Recommendations

1. The Wallace Institute strongly endorses the weight of evidence policy on cholinesterase inhibition outlined in the draft science policy.
   
   
2. The Wallace Institute supports using studies which feature plasma and red blood cell cholinesterase inhibition as critical effects as part of the comprehensive data base for the determination of risk.
   
   
3. The Wallace Institute recommends that the Environmental Protection Agency and its Office of Pesticide Programs (OPP) continue their close collaboration with the FIFRA Scientific Advisory on the development and review of risk assessment practices for cholinesterase inhibiting compounds.

Introduction

The Food Quality Protection Act (Public Law 104-170) significantly amends federal regulatory authority over the registration, use, and human health effects of pesticides. Many provisions of the FQPA, such as the concepts of common mechanism of toxicity and cumulative risk assessment, reflect the groundbreaking methodological advances embedded in the National Research Council's reports Regulating Pesticides in Food and Pesticides in the Diets of Infants and Children. To incorporate these analytical innovations into regulatory practice, the Office of Pesticide Programs, in conjunction which the EPA/USDA Tolerance Reassessment Advisory Committee, identified nine key science policy issues related to FQPA implementation (Federal Register, Volume 63, Number 209). Public comment on the nine draft science policies provides an important opportunity for stakeholders to help translate the new risk assessment tools found in the FQPA into risk management practices which are highly protective of human health.

Although the focus of FQPA implementation is often directed at its methodological breakthroughs, several of the science policy issues reflect traditional uncertainties in pesticide risk assessment. The OPP's science policy on "The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphate and Carbamate Pesticides" (FR 63, Number 214) addresses a subject which long precedes enactment of the FQPA. Restricted use pesticides which utilize cholinesterase inhibition (ChEI), such as organophosphates (OPs) and certain carbamates, are among the oldest and most widely used compounds. Determining the precise significance of ChEI at different points of exposure—in the bloodstream or within the nervous system itself—has always been important for estimating risk from these pesticides. The introduction to the draft science policy outlines many modifications in the OPP's interpretation of ChEI data over the past decade. A close working relationship between the OPP and the FIFRA Scientific Advisory Panel (SAP) has been central to the evolution of the Agency's ChEI policy. The current draft science policy is largely the product of a 1997 collaboration between OPP and the SAP on the interpretation of ChEI data. The Wallace Institute strongly recommends that the active dialogue between OPP and the SAP continue to inform the Agency's ChEI policy after the close of this important public comment opportunity.

ChEI Data and the Risk Assessment Process under the FQPA

The FQPA requires the EPA to re-evaluate existing tolerances within ten years while prioritizing those active ingredients which pose the greatest risk to human health. In conducting a risk assessment, the Agency uses toxicological studies to approximate the anticipated human response to exposure to a standardized dose of a pesticide delivered for a set time through a consistent route. The no-observed-effect-level (NOEL) is an important finding in these studies. The NOEL is used to determine both the reference dose (RfD) for chronic dietary risk, and the margin of exposure (MOE) in the analysis of acute dietary risk. In addition to a NOEL, animal studies are designed to determine a lowest-observed-effect-level (LOEL), or the smallest exposure which induces a detectable critical effect. Because it establishes the dose at which a pesticide triggers a response in an exposed individual, selection of an appropriate critical effect endpoint is vital to a study's significance. The choice of the critical effect endpoint essentially determines the NOEL, which is a principal factor for calculating chronic and acute dietary risk. The critical effect triggered by the LOEL must be sufficiently protective of human health to insure that exposure at the lower NOEL dose will indeed be safe.

Different types of ChEI data can be used for conducting human heath risk assessments. The choice of human subjects or laboratory animals, the decision to monitor clinical symptoms or actually measure ChEI, and whether to measure ChEI in the plasma, red blood cells or within the nervous system are the principal study variables. Procedural considerations often dictate the types of studies conducted. While it is possible to sacrifice laboratory animals and measure ChEI at different receptor sites in their nervous system, similar data from human subjects is unavailable. Animals can offer advantages even when post mortem analysis is not needed; they are, for example, easier subjects for long term trials. By contrast, humans make better subjects when the critical effect endpoint involves clinical symptoms of ChEI such as headache, anxiety, or nausea which can be most easily confirmed verbally. ChEI toxicological studies should be evaluated in the context of the potential health consequences of the critical effect endpoint on the species of test subject. By weighing the significance of every study's critical effect endpoint, the OPP has consistently been able to incorporate a wide variety of ChEI data into its human health risk assessment work.

