FIFRA Scientific Advisory Panel (SAP) February Meeting Agenda

January 31, 2002

OPEN MEETING
FEBRUARY 5-8, 2002
FIFRA SAP WEB SITE https://www.epa.gov/oscpmont/sap/
OPP Docket Telephone: (703)305-5805

TUESDAY, FEBRUARY 5, 2002
SHERATON CRYSTAL CITY HOTEL
1800 JEFFERSON DAVIS HIGHWAY
ARLINGTON, VIRGINIA 22202
703-486-1111

METHODS USED TO CONDUCT A PRELIMINARY CUMULATIVE RISK ASSESSMENT FOR ORGANOPHOSPHATE PESTICIDES

8:30 AM Introduction and identification of Panel members - Ronald J. Kendall, Ph.D. (FIFRA SAP Session Chair)
8:45 AM Administrative procedures by Designated Federal Official - Mr. Paul Lewis
8:50 AM Welcome - Mr. Stephen L. Johnson, Assistant Administrator, Office of Prevention, Pesticides and Toxic Substances, EPA
9:00 AM Opening Remarks - Ms. Marcia E. Mulkey Director (Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, EPA)
9:10 AM Introduction, goals and objectives - Ms. Margaret Stasikowski (Office of Pesticide Programs, EPA)
9:45 AM Public Comments Jennifer Sass, Ph.D., on behalf of the Natural Resources Defense Council
Mr. Daniel Botts, Florida Fruit & Vegetable Association, on behalf of the FQPA Implementation Working Group
Mr. Jeffrey Driver, Infoscientific.com, Inc., on behalf of the FQPA Implementation Working Group
Mr. Jack Zabik, Dow AgroSciences, on behalf of the FQPA Implementation Working Group
Mr. Adam Goldberg, on behalf of Consumers Union
10:30 AM BREAK
10:45 AM Public Comments (continued)
12:30 PM LUNCH
SESSION 1: HAZARD AND DOSE RESPONSE ANALYSIS
1:30 PM Hazard/relative potency factor - Anna B. Lowit, Ph.D (Office of Pesticide Programs, EPA), R. Woodrow Setzer, Ph.D. (Office of Research and Development, EPA) and Vicki Dellarco, Ph.D. (Office of Pesticide Programs, EPA)
3:00 PM BREAK
3:15 PM Public Comments Mr. Tim Pastoor, Syngenta Corporation, on behalf of the FQPA Implementation Working Group
4:00 PM Panel discussion
1. A) In September 2001, the FIFRA SAP made some specific recommendations to EPA concerning refinements of its dose response analysis of cholinesterase data on OPs such as:
- the derivation of the adjustment factor "B" and modification of the decision tree for use of "B";
- a formal analysis of residuals;
- minor revision to the agency's OPCumRisk program (i.e., revision of the calculation as of the goodness of fit statistic and deletion on p- and t-values);
- consideration of the appropriate measure of relative potency;
- expression of inhalation exposure in the same units as the oral doses and adjustment for actual treatment durations;
- consideration of the impact of individual animal data instead of summary information;
- and derivation of oral doses from the actual dietary intake rates.
Please comment on how the Agency addressed the recommendations listed above (I.B and III.B.3). Lead Discussant: Stephen Brimijoin, Ph.D. Associate Discussants: Patrick Durkin, Ph.D., Rory Conolly, Ph.D. and Eugene McConnell, D.V.M.
B) Several of these issues were addressed by the application of the nonlinear mixed effect model for combining cholinesterase data. In addition, EPA utilized the profile likelihood method for estimating horizontal asymptotes when they could not be estimated jointly with the other parameters. Please comment on the use of these statistical procedures in the dose-response assessment of the organophosphate pesticides.

Lead Discussant: Steven Heeringa, Ph.D. Associate Discussants: Christopher Portier, Ph.D., Peter Macdonald, D. Phil, and Lauren Zeise, Ph.D.
5:30 PM ADJOURNMENT
WEDNESDAY, FEBRUARY 6, 2002
SHERATON CRYSTAL CITY HOTEL
1800 JEFFERSON DAVIS HIGHWAY
ARLINGTON, VIRGINIA 22202
703-486-1111

METHODS USED TO CONDUCT A PRELIMINARY CUMULATIVE RISK ASSESSMENT FOR ORGANOPHOSPHATE PESTICIDES (CONTINUED)

