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QSAR prediction of physico-chemical QSAR prediction of physico-chemical properties and biological activities of properties and biological activities of emerging pollutants: emerging pollutants: brominated flame retardants and brominated flame retardants and perfluorinated-chemicals perfluorinated-chemicals Sixth Indo-US Workshop on Mathematical Chemistry Kolkata, 8-10 January 2010 Paola Gramatica Paola Gramatica Barun Bhhatarai, Barun Bhhatarai, Simona Kovarich and Ester Papa Simona Kovarich and Ester Papa QSAR Research Unit in Environmental Chemistry and Ecotoxicology QSAR Research Unit in Environmental Chemistry and Ecotoxicology DBSF -University of Insubria, Varese - Italy DBSF -University of Insubria, Varese - Italy E-mail: E-mail: [email protected] http://www.qsar.it http://www.qsar.it

QSAR prediction of physico-chemical properties and biological activities of emerging pollutants: brominated flame retardants and perfluorinated-chemicals

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  • QSAR prediction of physico-chemical properties and biological activities of emerging pollutants: brominated flame retardants and perfluorinated-chemicalsSixth Indo-US Workshop on Mathematical Chemistry Kolkata, 8-10 January 2010Paola Gramatica Barun Bhhatarai, Simona Kovarich and Ester PapaQSAR Research Unit in Environmental Chemistry and Ecotoxicology DBSF -University of Insubria, Varese - Italy E-mail: [email protected]://www.qsar.it

  • THE CHEMICAL UNIVERSEMore than 50.000.000 (sept.2009)34,849,353 on the marketRegulated 247,952Environmental fate?Human effects?

  • New EU-regulation:RegistrationEvaluationAuthorisationof ChemicalsThe use of predictive QSAR models is suggested :

    To highlight dangerous chemicals To prioritize chemicals and to focus the experimental tests To fill the data gapsLimited availability of experimental dataLack of knowledge of the properties and activities of existing substances Complexity of old regulationsINTRODUCTION REACH and QSAR

  • in Environmental Chemistryand EcotoxicologyStaff Prof. Paola Gramatica

    Dr. Ester Papa, Ph.D

    Dr. Simona Kovarich

    Dr. Jr. Mara Luini

    Dr. Barun Bhhatarai, Ph.D

    (Dr. Jiazhong Li, Ph.D)http://www.qsar.itDBSF - University of InsubriaVarese - Italy

  • INTRODUCTION Brominated Flame RetardantsClass of emerging pollutants used in a variety of consumer products (plastics, polyurethane foams, textiles, electronic equipments..) to increase fire resistancy

    Three most marked HPV products: Levels in the environment and humans increased since they came into use

    Ban of penta- and octa-BDE formulations (DecaBDE under evaluation); HBCD in candidate list?209 possibleCONGENERS

  • Background knowledge about BFRs:

    Low water solubilityHigh LogKow > 5Persistence in the environmentLiver toxicity, thyroid toxicity, developmental toxicityEndocrine disruptorsThe available amount of experimental data is very small and mainly related to already banned BFRs.INTRODUCTION Brominated Flame Retardants

  • Perfluorinated compounds (PFCs) are chemicals containing a long fluorinated carbon tail attached to different functional groups

    PFCs as perfluoro-octanesulfonate (PFOS), perfluoro-octanoate (PFOA) and perfluoro- octane sulfonylamide (PFOSA) are stable chemicals with a wide range of industrial and consumer applications

    Degradable products of commercial PFCs are found in environment and biota and diPAPs (a group of PFCs used on food wrappers) was recently reported in human blood

    PFCs are considered emerging pollutants and are believed to have potential toxic effects in humans and wildlife

    PFCs along with Polyfluoro compounds are studied for LC50 inhalation toxicity of Mouse and RatPredictive QSAR approaches is used to fill the data gap and to predict toxicity of 250 PFCs on two different species viz. Mouse and Rat*INTRODUCTION Perfluorinated Compounds

  • Aims of the Modelling StudiesDevelopment of QSAR models for available end-points paying attention to external validation and applicability domain analysis.Evaluation of environmental behaviour and physico-chemical properties of emerging pollutants: BFRs and PFCs.Identification of more toxic and dangerous chemicals based on the studied end-points.Prioritization of chemicals for experimental tests under CADASTER projectMechanistic interpretation of selected descriptors, highlighting the fate, distribution and properties of chemicals.EU-FP7 Project - CADASTER

  • To facilitate the consideration of a QSAR model for regulatory purposes, it should be associated with the following information: a defined endpoint an unambiguous algorithm a defined domain of applicability appropriate measures of goodness of fit, robustness and predictivity a mechanistic interpretation, if possible -OECD Principles for QSAR models in REACH

  • METHODSDefined end-points of Phys-chem and ToxicityUnambiguous algorithm: Chemical representation by theoretical molecular descriptors (DRAGON) selected by Genetic Algorithms Statistical method MLR regression (OLS)3. Validation for model stability and predictivity (internal and external validation)4. Applicability Domain Analysis: leverage approach by Hat matrix (MLR)5. Interpretation of the selected molecular descriptors, if possible.Application of the OECD principles for QSAR models

  • RESULTS QSAR/QSPR models developed for Brominated Flame RetardantsSimona Kovarich

  • RESULTS QSPR modelsE. Papa, S. Kovarich, P. Gramatica, 2009. Development, validation and inspection of the applicability domain of QSPR models for physico-chemical properties of polybrominated diphenyl ethers. QSAR & Comb. Sci., 28, 790-796.Physico-chemical and degradation Properties* Photodegradation

    EndpointModelTrainobj.Test obj.Desc.R2%Q2LOO%Q2EXT%AD% on 243 BFR LogKOA Full30-T(O..Br) 97.496.8-81.9 k-ANN Split24696.195.095.2-LogKOWFull20-T(O..Br) 96.495.6-86.0k-ANN Split14697.195.994.7-MPFull25-X2A84.481.9-95.9k-ANN Split20582.278.593.7-LogPLFull34-T(O..Br)98.798.5-83.1k-ANN Split28698.898.598.6-LogSFull12-Mor23m91.888.5-95.1LogHFull7 -BEHe7 96.993.3 -55.6LogKp*Full15 -MW94.993.8-91.4LogHLp*Full15 -T(O..Br)94.392.6-81.9

  • RESULTS - Model for Log KoaLogKoa= 6.654 +0.222 T(O..Br)Experimental range of LogKoa: 7.34 (mono-BDE) 11.96 (hepta-BDE)

    n ObjDescriptorR2%Q2boot%Q2 EXT(rand20%) %30T(O..Br)97.3696.7799.56

  • The same descriptor, i.e. T(O...Br), was selectedas the best modeling variable for three differentproperties which are related to each other (LogPL, LogKoa, LogKow, LogHLp). This descriptor gives a double structural information:its values increases according to both the number and the distance of bromine substituents from the oxygen ether, on each phenyl ring. Thus, T(O...Br) takes also into account the information related to the position of the bromine atoms on the phenyl rings.RESULTS Interpretation of descriptors

