Epidemiology : Incorporation into Pesticide Risk Assessment and - - PowerPoint PPT Presentation

Epidemiology:

Incorporation into Pesticide Risk Assessment and Management:

Daniel A. Goldstein, M.D.

Director, Medical Sciences and Outreach, Monsanto Current Chair, CLA-EHHWG (Epidemiology and Human Health Working Group)

Just when you thought it was SAFE to go back into the Agency…

 Exposure-Based Risk

Assessment

• Toxicology studies
• Exposure assessment
• Risk assessment
• Risk management

 Epidemiology

• HUMAN data
• REAL health effects

 Intuition tells us,

the light is over here!! BUT…..

We are used to a animal-data-driven, quantitative- risk-assessment approach- but INTUITION tells the PUBLIC that the street lamp shines HERE:

In reality, Epidemiology faces serious limits to knowledge:

 Short term outcomes- relatively easy (How many

people who ate peanut butter got salmonella?)

 Long term or delayed outcomes are difficult

(cancer, parkinsons, developmental, etc.)

• Metrics of past exposure are limited.
• Recall is subject to significant bias.
• Diagnosis can be challenging and unreliable.
• Alternative causes and contributors may be

difficult to identify and exclude.

• Ecological studies (lacking individual exposure

data) are problematic.

The problem is aggravated by “Hypothesis Generating” studies. (We don’t know what we are looking for…. So

we will look for everything.)

Hypothesis T esting

 Single or few a-priori

hypotheses to be tested.

 Design considers known or

suspect confounders and alternative hypotheses.

 Within limits of model, can

define likelihood of a “false positive” result. (Typically < 5%)

Hypothesis Generating

 Multiple hypotheses: Agents X Outcomes X Subgroups* = 10’s – 1000’s of hypotheses!  1 in 20 hypotheses will test

positive even if no real association exists 

 Design considers only general

confounders (age, smoking).

 Requires “confirmatory”

studies- but usually NOT done!

* Age, sex, genotype, etc. Thought required….. Computing required…..

The Ag Health Study

(AHS slides adapted from Alavanja M. , AHS update, APPCO April 6 2009)

• Prospective cohort study of 89,658 pesticide applicators &

spouses.

• 82% of target population enrolled 1993-1997.
• Little loss to follow-up (<2%).
• Cancer incidence and mortality updated annually.
• Comprehensive exposure assessment information on 82

pesticides collected at three points in time.

• Questionnaire exposure assessment evaluated with field

measurements of pesticides.

• Buccal cells collected on >35,000 study subjects.

And they have been busy…..

Herbicides:

• Alachlor –

trends for leukemia and myeloma

• Atrazine –

no associations

• Butylate –

prostate

• Cyanazine –

no associations

• Dicamba –

trend with colon and lung cancer

• EPTC –

leukemia and colon

• Glyphosate –

multiple myeloma

• Imazethapyr –

bladder and colon

• Metolachlor –

deficit for prostate, excess for lung

• Pendimethalin –

lung, trend with rectal cancer

• Trifluralin –

colon

Insecticides:

• Aldicarb –

colon

• Aldrin –

breast, deficit for colon

• Carbaryl –

melanoma and a deficit for prostate

• Carbofuran –

prostate, trend for lung cancer

• Chlordane/heptachlor– rectum, breast, leukemia
• Chlorpyrifos –

brain, rectum, lymphohematopoietic, trend for lung

• Coumaphos -

prostate

• Diazinon –

trends for leukemia and lung

• Dichlorvos –

no associations

• Dieldrin –

lung, breast

• Fonofos –

leukemia, prostate

• Lindane –

NHL

• Malathion –

breast, deficit for melanoma

• Methyl bromide –

prostate

• Permethrin -

prostate

• Phorate –

prostate among family history

• Toxaphene –

melanoma

Fungicides:

• Captan –

no associations

• Chlorothalonil –

no associations

Pressure on the Agency

 The AHS team has indicated that their data

alone are sufficient to establish causation.

 Existence of studies like AHS puts EPA under

some pressure to look at and incorporate epidemiologic data in risk-assessment.

 NGO’s and the public have been / will come in

behind the use of epidemiological data.

