title: Quantitative and qualitative models for carcinogenicity prediction for non-congeneric chemicals using CP ANN method for regulatory uses.
abstract: The new European chemicals regulation Registration, Evaluation, Authorization and Restriction of Chemicals entered into force in June 2007 and accelerated the development of quantitative structure-activity relationship (QSAR) models for a variety of endpoints, including carcinogenicity. Here, we would like to present quantitative (continuous) and qualitative (categorical) models for non-congeneric chemicals for prediction of carcinogenic potency. A dataset of 805 substances was obtained after a preliminary screening of findings of rodent carcinogenicity for 1,481 chemicals accessible via Distributed Structure-Searchable Toxicity (DSSTox) Public Database Network originated from the Lois Gold Carcinogenic Potency Database (CPDB). Twenty seven two-dimensional MDL descriptors were selected using Kohonen mapping and principal component analysis. The counter propagation artificial neural network (CP ANN) technique was applied. Quantitative models were developed exploring the relationship between the experimental and predicted carcinogenic potency expressed as a tumorgenic dose TD(50) for rats. The obtained models showed low prediction power with correlation coefficient less than 0.5 for the test set. In the next step, qualitative models were developed. We found that the qualitative models exhibit good accuracy for the training set (92%). The model demonstrated good predicted performance for the test set. It was obtained accuracy (68%), sensitivity (73%), and specificity (63%). We believe that CP ANN method is a good in silico approach for modeling and predicting rodent carcinogenicity for non-congeneric chemicals and may find application for other toxicological endpoints.
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia. natalja.fjodorova@ki.si
authors.forename: Natalja
authors.initials: N
authors.lastname: Fjodorova
authors.forename: Marjan
authors.initials: M
authors.lastname: Vračko
authors.forename: Marjan
authors.initials: M
authors.lastname: Tušar
authors.forename: Aneta
authors.initials: A
authors.lastname: Jezierska
authors.forename: Marjana
authors.initials: M
authors.lastname: Novič
authors.forename: Ralph
authors.initials: R
authors.lastname: Kühne
authors.forename: Gerrit
authors.initials: G
authors.lastname: Schüürmann
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D016208:Databases, Factual; D004335:Drug and Narcotic Control / Q000379:methods*; D006801:Humans; D016571:Neural Networks, Computer; D025341:Principal Component Analysis; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D051381:Rats
chemical_list: D002273:Carcinogens
references.citation: Cancer Res. 1971 Aug;31(8):1118-27
references.pmid: 5095977
references.citation: SAR QSAR Environ Res. 1998;8(1-2):93-107
references.pmid: 9517011
references.citation: Mol Divers. 2004;8(4):371-7
references.pmid: 15612641
references.citation: Drug Discov Today. 2007 Dec;12(23-24):1013-7
references.pmid: 18061879
references.citation: Chem Rev. 2005 May;105(5):1767-800
references.pmid: 15884789
references.citation: J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008 Jan-Mar;26(1):40-88
references.pmid: 18322867
references.citation: Carcinogenesis. 2001 Sep;22(9):1561-71
references.pmid: 11532881
references.citation: Adv Drug Deliv Rev. 2007 Jan 10;59(1):43-55
references.pmid: 17229485
references.citation: Environ Health Perspect. 1985 Sep;61:69-96
references.pmid: 3905382
references.citation: Toxicology. 1997 May 16;119(3):213-25
references.pmid: 9152017
references.citation: J Chem Inf Comput Sci. 2004 Mar-Apr;44(2):704-15
references.pmid: 15032553
