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FIFRA SCIENTIFIC ADVISORY PANEL (SAP)
OPEN MEETING: September 5-6, 2001

8/29/01


FIFRA SAP WEB SITE https://www.epa.gov/scipoly/sap/
OPP Docket Telephone: (703)305-5805

WEDNESDAY, SEPTEMBER 5, 2001
SHERATON CRYSTAL CITY HOTEL
1800 JEFFERSON DAVIS HIGHWAY
ARLINGTON, VIRGINIA 22202
703-486-1111

Preliminary Cumulative Hazard and Dose-response Assessment for Organophosphorus Pesticides: Determination of Relative Potency and Points of Departure for Cholinesterase Inhibition.

8:30 AM Introduction and Identification of Panel Members - Ronald J. Kendall, Ph.D (Chair, FIFRA SAP)

8:45 AM
Administrative Procedures by Designated Federal Official - Mr. Larry Dorsey
(Executive Secretary, FIFRA SAP)

8:50 AM
Welcome - Vanessa Vu, Ph.D., Director (Office of Science Coordination and Policy, Office of Prevention, Pesticides and Toxic Substances, EPA)

8:55 AM
Introductory Remarks - Ms. Marcia E. Mulkey, Director (Office of
Pesticide Programs, Office of Prevention, Pesticides and Toxic Substances, EPA)

9:00 AM
Background and Introduction - Vicki Dellarco, Ph.D., Health Effects Division, Office of Pesticide Programs, Office of Prevention, Pesticides and Toxic Substances, EPA

9:15 AM
Methods: Concepts and Overview - Anna Lowit, Ph.D., Health Effects Division, Office of Pesticide Programs, Office of Prevention, Pesticides and Toxic Substances, EPA

10:00 AM
Methods: Technical methodology - Woodrow Setzer, Ph.D., National Health and Environmental Effects Research Laboratory, Office of Research and Development, EPA.

11:00 AM
BREAK

11:15 AM
Results and Conclusions Anna Lowit, Ph.D., Office of Prevention, Pesticides and Toxic Substances, Health Effects Division, Office of Pesticide Programs, EPA

11:30 AM
Charge And Questions to the SAP - Vicki Dellarco, Ph.D., Health Effects Division, Office of Pesticide Programs, Office of Prevention, Pesticides and Toxic Substances, EPA

11:45 AM
Public Comments
Dr. Christopher Wilkinson, Ph.D. representing American Crop Protection Association

12:30 PM LUNCH

1:30 PM
Public Comments (continued)

2:00 PM Panel Discussion
Issue 1. Selection and Performance of Dose-Response Model

The Office of Pesticide Programs (OPP) used probit transformation to determine the relative potencies of organophosphorus pesticides in a pilot analysis presented to the FIFRA Scientific Advisory Panel (SAP) in September 2000. The SAP recommended that OPP reconsider the model selection and specifically suggested Michaelis-Menton kinetics or the exponential model as alternative methods. Both models were considered by OPP. The exponential model was selected over Michaelis-Menton kinetics because the exponential model provided a better fit of the available cholinesterase data.

An iterative approach was used to fit the cholinesterase data to the exponential function. This iterative approach included setting the y-asymptote to zero followed by sequentially dropping high doses until adequate model fit was achieved (p => 0.05) or only three dose groups remained. A total of 1312 individual cholinesterase data sets from oral toxicity studies were modeled. Although the toxicology studies used were not designed for purposes of dose response modeling, OPP concluded that the estimates derived from the exponential function were sufficient to determine relative potency of the organophosphorus pesticides.

Question 1.1
Does the revised dose-response approach to modeling the cholinesterase data address the SAP recommendations from the September 2000 meeting?
Discussants: Drs. Hattis, Conolly, MacDonald and Pope


Question 1.2
Is there a strong basis for considering an alternative model that would be more appropriate for the cholinesterase data on organophosphorus pesticides and could plausibly yield substantially different relative potency values compared to the exponential model recommended by the September 2000 SAP?
Discussants: Drs. Hattis, Conolly, MacDonald and Pope


3:30 PM BREAK
Question 1.3
Please comment on the performance of the exponential model and the model fitting procedure. Are the strengths of the approach, as well as the defaults and assumptions for the parameters of the model clearly articulated in the document?
Discussants: Drs. Hattis, MacDonald, Durkin and Conolly

(continue panel discussion of questions if time allows)

5:30 Adjournment


THURSDAY, SEPTEMBER 6, 2001
SHERATON CRYSTAL CITY HOTEL
1800 JEFFERSON DAVIS HIGHWAY
ARLINGTON, VIRGINIA 22202
703-486-1111

8:30 AM
Introduction of Panel members - Ronald J. Kendall, Ph.D (Chair, FIFRA SAP)

8:45 AM
Administrative procedures by Designated Federal Official - Mr. Larry Dorsey
( Executive Secretary, FIFRA SAP)

Issue 2. Combining Cholinesterase Data from Multiple Data sets to Derive Relative Potency and Benchmark Dose Estimates

The current dose-response approach used a hierarchical statistical model to combine estimates of potency for the oral cholinesterase data (average absolute potency values) for each organophosphorus pesticide. This approach was also used to combine estimates of benchmark dose for the oral, dermal, and inhalation studies on cholinesterase (i.e., average BMD10s for the index chemical). There are several advantages of combining estimates from multiple datasets compared to using estimates derived from single datasets/points. Combining data increases the precision of estimates, incorporates the variability among data sets into the overall estimate of uncertainty (standard errors or confidence limits), and maximizes the use of the available information.

