# Presentation: 265050

## Cumulative Risk Assessment: Determination of Relative Potency for the Organophosphorus Pesticides

*Cumulative Risk Assessment: *Determination of Relative Potency for the Organophosphorus Pesticides

- Technical Briefing

- U.S. EPA
- Office of Pesticide Programs
- August 22, 2001

## Lois Rossi, Director
Special Review and Reregistration Division
Margaret Stasikowski, Director
Health Effects Division

- Special Review and Reregistration Division
- Margaret Stasikowski, Director
- Health Effects Division

*Welcome and Introduction*

## Goals of Today’s Meeting

**Goals of Today’s Meeting**

**Lois Rossi**
- Director, SRRD

## Goals & Purpose of Briefing

- Part of process the Agency has developed in conjunction with CARAT Sub-Workgroup on OP Cumulative Process
- Update stakeholders
- Provide explanations of methods as early as possible

## Goal

- Stakeholders understand methods & data so that they can provide effective input

## Agency & Stakeholder Cooperation

- Due to development of many new methods for cumulative, the Agency is providing briefings on these methods & the status of the assessment _before_ the preliminary risk assessment is issued
- Stakeholders must recognize certain elements (both small & potentially large) may change
- Therefore, we all must work together cooperatively; to use the information constructively; and for the purpose of providing useful input

## Intro to the Cumulative Hazard Assessment

**Intro to the Cumulative Hazard Assessment**

**Margaret Stasikowski**
- Director, HED

## Developers of the Cumulative Hazard Assessment Methodology

- Office of Pesticide Programs
- Anna Lowit, Vicki Dellarco, Jessica Kidwell, Karl Baetcke, Kit Farwell, Bob Fricke, Linda Taylor, Bill Wooge
- Office of Research and Development, NHEERL
- Woodrow Setzer

## Outline for the Cumulative Hazard Assessment

- Basic Concepts and Terminology Used in Cumulative Assessment (Vicki Dellarco)
- The Organophosphate Cumulative Hazard Assessment (Randy Perfetti)

## Randy Perfetti, Ph.D. 
Vicki Dellarco, Ph.D.
Health Effects Division

- Vicki Dellarco, Ph.D.
- Health Effects Division

*Cumulative Assessment:**Determination of Relative Potency for the Organophosphorus Pesticides*

## Basic Concepts and Terminology 

**Basic Concepts and Terminology **

**Vicki Dellarco**
- Senior Scientist, HED

## Topics

- Cumulative Risk Assessment
- Progress to Date
- Overview of Process

## Topic:  Progress to Date

- FIFRA Scientific Advisory Panel reviews
- Guidance Document:  September & December 1999
- Pilot Analysis on 24 Organophosphorus Pesticides:  September & December 2000

** ****Public Comments**
-   June 2000:  FR Request
-  Comments at SAP meetings
-  July 2000 Workshop on Guidance

**Notes:**
Over the last several years we have made a great deal of progress in building a foundation for the Current OP risk assess which is the subject of today’s meeting 
We have developed a guidance document
Which we 1st presented to the Scientific Advisory Panel for review in  Sept 99 for hazard component & then Dec for the exposure
SAP recommended that we develop a complex case study to illustrate how OPP would apply its guidance 
Went back to SAP in last Sept & Dec with a pilot analysis on 24 organophosphate pesticides illustrating how to integrate cumulative risk for multiple pathways of exposure
In addition to input from a number of external SAP review, we have also had input from the publc
This guidance was Issued for comment in FR last June public
Technical workshop brief to explain guidance and answer questons

## Topic:  Progress to Date

- September 2001 SAP comments on Hazard & Dose-Response OP Case Study
- Consider alternative dose-response approach
- Careful selection of index chemical

** ****July 31****th**** SAP Document**
-  Reflects September 2000 SAP comments
-  SAP Review September 5-6, 2001

**Notes:**
I would like to emphasize that the SAP comments from last September were very instrument in shaping current hazard and dose response analysis on the OPs that you will hear this afternoon from Randy

There were a number of comments from that review , but in particular the SAP recommended that we consider an alternative dose-response approach and consider carefully the selection of the index chemical

