QSAR screening of 70,983 REACH substances for genotoxic carcinogenicity, mutagenicity and developmental toxicity in the ChemScreen project.

The ChemScreen project aimed to develop a screening system for reproductive toxicity based on alternative methods. QSARs can, if adequate, contribute to the evaluation of chemical substances under REACH and may in some cases be applied instead of experimental testing to fill data gaps for information requirements. As no testing for reproductive effects should be performed in REACH on known genotoxic carcinogens or germ cell mutagens with appropriate risk management measures implemented, a QSAR pre-screen for 70,983 REACH substances was performed. Sixteen models and three decision algorithms were used to reach overall predictions of substances with potential effects with the following result: 6.5% genotoxic carcinogens, 16.3% mutagens, 11.5% developmental toxicants. These results are similar to findings in earlier QSAR and experimental studies of chemical inventories, and illustrate how QSAR predictions may be used to identify potential genotoxic carcinogens, mutagens and developmental toxicants by high-throughput virtual screening.

[1]  R. Kapp,et al.  Current status of bioassays in genetic toxicology--the dominant lethal assay. A report of the U.S. Environmental Protection Agency Gene-Tox Program. , 1985, Mutation research.

[2]  Arthur Dalby,et al.  Description of several chemical structure file formats used by computer programs developed at Molecular Design Limited , 1992, J. Chem. Inf. Comput. Sci..

[3]  S. Tsuda,et al.  The Comet Assay with Multiple Mouse Organs: Comparison of Comet Assay Results and Carcinogenicity with 208 Chemicals Selected from the IARC Monographs and U.S. NTP Carcinogenicity Database** , 2000, Critical reviews in toxicology.

[4]  Gilles Klopman,et al.  MC4PC—An Artificial Intelligence Approach to the Discovery of Quantitative Structure–Toxic Activity Relationships , 2005 .

[5]  M C Cimino,et al.  The in vivo micronucleus assay in mammalian bone marrow and peripheral blood. A report of the U.S. Environmental Protection Agency Gene-Tox Program. , 1990, Mutation research.

[6]  Ovanes Mekenyan,et al.  Representation of Chemical Information in OASIS Centralized 3D Database for Existing Chemicals , 2006, J. Chem. Inf. Model..

[7]  Anthony R Scialli,et al.  The challenge of reproductive and developmental toxicology under REACH. , 2008, Regulatory toxicology and pharmacology : RTP.

[8]  M D Waters,et al.  The performance of short-term tests in identifying potential germ cell mutagens: a qualitative and quantitative analysis. , 1994, Mutation research.

[9]  H S Rosenkranz,et al.  Relationship between carcinogenicity in rodents and the induction of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. , 1990, Mutagenesis.

[10]  B H Margolin,et al.  The proportions of mutagens among chemicals in commerce. , 2000, Regulatory toxicology and pharmacology : RTP.

[11]  Eva Bay Wedebye,et al.  The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals. , 2015, Reproductive toxicology.

[12]  H. Rosenkranz,et al.  Prediction of the carcinogenicity of a second group of organic chemicals undergoing carcinogenicity testing. , 1996, Environmental health perspectives.

[13]  Rosa Draisci.  The new European Regulation 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP Regulation): basic features. Preface. , 2011, Annali dell'Istituto superiore di sanita.

[14]  T Sofuni,et al.  Evaluation of the rodent micronucleus assay in the screening of IARC carcinogens (groups 1, 2A and 2B) the summary report of the 6th collaborative study by CSGMT/JEMS MMS. Collaborative Study of the Micronucleus Group Test. Mammalian Mutagenicity Study Group. , 1997, Mutation research.

[15]  Makoto Hayashi,et al.  Relevance of chemical structure and cytotoxicity to the induction of chromosome aberrations based on the testing results of 98 high production volume industrial chemicals. , 2002, Mutation research.

[16]  R. Saracci,et al.  Describing the validity of carcinogen screening tests. , 1979, British Journal of Cancer.

[17]  J. Contrera,et al.  A new highly specific method for predicting the carcinogenic potential of pharmaceuticals in rodents using enhanced MCASE QSAR-ES software. , 1998, Regulatory toxicology and pharmacology : RTP.

[18]  Stefan Kramer,et al.  A Large‐Scale Empirical Evaluation of Cross‐Validation and External Test Set Validation in (Q)SAR , 2013, Molecular informatics.

[19]  J D Tucker,et al.  Sister-chromatid exchange: second report of the Gene-Tox Program. , 1981, Mutation research.

[20]  T Sofuni,et al.  Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals. , 1988, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[21]  H S Rosenkranz,et al.  Modeling the mouse lymphoma forward mutational assay: the Gene-Tox program database. , 2000, Mutation research.

[22]  H S Rosenkranz,et al.  Estimating the extent of the health hazard posed by high-production volume chemicals. , 2001, Environmental health perspectives.

[23]  Eva Bay Wedebye,et al.  Screening of 397 chemicals and development of a quantitative structure--activity relationship model for androgen receptor antagonism. , 2008, Chemical research in toxicology.

[24]  J. Kazius,et al.  Derivation and validation of toxicophores for mutagenicity prediction. , 2005, Journal of medicinal chemistry.

[25]  S. Abrahamson,et al.  The sex-linked recessive lethal test for mutagenesis in Drosophila melanogaster. A report of the U.S. Environmental Protection Agency Gene-Tox Program. , 1983, Mutation research.

[26]  H. Rosenkranz,et al.  Structural determinants associated with risk of human developmental toxicity. , 1997, American journal of obstetrics and gynecology.

[27]  E. B. Wedebye,et al.  QSAR models for anti-androgenic effect – a preliminary study , 2011, SAR and QSAR in environmental research.