By Carla N. Hutton
The European Food Safety Authority (EFSA) announced on March 15, 2021, that it has begun a public consultation on a draft updated Guidance on the assessment of exposure of operators, workers, residents, and bystanders in risk assessment for plant protection products (PPP). According to EFSA, the Guidance is designed to assist risk assessors and applicants when quantifying potential non-dietary, systemic exposures as part of the regulatory risk assessment for PPPs. The Guidance is based on the Scientific Opinion on “Preparation of a Guidance Document on Pesticide Exposure Assessment for Workers, Operators, Residents and Bystanders” developed by the EFSA Panel on Plant Protection Products and their Residues (PPR) in 2010. EFSA states that highlighting some inconsistencies between the approaches adopted by regulatory authorities, the PPR Panel proposed a number of changes to the practices in use (i.e., use of deterministic methods for individual PPPs; need to perform an acute risk assessment for PPPs that are acutely toxic; use of appropriate percentile for acute or longer term risk assessments). In the first version of the Guidance, issued in 2014, EFSA included several scenarios for outdoor uses, with an annexed calculator, as well as recommendations for further research. EFSA has updated the Guidance in 2021 to include additional scenarios and revise default values on the basis of the evaluation of additional evidence. To support users in performing the assessment of exposure and risk, EFSA further developed an online calculator that reflects the Guidance content. Comments on the draft updated Guidance are due May 9, 2021. EFSA will assess all comments submitted in line with the specified criteria. The relevant EFSA Panel will further consider the comments and take them into consideration if found to be relevant.
By Kelly N. Garson and Carla N. Hutton
On January 27, 2020, the U.S. Environmental Protection Agency’s (EPA) Office of Inspector General (OIG) issued a notification for Project Number OA&E-FY20-0095, announcing that it will begin fieldwork to audit EPA’s adherence to pesticide registration risk assessment regulations, policies, and procedures. In a memorandum addressed to EPA’s Office of Chemical Safety and Pollution Prevention (OCSPP), OIG stated that its objective is to evaluate EPA’s ability to address human health and environmental risks prior to pesticide product registration. OIG will conduct the audit from EPA headquarters. According to the memorandum, the anticipated benefits of this audit include determining whether EPA has adequate controls to address human health and environmental risks prior to pesticide product registration.
OIG is an independent office created by the Inspector General Act of 1978, as amended. Though located within EPA, Congress funds OIG separately to ensure independence as it conducts activities such as audits and investigations to determine the efficiency and effectiveness of EPA’s operations and programs. Following the audit, OIG will prepare a report that may include recommendations for corrective actions OCSPP should take based upon OIG’s findings. More information on OIG’s previous reports and audit system is available on OIG’s website. Recent OIG reports regarding the implementation of FIFRA include:
By Timothy D. Backstrom and James V. Aidala
On December 18, 2019, the Office of Pesticide Programs (OPP) of the U.S. Environmental Protection Agency (EPA) issued for comment a Proposed Interim Decision (PID) in the ongoing registration review process for each of the three registered triazine herbicides: atrazine, propazine, and simazine. EPA will allow 60 days for comment on each of these triazine PIDs, but the specific comment deadline will only be established after EPA has published notice concerning the proposed interim decisions in the Federal Register. EPA can utilize an “interim registration review decision” under 40 C.F.R. Section 155.56 whenever it is not yet ready to complete the registration review process, but EPA has nonetheless completed sufficient review to determine that new or interim risk mitigation measures are needed or that additional data or information should be submitted to complete the review. For each of the three triazine herbicides, EPA is proposing to impose specific risk mitigation measures for particular registered uses to mitigate potential health and environmental risks. For each triazine herbicide, EPA is not yet ready to make a final registration review decision because EPA has not made findings in the Endocrine Disruptor Screening Program (EDSP) or an effects determination under the Endangered Species Act (ESA). Several key factors that will affect the final registration review decision for each of the triazine herbicides are discussed below.
Common Factors for Triazine Risk Assessment
There are several common factors to consider with regard to the triazines risk assessment. These include:
- Atrazine, propazine, and simazine are all included in the chlorotriazine chemical class. EPA has determined that these three herbicides, along with three specific chlorinated metabolites, share a common mechanism of toxicity, so human health risks from all of these substances are being assessed by EPA together through one cumulative triazine risk assessment. The contribution of each product to aggregate human risk differs because of somewhat dissimilar use patterns. The combining of risks resulting from use of each triazine means, however, that it may be necessary for EPA to coordinate the ultimate registration review decisions for the three active ingredients.