  • Comparison with some existing models mono-tritetra-heptaPredicted and Experimental data for 30 PBDEs

    AuthorMethodN obj.N varsR2%Q2LOO%Q2 EXT %RMSE(30 obj)Papa et al. (2009)MLR30197.496.899.60.23Xu et al. (2007)MLR22297.697.2-0.31Chen et al. (2003)PLS131097.997.5--KoaWIN (Episuite)KOW/KAW0.81

    Grafico10

    7.3417.327.46.817

    7.4427.567.177.657

    8.3678.448.378.107

    8.4588.438.478.107

    8.13107.978.528.107

    8.52128.668.488.947

    8.54138.668.538.947

    8.61158.898.78.947

    9.39.3859.099.29.396

    9.37219.329.079.396

    9.549.6989.549.79.396

    8.94309.119.029.396

    9.18329.099.249.396

    9.48359.549.3810.236

    9.54379.779.4710.236

    10.3710.40610.210.4610.686

    10.5510.76710.4210.6310.686

    10.04699.9810.3810.686

    9.957510.2210.2510.686

    10.6610.76210.6510.4111.526

    10.868210.8711.1811.977

    11.6611.54911.0611.2811.977

    11.1911.48511.0911.211.157

    11.1311.1410.8611.411.977

    11.211911.0911.2911.977

    11.9711.99211.511.1812.817

    11.8312.1271212.3213.265

    11.9211.8911.7412.1813.265

    11.9712.6312.2412.0313.265

    11.9612.68112.7812.8914.554

    Exp. LogKoa

    Chen (2003)

    Papa (2008)

    Xu (2007)

    KoaWIN

    PBDE

    LogKoa

    Exp. vs. Pred. data

    KoaModPred

    No.ObjectStatusY Exp.Y-CalcY-PredLogKoa EPISUITEY-Pred (Xu)Y Exp.DHatErr.Calc.Err.Pred.Std.Err.Calc.Std.Err.Pred.