While the diversity of ChEI data benefits the risk assessment process, prioritizing that data remains a considerable challenge. Risk assessment requires weighing the relative significance of studies addressing different critical effect endpoints amongst a variety of species. Whether it is derived from the observation of clinical symptoms or the actual measurement of ChEI, there is disagreement over how experimental data should be interpreted and compared. Evaluating ChEI studies is further complicated by uncertainty whether the most commonly used critical effect endpoints—inhibition in red blood cells or in blood plasma—constitute adverse effects. The registrant community has argued against using evidence of ChEI in red blood cells or plasma as a critical effect endpoint because inhibition in these locations has no impact upon the test subject's neurological functioning. While generally agreeing that ChEI in the bloodstream is not in itself an adverse effect, the EPA contends that it still represents a useful critical effect endpoint. The Agency has stated that blood cholinesterase is a necessary, if indirect, indicator of adverse effects on the nervous system because data on ChEI in peripheral nervous tissues or target organs are rarely available.

The OPP's designation of organophosphates and carbamates as high risk pesticide classes requiring expedited tolerance reviews brought new significance to the debate over ChEI data. The determination of appropriate critical effect endpoints will be an extremely important issue for determining NOELs for all cholinesterase inhibiting pesticides. These NOELs will in turn drive the allowable exposures through the chronic and acute dietary risk assessment process. Additionally, the FQPA requires that the OPP consider the cumulative and aggregate effects of all pesticides which exhibit a common mechanism of toxicity. While the definition of a common mechanism of toxicity is still being established, cholinesterase inhibiting pesticides are widely considered logical and likely candidates for such a designation. Combining exposure from dietary and nondietary sources for multiple pesticides into a single risk assessment will likely result in an elevated estimate of total exposure. If allowable exposure is kept at a low level because of the critical effect endpoints used in the toxicological studies, tolerances, uses, and even registrations of active ingredients could be canceled.

Discussion

The Wallace Institute supports the weight of evidence (WOE) approach outlined by the OPP in "The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphates and Carbamate Pesticides." The proposal recognizes the variation that exists in the quality and suitability of different ChEI data sources. It creates a hierarchy which prioritizes clinical signs and symptoms in humans, other functional effects, measurement of central and peripheral nervous system inhibition, and ChEI in plasma and red blood cells. The OPP's approach balances its interest in using the most relevant and significant data with its responsibility to make regulatory decisions based on the best available information. Because of the difficulty of obtaining the most refined ChEI data, more accessible measures such as plasma and red blood cell inhibition are needed. The hierarchy enables the OPP to use the most refined data available without drawing a needlessly restrictive prohibition on more elementary studies.

The Wallace Institute sees clear justification for the cautious approach to risk assessment embodied in the OPP's ChEI weight of evidence methodology. The broad foundation for this approach is an explicit commitment to the safety and well being of high risk populations including infants and children. This commitment was central to the pesticide regulation reform recommendations developed by the National Research Council and became a statutory requirement with passage of the FQPA. Some provisions of the FQPA, including enhanced data requirements for pesticide residue levels and food consumption patterns, identify specific actions for protecting high risk populations. The draft policy on ChEI represents an opportunity to bring broader methodological procedures into line with the new, more protective provisions for data collection. In essence, the weight of evidence approach requires that all valid and relevant data be incorporated into the risk assessment process. Risk assessors may attach greater or lesser significance to certain types of data based on the total pool of available information, and there is a recognized hierarchy for ranking what data exists. By reviewing all credible ChEI data, the EPA enhances its ability to make the most conservative and comprehensive risk assessment determinations possible.

The Wallace Institute believes that the draft ChEI science policy is appropriate to fulfill the FQPA's obligation to protect infants and children. An improved understanding of how toxic substances impact sensitive populations has often triggered additional regulatory efforts to reduce exposure. This experience has been repeated with mercury, lead, PCBs, and we anticipate that similar precautions will be needed with cholinesterase inhibiting compounds. The groundbreaking work of the National Research Council pointed in this direction, and current research such as the Natural Resource Defense Council's publication Putting Children First indicate that existing toxicological models are not adequately protective of sensitive populations. Relying on all forms of ChEI data, including inhibition within the red blood cell and plasma fractions, can only enhance the EPA's to develop more protective, and precautionary, standards.

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