in vivo extrapolation
How to use in vitro data for the real in
vivo human situation (exposure)?
From qualitative to quantitative use of
in vitro data
Need of good ADME data to apply
PBPK, and eventually, PBPD models
Higher tier approach
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
In vitro – in vivo extrapolation
Take advantage from ongoing activities (e.g.
ILSI Risk 21 project)
Use existing PBPK models
Use existing ADME data for individual
compounds within a group to develop PBPK
models that may inform both in vivo
confirmatory studies and subsequent risk
assessment
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) (WP3)
 Application of models to existing dietary
and biomarker data (chlorpyrifos) (WP2)
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano
Intraction/integration between WPs
Occupational exposure data: WP 3
Dietary exposure data: WP 2 and WP 3
Description and evaluation of
uncertainties: WP 5
Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria
Azienda Ospedaliera “Luigi Sacco” - Milano