SESSION 1: HAZARD AND DOSE RESPONSE ANALYSIS (continued)
8:30 AM Introduction and identification of new Panel members - Ronald J. Kendall, Ph.D. (FIFRA SAP Session Chair)
8:45 AM Administrative procedures by Designated Federal Official - Mr. Paul Lewis
8:50 AM Follow-up from previous day's discussion - Randolph Perfetti, Ph.D. (Office of Pesticide Programs, EPA)
9:00 AM Panel discussion (continued)
2. An exponential model was utilized by EPA in the July, 2001 Preliminary Hazard and Dose-Response Assessment of the Organophosphate Pesticides. Based on the equation used in the July 2001 document, cholinesterase activity decreases linearly in the low dose region of the dose response curve. Stakeholders present at the Technical Briefing (August 2001) and also a few members of the SAP (September 2001) suggested that a flat low dose region may be a more appropriate modeling approach. In response to this issue, EPA has further investigated the shape of the low dose region of the dose-response curve. Two versions of the exponential model were used in the December 2001 hazard and dose-response assessment. One version, called the basic model, describes a linear low dose region and is similar to the approach used in the July 2001 document. All 29 OPs were fit to the basic model. The second version, called the expanded model, incorporates two additional variables, shape and displacement, which describe a flat low dose region of the dose-response curve. The female brain ChE data supported a flat low dose region for eight OPs (azinphos methyl, bensulide, disulfoton, malathion, methyl parathion, phorate, phosmet, and terbufos).

Please comment on the mathematical derivation of the expanded model in addition to the profile likelihood method for estimating the shape and displacement parameters when they could not be estimated jointly with the other parameters (I.B and III.B.1).

Lead Discussant: Peter Macdonald, D. Phil Associate Discussants: Jean Harry, Ph.D., Lorenz Rhomberg, Ph.D. Rory Conolly, Ph.D. and Patrick Durkin, Ph.D.
10:00 AM BREAK SESSION 2: ASSESSMENT OF FOOD EXPOSURE
10:15 AM Assessment of food exposure - William O. Smith, Ph.D. and Mr. David Miller (Office of Pesticide Programs, EPA)
11:45 AM LUNCH
12:45 PM Public Comments Ms. Ingrid Kelley, Bayer Corporation, on behalf of the FQPA Implementation Working Group
1:30 PM Panel discussion
1. In the Preliminary OP Cumulative Risk Assessment, OPP used all available PDP monitoring data generated since 1994 as the basis for the residue distributions of pesticides in treated foods. As a result, some foods have multiple years of data (as many as 5), while others have only a single year of data. All years of data were included to provide the most robust residue data set possible. These data were extended to cover foods and processed forms of foods for which data are not directly available. Additionally, some foods were included in the analysis based on less robust data from FDA.

OPP is conducting a sensitivity analysis in which the residue contributions from specific foods (either one at a time or in combination with other foods) are removed from the analysis. This analysis is being conducted as part of an effort to determine the contributions of specific food commodities and chemicals to the upper tail of the exposure distribution. Some preliminary results are shown in Table 1 of the addendum to this document.

Partly as a result of this exercise, OPP has observed that the more variables (e.g., commodities, chemicals, years of data) that are included in the exposure distribution, the more difficult it becomes to affect the tail of the distribution by removing commodity/pesticide combinations from the calculations. While removal of most exposure contributors results in a demonstrable change in the lower portion of the distribution, the exposures at the upper end of the tail (for example the 99.9^th percentile) are relatively unaffected by removal of a single commodity, even if it is identified by DEEM as a frequent contributor to the high end of the exposure distribution.

Please discuss the significance of this observation and its potential impact on interpretation of the output distributions and results from highly complex distributional analyses such as the Preliminary OP Cumulative Risk Assessment.

Lead Discussant: Steven Heeringa, Ph.D., Associate Discussants: Ruby Reed, Ph.D. , Rory Conolly, Ph.D. and Lauren Zeise, Ph.D.

2. A) The Calendex model can be used in a number of modes to develop a profile of exposure estimates. In the current assessment, OPP conducted a series of single-day assessments arrayed chronologically to develop a response surface of exposures. A constant percentile of exposure was selected to represent the potential exposure to a given percentile of the population. For example, the 99^th percentile for each day would be arrayed for 365 days to reflect the population estimate across the calendar year. Calendex can also be used in a multi-day sequential series analysis, also referred to as a "rolling time frame mode." A rolling time frame provides an estimate of the average of daily exposures for an individual calculated over multiple (7, 14, 21, or 28) days, for each multiple day period over the course of a year, (e.g., days 1 - 7, then days 2 - 8, then days 3 - 9, etc.). In this mode, an individual's food exposure is tracked across the calendar year by randomly selecting day one or day two of that individual's reported consumption from the CSFII and combining each commodity which comprises that consumption with randomly selected residue values for each day of the calendar year. These rolling averages for each individual are assembled to develop a distribution of rolling average exposures.

