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September 9-10, 1997 Meeting Status Report

The Office of Pesticide Program's Update on the
Food Quality Protection Act (FQPA) Activities To Date

Presented By

Stephanie R. Irene, Ph.D.
Associate Director
Health Effects Division

September 9th, 1997

Good morning Dr. McConnell and members of the Scientific Advisory Panel (SAP). I would like to introduce my coworkers, Dr. Elizabeth Doyle and Ms. Susan Makris. I am pleased to have the opportunity to address you this morning and bring you up to date on all of the activities which have been underway in our program to assist us in full implementation of the Food Quality Protection Act (FQPA). These topics include the areas of special sensitivity of infants and children exposed to pesticides and the progress made on the common mechanism of toxicity, aggregate exposure and cumulative risk. I will give you an overview of these activities and Dr. Doyle and Ms. Makris are here to answer any detailed questions you may have on these subjects.

My first topic will address the additional tenfold uncertainty factor for infants and children. As you know, the Food Quality Protection Act of August 3, 1996 requires that, in the case of threshold effects, and additional tenfold margin of safety for the pesticide residue an other sources of exposure shall be applied for infants and children to take into account the potential pre- and post- natal toxicity and the completeness of the data with respect to exposure and toxicity. The Agency may use different margin of safety for the pesticide only if reliable data indicate that such a margin will be safe for infants and children.

In October of 1996, the agency presented to the panel the approach that would be taken to determine whether or not the additional ten fold uncertainty factor as required by FQPA should consistently be retained on every chemical evaluated unless reliable data support using a different factor. The SAP agreed with the Agency position that a ten fold uncertainty actor for toxicity should not be applied in every case, but that each pesticide need to be evaluated on a case by case basis, focusing on the available database and using a weight of evidence approach for each uncertainty factor decision. Therefore, in response to the requirements of the law and the recommendations of the SAP, the Office of Pesticide programs (OPP) uses a two step process when developing a Reference Dose (RfD) for chronic dietary risk or a Margin of Exposure (MOE) for acute dietary risk. First we start with the presumption that the 10X FQPA factor is automatically applied and then, based on the analysis of individual toxicology studies, the integration of the results of all the toxicology studies within and across species, and sound scientific judgment, the 10X FQPA factor may be retained, it may be determined to be lower tan 10 or it may be removed if such is deemed appropriate.

A review of chemicals that have been peer reviewed within the Health Effects Division (HED) from November 1, 1996 through September 3, 1997 indicates that additional uncertainty factors for the protection of infants and children are being retained when the weight of the evidence indicates that there is uncertainty concerning the hazard for this population subgroup the following information was noted:

In the remaining 12 cases, the HED peer review committee evaluated the effects observed across studies and the completeness of the toxicology data bases, and the committee determined that an additional uncertainty factor of 10X be retained in 7 cases, the additional uncertainty factor of 3X be retained in 4 of the cases and, in one case, it was appropriate to retain only a 2X. These factors were all in addition to the standard 10X for inter- and 10X for intra- species variations. Some of the reasons for the retention of the additional FQPA factor are:

  1. In the 7 cases where the 10X was retained, the HED review committee was unable to rule out the lack of enhanced pre- or post- natal sensitivity from the studies submitted and/or the severity of effects and steepness of the dose response curves led to concern.
  2. In the 4 cases where the 3X factor was retained, the reason focused on the absence or the rejection of a required study. However, after evaluation of the rest of the database with special emphasis on the reproductive and developmental studies enhanced sensitivity of infants and children did not appear to be an issue. Thus, a 3X uncertainty factor was deemed adequate.
  3. The one chemical which retained a 2X factor did so only for added protection because it was the active isomer of a currently registered chemical. The currently registered chemical from which this isomer was isolated did not have missing data, and the totality of the toxicology database did not indicate enhanced sensitivity of infants and children.

In our efforts to further the advancement of scientific knowledge in the area of special sensitivities of infants and children in comparison to other populations, the Office of Pesticide Programs continues to provide support for the development and execution of a research program to address age related differences in susceptibility to pesticide chemicals. Until such time the program is fully established and the research is completed, the program has been using the above approach for hazard assessment to meet the mandates of the FQPA in this area.

