Development Of A Master Database Of Non-Cancer Threshold ... Biomed Biomed Biomed Biomed Biomed Biomed

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    Development Of A Master Database Of Non-Cancer Threshold Of Toxicological

    Concern And Potency Categorization Based On ToxPrint Chemotypes

    C. Yang1,2, M. Cheeseman4, MTD Cronin5, S. Enoch5, S. Escher6, E. Fioravanzo7,

    T. Steger-Hartmann8, I. Tluczkiewicz6, A. Tarkhov2, JF Rathman2, V. Vitcheva1, A. Mostrag1, A. Worth9

    1Molecular Networks GmbH, Erlangen, Germany, 2Altamira LLC, Columbus, OH, USA, 4Steptoe&Johnson, Washington, DC, 5 Liverpool John Moores University, Liverpool, United Kingdom, 6Fraunhofer (ITEM), Hanover, Germany,7S-IN, Vicenza, Italy, 8Investigational Toxicology, Bayer Pharma, Berlin, Germany, 9Joint Research Centre, European Commission, Ispra, Italy

    A2163/P647

    • eTOX project: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nº 115002 (eTOX), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contributions.

    BACKGROUND: Facts on Threshold of toxicological

    concern (TTC):

    DATABASE CURATION STRATEGY

    NEXT STEPS

    References

    Software

    • Represents an alternative approaches for the safety/risk assessment of food additives, metabolites of agrochemicals

    • Is mainly applied to chemicals used in low exposure when compound specific data are not available

    - could be a viable option for handling pharmaceutical impurities

    • Currently, chemicals are grouped into Cramer classes (I, II, III) for the likelihood of toxicity

    • For each Cramer Class, a threshold value has been established from a pre-existing database (such as Munro 1996 database)

    • Development of potency-aware chemotypes

    - Group compounds for findings category (pathology, clinical chemistry, hematology, etc.)

    - Group compounds for Chemical fragments (Chemotypes)6,7

    - Chemotypes are chemical fragments with encoded atom/bond and/or physicochemical properties

    A. Chemotyper and ToxPrint (http://chemotyper.org) B. ToxPrint (http://toxprint.org) C. Toxtree (http://toxtree.sourceforge.net/)

    • COSMOS project: The research has been also in part supported by COSMOS project through EU Community’s 7th Framework Program (FP7/2007-2013) COSMOS Project under grant agreement n° 266835 and from Cosmetics Europe

    OBJECTIVE: An alternative method to Cramer Classes

    CURRENT LIMITATIONS OF CRAMER CLASSES

    Munro 1996

    ToxRefDB

    eTOXsys Database

    TTC - 2400 chemicals

    pharmaceuticals from eTOX not included yet

    1

    2

    3

    4

    5 Hazard Evaluation Support System (HESS)

    (613 diverse chemicals)

    (552 cosmetics) (RepDose 628 industrial)

    (1185 industrial, agro, etc.)

    (455 industrial)

    Potency

    • 33 logical structural rules • Problems with interpretations • Mechanistically not transparent • Does not apply well to pharmaceuticals (see Poster 2684/P184)

    Class I: 4.1 mg/kg-bw/day Class II: 0.58 mg/kg-bw/day Class III: 0.77 mg/kg-bw/day

    Munro dataset

    COSMOS TTC

    Class I: 3.0 mg/kg/bw/day Class II: 0.91 mg/kg/bw/day Class III: 0.15 ,g/kg bw/day

    1. Yang C, et al. J. Chem. Inf. Model. 2015, 55, 510−528 2. Munro IC, et al Food and chemical Toxicology 34 (1996) 829-867

    DATABASE PROFILE - Potency

    Alcohol, aromatic Amine, aliphatic - aliphatic C>=8

    Amine (NH2), aromatic Carbamate/thiocarbamate

    Carboxamide Carboxylic acid/ester, aliphatic C>=8

    Carboxylic acid - aromatic Ether - aromatic

    Hydrazine Heterocycle - imidazole, generic

    Heterocycle - isothiazole, generic Ketone - aromatic

    Organic nitrile Organic nitro, aromatic

    Organohalide Organophosphorus

    Heterocycle - isoxazole, generic Heterocycle - pyran, generic

    Heterocycle - pyridine, generic Heterocycle - pyrimidine oxo/oxy, generic

    Heterocycle - triazine, generic Heterocycle - triazine oxo/oxy, generic (isocyanurate)

    Heterocycle - triazole, generic Quaternary ammonium ion

    Sulfonamide Surfactant - anionic

    Surfactant - cationic quaternary alkyl/aliphatic Surfactant - cationic quaternary benzenealky

    Surfactant - alcohol ethoxylate Urea

    Study Profile Potency Chemotype Profile

    2

    0

    c c

    c

    y y z

    n S

    n N

     

         

    y = NOEL/NOAEL values N = total number of observations (compounds) n0 = total number that do not have the chemotype nc = total number that do have the chemotype S= standard deviation of the whole set

    meanof thewhole set

    meanof the subsetcontaining thechemotypec

    y

    y

    FINDINGS

    CHEMOTYPES

    The association of study findings including phenotypes with chemotype categories allow mechanistic grouping.

    • Validate the potency-aware chemotype categories with data from e-Tox, REACH (ECHA), FDA CFSAN, or EFSA.

    • Include pharmaceuticals (with known pharm actions) from eTOX database.

    - Associate with each representative chemotypes with statistical significance for potency (2-D clustering heat map)

    • Need to develop a robust database with reliable NOAEL/NOEL data

    NOELs/NOAELs

    COSMOS DB workflow

    eTOX database - pharm action

    - NOELs/NOAELs

    Special thanks to ILSI Europe COSMOS EG1 including Kirk Arvidson and Kristi Jacobs!

    chihae.yang@mn-am.com