As you will hear this afternoon, we have taken this recommendations into consideration in preparing the July 31th document.  
This current assessment will go back to the SAP in a couple of weeks for their input how whether we adequately addressed their recommendations

T

## Topic: Overview of Cumulative Risk Assessment Process 

- Hazard & Dose-Response
- General concepts & definitions
- Relative Potency Factors
- Index Chemical
- Point of Departure

**Why & How**

**Notes:**
We realize that all of you have different backgrounds, and we felt it was important that we start with an overview of the CRA process, primarily discussing some general concepts and definitons and steps taken int conducting  the Hazard and Dose Response components of the cumulative process which pertains to the OP analysis so that 
everyone is on a common ground

## Steps for Conducting a Cumulative Risk Assessment

- Identify Common Mechanism Group

- Identify Potential Exposures

- Develop Detailed Exposure Scenarios
- for all Routes & Durations

- Determine Cumulative Assessment Group

- Establish Exposure Input Parameters

- Conduct Final Cumulative Risk Assessment

- Conduct Characterization of Cumulative Risk

- Characterize + Select Common
-  Mechanism Endpoint(s)

- Determine Absolute & Relative Toxic Potencies of Chemicals & Point of Departure for Index Chemical

## Hazard Assessment

_**Single Chemical**_
- Select the most important effect of **ALL Toxicities** observed on a chemical

_**Cumulative**_
- Select the **Common Effect** shared by a group of chemicals

- What Toxicities Occur?

**Notes:**
Single causes liver deve neuro toxic

## Cumulative Hazard Assessment

- 1st Step—Identify group of chemicals that share a common toxicity that arises via a common mechanism

**Pesticides**

*Cumulative Hazard Assessment*

*Common *
*Mechanism *
*Group*

## Cumulative Hazard Assessment

- Further analysis of Common Effect

-  Identify endpoints associated with common mechanism
-  Identify studies/species/sexes
-  Identify routes
-  Identify durations of exposure
-  Evaluate robustness of data (quality & adequacy)

**Notes:**
Refer to Randy’s and show how these areas were address in the OP analysis

## Cumulative Dose-Response Assessment

- Determine Relative Potency
- Estimate the Point of Departure for the Index Chemical

## Relative Potency

- Although the chemicals produce the same effect via a common mechanism, they will have different toxic strengths or potencies

**Notes:**
Same amount or dose of each will produce a different degree of response for the common toxic effect, some very potent some weak active

## Determine Relative Potency 

- Steps
- Estimate the Toxic Potencies of the Common Effect for each chemical
- Select an Index Chemical that will be used as the point of reference for standardizing the toxic potencies of each chemical
- Use Index Chemical to calculate Relative Potency Factors

## Estimate Toxic Potency – How?

- Put on an “*Equal Footing*” or *“Common Basis”* by using:

-  Same type of endpoint
-  Same species/sex
-  Studies with comparable methodology
-  Same measure of potency for the endpoint

**Notes:**
Because one needs to compare the toxic potencies for a common mechanism group, you want to look at true difference int their potencies not differences  due to study differences

## Estimate Toxic Potency – How?

- What are measures of toxic potency?

-  NOAEL/LOAEL approach
- Lowest Observed Adverse Effect Level (LOAEL) is the lowest dose at which toxicity is observed
- No Observed Adverse Effect Level (NOAEL) is next lower dose at which no toxicity is observed
-  Disadvantages
- Affected by gap between doses selected by a study
- Beyond the range of observable data

**Notes:**
Focus of NOAEL is only on the dose tested so it must be one of the experimental doses.
The dose response plays no role in determining the toxic potency, observed range of data

## Estimate Toxic Potency – How?

- What are measures of toxic potency?
- NOAEL/LOAEL Method
- More accurate method:  Dose-Response Modeling
- Effective Dose (ED)
- Slope Scaling Factor

**Notes:**

More desirable approach is to use all data and fit a math model to each chemical  the dose response data to identify a ED or a Slopes
Identify a dose producing some level of change in the common toxic effect of interest