The next update I would like to summarize is the revision of the guidelines for prenatal developmental toxicity and multi generation reproductive toxicity testing which has been an on-going process that was initiated in approximately 1991. In addition to meeting goals of interagency and international guideline harmonization, the intent of these revisions has been to increase the sensitivity of guideline studies in the detection of developmental and reproductive effects. The guideline revisions thereby meet many of the recommendations of the NAS Report on Pesticide in the Diets of Infants and Children, they enhance evaluation of endocrine-mediated effects and they provide additional hazard evaluation for susceptible populations, as required by the Food Quality Protection Act. Proposed revisions to these guidelines were presented to the SAP in 1993 and again in 1996. Comments from the Panel as well as input from the regulated community, have been invaluable in the process. Following the most recent (1996) SAP review of these guidelines and based upon recommendations received, changes were made to the two-generation reproduction study guideline that are believed to create a more manageable study protocol. These included revising numbers of animals required for postmortem examinations, adding triggers for ovarian primordial follicle counts, and revising weanling histopathological examination to include only treatment-related abnormalities noted at macroscopic examination,if appropriate and if such examination would contribute to the study interpretation. No changes to the prenatal developmental toxicity study were deemed necessary at this time. Since these revised guidelines were submitted as part of a package published in the Federal Register for an Office of Pollution Prevention and Toxic Substances (OPPTS) rulemaking, they will be finalized and published when the responses to comments on the OPPTS Rule are completed. It is anticipated the this will occur in the near future. In addition to all of the individual guideline development and revisions that have occurred over the past several years, the agency recognizes that there is a need to analyze and evaluate the current data requirements for pesticide registration in the Code of Federal Regulations part 158 for both hazard and exposure. This analysis and evaluation may lead to future changes in the overall data requirements.

The next topic to address is the development of criteria for determining when it would be appropriate to require in utero carcinogenicity testing. Pursuing the recommendations of the 1993 NAS Report on Pesticides in the Diets of Infants and Children and in response to the requirements of the 1996 Food Quality Protection Act, OPP scientists analyzed available data to determined the need for adding a perinatal component to standard carcinogenicity testing protocols. The results and conclusions of this analysis were presented to the SAP in October, 1996. In essence, OPP concluded that currently available data do not support the routine requirement of perinatal carcinogenicity testing in lieu of the standard carcinogenesis bioassay. OPP proposed to assess the need for a perinatal carcinogenicity study on a case-by-case basis. The SAP agreed with these conclusions an further stated that there is no convincing evidence that perinatal testing would necessarily increase the sensitivity of the standard carcinogenesis assay. It was, however, recommended the agency flesh out a list of factors the cold be used to determine the need for perinatal carcinogenicity testing of certain pesticides. Since the time, OPP scientists have developed these criteria and a weight-of-the-evidence approach to determining the need for such a study, and a proposed policy will be presented to the Panel this morning by Ms. Makris.

Now I would like to provide you with an update on how we are progressing with the activities underway in regard to the common mechanism of toxicity. OPP has reconstituted the Common Mechanism of Toxicity Workgroup to complete the development of a policy document for implementation of this portion of the FQPA. (1) This workgroup will incorporate the recommendations of the March SAP which were: to develop two or three case studies using non-cancer endpoints; (2) to expand on the language in the concept paper and to develop it more fully into a guidance document; and (3) to provide references, where possible, for statements in the document. The structure-activity tool ISIS has been installed in some division computers and selected staff have begun to work with it. We will continue to have additional staff trained in the use of this tool.

