Regulatory Developments

EPA Publishes Updated NAMs Work Plan

December 9, 2021 PRINT

On December 2, 2021, the U.S. Environmental Protection Agency (EPA) published an updated New Approach Methods (NAM) Work Plan (Updated Work Plan). EPA created the work plan to prioritize its efforts and resources toward activities that aim to reduce the use of vertebrate animal testing while continuing to protect human health and the environment. EPA describes its updated roadmap and identifies steps intended to reduce the use of vertebrate animals for toxicity testing and related research while ensuring that its regulatory, compliance, and enforcement activities remain protective of human health and the environment. In the Updated Work Plan, EPA discusses the near- and long-term strategies it will deploy through 2024 to accomplish its objectives, working across offices and with stakeholders, and the different deliverables on which it will focus.

The objectives that EPA laid out in its first NAMs Work Plan in June 2020 remain unchanged:

  • Evaluate regulatory flexibility for accommodating the use of NAMs;
     
  • Develop baselines and metrics for assessing progress;
     
  • Establish scientific confidence in NAMs and demonstrate application to regulatory decisions;
     
  • Develop NAMs that fill critical information gaps; and
     
  • Engage and communicate with stakeholders to incorporate their knowledge and address concerns.
     

EPA states that in the Updated Work Plan, the main objectives and strategies are unmodified. According to EPA, the primary changes include:

  • Expansion of the species covered in the work plan to include all vertebrate animals to be consistent with the Toxic Substances Control Act (TSCA);
     
  • Modified deliverables that provide revised timelines through 2024 that reflect the expansion of covered species and incorporate feedback received over the preceding years;
     
  • Updated scope of the National Academies of Sciences, Engineering, and Medicine (NASEM) study to include a review of validation and scientific confidence frameworks for NAMs in addition to evaluating the variability and relevance of existing mammalian toxicity tests;
     
  • Two new case studies for building confidence and demonstrating application of NAMs; and
     
  • A pilot study to develop NAMs training courses and materials for a broad range of stakeholders.
     

Evaluate Regulatory Flexibility for Accommodating the Use of NAMs

According to the Updated Work Plan, in particular cases, EPA’s regulatory authority “needs to be further refined or explained to accommodate the implementation of NAMs, requiring the development of rules, policies, and written guidance that represent the Agency’s interpretation or view of specific issues.” EPA conducted an initial review of the major environmental statutes and concluded that these statutes do not prevent EPA from considering information from NAMs when carrying out its responsibilities:

Major Environmental Statute Statutory Requirements for Vertebrate Animal Testing Regulatory Requirements for Vertebrate Animal Testing
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and Federal Food, Drug, and Cosmetic Act (FFDCA) None 40 C.F.R. Part 158 specifies FIFRA and FFDCA data requirements that include use of vertebrate animals (pesticide registration, registration review, and tolerance or exemptions from the requirements of a tolerance for a pesticide chemical residue)
Endangered Species Act (ESA) None None
Food Quality Protection Act (FQPA) amendments to the FFDCA and the Safe Drinking Water Act (SDWA) amendments None None
TSCA None, but TSCA Section 4(h) requires reducing use of vertebrate animals in testing 40 C.F.R. Parts 790 through 799 apply to TSCA Section 4 test rules
Clean Air Act (CAA) None Fuel and Fuel Additive Registration; Significant New Alternatives Policy (SNAP) programs
Clean Water Act (CWA) None None
Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) None None
Emergency Planning and Community Right-to-Know Act (EPCRA) None None
Resource Conservation and Recovery Act (RCRA) None None
SDWA None None

According to the Updated Work Plan, to ensure a “robust regulatory framework that accommodates the development and use of NAMs,” EPA will expand on its initial survey and perform a “thorough” review of existing statutes and programmatic regulations, policies, and guidance to identify vertebrate animal testing requirements that may not allow it the flexibility to apply NAMs. Following its review, EPA will consider options for introducing flexibility on implementing and/or using appropriate NAMs for regulatory purposes. The Updated Work Plan includes the following deliverable:

  • EPA report containing a review of existing statutes, programmatic regulations, policies, and guidance that relate to vertebrate animal testing and the potential implementation and use of appropriate NAMs for regulatory purposes. The EPA report will be delivered in 2022.
     

