July 1998 HED Status Update | Scientific Advisory Panel

HED Status Update to the Report of the Scientific Advisory Panel
on the FQPA Safety Factor for Infants and Children

Introduction

On March 25, 1998, a document entitled "Presentation for FIFRA Scientific Advisory Panel by Office of Pesticide Programs, Health Effects Division, on FQPA Safety Factor for Infants and Children" was presented to Scientific Advisory Panel (SAP) members by the Health Effects Division (HED) staff in a open meeting held in Arlington, Virginia. At that meeting, questions were posed to the Panel concerning the use of an FQPA 10X safety factor to address special sensitivity of infants and children to pesticides. The Panel issued their report on the proceedings, including responses to questions posed by HED, on May 5, 1998. The following represents a preliminary response by HED to the comments of the Panel.

General Comments from SAP Members

It is recognized that the SAP has restricted discussion to the science issues of the topic, with stated cognizance of the fact that policy plays a crucial role in the application of the FQPA safety factor. HED considers this approach to be both appropriate and constructive.

Points of general consensus:

The Panel identified two points of general consensus among members. The first was that "the developing human, especially its nervous system, is vulnerable to a variety of toxicants, both pesticides and non-pesticides, and is certainly deserving of our best efforts to afford it protection, consistent with the intent of the 1996 Food Quality Protection Act." HED agrees with this position, but further responds that the toxicological testing programs utilized by the Agency to characterize hazard and dose response to the immature animal assess many developing systems, some of which, depending on the specific test substance, may be even more sensitive to chemical insult than the nervous system. In response to the statement of the Panel, it is also necessary to reiterate the fact that consideration of the FQPA 10X safety factor, as described in the background paper presented to the Panel, applies only to the tolerance-setting process in the regulation of pesticides.

The second point of general consensus was "the suggestion that the Agency reconsider the protocols and endpoints within the required core tests to try to achieve results which more accurately assess the potential of chemicals to cause developmental toxicity, particularly developmental neurotoxicity." HED has demonstrated a firm commitment to guideline reevaluation and revision, as demonstrated by the process of revision of the developmental and reproductive toxicity testing guidelines (OPPTS 870.3700 and 870.3800). This project, which was officially initiated in 1991, has been a cooperative effort among scientific experts in numerous Agency offices (OPPTS, ORD, OW), has incorporated input from various national and international organizations (FDA/CFSN, Cal-EPA, Health Canada, OECD), has been presented to two Scientific Advisory Panels (in 1993 and 1996), and has addressed many of the issues of concern discussed in both the 1993 NAS report on "Pesticides in the Diets of Infants and Children" and in the 1996 FQPA. In addition, the Agency has commenced an effort to reevaluate the guideline for developmental neurotoxicity testing, recently released as OPPTS 870.6300. This guideline, was first issued in 1991, following extensive peer review by Agency scientists and their counterparts in the public sector and academia, including a workshop and review by an SAP. At the time it was finalized, it contained the most current screening methodologies to evaluate the potential for a chemical to affect functional development in the rat following pre- and/or postnatal exposure. Over the past seven years that this guideline has been available for use, the Agency has received and reviewed a total of eleven developmental neurotoxicity studies (eight for pesticides and three for toxic substances). A detailed evaluation of these data, in the context of the overall toxicity and risk assessment profiles for these chemicals, is currently underway. In addition, Agency experts in the areas of developmental and neurotoxicity have begun discussions on the adequacy of the guideline, with the express purpose of developing recommendations for revisions to the current US testing protocol, as deemed appropriate, and also within the context of drafting an OECD developmental neurotoxicity testing guideline.

Validation of new test guidelines:

It is not anticipated that a completely new guideline will be created to evaluate developmental neurotoxicity, but that endpoints and methodologies may be updated to reflect the current state of the science. It is recognized, however, that the Panel recommendation, to ensure validation of any new guideline adopted by the Agency, is a standard, accepted procedure for guideline implementation. The current developmental neurotoxicity testing guideline is, in fact, a validated protocol. Should new endpoints or tests be added to this existing guideline, or should new guidelines be proposed, e.g., for developmental immunotoxicity testing or testing to evaluate pre- and postnatal response from exposure to carcinogens, validation of test methodologies will be conducted and/or verified.