## Dose Response Modeling To Derive an Effective Dose (ED)

- Response

- Dose

- 50%

*Effect Doses that cause a 50% change in response*

- NOAELs

- A

- B

- C

- D

- E

- Observed
- Data Range

- 0

*Dose Response Modeling To Derive an Effective Dose (ED)*

**Notes:**
Take doses tested and response observed and use a mathematical equation to describe each chemicals dose response curve and from that curve you can determine a dose that causes a 50% for the effect

Allows to determine the ratios in potency among the chemicals

## Dose Response Modeling To Derive a Slope Scaling Factor

- Response

- Dose

- Use Entire Dose Response Curve

- 0

- A

- B

- C

- D

- E

*Dose Response Modeling To Derive a Slope Scaling Factor*

**Notes:**
Slope value which describes how the response changes with dose.  So a response that goes up steeply (a small change in dose with big effect) is more potent

Rise over run in building steps

## Dose Response Modeling To Derive a Slope Scaling Factor

- Dose

- 0% Activity

- 100%Cholinesterase Activity

- A

- B

- C

- D

- E

*Dose Response Modeling To Derive a Slope Scaling Factor*

**Notes:**
Increase in an undesirable effect such as tumors so curves were going up  but flipped because this is a plot of a reduction in a desirable effect such as a reduction in red blood cells or reduction CHE activity.

## Determine Relative Potency 

- Steps
- Estimate the Toxic Potencies of the common effect for each chemical

- Select an Index Chemical that will be used as the point of reference for standardizing the toxic potencies of each chemical
- Use Index Chemical to calculate Relative Potency Factors

**Notes:**
Summary Equal footing and using whole dose response curve not just one point
Once determine each chemicals potency those different potencies must be put on a common scale so the exposure to these can be combined  and 

## Relative Potency Factor Method

*Relative Potency Factor Method*

- Index Chemical:  Point of reference for standardizing the common toxicity of the chemicals

- An Example:  On a worldwide trip you’ve collected all these foreign coins.  How much US dollars do you have?

**Notes:**
Convert to same denomination before you add up your money

## The Index Chemical is Used to Put All Chemicals On a Common Denominator

*The Index Chemical is Used to Put All Chemicals On a *Common Denominator

- _5_
- 8

- +

- _6_
- 8

- +

- _4_
- 8

- _5_
- 8

- +

- _3_
- 4

- +

- _1_
- 2

*Convert to Index Units *
*by Multiplying by:*

**= **_**15**_
**     ****8**

**4**

**2**

**1**

- Index
- Chemical

- Exposure Equivalents of Index Chemical

**Notes:**
Multiple by 4 and 2

## Determine Relative Potency 

- Steps
- Estimate the Toxic Potencies of the common effect for each chemical
- Select an Index Chemical that will be used as the point of reference for standardizing the toxic potencies of each chemical

-  Use Index Chemical to calculate Relative Potency Factors

## Relative Potency Factor Method

- Calculate an Relative Potency Factor (RPF) for each chemical:

**Potency is portrayed as exposure equivalents to one chemical, the index chemical**

**Notes:**
RPF are simply the ratios of the toxic potency for each chemical to that of the index chemical  

## Relative Potency Factor Method

## Relative Potency Factor Method

- 160 ppm

- 100

- 20

- 5

- C

- 50

- 100

- 0.5

- B

- 10

- 10

- 1

- A (index)

- Exposure Equivalents of Index
- (ppm)

- Exposure (ppm)

- RPF

- Chemical

- Total Exposure Equivalents of Index Chemical =

**Notes:**
RPFs are used to convert exposures for each chemicals into  exposure equivalents of the index

## Cumulative Dose-Response Assessment

- Determine Relative Potency
- Estimate the Toxic Potencies
- Select an Index Chemical
- Calculate Relative Potency Factors

## Index Chemical

- Serves two functions:

** ****To Estimate Relative Potency Factors** in 	order to standardize the common toxicity 	for all the chemicals
** ****To Estimate Point of Departure** in order 	to determine the risk for the group

## Criteria for Selection of Index Chemical

- Hazard Considerations
- Dose-Response Considerations

-  Well-defined for common mechanism effects
-  Responses for common toxicity consistent with group

-  Well characterized with no big gap between the 	NOAEL & LOAEL
-  Strong data for all routes & durations of interest

**Notes:**
Well defined– studied in several species by different routes and durations.  And The common Toxic effect is its primarily toxicity and not some other toxicity unrelated to the common mechanism.  It would be desirable for it to be direct acting 
Toxic profile representative of the common mechanism group. So in general it produces effects consistent with the group among species and between the two species.  

