By Lynn L. Bergeson and Carla N. Hutton
 
The U.S. Environmental Protection Agency announced on August 4, 2023, that it is providing resources to help biotechnology developers exercise the full benefits of the exemptions available under the Plant Incorporated Protectants (PIP) exemption rule. These resources are available on EPA’s public website and include the following:

• Fact sheet and background information on PIPs rule;
• Examples of genetic modifications that are exempt under the rule;
• Description of how to submit a self-determination or a request for EPA confirmation of exemption under the rule; and
• Sample documents for submitting a self-determination or request for confirmation.

The PIPs Exemption Final Rule went into effect on July 31, 2023.  More information on the final rule is available in our June 2, 2023, memorandum.

Background

On May 31, 2023, EPA released a final rule exempting two categories of PIPs created using genetic engineering from certain registration requirements under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and from the food or feed residue tolerance requirements under the Federal Food, Drug, and Cosmetic Act (FFDCA). 88 Fed. Reg. 34756. EPA states that the rule ensures that human health and the environment are protected while reducing costs for the regulated community, consistent with the September 2022 Executive Order 14081 on Advancing Biotechnology. According to EPA, the rule may also result in increased research and development activities, commercialization of new pest control options for farmers, and reduced use of conventional pesticides.
 
EPA notes that the final rule reflects the biotechnological advances made since 2001, when it first exempted PIPs derived through conventional breeding from FIFRA registration and FFDCA tolerance requirements, but did not at that time exempt PIPs created through biotechnology. Specifically, the final rule exempts PIPs derived through genetic engineering from FIFRA registration and FFDCA tolerance requirements in cases where the PIPs are essentially equivalent to those exempted by the 2001 rule.
 
The rule contains conditions for exempting:

• PIPs in which genetic engineering has been used to insert a gene from a sexually compatible plant or to modify a gene to match a gene found in a sexually compatible plant. This category of PIPs requires EPA confirmation of eligibility for the exemption; and 
   
• Loss-of-function (LoF) PIPs, in which a gene is modified through genetic engineering to reduce or eliminate the activity of that gene. The loss of the activity of that gene then results in the pesticidal effect. EPA states that for this category of PIP, “biotechnology developers can make a self-determination that their PIP meets the exemption criteria, which requires notification but no EPA review, or request EPA confirmation of eligibility for the exemption.”

EPA notes that it indicated in the preamble to the final rule that it would consider exempting additional categories of PIPs from both FIFRA registration and FFDCA tolerance requirements and expanding the categories of PIPs that are allowed the option to self-determine and do not require EPA confirmation of eligibility for the exemption.

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By Lynn L. Bergeson and Carla N. Hutton
 
The Congressional Research Service (CRS) published an updated report on August 4, 2023, on the U.S. Department of Agriculture’s (USDA) Sustainable, Ecological, Consistent, Uniform, Responsible, Efficient (SECURE) rule. The revisions note that USDA’s Animal and Plant Health Inspection Service’s (APHIS) five-year Strategic Plan for fiscal years (FY) 2023-2027 states that “one of its objectives is to ensure the safe development of agricultural biotechnology products using a science-based regulatory framework, including efficient permit review for [genetically engineered (GE)] organisms, clear communication of regulations to stakeholders, coordination with other agencies, and harmonization of regulatory oversight for biotechnology products.”
 
As reported in in our September 13, 2022, blog item, in 2022, the Biden Administration issued Executive Order (EO) 14081, “Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy,” ordering USDA, the U.S. Food and Drug Administration (FDA), and the U.S. Environmental Protection Agency (EPA) to improve further the clarity and efficiency of regulatory processes for biotechnology products and increase coordination and communication among federal regulatory agencies. The report states that FDA “encourages developers of all new plant varieties to request premarket food safety consultations with the agency, which involves a discussion of the safety protocols and regulatory issues before the food is distributed in the market.” The report notes that in response to EO 14081, in May 2023, EPA announced changes to its regulations concerning GE plant-incorporated protectants (PIP). According to the report, these changes exempt certain PIPs from registration and tolerance requirements while implementing a notification process for transparency. EPA “intends to consider additional exemptions and expand the list of categories not requiring EPA confirmation as biotechnology progresses.” EPA’s rule (88 Fed. Reg. 34756) went into effect in July 2023.
 