 There are LOTS MORE STUDIES OUT THERE-

past, present and future! (Can YOU say National

Children’s Study?)

EPA Has begun to address the issue:

 Existing Risk Assessment guidance (water program) details

limitations and outlines assessment principles for epi data.

 New Epidemiology Branch created in Health Effects

Division under Mary Manibusan, with expertise “imported” from water program.

 White paper and internal review process underway, and

FIFRA SAP being developed.

 HED Director, Tina Levine, has an understanding and

appreciation of the limitations of bio-statistical methods.

 New Agency web-page indicates a Weight of Evidence

approach….

http://www.epa.gov/pesticides/health/ag-health.html

Agricultural Health Study – EPA’s Role and Plans

Current as of March 5, 2009 NOTE- selected excerpts only, emphasis (in red) added…

Developing a science-based process

In anticipation of results from current AHS studies, EPA is developing an approach for incorporating epidemiology information into human health risk assessments for pesticide chemicals. As a basis for this approach, EPA is using existing Agency and international guidance including: U.S. EPA 2005 Guidelines for Carcinogen Risk Assessment Reference Dose guidance IPCF Framework for Analysing the Relevance of a Cancer Mode af Action for Humans and Case-Studies (PDF) EPA relies on multiple lines of evidence to evaluate the safety of a pesticide, including animal toxicology studies as well as other sources of information such as how effects are caused (mechanisms of action), use patterns, what happens to the pesticide in the environment and how long it remains (environmental fate and persistence), food residue levels, and human exposure potential. Scientists evaluate all available data and weigh the evidence rather than relying on any one study. Incorporating epidemiology data into this process will expand the range of the evaluation. EPA’s approach to incorporating the AHS findings into existing hazard and exposure information will focus on: how the pesticide may cause potential harm (i.e., the pesticide’s mode of action) how the body handles the compound once exposed what the compound does when it is in the body An evaluation of exposure pathways, route (e.g., dermal, inhalation, oral), and duration will be an important component of the proposed approach. Another aspect of the approach will be to compare results of the AHS to those

• btained from toxicology studies done with rodents and other experimental animals. There are a variety
• f sophisticated models and tools available, which EPA will use as available and appropriate to evaluate risk.

Obtaining peer review and involving the public

EPA will present its scientific approach to integrating exposure, toxicology, and epidemiology in a white paper, which will be available along with draft case studies for review by the FIFRA Scientific Advisory Panel in 2009. EPA will also solicit comments from the public on the proposed approach.

And- Ag Health does admit at least some limitations….

General observations

(adapted from 2009 AHS update cited above, emphasis added)

• No pesticide associated with all/ many cancers
• Cancer associations do not cluster by chemical class
• Some associations occur for cancers not elevated among farmers (colon, rectum, lung,

bladder)

• Cancer excesses are small. This could indicate they are:
• due to chance or confounding
• real, but impact weak
• real, but impact reduced because of misclassification
• Exposure assessments need to be improved
• Need to replicate analyses

Epidemiology is Adapting to Criticisms

 Focus on single agents  Alternative exposure assessment techniques  Focus on high risk or susceptible populations

Agents: Paraquat and Maneb. Exposure assessment: California geographical use reporting system. Genetic sub-classification by Dopamine Transporter variants. Study has serious limitations, but findings are not easily dismissed by “traditional” objections

Developing a Response- Process

 Coordinate efforts with EU Epi Team  Continue conversations with HED

• Engagement in white paper review/ comment opportunity as

appropriate.

• Engagement with pending FIFRA SAP

 Consider engagement with broader epidemiology

community to:

• More fully understand the applications and limitations of

epidemiology.

• Encourage movement toward hypothesis selection and

refinement followed by focused hypothesis testing.

Developing a Response- Focus

 Quality of Design and

Proper Interpretation

• Hypothesis testing vs

generation

• Exposure assessment
• Model selection
• Bias, confounding
• Alternative causes

 Use of Weight of

Evidence Approach

• Bradford-Hill Criteria
• Classical animal testing
• Mechanism of Action
• Exposure pathways
• Dose-response based

risk assessment

Discussion