The Food Quality Protection Act (Public Law 104-170) significantly amends federal regulatory authority over the registration, use, and human health effects of pesticides. To ensure the highest standard of protection, the law changes the mechanisms and procedures used to regulate human exposure to pesticides and their residues. Beyond these structural refinements, however, the FQPA codifies a new approach to risk assessment which reflects breakthroughs in the biological and toxicological understanding of pesticide exposure. These breakthroughs result from an analysis of the cumulative effects of exposure to multiple active ingredients from dietary, residential, and other non-occupational sources. Advances in risk assessment make it possible to expand traditional one active ingredient, one source exposure models to incorporate a more representative understanding of multiple compounds and diverse vectors. The scientific rationale behind the FQPA moves beyond a static, one dimensional approach to risk assessment to more closely simulate real world exposure. In the evolution of pesticide regulation, the FQPA represents the next generation of thinking and will require innovation and determination to implement successfully.
The Environmental Protection Agency (EPA) is responsible for translating the new science embodied in the FQPA into new regulation. In drafting "Guidance for Identifying Pesticide Chemicals That Have a Common Mechanism of Toxicity for Use in Assessing the Cumulative Toxic Effects of Pesticides," the EPA addresses an emerging science policy issue which is critical to successful implementation of the Act. The understanding that pesticidal active ingredients can share structural and functional similarities is not new, but factoring these common characteristics into a comprehensive risk assessment certainly is. Adopting a common mechanism of toxicity approach was a key recommendation from the 1993 National Research Council (NRC) study Pesticides in the Diets of Infants and Children and its 1987 predecessor Regulating Pesticides in Food: The Delaney Paradox. In particular, Pesticides in the Diets of Infants and Children approached the fundamental objective of pesticide regulation—the determination of human safety—with an awareness of the important cumulative and potentially synergistic effects which active ingredients of a similar nature may induce. In drafting the FQPA, the House and Senate empowered the EPA Administrator to consider "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity" when determining pesticide tolerances. (Public Law 104-170, Section 408(b)(D)(v)). The NRC reports established the scientific foundation for incorporating consideration of a common mechanism of toxicity into human health risk assessments and the FQPA elevated the principle to a statutory responsibility. The EPA has ample scientific grounding and Congressional intent to support a broad interpretation of the common mechanism of toxicity principle.
In responding to the EPA’s draft guidance on common mechanism of toxicity, the Henry A. Wallace Institute of Alternative Agriculture commends the Agency for the considerable effort and progress it has made in this area. We are generally supportive of the positions outlined in the guidance; the statements made on the subject by the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Scientific Advisory Panel; and the conclusions reached in the preliminary analysis conducted by the Risk Science Institute’s (RSI) Working Group. While the guidance is generic and does not make reference to specific compounds, we will refer to the RSI’s case study on organophosphorous compounds to illustrate our position. The appropriate application of the common mechanism of toxicity principle is a crucial step forward in effectively understanding and mitigating the risks imposed by the pesticide products we rely upon.
I. Background
This section of the guidance makes important references to the new human health protection standard which underpins the FQPA. The desire to achieve a clearer, more communicable protection standard to replace the inconsistencies which existed between fresh and processed food products (the Delaney Paradox) had been a major objective in pesticide regulatory reform for years. In establishing criteria for setting tolerances, the FQPA defined safe to mean "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue...." (Public Law 104-170 Section 408(b)(2)(A)(ii)). In its report language, the Commerce Committee expanded the "reasonable certainty of no harm" principle to account for differences between threshold and non-threshold effects. For threshold effects, the Committee endorsed EPA’s traditional application of a 100-fold safety factor (tenfold intraspecies, tenfold interspecies) to the scientifically determined no observable effect level (U.S. House of Representatives, 1996). Public Law 104-170 Section 408(b)(2)(C)(ii) imposes an additional safety factor of up to tenfold to ensure the safety of infants and children. For non-threshold effects, the Committee directed the EPA to apply a one-in-a-million lifetime increase in cancer as the threshold for acceptable risk. The report noted that while the statutory language does not preclude the EPA from changing its risk assessment methodology, the Committee requested that any such changes be scientifically proven to be "equally protective of the public."