According to the updated report, Congress “may be interested in monitoring how USDA’s revised regulatory requirements have affected the development and commercialization of GE and genome-edited products.” The updated report suggests that beyond that, Congress may consider monitoring how USDA, FDA, and EPA are assessing the effectiveness of the revised regulations, “as underlined by the self-determination aspect of the exemption status of new GE and genome-edited products.” The updated report states that further, Congress may also oversee how well the three agencies are working together to harmonize the regulation of biotechnology products moving forward.

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By Lynn L. Bergeson and Carla N. Hutton
 
On July 27, 2023, the Organization for Economic Cooperation and Development (OECD) published a new document in its Series on Harmonization of Regulatory Oversight in Biotechnology, Safety Assessment of Transgenic Organisms in the Environment, Volume 10: OECD Consensus Document on Environmental Considerations for the Release of Transgenic Plants. The document addresses environmental risk/safety assessment at a broader level than previous consensus and guidance documents from the Working Party on the Harmonization of Regulatory Oversight in Biotechnology (WP-HROB). The purpose of the document is to describe an approach and provide illustrative examples for planning and structuring risk/safety assessments for the release of transgenic plants into the environment. It provides general information on key concepts and important points on which risk/safety assessors should focus when planning such assessments. According to OECD, these key features include the comparative approach, the familiarity with the biology of the unmodified plant species, the general protection goals, the assessment endpoints, the potential adverse effects associated with the environmental release, the pathways to harm and corresponding risk hypotheses, relevant information elements, and the use of environmental considerations in planning such assessment.
 
Annexes A through G describe seven examples of environmental considerations routinely examined by assessors and taken from actual experience gained during risk/safety assessment of transgenic plants intended for environmental release. OECD states that these environmental considerations are:

• Invasiveness and weediness;
• Vertical gene flow;
• Organisms (animals);
• Soil functions;
• Plant health;
• Crop management practices; and
• Biodiversity (protected species and habitats/ecosystems).

According to OECD, the set of science-based information and data contained in the volume “constitutes a solid reference and a practical tool for use during the biosafety assessment planning process.” This publication should be of interest to regulators and assessors from national authorities in charge of evaluating the risk/safety of transgenic plants prior to environmental release, as well as to plant breeders and the wider scientific community. The consensus documents published in Volumes 1 to 10 of the Series are available individually free of charge on the OECD Bio Track website.

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By Lynn L. Bergeson and Carla N. Hutton
 
On July 12, 2023, the U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) announced the release of its 2022 impact report. The 2022 impact report lists the following biotechnology activities:

• Fully implemented USDA’s revised biotechnology regulations, which allow APHIS to focus oversight on products that may pose a risk and reduce regulatory burden for developers of organisms that are unlikely to pose plant pest risks, providing over $8 million in annual cost savings;
• Issued two Regulatory Status Review (RSR) decisions, the first under the new RSR process in the revised regulations;
• Responded to nine requests for confirmation that a plant met the criteria for exemption from regulation, confirming all nine and issuing responses within an average of 39 days from receiving the requests;
• With state agricultural officials, performed more than 660 inspections of authorized field trials involving organisms developed using genetic engineering, with an 88 percent rate of compliance;
• Completed one petition for non-regulated status under the legacy regulations, bringing the total number of determinations to 136;
• Delivered more than 13 presentations to international stakeholders representing 40 countries to offer technical information and build capacity abroad for regulating biotechnology; and
• Processed over 758 authorizations in 42 states for the movement or field testing of organisms developed using genetic engineering.

