By Lisa M. Campbell, Lisa R. Burchi, and James V. Aidala
On December 7, 2020, the U.S. Environmental Protection Agency (EPA) issued for comment the Proposed Interim Decision (PID) for chlorpyrifos. 85 Fed. Reg. 78849. EPA announced it is proposing new risk mitigation measures to address potential human and environmental risks identified in EPA’s September 2020 draft risk assessments. The PID proposes the following measures:
- Label amendments limiting application to address potential drinking water risks of concern.
- Additional personal protection equipment and application restrictions to address potential occupational handler risks of concern.
- Spray drift mitigation, in combination with the use limitations and application restrictions identified to address drinking water and occupational risks, to reduce exposure to non-target organisms.
EPA states that the PID presents proposed mitigation with the 10-fold (10x) Food Quality Protection Act (FQPA) safety factor, reflecting the uncertainties around doses that may cause pre- and post-natal neurodevelopmental effects. Under FQPA, EPA evaluates new and existing pesticides to ensure they can be used with a reasonable certainty of no harm to infants, children, and adults. EPA is required to consider the special susceptibility of children to pesticides by using an additional 10x safety factor unless adequate data are available to support a different factor. EPA additionally included a FQPA factor of 1x to reflect the range of potential risk estimates of chlorpyrifos, as illustrated in the September 2020 draft risk assessments.
Comments on both the September 2020 draft risk assessments and the PID are due on or before February 5, 2021. EPA states that by holding the comment period for both actions at the same time, the public has access to more information and can provide more informed, robust comments. Comments can be submitted at EPA-HQ-OPP-2008-0850.
EPA announced that it will also consider the input and recommendations from the September 2020 Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) meeting once it releases its report in December 2020. Depending on the SAP’s conclusions, EPA may further revise the human health risk assessment.
The inclusion of both 1x and 10x calculations for the appropriate FQPA safety factor is unusual. EPA states the final decision on the appropriate FQPA safety factor is partly dependent on any recommendations expected from the SAP meeting, which reviewed the “use of new approach methodologies (NAMs) to derive extrapolation factors and evaluate developmental neurotoxicity for human health risk assessment.” This is part of a larger and longer evaluation of whether test methods that avoid using test animals can reliably substitute for current test guideline requirements, that is, whether it is appropriate to rely on in vitro test protocols to substitute for current in vivo testing protocols.
EPA’s articulation at this point in time of mitigation needed if the FQPA 10x safety factor is retained may indicate a prediction about the SAP’s likely recommendations. It will be important to monitor developments on this issue closely.
By Lisa M. Campbell, Timothy D. Backstrom, and James V. Aidala
On August 2, 2019, the U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP) announced that it has decided to reduce the Food Quality Protection Act (FQPA) safety factor for infants and children for pyrethroids from its current value of 3X to a new value of 1X. This decision is based on a July 1, 2019, OPP report entitled “USEPA Office of Pesticide Programs’ Re-evaluation of the FQPA Safety Factor for Pyrethroids: Updated Literature and CAPHRA Program Data Review.” Risk assessments incorporating the new lower FQPA safety factor for pyrethroids will be utilized in developing proposed registration review decisions for these compounds, and EPA has stated it will be taking public comment on the OPP report reducing the FQPA safety factor for pyrethroids after EPA publishes a notice of availability for the proposed registration review decisions.
Pyrethroids are a group of insecticides that includes natural pyrethrins (found in chrysanthemums) and more than 30 synthetic compounds with similar structure and activity. EPA has determined that it is appropriate to establish one FQPA safety factor for all pyrethroid active ingredients because these compounds all have the same mode of action and similar patterns of toxicity. Pyrethroid insecticides are widely used in and around residential structures, on pets, in treated clothing, for mosquito control, and in various agricultural applications. EPA indicates that although pyrethroids have relatively low mammalian toxicity, EPA believes that the principal concern for human risk assessment is a potential to cause acute neurotoxic effects.
The FQPA safety factor is intended to account for “potential pre- and post-natal toxicity and completeness of data with respect to exposure and toxicity to infants and children.” The FQPA safety factor is set by statute at a default value of 10X, but EPA may select a lower value for this safety factor if EPA determines based on “reliable data” that such a lower value will be safe for infants and children. This determination necessarily depends on EPA’s assessment of the quality of the data that address the susceptibility to adverse effects of the pesticide of infants and children. Based on current EPA guidance, OPP evaluates the need for the default FQPA safety factor of 10X in two components: a safety factor of about 3X assigned to pharmacodynamic (PD) differences and a safety factor of about 3X assigned to pharmacokinetic (PK) differences. PD differences refer to the sequence of events at the molecular or cellular level leading to a toxic response to a substance, while PK differences refer to absorption, distribution, metabolism, and excretion of the substance.