- As part of the ecological risk assessment for each triazine herbicide, EPA plans to make an effects determination for potentially vulnerable species under the ESA, which in turn will determine whether it is necessary for EPA to consult with the Fish and Wildlife Service or the National Marine Fisheries Service (the Services) concerning potential impacts of each active ingredient and relevant metabolites on endangered or threatened species. Atrazine, propazine, and simazine are all included in a stipulated settlement between the parties in Center for Biological Diversity et al. v. EPA et al. No. 3:11 cv 0293 (N.D. Cal.), and EPA agreed in that stipulated settlement to set August 14, 2021, as the deadline for EPA to make a nationwide effects determination for each active ingredient, and to request any required consultation with the Services, under ESA Section 7(a)(2).
- EPA states that the predominant human health effect of concern for all three of the triazine herbicides and their chlorinated metabolites is potential suppression of the luteinizing hormone (LH) surge, which is considered to be both a neuroendocrine and a developmental effect. Atrazine and simazine were both included on List 1 for screening testing under the EDSP required by the Food Quality Protection Act (FQPA) amendments. All of the required Tier 1 screening assays for each of these substances are complete and have been evaluated by EPA, but EPA has not yet made human health or environmental findings under the EDSP. The EDSP screening testing has not been completed yet for propazine.
Risk Mitigation Measures
Each PID proposes specific risk mitigation measures intended to address potential human and environmental risks identified by the EPA risk assessments.
For atrazine, the PID includes the following measures to mitigate aggregate human risk:
- Reduce the permissible application rates for use of granular and liquid formulations on residential turf.
- Require additional personal protective equipment (PPE) and engineering controls for certain uses.
- Restrict aerial applications to liquid formulations only.
- Limit backpack sprayer applications to landscape turf to spot treatment only.
- Prohibit pressurized handgun application to certain commodities.
To mitigate ecological risks, the atrazine PID proposes to require various spray drift reduction measures, to add a non-target advisory statement to labeling, and to adopt a nationwide stewardship program.
For propazine, the PID proposes to cancel the greenhouse use to mitigate aggregate human risk. Ecological risks would be mitigated by proposing to require various spray drift reduction measures and by adding a non-target advisory statement to labeling.
For simazine, the PID includes the following measures to mitigate aggregate human risk:
- Cancel simazine use on residential turf.
- Require additional PPE and engineering controls for certain uses.
- Limit pressurized handgun applications to certain commodities to spot treatment only.
Ecological risks would be mitigated by proposing to require various spray drift reduction measures and by adding a non-target advisory statement to labeling.
In each of the PIDs for the triazine herbicides, EPA has focused its efforts on adopting mitigation measures which should be efficacious in reducing human and ecological risks without materially impairing the availability of the products in question for key agricultural uses. In some instances, the PID documents explicitly state that the product registrants have agreed to proposed changes. An EPA Pesticide Program Update dated December 19, 2019, that discusses the interim decision for atrazine includes statements of support from several grower groups.
By Lara A. Hall, MS, RQAP-GLP and Barbara A. Christianson
On December 17, 2019, the U.S. Environmental Protection Agency (EPA) will host its first annual conference in Washington, D.C., to discuss alternative test methods and strategies to reduce animal testing. EPA states that its conference “will bring together some of the leading voices in environmental and health research to discuss efforts to reduce testing on mammals.” The conference will focus on the New Approach Methods (NAM), which include “any technologies, methodologies, approaches or combinations thereof that can be used to provide information on chemical hazard and potential human exposure that can avoid or significantly reduce the use of testing on animals,” and will have U.S. and international scientific experts present information on advancements in the field. On-site participants attending the conference will have an opportunity to exchange information about scientific advancements in the NAMs field to develop a better understanding of the state of the science, discuss approaches for developing scientific confidence in using alternatives, and summarize existing studies characterizing the uncertainties in results from animal testing.
This conference is part of Administrator Wheeler’s “Directive to Prioritize Efforts to Reduce Animal Testing,” issued on September 10, 2019, which outlines EPA’s pursuit to aggressively reduce animal testing. In his directive, Administrator Wheeler calls for EPA to reduce its requests for, and funding of, mammalian studies by 30 percent by 2025 and eliminate all mammalian study requests and funding by 2035. Any mammalian studies requested or funded by EPA after 2035 will require Administrator approval on a case-by-case basis. The directive also supports scientific advancements that allow scientists to predict potential hazards for risk assessments without using traditional animal testing methods.
Information on how to register to participate in the conference by webinar is available here.
By Jason E. Johnston
On October 15, 2019, EPA posted a total of 11 documents to the registration review docket for paraquat dichloride (EPA-HQ-OPP-2011-0855). Of primary interest in the registration review process under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) are the draft human health and ecological risk assessments. Additional supporting documents posted to the docket include dietary, residential, and occupational exposure assessments; a review of analytical chemistry and residue data; a label use summary; a screening level usage analysis, results of a drinking water jar test; open literature and epidemiology literature reviews; and an incident report summary.
