Skip to main content
SpringerLink
Log in
Book cover

Computational Toxicology pp 125–162Cite as

QSAR and Metabolic Assessment Tools in the Assessment of Genotoxicity

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 930))

Abstract

In this chapter, a range of computational tools for applying QSAR and grouping/read-across methods are described, and their integrated use in the computational assessment of genotoxicity is illustrated through the application of selected tools to two case-study compounds—2-amino-9H-pyrido[2,3-b]indole (AαC) and 2-aminoacetophenone (2-AAP). The first case study compound (AαC) is an environment pollutant and a food contaminant that can be formed during the cooking of protein-rich food. The second case study compound (2-AAP) is a naturally occurring compound in certain foods and also proposed for use as a flavoring agent. The overall aim is to describe and illustrate a possible way of combining different information sources and software tools for genotoxicity and metabolism prediction by means of a simple stepwise approach. The chapter is aimed at researchers and assessors who have a basic knowledge of computational toxicology and some familiarity with the practical use of computational tools. The emphasis is on how to evaluate the data generated by multiple tools, rather than the practical use of any specific tool.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. European Commission (2006a) Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. Official Journal of the European Union, L 396/1 of 30.12.2006. Office for Official Publications of the European Communities (OPOCE), Luxembourg 2006

    Google Scholar 

  2. European Commission (2006b) Directive 2006/121/EC of the European Parliament and of the Council of 18 December 2006 amending Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances in order to adapt it to Regulation (EC) No 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) and establishing a European Chemicals Agency. Official Journal of the European Union, L 396/850 of 30.12.2006. Office for Official Publications of the European Communities (OPOCE), Luxembourg 2006

    Google Scholar 

  3. European Commission (1998) Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing of biocidal products on the market. Official Journal of the European Union, L 132/1 of 24.04.1998. Office for Official Publications of the European Communities (OPOCE), Luxembourg 1998

    Google Scholar 

  4. European Commission (1991) Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market. Official Journal of the European Union, L 230/1 of 19.08.1991. Office for Official Publications of the European Communities (OPOCE), Luxembourg 1991

    Google Scholar 

  5. European Commission (2000a) Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for the Community action in the field of water policy. Official Journal of the European Union, L 327/1 of 22.12.2000. Office for Official Publications of the European Communities (OPOCE), Luxembourg 2000

    Google Scholar 

  6. European Commission (1976) Council Directive 76/768 of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products. Official Journal of the European Union, L 262/169 of 27.09.1976. Office for Official Publications of the European Communities (OPOCE), Luxembourg 1976

    Google Scholar 

  7. European Commission (2009) Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products (recast). Official Journal of the European Union, L 342/59 of 22.12.2009. Office for Official Publications of the European Communities (OPOCE), Luxembourg 2009

    Google Scholar 

  8. European Commission (1996) Regulation No 2232/96 of the European Parliament and of the Council of 28 October 1996 laying down a Community Procedure for flavouring substances used or intended for use in or on foodstuffs. Official Journal of the European Communities 23.11.1996, L 299, 1–4.

    Google Scholar 

  9. European Commission (2000b) Commission Regulation No 1565/2000 of 18 July 2000 laying down the measures necessary for the adoption of an evaluation programme in application of Regulation (EC) no. 2232/96. Official Journal of the European Communities 19.7.2000, L 180, 8–16

    Google Scholar 

  10. Worth AP (2010) The role of QSAR methodology in the regulatory assessment of chemicals. In: Puzyn T, Leszczynski J, Cronin MTD (eds) Recent advances in QSAR studies: methods and applications. Springer, Heidelberg, pp 367–382

    Chapter  Google Scholar 

  11. Lapenna S, Fuart-Gatnik M, Worth A (2010) Review of QSAR models and software tools for predicting acute and chronic systemic toxicity. JRC Technical Report EUR 24639 EN. Publications Office of the European Union, Luxembourg. http://ihcp.jrc.ec.europa.eu/our_labs/computational_toxicology/publications/

  12. Mostrag-Szlichtyng A, Worth A (2010) Review of QSAR models and software tools for predicting biokinetic properties. JRC Technical Report EUR 24377 EN. Publications Office of the European Union, Luxembourg. http://ihcp.jrc.ec.europa.eu/our_labs/computational_toxicology/publications/

