The Food Quality Protection Act of 1996 (FQPA) requires the EPA to consider 'available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity... in establishing, modifying, leaving in effect, or revoking a tolerance for a pesticide chemical residue.' This directive raises a number of scientific questions to be answered before the FQPA can be implemented. Among these questions is: What constitutes a common mechanism of toxicity? The ILSI Risk Science Institute (RSI) convened a group of experts to examine this and other scientific questions using the organophosphorus (OP) pesticides as the case study. OP pesticides share some characteristics attributed to compounds that act by a common mechanism, but produce a variety of clinical signs of toxicity not identical for all OP pesticides. The Working Group generated a testable hypothesis, anticholinesterase OP pesticides act by a common mechanism of toxicity, and generated alternative hypotheses that, if true, would cause rejection of the initial hypothesis and provide criteria for subgrouping OP compounds. Some of the alternate hypotheses were rejected outright and the rest were not supported by adequate data. The Working Group concluded that OP pesticides act by a common mechanism of toxicity if they inhibit acetylcholinesterase by phosphorylation and elicit any spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be used to determine if other classes or groups of pesticides that share structural and toxicological characteristics act by a common mechanism of toxicity or by distinct mechanisms.
Bibliographical noteFunding Information:
The authors, all members of the ILSI Risk Science Institute Working Group on Common Mechanism of Toxicity, acknowledge the contributions made by members of the Steering Committee for this project who did not participate as Working Group members: Dr. Karl Baetcke, Dr. Craig Barrow, Dr. Vickie Dellarco, Dr. Michael McClain, and Dr. Gary Patterson, and the contributions of the Executive Director of ILSI RSI, Dr. Jeffery Foran, and the Deputy Director of ILSI RSI, Dr. Stephen Olin. We also thank peer reviewers of this paper, Dr. John Doull, Dr. James Bus, and Dr. Robert Hollingworth, who provided many constructive suggestions for improving the paper. The secretarial support of Eugenia Macarthy is greatly appreciated. Funding for this project was provided through cooperative agreements between ILSI RSI and the U.S. EPA Office of Pesticide Programs and Office of Water, with additional support provided by the American Crop Protection Association.