    1BDE-001Training7.347.327.326.8177.47.340.5030.152 *-0.02-0.02-0.07-0.09

    2BDE-002Training7.447.557.567.6577.177.440.0970.1330.110.120.480.56

    3BDE-003Unknown--7.777.6577.28-0.1130.112----

    4BDE-004Unknown--7.998.1078.47-0.1170.097----

    5BDE-005Unknown--8.218.1078.26-0.1030.083----

    6BDE-006Unknown--8.218.1076.61-0.1030.083----

    7BDE-007Training8.368.438.448.1078.378.360.3330.0730.070.080.320.35

    8BDE-008Training8.458.438.438.1078.478.450.3230.073-0.02-0.02-0.08-0.08

    9BDE-009Unknown--8.218.1078.24-0.1030.083----

    10BDE-010Training8.137.997.978.1078.528.130.1370.099-0.14-0.16-0.63-0.7

    11BDE-011Unknown--8.438.9478.66-0.5170.071----

    12BDE-012Training8.528.658.668.9478.488.520.2870.0620.130.140.590.63

    13BDE-013Training8.548.658.668.9478.538.540.2870.0620.110.120.50.54

    14BDE-014Unknown--8.438.9478.31-0.5170.071----

    15BDE-015Training8.618.888.898.9478.78.610.0570.0530.270.281.161.23

    16BDE-016Unknown--8.889.3969.41-0.5160.052----

    17BDE-017Training9.39.19.099.3969.29.30.3060.046-0.2-0.21-0.88-0.92

    18BDE-018Unknown--8.889.3969.13-0.5160.052----

    19BDE-019Unknown--8.659.3969.48-0.7460.061----

    20BDE-020Unknown--9.19.3969.33-0.2960.045----

    21BDE-021Training9.379.329.329.3969.079.370.0760.04-0.05-0.05-0.22-0.23

    22BDE-022Unknown--9.329.3969.8-0.0760.04----

    23BDE-023Unknown--9.19.3968.98-0.2960.045----

    24BDE-024Unknown--8.889.3969.35-0.5160.052----

    25BDE-025Unknown--9.329.3969.02-0.0760.04----

    26BDE-026Unknown--9.19.3969.39-0.2960.045----

    27BDE-027Unknown--8.889.3969.33-0.5160.052----

    28BDE-028Training9.549.549.549.3969.79.540.1440.036000.010.01

    29BDE-029Unknown--9.329.3969.12-0.0760.04----

    30BDE-030Training8.949.19.119.3969.028.940.2860.0460.160.170.690.72

    31BDE-031Unknown--9.329.3969.73-0.0760.04----

    32BDE-032Training9.189.19.099.3969.249.180.3060.046-0.08-0.09-0.36-0.37

    33BDE-033Unknown--9.329.3969.54-0.0760.04----

    34BDE-034Unknown--9.19.3969.21-0.2960.045----

    35BDE-035Training9.489.549.5410.2369.389.480.6960.0360.060.060.270.28

    36BDE-036Unknown--9.3210.2369.34-0.9160.04----

    37BDE-037Training9.549.769.7710.2369.479.540.4660.0340.220.230.971

    38BDE-038Unknown--9.5410.2369.19-0.6960.036----

    39BDE-039Unknown--9.5410.2369.28-0.6960.036----

    40BDE-040Unknown--9.7610.68610.22-0.9260.034----

    41BDE-041Unknown--9.9910.68610.06-0.6960.033----

    42BDE-042Unknown--9.9910.68610.2-0.6960.033----

    43BDE-043Unknown--9.7610.68610.03-0.9260.034----

    44BDE-044Unknown--9.7610.68610.22-0.9260.034----

    45BDE-045Unknown--9.5410.68610.11-1.1460.036----

    46BDE-046Unknown--9.5410.68610.5-1.1460.036----

    47BDE-047Training10.3710.2110.210.68610.4610.370.4860.035-0.16-0.17-0.71-0.73

    48BDE-048Unknown--9.9910.6869.95-0.6960.033----

    49BDE-049Unknown--9.9910.68610.25-0.6960.033----

    50BDE-050Unknown--9.7610.68610.17-0.9260.034----

    51BDE-051Unknown--9.7610.68610.48-0.9260.034----

    52BDE-052Unknown--9.7610.68610.14-0.9260.034----

    53BDE-053Unknown--9.5410.68610.26-1.1460.036----

    54BDE-054Unknown--9.3210.68610.43-1.3660.04----

    55BDE-055Unknown--10.2110.68610.35-0.4760.035----

    56BDE-056Unknown--10.2110.68610.5-0.4760.035----

    57BDE-057Unknown--9.9910.68610.2-0.6960.033----

    58BDE-058Unknown--9.9910.68610.44-0.6960.033----

    59BDE-059Unknown--9.7610.68610.3-0.9260.034----

    60BDE-060Unknown--10.4310.68610.46-0.2560.037----

    61BDE-061Unknown--10.2110.68610.18-0.4760.035----

    62BDE-062Unknown--9.9910.6869.99-0.6960.033----

    63BDE-063Unknown--10.2110.68610.65-0.4760.035----

    64BDE-064Unknown--9.9910.68610.46-0.6960.033----

    65BDE-065Unknown--9.7610.68610.18-0.9260.034----

    66BDE-066Training10.5510.4310.4210.68610.6310.550.2660.038-0.12-0.13-0.53-0.55

    67BDE-067Unknown--10.2110.68610.26-0.4760.035----

    68BDE-068Unknown--10.2110.68610.25-0.4760.035----

    69BDE-069Training10.049.999.9810.68610.3810.040.7060.033-0.05-0.06-0.24-0.25

    70BDE-070Unknown--10.2110.68610.58-0.4760.035----

    71BDE-071Unknown--9.9910.68610.59-0.6960.033----

    72BDE-072Unknown--9.9910.68610.33-0.6960.033----

    73BDE-073Unknown--9.7610.68610.26-0.9260.034----

    74BDE-074Unknown--10.4310.68610.14-0.2560.037----

    75BDE-075Training9.9510.2110.2210.68610.259.950.4660.0350.260.271.111.15

    76BDE-076Unknown--10.2110.68610.1-0.4760.035----

    77BDE-077Training10.6610.6510.6511.52610.4110.660.8760.042-0.01-0.01-0.04-0.04

    78BDE-078Unknown--10.4311.52610.16-1.0960.037----

    79BDE-079Unknown--10.4311.52610.2-1.0960.037----

    80BDE-080Unknown--10.2111.52610.33-1.3160.035----

    81BDE-081Unknown--10.6511.52610.1-0.8760.042----

    82BDE-082Training10.8610.8710.8711.97711.1810.861.1070.0490.010.010.050.06

    83BDE-083Unknown--10.6511.97711.13-1.3270.042----

    84BDE-084Unknown--10.4311.97711.15-1.5470.037----

    85BDE-085Training11.6611.0911.0611.97711.2811.660.9170.057-0.57 *-0.60 *-2.48-2.63

    86BDE-086Unknown--10.8711.97711.07-1.1070.048----

    87BDE-087Unknown--10.8711.97711.2-1.1070.048----

    88BDE-088Unknown--10.6511.97711.12-1.3270.042----

    89BDE-089Unknown--10.6511.97711.45-1.3270.042----

    90BDE-090Unknown--10.8711.97711.29-1.1070.048----

    91BDE-091Unknown--10.6511.97711.33-1.3270.042----

    92BDE-092Unknown--10.6511.97711.06-1.3270.042----

    93BDE-093Unknown--10.4311.97711.11-1.5470.037----

    94BDE-094Unknown--10.4311.97711.08-1.5470.037----

    95BDE-095Unknown--10.4311.97711.04-1.5470.037----

    96BDE-096Unknown--10.2111.97711.15-1.7670.035----

    97BDE-097Unknown--10.8711.97710.97-1.1070.048----

    98BDE-098Unknown--10.6511.97711.23-1.3270.042----

    99BDE-099Training11.1911.0911.0911.15711.211.190.0670.057-0.1-0.1-0.42-0.45

    100BDE-100Training11.1310.8710.8611.97711.411.131.1170.049-0.26-0.27-1.12-1.18

    101BDE-101Unknown--10.8711.97711.29-1.1070.048----

    102BDE-102Unknown--10.6511.97711.17-1.3270.042----

    103BDE-103Unknown--10.6511.97711.15-1.3270.042----

    104BDE-104Unknown--10.4311.97711.14-1.5470.037----

    105BDE-105Unknown--11.3211.97711.54-0.6570.066----

    106BDE-106Unknown--11.0911.97711.16-0.8870.056----

    107BDE-107Unknown--11.0911.97711.31-0.8870.056----

    108BDE-108Unknown--11.0911.97711.38-0.8870.056----

    109BDE-109Unknown--10.8711.97711.12-1.1070.048----

    110BDE-110Unknown--10.8711.97711.26-1.1070.048----

    111BDE-111Unknown--10.8711.97711.07-1.1070.048----

    112BDE-112Unknown--10.6511.97711.05-1.3270.042----

    113BDE-113Unknown--10.6511.97711.23-1.3270.042----

    114BDE-114Unknown--11.3211.97711.12-0.6570.066----

    115BDE-115Unknown--11.0911.97711.26-0.8870.056----

    116BDE-116Unknown--10.8711.97711.66-1.1070.048----

    117BDE-117Unknown--10.8711.97711.32-1.1070.048----

    118BDE-118Unknown--11.3211.97711.31-0.6570.066----

    119BDE-119Training11.211.0911.0911.97711.2911.20.8870.057-0.11-0.11-0.46-0.49

    120BDE-120Unknown--11.0911.97711.62-0.8870.056----

    121BDE-121Unknown--10.8711.97711.04-1.1070.048----

    122BDE-122Unknown--11.0911.97711.3-0.8870.056----

    123BDE-123Unknown--11.3211.97711.03-0.6570.066----

    124BDE-124Unknown--11.0911.97711.51-0.8870.056----

    125BDE-125Unknown--10.8711.97711.01-1.1070.048----

    126BDE-126Training11.9711.5411.512.81711.1811.971.3170.078-0.43-0.47-1.92-2.08

    127BDE-127Unknown--11.3212.81711.36-1.4970.066----

    128BDE-128Unknown--11.9813.26512.5-1.2850.104----

    129BDE-129Unknown--11.7613.26511.7-1.5050.09----

    130BDE-130Unknown--11.7613.26512.04-1.5050.09----

    131BDE-131Unknown--11.5413.26512-1.7250.077----

    132BDE-132Unknown--11.5413.26512.33-1.7250.077----

    133BDE-133Unknown--11.5413.26512.17-1.7250.077----

    134BDE-134Unknown--11.3213.26512.03-1.9450.066----

    135BDE-135Unknown--11.3213.26511.79-1.9450.066----

    136BDE-136Unknown--11.0913.26511.83-2.1750.056----

    137BDE-137Unknown--11.9813.26512.1-1.2850.104----

    138BDE-138Unknown--11.9813.26512.06-1.2850.104----

    139BDE-139Unknown--11.7613.26512.33-1.5050.09----

    140BDE-140Unknown--11.7613.26512.34-1.5050.09----

    141BDE-141Unknown--11.7613.26512.06-1.5050.09----

    142BDE-142Unknown--11.5413.26511.84-1.7250.077----

    143BDE-143Unknown--11.5413.26511.91-1.7250.077----

    144BDE-144Unknown--11.5413.26512.1-1.7250.077----

    145BDE-145Unknown--11.3213.26511.87-1.9450.066----

    146BDE-146Unknown--11.7613.26512.18-1.5050.09----

    147BDE-147Unknown--11.5413.26512.18-1.7250.077----

    148BDE-148Unknown--11.5413.26512.11-1.7250.077----

    149BDE-149Unknown--11.5413.26512.01-1.7250.077----

    150BDE-150Unknown--11.3213.26511.94-1.9450.066----

    151BDE-151Unknown--11.3213.26512.2-1.9450.066----

    152BDE-152Unknown--11.0913.26511.72-2.1750.056----

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    154BDE-154Training11.9211.7611.7413.26512.1811.921.5250.092-0.16-0.18-0.72-0.79