Lots of doses tested

## Cumulative Dose-Response Assessment

- Determine Relative Potency
- Estimate the Toxic Potencies
- Select an Index Chemical
- Calculate Relative Potency Factors

**  **Estimate the Point of Departure                     	for the Index Chemical

## Point of Departure (PoD)

- Definition
- Point in the dose-response curve at which a change in response can be reliably said to be due to dosing with the chemical
- HAZARD X EXPOSURE = RISK
- Value used with exposure information to determine risk associated with lower environmentally relevant human exposures

**Notes:**
The dose where a chemical starts to cause effects.

## Point of Departure

- How are they used in risk assessment?

-  *HAZARD X EXPOSURE = RISK*

-  To Calculate RfDs (Reference Doses)
- PoD****Uncertainty Factors (e.g., 100X)
-  To Calculate MOEs (Margins of Exposures)
- PoD **** Exposure

## Point of Departure (PoD)

- Types of PoDs Used in Risk Assessment
- NOAEL/LOAEL Approach
- Lowest Observed Adverse Effect Level (LOAEL) is the lowest dose at which toxicity is observed
- No Observed Adverse Effect Level (NOAEL) is next lower dose at which no toxicity is observed

**Notes:**
OPP has used in single chemical assessments

## NOAEL/LOAEL Approach

- Dose

- “Observable
- Range of Data”

* *

- NOAEL

- 0

- LOAEL

*NOAEL/LOAEL Approach*

**Notes:**
NOAELs & LOAELs are a function of the study’s design–they depend on the doses chosen

## Point of Departure (PoD)

- Types of PoDs used in risk assessment
- NOAEL/LOAEL Approach
- Dose-Response Modeling Approach

**Notes:**
Alternative to NOAEL Approach
Let shape of DR play a role in determining acceptable doses

## NOAEL/LOAEL Approach

- Dose

- “Observable
- Range of Data”

* **Point of Departure*

- NOAEL

- 0

- LOAEL

*NOAEL/LOAEL Approach*

## Point of Departure

- Dose-Response Modeling Approach
- May estimate a more “Refined PoD”
- Need studies or data amenable to dose-response modeling
- Several doses (ranging from low to high) producing effects
- No big gaps between NOAEL & LOAEL

**Notes:**
Benchmark dose guidance last peer review last december final guidance anticipated at eand of calendar year.

## Point of Departure:   Benchmark Dose (BMDX)

- “Level of Change” or “X” depends on:
- Determine on a case-by-case basis   (e.g., 1%, 5%, 10%, etc.)
- Common Toxic Effect
- Normal variability of effect
- Measurement method

**Notes:**
What should be the level of change used to estimate the the PoD

Case by case some studies can detect a 10% change
Some studies can deterc a 10 % cnage  some can detect a lower change.

## Benchmark Dose Approach

- Dose

- “Observable
- Range of Data”

* **Point of Departure*

- 0

- “**Benchmark Dose (BMD****10****)**”

**“****10% Level of **
**Change**”

*Benchmark Dose Approach*

**Notes:**
A dose producing some level of change in response compare to control group
Use all experimental data by decribing it with a model So model data to esimte a PoDl 

## Calculation of RPFs & PoDs for Different Exposure Routes

- Potency may vary depending on route of exposure
- Route-specific data are preferred
- Extent & quality of data may differ, thus different methods may used for each route

**Oral**

**Dermal**

**Inhalation**

## Cumulative Risk AssessmentSummary

- Select studies & endpoints
- Determine Relative Potency using Index Chemical
- Determine the Index Chemical’s *Point of Departure* OR the “Endpoint”