references.citation: Environ Health Perspect. 2003 Aug;111(10):1391-401
references.pmid: 12896862
references.citation: Mutat Res. 1998 Feb 26;398(1-2):1-17
references.pmid: 9626960
references.citation: Mutat Res. 2005 Oct 3;586(2):138-46
references.pmid: 16112600
references.citation: Toxicology. 2006 Mar 1;220(1):51-62
references.pmid: 16414170
references.citation: Mutat Res. 1990 Dec;242(4):285-303
references.pmid: 2255323
references.citation: J Chem Inf Comput Sci. 2004 Mar-Apr;44(2):300-9
references.pmid: 15032504
references.citation: Mutat Res. 2003 Oct 7;540(2):153-63
references.pmid: 14550499
references.citation: Mutat Res. 2000 Nov 20;455(1-2):81-95
references.pmid: 11113469
references.citation: Br J Cancer. 1979 Jan;39(1):87-9
references.pmid: 758931
references.citation: Toxicology. 1995 Sep 1;102(1-2):23-8
references.pmid: 7482558
references.citation: Mutat Res. 1998 May 25;400(1-2):493-507
references.pmid: 9685707
references.citation: Regul Toxicol Pharmacol. 2003 Dec;38(3):243-59
references.pmid: 14623477
references.citation: Environ Health Perspect. 2003 Aug;111(10):1358-60
references.pmid: 12896859
references.citation: Altern Lab Anim. 2007 May;35(2):267-87
references.pmid: 17559315
references.citation: Altern Lab Anim. 2006 Mar;34 Suppl 1:139-47
references.pmid: 16555967
references.citation: Environ Toxicol Chem. 2003 Aug;22(8):1885-93
references.pmid: 12924587
references.citation: SAR QSAR Environ Res. 2001;12(1-2):55-74
references.pmid: 11697060
references.citation: J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008 Apr-Jun;26(2):201-36
references.pmid: 18569330
references.citation: Mutat Res. 2006 Aug 4;607(1):37-60
references.pmid: 16765631
references.citation: Chem Rev. 2000 Oct 11;100(10):3697-714
references.pmid: 11749325
references.citation: Farmaco. 2004 May;59(5):389-95
references.pmid: 15120318
references.citation: J Chem Inf Comput Sci. 1999 Nov-Dec;39(6):1076-80
references.pmid: 10614025
references.citation: Regul Toxicol Pharmacol. 1998 Dec;28(3):242-64
references.pmid: 10049796
references.citation: Curr Opin Chem Biol. 2004 Aug;8(4):349-58
references.pmid: 15288243
references.citation: SAR QSAR Environ Res. 1999;10(2-3):277-98
references.pmid: 10491854
references.citation: Adv Drug Deliv Rev. 2006 Nov 30;58(12-13):1326-56
references.pmid: 17092600
references.citation: J Chem Inf Model. 2007 Nov-Dec;47(6):2149-58
references.pmid: 17918926
references.citation: Regul Toxicol Pharmacol. 1995 Apr;21(2):250-1
references.pmid: 7644714
references.citation: Chem Biol Interact. 1992 Jan;81(1-2):149-80
references.pmid: 1730145
references.citation: Toxicol Sci. 2004 Oct;81(2):273-9
references.pmid: 15282409
references.citation: SAR QSAR Environ Res. 2002 Mar;13(1):1-19
references.pmid: 12074379
references.citation: Environ Mol Mutagen. 1996;28(1):31-50
references.pmid: 8698045
references.citation: J Comput Aided Mol Des. 1996 Dec;10(6):513-20
references.pmid: 9007685
references.citation: Environ Health Perspect. 1996 Oct;104 Suppl 5:1031-40
references.pmid: 8933051
references.citation: Bioinformatics. 2003 Jul 1;19(10):1194-200
references.pmid: 12835261
references.citation: Mutat Res. 2005 Jul 4;584(1-2):1-256
references.pmid: 15979392
references.citation: Mutat Res. 2008 Sep-Oct;659(3):248-61
references.pmid: 18621573
references.citation: Bioorg Med Chem. 2005 Apr 1;13(7):2477-88
references.pmid: 15755650
references.citation: Methods. 1998 Mar;14(3):264-76
references.pmid: 9571083
references.citation: Toxicol In Vitro. 2000 Aug;14(4):387-99
references.pmid: 10906445
references.citation: J Mol Graph Model. 2002 Jan;20(4):269-76
references.pmid: 11858635
references.citation: Basic Clin Pharmacol Toxicol. 2005 Mar;96(3):176-81
references.pmid: 15733212