Paraquat is currently registered in the United States for use as an herbicide on over 100 crops in agricultural and commercial settings. All paraquat products are restricted use products and may be applied only by certified pesticide applicators. EPA has previously imposed additional restrictions and conditions to ensure the safe use of paraquat consistent with label directions. These actions include a safety awareness campaign, changes to labels and product packaging, and specialized training for certified applicators using paraquat. Evaluation of the effectiveness of these steps will be conducted in the registration review process.
Potential risks of concern to workers applying paraquat or entering treated fields are identified in the draft human health risk assessment, as are potential risks to bystanders from spray drift. Prior submissions to EPA suggest a link between proper use of paraquat and Parkinson’s Disease, but EPA’s review of relevant data does not support a causal relationship. This conclusion is not without controversy, as evidenced by an October 15, 2019, press release from the Center for Biological Diversity that calls out EPA’s failure to recognize a link between paraquat exposures and Parkinson’s Disease. The ecological risk assessment identifies potential risks to mammals, birds, adult honey bees, terrestrial plants, and algae. EPA is seeking comments on these and other issues raised in the draft risk assessments for paraquat. Comments will be accepted on these documents until December 16, 2019.
By Susan M. Kirsch
On September 30, 2019, the U.S. Environmental Protection Agency (EPA) released an updated Aquatic Life Benchmarks Table for registered pesticides. The update includes four newly registered pesticides and their degradants as well as new values for more than 30 previously registered pesticides. The benchmarks inform state and local regulators in their interpretation of water quality monitoring data. Waterbodies where benchmarks are exceeded may be prioritized for further investigation. EPA derived the latest updates from toxicity values from the most recent ecological risk assessments for the registered pesticides as part of the regular registration review. EPA aims to update the table on an annual basis. The full table and links to source documents for each of the benchmarks are accessible on EPA’s website here.
By Kelly N. Garson and Carla N. Hutton
On September 17, 2019, the European Food Safety Authority (EFSA) opened a consultation period on two pilot assessments of the risks posed to humans by residues of multiple pesticides in food. EFSA is seeking comments from interested parties on the assessments. The first assessment considers the chronic effects of multiple pesticides on the thyroid system. The second looks at acute effects on the nervous system.
EFSA produced the assessments in collaboration with the National Institute for Public Health and the Environment for the Netherlands (RIVM) using monitoring data from 2014, 2015, and 2016. In approving pesticides for use in the European Union (EU), EFSA establishes a maximum level of pesticide residue (MRL) allowed in food or animal feed. The MRL considers the cumulative effects of pesticides. Pesticides may only be placed on the EU market if they have no harmful effects on humans, including cumulative effects. In the two pilot assessments, EFSA classified pesticides into “cumulative assessment groups” (CAG) based upon whether they produce similar toxic effects in a specific organ or system. EFSA states that “[t]he overall draft conclusion for both assessments is that consumer risk from dietary cumulative exposure is below the threshold that triggers regulatory action for all the population groups covered.”
In 2020, EFSA will prepare the assessments in final, which will serve to “inform risk managers in the European Commission and Member States who regulate the safe use of pesticides in the EU.”
EFSA will present the assessments at a special stakeholder event in Brussels, Belgium, on October 22, 2019. The meeting is intended to allow stakeholders with expertise and interest in the area to discuss the technical issues relating to the draft assessments. Registration for the meeting closes on October 11, 2019.
All comments must be submitted by November 15, 2019. Comments on the “Cumulative dietary risk characterisation of pesticides that have chronic effects on the thyroid” may be submitted at https://ec.europa.eu/eusurvey/runner/PC_CRA_Thyroid_Sept-2019. Comments on the “Cumulative dietary risk characterisation of pesticides that have acute effects on the nervous system” may be submitted at https://ec.europa.eu/eusurvey/runner/PC_CRA_Nerv_Syst_Sept-2019.
The two draft assessments are available on EFSA’s website.
By Lisa M. Campbell and Timothy D. Backstrom
On September 9, 2019, the U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP) published a notice in the Federal Register announcing the availability of, and an opportunity for comment on, a document describing an “interim process” that OPP’s Environmental Fate and Ecological Effects Division is currently using to evaluate potential synergistic effects of mixtures of pesticide active ingredients on non-target organisms. As part of a lawsuit challenging the 2012 decision by EPA to register Enlist Duo Herbicide (a combination of 2,4-D and glyphosate), OPP scientists learned that patent applications for some registered pesticide products included claims that particular combinations of active ingredients provide “synergistic” control of target species. Although EPA was not at that time considering potential synergies in assessing the risk for ecological effects on non-target organisms, based on the patent application claims regarding synergy for Enlist Duo, EPA decided to request that the reviewing court vacate its registration decision and remand the application for Enlist Duo for further study of these effects and any measures that might be needed to mitigate the risk to non-target organisms. This decision sparked much controversy, and many in industry were concerned that patent application claims were not being correctly interpreted by EPA for the category of pesticide products at issue.
