December 1998 - HED Standard Operating Procedures Presentation

Presentation for the FIFRA Scientific Panel by the
Health Effects Division (HED)
Standard Operating Procedures of the
HED FQPA Safety Factor Committee

Introduction | Background | Standard Operating Procedure Considerations
Current Criteria for Recommendations | Questions to the Panel Members

I. INTRODUCTION

This document has been prepared by the Health Effects Division (HED) of the Office of Pesticide Programs (OPP) for submission to the FIFRA Scientific Advisory Panel (SAP) for review and comment. It discusses the current approach used by the HED FQPA Safety Factor Committee in recommending the retention, reduction, or removal of the 10-fold safety factor for risk assessments prepared in support of tolerance decisions, as mandated by the 1996 Food Quality Protection Act (FQPA), to ensure the protection of infants and children. FQPA requires that in the case of threshold effects "an additional tenfold margin of safety for the pesticide chemical residue and other sources of exposure be applied to infants and children to take into account potential pre- and post-natal toxicity and completeness of the data with respect to exposure and toxicity to infants and children......the Administrator may use a different margin of safety for the pesticide chemical residue only if, on the basis of reliable data, such margin will be safe for infants and children". The HED FQPA Safety Factor Committee is seeking input from the Panel members regarding the interim approach currently used in recommending the retention, reduction, or removal of the 10-fold safety factor (described below).

There are currently several ongoing efforts that are expected to provide further guidance to the HED FQPA Safety Factor Committee for making FQPA safety factor recommendations. These include the finalization of the 10x position paper by the 10x Task Force, which is an interoffice working group assembled by OPPTS to facilitate the implementation of the FQPA 10x safety factor for the protection of infants and children. A position paper from this task force is expected to be released for review and comment in the near future which will include recommendations regarding the integration of toxicity and exposure data into the 10x decision for each chemical. In addition, the Agency has been actively engaged in discussions regarding this topic with several stakeholder groups including the Tolerance Reassessment Advisory Committee (TRAC). One of the nine FQPA science policy issues being considered by the TRAC involves "Establishing clear and transparent criteria for retaining, reducing, or removing the 10-fold safety factor." The final outcome of these Agency efforts, including the associated public comment, will be incorporated into the operating procedures of the HED FQPA Safety Factor Committee.

II. BACKGROUND

Prior to the formation of the HED FQPA Safety Factor Committee, the FQPA safety factor recommendation was made during the evaluation of the toxicology data base for dose and endpoint selection by the HED Hazard Identification Assessment Review Committee (HIARC). As mandated by FQPA, the HIARC assumed the 10-fold factor for the protection of infants and children to be in place initially for each chemical under evaluation and used the following criteria in determining whether the factor should be removed, reduced, or retained. The HIARC considered:

the completeness of the toxicology data base;
the assessment of neurotoxicity studies with regard to evidence of neuropathology in adult animals;
the qualitative and quantitative assessment of increased susceptibility in the prenatal developmental toxicity studies following in utero exposure to rats and rabbits; and the pre- and post-natal multi-generation reproductive toxicity studies; and
the requirement or results of a developmental neurotoxicity study.

The data from the adult neurotoxicity studies are used for hazard characterization, as well as in determining the need for a developmental neurotoxicity study. One "trigger" for a developmental neurotoxicity study, for example, would be neuropathology observed in these studies. When a developmental neurotoxicity study is required, it is because this study is expected to provide additional data on functional parameter development, potential increased susceptibility, and/or further characterize the effects on the development of the fetal nervous system. The HIARC continues to use this overall process in providing the hazard-based safety factor recommendation to the FQPA Safety Factor Committee.

The HED FQPA Safety Factor Committee (FQPA SFC) was formed in February, 1998. The purpose of creating this new committee was to shift activity related to developing the FQPA safety factor recommendation to a point later in the risk assessment process, allowing for a more thorough evaluation of the exposure information associated with each chemical (including characterization of the use pattern, the availability of actual data or surrogate exposure data based on reliable assumptions, and the completeness of the data base) in conjunction with the hazard evaluation provided by the HIARC. The FQPA SFC includes representatives of both science and regulatory divisions within the Office of Pesticide Programs including the Environmental Fate and Effects Division (EFED), Health Effects Division (HED), Special Review and Reregistration Division (SRRD), and Registration Division (RD).