Develop Baselines and Metrics for Assessing Progress

According to the Updated Work Plan, EPA has started developing baselines and metrics to track its progress toward its goal of reducing its use of vertebrate animals. EPA will initially develop baselines and metrics for the use of vertebrate animals for programs within the Office of Chemical Safety and Pollution Prevention (OCSPP) and the Office of Research and Development (ORD). As other EPA offices determine their contribution to the use of vertebrate animals, EPA will incorporate their baselines and metrics into the overall reporting mechanisms. The Updated Work Plan notes that due to the differences in statutory requirements and research uses, EPA will need to establish baselines and metrics that are specific to each program, building on the existing efforts and current data gathering initiatives. The Updated Work Plan includes the following deliverable:

  • Progress and summary metrics on reducing vertebrate animal testing requests and use. The metrics will be reported annually through its website starting in the fourth quarter of 2022.
     

Establish Scientific Confidence in NAMs and Demonstrate Application to Regulatory Decisions

To establish scientific confidence in NAMs and demonstrate application to regulatory decisions, EPA developed a three-part strategy that (1) characterizes the scientific quality and relevance of existing vertebrate animal tests; (2) develops recommended reporting requirements; and (3) demonstrates application of the NAMs to regulatory decisions through case studies. The Updated Work Plan includes the following deliverables:

  • NASEM study that evaluates the variability and relevance of existing mammalian toxicity tests and reviews frameworks for validation and establishing scientific confidence in testing methods. EPA is funding the study, but the timing is determined by NASEM and is currently scheduled for 2023.
     
  • Scientific confidence framework to evaluate the quality, reliability, and relevance of NAMs. The framework will be released as an EPA report in the fourth quarter of 2024.
     
  • Reporting templates that may be used by EPA and stakeholders that capture the range of specific NAMs used for EPA decisions. An initial set of reporting templates will be delivered in the fourth quarter of 2024.
     
  • Case studies for evaluating application of NAMs to risk assessment and demonstrating protection of human health and the environment. EPA will develop and communicate about case studies through the peer-reviewed scientific literature.
     

Develop NAMs to Address Scientific Challenges and Fill Important Information Gaps

The Updated Work Plan acknowledges that there are still scientific challenges and information gaps that limit a complete reliance on NAMs for decisions related to the assessment of a chemical’s potential risk to human health and the environment. According to the Updated Work Plan, examples of these scientific challenges and gaps include inadequate coverage of potential biological targets and pathways, reduced or distinct xenobiotic metabolism in in vitro test systems, limited capabilities to represent the complex cellular, tissue, organ, and organism-level interactions, and a lack of robust integrated approaches to testing and assessment (IATA) for higher tier endpoints of concern (e.g., development and reproductive toxicity). To refine and develop NAMs that address both the myriad EPA decisions and ways that chemicals can impact human health and the environment, EPA developed a two-part strategy that facilitates joint planning of NAM development by EPA research scientists and regulators, as well as encourages development and dissemination of NAMs by external parties. According to the Updated Work Plan, the strategy ensures that the NAMs being developed will meet the needs of end users for a specific context of use and provide an acceptable level of uncertainty, while also opening opportunities for innovation by scientists from academia, industry, and public interest organizations. The Updated Work Plan includes the following deliverables:

  • EPA Strategic Research Action Plans outlining research products to develop and apply NAMs. The next EPA Strategic Research Action Plans will be delivered in the first quarter of 2023.
     
  • Encourage development of NAMs through mechanisms such as the Science to Achieve Results (STAR) program and facilitate partnerships with organizations focused on establishing scientific confidence in alternative methods. This is an ongoing deliverable.
     

Engage and Communicate with Stakeholders

The Updated Work Plan states that the information and data resulting from NAMs have the capacity to replace vertebrate animal testing while still protecting public health and the environment. The widespread use and reliance on NAMs in EPA decisions require a fundamental change in thinking for regulators, the regulated community, the scientific and technical community, and other stakeholders, however. According to the Updated Work Plan, changes of this magnitude are difficult, as traditional approaches have been used for decades in both national and international regulatory decisions. Effective engagement and communication with stakeholders are essential to increase acceptance, obtain constructive feedback, and improve the acceptance of using NAMs to inform EPA decisions. The Updated Work Plan includes the following deliverables:

  • EPA website to house information about NAM efforts and progress upon release of the work plan.
     