**Hazard**
- (Index Chemical’s
- PoD for Group)

**Exposure**
- (Index Chemical
- Exposure Equivalents)

- = Risk

## Intro to the OrganophosphateCumulative Hazard Assessment

**Intro to the OrganophosphateCumulative Hazard Assessment**

**Margaret Stasikowski**
- Director, HED

## Accounting of OP’s in Cumulative Risk Assessment

- 39 Registered OPs

-  1 OP in registration process

- +

- 40 OPs

- 40 OPs That We Started With

## 40 Organophosphate Pesticides

- Dichlorvos

- Diazinon

- Coumaphos

- Chlorethoxyfos

- Chlorpyrifos methyl

- Chlorpyrifos

- Cadusafos

- Bensulide

- Azinphos methyl

- Acephate

- Trichlorfon

- Phosmet

- Fosthiazate*

- Tribuphos

- Phosalone

- Fenthion

- Tetrachlorvinphos

- Phorate

- Fenitrothion

- Terbufos

- Oxydemeton Methyl

- Fenamiphos

- Temephos

- Naled

- Ethyl Parathion

- Sulfotepp

- Mevinphos

- Ethoprop

- Propetamphos

- Methyl Parathion

- Ethion

- Profenofos

- Methamidophos

- Disulfoton

- Pirimiphos methyl

- Methidathion

- Dimethoate

- Phostebupirim

- Malathion

- Dicrotophos

- *A new chemical that will be examined in the assessment to determine if it might be considered for future registration (it’s a methyl bromide alternative)

## Accounting of OP’s in Cumulative Risk Assessment

- 40 Total OPs We Started With

-  8 OPs Not Considered

- -

- 32 OPs Under Consideration

- 32 Can Be Considered for Cumulative Assessment

## Why 8 OP’s Are Not Being Considered

- directly applied to livestock and swine bedding; EPA believes these residues will not transfer to meat and milk

- Coumaphos

- Propetamphos

- Temephos

- Fenitrothion

- individual assessments determined that there were negligible, if any, exposures

- Cadusaphos

- Sulfotepp

- Ethyl Parathion

- phase-out

- Ethion

- Reason

- Organophosphate

## Accounting of OP’s in Cumulative Risk Assessment

- 25 Are in Today’s Assessment

- 25 OPs in Today’s Assessment

- 32 Total Number for Consideration

- -

-  7 OPs Not in Today’s Assessment*

- *These may be added

## The 7 OP’s That Will Be Added

- drinking water assessment needed

- Ethoprop

- Dicrotophos

- Phostebupirim

- chemical may be supported

- Chlorpyrifos methyl

- adult mosquitocide

- Fenthion

- Profenofos

- Chlorethoxphos

- Reason for Addition

- Organophosphate

## A Few Facts About the 25

- 23 detected in the Pesticide Data Program
- 1 is a pesticide in the registration process (therefore it does not have PDP residues)
- 11 have residential/non-occupational uses

## Summary of What We’re Looking At

## The Organophosphate Cumulative Hazard Assessment 

**The Organophosphate Cumulative Hazard Assessment **

**Randy Perfetti**
- Associate Director, HED

## Steps for Conducting a Cumulative Risk Assessment

- Identify Common Mechanism Group

- Identify Potential Exposures

- Develop Detailed Exposure Scenarios
- for all Routes & Durations

- Determine Cumulative Assessment Group

- Establish Exposure Input Parameters

- Conduct Final Cumulative Risk Assessment

- Conduct Characterization of Cumulative Risk

- Characterize + Select Common
-  Mechanism Endpoint(s)

- Determine Absolute & Relative Toxic Potencies of Chemicals & Point of Departure for Index Chemical

## Topics

- Data Selection
- Methodology & Results
- Toxic Potency of each OP
- Index Compound
- Relative Potency Factors
- Point of Departure for Index OP

## Cumulative Hazard Assessment

- 1st Step—Identify group of chemicals that share a common toxicity that arises via a common mechanism