  13. Serafimova R, Fuart Gatnik M, Worth A (2010) Review of QSAR models and software tools for predicting genotoxicity and carcinogenicity. JRC Technical Report EUR 24427 EN. Publications Office of the European Union, Luxembourg. http://ihcp.jrc.ec.europa.eu/our_labs/computational_toxicology/publications/

  14. Sanderson DM, Earnshaw CG (1991) Computer prediction of possible toxic action from chemical structure; the DEREK system. Hum Exp Toxicol 10:261–273

    Article  PubMed  CAS  Google Scholar 

  15. Helma C (2006) Lazy structure-activity relationships (lazar) for the prediction of rodent carcinogenicity and Salmonella mutagenicity. Mol Divers 10:147–158

    Article  PubMed  CAS  Google Scholar 

  16. Maunz A, Helma C (2008) Prediction of chemical toxicity with local support vector regression and activity-specific kernels. SAR QSAR Environ Res 19(5–6):413–431

    Article  PubMed  CAS  Google Scholar 

  17. Button WG, Judson PN, Long A et al (2003) Using absolute and relative reasoning in the prediction of the potential metabolism of xenobiotics. J Chem Inf Comput Sci 43:1371–1377

    Article  PubMed  CAS  Google Scholar 

  18. Kroes R, Renwick AG, Cheeseman M et al (2004) Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem Toxicol 42:65–83

    Article  PubMed  CAS  Google Scholar 

  19. Enoch SJ, Madden JC, Cronin MT (2008) Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach. SAR QSAR Environ Res 19(5–6):555–578

    Article  PubMed  CAS  Google Scholar 

  20. Rydberg P, Gloriam DE, Olsen L (2010) The SMARTCyp cytochrome P450 metabolism prediction server. Bioinformatics 26:2988–2989

    Article  PubMed  CAS  Google Scholar 

  21. Bassan A, Worth AP (2008) The integrated use of models for the properties and effects of chemicals by means of a structured workflow. QSAR Comb Sci 27:6–20

    Article  CAS  Google Scholar 

  22. ECHA (2008) Guidance on information requirements and chemical safety assessment. European Chemicals Agency, Helsinki, Finland. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

  23. Worth A, Lapenna S, Lo Piparo E, Mostrag-Szlichtyng A, Serafimova R (2011) A Framework for assessing in silico toxicity predictions: case studies with selected pesticides. JRC Technical Report EUR 24705 EN. Publications Office of the European Union, Luxembourg. http://ihcp.jrc.ec.europa.eu/our_labs/computational_toxicology/publications/

  24. Dearden J (2011) Prediction of physicochemical properties. In: Resfeld B, Mayena AN (eds) Computational toxicology, Methods in molecular biology. Springer Science+Business Media, New York

    Google Scholar 

  25. Enoch SJ (2010) Chemical category formation and read-across for the prediction of toxicity. In: Puzyn T, Leszczynski J, Cronin MTD (eds) Recent advances in QSAR studies—methods and applications. Springer, Heidelberg, pp 209–219

    Chapter  Google Scholar 

  26. Patlewicz G, Jeliazkova N, Gallegos Saliner A et al (2008) Toxmatch—a new software tool to aid in the development and evaluation of chemically similar groups. SAR QSAR Environ Res 19:397–412

    Article  PubMed  CAS  Google Scholar 

  27. Franklin RB (2009) In silico studies in ADME/Tox: caveat emptor. Current computer-aided 2009. Drug Design 5:128–138

    CAS  Google Scholar 

  28. Frederiksen H (2005) Two food-borne heterocyclic amines: metabolism and DNA adduct formation of amino-α-carbolines. Mol Nutr Food Res 49:263–273

    Article  PubMed  CAS  Google Scholar 

  29. King RS, Teitel CH, Kadlubar FF (2000) In vitro bioactivation of N-hydroxy-2-amino-{alpha}-carboline. Carcinogenesis 21:1347–1354

    Article  PubMed  CAS  Google Scholar 

  30. Schut HAJ, Snyderwine EG (1999) DNA adducts of heterocyclic amine food mutagens: implications for mutagenesis and carcinogenesis. Carcinogenesis 20:353–368

    Article  PubMed  CAS  Google Scholar 

  31. Pfau W, Schulze C, Shirai T et al (1997) Identification of the major hepatic DNA adduct formed by the food mutagen 2-amino-9H-pyrido[2,3-b]indole (AαC). Chem Res Toxicol 10:1192–1197