The new document released by EPA for review and comments is entitled: “Process for Receiving and Evaluating Data Supporting Assertions of Greater Than Additive (GTA) Effects in Mixtures of Pesticide Active Ingredients and Associated Guidance for Registrants.” EPA states that it “has generally been applying this interim process since 2016.” The process described in the document has five steps: (1) registration applicants must search for any granted patents that include synergy (GTA) claims for combinations of pesticides; (2) applicants must review the patent claims and supporting data for relevance to ecological risk assessment; (3) applicants must report to EPA all effects testing data from the relevant patents; (4) applicants must do a statistical analysis (using a method prescribed by EPA) to determine whether any observations of GTA effects are statistically significant; and (5) EPA will review all submitted information to decide whether it should be utilized in ecological risk assessment.
In the Federal Register notice, OPP lists five specific areas pertaining to the interim risk assessment process described in the document on which it is requesting comment:
- Are there technical aspects of the interim process that warrant change? If so, what changes are recommended?
- What aspects of the process could be applied to the evaluation of open literature sources of GTA effects pesticide interactions?
- Should EPA consider standardizing a more detailed search and reporting approach, and how should EPA do that?
- Should EPA continue the evaluation process as described in this document? If so, what performance metrics (e.g., number of evaluations) should EPA consider before deciding the utility of this approach?
- What applicant burden is associated with the activities described in this memorandum, including compiling, analyzing, and submitting the information? Specifically, does an estimate of 80-240 hours of burden per applicant cover the respondent burden associated with the interim process?
When the National Research Council (NRC) evaluated the importance of toxicological interactions between pesticide active ingredients in 2013, the NRC concluded that such interactions are rare, but that EPA should nonetheless consider such interactions when the best available scientific evidence supports such an evaluation. In the current Federal Register notice, EPA makes it clear that it is uncertain concerning the utility for risk assessment of the information used by manufacturers to support synergistic effects claims in pesticide patents. According to EPA, 24 applicants for new registrations have submitted patent data to date, but only three of these submissions contained information that indicated a need for further testing and no submission ultimately led to any adjustment of the ecological risk assessment. At this juncture, EPA will continue collecting patent data that may be pertinent to GTA effects, but when it has sufficient experience upon to base a general policy it may either continue or improve this process or discontinue it after explaining why.
When EPA requested that the reviewing court vacate and remand the registration EPA had granted for Enlist Duo, the parties seeking judicial review located data in the patent applications that EPA had not previously seen or reviewed and that EPA believed could possibly be pertinent to potential adverse effects on non-target plants. EPA concluded that it should revisit the decision based on the additional data. Although EPA decided to request vacatur and remand, the applicant Dow AgroSciences had arguably followed all of the procedures then in place, because FIFRA Section 3(c)(5) allows EPA to waive data requirements pertaining to efficacy, and EPA typically registers pesticide product that are not intended to protect public health without any independent evaluation of efficacy data. Nevertheless, in general EPA may choose to evaluate pesticidal efficacy data; such circumstances in the past often involved cases where EPA was required to consider whether pesticide benefits are sufficient to outweigh identified risks. In the Enlist case, EPA determined that it should do so where potential synergy in pesticidal efficacy is pertinent to evaluating ecological effects on non-target species.
What EPA must decide now is how often efficacy data that has been deemed adequate by the Patent and Trademark Office to support a patent for a new pesticide mixture will have any material significance in the context of ecological risk assessment. Before EPA makes a determination whether or not patent data has sufficient pertinence to continue requiring routine collection and evaluation of such data, EPA has decided it is prudent to afford all stakeholders an opportunity to comment on whether EPA has been asking the right questions.
All comments on the draft document must be submitted no later than October 24, 2019.
By Jason E. Johnston
On September 4, 2019, the U.S. Environmental Protection Agency’s (EPA) Office of Pesticide Programs’ Environmental Fate and Effects Division (EFED) announced that the next Environmental Modeling Public Meeting (EMPM) will be held on October 16, 2019. The EMPM is a semi-annual public forum for EPA, pesticide registrants, and other stakeholders to discuss current issues related to modeling pesticide fate, transport, and exposure for risk assessments in a regulatory context.
In a press release to the public, EPA indicates that the topics covered at the October meeting will include sources of usage data (relating to the actual application of pesticides, in terms of the quantity applied or units treated); spatial applications of usage data; model parameterization; extrapolation of usage data to fill in gaps; temporal variability of usage; and updates on ongoing topics. Presentations concerning the incorporation of pesticide usage data into environmental exposure and ecological risk assessments will also be included.
Registration is required. Requests to participate in the meeting must be received on or before September 23, 2019, as noted in the Federal Register notice.
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.