**Pesticides**

*Cumulative Hazard Assessment*

*Common *
*Mechanism *
*Group*

## Identifying Common Mechanism Group: Organophosphorous Pesticides

- U.S. EPA 1999 Policy Paper

- Inhibition of cholinesterase
- Brain
- Peripheral nervous system (e.g., nerves in diaphragm, muscles)
- Surrogate/Indicator (RBC, Plasma)

*Nerve Axon*

## Data Selection

- Studies available:
- Rat, dog, mouse, rabbit, humans
- Both sexes
- Largest number of studies are on rats

## Data Selection

*Data Selection*

- Rats were selected:
- Cholinesterase inhibition (ChEI) in plasma,             red blood cells (RBC), brain
- Oral, dermal, inhalation
- Both sexes
- Many different doses & time durations of treatment

## Data Selection

- Point at which continued exposure at the same treatment dose will result in no further reduction in ChE activity
- OPs take 20 to 30 days to reach steady state for ChEI
- Used data measured at 21 days and longer

- Use of Steady State

## Data Selection

- Time

- Increasing Activity

*1 day*

*21 day*

- Steady State of ChEI

- D

- C

- B

- A

- A

- B

- B

- A

- C

- C

- D

- D

_**21 days**_

_**1 day**_

- Ranking at:

- “common dose”

## Data Selection

- Used steady state ChEI data for determining potencies (“scores”)
- More stable estimate of potency
- Puts OPs on an “equal footing” for scoring potencies
- Gives less uncertainty

- Use of Steady State

## Dose-Response and Potency

## Dose-Response and Potency

- Estimate the _toxic potencies_ of the common effect for each OP
- Select an _index chemical_ that will be used as the point of reference for standardizing the toxic potencies of each chemical
- Use index chemical to calculate _relative potency factors_
- Estimate the _point of departure_ for the index chemical

## Dose-Response and Potency

- Analyze dose-response to determine a “score” for each chemical
- How?
- Select technique that will allow us to assign a potency value or “score” to each OP

- Potency of Each Chemical

## Dose-Response and Potency

- What are measures of toxic potency?
- NOAEL
- More accurate method:  dose-response modeling
- Effective Dose
- Slope Scaling Factor

- How to Estimate Potency of Each Chemical

## Dose-Response and Potency

- Modeling of oral ChE data
- Oral data most extensive and amenable to modeling
- Dose-Response Model selected
- Descriptive of ChEI
- Nonlinear (exponential model) approach recommended by September 2000 SAP

- Potency of Each Chemical:  Oral

## Dose-Response and Potency

- Dose (mg/kg/day)

- Cholinesterase Inhibition (%)

- 0

- 100

- 0

- 5

- 10

- 15

- Background (m = 0)

-  (m = 0.05)

-  (m = 0.3)

-  (m = 1)

-  (m = 5)

- _Equation_:
- y=B+(A-B) x e-m*dose

*Dose-Response and Potency*

## Dose-Response and Potency

|  | Current | Pilot |
| --- | --- | --- |
| Type of Model: | Nonlinear (exponential) equation | Linear Equation |
| Studies Used: | All studies | One representative study |
| Data Used: | Mean CHEI, Standard deviation, sample size | Mean CHEI  |
| Variability: | Weighting of variance, confidence intervals | No measure |
| Model Uncertainty: | Goodness-of-Fit test | No measure |
| Potency Comparison: | Slope-scaling
Factor (m) | BMD50 |

*Dose-Response and Potency*

- Oral Potency

## Dose-Response and Potency

- Selection of tissue & sex
- Analyzed all the modeled data
- Selected male RBC for determining oral potencies
- Why male RBC?

- Oral Potency

## Why RBC?
Must consider both brain and                     peripheral nervous systems (PNS)
Very little data on PNS
RBC & Plasma surrogate/indicator of PNS and brain

- Must consider both brain and                     peripheral nervous systems (PNS)
- Very little data on PNS
- RBC & Plasma surrogate/indicator of PNS and brain

- Oral Potency

*Dose-Response and Potency*

## Dose-Response and Potency

- Why RBC?
- Brain data had limitations (fewer observations)
- RBC and brain potencies similar for OPs
- Index chemical’s PoD for RBC was comparable to that for brain
- Quality of RBC data was comparable to plasma

- Oral Potency

## Dose-Response and Potency

- Why males?
- No difference between male and female potency values across the OPs

- Oral Potency

## Dose-Response and Potency

- Calculate for each chemical and route:

- RPF

- mSpecific Chemical

- mIndex Chemical

- =

- Potency is portrayed as exposure equivalents to one chemical–the index chemical.