    155BDE-155Unknown--11.5413.26512.19-1.7250.077----

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    157BDE-157Unknown--12.213.26512.47-1.0650.12----

    158BDE-158Unknown--11.9813.26512.21-1.2850.104----

    159BDE-159Unknown--11.9813.26512-1.2850.104----

    160BDE-160Unknown--11.7613.26511.89-1.5050.09----

    161BDE-161Unknown--11.7613.26512.01-1.5050.09----

    162BDE-162Unknown--11.9813.26512.33-1.2850.104----

    163BDE-163Unknown--11.7613.26512.49-1.5050.09----

    164BDE-164Unknown--11.7613.26512.44-1.5050.09----

    165BDE-165Unknown--11.5413.26511.88-1.7250.077----

    166BDE-166Unknown--11.9813.26512.2-1.2850.104----

    167BDE-167Unknown--12.213.26512.56-1.0650.12----

    168BDE-168Unknown--11.9813.26512.14-1.2850.104----

    169BDE-169Unknown--12.4214.10512.49-1.6850.138----

    170BDE-170Unknown--12.8714.55412.99-1.6840.179----

    171BDE-171Unknown--12.6514.55413.13-1.9040.157----

    172BDE-172Unknown--12.6514.55412.98-1.9040.157----

    173BDE-173Unknown--12.4214.55412.91-2.1340.138----

    174BDE-174Unknown--12.4214.55412.84-2.1340.138----

    175BDE-175Unknown--12.4214.55412.96-2.1340.138----

    176BDE-176Unknown--12.214.55412.77-2.3540.12----

    177BDE-177Unknown--12.4214.55413.04-2.1340.138----

    178BDE-178Unknown--12.214.55412.98-2.3540.12----

    179BDE-179Unknown--11.9814.55412.81-2.5740.104----

    180BDE-180Unknown--12.8714.55413.14-1.6840.179----

    181BDE-181Unknown--12.6514.55412.91-1.9040.157----

    182BDE-182Unknown--12.6514.55413.07-1.9040.157----

    183BDE-183Training11.9612.6512.7814.55412.8911.961.7740.162 *0.69 **0.82 **3.193.81

    184BDE-184Unknown--12.4214.55413.25-2.1340.138----

    185BDE-185Unknown--12.4214.55412.85-2.1340.138----

    186BDE-186Unknown--12.214.55412.58-2.3540.12----

    187BDE-187Unknown--12.4214.55413.03-2.1340.138----

    188BDE-188Unknown--12.214.55412.96-2.3540.12----

    189BDE-189Unknown--13.0914.55413.23-1.4640.201----

    190BDE-190Unknown--12.8714.55412.78-1.6840.179----

    191BDE-191Unknown--12.8714.55412.94-1.6840.179----

    192BDE-192Unknown--12.6514.55412.62-1.9040.157----

    193BDE-193Unknown--12.6514.55413.3-1.9040.157----

    194BDE-194Unknown--13.7615.84514.17-2.0850.28----

    195BDE-195Unknown--13.5315.84513.78-2.3150.252----

    196BDE-196Unknown--13.5315.84513.95-2.3150.252----

    197BDE-197Unknown--13.3115.84514.05-2.5350.226----

    198BDE-198Unknown--13.3115.84513.96-2.5350.226----

    199BDE-199Unknown--13.3115.84514.14-2.5350.226----

    200BDE-200Unknown--13.0915.84513.47-2.7550.201----

    201BDE-201Unknown--13.0915.84513.8-2.7550.201----

    202BDE-202Unknown--12.8715.84513.93-2.9750.179----

    203BDE-203Unknown--13.5315.84514.15-2.3150.252----

    204BDE-204Unknown--13.3115.84513.76-2.5350.226----

    205BDE-205Unknown--13.7615.84514.07-2.0850.28----

    206BDE-206Unknown--14.4217.13415.01-2.7140.373----

    207BDE-207Unknown--14.217.13414.49-2.9340.34----

    208BDE-208Unknown--13.9817.13414.78-3.1540.309----

    209BDE-209Unknown--15.0918.42315.73-3.3330.481----

    210BDE-210Unknown--6.6612.747-6.0870.214----

    211BDE-211Unknown--9.3214.356-5.0360.04----

    212BDE-212Unknown--11.9815.647-3.6670.104----

    213BDE-213Unknown--14.6416.936-2.2960.407----

    214BDE-214Unknown--17.316.936-0.3640.949----

    215BDE-215Unknown--9.19.968-0.8680.045----

    216BDE-216Unknown--15.0914.188-0.9020.481----

    217BDE-217Unknown--6.669.649-2.9890.214----

    218BDE-218Unknown--14.8612.899-1.9610.443----

    219BDE-219Unknown--16.4214.188-2.2320.742----

    220BDE-220Unknown--17.9715.479-2.4911.122 *----

    221BDE-221Unknown--6.6611.893-5.2330.214----

    222BDE-222Unknown--32.3820.297-12.0838.534 **----

    223BDE-223Unknown--6.669.126-2.4660.214----

    Foglio1

    No.ObjectStatusXu (2007)Chen (2003)KoaWINPapa (2008)Exp. LogKoaY1= nostro ModNo.ObjectStatusY-PredLogKoa EPISUITEY-Pred (Xu)D (Y1-Y2)D (Y2 -Y3)No.ObjectStatusXu (2007)Chen (2003)Papa (2008)Y Exp.

    1BDE-001Training7.46.8177.327.34Y2= Episuite1BDE-001Training7.326.8177.40.5030.081BDE-001Training7.47.327.34

    2BDE-002Training7.177.6577.567.44Y2= Xu 20072BDE-002Training7.567.6577.170.0970.392BDE-002Training7.177.567.44

    7BDE-007Training8.378.1078.448.36Y4= Chen 20033BDE-003Unknown7.777.6577.280.1130.497BDE-007Training8.378.448.36

    8BDE-008Training8.478.1078.438.454BDE-004Unknown7.998.1078.470.1170.488BDE-008Training8.478.438.45

    10BDE-010Training8.528.1077.978.135BDE-005Unknown8.218.1078.260.1030.0510BDE-010Training8.527.978.13

    12BDE-012Training8.488.9478.668.526BDE-006Unknown8.218.1076.610.1031.612BDE-012Training8.488.668.52

    13BDE-013Training8.538.9478.668.547BDE-007Training8.448.1078.370.3330.0713BDE-013Training8.538.668.54

    15BDE-015Training8.78.9478.898.618BDE-008Training8.438.1078.470.3230.0415BDE-015Training8.78.898.61

    17BDE-017Training9.29.3859.3969.099.39BDE-009Unknown8.218.1078.240.1030.0317BDE-017Training9.29.3859.099.3

    21BDE-021Training9.079.3969.329.3710BDE-010Training7.978.1078.520.1370.5521BDE-021Training9.079.329.37

