In September 2020, the U.S. Environmental Protection Agency’s (EPA) Office of Pesticide Programs (OPP) plans to convene a Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) meeting to discuss New Approach Methodologies (NAM) for organophosphate (OP) pesticides. EPA states that these NAMs could reduce reliance on default uncertainty factors for human health risk assessment and also reduce animal testing.
Under Administrator Wheeler’s directive to prioritize efforts to reduce animal testing, EPA is developing NAMs based on in vitro techniques and computational approaches that will also provide the opportunity to incorporate information relevant to humans. OPP states that it is evaluating use of “in vitro data for 16 organophosphate compounds to reduce potentially reliance on default risk assessment uncertainty factors in favor of more refined data-derived factors.” Human health risk assessment for OP pesticides has recently been focused primarily on potential developmental neurotoxicity, and the Office of Research and Development (ORD) has been working to develop a NAM to evaluate developmental neurotoxicity. Initial analyses of data derived from neuron cell models have been completed for specific OP pesticides as a case study and, when possible, compared to in vivo results (an in vitro to in vivo extrapolation).
This case study of a NAM for developmental neurotoxicity using OP pesticides will be presented to the FIFRA SAP at the September meeting for its consideration and advice. EPA will request external review and public comment on this research before implementing NAMs in human health risk assessments. Additional details, including dates, times and agenda, will be forthcoming at www.epa.gov/sap.
EPA has for some time had a general policy that it will try to develop and to implement alternatives to in vivo animal testing. These alternatives to animal testing are typically based on new in vitro assays and modeling methodologies. It is interesting that OPP has selected an in vitro NAM to assess developmental neurotoxicity of OP pesticides as a case study, given the controversy surrounding EPA’s use of the default Food Quality Protection Act (FQPA) uncertainty factor for all OP pesticides, which was based primarily on epidemiology data that EPA claimed may suggest a link between chlorpyrifos exposure and developmental neurotoxicity. Prior to this determination, human health risk assessment for OP pesticides was generally based on expert judgments by EPA that neurotoxicity would not be expected below the established threshold for acetylcholinesterase (AChE) inhibition, and that infants and children are not likely to be more sensitive to neurotoxic effects than adults. OPP adopted the FQPA determination for all OP pesticides even though it could not determine or propose a mechanism for the presumed developmental neurotoxicity of chlorpyrifos below the threshold for AChE inhibition, or evaluate whether other OP pesticides might share a similar mechanism. Since the 2015 release of the Literature Review, additional epidemiology studies have become available and a number of concerns regarding the reliability of the epidemiology data have been raised. EPA has also expressed concerns with the availability and reliability of the epidemiology studies. These developments bring into question the accuracy and reliability of the Literature Review.
In its announcement, OPP states that the new NAM is intended “to reduce potentially reliance on default risk assessment uncertainty factors,” although it does not state which uncertainty factors may be supplanted or modified. Standard uncertainty factors which may be implicated include the factor for extrapolating from animal data to human effects (“interspecies variation”), the factor for human variability (“intraspecies variation”), and the default uncertainty factor for potential increased sensitivity of infants and children (“FQPA uncertainty factor”). The issues may spark additional controversy. Additionally, even if OPP and the FIFRA SAP conclude that the proposed NAM for developmental neurotoxicity is a viable approach to human health risk assessment for OP pesticides, there are likely to be many related policy issues. For example, it is unclear whether OPP would be sufficiently confident in the reliability of such an assay to propose cancellation or suspension of affected pesticide products based on a resultant human health risk assessment.