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By Lynn L. Bergeson and Carla N. Hutton
 
The U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) announced on June 27, 2023, that it recently reviewed soybean, tomato, and potato plants modified using genetic engineering. APHIS reviewed the plants to determine whether they presented an increased plant pest risk compared to similar cultivated soybean, tomato, and potato plants:

• InnerPlant modified two soybean plants and one tomato plant to produce an optical signal. One soybean plant was modified to emit the signal when there is pest damage, while the other soybean and the tomato plant continuously emit the signal. InnerPlant has a system to detect these signals using remote sensing devices from tractors, drones, airplanes, and satellites to aid crop management. APHIS states in its responses to the soybean requests that it determined that each soybean “is unlikely to pose an increased plant pest risk relative to its comparators.” APHIS made a similar response to the tomato request.
   
• Ohalo Genetics modified a potato plant to produce an increased concentration of beta-carotene for altered nutritional value. APHIS states in its response that it “did not identify any plausible pathway by which your modified potato would pose an increased plant pest risk relative to comparator potato plants.”

Regulatory Status Review (RSR) requests from InnerPlant and Ohalo Genetics and APHIS’ response letters are available on the APHIS website. APHIS notes that its responses are based on information from the developers and its own:
 
•           Familiarity with plant varieties;
 
•           Knowledge of the traits; and
 
•           Understanding of the modifications.
 
Under 7 C.F.R. Part 340, developers may request an RSR when they believe a modified plant is not subject to regulation. APHIS reviews the modified plant and considers whether it might pose an increased plant pest risk compared to a nonregulated plant. If its review finds a plant is unlikely to pose an increased plant pest risk relative to the comparator plant, APHIS issues a response indicating the plant is not subject to the regulations.

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By Lisa R. Burchi, James V. Aidala, and Heather F. Collins, M.S.

On May 31, 2023, the U.S. Environmental Protection Agency (EPA) released a final rule exempting a class of plant-incorporated protectants (PIP) created using genetic engineering, from registration requirements under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and from the food or feed residue tolerance requirements under the Federal Food, Drug, and Cosmetic Act (FFDCA). 88 Fed. Reg. 34756. PIPs are pesticidal substances produced by plants and the genetic material necessary for the plant to produce the substance. According to EPA’s May 25, 2023, press release, this rule will reduce costs for the regulated community and result in increased research and development activities, consistent with Executive Order 14081 on advancing biotechnology. EPA states that the rule also may result in the commercialization of new pest control options and reduced use of conventional pesticides. The final rule will be effective on July 31, 2023.

EPA states the final rule will allow PIPs to be exempt from FIFRA registration and FFDCA tolerance requirements in cases where they both pose no greater risk than PIPs that EPA has already concluded meet safety requirements, and when they could have otherwise been created through conventional breeding. The final rule reflects the biotechnological advances made since 2001, when EPA first exempted PIPs derived through conventional breeding from FIFRA registration and FFDCA tolerance requirements but did not at that time exempt PIPs created through biotechnology.

In the rule, EPA provides criteria and definitions that identify two categories of PIPs that are exempted through this action from FIFRA registration and FFDCA tolerance requirements:

• “PIPs created through genetic engineering from a sexually compatible plant” in which genetic engineering has been used to insert or modify a gene to match a gene found in a sexually compatible plant (to be codified at 40 C.F.R. Section 174.26); and
• “Loss-of-function PIPs” in which the genetically engineered modification reduces or eliminates the activity of a gene, which then helps make the plant resistant to pests (to be codified at 40 C.F.R. Section 174.27).

For the first exempted category, EPA will require a notification process for EPA to confirm that the PIP is eligible for the exemption. For the second exempted category (loss-of-function PIPs), developers of PIPs can submit to EPA a self-determination letter that the exemption applies. EPA also is establishing recordkeeping requirements for these exempted PIPs, clarifying general qualifications for exemption at 40 C.F.R. Section 174.21; clarifying the relationship between the existing exemptions for PIPs from sexually compatible plants (40 C.F.R. Section 174.25) and the newly issued exemption for “PIPs created through genetic engineering from a sexually compatible plant” (40 C.F.R. Section 174.26); and allowing the existing inert ingredient exemption at 40 C.F.R. Section 174.705 to include genetic engineering.