Next, since the Agency has made the commitment to reassess the tolerance of the organophosphate pesticides by August 3, 1999, the program sought the assistance of the International Life Sciences Institute/Risk Science Institute (ILSI/RSI) to convene a workgroup to evaluate the potential groupings of these insecticides based upon a common mechanism of toxicity. Three workgroup meetings have been conducted with 15 scientists representing academia, industry and the EPA. The workgroup considered such questions and issues as: what constitutes a common mechanism of toxicity; what general principles could be developed to assess whether two mor more chemicals induce toxicity by the same mechanism of action; and whether the process used for assessing the common mechanism question for OPS can be applied to other chemicals as well, etc. A draft report was prepared by the working group and a workshop is planned for late October to present the issues that were considered, to present the generic common mechanism of toxicity principles developed, to discuss how the workgroup reacher its conclusions and to discuss the paper which the workgroup developed. Comments from the workshop will be evaluated and incorporated into a final document, as appropriate, which will then be published in a scientific journal. ILSI will also coordinate a similar evaluation for the mechanism of toxicity of the carbamate insecticides beginning in early 1998.

Finally, a Common Mechanism of toxicity and Science assessment committee has been established to apply the guidance that is being developed by the Common Mechanism of Toxicity Workgroup. This committee is intended to help ensure that the guidance is applied uniformly and consistently across OPP. The committee is currently reviewing mechanistic data submitted for single chemicals in preparation for the impending simultaneous review of data from multiple chemicals.

In concluding this section, summarizing the ongoing activities conducted to select uncertainty factors, to improve toxicity testing guidelines, and to evaluate approaches for common mechanism of toxicity, I would like to report on a project which will assist in the selection of endpoints for organophosphate pesticides. As part of the cooperative agreement with EPA, ILSI/RSI is organizing a working group of scientist with specialized research expertise to identify methods and techniques that can be used to characterize acetylcholinesterase activity in the peripheral nervous system. This effort is a follow up to the conclusions and recommendations made by the SAP at the June 1997 meeting when the OPP policy on cholinesterase inhibition was presented. Human health risk assessments for organophosphate pesticides can currently be based on measures of cholinesterase inhibition in the plasma or red blood cells of test animals or humans, if the latter data are available. These measures are considerations surrogates for the peripheral nervous system. If direct measurement of acetylcholinesterase inhibition in the peripheral nervous system could be achieved, this measurement would allow risk assessment to be based on an adverse effect rather than a surrogate measure of that effect. The workgroup will be discussing such questions as "what peripheral tissues are most representative of the peripheral nervous system; what is the technical feasibility of routinely assaying these tissues and getting consistent results in the same lab and among different laboratories, and other items which pertain to potential difficulties that could be encountered in performing the study as well as the overall experimental design?" The working group will be charged with answering the above questions and developing research recommendations or proposals. Since the June SAP felt it reasonable to use blood cholinesterase measurements on an interim basis awaiting further information on cholinesterase inhibition in the peripheral tissues, it is hoped that generation of these data on the peripheral nervous system will improve risk assessments of organophosphate pesticides, especially where blood cholinesterase measures are the endpoints selected following a weight of the evidence analysis of the entire database of the chemical in question.

Now I would like to move on to the areas of aggregate exposure and drinking water assessments and tell you about the progress we have made and the numerous activities underway to date. The Food Quality Protection Act requires that pesticide risk assessments incorporate aggregate exposure analyses. These analyses must consider multiple routes and sources of exposure, including ingestion of food and drinking water, dermal uptake, and inhalation. An initial approach prepared by OPP was presented for discussion and comment by the SAP at the Marcy 1997 meeting. The SAP made numerous comments and recommendations on the preliminary approach.

In response to its recommendations, a workgroup was established within OPP to develop criteria for the acceptance of probabilistic exposure assessments for future incorporation into aggregate risk assessments. The work group has completed the first draft of a document which is referred to as a Standard Evaluation Procedure (SEP) which describes acceptable data criteria and distribution selection process for dietary and non-dietary assessments. This document will begin internal review for concept and completeness next week. OPP staff are also working with the Agency working group organized through the Risk Assessment forum to ensure that OPP procedure as documented in the SEP will not conflict with those that the Agency develops for probabilistic assessments. OPP has worked in concert with the Pyrethroids Working Group to develop methodology to conduct aggregate exposure assessments for ten pyrethroids facing tolerance expiration in November. This project permitted close interaction between OPP staff and industry representatives to work through the exercise of developing acceptable assumptions and data inputs for inclusion in the aggregate assessments. In addition, this exercise has permitted OPP to develop a number of policies for inclusion in the pending Standard Evaluation Procedure for reviewing probabilistic exposure assessments, as just described above.

