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3 New N ew C Chemicals hemicals P Program rogram IIndustrial ndustrial Chemicals Chemicals SStion tion 5 of of TTS TSCA SCA (Toxic (Toxic Substance Substance C Control ontrol A Act) ct) requires requires a m anufacturre er aand/or nd/o /or iimporter mporter of of a new new cchemical hemical manufacturer ssubstance ubstance tto o ssubmit ubmit a emanufacture emanufacture notice notice (PMN) (PMN) to to U PA 9 0 days days before before commencing commencing manufacture manufacture or or USS EEPA 90 iimport mport of of the the new new cchemical hemical 5 Disions D isions o often ften made made in in the the aabsence bsence of of any any e xperimental data data experimental methods SSAR AR m ethods aand nd ((Q)SAR Q)SAR d eveloped tto oh elp rreviews eviews developed help U PA evaluates evaluates aapoximately poximately USS EEPA PMN PMN cases cases a yyear ear 6

4 Predicted efft for Daphnia Magna with the US EPA ECOSAR for pesticides Hansen - Pesticides research, 2004 Quantitative structure-activity relationships (QSAR) and pesticides 7 Daphnia Magna TRAINING SET NC = 193 R 2 = 0.80.demetra-tox.net/ 8

5 Daphnia Magna TEST SETS EPA test set NC = 36 R 2 = 0.80 D-BBA test set NC = 101 R 2 = 0.70.demetra-tox.net/ 9 Daphnia Magna NC = 176 NC (training test) = 31 R 2 = 0.20.demetra-tox.net/ 10

6 HYBRID MODEL EPISUITE MODEL r-/ h a r o t / p r-p 11 Organizing Dissemination on results of RA ts Alternative Non-Testing methods Assessed for REACH Substances

7 QSAR models for REACH models for REACH ITS for REACH ITS models based on simple chemical descriptors descriptors developmentent grids for knowledge-oriented applications chemicals as contaminants in the food chain GRID endocrine disruptors screening SARs in mutagenicity and carcinogenicity workshop 2007 integration of in vivo, in vitro and in silico methods workshop 2006 evaluation of toxicity of pesticide residues in agriculture models for pesticides r-/ r / 14

8 r-/ r / 15 REACH is the new EU legislation dealing with chemicals in Europe. The philosophy is: NO DATA NO MARKET Hazard ofile and fe use should be granted for all substances marketed for more than 1 ton/year. Huge amount of data will be therefore needed since 2010 up to 2018 About 30,000 chemicals to be evaluated Billions of Euros for testing r-/ r / 16

9 (Q)SAR is mentioned among other alternatives to animal testing as an acceptable method to fill data gap According to REACH regulation (Annex XI) a (Q)SAR is VALID if: the model is rognized scientifically valid; the substance is included in the applicability domain of the model; results are adequate for classification and labelling and for risk assessment; adequate documentation of the methods ovided. r-/ r / 17 r-/ r / 18

10 19 r-/ h a r o t / p r-p r-/ h / r o / p r-p 20

11 r-/ h a r o t / p r-p 21 r-/ h / r o / p r-p 22

12 LogBCF Experimental LogBCF Canadian db EURAS Dimitrov Correlation between LogP and LogBCF LogP 4.5 > % 14.1% < % 14.7% vb B -2 Experimental LogP r-/ r / compounds CAESAR BCF model Predicted LogBCF nb B vb nb 83.39% 1.29% 0.37% Experimental LogBCF B 4.80% 1.66% 0.55% vb 0.74% 1.48% 5.72% r-/ r / 24

13 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% False negatives False positives True negatives True positives Training set Test set Good accuracy (considering reoducibility of the experimental data about 85%) A cost-sensitive model was also evaluated to reduce FN r-/ r / 25 CAESAR Test Set SUSPICIOUS taken as NON-MUTAGENIC SUSPICIOUS taken as MUTAGENIC accuracy: 83.3% 82.1% sensitivity: 88.3% 90.9% spificity: 77.1% 71.2% CONFIDENT CHOICE Accuracy close to the reliability of the experimental test (85%) PRUDENT CHOICE Sensitivity boosted over 90% r-/ r / 26

14 r-/ h a r o t / p r-p 27 CAESAR TOXTREE COMMERCIAL SOFTWARE MULTICASE SPECIFICITY SENSITIVITY ACCURACY CAESAR A r-/software/index.m /software re r-p ndex.m e/in 28

15 29 r-/software/index.m 30

16 r-/software/index.m 31 r-/software/index.m 32

17 r-/software/index.m 33