- Relative Potency Factors (RPF’s) for Oral

## The Residential OPs:
Oral dosing
Modeled potencies
Dermal & inhalation dosing
Could not model due to limited data
Used NOAELs

- The Residential OPs:
- Oral dosing
- Modeled potencies
- Dermal & inhalation dosing
- Could not model due to limited data
- Used NOAELs

*Dose-Response and Potency*

- Dermal and Inhalation

## Data used for dermal potency scores
RBC NOAELs
4 rat and 4 rabbit 
DDVP:  no dermal study

- RBC NOAELs
- 4 rat and 4 rabbit
- DDVP:  no dermal study

- Dermal Potency

*Dose-Response and Potency*

## Dose-Response and Potency

*Dose-Response and Potency*

- Data used for inhalation potency scores
- RBC NOAELs
- 7 rat studies for inhalation
- Bensulide and tetrachlorvinphos:            no studies available

## Dose-Response and Potency

- Calculate for each chemical and route:

- Potency is portrayed as exposure equivalents to one chemical–the index chemical.

- Relative Potency Factors (RPF’s) for Dermal and Inhalation

## Methodology Summary

## Index Chemical

- Estimate the _toxic potencies_ of the common effect for each OP
- Select an _index chemical_ that will be used as the point of reference for standardizing the toxic potencies of each chemical
- Use index chemical to calculate _relative potency factors_
- Estimate the _point of departure_ for the index chemical

## Index Chemical

- Criteria for selection of index chemical
- Hazard considerations
- Well-defined for common mechanism of toxicity
- Toxicological profile for common effect consistent with chemical group across species/sexes/tissues
- Dose-response considerations
- Well characterized with no big gap between the NOAEL and the LOAEL
- Strong database for all routes & durations of interest

## Index Chemical

- Methamidophos selected because:
- Direct acting:  no metabolic activation required
- High quality dose-response data for oral RBC AChEI
- Oral database has studies from very low to very high doses
- Rat dermal and inhalation studies are available and are appropriate for modeling
- For oral route:  potencies were similar among tissues and between sexes

## Relative Potency Factors

- Estimate the _toxic potencies_ of the common effect for each OP
- Select an _index chemical_ that will be used as the point of reference for standardizing the toxic potencies of each chemical
- Use index chemical to calculate _relative potency factors_
- Estimate the _point of departure_ for the index chemical

## Relative Potency Factors (RPF’s)

- Calculate for each chemical and route:

- Potency is portrayed as exposure equivalents to one chemical–the index chemical.

## Relative Potency Factors for Oral

| Chemical | Oral |
| --- | --- |
| Acephate | 0.02 |
| Azinphos-methyl | 0.29 |
| Bensulide | 0.02 |
| Chlorpyrifos | 0.08 |
| Diazinon | 0.12 |
| Dichlorvos | 0.12 |
| Dimethoate | 0.35 |
| Disulfoton | 2.89 |
| Fenamiphos | 0.46 |
| Fosthiazate | 0.22 |
| Malathion | 0.003 |
| Methamidophos | 1.00 |
| Methidathion | 0.20 |

| Chemical | Oral |
| --- | --- |
| Methyl-parathion | 0.25 |
| Mevinphos | 0.37 |
| Naled | 0.03 |
| Oxydemeton-methyl | 0.81 |
| Phorate | 2.46 |
| Phosalone | 0.07 |
| Phosmet | 0.10 |
| Pirimiphos-methyl | 0.03 |
| Terbufos | 3.08 |
| Tetrachlorvinphos | 0.002 |
| Tribufos | 0.23 |
| Trichlorfon | 0.004 |

