Advertisement

The Role of Qsar Methodology in the Regulatory Assessment of Chemicals

  • Andrew Paul Worth
Chapter
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 8)

Abstract

The aim of this chapter is to outline the different ways in which quantitative structure–activity relationship (QSAR) methods can be used in the regulatory assessment of chemicals. The chapter draws on experience gained in the European Union in the assessment of industrial chemicals, as well as recently developed guidance for the use of QSARs within specific legislative frameworks such as REACH and the Water Framework Directive. This chapter reviews the concepts of QSAR validity, applicability, and acceptability and emphasises that the use of individual QSAR estimates is highly context-dependent, which has implications in terms of the confidence needed in the model validity. In addition to the potential use of QSAR models as stand-alone estimation methods, it is expected that QSARs will be used within the context of broader weight-of-evidence approaches, such as chemical categories and integrated testing strategies; therefore, the role of (Q)SARs within these approaches is explained. This chapter also refers to a range of freely available software tools being developed to facilitate the use of QSARs for regulatory purposes. Finally, some conclusions are drawn concerning current needs for the further development and uptake of QSARs

Keywords

REACH Regulatory assessment Validity Applicability and adequacy of QSAR 

References

  1. 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), LuxembourgGoogle Scholar
  2. 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), LuxembourgGoogle Scholar
  3. 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), LuxembourgGoogle Scholar
  4. 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), LuxembourgGoogle Scholar
  5. 5.
    European Commission (2000) 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), LuxembourgGoogle Scholar
  6. 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), LuxembourgGoogle Scholar
  7. 7.
    Van Leeuwen CJ, Patlewicz GY, Worth AP (2007) Intelligent testing strategies. In: Van Leeuwen CJ, Vermeire TG (eds) Risk assessment of chemicals. An introduction, 2nd edn. Springer Publishers, Dordrecht, The Netherlands, pp 46–509Google Scholar
  8. 8.
    Grindon C, Combes R, Cronin MT et al. (2006) Integrated testing strategies for use in the EU REACH system. ATLA 34:407–427Google Scholar
  9. 9.
    Hoffmann S, Gallegos Saliner A, Patlewicz G et al. (2008) A feasibility study developing an integrated testing strategy assessing skin irritation potential of chemicals. Toxicol Lett 180:9–20CrossRefGoogle Scholar
  10. 10.
    Lessigiarska IV, Worth AP, Netzeva TI et al. (2006) Quantitative structure–activity–activity and quantitative structure–activity investigations of human and rodent toxicity. Chemosphere 65:1878–1887CrossRefGoogle Scholar
  11. 11.
    Dearden JC, Barratt MD, Benigni R et al. (1997) The development and validation of expert systems for predicting toxicity. The report and recommendations of an ECVAM/ECB workshop (ECVAM workshop 24). ATLA 25:223–252Google Scholar
  12. 12.
    OECD (2007) Guidance on grouping of chemicals. ENV/JM/MONO(2007)28 Series on Testing and Assessment Number 80, Organisation for Economic Co-operation and Development, Paris, France. Available at: http://www.oecd.org/
  13. 13.
    ECHA (2008) Guidance on information requirements and chemical safety assessment. European Chemicals Agency, Helsinki, Finland. Available at:http://reach.jrc.it/docs/guidance_document/information_requirements_en.htm/
  14. 14.
    OECD (2007) Report on the Regulatory Uses and Applications in OECD Member Countries of (Quantitative) Structure–Activity Relationship [(Q)SAR] Models in the Assessment of New and Existing Chemicals. ENV/JM/MONO(2006)25, Organisation for Economic Co-operation and Development, Paris, France. Available at: http://www.oecd.org/
  15. 15.
    Worth A, Patlewicz G (eds) (2007) A Compendium of Case Studies that helped to shape the REACH guidance on chemical categories and read across. European Commission report EUR 22481 EN. Office for Official Publications of the European Communities, Luxembourg. Available at: http://ecb.jrc.ec.europa.eu/qsar/publications/
  16. 16.
    Worth A, Bassan A, Fabjan E et al.(2007) The use of computational methods in the grouping and assessment of chemicals – preliminary investigations. European Commission report EUR 22941 EN, Office for Official Publications of the European Communities, Luxembourg, 2007. Available at: http://ecb.jrc.ec.europa.eu/qsar/publications/
  17. 17.
    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 19:397–412CrossRefGoogle Scholar
  18. 18.
    Gallegos Saliner A, Poater A, Jeliazkova N et al. (2008) Toxmatch – A chemical classification and activity prediction tool based on similarity measures. Regul Toxicol Pharmacol 52:77–84CrossRefGoogle Scholar
  19. 19.
    Pavan M, Worth A (2008) A set of case studies to illustrate the applicability of DART (Decision Analysis by Ranking Techniques) in the ranking of chemicals. European Commission report EUR 23481 EN, Office for Official Publications of the European Communities, Luxembourg, 2008. Available at: http://ecb.jrc.ec.europa.eu/qsar/publications/
  20. 20.
    Bassan A, Worth AP (2007) Computational tools for regulatory needs. In: Ekins S (ed) Computational toxicology: Risk assessment for pharmaceutical and environmental chemicals. John Wiley & Sons, Hoboken, NJ, pp 751–775Google Scholar
  21. 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 27:6–20CrossRefGoogle Scholar
  22. 22.