    28BDE-028Training9.79.6989.3969.549.5411BDE-011Unknown8.438.9478.660.5170.2328BDE-028Training9.79.6989.549.54

    30BDE-030Training9.029.3969.118.9412BDE-012Training8.668.9478.480.2870.1830BDE-030Training9.029.118.94

    32BDE-032Training9.249.3969.099.1813BDE-013Training8.668.9478.530.2870.1332BDE-032Training9.249.099.18

    35BDE-035Training9.3810.2369.549.4814BDE-014Unknown8.438.9478.310.5170.1235BDE-035Training9.389.549.48

    37BDE-037Training9.4710.2369.779.5415BDE-015Training8.898.9478.70.0570.1937BDE-037Training9.479.779.54

    47BDE-047Training10.4610.40610.68610.210.3716BDE-016Unknown8.889.3969.410.5160.5347BDE-047Training10.4610.40610.210.37

    66BDE-066Training10.6310.76710.68610.4210.5517BDE-017Training9.099.3969.20.3060.1166BDE-066Training10.6310.76710.4210.55

    69BDE-069Training10.3810.6869.9810.0418BDE-018Unknown8.889.3969.130.5160.2569BDE-069Training10.389.9810.04

    75BDE-075Training10.2510.68610.229.9519BDE-019Unknown8.659.3969.480.7460.8375BDE-075Training10.2510.229.95

    77BDE-077Training10.4110.76211.52610.6510.6620BDE-020Unknown9.19.3969.330.2960.2377BDE-077Training10.4110.76210.6510.66

    82BDE-082Training11.1811.97710.8710.8621BDE-021Training9.329.3969.070.0760.2582BDE-082Training11.1810.8710.86

    85BDE-085Training11.2811.54911.97711.0611.6622BDE-022Unknown9.329.3969.80.0760.4885BDE-085Training11.2811.54911.0611.66

    99BDE-099Training11.211.48511.15711.0911.1923BDE-023Unknown9.19.3968.980.2960.1299BDE-099Training11.211.48511.0911.19

    100BDE-100Training11.411.1411.97710.8611.1324BDE-024Unknown8.889.3969.350.5160.47100BDE-100Training11.411.1410.8611.13

    119BDE-119Training11.2911.97711.0911.225BDE-025Unknown9.329.3969.020.0760.3119BDE-119Training11.2911.0911.2

    126BDE-126Training11.1811.99212.81711.511.9726BDE-026Unknown9.19.3969.390.2960.29126BDE-126Training11.1811.99211.511.97

    153BDE-153Training12.3212.12713.2651211.8327BDE-027Unknown8.889.3969.330.5160.45153BDE-153Training12.3212.1271211.83

    154BDE-154Training12.1811.8913.26511.7411.9228BDE-028Training9.549.3969.70.1440.16154BDE-154Training12.1811.8911.7411.92

    156BDE-156Training12.0312.6313.26512.2411.9729BDE-029Unknown9.329.3969.120.0760.2156BDE-156Training12.0312.6312.2411.97

    183BDE-183Training12.8912.68114.55412.7811.9630BDE-030Training9.119.3969.020.2860.09183BDE-183Training12.8912.68112.7811.96