In addition to the report of the HIARC for each chemical evaluated, the FQPA SFC receives written responses to four sets of questions posed in the Committee's Standard Operating Procedure (SOP). These sets of SOP questions were designed to provide information regarding:

the contribution of the hazard and dose response evaluations in determining whether the FQPA safety factor should be retained, reduced, or removed;
the contribution of the exposure assessment(s) in evaluating whether retention, reduction, or removal of the safety factor is appropriate; and
the characterization of both the hazard (toxicology data base) and exposure data base(s).

The four sets of questions are categorized as: hazard considerations; dietary food exposure considerations; dietary drinking water exposure considerations; and residential exposure considerations. The responses to each set of questions are prepared by the appropriate HED and EFED scientists directly involved with the risk assessment for the chemical. Each of the four sets of questions included in the committee SOP follows.

III. STANDARD OPERATING PROCEDURE CONSIDERATIONS

A. Hazard Considerations:

The questions in this category are designed to describe the completeness of the toxicology data base and the quality of the toxicity studies submitted to satisfy the Subdivision F guideline requirements, as well as any ancillary data (e.g., literature data); and to assess the potential risk to infants and children. In general, the information that is requested for examination by the Committee consists of the following: summary of the data on pre- and/or postnatal toxicity in studies including the qualitative comparison of the toxicity observed in adult and young animals; assessment of dose-response; the relevance of the animal data to humans and of any additional data available.
1. Has the scientific quality of the toxicology data base and the confidence in the hazard endpoints and dose-response assessments been completely characterized?
2. Do we have adequate hazard studies for evaluation of risk to infants and children? These include, but are not limited to, developmental studies in 2 species; multi generation reproduction studies; neurotoxicity and developmental neurotoxicity studies as required for chemicals which affect the nervous system. Are additional studies being required?
3. Do these studies show enhanced susceptibility to infants and children? That is, do the effects in the young occur at doses not causing effects in the adults? Are the effects in the young at the same level but more severe? Completely describe the spectrum of effects in both adult and young animals (include the shape of the dose response curve, the reversibility of effects if known, etc.).
4. Have other studies (e.g., from the published literature) been considered which might influence a FQPA safety factor finding? Are there mode of action studies which may provide information on precursor effects at lower doses? Are there comparative metabolism and pharmacokinetic studies evaluating the dose at the target site or the duration of effect?

B. Dietary Food Exposure Considerations:

The questions in this category are designed to determine whether the population of concern (i.e., children) is expected to receive any dietary (food) exposure to the pesticide and to determine the adequacy of the data base for making a reliable dietary (food) exposure assessment. A dietary exposure analysis model [e.g., Dietary Risk Evaluation System (DRES) or Dietary Exposure Evaluation Model (DEEM)] is used to estimate exposure to constituents in food comprising the diets of the U.S. population and population subgroups. By using appropriate toxicological parameters associated with each chemical, the model can express risk as a function of dose through dietary exposure. In most cases, there is an intrinsic degree of protectiveness in the dietary exposure model which is dependent upon the level of refinement of the residue data utilized in the exposure algorithm. For example, residues found in the crops collected at the farm gate are often two or more orders of magnitude higher than residues that may remain in foods "on the dinner plate", that is, after typical preparation for consumption (washing, peeling, cooking, etc.). Consequently, information on the level of refinement in the exposure estimates provides characterization of the degree of conservatism in the exposure assessment.

