US EPA, Tolerance Reassessment Advisory Committee

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TRAC 5/28-29/98

Staff Paper # 2

TOPIC: FQPA SAFETY FACTOR (10X)

BACKGROUND:

The Food Quality Protection Act of 1996 (FQPA) provides important new protections for the Nation's consumers, with special emphasis on measures to ensure the protection of infants and children. These provisions have broad implications for how EPA conducts evaluations of pesticide uses, and in particular, how EPA establishes pesticide tolerances. For example, FQPA requires for the first time that EPA make an explicit determination that pesticide tolerances be set at levels that are safe for infants and children.

Before the enactment of FQPA, the National Academy of Sciences began a study of the scientific and policy issues concerning pesticides in the diets of infants and children. The 1993 National Academy report Pesticides in the Diets of Infants and Children recommended ways in which EPA could enhance existing policies and procedures to improve protection of infants and children, including expanding the use of additional safety factors to more fully ensure safety for infants and children. As one of its conclusions, the NAS Committee specifically recommended that "an uncertainty factor up to the 10-fold factor traditionally used for fetal developmental toxicity should also be considered for postnatal developmental toxicity and when data from toxicity testing are incomplete."

It was in this context that Congress crafted the new child-focused provisions in FQPA. Responding directly to the National Academy recommendation, FQPA provides for the use of an additional safety factor. For threshold effects, FQPA states that:

"an additional tenfold margin of safety for the pesticide chemical residue and other sources of exposure shall be applied for infants and children to take into account potential pre- and post-natal toxicity and completeness of data with respect to exposure and toxicity to infants and children. Notwithstanding such requirement for an additional margin of safety, 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."

This provision went into effect upon enactment of FQPA. All tolerance decisions either associated with tolerance reassessment or new registrations have been subject to this requirement.

Evolving Approach for Applying the FQPA Safety Factor (10X)

EPA's approach to implementing the FQPA safety factor has continued to evolve on the basis of new data, along with experience and a better understanding of potential toxicity to young animals from pre-natal or post-natal exposure to pesticides and continuing peer review of decisions and policy.

Pre-FQPA

Before the passage of the FQPA, EPA analyzed all the available toxicology studies to identify the most appropriate endpoints (e.g., cholinesterase inhibition, effects on central nervous system, reduced birth weight in young test animals) for risk assessments. Generally these endpoints represented the most sensitive endpoints in the most sensitive species, unless there were chemical-specific data available that identified information more appropriate for extrapolating to humans. These analyses included reproduction and developmental toxicity studies in animals, when they were available. These studies, however, were viewed as a part of the entire toxicology database and were used as the endpoint for regulation only if they represented the most appropriate/sensitive endpoint of concern.

Initial Approach

Following passage of FQPA, while still analyzing all of the available data, EPA began to look at developmental and reproduction studies in a more focused manner. After the entire toxicity database was studied and endpoints identified in the traditional manner, the developmental/reproduction studies were analyzed further to determine whether different endpoints should be used in the assessment of hazard to children and women 13 years of age and older. In general, decisions on the FQPA safety factor have been based on weight of the evidence and professional judgment with few formal decision criteria.

Current Approach

In January 1998, upon evaluation and review of the initial approach, EPA submitted a new formal approach to the FQPA safety factor to the Scientific Advisory Panel for review. This approach gives more clarity to how the Agency now considers the completeness of the toxicity database, the type and severity of the effect observed, and the nature and quality of the available exposure data. The application of the FQPA safety factor is not a matter simply of uncertainty, but is also a way of assuring an extra measure of protection for infants and children in cases where special sensitivity or exposure for these subgroups is identified. The retention, reduction, or removal of the FQPA safety factor is still based upon a weight-of-evidence evaluation of all applicable data and reflects sound scientific judgment and principles. An internal FQPA Safety Factor Committee consisting of toxicologists, exposure scientists, and risk managers recommends whether to retain, reduce, or remove the FQPA safety factor.

Review of EPA's Approach

To allow for transparency in the Agency's approach, EPA has asked advice on applying the FQPA safety factor from independent scientific experts and invited stakeholder consultation through the Scientific Advisory Panel (SAP) and the Pesticide Program Dialogue Committee (PPDC). The SAP was generally supportive of the new formal approach but identified the need for more clarity. The Agency will be sending a revised guidance on the FQPA safety factor to the SAP in July.