Question 2.1 Please comment on the present method for combining data to derive estimates of absolute potency for each OP and to derive benchmark dose estimates for the index chemical. Does the document sufficiently describe the methodology used in combining estimates?
Discussants: Drs. Pope, Roberts, Wallace and Portier

Issue 3. Approach for Selection of the Index Chemical

The September 2000 SAP recommended the careful selection of an index chemical with "the best and most complete data for the common endpoint(s)" to minimize the uncertainties in the estimation of cumulative risk. Methamidophos was selected as the index chemical following a comprehensive and systematic review of data availability and data quality on all 25 chemicals.

Question 3.1
Does the document adequately describe the rationale for selection of the index chemical? Should any additional factors be included in the rationale for the selection of methamidophos as the index chemical?
Discussants: Drs. Pope, Roberts, Wallace, and McConnell

Issue 4. Use of Steady State Cholinesterase Data for Estimating Both the Relative Potency and the Points of Departure

There are several key general principles for conducting a cumulative risk assessment (EPA 2000 Draft, "Proposed Guidance on Cumulative Risk Assessment of Pesticide Chemicals that Have a Common Mechanism of Toxicity"). One such principle concerns the time frame of both the exposure (e.g., What is the exposure duration?) and of the toxic effect (e.g., What are the time to peak effects and the time to recovery?). Both must be adequately defined prior to performing a cumulative risk assessment so that an individual's exposure is matched with relevant toxicological values in terms of duration. In the case of organophosphorus pesticides, potential human exposure may occur through food, drinking water, or from residential/nonoccupational uses of these pesticides. Thus, there will be short-term exposures to organophosphorus pesticides observed as peak exposures via food, residential/nonoccupational uses, and drinking water, as well as continuous exposure via food consumption. There are several important considerations with respect to the temporal characteristics of the cholinesterase inhibitory effects of organophosphorus pesticides in estimating their relative toxic potencies and in estimating the point of departures for the index compound.

Relative Toxic Potency: OPP has elected to use data reflecting steady state in the interest of producing relative potency factors (RPFs) that are reproducible and reflect less uncertainty due to rapidly changing, time-sensitive measures of cholinesterase. Also, when the compounds are at steady state, in principle, the differences in toxicokinetics among the OPs are less likely to impact the assessment. On average, the inhibitory effects of OPs on cholinesterase activity reaches steady state by approximately 30 days. Therefore, this analysis focused on studies of a duration of 21 days or greater in order to use cholinesterase data that attained steady state so that stable estimates of relative inhibitory capacity (i.e., relative potency) could be calculated among these compounds.

Point of Departure for Index Compound: Cholinesterase data that had attained steady state was also used to estimate the point of departure (i.e., the BMD10) for the index chemical (methamidophos). Thus, OPP has also elected to use steady state cholinesterase data to estimate the cumulative risk associated with different time periods ranging from a single day up to several months. Although toxicology studies of = > 21 days in duration do not directly reflect the time frame of interest (approximately one day exposures that might occur particularly with residential or drinking water exposures), there are reasons why steady state data are preferred over acute toxicity data for estimating the point of departures for the cumulative risk assessment.

First, recovery from the effects of exposure to organophosphorus pesticides generally ranges from several days to several weeks depending on the dose. Thus, although the exposure may be acute, the cholinesterase-inhibiting effects may persist. Secondly, the exposure scenarios are very complex in the OP cumulative exposure assessment, and there may not be a true acute exposure to these chemicals. Although there may be peaks of exposure via food, drinking water and residential/nonoccupational, there is some evidence that a relatively constant baseline of exposure to organophosphorus pesticides may occur. For example, the effects of one day exposures via food to one or more OPs may be extended by several days or weeks due to a home use or an episodic exposure in drinking water of other OPs. Although steady state data may not precisely reflect the one day exposure situations in the cumulative risk assessment of OPs, the use of steady state information to estimate the point of departure(s) for extrapolating human risk is viewed as a reasonable approach to approximate the complex multi-chemical exposure situations that involve the overlapping of different pathways (food, drinking water, residential/nonoccupational) having different exposure durations.

Question 4.1 Please comment on the use of steady state cholinesterase data to determine the relative potency of the organophosphorus pesticides.
Discussants: Drs. Hattis, Conolly, McConnell, Durkin and Reed

Question 4.2 Please comment on the use of steady state cholinesterase data to estimate the point of departures for extrapolating human cumulative risk.
Discussants: Drs. Durkin, Wallace, Conolly and Portier

Adjournment

Please be advised that agenda times are approximate. For further information, please contact the Designated Federal Official for this meeting, Mr. Paul Lewis, via telephone: (703) 305-5369; fax: (703) 605-0656; or email:lewis.paul@epa.gov.

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