A Common Mechanism of Action: The Organophosphate Pesticides
A Report to the Science Advisory Panel
13 February 1998
The recently enacted Food Quality Protection Act (FQPA, 1996) directs the US EPA to conduct assessments of potential human risks associated with exposure to pesticides using some fundamentally new approaches. Among the factors to be considered in performing tolerance assessments for pesticides is the mandate to consider "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity."
As part of an ongoing effort to implement the requirements of the FQPA, the Health Effects Division of the Office of Pesticide Programs has developed a number of guidance documents on science issues such as in utero testing, on factors to be considered in applying the 10X uncertainty factor to insure adequate protection for susceptible infants and children, and on how one is to determine whether exposures to two or more chemicals should be grouped, based on a common mechanism of action, when performing risk assessments.
The organophosphate pesticides, 39 of which are registered for use by the US EPA, have been assigned top priority for tolerance reassessment and draft risk assessment documents for many have been completed or are nearing completion. It must be determined whether exposures to two or more should be combined for risk assessments based on knowledge of a common mechanism of toxicity and on exposure considerations before tolerance reassessments can be completed. Although a guidance document is available which presents the approach to be taken when determining whether two or more chemicals operate by a common mechanism of action, a fundamental scientific question in need of resolution in the case of the organophosphate pesticides was whether cholinesterase inhibition alone was sufficient evidence of a common mechanism of action.
The importance of the issue of how to evaluate the cumulative effects of organophosphate pesticides led to the establishment of a series of projects on common mechanisms of action and on cumulative and aggregate risk assessment processes. A cooperative agreement was established with the Risk Sciences Institute (RSI) of the International Life Sciences Institute (ILSI) to address the topics. The initial effort of RSI focused on the issue of what constitutes a common mechanism of toxicity; the organophosphate pesticides were used as a case series of chemicals to answer the question. Following a series of workgroup meetings and a final workshop open to the public, RSI issued a report, to be published in Toxicological Sciences, which presents the conclusions of national and international experts regarding principles to be followed in determining whether any group of chemicals can be considered to exert effects through a common mechanism of toxicity as well as specific conclusions regarding common mechanisms of toxicity of the organophosphate pesticides. The RSI report (attached) provides the scientific basis for the science policy which the Office of Pesticide Programs intends to follow when assessing potential risks that may be associated with exposure to two or more organophosphate pesticides. The essence of the policy is that the organophosphate pesticides are considered to express toxicity through a common biochemical interaction with cholinesterase which may lead to a myriad of cholinergic effects and, consequently, the organophosphate pesticides should be considered as a group when performing cumulative risk assessments.Scientific Advisory Panel (SAP) March 1998 Meeting