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March 1998 - SAP Meeting Final Report

A Set of Scientific Issues Being Considered by the Agency in Connection with Common Mechanism of Action of Organophosphates.

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 Common Mechanism of Action of Organophosphates. The review was conducted in an open meeting held in Arlington, Virginia, on March 24, 1998. The meeting was chaired by Dr. Ernest E. McConnell (ToxPath, Inc.) Other Panel Members present were: Dr. Charles Capen (The Ohio State University), Dr. Janice Chambers (Mississippi State University), Dr. Amira Eldefrawi (University of Maryland), Dr. Dale Hattis (Clark University), Dr. Ernest Hodgson (North Carolina State University), Dr. Bruce Hope (Oregon Department of Environmental Quality), Dr. Ronald Kendall (Texas Tech University), Dr. Michele Medinsky (Chemical Industry Institute of Toxicology), Dr. Charles Menzie (Menzie-Cura and Associates), Dr. Robert Moore (University of Wisconsin), Dr. Herbert Needleman (University of Pittsburgh), Dr. B.K. Nelson (NIOSH), Dr. Christopher Portier (NIEHS), Dr. Lawrence Sirinek (Ohio Environmental Protection Agency), 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.

Common Mechanism of Action of Organophosphates

Oral statements were received from the following:
Dr. Charles Benbrook, Consumers Union.
Dr. Rudy Richardson University of Michigan.

Written statements were received from the following:
Consumers Union.

SAP Response to the Agency Presentation

The SAP commends the Agency on the progress to date on developing and implementing a strategy for assessing the risk of pesticides acting by common mechanisms of toxicity. The publication of the International Life Sciences Institute (ILSI) final report of a case study for organophosphate (OP) pesticides is especially noteworthy as this increases accessibility to the ILSI Working Group s deliberations and assures the transparency of the process (the term organophosphate pesticides is being used to describe organophosphorous compounds). The SAP is pleased that the ILSI Risk Sciences Institute (RSI), which convened the Working Group for the OP pesticides (Working Group), is sensitive to the issues of balance and scientific expertise in the Working Group composition. Continued inclusion of all stakeholders increases the broad acceptance of the Working Group's conclusions and recommendations.

SAP Members noted the limited charge of the Working Group in determining if OP pesticides operate by a common mechanism of toxicity. Considerations of pharmacokinetics (PK), pharmacodynamics (PD), and synergistic or interactive effects were not included in the initial charge to the Working Group. Also not included were consideration of dietary deficiencies or concurrent drug and non-pesticidal exposures. The Working Group operated using a very narrow definition of mechanism of toxicity, which involved the events following interaction of the pesticide with the target molecule. The particular molecular interaction was defined as the inhibition of acetylcholinesterase. The narrow scope of the charge to the Working Group precluded the consideration of how PK and PD factors contribute to the overall toxic response to any given compound. These PK and PD considerations are known to be important in evaluating the toxicity resulting from a compound. Despite the relatively large data base on OP s, there was still too limited a data base on factors considered important for the possible subgrouping of compounds. The Working Group excluded other factors in order to keep the considerations focused on the issue of common mechanism of toxicity of OP pesticides as defined.

The SAP acknowledges the value of the report of the Working Group in that the report made the issues associated with grouping chemicals by a common mechanism of toxicity accessible. However, the report did not communicate the difficulty of the task for the Working Group members. Additionally, it was the view of the SAP that the most significant challenges lie not in grouping chemicals, but in reducing the concepts to practice (reduction to practice, in this instance, is the process of starting with a general concept and then developing precise guidelines to define groups that can be considered while excluding chemicals that are inappropriate). Chemically related pesticides may have different modes of action while chemically unrelated pesticides may bring about the same toxic effect. Moreover, a particular chemical may have two or more toxic effects that are unrelated mechanistically to each other. Some factor related to absorption, metabolism, PK, etc., may become rate limiting in the cascade of events between absorption and toxic endpoint for one compound but not another, although the ultimate mode of action may be the same (e.g., cholinesterase inhibition, DNA adduct formation).

The Working Group could not reach resolution as to whether all three guideline principles needed to be fulfilled in order to group chemicals into a common mechanism of toxicity. The guideline principles were: (1) chemicals cause the same critical effect; (2) chemicals act on the same molecular target in the same target tissue; (3) chemicals act by the same biochemical mechanism of action and may share a common toxic intermediate. A Panel Member remarked that this is important to resolve and the consideration of how the outcome of the assessment would be used for risk assessment purposes.

Development of a set of principles that will provide guidance in determining whether or not a group of pesticides act with a common mechanism of toxicity is considered by the SAP as the most important objective for the Agency in formulating a workable strategy. The SAP also recognizes that the issue of common mechanism of toxicity may be even more difficult when the Agency must consider if two different groups of chemicals with distinct mechanistic differences should be combined. For example, OP pesticides and carbamates operate through phosphorylation and carbamylation of acetylcholinesterase, respectively. These biochemical mechanisms are not the same, with the former causing a relatively irreversible inhibition and the latter a reversible inhibition. This difference directly impacts consideration of cumulative versus transient effects.

The possibility of interaction indicates a need for some creativity in defining mechanisms of action for purposes of assessing the risks of combined exposures. A Panel Member provided an example of some pyrethroids and one chlorinated hydrocarbon (i.e. DDT) prolonging sodium channels opening. This would lead to greater release and levels of acetylcholine. The organochlorines or pyrethroids do not inhibit acetylcholinesterase and, therefore, would not be considered to share a common mechanism of toxicity with organophosphates, yet they may synergize each others toxic effects. A Panel Member recommended that combinations of pesticides, with different mechanisms of action, be studied to reveal possible synergisms.

Overall, the Panel was pleased with the progress made to date by the Agency in developing a strategy for grouping chemicals that operate through a common mechanism of toxicity. The Panel also recognizes the practical difficulties inherent in implementing such a strategy. The Agency is encouraged to continue to involve all stakeholders in development of a set of guidance principles and looks forward to reviewing these principles when appropriate.


Certified as an accurate report of findings:

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

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