Regulatory Risk Assessment of Crop Protection Products Risk Assessment for Residues in Food and Environment Georg Geisler Regulatory Policy Manager Global Registration Syngenta Crop Protection AG, Basel georg.geisler@syngenta.com
Regulatory Risk Assessment of Crop Protection Products Todays topics Principles of regulatory risk assessment How does CPP regulation work? Foundations of risk assessment: Studies Case studies: Dietary exposure; Environmental fate Wrap-up/Job perspectives 2
Safety for Humans and Environment No unacceptable effects on environment No harmful effect on human health Regulation (EC) No. 1107/2009 (main points of preamble summarised) Syngenta ensures the quality and safety of its products Risk assessment needed The Syngenta Code of Conduct, Section 19 3
Principle of Risk Assessment Risk depends on exposure to a hazard Low exposure Low hazard Low risk High exposure High hazard High risk 4
What Advice Helps You Best to Plan a Healthy Diet? - Hazard vs. Risk no evidence that pesticide thresholds had been exceeded The potential lifelong damage of pesticides is estimated to be only 4.2 and 3.2 min of life lost per person in Switzerland and the United States, respectively R. Juraske et al. / Chemosphere 77 (2009) 939 945 5
Principle of Risk Assessment (2) (Eco-)Toxicological studies Consumption data (Food) Residue studies (Crops or soil) Hazard (Reference doses) Exposure (Residue level) Risk Assessment 6
Exposure pathways Application Emission Concentration in different compartments Safeguard subjects 7
Processes Process type Process Cause Degradation Bio-degradation Fungi, bacteria, plants, etc. Munch, munch Hydrolysis ph Photolysis Sunlight Sorption Reversible ad/desorption Soil organic matter, clay (ionic substances) O OH O O O Aging of sorption Diffusion into pores (soil) O OH O Bound residues Incorporation into natural soil/plant constituents O O Transport Translocation Water/air fluxes (soil, water bodies, plants, etc.) Dilution Accumulation Mixing during translocation Soil; oil/fat matrices 8
Time Scale: Acute vs. Chronic Risk Assessment Acute Chronic Concentration at emission Acute effects Time-weighted average concentration Chronic effects 9
Calculation: Deterministic Risk Assessment Risk quotient: RQ = PEC PNEC (Realistic) worstcase scenario Lowest NOEC x Safety factor RQ 1 RQ > 1 => No unacceptable risk to ecosystem => Potential risk to ecosystem, need more realistic assessment PEC PNEC NOEC Predicted environmental concentration (concentration endpoint) Predicted no-effect concentration (ecotoxicity endpoint) No observed effect concentration from ecotoxicological study For risk assessment of crop protection products, each representative species is assessed separately 10
Calculation (2): Probabilistic Distribution Risk quotient: RQ = PEC Ecotox. endpoint Distribution Probability density Deterministic ecotox. endpoint PEC ecotox. endpoint distribution Concentration 11
Consumer Risk Assessment: What Scenario? Exposure pathway Processes Time scale Calculation Exposure endpoint Hazard endpoint 12
Consumer: Chronic vs. Acute Risk Assessment 0.3 ppm Chronic 0.08 ppm 0.05 ppm Acute Lifelong Long-term average consumption (all food) 1 day/1 meal Large portion consumption (one food) Population groups, e.g. adults, children Average residue level from worst-case crop field trials (STMR) Sum exposure for all food Toxicological reference dose: Acceptable Daily Intake (ADI) Highest residue level from worst-case crop field trials (HR) Exposure per food item Toxicological reference dose: Acute Reference Dose (ARfD) 13
