COMMON MECHANISM OF TOXICITY - A CASE-STUDY OF ORGANOPHOSPHORUS PESTICIDES

The Food Quality Protection Act of 1996 (FQPA) requires the EPA to con sider ''available information concerning the cumulative effects of suc h residues and other substances that have a common mechanism of toxici ty...in establishing, modifying, leaving in effect, or revoking a tole rance for a pesticide chemical residue.'' This directive raises a numb er of scientific questions to be answered before the FQPA can be imple mented. 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 orga nophosphorus (OF) pesticides as the case study. OP pesticides share so me characteristics attributed to compounds that act by a common mechan ism, but produce a variety of clinical signs of toxicity not identical for all OP pesticides. The Working Group generated a testable hypothe sis, anticholinesterase OP pesticides act by a common mechanism of tox icity, and generated alternative hypotheses that, if true, would cause rejection of the initial hypothesis and provide criteria for subgroup ing OP compounds. Some of the alternate hypotheses were rejected outri ght and the rest were not supported by adequate data. The Working Grou p concluded that OP pesticides act by a common mechanism of toxicity i f 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 grou ps of pesticides that share structural and toxicological characteristi cs act by a common mechanism of toxicity or by distinct mechanisms. (C ) 1998 Society of Toxicology.