The FQPA’s strict and explicit human health protection standard requires consideration of the common mechanism of toxicity principle when determining safe levels of exposure for all segments of the population. Public Law 104-170 Section 408(b)(2)(C)(i)(III) states that when determining a tolerance, the Administrator "shall assess the risk of the pesticide chemical residue based on available information concerning the cumulative effects on infants and children of such residues and other substances that have a common mechanism of toxicity." Public Law 104-170 Section 408(b)(2)(D)(v) establishes "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity" as one of nine relevant factors which the Administrator shall consider in determining tolerances. Congress clearly recognized the common mechanism of toxicity principle as an essential component of the strong human health protection standard it created through the FQPA.
II. Definitions of Specific Terms Used in this Notice
The terms toxic effect, mechanism of toxicity, and common mechanism of toxicity contain the key parameters for determining which active ingredients will require cumulative treatment in the risk assessment process.
As defined in the draft guidance, toxic effect refers to "an effect observed in humans that results from exposure to a chemical substance and that will or can reasonably be expected to endanger or adversely affect quality of life." The degree to which a verifiable reaction to exposure can be said to "endanger or adversely affect quality of life" becomes the key benchmark in determining if a toxic effect has been achieved. The examples provided in the guidance, including acute lethality and loss of hearing, suggest a measure of severity well beyond the neurological and behavioral effects often associated with exposure to pesticides. For example, numerous studies suggest that the repeated exposure of human subjects to organophosphate compounds can have long-lasting effects, sometimes even after the usual biochemical indices of exposure, such as serum cholinesterase, have returned to normal (Annau, 1992). However, it would be challenging to document and quantify such neurological effects in a manner similar to a straightforward determination of lives lost or hearing impairment. It should not be necessary for a verifiable response to an exposure or exposures to result in gross physical trauma for it to be considered a toxic effect.
The organophosphate compounds illustrate the difficulty of establishing appropriate and verifiable endpoints for the determination of a toxic effect. The biochemistry of acute exposure to these compounds is well understood; inhibition of acetylcholinesterase results in accumulation of acetylcholine and triggers excitation of the somatic and autonomic nervous systems. Classic toxic effects include nausea, headache, abdominal cramps, fixed pupils, random muscle twitches, and respiratory paralysis leading to death (Chambers, 1992). However, considerable clinical and real work exposure studies have documented neurological complications from chronic exposures to organophosphates, including memory deficits, linguistic disturbances, depression, anxiety, and irritability (Annau, 1992). Neurological and behavioral injury should be identified as appropriate toxic effects in the risk assessment process for all materials covered by the FQPA.
The development of methodology to incorporate common mechanism of toxicity concerns into risk assessments for exposure to pesticides was a significant accomplishment of the NRC’s Pesticides in the Diets of Infants and Children. However, the specificity of the mechanism of toxicity concept remains a critical but imprecise variable in calculating risk. There are two fundamental components of this variable: (1) How much must be known about the mechanism of toxicity before two active ingredients can be said to share a common one?, and (2) How much difference or variation can two materials exhibit and still be said to act similarly? The question of how much needs to be known addresses both the minimum requirements and the practical limitations of the data required to make a determination. Establishing a common mechanism of toxicity should certainly require an advanced understanding of the individual mechanisms. However, gaps in understanding of the mechanisms should not be used to delay or avoid a determination of common mechanism in cases where the preponderance of evidence points to similarity. It is not necessary and may not be possible to identify every step in the processes before concluding that they share a common mechanism of toxicity. Likewise, minor differences in the known mechanisms of toxicity among active ingredients should not be used to avoid a finding of a common mechanism when the ultimate toxic effect is essentially the same. Subtle differences among individual active ingredients should not outweigh a broader understanding of functional similarity when making the common mechanism determination.
In preparing to fulfill its obligations under the FQPA, the EPA developed two case studies on how to determine a common mechanism of toxicity. In 1997, the Office of Pesticide Programs prepared "The Grouping of a Series of Chloroacetanilide Pesticides Based on a Common Mechanism of Toxicity." This paper identified structural similarity as the rationale for bringing together the group of compounds under investigation. In 1998, the EPA collaborated with the International Life Science Institute (ILSI) in bringing together a group of experts to draft and publish "Common Mechanism of Toxicity: A Case Study of Organophosphorous Pesticides." The ILSI Working Group expanded the common mechanism criteria to include (1) causing the same effect; (2) acting on the same molecular target at the same target tissue; and (3) acting by the same biochemical mechanism of action, possibly sharing a common toxic intermediate (Mileson, et. al., 1998). The Working Group was undecided whether or not all three criteria had to be fulfilled in order for active ingredients to share a common mechanism of toxicity. The FIFRA Scientific Advisory Panel also contributed to the preparation of the current draft guidance and supported the ILSI’s conclusion that both structural and mechanistic similarity are appropriate criteria for determining similarity (FIFRA Scientific Advisory Panel, 1998).
