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2009/SOM2/SCSC/WKSP2/011

United States Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP): The

Vision for Global Pesticide Reviews

Submitted by: United States

Examination of Hot Issues in Risk Analysis Workshop Singapore

1-2 August 2009

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USEPA/OPP: The Vision USEPA/OPP: The Vision for Global Pesticide for Global Pesticide

ReviewsReviews

Mary Mary ManibusanManibusan, Chief, ChiefToxicology and Epidemiology BranchToxicology and Epidemiology Branch

Health Effects DivisionHealth Effects DivisionOffice of Pesticide ProgramsOffice of Pesticide Programs

OverviewOverview

Global Joint Pesticide Reviews: Can Global Joint Pesticide Reviews: Can MRLsMRLs be be harmonized?harmonized?

ChlorantraniliproleChlorantraniliprole: E2Y45 Global Review: E2Y45 Global Review•• Unique Insecticidal Mode of ActionUnique Insecticidal Mode of Action•• Risk Assessment Paradigm combining Hazard and Risk Assessment Paradigm combining Hazard and

ExposureExposure•• Lessons Learned: Challenges and AccomplishmentsLessons Learned: Challenges and Accomplishments

State of the Science for Risk AssessmentState of the Science for Risk Assessment•• Risk Assessment Paradigm Shift: Toxicity Testing 21st Risk Assessment Paradigm Shift: Toxicity Testing 21st

CenturyCentury•• Traditional Animal Testing vs. Integrative Testing Traditional Animal Testing vs. Integrative Testing

Approach: Shift in Weight of Evidence and Consideration Approach: Shift in Weight of Evidence and Consideration of Toxicity Pathwaysof Toxicity Pathways

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Mission of EPAMission of EPA’’s Office of s Office of Pesticide ProgramsPesticide Programs

Protect Human Health and the Protect Human Health and the EnvironmentEnvironment

Ensure that Society has access to Ensure that Society has access to safe pesticides and the associated safe pesticides and the associated benefitsbenefits

Promote global access to safe Promote global access to safe pesticides through joint registration pesticides through joint registration reviews and harmonization efforts reviews and harmonization efforts both internally and externallyboth internally and externally

Global Harmonization ToolsGlobal Harmonization Tools

OECD Working Group on PesticidesOECD Working Group on Pesticides•• Harmonized OECD test guidelinesHarmonized OECD test guidelines•• Standardized OECD .xml templates for data Standardized OECD .xml templates for data

reviews and summariesreviews and summaries•• Single Standard Dossiers submitted Single Standard Dossiers submitted

electronicallyelectronically•• Promote more efficient and effective global Promote more efficient and effective global

joint reviews joint reviews North American Free Trade Act (NAFTA)North American Free Trade Act (NAFTA)

•• Demonstrated that joint reviews can be Demonstrated that joint reviews can be accomplished (1997 accomplished (1997 –– present)present)

•• Paved the way to global joint reviewsPaved the way to global joint reviews

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Global Pesticide Reviews: Global Pesticide Reviews: Primary GoalsPrimary Goals

GOALGOAL: Single Global Maximum Pesticide : Single Global Maximum Pesticide Residue LevelResidue Level

Data generation, sharing, promote Data generation, sharing, promote regulatory efficienciesregulatory efficiencies

Joint/multiJoint/multi--lateral pesticide reviews offer lateral pesticide reviews offer transparency in risk assessments, transparency in risk assessments, scientifically sound technical peer review scientifically sound technical peer review process and ultimately promote better risk process and ultimately promote better risk characterizationscharacterizations

Benefits of a Global MRLBenefits of a Global MRL

Focus resources on newer pesticide Focus resources on newer pesticide chemistries, improved efficiency and chemistries, improved efficiency and reduced risk pesticidesreduced risk pesticides

Prospectively reduce and/or eliminate Prospectively reduce and/or eliminate potential trade barrierspotential trade barriers

Establish collaborative approach to Establish collaborative approach to harmonizing harmonizing MRLsMRLs

Cooperation and ultimate transparency Cooperation and ultimate transparency will increase harmonization of will increase harmonization of MRLsMRLs and and facilitate international tradefacilitate international trade

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Joint Reviews CompletedJoint Reviews Completed

PyroxsulamPyroxsulam: Herbicide : Herbicide ––Australia, Canada, USAustralia, Canada, US ChlorantraniliproleChlorantraniliprole: Insecticide (reduced risk) : Insecticide (reduced risk)

––Australia, Canada, EU (IR,UK), NZ, US; Australia, Canada, EU (IR,UK), NZ, US; ““global joint reviewglobal joint review”” registered April 2008. registered April 2008.