    31BDE-031Unknown9.329.3969.730.0760.41

    32BDE-032Training9.099.3969.240.3060.15

    33BDE-033Unknown9.329.3969.540.0760.22

    34BDE-034Unknown9.19.3969.210.2960.11

    35BDE-035Training9.5410.2369.380.6960.16

    36BDE-036Unknown9.3210.2369.340.9160.02

    37BDE-037Training9.7710.2369.470.4660.3

    38BDE-038Unknown9.5410.2369.190.6960.35

    39BDE-039Unknown9.5410.2369.280.6960.26

    40BDE-040Unknown9.7610.68610.220.9260.46

    41BDE-041Unknown9.9910.68610.060.6960.07

    42BDE-042Unknown9.9910.68610.20.6960.21

    43BDE-043Unknown9.7610.68610.030.9260.27

    44BDE-044Unknown9.7610.68610.220.9260.46

    45BDE-045Unknown9.5410.68610.111.1460.57

    46BDE-046Unknown9.5410.68610.51.1460.96

    47BDE-047Training10.210.68610.460.4860.26

    48BDE-048Unknown9.9910.6869.950.6960.04

    49BDE-049Unknown9.9910.68610.250.6960.26

    50BDE-050Unknown9.7610.68610.170.9260.41

    51BDE-051Unknown9.7610.68610.480.9260.72

    52BDE-052Unknown9.7610.68610.140.9260.38

    53BDE-053Unknown9.5410.68610.261.1460.72

    54BDE-054Unknown9.3210.68610.431.3661.11

    55BDE-055Unknown10.2110.68610.350.4760.14

    56BDE-056Unknown10.2110.68610.50.4760.29

    57BDE-057Unknown9.9910.68610.20.6960.21

    58BDE-058Unknown9.9910.68610.440.6960.45

    59BDE-059Unknown9.7610.68610.30.9260.54

    60BDE-060Unknown10.4310.68610.460.2560.03

    61BDE-061Unknown10.2110.68610.180.4760.03

    62BDE-062Unknown9.9910.6869.990.6960

    63BDE-063Unknown10.2110.68610.650.4760.44

    64BDE-064Unknown9.9910.68610.460.6960.47

    65BDE-065Unknown9.7610.68610.180.9260.42

    66BDE-066Training10.4210.68610.630.2660.21

    67BDE-067Unknown10.2110.68610.260.4760.05

    68BDE-068Unknown10.2110.68610.250.4760.04

    69BDE-069Training9.9810.68610.380.7060.4

    70BDE-070Unknown10.2110.68610.580.4760.37

    71BDE-071Unknown9.9910.68610.590.6960.6

    72BDE-072Unknown9.9910.68610.330.6960.34

    73BDE-073Unknown9.7610.68610.260.9260.5

    74BDE-074Unknown10.4310.68610.140.2560.29

    75BDE-075Training10.2210.68610.250.4660.03

    76BDE-076Unknown10.2110.68610.10.4760.11

    77BDE-077Training10.6511.52610.410.8760.24

    78BDE-078Unknown10.4311.52610.161.0960.27

    79BDE-079Unknown10.4311.52610.21.0960.23

    80BDE-080Unknown10.2111.52610.331.3160.12

    81BDE-081Unknown10.6511.52610.10.8760.55

    82BDE-082Training10.8711.97711.181.1070.31

    83BDE-083Unknown10.6511.97711.131.3270.48

    84BDE-084Unknown10.4311.97711.151.5470.72

    85BDE-085Training11.0611.97711.280.9170.22

    86BDE-086Unknown10.8711.97711.071.1070.2

    87BDE-087Unknown10.8711.97711.21.1070.33

    88BDE-088Unknown10.6511.97711.121.3270.47

    89BDE-089Unknown10.6511.97711.451.3270.8

    90BDE-090Unknown10.8711.97711.291.1070.42

    91BDE-091Unknown10.6511.97711.331.3270.68

    92BDE-092Unknown10.6511.97711.061.3270.41

    93BDE-093Unknown10.4311.97711.111.5470.68

    94BDE-094Unknown10.4311.97711.081.5470.65

    95BDE-095Unknown10.4311.97711.041.5470.61

    96BDE-096Unknown10.2111.97711.151.7670.94

    97BDE-097Unknown10.8711.97710.971.1070.1

    98BDE-098Unknown10.6511.97711.231.3270.58

    99BDE-099Training11.0911.15711.20.0670.11

    100BDE-100Training10.8611.97711.41.1170.54

    101BDE-101Unknown10.8711.97711.291.1070.42

    102BDE-102Unknown10.6511.97711.171.3270.52

    103BDE-103Unknown10.6511.97711.151.3270.5

    104BDE-104Unknown10.4311.97711.141.5470.71

    105BDE-105Unknown11.3211.97711.540.6570.22

    106BDE-106Unknown11.0911.97711.160.8870.07

    107BDE-107Unknown11.0911.97711.310.8870.22

    108BDE-108Unknown11.0911.97711.380.8870.29

    109BDE-109Unknown10.8711.97711.121.1070.25

    110BDE-110Unknown10.8711.97711.261.1070.39

    111BDE-111Unknown10.8711.97711.071.1070.2

    112BDE-112Unknown10.6511.97711.051.3270.4

    113BDE-113Unknown10.6511.97711.231.3270.58

    114BDE-114Unknown11.3211.97711.120.6570.2

    115BDE-115Unknown11.0911.97711.260.8870.17

    116BDE-116Unknown10.8711.97711.661.1070.79

    117BDE-117Unknown10.8711.97711.321.1070.45

    118BDE-118Unknown11.3211.97711.310.6570.01

    119BDE-119Training11.0911.97711.290.8870.2

    120BDE-120Unknown11.0911.97711.620.8870.53

    121BDE-121Unknown10.8711.97711.041.1070.17

    122BDE-122Unknown11.0911.97711.30.8870.21

    123BDE-123Unknown11.3211.97711.030.6570.29

    124BDE-124Unknown11.0911.97711.510.8870.42

    125BDE-125Unknown10.8711.97711.011.1070.14

    126BDE-126Training11.512.81711.181.3170.32

    127BDE-127Unknown11.3212.81711.361.4970.04

    128BDE-128Unknown11.9813.26512.51.2850.52

    129BDE-129Unknown11.7613.26511.71.5050.06

    130BDE-130Unknown11.7613.26512.041.5050.28

    131BDE-131Unknown11.5413.265121.7250.46

    132BDE-132Unknown11.5413.26512.331.7250.79

    133BDE-133Unknown11.5413.26512.171.7250.63

    134BDE-134Unknown11.3213.26512.031.9450.71

    135BDE-135Unknown11.3213.26511.791.9450.47

    136BDE-136Unknown11.0913.26511.832.1750.74

    137BDE-137Unknown11.9813.26512.11.2850.12

    138BDE-138Unknown11.9813.26512.061.2850.08

    139BDE-139Unknown11.7613.26512.331.5050.57

    140BDE-140Unknown11.7613.26512.341.5050.58

    141BDE-141Unknown11.7613.26512.061.5050.3

    142BDE-142Unknown11.5413.26511.841.7250.3

    143BDE-143Unknown11.5413.26511.911.7250.37

    144BDE-144Unknown11.5413.26512.11.7250.56

    145BDE-145Unknown11.3213.26511.871.9450.55

    146BDE-146Unknown11.7613.26512.181.5050.42

    147BDE-147Unknown11.5413.26512.181.7250.64

    148BDE-148Unknown11.5413.26512.111.7250.57

    149BDE-149Unknown11.5413.26512.011.7250.47

    150BDE-150Unknown11.3213.26511.941.9450.62

    151BDE-151Unknown11.3213.26512.21.9450.88

    152BDE-152Unknown11.0913.26511.722.1750.63

    153BDE-153Training1213.26512.321.2650.32

    154BDE-154Training11.7413.26512.181.5250.44

    155BDE-155Unknown11.5413.26512.191.7250.65

    156BDE-156Training12.2413.26512.031.0250.21

    157BDE-157Unknown12.213.26512.471.0650.27

    158BDE-158Unknown11.9813.26512.211.2850.23

    159BDE-159Unknown11.9813.265121.2850.02

    160BDE-160Unknown11.7613.26511.891.5050.13

    161BDE-161Unknown11.7613.26512.011.5050.25

    162BDE-162Unknown11.9813.26512.331.2850.35

    163BDE-163Unknown11.7613.26512.491.5050.73

    164BDE-164Unknown11.7613.26512.441.5050.68

    165BDE-165Unknown11.5413.26511.881.7250.34

    166BDE-166Unknown11.9813.26512.21.2850.22

    167BDE-167Unknown12.213.26512.561.0650.36

    168BDE-168Unknown11.9813.26512.141.2850.16

    169BDE-169Unknown12.4214.10512.491.6850.07

    170BDE-170Unknown12.8714.55412.991.6840.12

    171BDE-171Unknown12.6514.55413.131.9040.48

    172BDE-172Unknown12.6514.55412.981.9040.33