OPP has also developed Standard Operating Procedures (SOPs) for the conduct of residential exposure assessments. These SOPs were developed in concert with Cal EPA, Canada and the Office of Research and Development (ORD). They provide of a series of default assumptions that can be used in representative exposure scenarios if chemical specific data are not available. The SOPs are a Tier 1 type of assessment, which can be refined as additional data become available. The default assumptions included in the SOPs are accepted by OPP as reasonable estimates for inclusion in assessments, and their use should result in residential exposure assessments that are generally acceptable to the Agency. These SOPs were used in the discussion with the Pyethroids Working Group to help shape discussions of required exposure scenarios for inclusion in aggregate exposure assessments on the 10 synthetic pyrethroids. These SOPs will be presented for your consideration later this afternoon.

The next complex and important effort was initiated when ILSI/RSI through a cooperative agreement with the EPA Office of Pesticide Programs undertook the organization of a workshop on aggregate exposure methodologies to be held in January 1998. The ILSI has gathered industry, government representatives and members of nonprofit organizations to participate in a workshop to evaluate methodologies currently available and applicable to exposure assessment. The methodologies must integrate multi route, multi source exposures to pesticides.

To date, ILSI has assembled a team of scientist to apply the available exposure assessment models to the problem of aggregate exposure. In conjunction with the Health and Environmental Sciences Institute (HESI) it has been agreed to develop a composite exposure database with multiple sources and multiple potential routes of exposure to use as a case study. The composite database will be blinded such that individual compounds represented in the database will not be identifiable. The composite exposure database will include the following categories of data:

I. Dietary

A. Food

Market basket and or anticipated residue levels
B. Water

Ground (monitoring data)

Surface (Municipal tap survey)

II. Non-Dietary

A. Indoor Residential

Crack and Crevice Treatments



Pet Care


B. Outdoor Residential


In tandem with ILSI's organizational efforts, OP's workgroup has developed a list of some of the desired characteristics of an aggregate exposure assessment methodology. This list has been provided to ILSI, and will be used at a mid-September working group meeting to be held prior to the actual workshop in January 1998. The list is meant to provide direction and guidance to the scientists working on the aggregate exposure assessment methodologies. The criteria and components for an aggregate exposure assessment define, in part, OPP's minimum requirements for developing an acceptable assessment.

As a part of the January workshop, an independent panel of scientists and experts will be presented with the aggregate exposure assessment methodologies. These independent experts will comment on the methods/models presented and the aggregate exposure assessments they provide. Ideally, the end-product of the workshop will be a methodology/model that can be used to provide aggregate exposure assessments for pesticides. OPP ultimately intends to have an aggregate exposure methodology/model that can be used for data-rich and data-poor chemicals, accordingly. The test case used for the workshop will utilize a full exposure database built as a composite from several chemicals. This full exposure database will allow the scientists to develop a methodology that can be used for data-rich chemicals. In the case of data-poor chemicals, the method/model will need to include default assumptions. To this end, OPP is currently considering default assumptions available from the ORD Exposure Factors Handbook.

In addition to what has been described above, there are other ongoing activities related to aggregate exposure. OPP is consulting with the FQPA Implementation Working Group which is a grower/industry workgroup organized to identify typical use and usage data that will be useful in refining aggregate exposure assessments. These data may be available from the growers processors, other industry groups and USDA. In addition OPP plans to incorporate water consumption data available in the Exposure Factors Handbook from the Erchow/Cantor consumption study (1989) for possible use in our dietary evaluation system.

A project to resolve issues of data translation is nearing completion. This project was designed to permit conversion of USDA food consumption data (CSII 1994-1996) from foods to commodities for use in dietary risk assessments. OPP staff will meet with USDA staff next week to resolve the remaining recipe issues. Translation of the 1994-1996 food consumption data can then begin. When USDA completes the translation at the end of this calender year, the data will be available for use in dietary risk assessment, replacing the older 1977-1978 data we are currently using with newer dietary consumption values.

