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March, 1998 Final Report

A Set of Scientific Issues Being Considered by the Agency in Connection with the Use of FQPA 10x Safety Factor to Address Special Sensitivity of Infants and Children to Pesticides

The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) has completed its review of the set of scientific issues being considered by the Agency in connection with the Use of FQPA 10x Safety Factor to Address Special Sensitivity of Infants and Children to Pesticides. The review was conducted in an open meeting held in Arlington, Virginia on March 25, 1998. The meeting was chaired by Dr. Ernest E. McConnell (ToxPath, Inc.). Other Panel Members present were: Dr. John Adgate (University of Minnesota), Dr. Julian Andelman (University of Pittsburgh), Dr. Charles Capen (The Ohio State University)[recused], Dr. Janice Chambers (Mississippi State University), Dr. Amira Eldefrawi (University of Maryland), Dr. Natalie Freeman (EOHSI/University of Medicine and Dentistry of New Jersey), Dr. Ernest Hodgson (North Carolina State University), Dr. Ronald Kendall (Texas Tech University), Dr. John Kissel (University of Washington), Dr. Paul Kuznesof (Food and Drug Administration), Dr. Robert Kreiger (University of California at Riverside)[recused], Dr. Michele Medinsky (Chemical Industry Institute of Toxicology), Dr. Robert Moore (University of Wisconsin), Dr. Herbert Needleman (University of Pittsburgh), Dr. B.K. Nelson (NIOSH), Dr. Christopher Portier (NIEHS), Dr. J. Routt Reigart (Medical University of South Carolina), Dr. Mary Anna Thrall (Colorado State University), and Dr. John Wargo (Yale University).

Public Notice of the meeting was published in the Federal Register on February 11, 1998.

Use of FQPA 10x Safety Factor to Address Special Sensitivity of Infants and Children to Pesticides

Oral statements were received from the following:
Dr. Michael Dourson, Toxicology Excellence for Risk Assessment.
Dr. Stephen B. Harris and Neil Carmichael, Rhone-Poulenc.
Ms. Elizabeth Julien, Indiana University.
Ms. Jeannine Kenney, Consumers Union.
Dr. James Lamb for the American Crop Protection Association.
Ms. Lisa Lefferts, Mothers and Others for a Liveable Planet.
Dr. Rudy Richardson, University of Michigan.
Mr. James Tozzi, Multinational Business Services, Inc.
Dr. David Wallinga, Natural Resources Defense Council.
Mr. Richard Wiles, Environmental Working Group.

Written statements were received from the following:
American Crop Protection Association.
California Environmental Protection Agency.
Mothers and Others for a Liveable Planet.
Multinational Business Services, Inc.
Natural Resources Defense Council.
Novartis Crop Protection, Dow Agrosciences, Bayer Corporation and Rhone-Poulenc Ag Company.
Toxicology Excellence for Risk Assessment.

General Comments from SAP Members

The issues associated with this topic comprise both science and policy, and the Chair suggested that it would be more beneficial to restrict discussion to the science issues. Lengthy discussion occurred throughout the session, with many points of clarification brought to the Agency staff by the Panel Members. Consensus of the Panel Members on many points was reached during the discussion, but lack of consensus among the Panel Members was also the case for a few points. One point of consensus within the Panel 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 (FQPA).

Another general point of consensus within the Panel 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. The Panel believes that it is extremely important that the scientific basis for the tests, test protocols, and endpoints be determined so that the resultant data will yield the most reliable science regarding the protection of infants and children. The Panel recommends that the Agency continue evaluation of the core tests required and the design inherent in these required tests to optimize the likelihood of detection of developmental toxicity, including developmental neurotoxicity. The Panel urges the Agency to recruit appropriately trained scientists and health professionals to aggressively pursue revising these test methodologies to the current state-of-the-art methodology to satisfy FQPA requirements.

The Panel emphasized that any new test guideline adopted by the Agency requires validation. This entails producing reproducible results among laboratories and selection of endpoints in test animals that are applicable to humans.

The Panel strongly urges the Agency to reconsider the language and the intent of the background document presented to the Panel for discussion so that greater clarity is achieved regarding the application of the FQPA safety factor. In addition, because of the complexity of the topic presented at this session, the diverse opinions expressed by various individuals and groups, and the perceived need for further consideration and discussion of the topic, the Panel strongly urges the Agency to return its refinements to the SAP in the near future for further evaluation and comment.

There were several overall points raised during the Agency presentation, public comment, Panel general discussion and response to Agency questions, which the Panel wished to emphasize as overarching issues for the FQPA safety factor issue:

  1. In the process of implementing the FQPA 10x safety factor, it is important to note when it is most appropriate to consider the factor. The Agency proposed that the factor would be implemented after the analysis of all hazard and exposure data, but before the risk management process. The Panel agreed that implementation of the safety factor should occur as part of the risk assessment process but after the data analysis is complete, making a clear distinction between the FQPA safety factor and other uncertainty factors. The Panel also agrees that there is a need for scientific expertise to identify the sources of uncertainty for both hazard and exposure, and that all decisions concerning use of the FQPA 10x safety factor be science-driven.
  2. Several Panel Members were concerned regarding the scientific basis from which the FQPA safety factor emerges. The interspecies factor (to account for differences between animals and humans) and intraspecies factor (to account for differences among human subpopulations) were already utilized in the pre-FQPA risk assessments, generally resulting in a 100x safety factor. This implies that the most sensitive human subpopulation is 100x more sensitive than the most sensitive animal endpoint. Based on FQPA requirements, a third 10x safety factor for children must be applied to accommodate for factors related to both hazard and exposure. Several of the Panel Members noted that this issue of differences in susceptibility should be evaluated on a case-by-case basis.

    The Panel suggested that the magnitude and nature of the difference in sensitivity between adults and juveniles should be determined more thoroughly in animals. Some data are presently available, but several Panel Members were concerned that much of this existing information was generated in acute treatment experiments, frequently at very high exposure levels. Such data may not be appropriate to extrapolate to low-dose situations (e.g., organophosphates), where much, if not all, of the age-related differences may be attributable to differences in the magnitude of activity of detoxication enzymes. In such cases, differences in toxicity between adults and juveniles would be substantially greater at high doses where detoxication mechanisms are saturated than at low doses where they are not.

    A member of the Panel expressed concern that if the endpoint on which the risk assessment is currently based was a developmental endpoint, then an additional safety factor to protect children appears to have already been utilized. Unless the sensitivity of the measure of developmental toxicity is similar to those that would be applied to immature humans, the interspecies and intraspecies safety factors typically used cannot be accepted in place of the FQPA safety factor. Thus, the rationale for the use of the FQPA safety factor in such a case needs to be clarified.

    A Panel Member added that the evaluation of relative sensitivity of adults and infants and children (not "juveniles") would require models sensitive to lower-dose effects than the Agency has employed to date. Among the most sensitive targets for some pesticides is the central nervous system. Thus, probably the most important reason for increased sensitivity in infants is that their brains are still undergoing critical developmental changes during the period of exposure. Exposure to xenobiotics which are neuroactive will, by altering stimulations of neurons, alter the final architecture of the infant brain at doses that in the adult may only trigger a transitory response. Modeling the relative sensitivity of infants and adults in animals will demand the application of studies of the dynamics of brain development and complexity using quantitative measurement of ultrastructural changes. The current standard test protocols at the Agency s disposal are inadequate to address this issue.

    Several Panel Members questioned whether the additional 10x safety factor for children had the effect of removing part of the population from the existing 10x factor to account for human variations (i.e., intraspecies variation). This may result in reducing the extent of human variation and permitting a reduction of the earlier existing factor (i.e., interspecies and intraspecies factors). The Agency remarked that they have not considered this possibility.

  3. Several Panel Members commented that differences in exposure of children compared to adults tended generally to be much greater than any difference in susceptibility. Thus, the Agency should place at least as great an emphasis on differences in exposure between adults and children as on standard and non-standard testing for differences in susceptibility and corresponding effects. In addition, if there are uncertainties in the exposure data, then obviously a 10x safety factor should be applied.
  4. A Panel Member questioned how a chemical would be treated if it was more hazardous to adults than to juveniles, such as is the case with some peripheral neuropathies. The Agency commented that the FQPA safety factor may be decreased if greater sensitivity to adults occurs. However, another Panel Member expressed concern with this approach. While a chemical may demonstrate greater toxicity with adults versus juveniles, that may not indicate juveniles are less vulnerable to the compound.
  5. The Agency background document addressed reduction of the safety factor, while the FQPA notes that there could be a change in the factor (i.e., either decreases or increases from 10x would be possible). It was pointed out that the factor could be larger if the data indicated a greater than ten fold difference in sensitivity between adults and juveniles; larger factors have been used in the past based on identifiable hazard concerns.
  6. The Panel strongly endorsed the Agency s position to be completely transparent in explaining the decision process for including or excluding a given safety factor. Thus, a clear presentation of the scientific basis for retaining, reducing or increasing the FQPA safety factor is desirable.

Questions to the Scientific Advisory Panel

The Agency poses the following questions to the SAP concerning the use of a FQPA 10x safety factor to address special sensitivity of infants and children to pesticides.

  1. 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?

    The Panel did not reach a consensus on the response to this question. Some of the Panel Members thought that the currently required core tests could trigger (require) further testing of developmental toxicity, particularly neurotoxicity. The currently required tests use high dose levels (at or exceeding the maximum tolerated dose) over appreciable periods of development and elicit most potential toxic responses. Observations of test animals occurring during the conduct of these studies should be indicative of potential neurotoxicity. In this sense, additional studies would be driven by the nature of the data needed. It was noted that animals may appear to show signs of neurotoxicity at high doses which are artifacts of the overall high dose level effects on physiology. Panel Members suggested that the toxicity data available on several neurotoxic pesticides should be analyzed to assess whether these data sets would have triggered additional developmental neurotoxicity studies. In other words, do currently available data provide the Agency reasonable certainty that developmental neurotoxicity studies would be adequately triggered with the current test guidelines? It is understood that further studies may be required on a case- by-case basis using a weight-of-evidence evaluation to define the magnitude of the developmental dose/response effect.

    In contrast, others on the Panel believed that the currently required toxicity tests would not be adequate for detection of potential developmental toxicity, including neurotoxicity. Some Panel Members concluded that the current tests are outdated and utilize insensitive endpoints which will not identify subtle (or less obvious) effects. Functional endpoints may be far more meaningful than morphological endpoints, particularly for neurotoxicity. In addition, some Panel Members questioned whether standard teratology tests would identify developmental neurotoxicity because of the windows of susceptibility. The Panel was informed that the Agency has efforts underway to modify core tests. The Panel urges the Agency to continue evaluation of the core tests required and evaluation of the design inherent in these required tests to optimize the likelihood of detection of developmental toxicity. In addition, as noted previously, testing validation should be implemented for development of testing guidelines.

    Chronic exposure studies do not always yield the same results as studies using a limited exposure design; the required tests may not yield endpoints actually identifying NOAEL s. In addition, prenatal targets may be different from those in adults because of the development of the brain during this time. As an example, migration of nerve cells to their final locations during embryonic, fetal and neonatal development should be an endpoint in a developmental neurotoxicity study.

    The history of lead toxicity to children was reviewed by a Panel Member as an example of a neurotoxicant that was not originally recognized to be a developmental neurotoxicant with permanent effects to children. Although lead is not a pesticide, the chemical provides a unique comparison to pesticides in relation to developmental neurotoxicity. More is known about the effects of lead on children than any other toxicant, and the history of the development of knowledge of lead neurotoxicity could inform decision making about other neurotoxicants, including pesticides.

    A Panel Member applied the history of lead toxicity to pesticides. Gross observation of rodent behavior may be reported as normal whereas quantitative analyses disclose substantial deficits. The October, 1996, SAP report recommended the consideration of Schedule Controlled Analysis of Behavior to look for altered function. These methods, which are widely used, are considered much more sensitive to toxicant-induced alterations in neural function. Neurocognitive deficits from insecticide exposure have been reported in the literature, and some Panel Members thought that operant conditioning tests should be added to the tests required by the Agency (the Panel also recognizes that these methods require validation). However, there is no evidence that the 1996 SAP recommendation has been addressed by the Agency. Thus the Panel Member concluded that the question posed above was previously addressed by the SAP; the data as required are not sufficient to achieve this goal.

    The Panel also expressed concern that animal tests may not detect toxicities that could occur in humans and that perhaps epidemiological studies should be employed. However, the Panel acknowledged that epidemiology analyses generally are not very sensitive, and that new compounds which are candidates for registration would have no history for epidemiology studies.

    With respect to the requirement of pharmacokinetic data on young animals, the Panel indicated that these tests should not necessarily be routine. Directed pharmacokinetic studies may be useful, particularly in the case where an active metabolite is formed. If the parent compound exerts the toxic effect, the slower clearance in the juvenile would indicate enhanced sensitivity. If a metabolite exerts the toxic effect, the lower rate of bioactivation in the juvenile would suggest reduced sensitivity. Directed pharmacokinetic studies may be of great value in determining the appropriate magnitude of the FQPA safety factor. However, it was pointed out that pharmacokinetic studies of agents acting by covalent interactions with targets, such as the anticholinesterases, would probably not be useful or readily interpretable since the amount of covalent interaction, not the measured amount of compound in a tissue, is the critical factor for toxicity.

    Because of this disparity of opinion, the Panel believes it is imperative that the Agency re-evaluate the current toxicity testing guidelines that are pertinent to the implementation of the FQPA 10x safety factor, to ensure that the guideline studies develop the type of data that are required to assure safety to infants and children. The Panel encourages the Agency to review its current data base, especially on pesticides that are known to be neurotoxic, to evaluate how many pesticides with neurotoxic properties (especially those where there is evidence of effects on the developing fetus, etc.) would have been missed using such a triggering mechanism. The Panel also believes that it would be useful to survey the data base in a similar manner to see if the current data package is adequate to identify pesticides that would have specific effects on the developing immune and other systems.

  2. 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 background 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?

    The majority of the Panel agreed that the developmental neurotoxicity test should be a second tier test at this time, although it might be important to include it as part of the core tests in some cases. As an example, if a pesticide is considered a neurotoxicant to insects, then a developmental neurotoxicity study should be performed. In this regard, the Panel felt that Agency procedures for requiring developmental neurotoxicity studies need to be revised to address the need for such studies. The Panel indicated that adverse effects from tests of cognition, memory, and other higher brain functions be included in the neurotoxicity assessment, as an addition to the five criteria provided by the Agency (i.e., cause central nervous system malformations following prenatal exposure; affect brain weight in offspring, which does not appear to be related solely to general growth retardation, following pre- and/or postnatal exposure; cause neuropathology in developing or adult animals or neuropathy in humans; cause persistent functional changes in the offspring which may be the result of effects on the nervous system and; act to significantly modify hormonal responses associated with the development of the nervous system, leading to significant developmental effects such as effects on sexual maturation).

    In addition, ultrastructural anatomy investigations, using quantitative techniques to look at dendritogenesis, synaptic maturity and other alterations not visible at the gross or histologic level should be conducted, as necessary. Gross anatomic malformations, or pathologic changes, altered brain weight, etc., are insensitive measures of neurotoxicants and are open to large Type II errors. The Panel suggested that the developmental test guidelines be reevaluated based on FQPA 10x safety factor requirements for infants and children. Thus, as stated here and in response to other sections of this question as noted below, the Panel concluded that the criteria for determining the need for a developmental neurotoxicity study requires further enhancement.

    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)?

    Discussion by Panel Members indicated that any pesticide that works by poisoning the nervous system of insects should be considered for developmental neurotoxicity testing by the most sensitive validated methods available, as noted in the response to Question One. Panel Members differed on whether or not developmental neurotoxicity testing should be required for all pesticides.

    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?

    As noted previously, several Panel Members indicated that the approach proposed by the Agency is appropriate for any pesticide that is neurotoxic to insects. The Panel s response to Part D (below) provides additional comment to this question.

    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?

    Consensus was not reached on this point, with similar reasoning as discussed in the response to Question One. There was concern that the limited exposure time may not identify effects (effects may occur only at doses higher than the true LOAEL), and the data to address this concern are not available at this time. The Panel suggested that a workshop, including developmental toxicologists, be organized to address such issues as toxicity study protocol improvements. Thus, the Panel agreed that there was a need for a better toxicity data base for the necessary tests.

  3. Does the Panel have any specific comments on the general approaches described in the background document (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 remarked that if appropriate toxicity data are not available, the FQPA 10x safety factor should not be removed. The Agency responded that this would be an unusual situation, in which other data might be available in the literature which might address the issue. However, usually the FQPA safety factor would not be removed.

  4. Does the Panel have any specific comments on the general approaches described in the background document (p. 27) regarding the contribution of exposure assessment in determining if it is appropriate to remove or reduce the FQPA factor?

    The Panel questioned what precisely was meant by no detectable exposure in the Agency s background document, since it seems extremely unlikely that exposure would never occur under any circumstances. While the Agency responded that use pattern information would be used and that highly atypical exposure scenarios were not intended to be covered, the Panel believed that clarification was necessary. The Panel also concluded that it was important to increase the clarity of what is meant by reliable data and what would occur in the absence of exposure data. The Agency responded that it would not make a decision (e.g., registration) without exposure data. The Panel suggested that the Agency reevaluate whether such a decision could be made without exposure data, characterizing the uncertainty and/or lack of exposure data in the risk assessment and the level of uncertainty in exposure data acceptable before the FQPA 10x safety factor is applied.

  5. The following are general principles which are recommended for application of the FQPA safety factor to risk assessment as noted in the background document (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 agreed with the general principles for application of the FQPA 10x safety factor. However, the application of the FQPA 10x safety factor based on the above principles could be altered if a subpopulation is not identified as the sensitive subpopulation and for other considerations. The Panel also agreed that the Agency identified all subpopulations for application of the FQPA safety factor (i.e., females of child-bearing age [age 13+], adult males, and infants and children ages 0-1, 1-6, 6-12). The Panel questioned whether there are data on pesticides indicating developmental toxicity due to exposure of the adult male. This has occurred with some non-pesticidal compounds, but it appears to be a rare phenomenon. A Panel Member urged the Agency to investigate whether the adult male population is a likely target of developmental toxicity and reproductive toxicity (to include male-mediated developmental toxicity in the first or subsequent generations).

    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?

    The Panel provided limited comment to this question because the topic of endocrine disruptors is the subject of the May, 1998, SAP/SAB meeting.

    Are there any other issues raised by this paper upon which the Panel would like to comment?

    The Panel suggested that the finalized Agency position be published in the peer review literature. The Agency was urged to harmonize with other U.S. (e.g., Food and Drug Administration) and international agencies (e.g., Organisation for Economic Co-operation and Development).

FOR THE CHAIRPERSON:

Certified as an accurate report of findings:

Paul I. Lewis
Designated Federal Official
FIFRA/Scientific Advisory Panel
DATE:_____________________

Scientific Advisory Panel (SAP) March 1998 Meeting Final Report

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