Describe (semi-quantitatively) the typical use rates and frequency of application. Are there Codex MRL's for the compound?
What metabolites require regulation? Are the residues systemic? That is, are they distributed throughout the plant or likely to be removed during preparation (washing, peeling, etc.)? Is information available about the dissipation or half-life of the pesticide?
State and characterize the available residue databases for each crop (i.e field study data, sources of available monitoring data such as PDP, FDA, etc.). What are the limits of quantitation used ? Describe semi-quantitatively the results of residue testing (ranges, frequency of positive findings, etc.).
Is there information available on % crop treated? If so, what is the source of the information and the uncertainties around the number? What is the likely maximum % crop treated for each crop (based on potential market)?
Based on the consumption database used by Dietary Risk Evaluation System (DRES) or Dietary Exposure Evaluation Model (DEEM), which crops contribute significantly to the human diet for adults? Which contribute significantly to the diet of infants and children? Is there likelihood of transfer of residues to meat and/or milk? Describe the degree of refinement of the DRES or DEEM analyses for acute and chronic exposure.

C. Dietary Drinking Water Exposure Considerations:

The questions in this category are designed to determine whether the population of concern (i.e. children) is expected to receive any dietary (water) exposure to the pesticide and to determine the adequacy of the data base for making a reliable dietary (water) exposure assessment. Where possible, drinking water exposure estimates are based on reliable monitoring data from ground and/or surface water monitoring. Monitoring data sources include the Pesticides in Ground Water Database, STORET, small-scale prospective ground water studies, or runoff (surface water) studies. In the absence of, or as a supplement to monitoring data, a screening level assessment can be conducted using chemical-specific environmental fate data in the EFED simulation models, GENEEC for surface water estimates and SCI-GROW for ground water estimates. GENEEC provides an upper-bound estimate of the pesticide concentration that could be found in surface water. SCI-GROW outputs are also upper-bound estimates of the likely concentration in ground water if the pesticide is used at the maximum allowed label rate in areas where ground water is exceptionally vulnerable to contamination. In most cases, a majority of the use area will have ground water that is less vulnerable than the areas used to derive the SCI-GROW estimate. The available results from monitoring studies are compared to the model estimates to ensure that the models are not underestimating the potential concentration in ground and/or surface water. The following questions are intended to characterize the likelihood of drinking water contamination and the extent of potentially exposed populations.

Is the environmental fate database complete enough to characterize drinking water exposure?
- ) Provide a brief summary of the environmental fate assessment for this compound and any metabolite that may potentially get into drinking water based on metabolite fate characteristics.
  b) Is the compound or any of its metabolites mobile and persistent? (A bottom line summary statement on drinking water exposure potential should be included.)
Discuss method for drinking water exposure assessment (ex. monitoring data, modeling, combination).
- a) If models are used, discuss which models, describe the resulting estimated environmental concentrations (EECs), and the scenarios used in the model.
  b) If monitoring data are used (ground water or surface water), describe the monitoring data and conditions under which they were collected (e.g., from vulnerable areas at maximum label rates).
Please discuss the magnitude of the population potentially exposed to the pesticide via drinking water based on the extent of usage and whether the chemical characteristics indicate a likelihood of drinking water contamination.

D. Residential Exposure Considerations:

The questions in this category are designed to determine whether the population of concern (i.e. children) is expected to receive any non-dietary residential exposure to the pesticide and to determine the adequacy of the data base for making a reliable non-dietary residential exposure assessment. Where available, HED uses chemical-specific data from monitoring studies conducted to evaluate the potential exposure resulting from the use of a pesticide in residential settings. Since these type of data are rare, HED developed the DRAFT "Standard Operating Procedures (SOPs) for Residential Exposure Assessments" (presented to SAP in September 1997) which were designed to provide standard methods for residential exposure assessment in the absence of, or as a supplement to, chemical- and/or site-specific data. The DRAFT SOPs are intended as a screening level tool used to compute upper percentile to bounding estimates of exposure. The degree of refinement in the DRAFT SOPs varies significantly with the scenario. For example, many of the approaches and exposure factors used in the document are supported by a substantial pool of empirical data. In some cases, these data are highly refined and used throughout the agency as a standard risk assessment resource (e.g., Exposure Factors Handbook). In other cases, exposure factors and algorithms have been developed in lieu of data or using preliminary data in order to address exposure scenarios.

