United States Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP): The Vision for Global Pesticide Reviews

Transcription

1 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

2 USEPA/OPP: The Vision for Global Pesticide Reviews Mary Manibusan,, Chief Toxicology and Epidemiology Branch Health Effects Division Office of Pesticide Programs Overview Global Joint Pesticide Reviews: Can MRLs be harmonized? : : E2Y45 Global Review Unique Insecticidal Mode of Action Risk Assessment Paradigm combining Hazard and Exposure Lessons Learned: Challenges and Accomplishments State of the Science for Risk Assessment Risk Assessment Paradigm Shift: Toxicity Testing 21st Century Traditional Animal Testing vs. Integrative Testing Approach: Shift in Weight of Evidence and Consideration of Toxicity Pathways 1

3 Mission of EPA s s Office of Pesticide Programs Protect Human Health and the Environment Ensure that Society has access to safe pesticides and the associated benefits Promote global access to safe pesticides through joint registration reviews and harmonization efforts both internally and externally Global Harmonization Tools OECD Working Group on Pesticides Harmonized OECD test guidelines Standardized OECD.xml templates for data reviews and summaries Single Standard Dossiers submitted electronically Promote more efficient and effective global joint reviews North American Free Trade Act (NAFTA) Demonstrated that joint reviews can be accomplished (1997 present) Paved the way to global joint reviews 2

4 Global Pesticide Reviews: Primary Goals GOAL: : Single Global Maximum Pesticide Residue Level Data generation, sharing, promote regulatory efficiencies Joint/multi-lateral lateral pesticide reviews offer transparency in risk assessments, scientifically sound technical peer review process and ultimately promote better risk characterizations Benefits of a Global MRL Focus resources on newer pesticide chemistries, improved efficiency and reduced risk pesticides Prospectively reduce and/or eliminate potential trade barriers Establish collaborative approach to harmonizing MRLs Cooperation and ultimate transparency will increase harmonization of MRLs and facilitate international trade 3

5 Joint Reviews Completed Pyroxsulam: : Herbicide Australia, Canada, US : : Insecticide (reduced risk) Australia, Canada, EU (IR,UK), NZ, US; global joint review registered April Mandipropamid: : Fungicide (reduced risk) under review in US first; subsequently in Canada. Thiencarbazone/Cyprosulfamide: : Herbicide - Canada, EU (UK), US Spirotetramat: : Insecticide (Reduced Risk) - Canada, EU (Austria), US Global Pesticide Review: 4

6 Global workshare: : Australia Environmental fate, Ireland - Exposure, EU, Canada - chemistry and UK US lead on Toxicology First harmonized toxicology assessment across multiple countries based on reliance of histopathology data and weight of evidence approach Weight of evidence approach for adrenal cortex in male rats and liver toxicity in male mice Liver toxicity in male mice at highest dose tested include liver hypertrophy, liver weight increase and increased incidence of liver eosinophilic foci formed the bases of the chronic reference dose. /DPX-E2Y45 Anthranilic diamide class of insecticides used to control lepidopteran (moths, beetles, worms, caterpillars, etc.) Formulated as a suspension concentrate and a water dispersible granule for agricultural end-use products; and as a SC and granular formulations for use on turf and ornamental plants Agricultural crops: pome fruit, leafy vegetables, Brassica leafy vegetables, cucurbit vegetables, fruiting vegetables, cotton, grapes, potatoes and rice) Max application 0.2 lb ai/a, re-treatment intervals range from 5-10days 5 and PHIs range from days 5

7 : Mode of Insecticidal Action New mode of action focused on perturbation of intracellular calcium levels Activates ryanodine receptors resulting in unregulated calcium release and muscle contraction. Calcium stores eventually deplete resulting in muscle paralysis. Ryanodine receptors in mammals are several orders of magnitude less sensitive than insect ryanodine receptors. Biochemical Mode of Action 6

8 Selectivity of Receptor What Is Risk? Risk = Hazard x Exposure All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy. Paracelsus ( ) 1541) 7

9 Hazard Assessment Is there potential for harm, adverse effects? What does it do? How does it do it? Hazard Identification Dose Response Assessment Risk Characterization Exposure Assessment Current Testing Paradigm in vivo testing $Millions X X X X X Cancer Reproductive Toxicity Developmental Toxicity Neurotoxicity KidneyToxicity ImmunoTox Generates in vivo animal data for all possible outcomes to determine which of all possible effects are relevant. 8

10 Study Type Hazard Assessment: Standard Guideline Studies Acute Oral Rat Acute Dermal Acute Inhalation Rat Primary Eye Irritation Rabbit Primary Dermal Irritation Rabbit Dermal Sensitization Acute Neurotoxicity Rat Delayed Neurotoxicity - Hen 90-Day Oral Rodent (Rat/Mouse) Food Use Non Food Use 90-Day Oral Non Rodent (Dog) 21/28-Day Dermal 90-Day Dermal 90-Day Inhalation Rat 90-Day Neurotoxicity - Rat () NR Study Type Hazard Assessment: Standard Guideline Studies Chronic Oral- Rat Carcinogenicity - Mouse Carcinogenicity Rat Prenatal Developmental Rat Prenatal Developmental Rabbit Food Use Non Food Use Reproduction & Fertility Effects Developmental Neurotoxicity Bacterial Reverse Mutation Assay In Vivo Mammalian cell Assay In Vitro Cytogenetics Metabolism & Pharmacokinetics Companion Animal Safety Dermal Penetration Immunotoxicity 9

11 Weight-of of-evidence Approach Consistency and reproducibility of effects across species (rat, mouse, rabbit, dog, humans) Differences in metabolism and toxicity parameters across routes of exposure (oral, inhalation and dermal) Single vs. repeat and continuous exposure over time Low Mammalian Toxicity 28-day 28-day Dermal Dermal Dermal Dermal Absorption Absorption ADME ADME Study Study Acute Acute Toxicity Toxicity Oral Oral Dermal Dermal Inhalation Inhalation Eye Eye irritation irritation Skin Skin sensitization sensitization Oral Oral Subchronic Subchronic Rat Rat Dog Dog Mouse Mouse Chronic Chronic Studies Studies Genotoxicity Genotoxicity 2-generation 2-generation Reproduction Reproduction Developmental Developmental Immunotoxicity Immunotoxicity Neurotoxicity Neurotoxicity 10

12 Dose-Response Assessment How much of it causes what degree (or type) of effect? How much is safe? What risk is associated with x amount? Hazard Identification Dose Response Assessment Exposure Assessment Risk Characterization Hazard: Liver Toxicity Liver effects: weight increase,hypertrophy, eosinophilic foci Historical control data (0-1.92% for Crl:CD-1(I) mice) Characterization of liver effects: Minimal in severity, low incidence and do not display progression to tumors in the 18-month chronic mouse study. The eosinophilic foci were evident in only one species and one sex, categorized as minimal and no increase in severity with dose. 11

13 Hazard: ADI Endpoints Selected Chronic Reference Dose/ ADI based on 18-month male mouse study with a NOAEL of 158 mg/kg/day Weight of evidence supports liver toxicity at the high dose tested only. Harmonized across all Global partnering countries (Canada, Australia, UK, Germany, Ireland) Exposure Assessment How much of an agent reaches an individual? (How much gets to the target tissue?) How does it reach the individual? How long does exposure last? How frequently does the exposure occur? How many people are exposed? Dose Response Assessment Hazard Identification Exposure Assessment Risk Characterization 12

14 How does EPA assess dietary exposure? Dietary exposure estimates are derived from two distinct pieces of information: Exposure = Residue X Consumption Residue definitions include all metabolites & degradation products of toxicological concern Exposure: Residues of Concern Summary of Metabolites to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Rotational Crop Livestock Ruminant Poultry not applicable not applicable Drinking Water not applicable 13

15 Exposure: Residues of Concern Residue of concern in drinking water, plants and livestock for risk assessment and tolerance enforcement is LC/MS/MS methods are available for chlorantraniliprole in plants, livestock and processed commodities The validated limit of quantitation in plant and livestock matricies is 0.01 ppm; ; the method has undergone a successful independent laboratory validation and has been validated with the analysis of numerous field trial samples. Crop Field Trials Conducted on crops or representative commodities of crop groups Adequate field residue data for these crops based on geographic representation and number of field trials Residue field trials conducted using either WG or SC on the proposed crops at the maximum proposed use rate. 14

16 Environmental Fate Data: Drinking Water Residue: Laboratory data indicated chlorantraniliprole is persistent and mobile in terrestrial and aquatic environments Extended chlorantraniliprole use is expected to cause accumulation of residues in soil from year to year. Major environmental degradates are not expected to be different from parent compound. Environmental fate data on parent were used to model protective estimated drinking water concentrations in surface (PRZM-EXAMS) and ground water (SCI-GROW). Dietary Risk Characterization Long term oral exposure is the only route and duration with demonstrated mammalian toxicity at high dose only Chronic dietary (food and drinking water) exposure assessments were conducted using the dietary model DEEM-FCID which uses food consumption data from USDA s CSFII from and The modeled exposure estimates are based on tolerance level residues, assuming 100% crop treated and the highest modeled EDWC (3.650 ug/l) relevant to the chronic exposure scenario. Despite the conservative, health protective assumptions on the exposure side, the resulting chronic dietary exposures for all population subgroups were less than 1% of the cpad. No dietary exposure considerations that would preclude registration of chlorantraniliprole for the requested uses. 15

17 DEEM output (risk assessment) Result of Acute and Chronic Dietary Exposure and Risk Estimates for Population Subgroup cpad, mg/k g/day Chronic Estimates (Food only) Exposure, mg/kg/da y Risk, % cpad Chronic Estimates (Food and Drinking Water) Exposure, mg/kg/day Risk, % cpad U.S. Population All infants Children 1-2 yrs Children 3-5 yrs Children 6-12 yrs Youth yrs Adults yrs Adults 50+ yrs Females yrs Global Review Lessons Learned Success! Harmonization on endpoint selection and hazard determinations: Mode of Action and Weight of Evidence Characterization Although tolerance expression achieved harmonization, due predominately to differences in crop grouping and what crops were considered representative of a group, harmonization of MRLs was achieved only for potatoes and possibly cotton Food Quality Protection Act requires US to harmonize with codex MRLs 16

18 Global Review Lessons Learned Challenges Companies are trying to have more uniform uses around the world. Global Residue Study: : Compare residues between regions to support the concept of global zoning and crop group expansion and harmonization of crop groups is the ultimate goal leading to greater data use from other regions of the world results in less redundancy and saving of scarce resources. Includes 22 countries with 27 field trial sites Covers multiple global regions/zones Common crop is staked tomato Future of Joint Reviews Global Joint Reviews: Standard way of doing business Expansion of countries involved (Brazil and Japan) Expansion of companies involved (9 currently involved) Assessments in progress Metaflumizone: : Insecticide -under review in US, Canada, EU (UK), Australia. Saflufenacil:Herbicide Australia, Canada, US Pyroxasulfone: : Herbicide Australia, Canada, US Joint Reviews in Pre-Submission Discussion Phase 12 global reviews for new active ingredients under discussion 17

19 A Vision for Risk Assessment Work towards transition to new integrative and predictive molecular and computational techniques to enhance efficiency and accuracy and to reduce reliance on animal testing. Vision is consistent with the NRC 2007 report, Toxicity Testing in 21st Century: A Vision and a Strategy Sponsored by US EPA 2007 NAS Report Toxicity Testing in the 21 st Century Broader coverage of chemicals, end points, life stages Use fewer animals; least suffering for those used Consider New Molecular & Computational Technologies More robust scientific basis by providing mode of action & dosimetry information Reduce cost & time of testing, increase efficiency & flexibility 18

20 Future Testing Paradigm Improve ability to carry out mission of protecting public health & the environment Increase efficiency & reliability in assessing & managing risks appropriately by focusing on a pesticide s most likely hazards of concern for a given exposure situation Eliminate need for extensive animal testing Reduce cost & time in data development, review and processing Future Testing Strategy Efficient Animal Testing Near Term New Predictive Toxicity Approaches Research To Enhance Understanding of Toxicity Pathways Long Term 19

21 The End Thank You! United States Environmental Protection Agency Office of Pesticide Programs 20