By Lisa M. Campbell, Lara A. Hall, MS, RQAP-GLP, and Heather F. Collins, M.S.
On October 7, 2020, the U.S. Environmental Protection Agency (EPA) announced that it is requesting comments on its draft guidance that would allow registrants, in certain circumstances, to forgo testing chemicals on animal skin to determine whether a pesticide would lead to adverse effects. This new draft guidance is part of EPA’s continued efforts to reduce animal testing and achieve its goal of eliminating all EPA requests for studies and EPA funding of studies on mammals by 2035.
According to EPA, the draft dermal toxicity guidance would allow applicants to request waivers for acute dermal toxicity studies on single-active ingredients used to develop end-use products. The new draft guidance also allows EPA to harmonize with the Pest Management Regulatory Agency (PMRA) of Canada, which published guidance on acute dermal toxicity waivers for both formulations and technical chemicals in 2017. The draft guidance is in addition to the final guidance for waiving acute dermal toxicity tests published by EPA in November 2016 for pesticide formulations.
In developing the guidance, EPA states that it conducted a retrospective analysis of rat acute oral and acute dermal LD50 studies for 249 active ingredients across numerous chemical classes and toxicity categories. Fumigants and rodenticides were excluded from this analysis, based on their physical state and/or anticipated exposures to them. EPA concluded that for 67 percent of the 249 technical chemicals, the results of both oral and dermal acute toxicity studies fall within the same Toxicity Category. For 32 percent of the chemicals, the oral study falls within a lower (i.e., more protective) Toxicity Category; thus, for 99 percent of the chemicals in the analysis, if the dermal study had not been available and labeling had been based only on the Toxicity Category for the oral acute toxicity study, the labeling requirements would have been equally or more protective. For the two remaining chemicals (less than 1 percent), factors other than the dermal acute toxicity may influence labeling requirements. EPA concluded that its requirements for such acute dermal toxicity studies provide little to no added value in regulatory decision making. EPA states that this guidance, when finalized, is expected to reduce the number of test animals used annually by approximately 750, as well as save EPA, industry, and laboratory resources.
EPA states that it believes the retrospective analysis fully supports the conclusion that waivers may be granted for acute dermal toxicity studies for pesticide technical chemicals, except for fumigants and rodenticides. Waivers may be accepted for fumigants and rodenticides on a case-by-case basis with appropriate scientific rationale. Once the guidance is issued in final form, EPA states that applicants who wish to pursue waivers for these studies would submit formal waiver requests as part of the registration application through existing processes and cite the guidance as support for the requests. EPA maintains the ability to request acute dermal toxicity data on a case-by-case basis, but states that it anticipates granting the waiver in most cases.
Comments on the draft guidance are due on or before November 9, 2020, and can be submitted at http://www.regulations.gov under Docket ID No. EPA-HQ-OPP-2016-0093.
EPA also announced the launch of its new webpage that provides metrics and strategies for reducing and replacing animal testing, including links and resources to all pertinent guidance and work plans tied to the larger Toxicology in the 21st Century Initiative across the federal government. The directive, issued by EPA Administrator Andrew Wheeler in September 2019, calls for EPA to reduce animal testing and to reduce funding 30 percent by 2025 and eliminate it by 2035. EPA states that its actions to date to support these efforts include:
- In September 2019, EPA announced $4.25 million in funding for five universities to research and develop alternative test methods for evaluating chemical safety.
- In December 2019, EPA convened a conference for achieving reduced animal testing in chemical safety research and updated its list of New Approach Methodologies (NAM) that could be used in EPA’s work under the amended Toxic Substances Control Act, including adding 21 new test guidelines related to health and ecological effects and six additional EPA policies that reduce the use of animal testing.
- In June 2020, EPA released a NAMs work plan that details how EPA plans to develop, test, and apply chemical safety testing approaches without the use of animals.
- In February 2020, EPA issued final guidance waiving the subacute dietary testing of pesticides on birds when the additional information is unnecessary to support a pesticide registration decision, which is expected to save 720 test animals annually.
- In July 2020, EPA announced new guidance to reduce unnecessary testing on fish, which is expected to save 240 test animals annually.
EPA will host its Second Annual Conference on the State of the Science on Development and Use of NAMs for Chemical Safety Testing virtually on October 19 and 20, 2020. Additional information on EPA’s efforts to reduce animal testing is available here.
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.
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 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 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.