Hans Steinkellner - Metabolites for dietary risk assessment

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Hans Steinkellner - Metabolites for dietary risk assessment

  1. 1. Committed since 2002 to ensuring that Europe’s food is safe Toxicological Relevance of pesticide metabolites for dietary risk assessmentECPA – IBMA- EFSA WorkshopParma, 26th April 2012
  2. 2. Background Reg. 1107/2008 concerning the placing of PPPs on the marketrequires: • identification of metabolites • determination of their “toxicological relevance” for in/exclusion in the residue definition
  3. 3. BackgroundOECD guidance document on the Definition of Residue (Series on Pesticides, No. 31; Series on Testing and Assessment, No. 63):• Proposes a residue definition for risk assessment, reflecting the actual toxicological burden consisting of active substance and relevant metabolites• Requires a quantitative and qualitative (toxicological) assessment of metabolites
  4. 4. Pesticide metabolites as residues • In contrast to active substances usually very limited or no toxicological data available although their toxic potency and toxicological profile might differ from the parent compound • Reference values of parent compounds are applied for metabolites present in food commodities
  5. 5. Assessment tools Conventional testing of metabolites?• Number of metabolites• Difficulties in synthesising sufficient amounts• Costs• Research capacities• Animal welfare concerns
  6. 6. Assessment tools Preparatory Work• Project on Threshold of Toxicological Concern (TTC) Concept (CRD, UK)• Project: Impact of Metabolism on Toxicity (AGES, Austria)• 2 projects on (Quantitative) Structure-Activity Relationships (Q)SAR (JRC, EC)
  7. 7. Assessment tools - TTC Applicability of thresholds of toxicological concern in the dietary risk assessment of metabolites, degradation and reaction products of pesticides (published 24 March 2010) http://www.efsa.europa.eu/en/supporting/pub/44e.htm
  8. 8. Assessment tools - TTC • Review on the TTC concept and survey on it’s current use • Validation of TTC for pesticides: Comparison of 100 pesticide ADIs with TTC classification • Case study with 79 metabolites of 15 selected pesticidesConclusions: • TTC appropriate for assessment of metabolites • Exposure to metabolites considered to be covered by TTC thresholds allocated – critical is the genotoxicity threshold • QSARs predictions for genotoxicity considered reliable
  9. 9. Assessment tools – Impact of Metabolism Impact of metabolic and degradation processes on the toxicological properties of residues of pesticides in food commodities (published 6 May 2010) http://www.efsa.europa.eu/en/supporting/pub/49e.htm
  10. 10. Assessment tools – Impact of Metabolism• Review of transformation pathways (11 pesticide classes) and comparison with toxicity data (DARs, public literature)• Based on lack of other information analyses largely based on acute tox studies• 140 chemical changes identified – no clear tendency for toxification/detoxificationConclusions:• Toxification/detoxification cannot be attributed to certain metabolic steps (Conjugates not necessary less toxic due to cleavage)• Metabolite > 10% to be considered as contributing to toxicity• Metabolites found in livestock should be considered as present in rat• Improvement of ADME studies (more accuracy, more information) necessary
  11. 11. Assessment tools - QSARs Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment (published 7 May 2010) http://www.efsa.europa.eu/en/supporting/pub/50e.htm
  12. 12. Assessment tools - QSARs• Review on the use of QSAR for regulatory purposes• Extensive evaluation of potentially useful QSARs: (e.g. Toxtree, Lazar, Derek, Hazard Expert, Caesar, Topkat) using different data sets (Pesticide metabolites, EU classified substances, CPDB) for all relevant toxicity endpoints• Case studies focused on genotoxicity based on the outcome of the TTC project
  13. 13. Assessment tools - QSARs Conclusions:• Currently limited use of QSARs for regulatory purposes• Recommendations for the application of different models covering all relevant toxicological endpoints• Recommendations for further research• Combination of models recommended to optimise sensitivity and specificity in regard to genotoxicity
  14. 14. Assessment tools - QSARs• Refinement of proposed assessment approach based on chronic TTC levels for metabolites having effects upon acute exposure• Acute reference doses mainly triggered by reprotoxicity, developmental effects and neurotoxicity
  15. 15. Assessment tools - QSAR Applicability of QSAR analysis in the evaluation of developmental and neurotoxicity effects for the assessment of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment (published 16 June 2011) http://www.efsa.europa.eu/en/supporting/pub/169e.htm
  16. 16. Assessment tools - QSAR • Evaluation of QSAR models (Derek, Caesar, Topkat, Leadscope, Hazard Expert, PASS, ADME predictor, Accord) and read across (OECD toolbox) for assessment of reprotoxicity , developmental effects and neurotoxicityConclusions: • No appropriate QSAR models or neurotoxicity identified • Stepwise approach for developmental effects reprotoxicity combining read across and QSAR might be promising
  17. 17. Draft Scientific Opinion – Residue Part Chapters: • Residue definition - terminology • Comparison residue definition (EFSA vs. JMPR) • Analytical methods • Relevant metabolites • Types of exposure scenarios (focus on acute and chronic for MRL setting for case studies – limited data on metabolites; worst case assumption of parent/metabolite ratio to cover highest possible risk)
  18. 18. Draft Scientific Opinion – Residue Part Chapters: • Estimation of metabolite levels (STMR for chronic, HR for acute for case studies) • Calculation of acute/chronic exposures (UK NEDI and NESTI used for case studies) • Conversion factors • Decision tree for exposure assessments • Critical issues/Uncertainties • Appendices (Selected examples for residue definitions and differences EU/JMPR, parent/metabolite ratio; case studies for metabolite estimations and allocated TTC values)
  19. 19. Draft Scientific Opinion –Toxicology Part Chapters: • Projects on Impact of Metabolism, TTC and QSARs - Evaluation of PPR Panel • Derivation of acute exposure thresholds (TTC) • Toxicity assessment scheme for acute and for chronic exposure • Testing strategy for determination of relevance of metabolites • Critical Issues/Uncertainties • Appendices (Checklist for use of QSARs, data for acute TTC)
  20. 20. Draft Scientific Opinion – Isomer Part Extension of the mandate including assessment of isomers (September 2011) In order to: • investigate if the approaches proposed for assessment of metabolites are applicable for isomers • identify specific issues, suitable methodologies, research needs for isomers
  21. 21. Draft Scientific Opinion – Isomer Part Chapter:• Isomer terminology• Current approaches for assessment• Analytical methods• Suitability of assessment tools for isomers• Exposure assessment for isomers• Specific issues to be addressed• Research needs
  22. 22. Scientific Opinion Next steps:• Adoption of Scientific Opinion (June 2012)• Preparation of Guidance
  23. 23. PPR Working Group Members:Bernadette Ossendorp, Anita Stroemberg, ClaudiaBolognesi, Alan Boobis, Rebecca Scrivens, MariaTasheva, Markus Mueller, Christiane Vleminckx,Susanne Hougaard Bennekou, Karen Hirsch-ErnstPesticides Unit: Luc Mohimont, Istvan Sebestyen,Manuela Tiramani, Hans Steinkellner
  24. 24. Thank you!

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