Embed Size (px)
Citation preview
Dr. Emilio BenfenatiIstituto di ricerche Farmacologiche Mario Negri Milano 10/12/2014
LIFE-EDESIA workshop on
The role of in silico tools in supporting the application of the
substitution principle
Projects related to EU regulation:
www.caleidos-life.eu
Improved standardisation in the
use of NTMPractical information on NTM
A sound evaluation of QSAR
models applied to chemicals
registered under REACH
Evaluation of QSAR for HH, EN
and PhysChem endpoints
A comparison between read-
across and QSAR predictions
A network of experts aimed at
integrating scientific and policy
aspects
A freely available web tool for
the selected properties
Practical information on NTM
www.caleidos-life.eu
IRFMN IRCCS - Istituto di Ricerche Farmacologiche Mario Negri
INERIS Institut National de l’Environnement Industriel et des Risques
EAAu Umweltbundesamt GmbH
ISPRA Istituto Superiore per la Protezione e la Ricerca Ambientale
DGS Direcção-Geral da Saúde
POLIMI Politecnico di Milano, DEIB
URV Universitat Rovira i Virgili
INFOTOX INFOTOX - Consultores de Riscos Ambientais e Tecnológicos
CR Centro Reach S.r.l.
Caleidos partners:
Caleidos endpoints:
www.caleidos-life.eu
ENDPOINT:
Acute fish toxcity
BCF
Carcinogenicity
Log P
Mutagenicity (Ames test)
Reprotoxcity
Bioconcentration factor (vega):
6
Accuracy 0.91
Sensitivity 0.96
Specificity 0.45
Accuracy 0.86
Sensitivity 0.96
Specificity 0.35
Read Across QSAR model148 compounds 95 compounds
ADI ≥ 0.85
Thresholds [log units]
Tons/year 2.7 (CLP)
>1 X
>10 X
>100 X
www.caleidos-life.eu
Lethal Concentration 50 (LC50): 0.65 < Accuracy < 0.81
Mutagenicity: 0.57 < Accuracy < 0.88
http://www.vega-qsar.eu/
LIFE Prosil wants to adopt an attitude of innovation in order
to move the chemical industry towards a more responsible
approach to the environment
www.life-prosil.eu
Minimizing the effects on health through the
identification of safe chemicals in the specific
industrial sectors:
•Dyes
•Plant protection products
•UVCB substances of organic origin
PROSIL Partners:
www.life-prosil.eu
IRFMN Istituto Di Ricerche Farmacologiche Mario Negri
CR Centro Reach S.r.l
CRS4 Centro di ricerca, Sviluppo e Studi Superiori in Sardegna s.r.l. uninominale
FARBOTEX Farbotex S.p.A
GAMMACOLOR Gammacolor S.r.l
MACHIT Manifattura Chimica Italiana Trading S.r.l.
NIC_LJ Kemisjki Inštitut
OXON Oxon Italia S.p.A.
POLIMI Politecnico di Milano, Dipartimento di elettronica e informazione
PROSIL Endpoints:
www.life-prosil.eu
ENDPOINT
BCF
Carcinogenicity
Reprotox
Mutagenicity
Ready biodegradability
Aquatic toxicity:
- Fish Toxicity
- Daphnia Toxicity
Information retrieval of dyes:
• US EPA
• ENVIROMENT CANADA
• PROGRAM DEVELOPMENT AND ENGAGMENT DIVISION
• NATIONAL TECHNICAL INFORMATION SERVICE
• LABORATORY OF ECOTOXICOLOGY AND ENVIRONMENTAL MICROBIOLOGY “Dr. Abilio Lopes” (LIMEIRA, SP, BRAZIL)
• THE UNIVERSITY OF NORTH CAROLINA
• …
www.life-prosil.eu
Example:Colorante - color
indexCAS
no.Endpoint according to REACH Parameter
Measure units
Test resultSpecies/
StrainReference/DB
Acid Black 2 101357-
32-87.7 idrosolubilità solubile
Reports of Scientific Committee on Cosmetology
8.5.1 tossicità per via orale LD50 g/kg >4 rattoReports of Scientific
Committee on Cosmetology
8.1.1 irritazione cutanea in vivo non irritante coniglioReports of Scientific
Committee on Cosmetology
8.2.1 irritazione degli occhi in vivo non irritante coniglioReports of Scientific
Committee on Cosmetology
8.3 sensibilizzazione cutanea (LLNA)assenza
sensibilizzazioneguinea pig
Reports of Scientific Committee on Cosmetology
8.4.1 studio in vitro della mutazione genica dei batteri
non mutagenoS.
