regulatory risk assessment of plant protection products...regulatory risk assessment of crop...

Risk Assessment for Residues in Food and Environment

Regulatory Risk Assessment of Crop Protection Products

Georg Geisler

Regulatory Policy Manager

Global Registration

Syngenta Crop Protection AG, Basel

[email protected]

2


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

G. Geisler, Nov. 2014 at ETH Zürich

3

Safety for Humans and Environment

Risk assessment needed

Syngenta ensures the quality and safety of its products The Syngenta Code of Conduct, Section 19

No unacceptable effects on environment

No harmful effect on human health Regulation (EC) No. 1107/2009

(main points of preamble summarised)


4

Risk depends on exposure to a hazard

Principle of Risk Assessment

Low exposure

Low hazard

High exposure

High hazard

High risk Low risk


5

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

6

Principle of Risk Assessment (2)

Hazard

(Reference doses)

Exposure

(Residue level)

Risk Assessment

(Eco-)Toxicological

studies

Residue studies

(Crops or soil)

Consumption data

(Food)


7

Exposure pathways

Application

Emission – Concentration in different compartments – Safeguard subjects


8

Processes

Process type Process Cause

Degradation Bio-degradation Fungi, bacteria, plants, etc.

Hydrolysis pH

Photolysis Sunlight

Sorption Reversible

ad/desorption

Soil organic matter, clay (ionic substances)

Aging of sorption Diffusion into pores (soil)

Bound residues Incorporation into natural soil/plant

constituents

Transport Translocation Water/air fluxes (soil, water bodies,

plants, etc.)

Dilution Mixing during translocation

Accumulation Soil; oil/fat matrices

Munch,

munch

O

OO

O

OH

O

OO

O

OH

O

OO

O

OH

O

OO

O

OH


9

Time Scale: Acute vs. Chronic Risk Assessment

● Time-weighted average concentration

● Chronic effects

Chronic

● Concentration at emission

● Acute effects

Acute


10

Calculation: Deterministic Risk Assessment

RQ = PEC

PNEC

(Realistic) worst-

case scenario

Lowest NOEC x Safety factor

Risk quotient:

RQ ≤ 1 => No unacceptable risk to ecosystem

RQ > 1 => Potential risk to ecosystem, need more realistic

assessment

For risk assessment of crop protection products, each representative species is assessed separately

PEC Predicted environmental concentration (concentration endpoint)

PNEC Predicted no-effect concentration (ecotoxicity endpoint)

NOEC No observed effect concentration from ecotoxicological study


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Calculation (2): Probabilistic

Distribution

Distribution

RQ = PEC

Ecotox. endpoint

Concentration

Probability

density

PEC ecotox.

endpoint

distribution

Risk quotient:

Deterministic

ecotox.

endpoint


12

Consumer Risk Assessment: What Scenario?

● Exposure pathway

● Processes

● Time scale

● Calculation

● Exposure endpoint

● Hazard endpoint


13

Consumer: Chronic vs. Acute Risk Assessment

• Lifelong

• Long-term average consumption

(all food)

• Average residue level from worst-case

crop field trials (STMR)

• Sum exposure for all food

• Toxicological reference dose:

Acceptable Daily Intake (ADI)

• 1 day/1 meal

• Large portion consumption

(one food)

• Highest residue level from worst-case

crop field trials (HR)

• Exposure per food item

• Toxicological reference dose:

Acute Reference Dose (ARfD)

Chronic Acute

• Population groups, e.g. adults, children

0.08 ppm

0.05 ppm

0.3 ppm

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Intake < 100% of ADI

Deterministic Risk Assessment: Consumer (chronic)

Intake = S Consumptioni * STMRi

ADI

Intake < 100% of ADI => No unacceptable risk to consumer

=> Potential consumer risk, need more realistic

assessment

* 100%

Consumption Amount of food consumed (part of exposure endpoint)

STMR Supervised trial mean residue level (part of exposure endpoint)

ADI Acceptable daily intake (human toxicity endpoint)