    Article  PubMed  CAS  Google Scholar 

  32. Frederiksen H, Frandsen H, Pfau W (2004) Syntheses of DNA adducts of two heterocyclic amines, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA{alpha}C) and 2-amino-9H-pyrido[2,3-b]indole (A{alpha}C) and identification of DNA adducts in organs from rats dosed with MeA{alpha}C. Carcinogenesis 25:1525–1533

    Article  PubMed  CAS  Google Scholar 

  33. Benigni R, Bossa C (2008) Structure alerts for carcinogenicity, and the Salmonella assay system: a novel insight through the chemical relational databases technology. Mutat Res 659:248–261

    Article  PubMed  CAS  Google Scholar 

  34. Enoch SJ, Cronin MTD (2010) A review of the electrophilic reaction chemistry involved in covalent DNA binding. Crit Rev Toxicol 40:728–748

    Article  PubMed  CAS  Google Scholar 

  35. EFSA (2008) Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from Commission on Flavouring group evaluation 48: Aminoacetophenone. EFSA J 797:1–25, http://www.efsa.europa.eu/en/scdocs/doc/797.pdf

    Google Scholar 

  36. TNO (2000) Volatile compounds in food—VCF Database. TNO Nutrition and Food Research Institute, Boelens Aroma Chemical Information Service BACIS, Zeist

    Google Scholar 

  37. EFSA (2010) EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids. Draft Guidance on the data required for the risk assessment of flavourings. EFSA J 8(6):1623, http://www.efsa.europa.eu/en/scdocs/scdoc/1623.htm

    Google Scholar 

  38. Colvin M, Hatch F, Felton J (1998) Chemical and biological factors affecting mutagen potency. Mutat Res 400:479–492

    Article  PubMed  CAS  Google Scholar 

  39. Miller E, Miller J (1981) Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer 47:2327–2345

    Article  PubMed  CAS  Google Scholar 

  40. Tates A, Kriek E (1981) Induction of chromosomal aberrations and sister-chromatid exchanges in Chinese hamster cells in vitro by some proximate and ultimate carcinogenic arylamide derivatives. Mutat Res 88:397–410

    Article  PubMed  CAS  Google Scholar 

  41. Popescu N, Turnbull D, DiPaolo J (1977) Sister chromatid exchange and chromosome aberration analysis with the use of several carcinogens and noncarcinogens: brief communication. J Natl Cancer Inst 59:289–293

    PubMed  CAS  Google Scholar 

  42. Kazius J, McGuire R, Bursi R (2004) Derivation and validation of toxicophores for mutagenicity prediction. J Med Chem 48:312–320

    Article  Google Scholar 

  43. Kirkland D, Aardema M, Henderson L et al (2005) Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens: I. Sensitivity, specificity and relative predictivity. Mutat Res 584:1–256

    Article  PubMed  CAS  Google Scholar 

  44. Aeschbacher H-U, Turesky RJ (1991) Mammalian cell mutagenicity and metabolism of heterocyclic aromatic amines. Mutat Res 259:235–250

    Article  PubMed  CAS  Google Scholar 

  45. Bowden J, Chung K, Andrews A (1976) Mutagenic activity of tryptophan metabolites produced by rat intestinal microflora. J Natl Cancer Inst 57:921–924

    PubMed  CAS  Google Scholar 

  46. Thompson C, Hill L, Epp J et al (1983) The induction of bacterial mutation and hepatocyte unscheduled DNA synthesis by monosubstituted anilines. Environ Mutagen 5:803–811

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Health and Consumer Protection, European Commission–Joint Research Centre, Ispra, VA, Italy

    Andrew P. Worth, Silvia Lapenna & Rositsa Serafimova

Authors
  1. Andrew P. Worth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Lapenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rositsa Serafimova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew P. Worth .

Editor information

Editors and Affiliations

  1. School of Biomedical Engineering, Chemical & Biological Engineering, Colorado State University, Campus Delivery 1370, Fort Collins, 80523-1370, Colorado, USA

    Brad Reisfeld

  2. , Chemical & Biological Engineering, Colorado State University, Campus Delivery 1370, Fort Collins, 80523-1370, Colorado, USA

    Arthur N. Mayeno

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Worth, A.P., Lapenna, S., Serafimova, R. (2013). QSAR and Metabolic Assessment Tools in the Assessment of Genotoxicity. In: Reisfeld, B., Mayeno, A. (eds) Computational Toxicology. Methods in Molecular Biology, vol 930. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-059-5_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-059-5_6

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-058-8

  • Online ISBN: 978-1-62703-059-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation