Pesticide Risk Assessment and Management

Jeffrey Jenkins, Ph.D.Department of Environmental and

Molecular ToxicologyOregon State University

Risk Assessment and Management

US Environmental Protection Agency Structure

Current EPA Administrator: Gina McCarthy (appointed 2013)

First EPA Administrator: William Ruckelshaus, 1970

Office of the Administrator

Administration and Resource

Management

Office of Air and Radiation

Office of Compliance and Enforcement

Office of the Chief Financial Officer

Office of the General Council

Office of the Inspector General

InternationalPrograms

Office of Environmental

Information

Office of Chemical Safety and Pollution

Prevention

Office of Research and Development

Office of Land and Emergency

ManagementOffice of Water

Regional Offices (1-10)

EPA Organizational Structure

Office of Pesticide Programs

U.S. EPA (2014)

FIFRA/FQPA Federal – State Partnerships designed to Achieve Safe and Beneficial Pesticide Use

Risk characterization through sound

science

Cost effective requirements to insure safe use

Clear understanding

of label restrictions and use mandates

Informed decision-making at the frontline of pesticide use

Pesticide registration under FIFRA (as amended by FQPA)

• 40 CFR 158 Rulemaking; data requirements

• The Harmonized Test Guidelines

• Used by OPP, OCSPP, and OECD

• Both are constantly under review and are frequently updated

Pesticide Reregistration• The 1988 amendments to the Federal Insecticide, Fungicide,

and Rodenticide Act (FIFRA) authorized EPA to conduct the pesticide reregistration program.

– review supporting scientific studies– update human health and ecological risk assessments using current

science– cancel or re-register uses– develop risk mitigation measures (new label language)

• Determination summarized in a Reregistration Eligibility Decision (RED)

• Reregister a pesticide if it can be used “without unreasonable adverse effects on human health or the environment.”

Scope and Status of Reregistration• Approximately 1,150 pesticide active ingredients

organized into 613 “cases” or related groups.

• Completed the last of 384 REDs in 2008 (20 years).

• The Food Quality Protection Act of 1996 (FQPA) required EPA to reassess within 10 years the 9,721 existing tolerances (MRLs) and tolerance exemptions (completed in 2007).

• Tolerances must meet the new “reasonable certainty of no harm” safety standard.

• Current goal – reevaluate each registered pesticide at least every 15 years.

Cumulative Risk Assessment• FQPA (1996) directs EPA to assess the cumulative risks

of pesticides that share common mechanisms of toxicity.

• Cumulative risk assessments completed:

– Organophosphates – N-methyl carbamates– Triazines– Chloroacetanilides– Pyrethrins/Pyrethroid

• Consider exposures from food, drinking water, and residential sources (i.e., aggregate exposure).

• European Food Safety Authority (EFSA) is developing a comprehensive cumulative risk assessment policy.

Data for Pesticide Reassessment• Studies accepted by U.S. EPA for pesticide registration or

reregistration purposes must comply with Good Laboratory Practices (GLPs).

• GLPs are federal regulations; 21 CFR Part 58 (U.S. Food and Drug Administration) and 40 CFR Part 160 (U.S. EPA)

• GLP regulations describe the minimal standards for conducting laboratory and field studies that support or are intended to support pesticide registration or reregistration.

• U.S. EPA also considers information in the open literature as a part of the registration or reregistration process; greater weight is given to those studies that were specifically designed to be used for risk assessment purposes, and those conducted under GLPs.

Pesticide registration or reassessment• Registrants submit new data or in response to a EPA data call in.

• Data comes from studies that they follow a relatively uniform set of guidelines or study protocols.

• These guidelines are harmonized with the EU/other developed countries.

• The Office of Chemical Safety and Pollution Prevention (OCSPP) harmonized guidelines are organized in the following 11 series:

– 810 - Product Performance Test Guidelines– 830 - Product Properties Test Guidelines– 835 - Fate, Transport and Transformation Test Guidelines– 840 - Spray Drift Test Guidelines– 850 - Ecological Effects Test Guidelines– 860 - Residue Chemistry Test Guidelines– 870 - Health Effects Test Guidelines– 875 - Occupational and Residential Exposure Test Guidelines– 880 - Biochemicals Test Guidelines– 885 - Microbial Pesticide Test Guidelines– 890 - Endocrine Disruptor Screening Program Test Guidelines

Pesticide Registration Application

• Chemistry for each pesticide product.

– Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)

– Federal Food, Drug, and Cosmetic Act (FFDCA)– Food Quality Protection Act (FQPA)– 40CFR parts 158.320 to 158.355– OPPT Test Guidelines Series 830 Product Properties

Types of Pesticide Products (Food or non-Food Use)

• Technical Grade Active Ingredient (TGAI) or Manufacturing Use Product (MUP)

• End-use or formulated products

• For food uses, Tolerance/Maximum Residue Level (MRL) must be established for each active ingredient (A.I.)

Series 830 - Product Properties Test Guidelines1

Group A — Product Identity, Composition, and Analysis Test Guidelines

830.1000 - Background for Product Properties Test Guidelines (March 1998)830.1550 - Product Identity and Composition (August 1996)830.1600 - Description of Materials Used to Produce the Product (August 1996)830.1620 - Description of Production Process (August 1996)830.1650 - Description of Formulation Process (August 1996)830.1670 - Discussion of Formation of Impurities (August 1996)830.1700 - Preliminary Analysis (August 1996)830.1750 - Certified Limits (August 1996)830.1800 - Enforcement Analytical Method (August 1996)830.1900 - Submittal of Samples (November 2008)

1The final Product Properties Test Guidelines are generally intended to meet testing requirements for physical and chemical properties of pesticide products under FIFRA and toxic substances under TSCA.

Series 830 - Product Properties Test GuidelinesGroup B — Physical/Chemical Properties Test Guidelines

830.6302 - Color (August 1996)830.6303 - Physical State (August 1996)830.6304 - Odor (August 1996)830.6313 - Stability to Normal and Elevated Temperatures, Metals, and Metal Ions (August 1996)830.6314 - Oxidation/Reduction Chemical Incompatibility (August 1996)830.6315 - Flammability (August 1996)830.6316 - Explodability (August 1996)830.6317 - Storage Stability (June 2002)830.6319 - Miscibility (August 1996)830.6320 - Corrosion Characteristics (August 1996)830.6321 - Dielectric Breakdown Voltage (August 1996)830.7000 - pH (August 1996)830.7050 - UV/Visible Absorption (August 1996)830.7100 - Viscosity (August 1996)830.7200 - Melting Point/Melting Range (March 1998)830.7220 - Boiling Point/Boiling Range (August 1996)830.7300 - Density/Relative Density/Bulk Density (June 2002)830.7370 - Dissociation Constants in Water (August 1996)830.7520 - Particle Size, Fiber Length, and Diameter Distribution (August 1996)830.7550 - Partition Coefficient (n-octanol/water), Shake Flask Method (August 1996)830.7560 - Partition Coefficient (n-octanol/water), Generator Column Method (August 1996)830.7570 - Partition Coefficient (n-octanol/water), Estimation by Liquid Chromatography (August 1996)830.7840 - Water Solubility: Column Elution Method; Shake Flask Method (March 1998)

How Does the US Environmental Protection Agency (EPA) Assess Risk?

National Academy of Sciences (NAS) 4-step risk assessment Paradigm*:

* From the National Research Council’s Risk Assessment in the Federal Government: Managing the Process, 1983.

HazardIdentification

Risk Characterization

ExposureDose-

Response Assessment

Pesticide Risk AssessmentHazard

Identification

Dose-Response

Assessment

Exposure Assessment

Risk Characterization

• Have all plausible toxicological effects been considered for the general population and sensitive sub-populations?

• At what dose level do the effects occur; what is the critical effect; what is the NOAEL, LOAEL, benchmark dose (BMD), cancer slope factor? ADME?

• What is the route and pattern of exposure; food consumption patterns, aggregate exposure?

• Combine hazard, dose-response, and exposure; what is the ADI, TMDI, cancer risk; consider cumulative risk for pesticides with the same mode of action?

Risk: Conceptual Framework

Pesticide Use Practices

Human/wildlife Susceptibility and Behavior

Human-Wildlife

Risk

Opportunities for Pesticide

Exposure

Human Exposure to Pesticides• Occupational

– Mixer/loader/applicator (handler) – Re-entry activities - harvest, irrigation, pruning, thinning, weeding, and

scouting.

• Non-occupational

– Household use– Use in public areas (schools, parks, golf course, restaurants)– Bystander exposure near agricultural or other applications– Dietary exposure – food, drinking water, incidental ingestion of soil, water– Bathing or clothes washing in contaminated water

• Exposure route and duration – estimate from pesticide properties, monitoring data (including biomarkers), environmental fate models

How Is Dose-Response Assessed?

• Depends on: – Duration of exposure (acute, chronic)

– Type of toxic effect (cancer; non-cancer)

– Route of exposure (inhalation, dermal, oral)

– Type of risk assessment (dietary; residential; occupational)

How Is The Toxicity Part Expressed?

• Look at animal studies to see what effects the pesticide causes (hazard identification)– short-term (acute)– intermediate-term (subchronic)– long-term (chronic)

• Determine at what dose level the effects are occurring (dose-response)

Risk = f (toxicity, exposure)

National Academy of ScienceToxicity Testing for the Assessment of Environmental Agents (2006)

Acute, subchronic, and chronicanimal studies, and in vitro assays, designed to assessall plausible toxic endpointsand dose-response (potency)

Toxicity Testing for NewPesticides under FIFRA

Risk Assessment:

Toxicity Part

Threshold There is some dose, below which there will be no effect.

Non-threshold (cancer)Potency estimated from the probability of developing cancer over a lifetime of exposure.

DOSE0 2 4 6 8

RES

PON

SE (m

alai

se)

2

0

4

• Non-Linearly (Threshold)

6

8

NOAEL (the "threshold")

DOSE0 2 4 6 8

RES

PON

SE (t

umor

s)

2

0

4

•Linearly (Non-Threshold)

(low-dose extrapolation)6

8

Toxicological effects are believed to occur either:

NOAEL: No Observable Adverse Effect Level

Risk Assessment – Threshold Effects

• Evaluate the results of animal testing

• Choose most sensitive test

• The highest dose which caused no observable harm or side effects is the No-Observable Adverse Effect Level or NOAEL.

• Scale dose from test animals to humans

No Observable Adverse Effect Level (NOAEL)

DOSE

0 2 4 6 8

RES

PON

SE (m

alai

se)

2

0

4

6

8

NOAEL (the "threshold")

LOAEL

Critical Reviews in Toxicology, 36:37–68, 2006

90 day rat NOAEL

(mg/kg/day)

90 day dog NOAEL

(mg/kg/day)

1-year dog NOAEL

(mg/kg/day)

2-year rat NOAEL

(mg/kg/day)

Lowest NOAEL

(mg/kg/day)

2,4 D 15 1 1 5 1

Atrazine 1 6 5 3.5 1

Carbaryl 125 1 3.1 10 1

Dimethoate 2 <0.25 <0.18 0.05 0.05

Mevinphos 0.251 0.0631 0.025 0.025 0.025

No-observable Adverse Effect Levels (NOAELs)

1LOAEL

Threshold-based Risk Assessment

Threshold: there is some dose, below which there will be no effect.

• RFD1: The Reference Dose is the amount of a pesticide residue a person could consume daily for 70 years with no harmful non-cancer effects.

1Acceptable daily intake or ADI

Sensitive populations: Bimodal Frequency Distribution

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Most?Sensitive

MoreSensitive

LeastSensitive

In humans two single nucleotide polymorphisms (SNPs) occur in about 2,200 nucleotides (~15 million differences between individuals).

Pesticide Risk AssessmentUncertainty Factors

• The RFD/ADI is determined by dividing the NOAEL by a uncertainty factor (UF), usually between 100 and 1000

• 10X – uncertainty in extrapolating from animal studies to humans (interspecies).

• 10X – to account for variation in human susceptibility (intraspecies).

• 2-10X – optional factor for inconsistent data • 2-10X – to account for sensitive sub-populations1 (e.g. kids)

used to determine Population Adjusted dose (PAD)

1 The Food Quality Protection Act of 1996 (FQPA) requires EPA to make a determination if an additional factor necessary.

Reference Dose (Non-cancer risk)

• Start with the NOAEL (mg/kg BW/day)

• Calculate a reference dose (RfD/ADI):

RfD =UF

NOAEL

UF: 10X for Interspecies 10X for IntraspeciesOther (as needed) Uncertainty Factors

Risk = f (toxicity, exposure)

Reference Dose relative to NOAEL

RfD = UFNOAEL RfD = 10 x10

3 = 0.03 mg/kg/day

DOSE0 2 4 6 8

RES

PON

SE

2

0

4

6

8

NOAEL (the "threshold")

0.30.03

RfD

PAD =10x10x103 = 0.003 mg/kg/day

Cancer Risk Extrapolation Methods

Actuarial Risk: predict future events based upon past occurrences

Population Risk: probability of injury from well defined random events

Individual Risk: better explained with plausibility rather than probability 5 x 10-6 =

5 in a million

Cancer “Prevention”

• EPA cancer risk assessment goal:

prevent excess cancers due to chemical exposure

• Often assumes a lifetime daily dose (mg/kg/d)

• Excess cancer: >1 in 4 U.S. population

Excess Cancer Risk Terminology• U.S. cancer rate: 1 in 4 or ¼ or 0.25

• Acceptable excess cancer rate for each chemical exposure = 0.25 + ?

• How about 0.25 + 0.000001=.250001*

• 0.000001 = 1.0 x 10-6, often referred to as 10-6 cancer risk, this means that assuming daily exposure over a 70 year lifetime that an individual would have a 1 in 1 million risk of cancer above normal probability.

*Population risk, individual risk will vary with genetic predisposition to cancer, lifestyle, and other factors.

Cancer Risk Assessment:(Non-threshold)

• Cancer risk: The amount of a chemical a person could consume daily for 70 years that would result in no more than 1-in-a-million (10-6) increased chance of developing cancer as a direct result of consumption of (exposure to) that chemical.

Data Sources for Hazard ID

• Epidemiologic Studies

• Short-term studies (genotoxicity)

• Long-term animal studies

• Pharmacokinetic Studies

• Structure-activity relationships

Questions when Evaluating Epidemiologic Studies

• Chance

• Selection bias

• Confounding factors

• Measurement error

Currently EPA makes very limited use of epidemiological data in cancer risk assessment

Long-term Animal Study Assumptions

High dose, short term, exposure of animals will predict adverse effects of low dose, long term, exposure in humans.

Animal models will predict cancer in humans.

Weight-of-the-evidence approach

• Summarize human and animal data: sufficient, limited, inadequate, no data, no evidence

• Look at other evidence: short-term tests, pharmacokinetics, structure-activity relationships…

• Classify overall weight-of-the-evidence

Weight-of-the-evidence approach

• Critical analysis of each study to determine its quality and reliability.

• Entire body of evidence is integrated and examined for – consistency (repeatability of findings in studies), – cohesiveness (a logical pattern of responses), – biological plausibility (i.e., are the observed findings

consistent with current understanding of carcinogenic processes).