typhimuriumReports of Scientific
Committee on Cosmetology
Acid Black 194 /172 57693-
14-88.1.1 irritazione cutanea in vivo non irritante coniglio österreich database 2
8.2.1 irritazione degli occhi in vivo irritante coniglio österreich database 2
8.5.1 tossicità per via orale LD50 mg/kg >5000 ratto österreich database 2
9.2 degradazione % 50-100 österreich database 2
www.life-prosil.eu
(Q)SARs are computer based models designed to predict properties from knowledge of the chemical structure.
Read-across is a method of filling in data gaps for a substance by using surrogate data from another substance.
• A case-to-case basis• Reliability supported by specific explanation• Supporting data needed (generic and/or substance-specific)• Subjective expert assessment
• Pre-built model• Reliability supported by the applicability
domain • Supporting examples from training sets• Objective output (though it requires an
evaluation by the expert)
READ ACROSS and QSAR
www.life-prosil.eu
Common data comes from experience
www.life-prosil.eu
Read across: real data from otherchemicals
www.life-prosil.eu
QSAR: real data combined into a complex architecture
www.life-prosil.eu
New model for Read-across: ToxRead3 aims
– exploration of different conditions
– reproducible - objective
– easily taylored by expert
• read across at the intersection between chemicals
and ontologies
= ToxRead takes into account experimental evidence and
(available)theory on toxicity
www.toxgate.eu
www.toxgate.eu
ToxRead user interface
www.toxgate.eu
A graph with pop up windows:
– Centered in the target molecule
– Target directly connected to the most similar molecules (in the inner circle)
– The structural alerts are in the second circle
– Paths connect molecules sharing the same structural alert
– Shape: circular nodes are molecules, triangle nodes are structural alerts
– Circle dimension: related to similarity
– Color: red or green with different saturation indicates active-non active at different levels
– Clicking on nodes shows the structure, the explanation, the list of chemicals, etc.
Example of conflicting rules: exception to BB rules SA10 and SA12
Target compound CAS: 527-61-7O=C1C=C(C(=O)C(=C1)C)C
Similarity to target=1
NM_metil_quinone
SA12 Quinones(Benigni/Bossa)
www.toxgate.eu
Developmental and reproductive toxicity model from Procter & Gamble
– DART model is composed by 25 categories
– All categories have some sub-categories
– All sub-categories are made by many structural alerts
– DART model have ~ 185000 structural alerts
www.life-prosil.eu
P&G dataset
Total compunds 672
Positive compounds 615
Negative compunds 57
DART rules implemented in Instant JChem software
DART results in Instant JChem
Accuracy 0,88
Sensitivity 0,95
Specificity 0,05
MCC 0,005
www.life-prosil.eu
Developmental and reproductive toxicity model from Procter & Gamble
P&G dataset
Total compunds 672
Positive compounds 615
Negative compunds 57
DART rules implemented in Instant JChem software
DART results in Instant Jchemcategory 8 excluded
Accuracy 0,82
Sensitivity 0,88
Specificity 0,18
MCC 0,043
www.life-prosil.eu
Developmental and reproductive toxicity model from Procter & Gamble
P&G dataset
Total compunds 672
Positive compounds 615
Negative compunds 57
We did a corrections of some categories that generate false positive in DART rules and implemented their in Instant JChem software
DART results in Instant JChem
Accuracy 0,87
Sensitivity 0,89
Specificity 0,70
MCC 0,448
www.life-prosil.eu
Developmental and reproductive toxicity model from Procter & Gamble
P&G dataset
Total Compunds 672
Positive compounds 615
Negative compunds 57
DART rules implemented in JAVA platform
DART results in JAVA platform
Accuracy 0,70
Sensitivity 0,26
Specificity 0,78
MCC 0,026
www.life-prosil.eu
Developmental and reproductive toxicity model from Procter & Gamble