NOAEL No observed adverse effect level

(Inter-)national databases

NOAEL * Safety factor

Crop field trials


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Todays topics




Case studies: Environmental fate; Dietary exposure



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Regulatory procedure

Manufacturer

Dossier

Authorites

Further modelling/

testing/ assessment

Evaluation,

requirements

Approval

(Mitigation)

(Restrictions)

Time, years

0

> 5

Ex

am

ple

: p

es

tic

ide

s


17

Regulatory testing/modelling: Tiered approach

Tier 1 Basic standardised

tests / modelling

Tier 2

Cost, time

Advanced tests /

modelling

Tailor-made tests

/ modelling

Higher

tier


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Todays topics







19

What?

How much

of it?

Studies: Types and Sequence

Metabolism

studies

Compounds relevant to

consumer/environmental safety

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

Plant

metabolism

Soil

metabolism

Magnitude-of-

residue studies Crop field

trials

Soil

degradation


http://titania.sourceoecd.org/vl=36183586/cl=23/nw=1/rpsv/periodical/p15_about.htm?jnlissn=1607310x

http://titania.sourceoecd.org/vl=36183586/cl=23/nw=1/rpsv/periodical/p15_about.htm?jnlissn=1607310x

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Metabolism: Plants

● Representative

crops

● Worst-case treatment (14C)

● Elucidate metabolism

● Sampling

Source: Codex Evaluation 2008


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Estimation QSAR

Laboratory OECD standard test

Field studies Field degradation

Testing tier Test method

Realism,

cost

Interpretability,

generalizability

Monitoring Field accumulation

Semi-field Lysimeter

Soil Degradation: Tiered Experimental Approach

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Experimental: OECD 307

mapplied

Apply

Mix

Balance:

CO2

Volatile compounds

cextracted

cbound

Target: 90-110 % of mapplied

Aerate

Traps

Munch,

munch

Mmm, tasty!

Extract/

analyse

cextractable(t1)

cextractable(t2)

cextractable(t3)

cbound(t1)

cbound(t2)

cbound(t3)

Snore,

snore

Studies: Laboratory Degradation

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Substance Properties: Fitting degradation half-life (DT50)

First-order kinetics:

tkexpcc

ckdt

dc

0t

k

2ln50DT Half-life: Degradation rate:

0

20

40

60

80

100

0 20 40 60 80 100 120

Time, days

Co

nce

ntr

ati

on

, %

of

ap

plied Fitting results: t0315.0exp2.95c

Rate constant (k)

En guete!En guete!

Co-metabolism

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Substance Properties: Metabolites

0 50 100 150

Time, days

0

500

1000

1500

2000

Co

ncen

trati

on

, µ

g/k

g

Parent

M1metabmetabparentparent

metab

parentparent

parent

ckckfdt

dc

ckdt

dc

Degradation rates:

Parallel degradation reactions: Parent

Metabolite CO2

f (1-f)

Parent

Metabolite


25

Degradation half-lives: Tiered Testing

Laboratory test: Microbial viability decreases with time

0

0.02

0.04

0.06

0.08

0.1

0.12

0 20 40 60 80 100 120 140

Time, days

Co

nc

en

trati

on

, m

g/k

g

Bi-phasic (FOMC)

First-order

Laboratory degradation often slower than field

Degradation rate decreases over time

=> Non-SFO kinetics (e.g. bi-phasic)

Field degradation studies give a more realistic picture!


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Todays topics







27

Case study: Dietary exposure of consumers


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Consumption Data: GEMS/food Cluster Diets (WHO/FAO)

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Chronic Consumer Risk Assessment

Total Maximum Daily Intake (TMDI): 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 IEDI = S STMRi * Consumptioni / bw

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

TMDI = S MRLi * Consumptioni / bw

International Estimated Daily Intake (IEDI):


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Chronic Consumer Risk Assessment

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%

● 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/


http://www.who.int/foodsafety/chem/acute_data/en/

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Realistic exposure: EU official monitoring 2009, 2010

● 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


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

2010:

97.2%

http://www.efsa.europa.eu/en/publications.htm




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● 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»

● US: No additional risk compared to individual assessments

- Organophosphates; N-methyl carbamates; Chloroacetanilides; Pyrethroids

Realistic exposure: Cumulative dietary risk assessment


“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

33

Case study: Environment


34

Predicted Environmental Concentrations: Pathways

Surface water

Runoff

Drainage

Deposition

Volatilisation

Interception

Leaching

Spray drift

Groundwater

Field soil

Spray

application

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Tier-1 Model (EXPOSIT): Drainage

Application rate

Drainage loss:

fraction of soil residue

Ditch of 40 m3

(baseflow + drainage

water)

Soil concentration

(3 days after application)

water

cetansubsini

V

drainageM)drainage(PECsw


36

Mass of substance in soil, kg/ha Msubstance,soil Degradation half-life

(time horizon)

Definition Parameter Modeller choices

3 days after application, first-order kinetics

Fraction of pesticide lost by drainage fdrainage Appropriate default

value Default values (season of application; adsorption)

Volume of waterbody Vwaterbody None

Worst-case ditch: default volumes (season of

application)

Default dilution factor of 2, flowing ditch fdilution None

dilutionwaterbody

drainagefieldsoil,cetansubs

ini

water

drainage,cetansubs

ini

fV

fA)t(M)drainage(PECsw

V

M)drainage(PECsw

Tier-1 Model (EXPOSIT): Drainage

37

Fraction of application rate intercepted by the crop

(i.e., not reaching soil)

finterception Default values according

to growth stage of crop

Definition Parameter Modeller choices

Degradation rate (first-order kinetics), d-1 k Appropriate value

Time, d t Default: 3 days

dilutionwaterbody

drainagefield

tk

erceptionint

inifV

fAef1apprate)drainage(PECsw

tk

erceptionintsoil,cetansubs ef1apprate)t(M

Tier-1 Model: Soil Concentration

38

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


39

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!!!


40

Higher-Tier Model: FOCUS Surface Water

D6

R3 R4 R2

D5 R1

D3

D4

D2

D1

~ 90th percentile vulnerability

=> Realistic worst-case


41

FOCUS Surface Water: Coverage

42

FOCUS Surface Water: Models

Application rate

Spray drift (SWASH)

Surface water

(TOXSWA)

Drainage loss (MACRO)

Runoff (PRZM)


43

100 m

100 ha upstream

catchment,

20% treated

Ditch, Pond, Stream

Drainage and/or runoff

Runoff (water + sediment) from 20 m zone

Water baseflow + runoff volume

Pond (drift, runoff)

100 m

Stream (drift, runoff) Ditch (drift, drainage, runoff)

1 ha

treated 1 ha

treated

0.45 ha

2 ha

untreated

FOCUS Surface Water: Water Body Types

44

Case-study ‘Herbistrike 10’: PECsw with FOCUS

Skousbo (D4):

Stream with drainage Vreedepeel (D3):

Ditch with drainage

Weiherbach (R1):

Stream with runoff

Weiherbach (R1):

Pond with runoff

Spray drift entry

Runoff entry


45

Happy end for everybody!

Spray drift ok at tier-1, using

mitigation (buffer zone)

Drainage shown to be

negligible at higher tier

=> Assessment passed

46


Todays topics







47

Risk Assessment: Wrap-up

● Risk vs. hazard

● Relevant exposure pathways, processes

● Sound underlying data (studies/monitoring)

● Tiered approach (studies, assessment)

● Mitigation

Application

Munch,

munch

O

OO

O

OH

O

OO

O

OH

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!!!


48

Environmental Risk Assessment: Jobs 1. Employers

Plant protection industry

Chemical industry

Pharmaceutical industry

Contract Research (CRO)

Regulatory Affairs Expert Study Director

Authorities

(national/EU)

Academia/Research

2. Job profiles


49

Danke schön! Thank you!

[email protected]


regulatory risk assessment of plant protection products...regulatory risk assessment of crop...

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