## Relative Potency Factors for Dermal and Inhalation

- 0.028

- NA

- 0.78

- 1.00

- 0.01

- 0.286

- 6.25

- 20

- NA

- 0.18

- Inhalation

- 0.075

- Naled

- 0.001

- Tetrachlorvinphos

- 0.007

- Trichlorfon

- 1.00

- Methamidophos

- 0.015

- Malathion

- 0.300

- Fenamiphos

- 0.936

- Disulfoton

- NA

- Dichlorvos

- 0.001

- Bensulide

- 0.002

- Acephate

- Dermal

- Chemical

## Oral Relative Potency Factors for RBC ChE Activity:  Male Rat

**TETRACLOROVINPHOS**

**Relative potency**
**(95% confidence limits) **

**MALATHION**

**TRICHLORFON**

**ACEPHATE**

**BENSULIDE**

**NALED**

**PIRIMIPHOSMet**

**PHOSALONE**

**CHLORPYRIFOS**

**PHOSMET**

**DICHLORVOS**

**DIAZINON**

**METHIDATHION**

**FOSTHIAZATE**

**TRIBUFOS**

**METHYLPARATHION**

**AZINPHOSMet**

**DIMETHOATE**

**MEVINPHOS**

**FENAMIPHOS**

**ODM**

**METHAMIDOPHOS**

**PHORATE**

**DISULFOTON**

**TERBUFOS**

**0.0001**

**0.001**

**0.01**

**0.1**

**1**

**10**

**100**

## Point of Departure

- Estimate the _toxic potencies_ of the common effect for each OP
- Select an _index chemical_ that will be used as the point of reference for standardizing the toxic potencies of each chemical
- Use index chemical to calculate _relative potency factors_
- Estimate the _point of departure_ for the index chemical

## Determine Point of Departure

- Used steady state to calculate BMD10 for methamidophos
- Timing of effects
- OP effects are not readily reversible (persist after exposure)
- Durations of interest
- Evidence to indicate a continuous exposure to OPs
- Exposure for residential/non-occupational treatments can last for more than one day

- Use of Steady State

## Determine Point of Departure

- BMD10 (benchmark dose)
- The dose at which cholinesterase activity is reduced by 10 percent compared to the background level of cholinesterase activity

## BMD10
This is the point at which cholinesterase inhibition can be reliably said to have changed by 10% due to dosing

- This is the point at which cholinesterase inhibition can be reliably said to have changed by 10% due to dosing

*Determine Point of Departure*

## Look at methamidophos studies

*Determine Point of Departure*

- Derive a curve using these data for all three routes
- Identify the BMD10

## BMD10 and NOAELs for Methamidophos

| Route of Administration | BMD10 | NOAELs |
| --- | --- | --- |
| Oral | 0.09 mg/kg/day | 0.03 mg/kg/day |
| Dermal | 1.21 mg/kg/day | 0.75 mg/kg/day |
| Inhalation | 0.0042 mg/L | 0.001 mg/L |

## In Closing...

**In Closing...**

**Margaret Stasikowski**
- Director, HED

## Issues to Be Brought to the SAP

- Selection and performance of dose-response model
- Combining cholinesterase data from multiple datasets to derive relative potency and benchmark dose estimates
- Approach for selection of the index chemical
- Use of steady state cholinesterase data for estimating both the relative potency and the points of departure

## Lois Rossi, Director
Special Review and Reregistration Division

- Special Review and Reregistration Division

*Next Steps*

## Next Steps

**August 23, 2001.**  CARAT Sub-Workgroup Meeting
**August 2001.**  Release Plain English Guide
**September 5-6, 2001.**  SAP Meeting on the hazard portion of the cumulative assessment
**September, October 2001.**  Release various revised science policy papers
**October 2001.**  Technical briefing(s) on exposure methodologies
**December 2001.**  Release preliminary risk assessment; tech briefing
**Winter 2002.**  60-day comment period on preliminary risk assessment
**August 2002.**  Release revised risk assessment

## Next Steps

- For the most up-to-date information, visit:
- _http://www.epa.gov/pesticides/cumulative/_
- To receive OPP Updates via e-mail:
- See the sign-up sheet at the registration desk