Clarity regarding the application of the FQPA safety factor:

The Panel also recommended that the Agency reconsider the language and intent of the background document presented to the Panel for discussion, and provide refinements of the document to the SAP in the near future, including greater clarity regarding application of the FQPA safety factor. HED recognizes the need for revision and finalization of this document, ensuring that all comments and recommendations are adequately addressed. At this time, there are numerous on-going efforts that are expected to contribute to the final 10X policy paper. These include the 10X Task Force, an interoffice working group which has been assembled by OPPTS to discuss all aspects of implementation of the 10X safety factor for the protection of infants and children. A position paper from this task force is expected to be released in the near future and will include discussions of reliable toxicity and exposure data, as well as recommendations regarding the integration of these data into a 10X decision for each chemical. In addition, the Agency has been actively engaged in discussions with several stakeholder groups regarding this topic. It would be premature to issue a final policy document at this time, without consideration of the input from all of the above-mentioned sources.

Points raised as overarching issues by the Panel

In general, the Panel agreed with HED regarding when the FQPA safety factor should be considered (after analysis of all hazard and exposure data, in the later stages of the risk assessment process), that there be a clear distinction between the FQPA safety factor and other uncertainty factors, and that the determination should utilize scientific expertise in the identification of all sources of uncertainty. In addition, however, HED realizes that the decision, while science-based and science-informed, also has an important policy component. Further discussion of these aspects of the decision-making process will be addressed by the 10X Task Force, and ultimately by HED in the final 10X policy paper.
Concerns were expressed regarding the scientific basis from which the FQPA safety factor emerges. It was suggested that the magnitude and nature of the differences in sensitivity between adults and juveniles should be determined more thoroughly in animals, in experiments other than those that are conducted at high, acute doses. It is recognized by the Agency that there is a paucity of such data on age-related differences. It is hoped that on-going research programs will add to this knowledge base from a broad perspective, although chemical-specific data would be of more value from a regulatory perspective. HED has recently begun to discuss the development of testing guidelines for studies that evaluate and compare the pharmacokinetics of adults versus prenatal and/or juvenile animals, and the possibility of the addition of such guidelines to the studies routinely required under 40 CFR Part 158. Additional discussion of this topic can be found in the responses to Question 1, below.
One Panel member expressed concern about the utilization of the 10X FQPA safety factor in the situation in which the endpoint upon which the risk assessment is currently being based is a developmental endpoint. Clarification of this situation was recommended and will be provided in the final HED document. In brief, the selection of a developmental endpoint for risk assessment carries with it an assumption that the toxicological finding of concern is the most sensitive and appropriate endpoint observed for the time period being assessed. A fetal developmental endpoint is often used for risk assessment for acute exposure, with the assumption that the effect could have occurred following a single dose of the test substance to the maternal animal. Occasionally, a developmental endpoint is used for long-term risk assessment, generally due to lack of other toxicity in the data base or because it represents the most sensitive endpoint and best NOEL for all durations of exposure. Likewise, an endpoint observed in the offspring in a reproduction study could be selected for use in risk assessment. Following selection of the endpoint(s), an acute and/or chronic reference dose (RfD) can be calculated, utilizing the appropriate uncertainty factors, such as 10X for interspecies variability and 10X for intraspecies variability, and any other appropriate factors (e.g., the use of a short term study such as the developmental toxicity study in a chronic risk assessment). The calculation of the RfD values is based entirely upon hazard and dose-response information and an assessment of completeness of the toxicity data base. As discussed previously, at this point in the process, the 10X FQPA safety factor for infants and children has not yet been considered; therefore, the RfD does not incorporate the decision on the FQPA safety factor. FQPA assumes that a 10X factor for infants and children must be applied, unless the toxicity and exposure data indicate that it can be reduced or removed. The need for this factor is evaluated by the FQPA Safety Factor Committee. It is not intended that any factors that have been required for the RfD be double counted, e.g., if a developmental rabbit study is not available, the RfD value(s) may include an uncertainty factor of up to 10X for this missing study. The FQPA Safety Factor Committee would not then recommend retention of an additional 10X for the same missing data. However, should the hazard or exposure profiles indicate that there is a significant issue of enhanced sensitivity of the offspring or if there is other evidence of unacceptable risk to infants and children, retention of an FQPA safety factor may be warranted. Thus, even though a risk assessment is based upon an offspring endpoint derived from a developmental or reproductive toxicity study, the 10X safety factor may still be retained under some circumstances. Since these evaluations are performed individually for each chemical, and because each data base is unique, it is imperative that the documentation describing the hazard and exposure data bases and the selection of endpoints and uncertainty factors for risk assessment, and the decision logic regarding the retention, reduction, or removal of the 10X FQPA safety factor for infants and children be complete, accurate, and transparent.

Concerns were expressed by one Panel member that assessment of the relative sensitivity of adults versus infants and children "would require models sensitive to lower-dose effects than the Agency has employed to date" including the "application of studies of the dynamics of brain development and complexity using quantitative measurement of ultrastructural changes." It was also stated that the "current standard test protocols at the Agency's disposal are inadequate to address this issue." Although morphometric analysis of postnatal day (PND) 11 rat pup brains is currently required in the developmental neurotoxicity study protocol, it is recognized that this study is not conducted for every chemical. Therefore, the comments received from the Panel will be considered carefully while the Agency continues to review the adequacy of the developmental neurotoxicity guideline itself and the criteria used to determine the need for this study. Furthermore, specific recommendations from the Panel regarding validated protocols for such testing would be welcome, specifically addressing the endpoints suggested in the Panel response to Question 2 (see below).

A question was posed by several of the Panel members: whether the factor applied for intraspecies variation could be reduced due to the use of the 10X safety factor for infants and children. The uncertainty factor applied for intraspecies variation does, in fact, include differences in response due to age. The NAS report, Pesticides in the Diets of Infants and Children (1993) states that "Although the committee believes that the latter uncertainty factor [accommodating variation in the human population] generally provides adequate protection for infants and children, this population subgroup may be uniquely susceptible to chemical exposure at particularly sensitive stages of development." This susceptibility would, however, be virtually impossible to quantify for any chemical without extensive human data in both adults and children; therefore, this approach, while appearing to be worthy of consideration, is not expected to be particularly feasible at this time.
The Agency recognizes the potential for increased exposure to children as compared to adults and is actively pursuing knowledge in this area. In general, the presence of uncertainties in the data regarding exposure to children will result in the application of what the Program believes are conservative assumptions and models in the calculation of risk. These are believed to overestimate exposure, thus providing an additional level of protection to infants and children, although the level of protection is not quantifiable at this time. HED will be working to describe these assumptions in more quantifiable terms. Nevertheless, HED acknowledges that there may be some situations in which the uncertainties regarding exposure to children, in the presence of hazard concerns, may be significant enough to warrant the retention of the FQPA safety factor. It is also noted that this topic is being addressed in detail by the 10X Task Force.
Concerns were expressed by one Panel member regarding the reduction of the 10X factor in the presence of data that indicate toxicity to adults but not their offspring. The cause for concern was that "while a chemical may demonstrate greater toxicity with adults versus juveniles, that may not indicate juveniles are less vulnerable to the compound." This statement assumes that the toxicity to the offspring has not been measured, which could occur if the endpoint of concern were not examined. For that very reason, HED recognizes that adequate toxicology testing protocols and data requirements are critical to the assessment of potential hazard to infants and children and has committed resources to updating the testing guidelines and the testing requirements in 40 CFR Part 158. When there is sufficient confidence in the adequacy of the available data set for the assessment of effects on the offspring for any particular chemical, an assumption can be made that an adequate evaluation of juvenile vulnerability has also been performed.
As recognized by the Panel and acknowledged by HED, it is possible that the 10X FQPA safety factor could be increased under some circumstances. To date, this has not happened. The final HED document will make this point more clearly.
HED agrees with the Panel that the Agency's position on the 10X FQPA safety factor and decision process for the determination of all uncertainty factors as well as the 10X FQPA safety factor must be completely transparent, and every attempt will be made to provide a final document that provides such clarity.

Questions to the Scientific Advisory Panel

Are the standard toxicity data evaluated by HED in the process of registration and reregistration of pesticides with food uses (including prenatal developmental toxicity studies in rodents and nonrodents, a multigeneration reproduction study in rodents, and, in some cases, a developmental neurotoxicity study in rats) generally sufficient to define the relative susceptibility of infants and children? Should we routinely require pharmacokinetics data to make this determination? Are there any other tests that should be required?
In view of the fact that the Panel did not reach consensus on the response to this question, HED recognizes that completion of on-going efforts to retrospectively analyze pesticide data, particularly in the area of neurotoxicity, are critical. These analyses will be presented to the SAP in the near future, as part of the further consideration of the 10X safety factor issues. Additionally, the 10X Task Force is currently addressing the issue of what is a complete and reliable data base for the evaluation of potential toxicity to infants and children. Other specific points raised by the Panel are discussed below.

As previously noted, there are current and on-going activities to evaluate the existing guidelines for developmental, reproductive, and developmental neurotoxicity testing. The recommendation to ensure that "migration of nerve cells to their final locations during embryonic, fetal, and neonatal development should be an endpoint in a developmental neurotoxicity study" will be addressed in these deliberations.

One Panelist commented that the guideline for the evaluation of schedule controlled operant behavior is necessary to fully characterize the neurotoxic potential of a chemical. It is noted that this topic has been previously reviewed by a Scientific Advisory Panel. In response to recommendations that resulted from that meeting, the guideline was recently finalized as OPPTS 870.6500, and has been added as a proposed revision to the 40 CFR Part 158 toxicology data requirements as a conditional requirement. The Agency believes that data on schedule controlled operant behavior represent an integrative measure of complex performance. An organism's ability to respond to its environment is a fundamental property of behavior. Deficits in this ability are one central aspect of what defines adversity, a critical statutory term for both FIFRA and TSCA. However, the Agency has not derived a generic set of triggers for this study for many reasons, principally that it is not clear that the other data available provide sufficient suitable information to indicate the need (or lack of need) for such a study. This is a dilemma for which we would welcome further suggestion.

In regard to the use of epidemiological studies, it is noted that HED routinely considers such data, as well as case studies found in the peer reviewed literature. These studies, as pointed out by the Panel, are often not sensitive, and may in fact be seriously flawed. Therefore, such studies are generally considered as part of the overall toxicity profile of the chemical, but may (or may not) be included in any weight of evidence considerations.

Currently, a metabolism study must be provided as part of the overall required data package for a food use pesticide, but this study is conducted only in adult animals. The routine use of comparative (adult versus offspring) pharmacokinetic data was not believed to be useful by the Panel. Nevertheless, Agency scientists are convinced that comparative pharmacokinetic studies could provide important information, particularly if conducted early in the process of toxicological evaluation of a chemical. For instance, such studies could assist in dose-setting for the developmental, reproduction, and developmental neurotoxicity studies. They could also provide a more complete knowledge of target organs in adults and offspring, allowing the inclusion of more appropriate endpoints into the study design. Comparative pharmacokinetic studies could provide information regarding whether or not offspring are more (or less) sensitive to the effects of the chemical. For example, if the chemical requires metabolic activation, and the offspring do not have the mature enzyme systems for this task, the chemical may actually be more toxic to adults. The opposite could also be true, in that if the offspring lack the enzymes necessary for metabolic inactivation of a chemical, it may be more toxic to the offspring. However, it is not known if a "directed pharmacokinetic study" would provide information that could be used to determine the appropriate magnitude of the FQPA safety factor, as suggested by the Panel. The Agency is pursuing discussions regarding such a study protocol and HED will provide more information to the SAP at a future date.
The Panel is asked to respond to the following questions on the topic of determining the need for a developmental neurotoxicity study. As discussed in the paper (pp. 14-17), HED proposes that a developmental neurotoxicity study be required when the chemical profile meets any of the five listed criteria, and can be required based upon the additional list of weight-of-evidence considerations (all of which are consistent with the OMB Data-Call-In criteria, 1991).
A)  Are the criteria that have been proposed for determining the need for a developmental neurotoxicity study appropriate and adequate? Are there criteria that should be added to this list?
B)  Should the developmental neurotoxicity study be considered mandatory for every chemical with any evidence of treatment-related neurotoxicity in adult animals (including those chemicals which only exhibit alterations of neurochemistry or minimal and/or nonpersistent behavioral/functional changes, in the absence of neuropathology)?
C)  Is the described approach appropriate for all chemicals? If not, are there, for instance, certain classes of chemicals for which the developmental neurotoxicity study should be required as part of the standard data base?

A majority of the Panel agreed that the developmental neurotoxicity study should be a second tier test at this time. Nevertheless, the suggestion was put forward that it might be important to include the developmental neurotoxicity study as part of the core tests in some cases. OPP is proposing requiring the developmental neurotoxicity study for any chemical which acts as a neurotoxicant in insects, unless other information about the chemical, such as pharmacokinetic or pharmacodynamic data, demonstrate the inappropriateness of such testing. This position is believed to be consistent with recommendations of the Panel. OPP intends to utilize one additional criterion for triggering the conduct of a developmental neurotoxicity study, which was suggested by the Panel: evidence of adverse effects from tests of cognition, memory, and other higher brain functions. These issues are currently under consideration by HED scientists, in collaboration with neurotoxicologists and developmental toxicologists from other Agency offices. It is noted that final Agency consensus on all aspects of these issues has not been achieved at this time, and further discussion and deliberation are required; input from the 10X Task Force will be considered in the final OPP decision. At this point, OPP would appreciate further comment from the SAP, specifically: 1) Do the positions described above accurately reflect the recommendations by the Panel? 2) If and when the requirement for the developmental neurotoxicity study is extended, under what circumstances, if any, should this trigger the retention of an FQPA safety factor?

The inclusion of "ultrastructural anatomy investigations, using quantitative techniques to look at dendritogenesis, synaptic maturity, and other alterations not visible at the gross or histologic level," as recommended by the Panel, will be discussed in Agency deliberations on the adequacy of the developmental neurotoxicity study protocol. These discussions will be initiated in the very near future, and it is anticipated that the resultant findings and recommendations will be brought to the Scientific Advisory Panel for review within the upcoming year.

D)  If there are certain chemicals that require the developmental neurotoxicity study, based on minimal weight-of-evidence or class of chemical, would this study be expected to provide information that is needed to address concerns on neurotoxicity and enhanced susceptibility to infants and children?

The Panel expressed concern that the current study design for the developmental neurotoxicity study, which includes maternal exposure from gestation day 6 through postnatal day 10, is insufficient to elicit observable changes in the offspring or to identify an accurate LOEL. This issue has been under discussion by HED and other Agency scientists for some time, and recommendations for guideline revision are expected to result from on-going discussions on the adequacy of the protocol.
Does the Panel have any specific comments on the general approaches described in the paper (pp. 24-26) regarding the contribution of hazard and dose-response characterization in determining if it is appropriate to remove or reduce the FQPA factor?
The Panel response to this question appeared to pertain to the third of six general approach points presented in the background document. It is recognized that this point, as written in the document, lacks clarity, and it will be elaborated upon in the final version. HED acknowledges that in most circumstances, in the absence of adequate core studies for the assessment of toxicity to infants and children, an FQPA safety factor would be retained if it has not already been accounted for by the use of an additional uncertainty factor for deficiencies in the database during the derivation of the RfD.
Does the Panel have any specific comments on the general approaches described in the paper (p. 27) regarding the contribution of exposure assessment in determining if it is appropriate to remove or reduce the FQPA factor?
Issues pertaining to exposure, such as the definition of reliable data, what steps are taken in the absence of adequate exposure data, and what level of uncertainty is acceptable before it is deemed necessary to retain the 10X FQPA factor, are currently being discussed at length by an Exposure Subgroup of the 10X Task Force. HED is currently awaiting input from this group, but has also been working over the past several years to develop standardized policies and procedures regarding exposure assessment relative to FQPA. Several documents have been presented to the SAP, and will be referenced in the final 10X paper. These include proposals on methodologies for aggregate exposure (3/97), residential scenarios (9/97), and estimating drinking water exposure as a component of the dietary risk assessment (12/97).

In many cases, the exposure scenarios are believed to result in conservative assessments that would not necessarily require an additional safety factor. However, each exposure assessment should characterize the areas of conservative assumptions, the quality of data, and areas where the degree of conservatism is unknown, and attempt to quantify that conservatism. Where many unknowns exist, the need for an additional safety factor would have to be assessed.
The following are general principles which are recommended for application of the FQPA safety factor to risk assessment (pp. 30-33):
a. The appropriate FQPA safety factor should be used only for risk assessments that address the specific susceptible subpopulation or the subpopulation for which there is uncertainty.
b. Assuming that there is exposure to infants and children, the FQPA safety factor should be retained for acute exposure risk assessments, for chronic exposure risk assessments, or for both, depending on the toxicity profile of the chemical.
Does the Panel agree with these principles and/or have any additional recommendations?

The Panel, while agreeing with the general principles for application of the 10X FQPA safety factor and with the subpopulations used in the risk assessment, correctly assumed that there would be specific situations in which the safety factor would not actually be applied, for instance, if a subpopulation is not identified as the sensitive subpopulation.

The Panel expressed concern regarding male mediated developmental toxicity, which has been demonstrated for a few non-pesticide chemicals. At this time, HED has not identified any studies in the registration database or in the peer reviewed literature that have clearly identified male-mediated developmental toxicity following pesticide exposure. It is assumed that the reproductive toxicity study might identify some male-mediated effects on offspring; however, due to the current study design (i.e., both parents are exposed), it is generally not possible to determine the source of the effect in the offspring (i.e., maternal, paternal, or direct pre- and/or postnatal toxicity). In the dominant lethal study, embryolethality is used as a marker for genotoxic effects on the male germ cell; however this study is not conducted for every chemical and would not identify subtle prenatal toxicity or any postnatal effects. This issue is currently being further discussed by the Toxicity Subgroup of the 10X Task Force.
Does the Panel have any suggestions for thinking about how the FQPA safety factor analysis set forth in the paper would relate to a) endocrine disruption evidence and b) nonthreshold effects?
Limited comment was provided by the Panel on this question, due to the anticipated May SAP/SAB meeting at which the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) recommendations were to be presented. Although that meeting has since passed, it was conducted as an informational meeting only and provided no additional information that could contribute to Panel deliberations at this time. The EDSTAC recommendations and Agency position will be presented for consideration in an SAP/SAB meeting to be held in December, 1998.
Are there any other issues raised by this paper upon which the Panel would like to comment?
The Panel recommended that the final Agency 10X policy be published in the peer reviewed literature. HED agrees with this recommendation, recognizing that such publication will only occur following completion of on-going internal (Agency) and external review processes, and a similar but even more extensive review of the final position document, including presentation to a future SAP.

There was a suggestion that the 10X policy be harmonized with other US and international agencies. This is currently being addressed in part by the 10X Task Force, which included consultation with USDA. The subject of international harmonization has not yet been addressed substantively by the Agency. This is clearly a step that requires much careful consideration and future discussion.

Summary and Conclusions

It is anticipated that finalization of the HED10X FQPA document will occur in December, 1998. This will follow review and response to comments from the Panel and the public sector on the July, 1998 HED update; issuance of the draft final 10X FQPA document in October, 1998 for a 30-day comment period; and subsequent response by HED to the comments received on the final draft.

There are a number of on-going activities in OPP and the Agency that are directly related to the resolution of issues identified in the background paper and the SAP response document. These include the interoffice Agency 10X Task Force (and its subgroups that are addressing toxicity, exposure, and integration) as well as a number of stakeholder groups that have been formed under the auspices of the FACA. In addition, Agency resources are being applied to the retrospective analysis of developmental neurotoxicity studies that have been submitted to OPP, along with a comprehensive review of other issues related to the triggering of the developmental neurotoxicity study. Connected to this analysis, is the reevaluation of the developmental neurotoxicity testing guideline, development of other guidelines and criteria for testing (e.g., appropriate testing to identify in utero carcinogenesis, developmental immunotoxicity testing guidelines, and protocols for direct postnatal dosing studies), and the continuing reevaluation of the developmental and reproduction study guidelines in light of recommendations from public interest groups and from the FQPA-driven EDSTAC effort.

Meanwhile, however, OPP is continuing all registration and reregistration activities. In order to accomplish this, HED has instituted the FQPA Safety Factor Committee, which performs the assessment of the FQPA 10X Safety Factor for every chemical destined for risk assessment. At this time, the FQPA Safety Factor Committee uses the guidance provided in the background policy paper that was presented to the SAP on March 25, 1998. Additionally, a draft document entitled Standard Operating Procedures for FQPA Safety Factor Committee (April 6, 1998) is utilized in defining the function and procedures of the committee. This draft document is attached as a reference and provides further illumination of the process that results in a decision regarding the retention of the FQPA safety factor. Review and comment on this document are requested of the Panel.

HED recognizes that greater clarity must be achieved in explaining the decision logic utilized in the determination of when to retain, reduce, or remove the FQPA 10X safety factor. Recently, in a Q&A document, Marcia Mulkey, Director of the Office of Pesticide Programs, drafted the following plain language description of how EPA applies the 10X safety factor. This explanation discusses the contribution of the hazard and dose-response assessments, as well as the exposure evaluation, to the overall determination of the need to retain the FQPA factor. Although the specifics will still need to be explained in much more detail in the final HED document, a brief summary such as presented below is being considered as a more easily understood summary of the procedures in use within HED.

"As the law requires, we begin with the assumption that the additional safety factor applies, but we examine all reliable data to determine if it can be reduced or removed while still assuring the safety of infants and children.

First, if there is no or virtually no exposure to children, the factor is removed.

If there are significant exposures for infants and children, we examine all of the data we have on the pesticide and weigh the evidence to determine whether there is adequate safety assurance.

a) If we lack fundamental information on whether infants or children are likely to be more susceptible to the pesticide, we retain the safety factor unless and until the data are generated. b) Where we have the full basic data on developmental effects of the pesticide, we would retain some or all of the safety factor where the evidence shows:

additional sensitivity of infants and children which involves

adverse effects of concern which are

unequivocal

significant,

with elements like severity, irreversibility, dose-response characteristics or other indications that safety to children may not otherwise be assured.

c) If we lack fundamental information on whether infants and children are likely to be exposed at levels which could exceed our estimates of exposure, we would retain the safety factor unless and until we can be confident that safety of children is assured.

In some instances, the basic data set is completed and EPA concludes that either the individual chemical or a category of chemicals require further testing on toxicity or exposure to infants and children. While awaiting such data, EPA will evaluate all the available data on such chemicals and will make a case-by-case, weight of the evidence determination about whether the additional safety factor must be retained or can be reduced or removed, as described above."

It is clear that generation of a final position paper on the 10X issue by HED would be premature at this point. However, there is significant movement towards that ultimate goal. It is imperative that HED receive input from all critical sources before developing the final position paper. This final draft 10X paper, reflecting input from the rest of the Agency and other interested parties, would then be presented to a Scientific Advisory Panel for review and comment. Finalization, and publication in the peer reviewed literature, could then proceed.

Meanwhile, important corollary efforts, such as the retrospective analysis of developmental neurotoxicity data and the development of other testing guidelines for the evaluation of potential toxicity to infants and children, will also be completed and presented at future Scientific Advisory Panel meetings. They may precede or follow finalization of the 10X policy paper.