EPA previously evaluated the adequacy of the database concerning risks to infants and children posed by pyrethroid active ingredients in 2011. At that time, EPA decided that there were sufficient data concerning the mechanism for potential neurotoxic effects of pyrethroids to allow EPA to reduce the factor for PD differences to 1X, but EPA retained the 3X factor for PK differences because EPA believed that the available pharmacokinetic data for pyrethroids was not sufficient for EPA to conclude that infants and children would not confront a greater risk of neurotoxic outcomes. After EPA made the 2011 determinations, the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA) conducted a variety of additional research to address whether children are more sensitive to the neurotoxic effects of pyrethroid exposure, and this research assessed both PD and PK differences. CAPHRA submitted a peer-reviewed physiologically based pharmacokinetic (PbPk) model for pyrethroids to EPA in 2018. After reviewing the new CAPHRA data and the current public literature for pyrethroids, EPA has now concluded that the factor for PD differences should be maintained at 1X, but the factor for PK differences should be reduced from 3X to 1X. Collectively, these determinations mean that EPA has concluded that there are reliable data to support a determination that infants and children are not more susceptible to the neurotoxic effects of pyrethroids than adults, so there is no need to retain either the default FQPA safety factor of 10X or the previous FQPA safety factor used for pyrethroids of 3X.
The adoption by EPA of a new FQPA safety factor of 1X for all pyrethroid active ingredients will likely facilitate retention of existing use patterns and use directions for a large number of pyrethroid insecticides that are commonly used in and around human residences and workplaces.
From a larger perspective, the process by which EPA evaluated and selected a proposed FQPA safety factor for pyrethroids may be seen as typical for most pesticides or classes of pesticides. The selection of a FQPA safety factor for a particular pesticide usually is based on review of available animal data, including PD and PK data, to determine whether there is any basis for concluding that infants and children may be more susceptible to adverse effects of that pesticide than adults. Where EPA decides that the animal data addressing this question are insufficient, affected registrants and other proponents of registration can consult with EPA concerning studies that will address the uncertainties. Depending on the outcome of such studies, EPA may be able to conclude that there is a scientific basis for a partial or complete reduction of the default FQPA safety factor.
Compared to this typical evaluation process, the recent decision by EPA to retain the default FQPA safety factor for all organophosphate (OP) active ingredients, which was based on EPA’s interpretation of neurodevelopmental effects reported at low exposure levels (below the threshold for acetylcholinesterase inhibition) in epidemiology studies for chlorpyrifos, may be seen as an aberration. EPA’s decision to rely on epidemiology studies that may be susceptible to methodological biases, and the decision to utilize epidemiology studies for chlorpyrifos to set the FQPA safety factors for all OP pesticides, have both been controversial.
EPA’s recent decision to retain the current tolerances and registrations for chlorpyrifos was based in significant part on EPA’s interpretation of a PbPk model for chlorpyrifos previously submitted by DowAgro (now Corteva), which mitigated to some degree EPA’s retention of the default FQPA safety factor for chlorpyrifos. Corteva may submit further data addressing PD and PK differences for chlorpyrifos, and EPA has also stated that it intends to review some new animal studies for chlopyrifos, which purport to show neurodevelopmental effects at low exposure levels. Perhaps these data will allow EPA to establish a point of departure (POD) for chlorpyrifos risk assessment without any need for a further excursion into the unfamiliar risk assessment territory represented by EPA’s use of epidemiology data for chlorpyrifos.
By James V. Aidala and Margaret R. Graham
On September 28, 2018, the U.S. Environmental Protection Agency (EPA) announced it was accepting public nominations of scientific experts to be considered for ad hoc participation on the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) through membership on the Food Quality Protection Act (FQPA) Science Review Board (SRB). 83 Fed. Reg. 49091. EPA states that “all nominees will be considered for ad hoc participation providing independent scientific advice to the EPA on health and safety issues related to pesticides” and requests that any individuals nominated have expertise in one or more of the following areas: biochemistry; chemistry; epidemiology; human health risk assessment; pathology; physiologically based pharmacokinetic (PBPK) modeling; aquatic modeling; pharmacology; ecological risk assessment; environmental exposure and fate; environmental toxicology; occupational, consumer, and general exposure assessment; toxicology; dose response modeling; environmental engineering; statistics; water quality monitoring; hydrologist; Geographic Information Systems (GIS) specialist; computational toxicology; entomology; veterinary entomology; medical entomology, insect ecology, allergenicity, research veterinarian; inhalation toxicology; volatile organics; endocrinology, alternative testing methods, high throughput testing approaches, adverse outcome pathways, cross species extrapolation, and systematic review. The Designated Federal Officer’s to whom nominations should be provided is listed in the Federal Register notice. Nominations are due by November 13, 2018.