Hazard classification under the 1986cancer guidelines1

A Human carcinogen Sufficient human evidence

B1Probable human carcinogen

Limited human evidence

B2 Probable human carcinogen Sufficient animal evidence

C Possible human carcinogen Limited animal evidence

D Not classifiable Inadequate human and animal evidence

E Evidence of noncarcinogenicity Sufficient negative evidence

1Adapted from the WHO IARC cancer hazard classification

EPA 2005 GuidelinesWeight-of-evidence narrative

• EPA weight of evidence descriptors : – Carcinogenic to humans – Likely to be carcinogenic to humans– Suggestive evidence of carcinogenic potential – Inadequate information to assess carcinogenic

potential – Not likely to be carcinogenic to humans

Pesticides: Expressing riskRisks at EPA OPP are generally expressed

in the following ways:

• % Reference Dose (%RfD)• % Population Adjusted Dose (%PAD)• Margin of Exposure (MOE)• Cancer Probability

NIEHS National Toxicology Program Weight-of-evidence narrative

• Weight of evidence descriptors – Clear Evidence of Carcinogenic Activity– Some Evidence of Carcinogenic Activity – Equivocal Evidence of Carcinogenic Activity – No Evidence of Carcinogenic Activity – Inadequate Study of Carcinogenic Activity

GMO Corn &Glyphosate

Protests and cancer concerns raise doubts for Roundup's future in Europe

Demonstrators participate in a protest march against Monsanto in Paris, France, May 23, 2015. People in 48 countries and 421 cities took part in protest marches against Monsanto and its glyphosate-containing Roundup herbicide.

Credit: Reuters

Is Glyphosate a Carcinogen?US NIEHS National Toxicology Program - No Evidence of Carcinogenic Activity

US EPA - Group E: "Evidence of Non-Carcinogenicity for Humans"

"This group is used for agents that show no evidence for carcinogenicity in at least two adequate animal tests in different species or in both adequate epidemiologic and animal studies.

The designation of an agent as being in Group E is based on the available evidence and should not be interpreted as a definitive conclusion that the agent will not be a carcinogen under any circumstances.“

Governments of EU, Canada, Australia, Japan – concurrence with US EPA

European Food Safety Authority (EFSA)Glyphosate Renewal Assessment Report (RAR)

• Germany – EU rapporteur member state (RMS)

• Submitted glyphosate RAR To EFSA in January 2014

• Recommended re-approval– increase ADI (RfD) from 0.3 to 0.5 mg/kg

body weight per day. – No evidence of carcinogenicity

• March 2015 – WHO International Agency for Research on Cancer (IARC) – Glyphosate probable human carcinogen

WHO IARC Monographs Programme• Program officials appoint expert working groups composed of

internationally recognized experts chosen based on their knowledge and experience.

• Working groups meet for 7 to 8 days with the goal of forging consensus; make determinations about the likelihood that selected agents cause cancer in humans —defined as:

– specific chemicals– groups of related chemicals– complex mixtures– occupational or environmental exposures– cultural or behavioral practices– biological organisms and physical agents

IARC’s Practice for Carcinogen Identification and Evaluation

WHO IARC Monographs Programme

• Agents classified by IARC, Volumes 1–114

Group 1 Carcinogenic to humans 118 Group 2A Probably carcinogenic to humans 75Group 2B Possibly carcinogenic to humans 288Group 3 Not classifiable as to its carcinogenicity to humans 503Group 4 Probably not carcinogenic to humans 1

Agents classified by IARC, Volumes 1–114• Red meat 1• Ethanol in alcoholic beverages 1• Solar radiation 1• Wood dust 1• Hairdresser or Barber 2A• Glyphosate 2A• Coffee 2B• Gasoline 2B• Radiofrequency electromagnetic fields (cell phones) 2B

Group 1 Carcinogenic to humansGroup 2A Probably carcinogenic to humansGroup 2B Possibly carcinogenic to humansGroup 3 Not classifiable as to its carcinogenicity to humans Group 4 Probably not carcinogenic to humans

Hazard vs Risk• EPA, EU and other governments of the developed world,

evaluate cancer risk; an estimate of the carcinogenic effects expected from exposure to a cancer hazard.

• WHO’s IARC Monographs Programme evaluates cancerhazard; is an agent capable of causing cancer under some circumstances.