EPA notes that in the future, as biotechnology advances further, it intends to consider exempting additional categories of PIPs from both FIFRA registration and FFDCA tolerance requirements as well as adding categories of exempted PIPs to the list of categories that do not require EPA confirmation of eligibility.

Additional information, including the response to comment document, is available in docket EPA-HQ-OPP-2019-0508.

Commentary

This final rule is the next step for EPA’s Office of Pesticide Programs (OPP) on the path of EPA’s regulation of biotechnology pesticide products. It sets forth how OPP will handle products created by “Clustered Regularly Interspaced Short Palindromic Repeats” (CRISPR). In more general terms, CRISPR refers to manipulating plant genes with a method that was not available at the time the first biotechnology regulations were developed by EPA in the mid-1990s. This is why EPA needs to “update” its regulations, which is the purpose of the final rule.

Proponents of biotechnology methods argue that CRISPR allows the genes of plants to be manipulated more precisely and can be used to “simply” drop out a gene or add one from the same -- sexually compatible -- genome of the target plant. It follows that this is much like “traditional plant breeding” only done more precisely and more rapidly. Critics will likely raise questions about whether any product using this method, and not using traditional methods, might have some kind of unexpected result or unintended eventual effect. One can expect some adverse comments regarding these products even though EPA (among many others) lays out a rationale that this is an extension of its current regulations exempting products of traditional plant breeding from regulation under FIFRA/FFDCA (and not exempting such products from other regulatory authorities).

There also were concerns raised in comments submitted in response to the October 9, 2020, proposed rule. In particular, some in industry remain concerned that the final rule creates differential treatment for products due solely to the methods of development (i.e., biotechnology vs. conventional), thus subjecting products created using biotechnology to additional regulatory and recordkeeping requirements, even in cases when those products could have been created using older research and development approaches.

EPA’s basic requirements for biotechnology products that regulate inter-species gene manipulation would not change. Also worth noting is that the rule also would allow a developer to submit the product for EPA review to affirm that it qualifies for the exemption (i.e., a M009 Pesticide Registration Improvement Act (PRIA) action, which can lead to EPA delays in processing). The EPA docket includes a slide deck with a helpful summary of the final rule and its rationale.

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By Lynn L. Bergeson and Carla N. Hutton
 
The U.S. Government Accountability Office (GAO) published a “Science & Tech Spotlight” on synthetic biology on April 17, 2023. GAO defines synthetic biology as “a multidisciplinary field of biotechnology that involves engineering the genetic material of organisms -- such as viruses, bacteria, yeast, plants, or animals -- to have new characteristics.” According to GAO, scientists are currently exploring the use of synthetic biology to address environmental challenges by engineering organisms to use carbon dioxide, produce biofuels for vehicles, and transform methane into biodegradable plastics. GAO notes that the synthetic biology market could grow from about $10 billion in 2021 to between $37 billion and $100 billion dollars by 2030. Opportunities include:

• Widely adaptable. Synthetic biology holds the potential to help diagnose and treat diseases, improve industrial processes, and address some environmental challenges;
• More equitable access to biotechnology. Some of the tools needed for synthetic biology are low-cost and widely available, which could make access to beneficial applications more equitable; and
• Conservation efforts. Synthetic biology could support endangered species conservation, for example, by altering the genes of endangered plants to make them resilient to diseases.

GAO notes the following challenges:

• Safety and security concerns. Synthetic biology could pose a significant threat to national security if it were used for nefarious purposes, such as developing new biological or chemical weapons. Additionally, the computational tools used for synthetic biology could be vulnerable to cyberthreats such as automation hacking. For example, a bad actor could manipulate or steal information and use it to create drugs, weapons, or other harmful products.
• Environmental effects. Organisms made using synthetic biology and released into the environment could have unknown, unintended, and potentially irreversible effects on ecosystems. Such effects could be widespread if, for example, these organisms negatively affected food or water systems.
• Public acceptance and access. The public may hesitate to accept certain applications of synthetic biology due to concerns about interfering with nature and about unintended effects. In addition, some medical applications could be inaccessible for some patients due to cost or location of treatment centers.

