The U.S. Environmental Protection Agency (EPA) announced on January 19, 2023, the availability of and solicited public comment on a draft white paper entitled “Availability of New Approach Methodologies (NAMs) in the Endocrine Disruptor Screening Program (EDSP).” 88 Fed. Reg. 3406. EPA states that it developed the draft white paper pursuant to the Federal, Food, Drug, and Cosmetic Act (FFDCA), which requires EPA to develop a screening program to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen or other endocrine effects. The draft white paper announces that certain NAMs have been validated and may now be accepted by EPA as alternatives for certain EDSP Tier 1 assays, while others are useful for prioritization purposes and for use as other scientifically relevant information, where appropriate, in weight of evidence (WoE) evaluations. Comments on the draft white paper are due March 20, 2023.

In its January 19, 2023, press release, EPA states that the draft white paper “is a key step in EPA’s work to reinvigorate its efforts to meet its requirement for EDSP screening of chemicals and continue to provide transparency of EDSP Tier 1 testing, which is the step in the EDSP that determines the potential for endocrine-disrupting effects and whether there is a need to obtain more data by requiring additional Tier 2 tests.” According to EPA, the approaches described in the draft white paper would accelerate the pace of screening of all chemicals, including pesticide active ingredients, for potential impacts on the endocrine system; add efficiencies and decrease costs in the Agency’s review; and reduce animal testing.

The draft white paper presents several NAMs that would allow EPA to screen chemicals faster and more efficiently using alternatives to vertebrate animal testing and other in vitro assays. EPA states that NAMs are defined as any technology, methodology, approach, or combination that can provide information on chemical hazard and risk assessment to avoid the use of animal testing. According to EPA, NAMs are technologies and approaches developed by using advances in molecular, cellular, and computational sciences that can supplement or replace more traditional methods of testing chemicals for potential hazards. EPA notes that if it finds that data for a particular chemical reveal an effect in humans similar to an effect produced by a naturally occurring estrogen or other endocrine effects, it will take action to ensure that any needed protections are implemented.

EDSP White Paper and Next Steps for the Program

EPA states that it invested in the development of NAMs to screen chemicals more quickly for endocrine disruption, reduce the use of vertebrate animal testing, and ensure that pesticide decisions continue to protect human health and the environment. The EDSP uses a tiered approach for screening chemicals. EPA uses Tier 1 screening data to identify substances that have the potential to interact with the endocrine system. Chemicals that go through Tier 1 screening and are found to exhibit potential to interact with the estrogen, androgen, or thyroid hormone systems will proceed to Tier 2 for testing.

Tier 2 testing data identify adverse endocrine-related effects caused by the substance and establishes a quantitative relationship between the dose and that adverse effect. EPA will combine the results of Tier 2 testing with other hazard information and exposure assessments on a given chemical, resulting in a risk assessment.

EPA notes that the draft white paper also identifies NAMs for priority setting and WoE evaluations. EPA states that “[p]riority setting is important for EPA to test the chemicals posing the greatest risk first, while WoE is the process by which the strengths and weaknesses of a data collection are judged to render an overall conclusion that may not be evident from considering the data individually.” EPA conducts WoE evaluations as part of evaluating EDSP Tier 1 screening data to identify the need for Tier 2 testing.

According to EPA, because of the cost (EPA estimated industry costs in conducting a full Tier 1 battery to be approximately $1 million per chemical, largely due to the laboratory animal testing) and time (up to six years) involved in conducting and reviewing the full battery of Tier 1 assays, EPA has screened only “a fraction of the thousands of chemicals that are subject to EDSP for their potential endocrine-disrupting effects.” EPA states that the validated NAMs described in the draft white paper, when used alongside traditional approaches to chemical testing, “will expedite the Tier 1 screening of thousands of chemicals to assess whether they affect the endocrine system,” speeding up the risk assessment process and enabling EPA “to protect people and their communities faster from potentially harmful endocrine effects.”

EPA notes that the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) reviewed these validated NAMs in 2014 and 2017, and the validated NAMs are now considered validated alternatives to four EDSP Tier 1 assays. EPA may use the data derived from these validated models and assays to satisfy specified EDSP data needs, depending on a pesticide’s properties.

Commentary

Bergeson & Campbell, P.C. (B&C^®) applauds EPA’s NAM approach to assessing endocrine disruptor effects. There are clear benefits to manufacturers, EPA, and public health for EPA to screen substances efficiently without testing on vertebrates. The EDSP NAMs will be consequential across EPA program offices, most notably the Office of Pesticide Programs and the Office of Pollution Prevention and Toxics.

Beyond the EDSP, B&C anticipates that EPA’s pending adoption of these NAMs will inform EPA’s evaluation of chemical substances under the Toxic Substances Control Act (TSCA). On June 14, 2013, EPA published its Final Second EDSP List of Chemicals for Tier 1 Screening. This list included 109 chemical substances. That list of 109 substances includes seven of the “First 10” high-priority chemical substances, six of the “Next 20” high-priority chemicals, and six chemical substances from EPA’s 2014 Update to the TSCA Work Plan.

As EPA has completed the risk evaluations for the First 10 chemical substances, EPA will be unable to incorporate the endocrine disruption NAM results in EPA’s risk management rule proposals. It is not clear whether EPA’s schedule for the Next 20 high-priority chemicals may afford EPA an opportunity to order the endocrine disruption NAM testing and incorporate those results into the risk evaluations. We view it more likely that EPA will consider issuing additional TSCA Section 4(a)(2) test orders for the EDSP NAMs on the six substances among the Next 20 and TSCA Section 4(a)(1) test orders on the six listed TSCA Work Plan chemical substances that EPA has not yet designated as high priority for risk evaluation.

A notable limitation in EPA’s announcement is the absence of validated NAMs for informing EDSP Tier 1 testing on chemical substances that may cause thyroid disruption. EPA has made advances in this space, although the available NAMs are limited to screening substances, whereas definitive evaluations require the in vivo Tier 2 testing. We mention this because EPA’s test order authority under TSCA could serve as an effective pathway for developing in vivo data on a variety of chemical substances under TSCA that could aid with EPA’s research and development on high-throughput screening assays for thyroid-relevant targets. This would be consistent with the collaborative research partnership between EPA’s Office of Chemical Safety and Pollution Prevention and the Office of Research and Development. Of course, the test order authority will have to be applied consistent with the requirements under TSCA Section 4(a)(2). EPA cannot simply order testing to complete its data set for validating the thyroid NAM assay.