During previous SAP meetings, the Panel has expressed concern about the use of CSFII records to represent longitudinal consumption patterns for individuals. Concern arose as a result of the design of the CSFII study, in which two nonconsecutive days of data (separated by 3 to 10 days) were collected for each individual.

Please comment on the use of CSFII data to support each of these two modes of Calendex as they pertain to the cumulative risk assessment of pesticides in foods.

Lead Discussant: Peter Macdonald, D. Phil Associate Discussants: Natalie Freeman, Ph.D. Ruby Reed, Ph.D. and Steven Heeringa, Ph.D.

B) The random selection of PDP residue values assumes that the residues in foods consumed across a series of days are independent of each other. In other words, foods consumed are from unrelated sources and there is no carryover from one day to another. This assumption may be inappropriate given that many consumers obtain food in bulk (i.e., multi-day) quantities that may have similar treatment history and would typically consume this food over a short multi-day period (e.g., leftovers). In such a case the residues contained in the foods would violate the assumption of independence.

Please comment on the use of PDP data to support each of these two modes of Calendex as they pertain to the cumulative risk assessment of pesticides in foods. What issues are likely to accrue from the assumption of independence in residue data?

Lead Discussant: Ruby Reed, Ph.D. Associate Discussants: Steven Heeringa, Ph.D., Peter Macdonald, D. Phil and Lauren Zeise, Ph.D.
3:15 PM BREAK
SESSION 3: ASSESSMENT OF DRINKING WATER EXPOSURE
3:30 PM Assessment of drinking water exposure - Mr. Kevin Costello (Office of Pesticide Programs, EPA) and Mr. Nelson Thurman (Office of Pesticide Programs, EPA)
4:30 PM Public Comments Mr. Ray Layton, Du Pont, on behalf of the FQPA Implementation Working Group
5:15 PM ADJOURNMENT
THURSDAY, FEBRUARY 7, 2002
SHERATON CRYSTAL CITY HOTEL
1800 JEFFERSON DAVIS HIGHWAY
ARLINGTON, VIRGINIA 22202
703-486-1111

METHODS USED TO CONDUCT A PRELIMINARY CUMULATIVE RISK ASSESSMENT FOR ORGANOPHOSPHATE PESTICIDES (CONTINUED)

SESSION 3: ASSESSMENT OF DRINKING WATER EXPOSURE (continued)
8:30 AM Introduction and identification of new Panel members - Ronald J. Kendall, Ph.D. (FIFRA SAP Session Chair)
8:45 AM Administrative procedures by Designated Federal Official - Ms. Olga Odiott
8:50 AM Follow-up from previous day's discussion - Randolph Perfetti, Ph.D. (Office of Pesticide Programs, EPA)
9:00 AM Panel discussion
1. After evaluation of available monitoring data and consideration of the available tools for estimating pesticide exposure in drinking water, the agency adapted available tools to provide watershed-level estimates of residues in drinking water sources. These tools have been presented to the SAP in the past in relation to individual chemical assessments and have been improved as a result of panel feedback. Because of differences between individual and cumulative assessments, this assessment reflects novel uses for some of these tools. The approach used in the Preliminary OP Cumulative Risk Assessment:
- Used PRZM/EXAMS with the Index Reservoir, along with local site characteristics to estimate concentrations in the drinking water reservoir
- Simulated multiple OP uses on multiple fields within that watershed
- Adjusted for area within the watershed that potentially contributed OP loads to the reservoir using a cumulative adjustment factor
- Provided a qualitative, rather than quantitative, assessment of treatment effects on residues
Are there significant flaws in this approach and its assumptions that would be likely to lead to consistent significant underestimation of daily levels of residues in surface water across the calendar year (for instance, an order of magnitude)? If such flaws exist, what can be done to correct them? What additional information and/or tools might be available that will meet the goals/needs of the cumulative OP assessment?

Lead Discussant: Paul Capel, Ph.D. Associate Discussants: Bernard Engel, Ph.D., Peter Richards, Ph.D. and Richard Bull, Ph.D.

2. It is not feasible to conduct drinking water assessments for every watershed in which OP pesticides are used. Therefore, regional water exposure assessments were used to represent exposures from typical OP usage conditions at one of the more vulnerable surface watersheds in the region. Each regional assessment focuses on areas where combined OP exposure is likely to be among the highest within the region as a result of total OP usage and vulnerability of the drinking water sources. In this manner, OPP is confident that if the regional cumulative risk assessment finds that exposure in water is not a significant contributor to the overall OP exposure in that area, it will not be a significant contributor in other areas in the region.