In addition, on February 25, 1998, EPA Administrator Carol M. Browner and Deputy Administrator Fred Hansen requested that the Office of Prevention, Pesticides, and Toxic Substances, the Office of Research and Development, and the Office of Children's Health Protection conduct an evaluation of the Agency's implementation efforts regarding the FQPA safety factor. An intra-Agency workgroup established in response to this request will soon release its initial report. The group is evaluating both the adequacy of the data used for making decisions about the additional factor and also the adequacy of procedures for consistency, transparency, and documentation.

CASE STUDIES

Pesticide A

In Spring 1997, EPA denied a request submitted by Texas and other states for a Section 18 emergency exemption to use pesticide A on cotton. The request was denied because of concern for acute effects to people from dietary exposure. Agency scientists concluded that the extra ten-fold safety factor should be retained in part to provide an appropriate margin of safety for children in light of uncertainties regarding dietary exposure to people and concerns for special sensitivity to infants and children. With a 50-day window in which to make decisions on section 18s, it was not possible to peer review this decision.

This year, EPA approved a similar request for a Section 18 emergency exemption for pesticide A on cotton, but this time, the Agency applied a three-fold safety factor. The reason for this is that since last year, the Agency has received new information on pesticide A regarding the actual and potential dietary exposures to people. In addition, during a summer 1997 external peer review of the toxicity database for pesticide A, experts advised EPA that no additional safety factor was needed to account for children's sensitivity but that a three-fold safety factor was warranted to account for deficiencies in the studies involved. In short, in this case, EPA's decision to apply a three-fold safety factor was motivated by deficiencies in the final data set, and not because of a particular known hazard to infants and children.

Pesticide B

In May 1997, EPA granted a time-limited tolerance for a pesticide without retaining the application of an additional safety factor. The decision to remove the FQPA safety factor was based upon the completeness of the toxicity database. However in December 1997, the Agency concluded that it was appropriate to retain the additional ten-fold safety factor to assure an extra measure of protection for infants and children because the available toxicity studies clearly indicated increased sensitivity to infants and children.

This scenario highlights the benefit of acquired experience in applying the FQPA safety factor. In the interval between the two decisions, EPA reviewed numerous chemicals which posed a potential hazard to the developing fetus. Based on this acquired knowledge, particularly an increased understanding of the significance of potential toxicity to young animals resulting from pre-natal or post-natal exposures, the Agency placed greater significance on these effects. This increased emphasis on measures to ensure the protection of infants and children compelled the Agency's revised decision to retain the additional ten-fold safety factor for pesticide B.

For pesticide B, new data on anticipated dietary exposures showed that the margin of safety was adequate even with the additional 10X safety factor. In May 1998, the Agency approved the use.

QUESTIONS THAT TRAC MIGHT ADDRESS:

Many feel that within the legal framework of FQPA's "reasonable certainty of no harm," a "complete" toxicity data set can be defined. Although no amount of testing is likely to ever provide complete safety against unknown effects, it is believed that a well-developed testing scheme, updated periodically to include new scientific developments, provides a reasonable basis for risk assessment for infants and children under the statutory standard of "reasonable certainty of no harm."

How is the definition of "completeness" affected by emerging science and new data requirements? As new data requirements are identified, should the Agency re-evaluate previous decisions to retain, reduce or remove the safety factor?

The definition of what constitutes "reliable data" is central to implementation of FQPA, and ongoing Agency effort is focused on defining what level of data on toxicity and exposure constitutes "reliable data". There is general agreement that toxicology data required by Agency regulations (40 Code of Federal Regulations Part 158) are comprehensive; notwithstanding, there is also agreement that data requirements and test guidelines should be updated to include the adult and developmental neurotoxicity guidelines, as well as the criteria and weight of evidence factors for triggering developmental neurotoxicity studies. In addition, it has also been recommended that the revised two-generation reproduction, the pre-natal developmental toxicity testing, and the immunotoxicity guidelines be incorporated into Part 158.

In situations where as a result of the Agency's review, a need arises for additional testing, should the Agency automatically retain all or a portion of the FQPA safety factor even where the registrant has satisfied all of the requirements of Part 158, or should this decision be made by a case-by-case application of the weight of evidence approach?

In light of any newly-identified data needs, the Agency could elect to retain the FQPA safety factor.

If the Agency retains the FQPA safety factor based upon the need to acquire and review these newly-identified studies, what regulatory action should the Agency take if the estimated risks exceed this newly revised "risk cup"? Should the Agency do a data call-in? Should the Agency consider delaying regulatory action until it has had the chance to gather and evaluate data generated to support these new information needs? Would the answer be the same for new pesticides as for existing pesticides?