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By Lisa M. Campbell, Timothy D. Backstrom, and James V. Aidala

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.

Commentary

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.


 

By Lisa M. Campbell, Timothy D. Backstrom, and James V. Aidala

A noteworthy development in the U.S. Environmental Protection Agency’s (EPA) ongoing and controversial consideration of the potential use of epidemiological data in its pesticide risk assessments occurred on May 25, 2017, when EPA placed in the public dockets for certain organophosphate (OP) pesticides an “update” of the September 15, 2015, Literature Review and Food Quality Protection Act (FQPA) determination, along with a response to comments on the original document.  These documents were signed by EPA scientists on December 29, 2016, prior to the new Administration, but were placed in the docket only last month, under the new Administration.  The documents attempt to rebut the various criticisms of EPA’s assessment of the epidemiology studies for chlorpyrifos and the original FQPA safety factor determination for OP pesticides, and they reaffirm the policy embodied in the original Literature Review.  Because these new documents were signed in the last days of the Obama Administration, they may be viewed by some industry stakeholders as an effort by some at EPA to “lock in” the prior policy concerning OP pesticides.

The public release of the “updated” Literature Review and response to comments must be considered in the context of the ongoing chlorpyrifos battles that have received significant public attention.  During the five months between the date that these “update” documents were signed and the date that EPA placed them in the public docket, EPA Administrator Pruitt issued a decision on March 29, 2017, to deny the petition filed by the Pesticide Action Network North America (PANNA) and the National Resources Defense Council (NRDC) requesting that EPA revoke all tolerances and cancel all registrations for chlorpyrifos products.  See EPA Denies Petition to Ban Chlorpyrifos.  In his denial decision, Administrator Pruitt concluded it would be appropriate for EPA to defer determining whether chlorpyrifos is likely to cause neurodevelopmental effects at exposure levels below the levels that cause acetylcholinesterase (AChE) inhibition until the completion of the registration review process for chlorpyrifos.  Administrator Pruitt based his decision on the premise that “the science addressing neurodevelopmental effects remains unresolved” and that “significant uncertainty … exists regarding the potential for chlorpyrifos to cause adverse neurodevelopmental effects.”

Some industry stakeholders may argue that the decision by the EPA scientists who prepared the “updated” Literature Review which concluded that EPA should retain the 10X FQPA uncertainty factor for OP pesticides can be reconciled with Administrator Pruitt’s subsequent denial decision, because the “updated” FQPA safety factor determination does not preclude further scientific discussion concerning the potential for neurodevelopmental effects from OP pesticide exposures.  On the other hand, other industry stakeholders may be concerned about the immediate adverse impact of this “updated” FQPA determination on the risk assessments prepared by EPA for OP pesticides and the measures that will be demanded by EPA to mitigate purported risks.

On April 5, 2017, PANNA and NRDC responded to Administrator Pruitt’s March 29, 2017, decision to deny their petition to revoke the tolerances and cancel the registrations for chlorpyrifos by submitting to the Ninth Circuit Court of Appeals a Motion for Further Mandamus Relief.  That motion was substantially based on the premise that EPA does not “suggest that it has reconsidered its finding that chlorpyrifos is unsafe.”  The briefing on the new mandamus motion was completed on May 5, 2017, several weeks before EPA disclosed the documents concerning the “updated” FQPA determination.  Nevertheless, petitioners could try to argue that these documents constitute further evidence supporting their key premise that EPA has not actually revisited its prior determination that chlorpyrifos exposures are unsafe.

The legal and policy issues posed by EPA’s evaluation of the epidemiological data for chlorpyrifos and by EPA’s determination that these data create sufficient uncertainty to warrant retention of the FQPA 10X safety factor for all OP pesticides will be a continued source of controversy, and will be watched with interest by all stakeholders.

More information and updates on chlorpyrifos, the epidemiological data, and their surrounding legal issues is available on our blog item under keyword chlorpyrifos.