Now I will move on to summarizing the drinking water activities. Particularly important in the assessment of aggregate exposure for pesticides is consideration of exposure through drinking water, which requires a knowledge of concentrations of pesticides in drinking water. However, currently, there are many more pesticide active ingredients registered for use with potential impacts on potable water sources than are monitored under the use Drinking water Act (SDWA). This necessitates and estimate or prediction of concentrations that may occur in potable ground water and surface water.

One approach to this task is to gather all readily available monitoring data for pesticides in surface water and ground water. In some cases, there is a considerable amount of ambient monitoring data, that is monitoring data not specifically associated with a specific pesticide's use pattern. Sources of these data include the EPA's Storage and Retrieval Database (STORET), the U.S. Geological Survey's National Water quality Assessment program (NAWQA), and independent research projects going on in various states and universities. Another approach is to use computer simulation models to predict concentrations of pesticides that may impact ground and surface water sources. Currently, OPP has several screening level models that provider very conservative, upper-bound estimates of pesticide concentrations in surface waters (GENEEC and PRZM/EXAMS), and more realistic estimates for ground water (SCI.-GROW). However, these surface water screening level models were designed to provide estimates of pesticides in ecosystems to be used in ecological risk assessments.

To improve our existing screening techniques for pesticide that may impact sources of drinking water, OPP is working with ILSI to organize a workshop with the Environmental Fate and Effects Division (EFED). ILSI will convene a working group with expertise in fate, transport, and occurrence of pesticides in surface water and ground water. The working group will be asked to identify and critique currently available methods to estimate concentrations of pesticides in ground- and surface waters using models and monitoring data. The workshop is scheduled for early this fall. The working group organized through ILSI will be asked further to consider the problem of predicting pesticide concentrations in various drinking water sources, for inclusion in aggregate exposure analyses for pesticide human health risk assessments.

In the interim, HED and EFED are working together to provide the best drinking water exposure assessments for pesticides given our available tools and data. HED and EFED have formed a Drinking Water Workgroup to draft standard operating Procedures (SOPs) for in-house use to facilitate interaction and communication between the divisions. We are handling our registration and reregistration actions on a case-by-case basis until our processes are stream-lined. OPP hopes to interact more with EPA's Office of Water (OW) and professional groups, such as the American Water Works Association (AWWA), regarding the issue of pesticides in drinking water and their impact on human health. W are beginning conversations with both to clarify our needs and goals under FQPA. Ultimately, OPP intends to use the best estimates of pesticide concentrations in potable sources of water from various sources a an integral part of our dietary i.e. that is (food and water) exposure and risk assessments that will be a part of our overall aggregate exposure and risk estimates. OPP is continuing to work toward a process for conducting aggregate exposure and risk assessments.

Finally, the Health Effects Division has organized an aggregate exposure workgroup including members from EPA's Office of Water (OW), Research and development (ORD), and Policy, Planning and Evaluation (OPPE) that is charged with taking all of the individual pieces of an aggregate exposure assessment described above for a given chemical and combine them together to produce a complete aggregate exposure assessment on that chemical.

Last but not least, as the performance of a cumulative risk assessment, that is, assessing the risks from multiple chemicals with common mechanism of toxicity and multiple sources of exposure. We will be working with ILSI/RSI to assemble a workgroup to determine how bet to conduct a quantitative cumulative risk assessment on a group o chemicals, perhaps using the organophosphate as a case study. The workgroup will be asked to address the utility and propriety of such approaches as the hazard index, toxicity equivalency factors and the margin of exposure. This workgroup will be formed and given its charge after the work on combining chemicals with common mechanism of action and aggregate exposure assessments is completed. There are additional ongoing projects that will assist us in the full implementation of the FQPA. A compilation of activities on the hazard, exposure an risk assessment is available and I would be happy to provide you with this information in the near future following internal review.

Does the panel have any comments or questions concerning this presentation?

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