GAO concludes the “Science & Tech Spotlight” with the following policy context and questions:

• Do policymakers have adequate access to expertise and resources to evaluate the societal effects and public policy implications of synthetic biology research and development?
• How effective is the coordination among 1) domestic and 2) global stakeholders for monitoring and assessing the risks associated with advances in synthetic biology research and applications?
• Is the current regulatory framework sufficient to address ongoing and future applications and their effects without unnecessarily hindering U.S. competitiveness in synthetic biology?

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By Lynn L. Bergeson and Carla N. Hutton
 
The U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) announced on April 10, 2023, that it is inviting public comment on a draft Environmental Assessment (EA) and draft Plant Pest Risk Assessment (PPRA). 88 Fed. Reg. 21602. APHIS states that it produced these documents in response to a petition from Pioneer Hi-Bred International, Inc. seeking deregulation of a corn variety developed using genetic engineering to resist corn rootworm and tolerate glufosinate herbicides. APHIS is seeking public comment on these documents for 30 days. APHIS will thoroughly review and consider all public input submitted during the comment period and will use this information to complete and publish final environmental documents and its regulatory determination. Comments are due May 11, 2023. APHIS has posted the following documents:

• Petition;
• Draft Environmental Assessment; and
• Draft Plant Pest Risk Assessment.

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By Lynn L. Bergeson and Carla N. Hutton
 
The U.S. Environmental Protection Agency (EPA) will hold training on May 23, 2023, on Generalized Read-Across (GenRA), a publicly available tool that uses an automated approach to make reproducible read-across predictions of toxicity. EPA states that read-across “is a commonly used data gap filling technique whereby endpoint information for one substance is used to predict the same endpoint for another substance, supported by structural or other feature similarities.” According to EPA, while read-across sometimes relies on subjective or expert judgement, use of the GenRA tool could provide more objective and reproducible read-across predictions. Specifically targeted for decision-makers, this training will provide:

• A presentation overview of GenRA’s purpose and scope;
• A demonstration of GenRA’s interface and navigation; and
• Opportunities for participatory learning and engagement.

The virtual training will feature EPA’s Dr. Grace Patlewicz. The training will include a plenary presentation, small group discussions, and a chance to try out GenRA. EPA has divided the training into two parts to accommodate a variety of interests and schedules. Registration for one or both sessions is free but required.

• Session 1 (Presentation and Questions and Answers (Q&A)) 11:00 a.m. - 12:30 p.m. (EDT)

This session will provide an overview of GenRA content and function with opportunities for participation and Q&A.

• Session 2 (Breakout Sessions) 12:30 - 1:30 p.m. (EDT)

This session will break participants into breakout rooms to work on exercises in small groups, aided by facilitators.

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By Lynn L. Bergeson and Carla N. Hutton
 
The U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) announced on March 23, 2023, the availability of a draft guide detailing the information requirements and process for submitting permit applications for microorganisms developed using genetic engineering. The draft Guide for Submitting Permit Applications for Microorganisms Developed Using Genetic Engineering under 7 CFR Part 340 is intended to assist developers with preparing a permit application for movement activities with modified microorganisms under 7 C.F.R. Part 340 (Movement of Organisms Modified or Produced through Genetic Engineering). The draft guide states that genetic engineering is defined in 7 C.F.R. Section 340.3 as “techniques that use recombinant, synthesized, or amplified nucleic acids to modify or create a genome.” According to the draft guide, regulated microorganisms include plant pests and other modified microorganisms that could pose a plant pest risk. Developers require a permit for regulated activities involving any modified microorganism that:

• Meets the definition of a plant pest in Section 340.3; or
• Is not a plant but has received deoxyribonucleic acid (DNA) from a plant pest, as defined in Section 340.3, and the DNA from the donor organism is either capable of producing an infectious agent that causes plant disease or encodes a compound that is capable of causing plant disease; or
• Is a microorganism used to control plant pests and could pose a plant pest risk.

Comments on the draft guide are due May 22, 2023. APHIS states that it will consider all comments received by May 22, 2023, prior to issuing the final version of the guide.

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