Review of this literature supports the interpretations of mechanism of toxicity and common mechanism of toxicity contained in the draft guidance. In particular, we concur with the EPA’s assessment that:
"...mechanism of toxicity is defined as the major steps leading to an adverse health effect following interaction of a pesticide with biomolecular sites. All steps leading to an effect do not need to be specifically understood. Rather, it is the identification of the crucial events following chemical interaction that are required in being able to describe mechanism of toxicity."
Additionally, we support the definition of common mechanism of toxicity as applicable to "two or more pesticide chemicals that produce an adverse effect(s) to human health by the same, or essentially the same, sequence of major biochemical events." These definitions will prevent data gaps and inconsequential variation among active ingredients from disrupting the Agency’s ability to make a finding of common mechanism of toxicity. The current guidance is sufficient to support the common mechanism of toxicity finding for large groups of compounds such as the organophosphates where functional similarity is well established and understood. We believe that in this respect, the guidance is consistent with the intent of the FQPA and thoroughly grounded in the advances in risk assessment which have made use of the common mechanism of toxicity principle possible.
III. Identifying Pesticide Chemicals that are Toxic from a Common Mechanism
IIIa. Selection of Pesticides that are likely to have a Common Mechanism of Toxicity
The guidance identifies structural similarity, mechanism of pesticidal action, and common toxic effect as appropriate criteria for grouping chemicals under consideration for a common mechanism of toxicity. Structural similarity extends to a variety of features including toxicophore, base structure, or functional group. The structural similarity criterion accommodates a degree of variation; by definition, no two distinct active ingredients could be structurally identical. As the FIFRA Scientific Advisory Panel noted in its comments on an earlier draft of the guidance, "Chemicals with similar structures may not have the same mechanism of action. However, grouping chemicals with structural similarities can serve as a starting point or a convenient way to triage chemicals for examining the basis for common mechanisms." (FIFRA Scientific Advisory Panel, 1998). The mechanism of pesticidal action criterion reflects the fact that the pathways and outcomes of the toxic effect in a target species can be essentially identical to those in humans. The inhibition of acetylcholinesterase which exposure to organophosphates triggers in insects and humans illustrates this principle. The guidance also identifies a shared toxic effect as a valid criterion for identifying compounds with a potential common mechanism of toxicity. Since a common effect could be attributable to a variety of essentially unique causes, this criterion, like structural similarity, should only be used as a starting point for investigation. We support retaining all three criteria in the draft guidance as the foundation of a conservative approach of casting the widest possible net in the preliminary grouping process. This approach will quickly establish a universe of possible groupings of active ingredients operating through a common mechanism of toxicity, which can then be addressed individually.
IIIb. Identification of the Toxic Effects Caused by each Pesticide Chemical
In the draft guidance, the EPA indicates that it will use the primary database generated in support of registration and reregistration activities for determining the toxic effects of active ingredients under FQPA review. This should provide the Agency with the most comprehensive database available on developmental toxicity, reproductive fertility, carcinogenicity, neurotoxicity, and immunotoxicity. The EPA should utilize this data for determining which active ingredients may share a common mechanism of toxicity. However, there are concerns that the EPA’s current testing guidelines are insufficient for uncovering the full range of toxic effects which exposure may induce. For example, as of April, 1998, the EPA had received data from developmental neurotoxicity testing for only six of the several hundred active ingredients currently registered for use as pesticides (Wallinga, 1998). Developmental neurotoxicity studies are designed specifically to assess the effects of pesticides on the developing brain and nervous system and can help identify the delayed effects of prenatal exposure. At a minimum, we strongly recommend that developmental neurotoxicity studies be conducted for all active ingredients whose toxic effects involve suppression or disruption of the central nervous system.