Deterministic Risk Assessment: Consumer (chronic) (Inter-)national databases Crop field trials Intake = S Consumption i * STMR i ADI * 100% NOAEL * Safety factor Intake < 100% of ADI => No unacceptable risk to consumer Intake < 100% of ADI => Potential consumer risk, need more realistic assessment Consumption STMR ADI NOAEL Amount of food consumed (part of exposure endpoint) Supervised trial mean residue level (part of exposure endpoint) Acceptable daily intake (human toxicity endpoint) No observed adverse effect level 14
Regulatory Risk Assessment of Crop Protection Products Todays topics Principles of regulatory risk assessment How does CPP regulation work? Foundations of risk assessment: Studies Case studies: Environmental fate; Dietary exposure Wrap-up/Job perspectives 15
Example: pesticides Regulatory procedure Time, years 0 Dossier Manufacturer Evaluation, requirements Authorites Further modelling/ testing/ assessment > 5 Approval (Mitigation) (Restrictions) 16
Regulatory testing/modelling: Tiered approach Cost, time Higher tier Tailor-made tests / modelling Tier 2 Advanced tests / modelling Tier 1 Basic standardised tests / modelling 17
Regulatory Risk Assessment of Crop Protection Products Todays topics Principles of regulatory risk assessment How does CPP regulation work? Foundations of risk assessment: Studies Case studies: Environmental fate; Dietary exposure Wrap-up/Job perspectives 18
Studies: Types and Sequence What? Metabolism studies Compounds relevant to consumer/environmental safety Plant metabolism Soil metabolism How much of it? Magnitude-ofresidue studies Crop field trials Soil degradation Risk assessment Study protocols defined by OECD Test Guidelines: http://titania.sourceoecd.org/vl=36183586/cl=23/nw=1/rps v/periodical/p15_about.htm?jnlissn=1607310x 19
Metabolism: Plants Representative crops Worst-case treatment ( 14 C) Sampling Elucidate metabolism Source: Codex Evaluation 2008 20
Soil Degradation: Tiered Experimental Approach Realism, cost Interpretability, generalizability Testing tier Test method Monitoring Field accumulation Field studies Field degradation Semi-field Lysimeter Laboratory OECD standard test Estimation QSAR 21
Studies: Laboratory Degradation Experimental: OECD 307 Aerate Snore, snore Extract/ analyse m applied Apply c extractable (t 1 ) Mix Traps c bound (t 1 ) c extractable (t 2 ) c bound (t 2 ) Mmm, tasty! Munch, munch c extractable (t 3 ) c bound (t 3 ) 22 Balance: CO 2 Volatile compounds c extracted c bound Target: 90-110 % of m applied
Concentration, % of applied Substance Properties: Fitting degradation half-life (DT50) First-order kinetics: Co-metabolism Degradation rate: dc k c dt c c exp t 0 k t Half-life: DT50 ln2 k 100 80 Fitting results: c 95.2 exp 0.0315 t 60 Rate constant (k) 40 20 En guete! 0 0 20 40 60 80 100 120 Time, days 23
Concentration, µg/kg Substance Properties: Metabolites Parallel degradation reactions: Parent f (1-f) Metabolite CO 2 2000 Degradation rates: dc parent dt dc dt metab k f k parent parent c c parent parent k metab c metab 1500 1000 500 Parent Metabolite 0 0 50 100 Time, days 24
Concentration, mg/kg Degradation half-lives: Tiered Testing Laboratory test: Microbial viability decreases with time Laboratory degradation often slower than field Degradation rate decreases over time => Non-SFO kinetics (e.g. bi-phasic) 0.12 0.1 Bi-phasic (FOMC) First-order 0.08 0.06 0.04 0.02 0 0 20 40 60 80 100 120 140 Time, days Field degradation studies give a more realistic picture! 25
Regulatory Risk Assessment of Crop Protection Products Todays topics Principles of regulatory risk assessment How does CPP regulation work? Foundations of risk assessment: Studies Case studies: Environmental fate; Dietary exposure Wrap-up/Job perspectives 26