Does the SAP see anything that would call this assumption into question? If the regional approach, with its assumptions is inadequate, what can be done to improve the approach?

Lead Discussant: Peter Richards, Ph.D. Associate Discussants: Richard Bull, Ph.D., Bernard Engel, Ph.D. and Paul Capel, Ph.D.
10:30 AM BREAK SESSION 4: ASSESSMENT OF RESIDENTIAL/NON-OCCUPATIONAL EXPOSURE
10:45 AM Assessment of residential/non-occupational exposure - Mr. Jeff Evans (Office of Pesticide Programs, EPA)
11:30 AM Public Comments Jeffrey Driver, Infoscientific.com, on behalf of the FQPA Implementation Working Group
12:15 PM LUNCH
1:15 PM Panel discussion
1. Historically, the Agency has relied on means (primarily arithmetic or geometric) from residue and exposure studies for key input variables in exposure assessments. The recent development of calendar based models and others having features to incorporate distributions of exposure values has presented the Agency an opportunity to consider using all available data points from existing exposure and residue studies. In the Cumulative Risk Assessment Case study presented to the FIFRA Scientific Advisory Panel in September, 2000, most of the exposure variables were presented as uniform distributions. The exceptions were for variables that are reasonably well established , such as exposure durations taken from the Agency's Exposure Factors Handbook. The data used in the Case Study and in the preliminary CRA, are believed to be from well conducted studies of generally high quality. However, these data sets tend to be small (e.g., n = 10 - 30) and are being used to address wide variety of exposure situations. The uniform distribution appears to be most appropriate for these relatively small data sets because it relies on easily established values such as the minimum and maximum and provides the most conservative estimate of the standard deviation (riskanalal@lyris.pnl.gov).

Does the Panel have any additional comments or thoughts on OPP's use of the uniform distribution in general or on OPP's selection of the uniform distribution for the specific parameters chosen? What criteria, if any, would the SAP recommend for developing parametric input distributions from available data? Under what circumstances, if any, would it be appropriate to use available data empirically? Does the Panel have any recommendations on how sensitivity analyses could be performed to determine if the assumption of a uniform distribution is responsible for a majority of the risk at the tails of the exposure distribution.

Lead Discussant: John Adgate, Ph.D. Associate Discussants: Natalie Freeman, Ph.D., Dale Hattis, Ph.D., and Richard Bull, Ph.D.

2. The use of calendar based models also allows exposure assessors to consider exposure from a variety of sources from the same or from different chemicals. Longitudinal survey data such as the National Human Activity Pattern Survey (NHAPS) are available for consideration by HED for use in future assessments. In addition, from a practical standpoint, the use of such survey data ensures combinations of exposure do not come from unrealistic random combinations that current models may produce (e.g., activities adding up more than 24 hours in a day).

The use of calendar based models provides an opportunity to explore the potential for the co-occurrence of multiple sources of exposures from residential pathways. In the cumulative assessment, OPP used summary statistics from sources such as the Exposure Factors Handbook (EFH) regarding the time spent indoors, time spent on lawns and time spent at other outdoor locations. In the preliminary assessment, we assumed these activities were stochastically independent. OPP is currently evaluating data in the EFH such as data from the National Human Activity Pattern Survey (NHAPS) to determine if it can directly incorporate (i.e., empirically) information on an individual's activity patterns over a full day from this database to account for the likelihood and duration that an individual might be exposed to a pesticide through various activities over the course of a day. Please comment on whether and how OPP might directly incorporate NHAPS (or similar time use data) into the software to better account for variation in activities across individuals?

Lead Discussant: Natalie Freeman, Ph.D. Associate Discussants: John Adgate, Ph.D. , Dale Hattis, Ph.D., Ruby Reed, Ph.D. and Patrick Durkin, Ph.D.
2:45 PM BREAK
SESSION 5: RISK CHARACTERIZATION
3:00 PM Risk characterization - Mr. David Miller and Elizabeth Doyle, Ph.D. (Office of Pesticide Programs, EPA)
4:00 PM Public Comments Mr. Jack Zabik, Dow AgroSciences, on behalf of the FQPA Implementation Working Group
5:00 PM ADJOURNMENT
FRIDAY, FEBRUARY 8, 2002 SHERATON CRYSTAL CITY HOTEL 1800 JEFFERSON DAVIS HIGHWAY ARLINGTON, VIRGINIA 22202 703-486-1111

METHODS USED TO CONDUCT A PRELIMINARY CUMULATIVE RISK ASSESSMENT FOR ORGANOPHOSPHATE PESTICIDES (CONTINUED)