  • Public webinars and peer review, where appropriate, on deliverables from the work plan. This is an ongoing deliverable.
     
  • Completion of a NAMs pilot training program in the fourth quarter of 2023 and provision of regular scientific exchanges and progress updates through EPA-sponsored and partner-organized events.
     

Commentary

EPA’s Updated Work Plan reflects EPA’s commitment and continued effort in developing and utilizing NAMs in its decision-making. B&C acknowledges that EPA’s Office of Pollution Prevention and Toxics (OPPT) used or requested NAMs for informing endpoints in its recent final risk revaluations, final scope documents on manufacturer-requested risk evaluations (MRRE), and test orders on existing chemical substances. For example, OPPT used a NAM known as the “BCFBAF” to estimate the bioconcentration factor (BCF) and bioaccumulation factor (BAF) in aquatic organisms in the final risk evaluation for N-methylpyrrolidone (NMP) and the BAF in aquatic organisms in the final scope document of the risk evaluation for di-isodecyl phthalate (DIDP). EPA also ordered in vitro skin absorption testing according to the Organization for Economic Cooperation and Development (OECD) Test Guideline 428 on several existing chemical substances currently undergoing risk evaluation. These actions confirm that OPPT has used NAMs in its decision-making under TSCA Section 6 for both OPPT-initiated risk evaluations and MRREs and has required NAMs under TSCA Section 4 for its test orders.

B&C also acknowledges that OPPT has used NAMs for its decision-making on actions taken on new chemical substances under TSCA Section 5. For example, OPPT used data from an in vitro biosolubility study to determine that a chemical substance was not a hazard concern for effects resulting from poorly soluble particles and lung overload. Based on these data, OPPT revoked a significant new use rule on the chemical substance for which it had previously required a 90-day subchronic inhalation toxicity study in rats, if certain conditions were not met. We support and applaud EPA’s efforts in this regard. We recognize some will be disappointed by the removal of reference to a goal of eliminating “mammal study requests” by 2035, which had been included in the prior version of the work plan. The Updated Work Plan did, however, expand the coverage of species to include “all vertebrate animals.”

B&C notes, however, that there are inconsistencies with EPA’s use of NAMs and the stated assurance of “transparency and accountability” in the Updated Work Plan. For example, in October 2021, EPA issued its National PFAS Testing Strategy (Strategy). The Strategy included a tiered-testing approach on PFAS that EPA stated was consistent with its mandate to reduce and replace the use of vertebrate animals under TSCA Section 4(h). The tiered-testing approach included, however, requirements for inhalation toxicity testing on vertebrate animals for those PFAS identified with surfactant properties. The tiered-testing approach in the Strategy is, in our view, inconsistent with the IATA on surfactants that EPA presented at the Society of Toxicology’s Virtual Meeting in March 2021. The IATA on surfactants was also accepted for peer review in the scientific literature. EPA did not, however, provide an explanation in the Strategy for this apparent inconsistency.

We note also that the above examples of OPPT’s use of NAMs under TSCA Sections 5 and 6 predate EPA’s issuance of the Strategy. It is unclear if the tiered-testing approach in the Strategy was an oversight or if it reflects a change in EPA’s (or OPPT’s) mindset about the use of NAMs for decision-making. B&C encourages entities that are exploring the use of NAMs to satisfy data requirements under TSCA to actively consult with EPA. Doing so will ensure an open and transparent dialogue involving the technical aspects of NAMs and how they provide information that is equivalent to or of better quality and relevance to vertebrate animal tests.

B&C also notes that EPA’s Updated Work Plan includes its commitment for engagement and communication. B&C expects EPA to provide substantive comment to stakeholders that is consistent with the goals of the Updated Work Plan and based on the best available science and weight of scientific evidence as required under TSCA Sections 26(h) and 26(i), particularly in those instances when EPA rejects the use of a NAM. The Updated Work Plan presents goals and objectives that, if adhered to, will aid EPA and the regulated community with establishing approaches that build scientific confidence in NAMs, address data needs (rather than data gaps) without the use of vertebrate animal tests, and ensure transparency in the process.


 
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