Case study: Dietary exposure of consumers 27
Consumption Data: GEMS/food Cluster Diets (WHO/FAO) 28
Chronic Consumer Risk Assessment Total Maximum Daily Intake (TMDI): TMDI = S MRL i * Consumption i / bw International Estimated Daily Intake (IEDI): IEDI = S STMR i * Consumption i / bw MRL Maximum residue level, mg/kg STMR Supervised trials mean residue level, mg/kg Consumption, kg/person i commodity (plant or animal) bw body weight, kg ADI Acceptable daily intake, mg/kg bw/day Risk: expressed as % of ADI TMDI, IEDI overestimations: MRL is maximum residue (95th percentile); STMR is mean residue, but from worst-case field trials => EU official monitoring: residues in food mostly << STMR Assumes 100% crop treated No dissipation during storage/processing GEMS/Food consumption data overestimates actual consumption 29
Chronic Consumer Risk Assessment ADI = 0.005 mg/kg bw/day Used in citrus, apple, grapes, tomato, maize Body weight: 60 kg/person GEMS/food consumption data (Cluster B = Mediterranean) and calculation methods of WHO/FAO http://www.who.int/foodsafety/chem/acute_data/en/ Food Consumption, kg/person/day MRL (maximum), mg/kg TMDI, µg/person/ day STMR (mean), mg/kg IEDI, µg/person/ day Citrus fruit 0.101 0.5 50.3 0.21 21.2 Apple 0.061 0.5 30.5 0.15 9.2 Grape (incl. wine) 0.129 0.5 64.5 0.28 36.1 Tomato 0.185 0.8 148.0 0.34 62.9 Maize 0.148 0.05 7.4 0.021 3.1 Total intake = 300.7 132.5 %ADI = 100.2% 44% 30
Realistic exposure: EU official monitoring 2009, 2010 2010: 97.2% No chronic dietary risk Acute dietary risk for <= 0.4% of samples Multiple resdiues ca. 1/4 of samples (citrus, grape, strawberry, pepper) 2010: 50.7% of samples no quantifiable residues 31 2009 EU Report on Pesticide Residues. EFSA Journal 2011; 9(11):2430. http://www.efsa.europa.eu/en/publications.htm 2010 EU Report on Pesticide Residues. EFSA Journal 2013; 11(3):3130. http://www.efsa.europa.eu/en/publications.htm
Realistic exposure: Cumulative dietary risk assessment Scope: - Cumulation: residues of several compounds in all food commodities - Aggregation: food + drinking water (+ other pathways) Method/data: - Exposure: Consumption; realistic residue levels; co-occurrence - Hazard: Common assessment groups (common mode of toxic action; common target organ) EU: Method development ongoing - Major challenge: «Common Assessment Groups» no assessment of actual cumulative exposure conducted so far has indicated any significant risks from exposure to multiple chemicals belonging to a CAG where the individual compounds presented no unacceptable risks EFSA Journal (2008) 704, p. 57 US: No additional risk compared to individual assessments - Organophosphates; N-methyl carbamates; Chloroacetanilides; Pyrethroids 32
Case study: Environment 33
Predicted Environmental Concentrations: Pathways Spray application Interception Spray drift Volatilisation Deposition Runoff Field soil Leaching Drainage Surface water 34 Groundwater
Tier-1 Model (EXPOSIT): Drainage Application rate PECsw ini (drainage) M substance V drainage water Soil concentration (3 days after application) Ditch of 40 m 3 (baseflow + drainage water) Drainage loss: fraction of soil residue 35
Tier-1 Model (EXPOSIT): Drainage PECsw PECsw ini ini (drainage) (drainage) M M substance,drainage V water substance,soil V (t) A waterbody f field f dilution drainage Parameter M substance,soil Definition Mass of substance in soil, kg/ha 3 days after application, first-order kinetics Modeller choices Degradation half-life (time horizon) f drainage Fraction of pesticide lost by drainage Default values (season of application; adsorption) Appropriate default value V waterbody Volume of waterbody Worst-case ditch: default volumes (season of application) None f 36 dilution Default dilution factor of 2, flowing ditch None