SESSION 5: RISK CHARACTERIZATION (continued)
8:30 AM Introduction - Stephen Roberts, Ph.D. (FIFRA SAP Session Chair)
8:45 AM Administrative procedures by Designated Federal Official - Ms. Olga Odiott
8:50 AM Follow-up from previous day's discussion - Randolph Perfetti, Ph.D. (Office of Pesticide Programs, EPA)
9:00 AM Panel discussion
1. There are several key principles for conducting a cumulative risk assessment. 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 characterized prior to performing a cumulative risk assessment so that an individual's exposure is matched with relevant toxicological values in terms of duration. There are several important considerations with respect to the temporal characteristics of the exposures and of the cholinesterase inhibitory effects of organophosphorus pesticides in estimating their cumulative risk.
There may be single day (spike) or short-term exposures to organophosphorus pesticides via food, nonoccupational/residential uses, and drinking water, as well as more or less continuous exposure via the diet (food).
In the Preliminary OP Cumulative Risk Assessment, OPP used relative potency factors and points of departure developed from cholinesterase inhibition in rats exposed to pesticides for 21 days or more. This practice was adopted to reflect cholinesterase inhibition at a point in the treatment schedule at which a steady state had been achieved. OPP elected to use data reflecting a 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. In addition, when the compounds are at steady state, the differences in toxicokinetics among the OPs are less likely to impact the assessment.
OPP has information that indicates that the American population, in general, has some continuous level of exposure to OPs. Biomonitoring data from NHANES suggests that more than 80% of the American public have urinary metabolites indicating possible exposure to OPs.
Most animal data available to OPP are developed using laboratory animals that were not previously exposed to OPs. In other words, the laboratory animals used in the toxicology studies were naive in their exposure to OPs. These studies show that OP's can produce cholinesterase inhibition after a single exposure. A rough comparison of the BMD₁₀s derived from female brain rat cholinesterase data from 21 days or longer duration with NOAELs based on cholinesterase data from single-dose studies reveals good similarity of values, with differences rarely exceeding two- to three-fold.
Animal data suggest that recovery from a single exposure may take days to weeks.
In light of all these factors, OPP wants to evaluate exposure across the most appropriate time frame(s). In the Preliminary OP Cumulative Risk Assessment, OPP developed a distribution of single consecutive day exposures, considering the pattern of MOEs occurring at a particular percentile of exposure across the calendar year. This approach focuses on exposure to the population of interest as a whole rather than attempting to track the variation in an individual's exposure from various sources of pesticide exposure. As an example, at the 95^th percentile of exposure, each day of the year will reflect a 95th percentile exposure for the entire population and not reflect what may be lower, multi-day average exposures for any given individual.

Calendex allows calculation of multi-day, rolling averages of exposure estimates for the individuals within the population. While this may allow for a match between selected exposure time frames (e.g., 7 day or longer) and the hazard endpoint, OPP is concerned that this may not adequately permit estimates of risk associated with shorter duration exposures.

Please comment on how best to evaluate risk, taking into account the temporal characteristics of the hazard endpoint (i.e., cholinesterase inhibition) and the temporal characteristics of the exposure patterns for the food, drinking water, and residential/nonoccupational pathways, with specific reference to:
the pros and cons of various approaches of combining the exposure and hazard time frames to estimate cumulative risk, and
methods to bound or estimate the biases in each approach. Lead Discussant: Lorenz Rhomberg, Ph.D. Associate Discussants: Stephen Brimijoin, Ph.D., Peter Richards, Ph.D. Ruby Reed, Ph.D. Dale Hattis, Ph.D. Natalie Freeman, Ph.D. and Steven Heeringa, Ph.D. and Patrick Durkin, Ph.D.
2. In the Preliminary OP Cumulative Risk Assessment, Section I.H lists a number of potential follow-up activities proposed by OPP. This list is not exhaustive. Does the Panel recommend any additional follow-up activities or sensitivity analyses beyond those listed? Does the Panel have any thoughts or recommendations about how these additional analyses should be conducted? Which activities should receive the greatest priority?

Lead Discussant: Dale Hattis, Ph.D. Associate Discussants: Lorenz Rhomberg, Ph.D., Rory Conolly, Ph.D., Eugene McConnell, D.V.M., Patrick Durkin, Ph.D., Peter Macdonald, D. Phil, Jean Harry, Ph.D. and John Adgate, Ph.D.
12:00 PM 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: (202) 564-8450; fax: (202) 564-8382; or email:lewis.paul@epa.gov.

FIFRA Scientific Advisory Panel (SAP) February Meeting Agenda

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