The characterization of each scenario is dependent upon the data and approaches upon which it is based. For scenarios that were developed with more refined data, a better characterization of the calculated exposures is possible and is developed based on the exposure factors (i.e., all are intended to be upper percentile values). For scenarios that were developed using extremely limited or no data, the models and exposure factors were selected/developed in a manner that is known to be conservative. Therefore, the DRAFT SOPs for Residential Exposure Assessment are thought to be conservative in all cases, the degree of conservatism is generally reflective of the quality of the data upon which each was developed.

Exposure to pesticides used in residential settings can occur via several routes: inhalation, dermal absorption, and oral ingestion. In determining whether to retain the 10X FQPA factor, unique attributes of children's exposure via these routes need to be evaluated.

For inhalation, the major difference is that the rate of air consumption compared with body weight is larger for children than adults; this is addressed by using appropriate body weight and intake estimates. Children are also both smaller and spend more time on the floor, so if compounds have higher concentrations lower to the ground this should be taken into account.

For dermal absorption, there are three factors that should be considered:

use appropriate factors for skin surface as a percentage of body weight,
use appropriate permeability factors since children's skin may be more permeable than adults', and
consider children's behaviors that contribute to dermal exposure, such as crawling on a carpet or lawn or handling toys and other objects with pesticide residues.

For oral ingestion, hand-to-mouth and object-to-mouth behavior as well as ingestion of turf or soil containing residues should be taken into account.

The following questions are intended to identify the potential exposure to infants and children as well as describe the nature of that exposure, and the likelihood that the data and/or assumptions made might understate /overestimate such exposures.

Is the compound used around the home in such a way that children and infants may be exposed? What is the frequency and rate of application?
Have Pesticide Handler Exposure Database (PHED) data been used in estimating the exposure? How well does the PHED scenario reflect the actual use pattern? Rate the data used based on the PHED grading criteria (high quality, medium quality, or low quality). If chemical- specific or other non-PHED data have been used, describe the scope of the study, resulting exposure values, and general quality of the study.
For residential post application exposure scenarios, have the DRAFT Standard Operating Procedures for Residential Exposure Assessments been used as the basis for all calculations? Describe any deviations from SOP calculations and the impact on the assessment results (e.g., assessment reflects a less conservative approach by altering transfer coefficient value for dermal exposure).
Is chemical-specific product use information available through BEAD or some other source? Has the assessment been developed to reflect this information? Has this information been used as a basis for characterizing the populations considered in the assessment?
Are reliable biologically-based exposure data or epidemiology data available to support the results of the assessment (e.g., incident report, CDC biomonitoring data, etc.)?
Have models other than PHED or those presented in the DRAFT Residential SOPs been used to calculate dose in any aspect of the assessment (e.g., CONSEXPO, TherDbase, etc)? Summarize how these are integrated into the assessment.
Is 100% dermal absorption assumed (when dermal endpoints are derived from oral studies)? Or, are there chemical-specific data available that indicate a different dermal absorption rate?

IV. CURRENT CRITERIA FOR RECOMMENDATIONS

After careful consideration of the information obtained from the responses to the FQPA SFC SOP questions on the exposure associated with the use of the chemical, along with the HIARC's evaluation of the pre- and/or post-natal effects, the Committee deliberates and recommends retention, reduction, or removal of the 10-fold FQPA safety factor. The following criteria are used for recommending that the factor be reduced or removed:

The data on the pre- and/or post-natal effects are complete and reliable. A weight-of- evidence approach is used in evaluating the toxicology data base for the chemical and the potential risks for the developing fetus, infant, and child as well as other populations.
The assessments of all exposure scenarios associated with the use of the chemical are based on reliable data, either directly or through the appropriate use of conservative assumptions which themselves are based on reliable data.

V. QUESTIONS TO THE PANEL MEMBERS

Are the members of the Panel in agreement with the criteria used (Section IV. Above) in making the recommendation to retain, reduce, or remove the FQPA 10-fold safety factor? If not, what modifications to these criteria would the Panel recommend?
Considering the questions within each of the categories (hazard, dietary food exposure, dietary drinking water exposure, and residential exposure considerations) included in the current draft of the FQPA Safety Factor Committee Standard Operating Procedure, what additional hazard and/or exposure characterization is required for improving the FQPA safety factor recommendation process?

Scientific Advisory Panel (SAP) December 1998 Meeting