Tier-1 Model: Soil Concentration M subs tan ce,soil (t) apprate k t 1 f e int erception PECsw ini (drainage) apprate 1 f int erception V waterbody e f k t dilution A field f drainage Parameter f interception Definition Fraction of application rate intercepted by the crop (i.e., not reaching soil) Modeller choices Default values according to growth stage of crop k Degradation rate (first-order kinetics), d -1 Appropriate value t 37 Time, d Default: 3 days
Case Study Herbistrike 10 : Soil Degradation Half-Lives Laboratory degradation studies Field degradation studies Soil type Half-life, days Location Half-life, days sandy clay 5.4 Germany 1 4.7 loamy sand 9.9 Germany 2 3.9 sandy loam 12.0 Northern France 1 3.2 loam 56.0 Northern France 2 9.6 clay loam 1 11.1 Southern France 1 15.4 clay loam 2 11.7 Southern France 2 16.0 Italy 1 36.1 Italy 2 8.9 Italy 3 15.2 Maximum 56.0 Maximum 36.1 90th percentile 34.0 90th percentile 20.0 Geometric mean 12.9 Geometric mean 9.6 Arithmetic mean 17.7 Arithmetic mean 12.6 Median 11.4 Median 9.6 All half-lives following first-order kinetics 38
Case Study Herbistrike 10 : Tier-1 Evaluation Spray drift: Mitigation (10 m buffer zone) Drainage: Tier-1 model simplified worst-case Higher-tier drainage model (water body, weather data, application season) Buffer width, m fdrift, % PECsw,ini(drift), g/l RQ (incl. SF) 1 2.77 4.62 6.16 fail 5 0.57 0.95 1.27 fail 10 0.29 0.48 0.64 pass! 20 0.15 0.25 0.33 30 0.1 0.17 0.22 40 0.07 0.12 0.16 50 0.06 0.10 0.13 fdrainage, PECsw,ini(drainage), % g/l 0.025 0.976 1.30 Fail!!! 39
Higher-Tier Model: FOCUS Surface Water ~ 90th percentile vulnerability => Realistic worst-case D1 D2 D5 D3 R1 D4 R2 R4 R3 D6 40
FOCUS Surface Water: Coverage 41
FOCUS Surface Water: Models Application rate Spray drift (SWASH) Runoff (PRZM) Drainage loss (MACRO) Surface water (TOXSWA) 42
FOCUS Surface Water: Water Body Types Ditch, Pond, Stream Drainage and/or runoff Runoff (water + sediment) from 20 m zone Water baseflow + runoff volume Pond (drift, runoff) 0.45 ha Ditch (drift, drainage, runoff) Stream (drift, runoff) 2 ha untreated 100 ha upstream catchment, 20% treated 100 m 43 1 ha treated 100 m 1 ha treated
Case-study Herbistrike 10 : PECsw with FOCUS Skousbo (D4): Stream with drainage Vreedepeel (D3): Ditch with drainage Spray drift entry Weiherbach (R1): Stream with runoff Weiherbach (R1): Pond with runoff Runoff entry 44
Happy end for everybody! Spray drift ok at tier-1, using mitigation (buffer zone) Drainage shown to be negligible at higher tier => Assessment passed 45
Regulatory Risk Assessment of Crop Protection Products Todays topics Principles of regulatory risk assessment How does CPP regulation work? Foundations of risk assessment: Studies Case studies: Environmental fate; Dietary exposure Wrap-up/Job perspectives 46
O O O O Risk Assessment: Wrap-up Risk vs. hazard Application Relevant exposure pathways, processes Munch, munch OH Sound underlying data (studies/monitoring) Tiered approach (studies, assessment) Mitigation 47 Buffer width, m fdrift, % PECsw,ini(drift), g/l RQ (incl. SF) 1 2.77 4.62 6.16 fail 5 0.57 0.95 1.27 fail 10 0.29 0.48 0.64 pass! 20 0.15 0.25 0.33 30 0.1 0.17 0.22 40 0.07 0.12 0.16 50 0.06 0.10 0.13 fdrainage, PECsw,ini(drainage), % g/l 0.025 0.976 1.30 Fail!!!
Environmental Risk Assessment: Jobs 1. Employers Plant protection industry Chemical industry Pharmaceutical industry Contract Research (CRO) Authorities (national/eu) Academia/Research 2. Job profiles Study Director Expert Regulatory Affairs 48
Danke schön! Thank you! georg.geisler@syngenta.com 49