    173BDE-173Unknown12.4214.55412.912.1340.49

    174BDE-174Unknown12.4214.55412.842.1340.42

    175BDE-175Unknown12.4214.55412.962.1340.54

    176BDE-176Unknown12.214.55412.772.3540.57

    177BDE-177Unknown12.4214.55413.042.1340.62

    178BDE-178Unknown12.214.55412.982.3540.78

    179BDE-179Unknown11.9814.55412.812.5740.83

    180BDE-180Unknown12.8714.55413.141.6840.27

    181BDE-181Unknown12.6514.55412.911.9040.26

    182BDE-182Unknown12.6514.55413.071.9040.42

    183BDE-183Training12.7814.55412.891.7740.11

    184BDE-184Unknown12.4214.55413.252.1340.83

    185BDE-185Unknown12.4214.55412.852.1340.43

    186BDE-186Unknown12.214.55412.582.3540.38

    187BDE-187Unknown12.4214.55413.032.1340.61

    188BDE-188Unknown12.214.55412.962.3540.76

    189BDE-189Unknown13.0914.55413.231.4640.14

    190BDE-190Unknown12.8714.55412.781.6840.09

    191BDE-191Unknown12.8714.55412.941.6840.07

    192BDE-192Unknown12.6514.55412.621.9040.03

    193BDE-193Unknown12.6514.55413.31.9040.65

    194BDE-194Unknown13.7615.84514.172.0850.41

    195BDE-195Unknown13.5315.84513.782.3150.25

    196BDE-196Unknown13.5315.84513.952.3150.42

    197BDE-197Unknown13.3115.84514.052.5350.74

    198BDE-198Unknown13.3115.84513.962.5350.65

    199BDE-199Unknown13.3115.84514.142.5350.83

    200BDE-200Unknown13.0915.84513.472.7550.38

    201BDE-201Unknown13.0915.84513.82.7550.71

    202BDE-202Unknown12.8715.84513.932.9751.06

    203BDE-203Unknown13.5315.84514.152.3150.62

    204BDE-204Unknown13.3115.84513.762.5350.45

    205BDE-205Unknown13.7615.84514.072.0850.31

    206BDE-206Unknown14.4217.13415.012.7140.59

    207BDE-207Unknown14.217.13414.492.9340.29

    208BDE-208Unknown13.9817.13414.783.1540.8

    209BDE-209Unknown15.0918.42315.733.3330.64

    210BDE-210Unknown6.6612.747

    211BDE-211Unknown9.3214.356

    212BDE-212Unknown11.9815.647

    213BDE-213Unknown14.6416.936

    214BDE-214Unknown17.316.936

    215BDE-215Unknown9.19.968

    216BDE-216Unknown15.0914.188

    217BDE-217Unknown6.669.649

    218BDE-218Unknown14.8612.899

    219BDE-219Unknown16.4214.188

    220BDE-220Unknown17.9715.479

    221BDE-221Unknown6.6611.893

    222BDE-222Unknown32.3820.297

    223BDE-223Unknown6.669.126

    Foglio1

    Exp. LogKoa

    Chen (2003)

    Papa (2008)

    Xu (2007)

    KoaWIN

    BDE

    LogKoa

    Exp. vs. Pred. data

    D (Y1-Y2)

    D (Y2 -Y3)

    BDE

    Delta

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    0000

    Xu (2007)

    Chen (2003)

    Papa (2008)

    Y Exp.

    BDE

    Log Koa

    Exp. vs. Pred. data

  • YPapa = Predictions by our model (range Log Koa: 7.32 15.09)YEpisuite = Predictions by KoaWIN (Dmax = 3.33 log units; range Log Koa: 6.81-18.23)YXu = Predictions by Xu et al. (2007) (Dmax =1.06 log units; range Log Koa: 7.4-15.73) Predictions for 209 PBDEs Comparison with some existing models High difference with EPISUITE for highly brominated PBDEs

    Chart3

    0.23766666670.32

    0.24033333330.3058333333

    0.37341666670.2808333333

    0.75242857140.3397619048

    1.12613043480.3904347826

    1.57166666670.4226190476

    2.01358333330.42625

    2.47833333330.5691666667

    2.9340.56

    3.3330.64

    average (|YPapa- YKoaWIN|)

    average (|YPapa-YXu|)

    D log units

    Sheet1

    nome interoComposto1-Pred TESI(T(O..Br)2-Pred EPI3-MLOGP4-ALOGP (|Y1- Y2|) (|Y1-Y3|) (|Y1-Y4|)average (|YPapa- YKowwin|)average (|YPapa-YMlogP|)average (|YPapa-YAlogP|)

    12-monoBDEBDE-0014.164.14.0684.1390.060.0920.021monoBDE0.37666666670.25533333330.18433333330.911.121.17

    13-monoBDEBDE-0024.324.944.0684.1390.620.2520.181diBDE0.41250.22883333330.1580.800.510.90

    14-monoBDEBDE-0034.494.944.0684.1390.450.4220.351triBDE0.51250.44850.17541666670.710.650.65

    0.37666666670.25533333330.1843333333tetraBDE0.72619047620.69080952380.27171428570.770.720.72

    22,2'-diBDEBDE-0044.654.994.7234.8870.340.0730.237pentaBDE0.93760869570.95991304350.37778260870.780.780.74

    22,3-diBDEBDE-0054.814.994.7234.8870.180.0870.077hexaBDE1.19857142861.23542857140.510.820.820.78

    22,3'-diBDEBDE-0064.814.994.7234.8870.180.0870.077heptaBDE1.46708333331.51091666670.65608333330.840.840.82

    22,4-diBDEBDE-0074.974.994.7234.8870.020.2470.083octaBDE1.75083333331.79916666670.79783333330.860.860.85

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    Sheet1

    average (|YPapa- YKowwin|)

    average (|YPapa-YMlogP|)

    average (|YPapa-YAlogP|)

    D log units

    Sheet2

    nome interoComposto |(Y1-Y2)| |(Y1 -Y3)|average (|YPapa- YKoaWIN|)average (|YPapa-YXu|)

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    0.23766666670.32tetraBDE0.75242857140.3397619048

    22,2'-diBDEBDE-0040.1170.48pentaBDE1.12613043480.3904347826

    22,3-diBDEBDE-0050.1030.05hexaBDE1.57166666670.4226190476

    22,3'-diBDEBDE-0060.1031.6heptaBDE2.01358333330.42625

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    63,3',4,4',5,5'-hexaBDEBDE-1691.6850.07

    1.57166666670.4226190476

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    82,2',3,3',4,5',6,6'-octaBDEBDE-2012.7550.71

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    2.9340.56

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    Sheet2

    average (|YPapa- YKoaWIN|)

    average (|YPapa-YXu|)

    D log units

    Sheet3

  • RESULTS Environmental fate of BFRs5
  • RESULTS QSAR modelsEndocrine Disrupting ActivityRBA = AhR Relative Binding Affinity = EC50(TCDD) / EC50(BFR)

    PRANT = Progesterone Receptor Antagonism

    T4-REP = T4-TTR Relative Competition = IC50(T4) / IC50(BFR)

    E2SULT-REP = E2SULT Relative Inhibition = IC50(E2) / IC50(BFR)E. Papa, S. Kovarich, P. Gramatica, QSAR modeling and prediction of the Endocrine disrupting potencies of brominated flame retardants, Submitted to J. Chem. Inf. Mod., 2010.

    Endpoint ModelTrainobj.Test obj.Desc.R2%Q2LOO%Q2EXT%AD% on 243 BFR Log1/RBA Full18-RDF080vRDF035v86.179.3-88.5 Random Split10887.274.076.8Log1/IC50 PRANTFull19-R7e+ GATS8e85.981.7-94.2Random Split10991.385.971.2Log T4-REPFull17-qpmax MATS6v95.292.9-97.9Random Split9896.791.990.5LogE2SULT-REP Full21-B08[C-O] GGI787.683.6-100 Random Split111087.273.287.6

  • RESULTS - Model for LogE2SULT-REPLogE2SULT-REP = -0.56 + 2.10 B08[C-O] 2.77 GGI7Equation of the Split Model (Random 50%): R2 = 0.87Q2LOO = 0.73Q2EXT = 0.88

  • RESULTS QSAR/QSPR models developed for Per-fluorinated ChemicalsBarun Bhhatarai

  • Results: QSAR models for LC50 inhalation*Barun Bhhatarai and Paola Gramatica, Per- and Poly-fluoro Toxicity (LC50 inhalation) Study in Rat and Mouse using QSAR Modeling, Chem.Res. Toxicol, 2010, in press.

