Toxicological Relevance of pesticide metabolites

for dietary risk assessment

Committed since 2002 to ensuring that Europe’s food is safe

ECPA – IBMA- EFSA Workshop Parma, 26th April 2012

Background

Reg. 1107/2008 concerning the placing of PPPs on the market

requires: • identification of metabolites • determination of their “toxicological relevance” for in/exclusion in the residue definition

Background

OECD 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

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

Assessment tools

Conventional testing of metabolites? • Number of metabolites • Difficulties in synthesising sufficient amounts • Costs • Research capacities • Animal welfare concerns

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)

Assessment tools

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

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 pesticides

Conclusions: • 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

Assessment tools - TTC

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

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/detoxification Conclusions: • 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

Assessment tools – Impact of Metabolism

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

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

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

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

Assessment tools - QSARs

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

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 neurotoxicity

Conclusions:

• No appropriate QSAR models or neurotoxicity identified • Stepwise approach for developmental effects

reprotoxicity combining read across and QSAR might be promising

Assessment tools - QSAR

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)

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)

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)

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

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

Draft Scientific Opinion – Isomer Part

Next steps:

• Adoption of Scientific Opinion (June 2012) • Preparation of Guidance

Scientific Opinion

PPR Working Group Members:

Bernadette Ossendorp, Anita Stroemberg, Claudia Bolognesi, Alan Boobis, Rebecca Scrivens, Maria Tasheva, Markus Mueller, Christiane Vleminckx, Susanne Hougaard Bennekou, Karen Hirsch-Ernst

Pesticides Unit: Luc Mohimont, Istvan Sebestyen,

Manuela Tiramani, Hans Steinkellner

Thank you!