MandipropamidMandipropamid: Fungicide (reduced risk) : Fungicide (reduced risk) ––under review in US first; subsequently in under review in US first; subsequently in Canada. Canada.

Thiencarbazone/CyprosulfamideThiencarbazone/Cyprosulfamide: Herbicide : Herbicide --Canada, EU (UK), USCanada, EU (UK), US

SpirotetramatSpirotetramat: Insecticide (Reduced Risk) : Insecticide (Reduced Risk) --Canada, EU (Austria), USCanada, EU (Austria), US

Global Pesticide Review: Global Pesticide Review: ChlorantraniliproleChlorantraniliprole

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ChlorantraniliproleChlorantraniliprole

Global Global workshareworkshare: Australia : Australia –– Environmental fate, Ireland Environmental fate, Ireland --Exposure, EU, Canada Exposure, EU, Canada -- chemistry and UK chemistry and UK –– US lead on US lead on ToxicologyToxicology

First harmonized toxicology assessment across multiple First harmonized toxicology assessment across multiple countries based on reliance of histopathology data and countries based on reliance of histopathology data and weight of evidence approachweight of evidence approach

Weight of evidence approach for adrenal cortex in male rats Weight of evidence approach for adrenal cortex in male rats and liver toxicity in male miceand liver toxicity in male mice

Liver toxicity in male mice at highest dose tested include Liver toxicity in male mice at highest dose tested include liver hypertrophy, liver weight increase and increased liver hypertrophy, liver weight increase and increased incidence of liver incidence of liver eosinophiliceosinophilic foci formed the bases of the foci formed the bases of the chronic reference dose.chronic reference dose.

Chlorantraniliprole/DPXChlorantraniliprole/DPX--E2Y45E2Y45

AnthranilicAnthranilic diamidediamide class of insecticides used to class of insecticides used to control control lepidopteranlepidopteran (moths, beetles, worms, (moths, beetles, worms, caterpillars, etc.)caterpillars, etc.)

Formulated as a suspension concentrate and a Formulated as a suspension concentrate and a water dispersible granule for agricultural endwater dispersible granule for agricultural end--use use products; and as a SC and granular formulations products; and as a SC and granular formulations for use on turf and ornamental plantsfor use on turf and ornamental plants

Agricultural crops: Agricultural crops: pomepome fruit, leafy vegetables, fruit, leafy vegetables, BrassicaBrassica leafy vegetables, cucurbit vegetables, leafy vegetables, cucurbit vegetables, fruiting vegetables, cotton, grapes, potatoes and fruiting vegetables, cotton, grapes, potatoes and rice)rice)

Max application 0.2 lb Max application 0.2 lb aiai/A, re/A, re--treatment treatment intervals range from 5intervals range from 5--10days and 10days and PHIsPHIs range range from 1from 1--21 days 21 days

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ChlorantraniliproleChlorantraniliprole: : Mode of Insecticidal ActionMode of Insecticidal Action

New mode of action focused on New mode of action focused on perturbation of intracellular calcium levelsperturbation of intracellular calcium levels•• Activates Activates ryanodineryanodine receptors resulting in receptors resulting in

unregulated calcium release and muscle unregulated calcium release and muscle contraction.contraction.

•• Calcium stores eventually deplete resulting in Calcium stores eventually deplete resulting in muscle paralysis.muscle paralysis.

•• RyanodineRyanodine receptors in mammals are several receptors in mammals are several orders of magnitude less sensitive than insect orders of magnitude less sensitive than insect ryanodineryanodine receptors.receptors.

Biochemical Mode of ActionBiochemical Mode of Action

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Selectivity of ReceptorSelectivity of Receptor

What Is Risk?What Is Risk?

Risk = Hazard x Exposure

““All substances are poisons; there isAll substances are poisons; there isnone which is not a poison.none which is not a poison. The right The right dose differentiates a poison fromdose differentiates a poison froma remedy.a remedy.””

Paracelsus (1493Paracelsus (1493--1541)1541)

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Hazard Identification

Dose Response Assessment

Risk Characterization

ExposureAssessment

Hazard AssessmentHazard Assessment

Is there potential Is there potential for harm, adverse for harm, adverse effects?effects?

What does it do?What does it do? How does it do it?How does it do it?

Current Testing ParadigmCurrent Testing Paradigm

Cancer

Reproductive Toxicity

Developmental Toxicity

Neurotoxicity

KidneyToxicity

ImmunoTox

in vivo testing

$Millions

Generates in vivo animal data for all possible outcomes to determinewhich of all possible effects are relevant.

X

X

XX

X

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Hazard Assessment: Hazard Assessment: Standard Guideline StudiesStandard Guideline Studies

RequiredRequiredRequiredRequired9090--Day Neurotoxicity Day Neurotoxicity -- RatRat

CRCR(CR)(CR)9090--Day Inhalation Day Inhalation –– RatRat

RequiredRequiredCRCR9090--Day DermalDay Dermal

NRNRRequiredRequired21/2821/28--Day DermalDay Dermal

CRCRRequiredRequired9090--Day OralDay Oral–– Non Rodent (Dog)Non Rodent (Dog)

CRCRRequiredRequired9090--Day Oral Day Oral –– Rodent (Rat/Mouse)Rodent (Rat/Mouse)

CRCRCRCRDelayed Neurotoxicity Delayed Neurotoxicity -- HenHen

RequiredRequiredRequiredRequiredAcute Neurotoxicity Acute Neurotoxicity –– RatRat

RequiredRequiredRequiredRequiredDermal SensitizationDermal Sensitization

RequiredRequiredRequiredRequiredPrimary Dermal Irritation Primary Dermal Irritation –– RabbitRabbit

RequiredRequiredRequiredRequiredPrimary Eye Irritation Primary Eye Irritation –– RabbitRabbit

RequiredRequiredRequiredRequiredAcute Inhalation Acute Inhalation –– RatRat

RequiredRequiredRequiredRequiredAcute DermalAcute Dermal

RequiredRequiredRequiredRequiredAcute Oral Acute Oral –– RatRat

Non Food UseNon Food UseFood UseFood UseStudy TypeStudy Type

Hazard Assessment: Hazard Assessment: Standard Guideline StudiesStandard Guideline Studies

RequiredRequiredRequiredRequiredImmunotoxicityImmunotoxicity

CRCRCRCRDermal PenetrationDermal Penetration

CRCRCRCRCompanion Animal SafetyCompanion Animal Safety

CRCRRequiredRequiredMetabolism & PharmacokineticsMetabolism & Pharmacokinetics

RequiredRequiredRequiredRequiredIn Vitro In Vitro CytogeneticsCytogenetics

RequiredRequiredRequiredRequiredIn Vivo Mammalian cell AssayIn Vivo Mammalian cell Assay

RequiredRequiredRequiredRequiredBacterial Reverse Mutation AssayBacterial Reverse Mutation Assay

CRCRCRCRDevelopmental NeurotoxicityDevelopmental Neurotoxicity

Required Required RequiredRequiredReproduction & Fertility EffectsReproduction & Fertility Effects

RequiredRequiredRequiredRequiredPrenatal Developmental Prenatal Developmental –– RabbitRabbit

Required Required RequiredRequiredPrenatal Developmental Prenatal Developmental –– RatRat

CRCRRequiredRequiredCarcinogenicity Carcinogenicity ––RatRat

CRCRRequiredRequiredCarcinogenicity Carcinogenicity -- Mouse Mouse

CRCRRequiredRequiredChronic OralChronic Oral-- RatRat

Non Food UseNon Food UseFood UseFood UseStudy TypeStudy Type

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WeightWeight--ofof--Evidence ApproachEvidence Approach

•• Consistency and reproducibility of Consistency and reproducibility of effects across species (rat, mouse, effects across species (rat, mouse, rabbit, dog, humans)rabbit, dog, humans)

•• Differences in metabolism and toxicity Differences in metabolism and toxicity parameters across routes of exposure parameters across routes of exposure (oral, inhalation and dermal)(oral, inhalation and dermal)

•• Single vs. repeat and continuous Single vs. repeat and continuous exposure over timeexposure over time

Low Mammalian ToxicityLow Mammalian Toxicity

28-day DermalDermal Absorption

ADME Study

28-day DermalDermal Absorption

ADME Study

GenotoxicityGenotoxicity

Immunotoxicity

Neurotoxicity

Immunotoxicity

Neurotoxicity

2-generationReproduction

Developmental

2-generationReproduction

Developmental

Oral SubchronicRatDog

MouseChronic Studies

Oral SubchronicRatDog

MouseChronic Studies

Acute ToxicityOral

DermalInhalation

Eye irritationSkin sensitization

Acute ToxicityOral

DermalInhalation

Eye irritationSkin sensitization

ChlorantraniliproleChlorantraniliprole

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Hazard Identification

Dose Response Assessment

Risk Characterization

ExposureAssessment

DoseDose--Response AssessmentResponse Assessment

How much of it How much of it causes what causes what degree (or type) degree (or type) of effect?of effect?

How much is How much is ““safesafe””??

What risk is What risk is associated with x associated with x amount?amount?

Hazard: Liver ToxicityHazard: Liver Toxicity Liver effects: weight Liver effects: weight increase,hypertrophyincrease,hypertrophy, ,

eosinophiliceosinophilic focifoci Historical control data (0Historical control data (0--1.92% for 1.92% for

Crl:CDCrl:CD--1(ICR) mice)1(ICR) mice) Characterization of liver effects:Characterization of liver effects:

Minimal in severity, low incidence and do Minimal in severity, low incidence and do not display progression to tumors in the not display progression to tumors in the 1818--month chronic mouse study. The month chronic mouse study. The eosinophiliceosinophilic foci were evident in only one foci were evident in only one species and one sex, categorized as species and one sex, categorized as minimal and no increase in severity with minimal and no increase in severity with dose.dose.

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Hazard: ADI Endpoints SelectedHazard: ADI Endpoints Selected

Chronic Reference Dose/ ADI based Chronic Reference Dose/ ADI based on 18on 18--month male mouse study with month male mouse study with a NOAEL of 158 mg/kg/daya NOAEL of 158 mg/kg/day

Weight of evidence supports liver Weight of evidence supports liver toxicity at the high dose tested toxicity at the high dose tested onlyonly. .

Harmonized across all Global Harmonized across all Global partnering countries (Canada, partnering countries (Canada, Australia, UK, Germany, Ireland)Australia, UK, Germany, Ireland)

Hazard Identification

Dose Response Assessment

Risk Characterization

ExposureAssessment

Exposure AssessmentExposure Assessment

How much of an How much of an agent reaches an agent reaches an individual? (How individual? (How much gets to the much gets to the target tissue?)target tissue?)

How does it reach How does it reach the individual?the individual?

How long does How long does exposure last?exposure last?

How frequently does How frequently does the exposure occur? the exposure occur?

How many people How many people are exposed?are exposed?

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How does EPA assess dietary How does EPA assess dietary exposure?exposure?

Exposure = Residue X ConsumptionExposure = Residue X Consumption

Residue definitions include all metabolites & degradation products

of toxicological concern

Dietary exposure estimates are derived from two distinct pieces of information:

Exposure: Residues of ConcernExposure: Residues of Concern

not applicableChlorantraniliproleDrinking Water

not applicablenot applicablePoultry

ChlorantraniliproleChlorantraniliproleRuminantLivestock

ChlorantraniliproleChlorantraniliproleRotational Crop

ChlorantraniliproleChlorantraniliprolePrimary CropPlants

Residues included in Tolerance Expression

Residues included in Risk Assessment

Matrix

Summary of Metabolites to be included in the Risk Assessment and Tolerance Expression

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Exposure: Residues of ConcernExposure: Residues of Concern

Residue of concern in drinking water, Residue of concern in drinking water, plants and livestock for risk assessment plants and livestock for risk assessment and tolerance enforcement is and tolerance enforcement is ChlorantraniliproleChlorantraniliprole

LC/MS/MS methods are available for LC/MS/MS methods are available for chlorantraniliprolechlorantraniliprole in plants, livestock and in plants, livestock and processed commoditiesprocessed commodities

The validated limit of The validated limit of quantitationquantitation in plant in plant and livestock and livestock matriciesmatricies is 0.01 is 0.01 ppmppm; the ; the method has undergone a successful method has undergone a successful independent laboratory validation and has independent laboratory validation and has been validated with the analysis of been validated with the analysis of numerous field trial samples.numerous field trial samples.

Crop Field TrialsCrop Field Trials

Conducted on crops or representative Conducted on crops or representative commodities of crop groupscommodities of crop groups

Adequate field residue data for these Adequate field residue data for these crops based on geographic representation crops based on geographic representation and number of field trialsand number of field trials

Residue field trials conducted using either Residue field trials conducted using either WG or SC WG or SC on the proposed crops at the on the proposed crops at the maximum proposed use ratemaximum proposed use rate..

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Environmental Fate Data: Environmental Fate Data: Drinking Water Residue:Drinking Water Residue:

Laboratory data indicated Laboratory data indicated chlorantraniliprolechlorantraniliprole is is persistent and mobile in terrestrial and aquatic persistent and mobile in terrestrial and aquatic environmentsenvironments

Extended Extended chlorantraniliprolechlorantraniliprole use is expected to use is expected to cause accumulation of residues in soil from year cause accumulation of residues in soil from year to year.to year.

Major environmental degradates are not expected Major environmental degradates are not expected to be different from parent compound.to be different from parent compound.

Environmental fate data on parent were used to Environmental fate data on parent were used to model protective estimated drinking water model protective estimated drinking water concentrations in surface (PRZMconcentrations in surface (PRZM--EXAMS) and EXAMS) and ground water (SCIground water (SCI--GROW).GROW).

Dietary Risk CharacterizationDietary Risk Characterization

Long term oral exposure is the only route and duration with Long term oral exposure is the only route and duration with demonstrated mammalian toxicity at high dose onlydemonstrated mammalian toxicity at high dose only

Chronic dietary (food and drinking water) exposure Chronic dietary (food and drinking water) exposure assessments were conducted using the dietary model assessments were conducted using the dietary model DEEMDEEM--FCID which uses food consumption data from USDAFCID which uses food consumption data from USDA’’s s CSFII from 1994CSFII from 1994--1996 and 1998. 1996 and 1998.

The modeled exposure estimates are based on tolerance The modeled exposure estimates are based on tolerance level residues, assuming 100% crop treated and the level residues, assuming 100% crop treated and the highest modeled EDWC (3.650 highest modeled EDWC (3.650 ugug/L) relevant to the chronic /L) relevant to the chronic exposure scenario.exposure scenario.

Despite the conservative, health protective assumptions on Despite the conservative, health protective assumptions on the exposure side, the resulting chronic dietary exposures the exposure side, the resulting chronic dietary exposures for all population subgroups were less than 1% of the for all population subgroups were less than 1% of the cPADcPAD..

No dietary exposure considerations that would preclude No dietary exposure considerations that would preclude registration of registration of chlorantraniliprolechlorantraniliprole for the requested uses.for the requested uses.

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DEEM output (risk assessment) DEEM output (risk assessment)

0.50.0072630.50.007191Females 13-49 yrs

0.50.0076470.50.007572Adults 50+ yrs

0.50.0071300.40.007058Adults 20-49 yrs

0.40.0058880.40.005832Youth 13-19 yrs

0.50.0080360.50.007962Children 6-12 yrs

0.80.0120920.80.011985Children 3-5 yrs

0.90.0148890.90.014775Children 1-2 yrs

0.50.0080720.50.007820All infants

0.50.0077230.50.0076461.58U.S. Population

Risk, % cPADExposure, mg/kg/day

Risk, % cPADExposure, mg/kg/da

y

Chronic Estimates(Food and Drinking Water)

Chronic Estimates(Food only)

cPAD, mg/kg/day

Population Subgroup

Result of Acute and Chronic Dietary Exposure and Risk Estimates for Chlorantraniliprole

Global Review Lessons LearnedGlobal Review Lessons Learned

Success!Success! Harmonization on endpoint selection and hazard Harmonization on endpoint selection and hazard

determinations: Mode of Action and Weight of determinations: Mode of Action and Weight of Evidence CharacterizationEvidence Characterization

