Endocrine Disruptor Screening Program

What is EPA’s Endocrine Disruptor Screening Program?
In August 1996, Congress passed the Food Quality Protection Act and Safe Drinking Water Act (SDWA) Amendments which requires the U.S. EPA to initiate the Endocrine Disruptor Screening Program (EDSP) to screen pesticides, commercial chemicals and environmental contaminants for their potential effect on the endocrine systems of humans and wildlife. EDSP is a two-tiered screening process aimed at identifying chemicals and determining their potential to disrupt the endocrine systems of mammals, birds and fish. The two-tiered screening and testing process is structured as follows:

    ▲ Tier 1: EPA will identify chemicals that have the potential to interact with the endocrine system.

    ▲ Tier 2: EPA will determine the endocrine-related effects caused by each chemical and obtain information about effects at
various doses.

EPA implements EDSP by publishing lists of chemicals to be tested for endocrine disruption properties. EPA then issues test orders (requests for data) to registrants of a substance for which testing is required, or to persons who manufacture or import substances that are being considered for testing. The data submitted in response is evaluated by EPA to determine if – and to what extent – said chemicals pose a hazard to humans and wildlife.

What is the current status of the Endocrine Disruptor Screening Program?
The initial Tier 1, List 1 test orders were issued in October 2009. With screening in progress, EPA is now reviewing the List 1 test order responses and publishing the status/test order responses and/or any decisions regarding testing requirements. That document is available here.

On June 14, 2013, EPA issued a revised
second list of chemicals (“List 2”) for screening under Tier 1. EPA expects to receive Tier 1 studies for the 109 List 2 chemicals between 2014 and 2015; therefore, test orders are anticipated to be issued between late 2013 to mid 2014.

How did EPA determine which chemicals to choose for List 2?
EPA focused on a subset of chemicals and substances that have been listed as priorities within EPA’s drinking water and pesticide programs. EPA started by identifying candidate chemicals that are either contaminants regulated with a national primary drinking water regulation (NPDWR) or unregulated contaminants that are listed on the third Contaminant Candidate List (CCL 3). EPA then focused its attention towards candidate chemicals from the Office of Pesticide Programs (OPP) based on pesticides that were scheduled for Registration Review during fiscal years 2007 and 2008 (this was part of EPA’s efforts to efficiently manage pesticide testing by conducting the testing in parallel or as part of the OPP Registration Review program).

The Agency consolidated the lists from the Office of Water (OW) and OPP, resulting in over 200 chemicals. EPA filtered this list by excluding any chemical that fell into one or more of the following categories:

    1. Biological agent and naturally-occurring chemicals (e.g., microbials, microbial toxins, inorganics, radionuclides);

    2. Chemicals for which the manufacturer, importer or registrant cannot be clearly identified (e.g., disinfection byproducts
or DBPs, microbes, microbial toxins, degradate compounds with more than one possible source, etc.);

    3. Chemicals already included on the first EDSP list;

    4. Chemicals that are hormones with confirmed endocrine effects;

    5. Chemicals that are not likely to be biologically active or which are incompatible with testing assays for various reasons
due to one or more of their physiochemical properties (e.g., gases, strongly acidic or basic, solubility, vapor pressure
molecular weight); and

    6. Pesticides that are scheduled for registration review after FY 2008.

The refined list contained 134 chemicals that EPA proposed to include in its EDSP. After a public comment period, EPA announced a revised list of 109 chemicals in which it is planning to issue test orders in the near future.

What happens when I receive a test order?
Once EPA issues test orders for a particular chemical, companies have 90 days to respond. Test order recipients may submit or cite existing data, independently generate new data, or join a task force so members can share the data generation costs and collectively own and use the data. Additional response options include requesting a voluntary cancellation of a current registration, submitting a claim that the recipient is not subject to the test order, or submitting a request to EPA for an extension of the data submission period.

What are the test order requirements?
The EDSP Tier 1 assay battery consists of 11 assays evaluating a broad range of endpoints, including receptor binding, steroidogenesis, amphibian metamorphosis, fish reproduction, thyroid function and effects on pubertal development. EDSP Tier 1 assays measure a range of effects at different levels of biological organization from in vitro molecular effects to apical endpoints in vivo.

Tier 1, List 2 screening assays include the following:

In vitro

Estrogen receptor (ER) binding – rate uterine cytosol

    ▲ Estrogen receptor – (hERα) transcriptional activation – Human cell line (HeLa-9903)

    ▲ Androgen receptor (AR) binding – rate prostate cytosol

    ▲ Steoidogenesis – Human cell line (H295R)

    ▲ Aromatase – Human recombinant microsomes

In vivo

   ▲ Uterotrophic (rat)

    ▲ Hershberger (rat)

    ▲ Pubertal female (rat)

    ▲ Pubertal male (rat)

    ▲ Amphibian metamorphosis (frog)

    ▲ Fish short-term reproduction

How can I respond to the test orders?
Once a test order is issued, companies have 90 days to respond; therefore, it is important for recipients to quickly determine and execute an approach that will satisfy the test order requirements. The EDSP Tier 1 battery of in vitro and in vivo screening assays is significant, and EPA estimates that testing costs could range from $500,000 to $800,000 per chemical. In some cases, costs could be much higher. If Tier 1 results require Tier 2 testing, the costs will be $2,000,000 or more.

Generate Data: Test order recipients can individually generate new data for each test specified in the order, which must also comply with the procedures prescribed in the order. All data must be Good Laboratory Practice (GLP) compliant and the tests must be conducted according to protocol requirements described in the order.

Submit or Cite Existing Data: Submitting or citing existing studies in response to the test order is common for companies that can provide data that meets EPA’s current testing requirements. An initial response must include either the data or a reference to the data for each test that is required, along with a rationale that explains how the study that is cited/submitted satisfies all or part of the order.

Form a Task Force or Offer to Join a Task Force: The costs associated with generating new data on a listed chemical increase exponentially depending on the level of complexity of the project. Data generation costs can seem daunting and expensive to many registrants, manufacturers and importers. A task force allows companies to collectively share in the cost of producing the required data, and can offer other unique advantages that may help to mitigate the costs of generating data, such as employing a set of data to support more than one chemical that are chemically very similar.

TSG Response Services
TSG has the regulatory and scientific experts needed to successfully respond to the Tier 1, List 2 test orders being issued. TSG assists companies with the following:

    ▲ Providing guidance and strategy on responding to the test order;

    ▲ Identifying and qualifying testing laboratories;

    ▲ Placing studies and reviewing protocol;

    ▲ Monitoring studies and reviewing draft reports;

    ▲ Interacting with EPA and acting as a company’s advocate; and

    ▲ Managing a task force.

TSG Qualifications
TSG’s regulatory and scientific experts are highly familiar with EPA’s Endocrine Disruptor Screening Program and have the expertise to assist companies in responding to test orders. TSG helped organize and co-sponsor the September 9-10, 2009 International Society of Regulatory Toxicology and Pharmacology (ISRTP) workshop entitled The Endocrine Disruptor Screening Program: What Can Screening Results Tell Us About Potential Adverse Endocrine Effects? TSG’s staff also has significant experience with task force participation and management, including previous task force involvement as part of industry, and developing and acting as the technical manager for task forces while at TSG.

In addition, TSG’s regulatory experts have strong working relationships with government officials. The relationships developed with these regulators puts TSG in a unique position to effectively communicate and resolve client issues and obtain quick responses in areas not explicitly addressed in written material. Our consultants provide effective advocacy and strategic positioning within EPA, which enables us to help our clients successfully respond to EPA’s EDSP test orders.

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