    SplittingCompoundsVariables selectedR2 (%)Q2 LOO Q2BOOTQ2 ext R2-YScrm

    Mouse Inhalation56 compoundsSOM28.5%Train: 40Test: 16X3v; H-048; MLOGP; F01[C-C]82.9978.0975.4671.6210.32Random by Activity20%Train: 44Test: 1277.0771.7369.8985.118.99Full model79.8376.3175.38-7.05Rat Inhalation52 compoundsSOM18.9%Train: 42Test: 10Jhetv:PCR;MLOGP; B02[Cl-Cl]78.3672.9971.9575.478.75Random by Activity20%Train: 42Test: 1080.0175.2174.1266.709.91Full model78.1473.8573.26-7.64

  • Regression plots for the models ondatasets split by SOM*

  • Descriptor analysis

    Common descriptor characterizing Hydrophobicity was negative for both species

    JhetV and X3v have similar chemical meanings and are positive for both species * B02[Cl-Cl] present for 5 of 52 compounds fitting (?) descriptor to include all Freons

  • Applicability Domain (AD) study on 250 PFCs

    75.6% coverage of PFCs in Mouse model (61 compounds are out of structural domain) and 76.8% coverage in Rat model (53 out).*Arbitrary cutoff 0.5 (dotted lines): 11 common compounds are out of domain

  • Predicted compounds out of applicability domain of both Mouse and Rat model are long chain PFCs (>15-Carbon)

    They are probably extrapolated as the longest compounds in the training sets are with 7-Carbon Focus on AD: Common Out-of-domain compounds *

  • Increasing Toxicity*Toxicity Trend

  • More Toxic Chemicals Predicted: by PCA analysisPFOS is under investigation as toxic *PFOA

  • *QSPR of Melting point: Data splittingPerfluorinated chemicals (PERFORCE)

  • *Results: Melting point (94+17)AAC = mean information index on atomic correlations, information indicesF02[C-F] = frequency of C-F at topological distance 02, 2D frequency fingerprintC-013 = corresponds to CRX3 (X =electronegative atom), atom-centered fragments*Consonni, V., et al. J. Chem. Inf. Model., 49, 1669-1678.

    VariablesTrainSetR2Q2looQ2boot RMSE trainRMSE extQ2ext*R2YscrAACF02[C-F]C-013 53Prediction I SOM 41 test77.1173.3571.8940.8646.6570.165.18Prediction II17 test71.9025.0491.405.16

    48Prediction I Response46 test82.8579.3077.4838.0748.5272.165.84Prediction II17 test77.3624.6092.846.59

    Total 11178.4576.8276.6040.3641.86(cv)-2.82

  • *Analysis of Melting Point Model MP = 148.81 (18.43) AAC + 4.03 (0.66) F02[C-F] 14.47 (6.88) C-013 269.25 n=111

  • *QSPR of Boiling point: Data splittingPerfluorinated chemicals (PERFORCE)

  • *Results: Boiling point (105+25)Ms = mean electro-topological state, constitutional descriptorATS1m = Autocorrelation of a topological structure, 2D autocorrelationsnROH = number of OH groups, functional group counts*Consonni, V., et al. J. Chem. Inf. Model., 49, 1669-1678.

    VariablesTrainSetR2Q2looQ2boot RMSE trainRMSE extQ2ext*R2YscrMsATS1mnROH 55Prediction I SOM 50 test87.5085.2583.1624.7834.5475.715.73Prediction II 25 test86.2629.1485.175.55

    53Prediction I Response 52 test86.4083.5581.3830.2328.9887.506.12Prediction II 25 test80.7826.2089.535.35

    Total 13088.5487.5487.3728.2129.42 (cv)-2.41

  • *Analysis of Boiling Point ModelBP = 128.43 (5.295)ATS1m + 93.833 (5.85)nROH 54.23 (4.25)Ms 43.098 n=130

  • *QSPR of Vapor Pressure: Data splitting+ PERFORCE data

  • *Results: Vapor Pressure (35)nDB = number of double bonds, constitutional descriptorAAC = mean information index on atomic composition , information indicesF03[C-F] = frequency of C-F at topological distance 03, 2D frequency fingerprints*Consonni, V., et al. J. Chem. Inf. Model., 49, 1669-1678.

    VariablesSetR2Q2looQ2boot RMSE trainRMSE extQ2ext*R2YscrnDB;AAC;F03[C-F]Prediction I SOM 11 test91.0784.3381.630.830.9787.7812.69Prediction I Response 13 test93.7591.2382.130.641.1480.3614.08Total 3590.9388.2186.060.83 0.95 (cv)-8.95

  • * Analysis of Vapour Pressure Modellog VP = 0.642 (0.405) nDB 3.164 (0.924) AAC 0.165 (0.025) F03[C-F] + 7.97 n=35

  • Summary of QSPR models on PFCs:** http://www.epa.gov/oppt/exposure/pubs/episuite.htm All our models have smaller RMSE in comparison to EPISUITE models

  • ConclusionsPrediction of data for ~250 compounds was done for each set of chemicals: BFRs and PFCsApplicability domain analysis also for new compounds was doneQSA(P)Rs developed could be used to fill data gaps according to the new REACH regulation, facilitating the screening and prioritization of chemicals, reducing animal testing as well as for design of alternative and safer chemicals Predictive models were developed ad-hoc for several toxicity end-points and physico-chemical propertiesOECD principles for the validation of QSAR models, for regulatory applicability was strictly followedSimplicity (linear analysis, few descriptors, robust models) with external validation were used

  • *Thanks for your attention !!AcknowledgementsFinancial support by the FP7th-EU Project CADASTERhttp://www.qsar.it

    ***So, first of all why did we decided to study PBDE? Well as i said these chemicals are a class of flame retardants widely used as industrial additives to many daily use products. These compounds have been marketed in different formulations which includes different percentages of varously brominated PBDEs. Unfortunately the levels f these compounds in the environment increased since they came into use and, also due to the toxic effect which are connected to teir presence, the penta and octa formulations were banned since 2004 and the ban of the deca is now under evaluation*The general knowledge about PBDE describe them as not soluble and highly hydrophobic compounds which can be also persistent in the environment. In particular data related to their degradation patterns in the environment show that the highly brominated BDE (deca-hepta) are degraded to medium brominated congeners (tetra hexa) by debromination mechanism. Moreover different potential long term effects of concern are known to be connected to PBDEs such as the endocrine disrupting activity or developmental toxicity. However this general knowledge was derived from experimental data known for the most abundant congeners, while only while insufficient information is available to describe the environmental behavour and toxicity of all the remaining 200 congeners. Thus there is the need to know more about the potential behavour of PBDE and the related risks for human and environment.

    *This Study was carried on trying to reach different goals focussing on the study of the phisico chemical properties od PBDEs. Our first aim was then to make an overview of all the experimantal data available for these compounds in order to define a data set and decide if the available data were enough to start with the development of QSARs. The QSPRs that we wanted to obtain were linear regression models, also providing strong external validation, which could be compared to other existing QSPRs, in order to analyse differences and to highlight problems which could arise applying these QSPRs to the 209 PBDEs*Nella parte sx del grafico si distribuiscono i PBDE poco e mediamente bromurati (tri-penta), caratterizzati da maggior mobilit, persistenza, e, considerando che presentano valori di 5