IIIc. Identification of the Toxic Mechanism(s) of each Pesticide Chemical
This portion of the guidance addresses the biochemical pathways by which individual active ingredients cause their primary toxic effect. We concur with the statement in the guidance that:
"While desirable, all of the specific biochemical events involving a pesticide in the causation of its toxicity do not need to be known or completely characterized in order to describe its mechanism of toxicity. What is needed, as a minimum, is an understanding of those biochemical events that are most crucial in causing the toxicity."
For the practical and timely implementation of the FQPA, the EPA must be prepared to make decisions when the weight of evidence strongly suggests an appropriate course of action. The statutory language pertaining to the common mechanism of toxicity principle supports an expedited review and decision making process. The law instructs the Administrator to utilize "available information" when determining "cumulative effects of residues and other substances that a have a common mechanism of toxicity." (Public Law 104-170, Sections 408(b)(2)(C)(III) and 408(b)(2)(D)(v)). The EPA has the ability to conduct a data call in for areas in which genuine uncertainty exists, but the primary database used in the registration and reregistration processes plus the available scientific literature should most often be sufficient to determine when a common mechanism of toxicity exists. As cited in the guidance, data pertaining to analogs of a pesticide can be useful as surrogate data when such information is lacking for the pesticide itself. This is a clear example of how available information can serve as the basis for effective regulatory action when the pursuit of new or additional data could lead to an unreasonable delay. While we believe that the existing data base should be sufficient to expedite implementation of the law, we emphasize that the FQPA has as its primary purpose the protection of human health. The EPA should diligently incorporate precaution into every stage of the risk assessment process.
IIId. Comparison of Mechanisms of Toxicity: Identification and Categorization of Chemicals that are Toxic from a Common Mechanism
This section of the guidance helps explain how the Agency will compare separate compounds once their individual mechanisms of toxicity have been determined. We find the guidelines in this area to be thin relative to the specificity found elsewhere in the draft. For example, the guidance identifies the nature and sequence of the major biochemical events that cause toxicity as the basis for determining a common mechanism. The subsequent explanatory language does not, however, provide meaningful insight into the degree of similarity which the Agency will consider adequate. Would a shared toxic effect—suppression of acetylcholinesterase—be sufficient for all organophosphate and carbamate compounds to be treated as acting with a common mechanism? We believe that strong arguments exist to support a finding of common mechanism of toxicity for all organophosphate and carbamate compounds, yet recognize that significant mechanistic differences exist among individual compounds. We seek additional elaboration from the EPA on its rationale for comparing individual mechanisms of toxicity.
IIIe. External Review
We support strongly the EPA’s commitment to seek and incorporate external peer review for the critical issues pertinent to FQPA implementation. The FIFRA Scientific Advisory Panel and the ILSI Risk Management Institute are examples of peer review bodies which have made considerable contributions to improved understanding and consensus building surrounding the new approaches and methodologies which the law requires.
Submitted September 3, 1998
by Mark Keating, Policy Analyst
on behalf of the Henry A. Wallace Institute for Alternative Agriculture
Annau, Z. 1992. "Neurobehavioral effects of organophosphorous compounds." Organophosphates - Chemistry, Fate, and Effects. J.E. Chambers and P.E. Levi, (eds.). San Diego: Academic Press.
Chambers, H.W. 1992. "Organophosphorous compounds: An overview." Organophosphates - Chemistry, Fate, and Effects. J.E. Chambers and P.E. Levi, (eds.). San Diego: Academic Press.
FIFRA Scientific Advisory Panel. 1997. A Set of Scientific Issues Being Considered by the Agency to Discuss and Evaluate the Common Mechanism of Toxicity. Notes published following an open meeting held on March 20, 1997.
Mileson, et. al. 1998. "Common Mechanism of Toxicity: A Case Study of Organophosphorous Pesticides". Toxicological Review 41:8-20.
National Research Council. 1987. Regulating Pesticides in Food: The Delaney Paradox. Washington, DC: National Academy Press.
National Research Council. 1993. Pesticides in the Diets of Infants and Children. Washington, DC: National Academy Press.
U.S. House of Representatives, 104th Congress, Second Session. 1996. Committee on Commerce Report on the Food Quality Protection Act. Report 104 669.
Wallinga, David. 1998. Putting Children First: Making Pesticide Levels in Food Safer for Infants & Children. Washington, DC: Natural Resources Defense Council.
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