FPQA added this SRB to the previous authorization for the SAP to recognize the expanding universe of scientific questions which often underlie issues surrounding pesticide registration. The FQPA amendment simply adds that “60 scientists who shall be available to the SAP” without specifying any particular disciplines or skills which might be useful to assist with the deliberations and review by the SAP. This was intended to continually allow EPA to adapt to changing or evolving scientific questions without constantly tinkering with the membership of the SAP itself. At the same time, it allows these ad hoc members to be recognized for their contributions and to be compensated in the same manner as SAP members.
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.
By Lisa M. Campbell, James V. Aidala, and Susan Hunter Youngren, Ph.D.
The U.S. Environmental Protection Agency’s (EPA) January 5, 2015, release for public comment of the revised human health risk assessment of chlorpyrifos (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-0850-0195) reflects another step taken to implement its new spray drift and volatilization policies. These policies were long in the making and the subject of significant discussion and controversy over the years. EPA, with this assessment, has also taken a very public step to implement its controversial policy, announced in December 2009, to apply, effectively, Food Quality Protection Act (FQPA) risk assessment techniques to pesticide uses not subject to FQPA, as part of its commitment to environmental justice.
The spray drift and volatilization policies were discussed in an October 2014 webinar and discussed in our September 17, 2014, memorandum. EPA’s Revised Risk Assessment Methods for Workers, Children of Workers in Agricultural Fields, and Pesticides with No Food Uses, issued in 2009, is discussed in our December 8, 2009, memorandum.
Spray Drift and Volatilization
EPA had been assessing spray drift and volatilization for chlorpyrifos for a number of years, and many of the EPA-derived spray drift and volatilization tools are based on chlorpyrifos data. The January 5 assessment updates the assessment conducted in 2011. This document assesses both potential risks to workers (mixing/loading/applying and re-entry) as well as potential risks to residents (bystanders and food/water consumption). The bystander assessment uses the new tools that EPA released in Spring 2014 to assess potential risks from volatilization and spray drift (as discussed in the B&C webinar). The buffer zones EPA had previously estimated to mitigate spray drift are reduced in the new assessment. The risks noted in the assessment were for workers and specific water areas.
FQPA Risk Assessment Methods Use for Non-FQPA Assessment
In addition to implementing its spray drift and volatilization policies, EPA also assessed exposure in a manner that appears intended to implement the 2009 policy that was the subject of much concern when released for public comment. In that policy, EPA stated its intent to apply risk assessment techniques developed in implementing FQPA’s “extra safety factor” to any pesticide product’s risk assessment, regardless of whether it falls under FQPA, “so long as application of the risk assessment technique is consistent with good scientific practice and is not otherwise prohibited by law.” EPA stated then that this would include “using an additional safety/uncertainty factor to protect children,” as well a number of other factors. EPA announced this policy originally as part of its commitment to considerations of environmental justice.
The chlorpyrifos assessment is based on a physiologically-based, pharmacokinetic-pharmacodynamic (PBPK-PD) model to estimate the toxicologic Points of Departure (POD), thus deriving different toxicological values of concern based on the age, sex, and duration of exposure. The PBPK-PD model is also used to estimate intra-species uncertainty factors (UF), as there is no need for inter-species factors because the model estimates human red blood cell (RBC) acetylcholinesterase/cholinesterase (AChE/ChE) inhibition. Based on the PBPK-PD model, a 10X intra-species factor was used for females of childbearing years whereas it was 4X for all other groups assessed.
The worker of concern in the assessment is defined to be a female of childbearing years due to concern of not only RBC AChE/ChE inhibition, but also the potential for neurodevelopmental effects as seen in epidemiological studies. The epidemiological studies are controversial because there have been many questions about actual exposure to chlorpyrifos, particularly as two studies measured a biomarker that can be seen from exposure to other organophosphates (OP). The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Science Advisory Panel (SAP) reviewed EPA’s assessments of these studies in 2008 and 2012. The SAP concluded that “chlorpyrifos likely played a role” in the observed neurodevelopmental outcomes. EPA determined that based on the weight of evidence (WOE) from animal studies and epidemiological studies, reduction of the 10x “FQPA Safety Factor (SF)” was not appropriate. The residential dietary assessments were compared to a Margin of Exposure (MOE) of 100 (10X FQPA SF x 10X intra-species factor) for women and an MOE of 40 (10X FQPA SF x 4X intra-species factor) for all other ages. The occupational assessments were compared to an MOE of 100 for women and 40 for all other age groups (with no explanation of the reasoning behind those values).
This is noteworthy and should be examined closely because EPA has effectively used an additional “FQPA factor” as a safety factor for occupational assessments. EPA stated in its press release announcing the assessment that potential restrictions may be necessary to protect workers and water.
There is a 60-day comment period for this document, which are due on or before March 16, 2015. Among the issues commenters are likely to address include:
Use of the PBPK-PD model to estimate PODs;
Use of the PBPK-PD model to estimate intra-species uncertainty factors;
Use of the epidemiological data; and
Use of a 10X SF for occupational exposure.
The full impact of this assessment is not yet clear, but it raises many issues of interest to registrants.