Endocrine disruptors are described as substances that may affect the production, release, transport, metabolism, binding, action, or elimination of hormones in the body. Still under debate are the interpretation of what actually constitutes endocrine disruption and whether a hormonal modulation in a constantly fluctuating system, or any dose of a weakly hormonally active substance, is potentially adverse.
During the early to mid 1990s, articles in some scientific journals, along with publication of the book, Our Stolen Future, raised concerns that low-level environmental exposure to weak hormonally active compounds, either naturally occurring or synthetic substances, were disrupting the endocrine systems of wildlife and humans (Kavlock 1997). The controversy has fostered U.S. and international regulatory initiatives and cooperation to evaluate potential endocrine disruption through the development of validated screens and tests. Enactment of the 1996 Food Quality Protection Act required the U.S. Environmental Protection Agency (EPA) to “…develop a screening program using appropriate validated test systems and other scientifically relevant information…”
EPA’s Endocrine Disruption Screening Program (EDSP)
In December 1996, EPA convened an Endocrine Disruption Screening and Testing Advisory Committee (EDSTAC) whose final report (U.S. EPA 1998) established a framework and priority-setting process to assess—through Tier I screening and, when necessary, follow-on Tier II testing—estrogen, androgen, and thyroid (EAT) hormonal effects in both mammalian and wildlife assays. Overall, the development and validation of Tier 1 was technically difficult, and over more than 10 years, required a concerted effort by U.S., EU, and other Organisation for Economic Co-operation and Development (OECD) scientists from government, academia, industry, and non-governmental organizations.
On April 15, 2009, EPA released a final list of 67 pesticide and High Production Volume (HPV) pesticide inert ingredients for evaluation in the EDSP Tier 1 assays. The EDSP Tier 1 protocols were published in the Federal Register on October 21, 2009. On the same day, the Agency announced the schedule for EDSP Tier 1 test orders that would be issued to registrants of the 67 high-priority chemicals during regular intervals from October 2009 through February 2010. EPA published the second list of chemicals for Tier 1 Screening on November 17, 2010.
The international community is also involved in the evaluation and potential regulation of chemicals designated as endocrine disruptors. Chemicals are designated as such based on Tier 1 EDSP assays or other testing, and may be vulnerable in the EU; the new Pesticides Authorisation Regulation (EC 1107/2009, replacing directive 91/414/EEC) includes endocrine disruption as an exclusion criterion. Similar wording is under consideration in revision of the Biocides Directive (98/8) and the EU REACH regulation requires that endocrine disruptors progress to the stage of “authorisation” as substances of very high concern. Overall, being labeled as a potential endocrine disruptor based on screening results alone, without confirmatory Tier 2 testing, could result in increased regulatory pressure, market deselection, and or restrictions within the U.S. and abroad.
Addressing EPA EDSP Test Orders
Registrants will have up to 90 days to respond to EPA test orders, and up to two years total from the time of receiving the test orders, to submit the results of EDSP Tier 1 screening to EPA. EDSP Tier 1 screening assays are designed to provide information on estrogen-, androgen-, and thyroid-mediated endocrine effects. The weight of the evidence from the Tier 1 screening will probably determine whether it will be necessary to conduct additional Tier 2 testing. The EDSP Tier 1 screening battery comprises the following assays:
Mammalian in vitro
- Estrogen receptor binding (rat uterus) and ER transcriptional activation (HeLa cells)
- Androgen receptor binding
- Aromatase
- Steroidogenesis
Mammalian in vivo
- Uterotrophic – rat
- Hershberger – rat
- Female pubertal – rat
- Male pubertal – rat
Wildlife in vivo
- Amphibian metamorphosis – Xenopus (frog)
- Fish short-term reproduction – Pimephales promelas (fathead minnow)
Addressing the full battery of Tier 1 EDSP assays for the initial 67 priority compounds will require a significant expenditure of contract laboratory, industry, and government regulatory resources, and EPA is encouraging data sharing through the efforts of several companies or consortia. Additionally, EPA has proposed that “anyone may provide other scientifically relevant information (OSRI)” for the Agency to determine, on a case-by-case basis, whether the information can be used to satisfy part of or the entire testing requirement.
“Other scientifically relevant information” is information that informs the determination as to whether the substance may have an effect that is similar to an effect roduced by a substance that interacts with the estrogen, androgen, and/or thyroid hormonal systems (e.g., information that identifies substances as having the potential to interact with the estrogen, androgen, and/or thyroid system(s); information demonstrating whether substances have an effect on the functioning of the endocrine system). OSRI may either be functionally equivalent to information obtained from the Tier 1 assays—that is, data from assays that perform the same function as EDSP Tier 1 assays—or may include data that provide information on a potential consequence or effect that could be due to effects on the estrogen, androgen or thyroid systems.” The priority pesticides that have undergone 40 CFR Part 158 testing, and some well-studied HPV chemicals, may have existing publically available and proprietary data that qualify as OSRI. The decision as to whether OSRI submissions suffice for all or part of the EDSP Tier 1 assays will be made by EPA.
How Exponent Can Help
Exponent scientists have been recognized leaders in endocrine disruption mammalian and wildlife science and policy. Our consultants have served on National Academy of Science, International Life Science Institute (ILSI), or government advisory committees, including the Endocrine Disruption Screening and Testing Advisory Committee. Our expert scientists have been invited participants at workshops, conferences, and other scientific forums both in the U.S. and abroad. Our experience and accomplishments include conducting and evaluating significant endocrine studies.
Exponent is well qualified to offer creative solutions to complex endocrine disruption problems. Our experience has been applied to a wide variety of molecules, including BPA, phthalates, pesticides, industrial (HPV) chemicals, and pesticide inert ingredient surfactants. Our endocrine disruption consultation includes the following services:
- Mammalian and wildlife OSRI identification, evaluation, and strategy
- Consortia organization and management
- Identification of potential endocrine disruption issues
- Development of EDSP Tier 1 and Tier 2 testing strategy
- Preparation and submission of OSRI and Tier 1 data development plans
- EDSP Tier 1 assay placement and monitoring
- Submission of EDSP Tier 1 study results and dossiers to EPA
- Representation to EPA, EU, and international regulatory authorities
- EU REACH, Agrochemicals, and Biocides vulnerability and registration strategy
- Critical assessment of published chemical-specific literature compared to GLP study data