Although tolerance expression achieved Although tolerance expression achieved harmonization, due predominately to differences harmonization, due predominately to differences in crop grouping and what crops were considered in crop grouping and what crops were considered representative of a group, harmonization of representative of a group, harmonization of MRLsMRLswas achieved only for potatoes and possibly was achieved only for potatoes and possibly cottoncotton

Food Quality Protection Act requires US to Food Quality Protection Act requires US to harmonize with codex harmonize with codex MRLsMRLs

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Global Review Lessons LearnedGlobal Review Lessons Learned

ChallengesChallenges•• Companies are trying to have more uniform Companies are trying to have more uniform

uses around the world.uses around the world.•• Global Residue StudyGlobal Residue Study: Compare residues : Compare residues

between regions to support the concept of between regions to support the concept of global zoning and crop group expansion and global zoning and crop group expansion and harmonization of crop groups is the ultimate harmonization of crop groups is the ultimate goal goal ––leading to greater data use from other leading to greater data use from other regions of the world regions of the world ––results in less results in less redundancy and saving of scarce resources. redundancy and saving of scarce resources. Includes 22 countries with 27 field trial sitesIncludes 22 countries with 27 field trial sites Covers multiple global regions/zonesCovers multiple global regions/zones Common crop is staked tomatoCommon crop is staked tomato

Future of Joint Reviews Future of Joint Reviews

Global Joint Reviews:Global Joint Reviews:•• Standard way of doing businessStandard way of doing business•• Expansion of countries involved (Brazil and Japan)Expansion of countries involved (Brazil and Japan)•• Expansion of companies involved (9 currently involved)Expansion of companies involved (9 currently involved)

Assessments in progressAssessments in progress•• MetaflumizoneMetaflumizone: Insecticide : Insecticide --under review in US, Canada, under review in US, Canada,

EU (UK), Australia.EU (UK), Australia.•• Saflufenacil:HerbicideSaflufenacil:Herbicide ––Australia, Canada, USAustralia, Canada, US•• PyroxasulfonePyroxasulfone: Herbicide : Herbicide ––Australia, Canada, USAustralia, Canada, US•• Joint Reviews in PreJoint Reviews in Pre--Submission Discussion Phase 12 Submission Discussion Phase 12

global reviews for new active ingredients under global reviews for new active ingredients under discussiondiscussion

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A Vision for Risk AssessmentA Vision for Risk Assessment

Work towards transition to new Work towards transition to new integrative and predictive molecular integrative and predictive molecular and computational techniques to and computational techniques to enhance efficiency and accuracy and enhance efficiency and accuracy and to reduce reliance on animal testing.to reduce reliance on animal testing.

Vision is consistent with the NRC Vision is consistent with the NRC 2007 report, 2007 report, ““Toxicity Testing in 21st Toxicity Testing in 21st Century: A Vision and a StrategyCentury: A Vision and a Strategy””

2007 NAS Report 2007 NAS Report Toxicity Testing in Toxicity Testing in the 21the 21stst CenturyCentury

More robust scientific basis by providing mode of action &

dosimetry information

Broader coverage of chemicals, end points, life stages

Use fewer animals; least suffering for those used

Reduce cost & time of testing,

increase efficiency & flexibility

Consider NewMolecular & Computational

Technologies

Sponsored by US EPA

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Future Testing ParadigmFuture Testing Paradigm

Improve ability to carry out mission of Improve ability to carry out mission of protecting public health & the protecting public health & the environmentenvironment

Increase efficiency & reliability in Increase efficiency & reliability in assessing & managing risks assessing & managing risks appropriately by focusing on a pesticideappropriately by focusing on a pesticide’’s s most likely hazards of concern for a most likely hazards of concern for a given exposure situationgiven exposure situation

Eliminate need for extensive animal Eliminate need for extensive animal testing testing

Reduce cost & time in data development, Reduce cost & time in data development, review and processingreview and processing

Efficient Animal Testing Research To Enhance Understanding of Toxicity Pathways

Near Term

Long Term

New Predictive Toxicity

Approaches

Future Testing StrategyFuture Testing Strategy

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The End The End –– Thank You!Thank You!

United States Environmental Protection AgencyOffice of Pesticide Programs