    OECD (2007) Guidance document on the validation of (quantitative) structure activity relationship [(Q)SAR] models. OECD Series on Testing and Assessment No. 69. ENV/JM/MONO(2007)2. Organisation for Economic Cooperation and Development, Paris, France. Available at: http://www.oecd.org/
  23. 23.
    OECD (2004) The report from the expert group on (quantitative) structure activity relationship ([Q]SARs) on the principles for the validation of (Q)SARs, Series on Testing and Assessment No. 49 (ENV/JM/MONO(2004)24). Organisation for Economic Cooperation and Development, Paris, France. Available at: http://www.oecd.org/
  24. 24.
    Jaworska JS, Comber M, Auer C et al. (2003) Summary of a workshop on regulatory acceptance of (Q)SARs for human health and environmental endpoints. Environ Health Perspect 111:1358–1360CrossRefGoogle Scholar
  25. 25.
    Eriksson L, Jaworska JS, Worth AP et al. (2003) Methods for reliability, uncertainty assessment, and applicability evaluations of classification and regression based QSARs. Environ Health Perspect 111:1361–1375CrossRefGoogle Scholar
  26. 26.
    Cronin MTD, Walker JD, Jaworska JS et al. (2003) Use of quantitative structure-activity relationships in international decision-making frameworks to predict ecologic effects and environmental fate of chemical substances. Environ Health Perspect 111:1376–1390CrossRefGoogle Scholar
  27. 27.
    Cronin MTD, Jaworska JS, Walker J et al. (2003) Use of quantitative structure-activity relationships in international decision-making frameworks to predict health effects of chemical substances. Environ Health Perspect 111:1391–1401CrossRefGoogle Scholar
  28. 28.
    JRC QSAR Model Database. http://qsardb.jrc.it
  29. 29.
    Netzeva TI, Worth AP Aldenberg T et al. (2005) Current status of methods for defining the applicability domain of (quantitative) structure-activity relationships. The report and recommendations of ECVAM workshop 52. ATLA 33:155–173Google Scholar
  30. 30.
    Pavan M, Worth AP (2008) Review of estimation models for biodegradation. QSAR Comb Sci 27:32–40CrossRefGoogle Scholar
  31. 31.
    Patlewicz G, Aptula AO, Roberts DW, Uriarte E (2008) A minireview of available skin sensitization (Q)SARs/expert systems. QSAR Comb Sci 27:60–76CrossRefGoogle Scholar
  32. 32.
    Worth AP, Bassan A, de Bruijn J et al. (2007) The role of the European Chemicals Bureau in promoting the regulatory use of (Q)SAR methods. SAR QSAR Environ Res 18:111–125CrossRefGoogle Scholar
  33. 33.
  34. 34.
    OECD QSAR Application Toolbox. http://www.oecd.org/env/existingchemicals/qsar/
  35. 35.
  36. 36.
    Pavan M, Worth A (2008) Publicly-accessible QSAR software tools developed by the Joint Research Centre. SAR QSAR Environ Res 19:785–799CrossRefGoogle Scholar
  37. 37.
    Enoch SJ, Hewitt M, Cronin MT et al. (2008) Classification of chemicals according to mechanism of aquatic toxicity: An evaluation of the implementation of the Verhaar scheme in Toxtree. Chemosphere 73:243–248CrossRefGoogle Scholar
  38. 38.
    Benigni R, Bossa C, Jeliazkova N et al. (2008) The Benigni/Bossa rulebase for mutagenicity and carcinogenicity – a module of Toxtree, European Commission report EUR 23241 EN, Office for Official Publications of the European Communities, LuxembourgGoogle Scholar
  39. 39.
    Patlewicz G, Jeliazkova N, Safford RJ et al. (2008) An evaluation of the implementation of the Cramer classification scheme in the Toxtree software. SAR QSAR Environ Res 19:397–412CrossRefGoogle Scholar
  40. 40.
    Jaworska J, Nikolova-Jeliazkova N (2007) How can structural similarity analysis help in category formation. SAR QSAR Environ Res 18:195–207CrossRefGoogle Scholar
  41. 41.
    Combes R, Grindon C, Cronin MT et al. (2007) Proposed integrated decision-tree testing strategies for mutagenicity and carcinogenicity in relation to the EU REACH legislation. ATLA 35:267–287Google Scholar
  42. 42.
    Grindon C, Combes R, Cronin MT et al. (2007a) Integrated decision-tree testing strategies for skin corrosion and irritation with respect to the requirements of the EU REACH legislation. ATLA 35:673–682Google Scholar
  43. 43.
    Grindon C, Combes R, Cronin MT et al. (2007b) An integrated decision-tree testing strategy for skin sensitisation with respect to the requirements of the EU REACH legislation. ATLA 35:683–697Google Scholar
  44. 44.
    Combes R, Grindon C, Cronin MT et al. (2008) Integrated decision-tree testing strategies for acute systemic toxicity and toxicokinetics with respect to the requirements of the EU REACH legislation. ATLA 36:45–63Google Scholar
  45. 45.
    Grindon C, Combes R, Cronin MT et al. (2008a) Integrated decision-tree testing strategies for developmental and reproductive toxicity with respect to the requirements of the EU REACH legislation. ATLA 36:65–80Google Scholar
  46. 46.
    Grindon C, Combes R, Cronin MT et al. (2008b) An integrated decision-tree testing strategy for eye irritation with respect to the requirements of the EU REACH legislation. ATLA 36:81–92Google Scholar
  47. 47.
    Grindon C, Combes R, Cronin MT et al. (2008c) An integrated decision-tree testing strategy for repeat dose toxicity with respect to the requirements of the EU REACH legislation. ATLA 36:93–101Google Scholar
  48. 48.
    Barlow S (2005) Threshold of toxicological concern (TTC) – A tool for assessing substances of unknown toxicity present at low levels in the diet. ILSI Europe Concise Monographs Series, International Life Sciences Institute, Brussels, 2005. Available at: http://europe.ilsi.org/publications/Monographs/
  49. 49.

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Institute for Health & Consumer Protection, European Commission - Joint Research CentreIspraItaly

Personalised recommendations